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Clayton LM, Vakrinou A, Balestrini S, Sisodiya SM. Monogenic Epilepsies in Adult Epilepsy Clinics and Gene-Driven Approaches to Treatment. Curr Neurol Neurosci Rep 2025; 25:35. [PMID: 40381056 DOI: 10.1007/s11910-025-01413-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 05/19/2025]
Abstract
PURPOSE OF REVIEW Genetic factors play an important contribution to the aetiology of epilepsy and may have implications for management. Whilst the study of monogenic epilepsies has predominantly centred around children, there is a critical need to understand the burden of monogenic epilepsies in adults. This understanding is essential to steer the application of genetic testing and to facilitate access to gene-driven therapies in adults with epilepsy. RECENT FINDINGS The yield of diagnostic genetic testing in adults with epilepsy and neurodevelopmental disorders is similar to that in children (ranging from 23-50%). Distinct causal genes underlie the most common monogenic epilepsies identified in adulthood compared to childhood, although SCN1A is the most commonly implicated gene across both populations. Genetic diagnoses made in adults with epilepsy frequently have direct implications for clinical management. However, very few gene-driven therapies are supported by evidence from formal studies. Genetic testing should be considered in adults with unexplained epilepsy and may have important implications for management, including the potential for gene-driven therapies. However, further work is needed to understand the outcomes of gene-driven therapies in adults with epilepsy.
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Affiliation(s)
- Lisa M Clayton
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK.
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK.
| | - Angeliki Vakrinou
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - Simona Balestrini
- Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy
- Neuroscience and Medical Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK
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Zhang X, Nie X, Yu W, Du G, Liu S, Song Y. Double-Flapped Dumbbell Probe Functionalized with Silver Nanoclusters for Sensitive Fluorometric Detection of miRNA. Appl Biochem Biotechnol 2025:10.1007/s12010-025-05264-7. [PMID: 40381098 DOI: 10.1007/s12010-025-05264-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2025] [Indexed: 05/19/2025]
Abstract
MicroRNA (miRNA) has emerged as a potential diagnostic marker for malignancies, such as prostate cancer; yet, few analytical approaches have been established for the simple and effective identification and quantification of miRNA. We depict here a fluorescent dumbbell probe utilizing DNA-silver nanoclusters (DNA-AgNCs) to facilitate the simple and label-free quantification of miRNA. The fluorescent probe was methodically engineered using a double-flapped dumbbell structure, wherein the 5' flap was synthesized using DNA-AgNCs, and the 3' flap was extended by a G-rich sequence. The DNA scaffold rigidifies the DNA-AgNCs and the G-rich sequence, bringing them into close contact, which leads to enhanced fluorescence due to the activation of DNA-AgNCs by the G-rich sequence. Upon the introduction of miRNA, the 5' flap of the probe unfolds, liberating the G-rich sequence from the probe, disrupting the closeness between DNA-AgNCs and the G-rich region, and resulting in decreased fluorescence. The proposed method, by incorporating target recycling and polymerase/endonuclease-assisted cycles, enables sensitive detection of miRNA with a detection limit of 4.2 fM and demonstrates high specificity for monitoring target miRNA in clinical samples, offering a robust platform for miRNA monitoring and disease diagnosis.
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Affiliation(s)
- Xiuju Zhang
- Andrology Department, Xiyuan Hospital of CACMS (China Academy of Chinese Medical Sciences), Beijing, 100091, China
| | - Xiaowei Nie
- Comprehensive Department of Traditional Chinese Medicine, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, 100029, China
| | - Wenxiao Yu
- Andrology Department, Xiyuan Hospital of CACMS (China Academy of Chinese Medical Sciences), Beijing, 100091, China
| | - Guanchao Du
- Andrology Department, Xiyuan Hospital of CACMS (China Academy of Chinese Medical Sciences), Beijing, 100091, China
| | - Shaoming Liu
- Comprehensive Surgery, Dongfang Hospital of Beijing University of Traditional Chinese Medicine, Beijing, 100091, China.
| | - Yewen Song
- Emergency Department, Xiyuan Hospital of CACMS (China Academy of Chinese Medical Sciences), Beijing, 100091, China.
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Tang S, Wang Q, Wang Z, Cai L, Pan D, Li J, Chen Q, Zhou Y, Shen YQ. NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration. J Pathol 2025. [PMID: 40371884 DOI: 10.1002/path.6430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/20/2025] [Accepted: 03/24/2025] [Indexed: 05/16/2025]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the most common malignant tumors in the head and neck region, characterized by a high recurrence rate and early metastasis. Despite advances in treatment, patient outcomes and prognosis remain poor, highlighting the urgent need for new therapeutic strategies. Recent research has increasingly focused on targeting glucose metabolism as a therapeutic strategy for cancer, revealing multiple promising targets and potential drugs. However, the metabolic heterogeneity among tumors leads to variable sensitivity to metabolic inhibitors in different patients, limiting their clinical utility. In this study, we employed bioinformatics analysis, cell experiments, animal models, and multi-omics approaches to reveal differences in glucose metabolism phenotypes among HNSCC patients and elucidated the underlying molecular mechanisms driving these differences. Our findings showed that NSD1 mutation status affects the glucose metabolism phenotype in HNSCC, with NSD1 wild-type HNSCC exhibiting higher mitochondrial respiration and NSD1 mutant HNSCC showing weaker mitochondrial respiration but enhanced glycolysis. We further demonstrated that NSD1 regulates mitochondrial respiration in HNSCC via epigenetic modulation of the TGFB2/PPARGC1A signaling axis. Additionally, we found that NSD1 wild-type HNSCC is more sensitive to mitochondrial respiration inhibitors, whereas NSD1 mutant HNSCC shows increased sensitivity to glycolysis inhibitors. In summary, we found that NSD1 can epigenetically regulate the TGFB2/PPARGC1A axis to modulate mitochondrial respiration and sensitivity to metabolic inhibitors in HNSCC. These findings suggest a novel strategy for selecting metabolic inhibitors for HNSCC based on the NSD1 gene status of patients. © 2025 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Shouyi Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
- Yunnan Key Laboratory of Stomatology, Kunming Medical University, Kunming, PR China
| | - Qing Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Zhen Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Luyao Cai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Dan Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
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Zhang Q, He S, Ji Z, Zhang X, Yuan B, Liu R, Yang Y, Ding Y. Integrated bioinformatic analysis identifies GADD45B as an immune-related prognostic biomarker in skin cutaneous melanoma. Hereditas 2025; 162:74. [PMID: 40350499 PMCID: PMC12067689 DOI: 10.1186/s41065-025-00437-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 04/21/2025] [Indexed: 05/14/2025] Open
Abstract
Skin cutaneous melanoma (SKCM) arises from melanocytes and is an aggressive form of skin cancer. If left untreated, most melanomas will metastasize, posing a major health risk. GADD45B, a member of the GADD45 family, is known to be involved in DNA damage repair; however, its specific role in SKCM remains largely unclear. In this study, we comprehensively investigated the function of GADD45B in SKCM. By integrating 26 SKCM-related datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), cBioPortal for Cancer Genomics (cBioPortal), Gene Expression Omnibus (GEO), and other databases, we conducted functional enrichment, immune infiltration, and single-cell analyses using R. Additionally, transcriptome sequencing of 30 human SKCM cell lines, phenotype characterization of 29 SKCM lines in vitro, and macrophage polarization analysis were performed. We found that GADD45B expression was significantly downregulated in SKCM patients compared to normal controls (p < 0.001), and higher GADD45B levels correlated with better prognosis (p < 0.05). GADD45B also showed high diagnostic accuracy, with an area under the curve (AUC) of 0.986. GO and KEGG analyses revealed a strong association between GADD45B and immune-related pathways. Gene Set Variation Analysis (GSVA) and single-cell sequencing suggested that GADD45B may serve as a novel immune checkpoint, predominantly expressed in macrophages and promoting M1 polarization. In vitro, overexpression of GADD45B significantly inhibited SKCM cell proliferation, potentially via suppression of the PI3K/Akt signaling pathway, and also reduced chemotherapy resistance. Furthermore, in vivo experiments using a xenograft mouse model demonstrated that GADD45B overexpression significantly suppressed tumor growth. Mice injected with GADD45B-overexpressing tumor cells exhibited smaller tumor volumes from day 15 onwards compared to controls, with markedly reduced tumor volume and weight at the endpoint. These results underscore the potential of GADD45B as an effective tumor suppressor in SKCM. In conclusion, our findings highlight GADD45B as a key regulator in SKCM progression, capable of restraining tumor cell proliferation and enhancing apoptosis. GADD45B holds promise as a novel diagnostic and prognostic biomarker and a potential target for SKCM immunotherapy.
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Affiliation(s)
- Qing Zhang
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
| | - Song He
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
- Department of Thoracic Surgery, Institute of Thoracic Oncology, Frontiers Science Center for Disease-Molecular Network, West China Hospital of Sichuan University, Chengdu, 610097, P.R. China
| | - Zhonghao Ji
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
- Department of Basic Medicine, Changzhi Medical College, Changzhi, Shanxi, 046000, P.R. China
| | - Xiwen Zhang
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
| | - Bao Yuan
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
| | - Ruirui Liu
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China
| | - Yimin Yang
- Department of Intensive Care Unit, First Hospital of Jilin University, Changchun, Jilin, 130021, P.R. China.
| | - Yu Ding
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, Jilin, 130062, P.R. China.
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Zhou Y, Wang X, Zhang D, Cui H, Tian X, Du W, Yang Z, Wan D, Qiu Z, Liu C, Yang Z, Zhang L, Yang Q, Xu X, Li W, Wang D, Huang H, Wu W. Precision-Guided Stealth Missiles in Biomedicine: Biological Carrier-Mediated Nanomedicine Hitchhiking Strategy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2504672. [PMID: 40345158 DOI: 10.1002/advs.202504672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/14/2025] [Indexed: 05/11/2025]
Abstract
Nanodrug delivery systems (NDDS) have demonstrated broad application prospects in disease treatment, prevention, and diagnosis due to several advantages, including functionalization capability, high drug-loading capacity, drug stability protection, and the enhanced permeability and retention (EPR) effect. However, their clinical translation still faces multiple challenges, including rapid clearance by the reticuloendothelial system (RES), poor targeting specificity, and insufficient efficiency in crossing biological barriers. To address these limitations, researchers have developed the biological carrier-mediated nanomedicine hitchhiking strategy (BCM-NHS), which leverages circulating cells, proteins, or bacteria as natural "mobile carriers" to enhance drug delivery. This approach enables nanocarriers to inherit the intrinsic biological properties, endowing them with immune evasion, prolonged circulation, dynamic targeting, biocompatibility, biodegradability, and naturally optimized biological interfaces. Here, a systematic overview of the BCM-NHS is provided. First, the review delves into the methods of nanoparticles (NPs) binding and immobilization, encompassing both the surface-attachment-mediated "backpack" strategy and the encapsulation-based "Trojan horse" strategy. Second, the classification of biological carriers, including both cell-based and non-cell-based carriers, is elucidated. Third, the physical properties and release mechanisms of these nanomaterials are thoroughly described. Finally, the latest applications of BCM-NHS in therapeutic and diagnostic contexts across various disease models including tumor, ischemic stroke, and pneumonia are highlighted.
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Affiliation(s)
- Yuyan Zhou
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Xinyue Wang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Deyu Zhang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Hanxiao Cui
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Xiaorong Tian
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wei Du
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhenghui Yang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Dongling Wan
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhiwei Qiu
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Chao Liu
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhicheng Yang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Lizhihong Zhang
- Department of Stomatology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong Province, 519041, China
| | - Qiusheng Yang
- Department of Infectious Diseases, Fujian Provincial Hospital, Fuzhou, Fujian, 350001, China
| | - Xuefeng Xu
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, Fujian, 350001, China
| | - Wenhao Li
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China
| | - Dong Wang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China
| | - Haojie Huang
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wencheng Wu
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China
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Alali M, Imani M. Deep Reinforcement Learning Data Collection for Bayesian Inference of Hidden Markov Models. IEEE TRANSACTIONS ON ARTIFICIAL INTELLIGENCE 2025; 6:1217-1232. [PMID: 40313356 PMCID: PMC12045110 DOI: 10.1109/tai.2024.3515939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Hidden Markov Models (HMMs) are a powerful class of dynamical models for representing complex systems that are partially observed through sensory data. Existing data collection methods for HMMs, typically based on active learning or heuristic approaches, face challenges in terms of efficiency in stochastic domains with costly data. This paper introduces a Bayesian lookahead data collection method for inferring HMMs with finite state and parameter spaces. The method optimizes data collection under uncertainty using a belief state that captures the joint distribution of system states and models. Unlike traditional approaches that prioritize short-term gains, this policy accounts for the long-term impact of data collection decisions to improve inference performance over time. We develop a deep reinforcement learning policy that approximates the optimal Bayesian solution by simulating system trajectories offline. This pre-trained policy can be executed in real-time, dynamically adapting to new conditions as data is collected. The proposed framework supports a wide range of inference objectives, including point-based, distribution-based, and causal inference. Experimental results across three distinct systems demonstrate significant improvements in inference accuracy and robustness, showcasing the effectiveness of the approach in uncertain and data-limited environments.
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Affiliation(s)
- Mohammad Alali
- Department of Electrical and Computer Engineering at Northeastern University
| | - Mahdi Imani
- Department of Electrical and Computer Engineering at Northeastern University
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Jeyaraman M, Jeyaraman N, Ramasubramanian S, Balaji S. Navigating the ethical terrain: Off-label and experimental treatments in medical case reports. World J Methodol 2025; 15:94833. [PMID: 40115396 PMCID: PMC11525891 DOI: 10.5662/wjm.v15.i1.94833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 09/29/2024] Open
Abstract
This article explores the ethical considerations surrounding the reporting of off-label and experimental treatments in medical case reports, with a focus on fields such as oncology, psychiatry, and pediatrics. It emphasizes the balance between innovation and evidence-based medicine, highlighting the critical role of case reports in disseminating clinical experiences and advancing medical knowledge. The discussion delves into the ethical framework guiding case reporting, including principles of patient autonomy, informed consent, non-maleficence, beneficence, justice, and transparency. Challenges such as negative outcome reporting, commercial interests, and the balance between innovation and caution are examined. Recommendations for ethical vigilance, the development of comprehensive guidelines, and the role of regulatory bodies are proposed to ensure patient safety and uphold scientific integrity. The article concludes by underscoring the importance of a collaborative effort among clinicians, researchers, ethicists, and regulatory bodies to foster the responsible advancement of medical science while adhering to the highest ethical standards.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, India
| | - Naveen Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, India
| | | | - Sangeetha Balaji
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, India
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Parvanova A, Abbate M, Reseghetti E, Ruggenenti P. Mechanisms and treatment of obesity-related hypertension-Part 2: Treatments. Clin Kidney J 2025; 18:sfaf035. [PMID: 40130230 PMCID: PMC11932351 DOI: 10.1093/ckj/sfaf035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Indexed: 03/26/2025] Open
Abstract
Hypertension is a frequent comorbidity of obesity that significantly and independently increases the risk of cardiovascular and renal events. Obesity-related hypertension is a major challenge to the healthcare system because of the rapid increase in obesity prevalence worldwide. However, its treatment is still not specifically addressed by current guidelines. Weight loss (WL) per se reduces blood pressure (BP) and increases patient responsiveness to BP-lowering medications. Thus, a weight-centric approach is essential for the treatment of obesity-related hypertension. Diet and physical activity are key components of lifestyle interventions for obesity-related hypertension, but, in real life, their efficacy is limited by poor long-term patient adherence and frequently require pharmacotherapy implementation to achieve target BP. In this context, first-generation anti-obesity drugs such as orlistat, phentermine/topiramate, and naltrexone/bupropion are poorly effective, whereas second-generation incretin receptor agonists, including the GLP-1 receptor agonists liraglutide and semaglutide, and in particular the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) co-agonist tirzepatide, substantially contribute to effective WL and BP control in obesity. SGLT2 inhibitors are weak body weight and BP-lowering medications, but clearly synergize the benefits of these medications. Bariatric surgery remains the gold standard treatment for severe "pathological" obesity and related life-threatening complications. Renal denervation is a valuable rescue treatment for drug-resistant hypertension, commonly related to obesity. Integrating a multifaceted weight-based approach with other strategies, such as antihypertensive drugs and renal denervation, could specifically target the main neuro-hormonal and renal pathophysiological mechanisms of obesity-related hypertension, including sympathetic-nervous and renin-angiotensin-aldosterone systems overactivity, salt retention, and volume expansion. This comprehensive strategy can provide a personalized algorithm for managing hypertension in obesity within the context of "precision medicine" principles.
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Affiliation(s)
- Aneliya Parvanova
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”: Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy
| | - Manuela Abbate
- Research Group on Global Health, University of the Balearic Islands, and Research Group on Nursing, Community & Global Health, Health Research Institute of the Balearic Islands (IdISBa), both in Palma, Spain
| | - Elia Reseghetti
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Piero Ruggenenti
- Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”: Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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易 珈, 孙 丹. [Efficacy and safety of perampanel add-on therapy in children with epilepsy of genetic etiology]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2025; 27:171-175. [PMID: 39962779 PMCID: PMC11838030 DOI: 10.7499/j.issn.1008-8830.2409069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/07/2025] [Indexed: 02/21/2025]
Abstract
OBJECTIVES To investigate the efficacy and safety of perampanel (PER) add-on therapy in children with epilepsy of genetic etiology. METHODS A retrospective analysis was conducted on the clinical data of 53 children who attended the Department of Neurology, Wuhan Children's Hospital, from November 2020 to April 2023. All children received PER add-on therapy and were diagnosed with epilepsy of genetic etiology based on whole-exome sequencing. The primary outcome measure was the proportion of children with a reduction in seizure frequency of ≥50% at month 12 of PER treatment (i.e., response rate), and the secondary outcome measures were response rates at months 3 and 6 of treatment. The influencing factors for the efficacy of PER add-on therapy in the treatment of epilepsy of genetic etiology were analyzed, and adverse events were recorded. RESULTS The median follow-up duration was 13.10 months. After 12 months of follow-up, 42 children were included in the analysis, comprising 25 boys (60%) and 17 girls (40%). The median initial dose of PER was 1.5 (1.0, 2.0) mg/d, and the median maintenance dose was 4.0 (3.0, 8.0) mg/d. The response rates to PER at months 3, 6, and 12 of treatment were 61% (30/49), 54% (25/46), and 48% (20/42), respectively. No significant difference in the efficacy of PER was observed between children with mutations in genes encoding different protein functions (P>0.05). The most common adverse event reported was fatigue, observed in 3 children (6%). CONCLUSIONS PER add-on therapy demonstrates good efficacy and safety in children with epilepsy of genetic etiology. No influencing factors for the efficacy of PER have been identified to date.
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Kessler SK. Epilepsy Genetics. Continuum (Minneap Minn) 2025; 31:81-94. [PMID: 39899097 DOI: 10.1212/con.0000000000001520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
OBJECTIVE This article reviews essential concepts and terminology in epilepsy genetics, discusses current guidance on when and how to pursue genetic evaluation, provides an overview of genetic syndromes, and offers illustrative examples of the effect of genetic diagnosis in epilepsy patient care. LATEST DEVELOPMENTS The growing availability of next-generation genetic sequencing methods for clinical use provides an opportunity to make etiologic diagnoses in a larger number of epilepsy patients, which can affect therapeutic management, prognostic counseling, surveillance for comorbid conditions, and other aspects of epilepsy care. Exome and genome sequencing may have high diagnostic yields in patients with unexplained epilepsy. The body of knowledge in epilepsy genetics is growing more complex, not only because of gene discovery but also because of an increasingly nuanced understanding of the varying pathophysiologic effects of specific types of variation within epilepsy genes. ESSENTIAL POINTS Genetic testing plays a key role in the evaluation of epilepsy patients. Clinicians caring for patients with epilepsy should understand patient selection, test selection, and result interpretation in genetic testing. The recommended first-line test in most patients is exome or genome sequencing.
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Yao Y, Wang X, Zhao Z, Li Z. A 5-lncRNA signature predicts clinical prognosis and demonstrates a different mRNA expression in adult soft tissue sarcoma. Transl Cancer Res 2025; 14:179-196. [PMID: 39974396 PMCID: PMC11833409 DOI: 10.21037/tcr-24-203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 10/16/2024] [Indexed: 02/21/2025]
Abstract
Background Adult soft tissue sarcoma (SARC) is a highly aggressive malignancy. A growing number of long non-coding RNAs (lncRNAs) have been linked to malignancies, and many researchers consider lncRNAs potential biomarkers for prognosis. However, there is limited evidence available to determine the role of lncRNAs in the prognosis of SARC. In this study, we collected The Cancer Genome Atlas (TCGA) data to identify prognosis-related lncRNAs for SARC and explore the relationship between lncRNAs and gene expression. Methods TCGA datasets, which included 259 samples, served as data sources in this study. Univariable Cox regression analysis, robust analysis, and multivariable Cox regression analysis were used to construct a 5-lncRNA signature Cox regression model. Then, based on the median risk score, high- and low-risk groups were identified. The Kaplan-Meier method was applied to survival analysis in the training set, testing set, complete set, and different pathological type sets. To explore the relationship between lncRNAs and messenger RNAs (mRNAs), differentially expressed mRNAs (DEmRNAs) between the high- and low-risk groups were identified. The function of DEmRNAs was predicted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The relationships between the 5 lncRNAs and DEmRNAs were calculated using the Spearman correlation coefficient. A total of 18 DEmRNAs that showed a strong correlation with risk score (|Spearman's r|>0.6) in leiomyosarcoma (LMS) samples were identified, and a protein-protein interaction (PPI) network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Results A Cox regression model was built in this study with the risk score= (-0.5698*AC018645.2) + 0.1732*LINC02454 + 0.387*ERICD + 0.6262*DSCR9 + 0.9781*AL031770.1. The study found that this 5-lncRNA signature could predict prognosis well, especially in LMS, a subtype of SARC, with P value =1.19e-06 [hazard ratio (HR) 6.134, 95% confidence interval (CI): 2.951-12.752]. Additionally, 44 DEmRNAs were observed between the high- and low-risk groups, and the expression levels of DEmRNAs in LMS samples differed from other pathology types. The PPI network analysis revealed that MYH11, MYLK, and CNN1 were the most important hub genes among the 18 DEmRNAs, all of which are essential for muscle function. Conclusions In this study, a predictive clinical model for SARC was successfully established, showing better prediction accuracy in patients with LMS. Importantly, we identified MYH11, MYLK, and CNN1 as potential therapeutic targets for SARC.
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Affiliation(s)
- Ye Yao
- School of Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, China
- Department of Nephrology, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China
| | - Xiaojuan Wang
- Department of Nephrology, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China
| | - Ziwei Zhao
- Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Zhipeng Li
- Department of Nephrology, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China
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12
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Singh P, Nisa K, Mavi R, Yadav S, Kumar R. Recent Progresses in Development of Heterocyclic Compounds for Epilepsy Treatment: Key Research Highlights from 2019-2024. Chem Biodivers 2025; 22:e202401620. [PMID: 39235237 DOI: 10.1002/cbdv.202401620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/30/2024] [Accepted: 09/05/2024] [Indexed: 09/06/2024]
Abstract
Epilepsy which is a chronic neurological disorder is characterized by recurrent seizure poses a significant challenge to healthcare professionals worldwide. Most of antiepileptic drugs have serious side effects that might affect the quality of life such as fatigue, dizziness, weight gain and cognitive impairments. In this context, the search for more effective and potential antiepileptic drug candidate has led to a growing interest in the field of synthesis of heterocyclic compounds. This review will focus on the utilization of heterocyclic moieties including imidazole, indole, thiazole, triazine, quinazoline and oxazole which show remarkable anticonvulsant properties. Furthermore, the exploration of various methodologies for the synthesis of heterocyclic anticonvulsant drugs such as green methodologies and microwave assisted protocols have contributed to the development of environment friendly, more efficient and potential approaches. The review will distinguish from previous ones by specifically focusing on innovative synthetic methodologies, including greener methodologies and micro-assisted techniques, that contribute to eco-friendly and environment benign approaches during 2019-2024. In addition to this, the review will focus on the Structure Activity Relationship (SAR) studies of heterocyclic compounds in order to offer insight into the design of next generation antiepileptic drugs with improved efficacy and reduced side effects.
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Affiliation(s)
- Preeti Singh
- Department of Chemistry, Faculty of Science, Swami Vivekanand Subharti University, Meerut, 250005, U.P. India
| | - Kharu Nisa
- Department of Chemistry, Material Chemistry Laboratory, National Institute of Technology, Srinagar, 190006, India
| | - Renu Mavi
- Department of Chemistry, Faculty of Science, Swami Vivekanand Subharti University, Meerut, 250005, U.P. India
| | - Soni Yadav
- Department of Chemistry, Faculty of Science, Meerut Institute of Engineering & Technology, Meerut, 250005, India
| | - Ravi Kumar
- Department of Chemistry, Material Chemistry Laboratory, National Institute of Technology, Srinagar, 190006, India
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Tonk M, Singh I, Sharma RJ, Chauhan SB. A Revolutionary Approach for Combating Efflux Transporter-mediated Resistant Epilepsy: Advanced Drug Delivery Systems. Curr Pharm Des 2025; 31:95-106. [PMID: 39279709 DOI: 10.2174/0113816128332345240823111524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 09/18/2024]
Abstract
Epilepsy is a persistent neurological condition that affects 60 million individuals globally, with recurrent spontaneous seizures affecting 80% of patients. Antiepileptic drugs (AEDs) are the main course of therapy for approximately 65% of epileptic patients, and the remaining 35% develop resistance to medication, which leads to drug-resistant epilepsy (DRE). DRE continues to be an important challenge in clinical epileptology. There are several theories that attempt to explain the neurological causes of pharmacoresistance in epilepsy. The theory that has been studied the most is the transporter hypothesis. Therefore, it is believed that upregulation of multidrug efflux transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp), which extrudes AEDs from their target location, is the major cause, leading to pharmacoresistance in epilepsy. The most effective strategies for managing this DRE are peripheral and central inhibition of P-gp and maintaining an effective concentration of the drug in the brain parenchyma. Presently, no medicinal product that inhibits Pgp is being used in clinical practice. In this review, several innovative and promising treatment methods, including gene therapy, intracranial injections, Pgp inhibitors, nanocarriers, and precision medicine, are discussed. The primary goal of this work is to review the P-gp transporter, its substrates, and the latest novel treatment methods for the management of DRE.
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Affiliation(s)
- Megha Tonk
- Raj Kumar Goel Institute of Technology (Pharmacy), 5-Km, Stone, Delhi-Meerut Road, Ghaziabad, Uttar Pradesh 201017, India
| | - Indu Singh
- Amity Institute of Pharmacy, Amity University, Noida 201301, India
| | - Ram Jee Sharma
- Indian Herbs Specialities Pvt. Ltd., Nawada Road, Saharanpur (U.P.) 247001, India
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Andrade P, Santamarina AB, de Freitas JA, Marum ABRF, Pessoa AFM. Personalized nutrition and precision medicine in perimenopausal women: A minireview of genetic polymorphisms COMT, FUT2, and MTHFR. Clinics (Sao Paulo) 2024; 80:100549. [PMID: 39642577 DOI: 10.1016/j.clinsp.2024.100549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 11/09/2024] [Indexed: 12/09/2024] Open
Abstract
This mini-review explores the potential of precision medicine and personalized nutrition in addressing health challenges faced by perimenopausal women, focusing on the role of genetic polymorphisms in key metabolic pathways. Specifically focus on the single nucleotide polymorphisms (SNPs) in the COMT, FUT2, and MTHFR genes, which influence neurotransmitter metabolism, gut microbiota composition, and folate homeostasis, respectively. These polymorphisms are critical in modulating hormonal fluctuations, metabolic imbalances, and nutrient absorption during perimenopause. The review highlights the impact of COMT rs4680 on stress response and mood disorders, FUT2 rs602662 and rs601338 on vitamin B12 absorption and cortisol metabolism, and MTHFR rs1801133 and rs1801131 on homocysteine levels and cardiovascular risk. Furthermore, the integration of machine learning in precision medicine is discussed, offering insights into how genetic data can optimize personalized interventions. This approach enables targeted nutritional and therapeutic strategies to mitigate the metabolic and psychological effects of perimenopause. Overall, this review underscores the importance of incorporating genetic testing into preventive care for perimenopausal women to enhance quality of life and promote healthy aging.
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Affiliation(s)
- Pedro Andrade
- Instituto Medicina e Nutrição de Precisão, São Paulo, Brazil; Laboratório de Parasitologia Médica (LIM-46), Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil
| | - Aline Boveto Santamarina
- Laboratório de Produtos e Derivados Naturais, Laboratório de Investigação Médica-26 (LIM-26), Departamento de Cirurgia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil
| | - Jéssica Alves de Freitas
- Laboratório de Produtos e Derivados Naturais, Laboratório de Investigação Médica-26 (LIM-26), Departamento de Cirurgia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil; Laboratório de Parasitologia Médica (LIM-46), Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil
| | - Annete Bressan Rente Ferreira Marum
- Instituto Medicina e Nutrição de Precisão, São Paulo, Brazil; Paulista School of Medicine, Federal University of São Paulo - UNIFESP, São Paulo, SP 04021-001, Brazil; Laboratório de Parasitologia Médica (LIM-46), Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil
| | - Ana Flávia Marçal Pessoa
- Laboratório de Produtos e Derivados Naturais, Laboratório de Investigação Médica-26 (LIM-26), Departamento de Cirurgia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil; Laboratório de Parasitologia Médica (LIM-46), Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil; Botânio Pesquisa e Desenvolvimento Ltda, São Paulo, SP 05545010, Brazil.
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Cubria T, Nairon EB, Landers J, Joseph S, Chandra M, Denbow ME, Hays R, Olson DM. Implementation of a Novel Seizure Assessment Tool for Unified Seizure Evaluation Improves Nurse Response. J Neurosci Nurs 2024; 56:245-249. [PMID: 39231436 DOI: 10.1097/jnn.0000000000000784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/06/2024]
Abstract
ABSTRACT BACKGROUND: Ictal and postictal testing is an essential aspect of clinical care when diagnosing and treating seizures. The epilepsy monitoring unit (EMU) has standard operating procedures for nursing care during and after seizure events, but there is limited interrater reliability. Streamlining ictal and postictal testing processes may enhance care consistency for patients in the EMU unit. The purpose of this study was to create an ictal and postictal seizure assessment tool that would increase the consistency of nursing assessment for EMU patients. METHODS: This prospective study had 4 phases: baseline assessment, instrument development, staff education, and field testing. During baseline assessment, an advanced practice provider and an epilepsy fellow graded nurse ictal and postictal assessment via survey questions. After instrument development, education, and implementation, the same survey was administered to determine if nursing consistency in assessing seizure events improved. The tool used in this study was created by a team of clinical experts to ensure consistency in the assessment of seizure patients. RESULTS: A total of 58 first seizure events were collected over a 6-month intervention period; 27 in the pretest and 31 in the posttest. Paired t test analyses revealed significant improvement in the clinical testing domains of verbal language function ( P < .005), motor function ( P < .0005), and item assessment order ( P < .005) postintervention. There was nonsignificant improvement in the domains of responsiveness (feeling [ P = .597], using a code word [ P = .093]) and visual language function ( P = .602). CONCLUSION: The data captured in this study support the need for this instrument. There is strong need to increase consistency in assessing seizure events and to promote continued collaboration among clinical teams to enhance care to EMU patients. Validation of this instrument will further improve team collaboration by allowing nurses to contribute to their fullest extent.
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16
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Han B, Liu Y, Zhou Q, Yu Y, Liu X, Guo Y, Zheng X, Zhou M, Yu H, Wang W. The advance of ultrasound-enabled diagnostics and therapeutics. J Control Release 2024; 375:1-19. [PMID: 39208935 DOI: 10.1016/j.jconrel.2024.08.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/27/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
Point-of-care ultrasound demonstrates significant potential in biomedical research due to its noninvasive, real-time visualization, cost-effectiveness, and other biological benefits. Ultrasound irradiation can precisely control the mechanical and physicochemical effects on pathogenic lesions, enabling real-time visualization, tunable tissue penetration depth, and therapeutic applications. This review summarizes recent advancements in ultrasound-enabled diagnostics and therapeutics, focusing on mechanochemical effects that can be directly integrated into biomedical applications. Additionally, the structure-functionality relationships of sonotheranostic nanoplatforms are systematically discussed, providing insights into the underlying biological effects. Finally, the limitations of current ultrasonic medicine are discussed, along with potential expansions to facilitate patient-centered translations.
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Affiliation(s)
- Biying Han
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Yan Liu
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Qianqian Zhou
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Yuting Yu
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Xingxing Liu
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Yu Guo
- State Key Laboratory of Chemical Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaohua Zheng
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Mengjiao Zhou
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China.
| | - Haijun Yu
- State Key Laboratory of Chemical Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Weiqi Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China.
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17
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Chen J, Cao W, Li Y, Zhu J. Comprehensive analysis of the expression level, prognostic value, and immune infiltration of cuproptosis-related genes in human breast cancer. Medicine (Baltimore) 2024; 103:e40132. [PMID: 39432636 PMCID: PMC11495725 DOI: 10.1097/md.0000000000040132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 09/27/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND As a novel cell death form, cuproptosis results from copper combining with lipidated proteins in the tricarboxylic acid cycle. To the best of our knowledge no study has yet comprehensively analyzed the relationship between cuproptosis-related genes and breast cancer. METHODS The expression, prognostic value, mutations, chemosensitivity, and immune infiltration of cuproptosis-related genes in breast carcinoma patients were analyzed, PPI networks were constructed, and enrichment analyses were performed based on these genes. TIMER, UALCAN, Kaplan-Meier plotter, Human Protein Atlas, cBioPortal, STRING, GeneMANIA, DAVID, and R program v4.0.3 were used to accomplish the analyses above. RESULTS Compared to normal breast tissues, FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, MTF1, and GLS were down-regulated in breast cancer tissues, while CDKN2A was up-regulated. High expression of FDX1, LIAS, DLD, DLAT, MTF1, GLS, and CDKN2A were associated with favorable overall survival. Cuproptosis-related genes showed a high alteration rate (51.3%) in breast cancer, contributing to worse clinical outcomes. The expression levels of FDX1, LIPT1, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, and CDKN2A were associated positively with 1 or more immune cell infiltrations in breast cancer. Patients with high levels of B cell, CD4+ T cell, CD8+ T cell, and dendritic cell infiltration had a higher survival rate at 10 years. CONCLUSION This study comprehensively investigated relationships between cuproptosis and breast cancer by bioinformatic analyses. We found that cuproptosis-related genes were generally lowly expressed in breast carcinoma tissue. As the critical gene of cuproptosis, high expression of FDX1 was related to favorable prognoses in breast cancer patients; thus, it might be a potential prognostic marker. Moreover, genes associated with cuproptosis were linked to immune infiltration in breast cancer and this relationship affected the prognosis of breast cancer.
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Affiliation(s)
- Jian Chen
- Breast Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Cao
- Breast Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yingliang Li
- Breast Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jia Zhu
- Breast Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
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Qin H, Yang S, Feng Z, Wu S, Cai T, Xie Z, Hu H. RNA modification-related EIF4G2 is an immunotherapy determinant in osteosarcoma: A single-cell sequencing analysis. ENVIRONMENTAL TOXICOLOGY 2024; 39:4547-4561. [PMID: 38578024 DOI: 10.1002/tox.24261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/08/2024] [Accepted: 03/23/2024] [Indexed: 04/06/2024]
Abstract
The clinical outcomes of osteosarcoma are relatively dismal. As immunotherapy has revolutionized treatment for solid tumors, exploring novel immunotherapy-related therapeutic targets for osteosarcoma is important. In this study, we aimed to establish the connection between RNA modification and immunotherapy in osteosarcoma to identify novel therapeutic targets. An RNA modification-related signature was first developed using weight gene correlation network analysis and a machine-learning algorithm, random forest. The signature's prognostic value, drug prediction, and immune characteristics were analyzed. EIF4G2 from the signature was next identified as a critical immunotherapy determinant. EIF4G2 could also promote tumor proliferation, migration, and M2 macrophage migration by single-cell sequencing analysis and in vitro validation. Our signature and EIF4G2 are expected to provide valuable insights into the clinical management of osteosarcoma.
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Affiliation(s)
- Haocheng Qin
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shu Yang
- Respiratory Intensive Care Unit, The First Affiliated Hospital, Hunan Normal University Hunan Provincial People's Hospital, Changsha, China
| | - Zhennan Feng
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Song Wu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ting Cai
- Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, China
| | - Zijing Xie
- Hunan Provincial Key Laboratory of the Traditional Chinese Medicine Agricultural Biogenomics, Changsha Medical University, Changsha, China
| | - Hai Hu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, China
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Al-Dewik N, Abuarja T, Younes S, Nasrallah G, Alsharshani M, Ibrahim FE, Samara M, Farrell T, Abdulrouf PV, Qoronfleh MW, Al Rifai H. Precision medicine activities and opportunities for shaping maternal and neonatal health in Qatar. Per Med 2024; 21:313-333. [PMID: 39347749 DOI: 10.1080/17410541.2024.2394397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
Precision Medicine (PM) is a transformative clinical medicine strategy that aims to revolutionize healthcare by leveraging biological information and biomarkers. In the context of maternal and neonatal health, PM enables personalized care from preconception through the postnatal period. Qatar has emerged as a key player in PM research, with dedicated programs driving advancements and translating cutting-edge research into clinical applications. This article delves into neonatal and maternal health in Qatar, emphasizing PM programs and initiatives that have been implemented. It also features noteworthy clinical cases that demonstrate the effectiveness of precision interventions. Furthermore, the article highlights the role of pharmacogenomics in addressing various maternal health conditions. The review further explores potential advancements in the application of PM in maternal and neonatal healthcare in Qatar.
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Affiliation(s)
- Nader Al-Dewik
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Department of Neonatology, Neonatal Intensive Care Unit, Newborn Screening Unit, Women's Wellness & Research Center, Hamad Medical Corporation, Doha, 3050, Qatar
- Translational Research Institute (TRI), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Genomics & Precision Medicine (GPM), College of Health & Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha, 34110, Qatar
| | - Tala Abuarja
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Salma Younes
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University (QU), Doha, 2713, Qatar
| | - Gheyath Nasrallah
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University (QU), Doha, 2713, Qatar
| | - Mohamed Alsharshani
- Diagnostic Genetics Division (DGD), Department of Laboratory Medicine & Pathology (DLMP), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Faisal E Ibrahim
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Muthanna Samara
- Department of Psychology, Kingston University London, Kingston upon Thames, London, KT1 2EE, United Kingdom
| | - Thomas Farrell
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Palli Valapila Abdulrouf
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - M Walid Qoronfleh
- Q3 Research Institute (QRI), Healthcare Research & Policy Division, 7227 Rachel Drive, Ypsilanti, MI 48917, USA
| | - Hilal Al Rifai
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Department of Neonatology, Neonatal Intensive Care Unit, Newborn Screening Unit, Women's Wellness & Research Center, Hamad Medical Corporation, Doha, 3050, Qatar
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Klein P, Kaminski RM, Koepp M, Löscher W. New epilepsy therapies in development. Nat Rev Drug Discov 2024; 23:682-708. [PMID: 39039153 DOI: 10.1038/s41573-024-00981-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/24/2024]
Abstract
Epilepsy is a common brain disorder, characterized by spontaneous recurrent seizures, with associated neuropsychiatric and cognitive comorbidities and increased mortality. Although people at risk can often be identified, interventions to prevent the development of the disorder are not available. Moreover, in at least 30% of patients, epilepsy cannot be controlled by current antiseizure medications (ASMs). As a result of considerable progress in epilepsy genetics and the development of novel disease models, drug screening technologies and innovative therapeutic modalities over the past 10 years, more than 200 novel epilepsy therapies are currently in the preclinical or clinical pipeline, including many treatments that act by new mechanisms. Assisted by diagnostic and predictive biomarkers, the treatment of epilepsy is undergoing paradigm shifts from symptom-only ASMs to disease prevention, and from broad trial-and-error treatments for seizures in general to mechanism-based treatments for specific epilepsy syndromes. In this Review, we assess recent progress in ASM development and outline future directions for the development of new therapies for the treatment and prevention of epilepsy.
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Affiliation(s)
- Pavel Klein
- Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA.
| | | | - Matthias Koepp
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Wolfgang Löscher
- Translational Neuropharmacology Lab., NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany.
- Center for Systems Neuroscience, Hannover, Germany.
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Wang YM, Sun JH, Sun RX, Liu XY, Li JF, Li RZ, Du YR, Zhou XZ. Treating chronic atrophic gastritis: identifying sub-population based on real-world TCM electronic medical records. Front Pharmacol 2024; 15:1444733. [PMID: 39170704 PMCID: PMC11335612 DOI: 10.3389/fphar.2024.1444733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Background and Objective Chronic atrophic gastritis (CAG) is a complex chronic disease caused by multiple factors that frequently occurs disease in the clinic. The worldwide prevalence of CAG is high. Interestingly, clinical CAG patients often present with a variety of symptom phenotypes, which makes it more difficult for clinicians to treat. Therefore, there is an urgent need to improve our understanding of the complexity of the clinical CAG population, obtain more accurate disease subtypes, and explore the relationship between clinical symptoms and medication. Therefore, based on the integrated platform of complex networks and clinical research, we classified the collected patients with CAG according to their different clinical characteristics and conducted correlation analysis on the classification results to identify more accurate disease subtypes to aid in personalized clinical treatment. Method Traditional Chinese medicine (TCM) offers an empirical understanding of the clinical subtypes of complicated disorders since TCM therapy is tailored to the patient's symptom profile. We gathered 6,253 TCM clinical electronic medical records (EMRs) from CAG patients and manually annotated, extracted, and preprocessed the data. A shared symptom-patient similarity network (PSN) was created. CAG patient subgroups were established, and their clinical features were determined through enrichment analysis employing community identification methods. Different clinical features of relevant subgroups were correlated based on effectiveness to identify symptom-botanical botanical drugs correspondence. Moreover, network pharmacology was employed to identify possible biological relationships between screened symptoms and medications and to identify various clinical and molecular aspects of the key subtypes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results 5,132 patients were included in the study: 2,699 males (52.60%) and 2,433 females (47.41%). The population was divided into 176 modules. We selected the first 3 modules (M29, M3, and M0) to illustrate the characteristic phenotypes and genotypes of CAG disease subtypes. The M29 subgroup was characterized by gastric fullness disease and internal syndrome of turbidity and poison. The M3 subgroup was characterized by epigastric pain and disharmony between the liver and stomach. The M0 subgroup was characterized by epigastric pain and dampness-heat syndrome. In symptom analysis, The top symptoms for symptom improvement in all three subgroups were stomach pain, bloating, insomnia, poor appetite, and heartburn. However, the three groups were different. The M29 subgroup was more likely to have stomach distention, anorexia, and palpitations. Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon were the most popular botanical drugs. The M3 subgroup has a higher incidence of yellow urine, a bitter tongue, and stomachaches. Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora were the botanical drugs used. Vomiting, nausea, stomach pain, and appetite loss are common in the M0 subgroup. The primary medications are Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia. Through GO and KEGG pathway analysis, We found that in the M29 subgroup, Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon may exert their therapeutic effects on the symptoms of gastric distension, anorexia, and palpitations by modulating apoptosis and NF-κB signaling pathways. In the M3 subgroup, Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora may be treated by NF-κB and JAK-STAT signaling pathway for the treatment of stomach pain, bitter mouth, and yellow urine. In the M0 subgroup, Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia may exert their therapeutic effects on poor appetite, stomach pain, vomiting, and nausea through the PI3K-Akt signaling pathway. Conclusion Based on PSN identification and community detection analysis, CAG population division can provide useful recommendations for clinical CAG treatment. This method is useful for CAG illness classification and genotyping investigations and can be used for other complicated chronic diseases.
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Affiliation(s)
- Yu-man Wang
- Graduate School of Hebei University of Traditional Chinese Medicine, Hebei, China
| | - Jian-hui Sun
- Hebei Hospital of Traditional Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Turbidity and Toxicology, Hebei, China
| | - Run-xue Sun
- Hebei Hospital of Traditional Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Turbidity and Toxicology, Hebei, China
| | - Xiao-yu Liu
- Graduate School of Hebei University of Traditional Chinese Medicine, Hebei, China
| | - Jing-fan Li
- Graduate School of Hebei University of Traditional Chinese Medicine, Hebei, China
| | - Run-ze Li
- Graduate School of Hebei University of Traditional Chinese Medicine, Hebei, China
| | - Yan-ru Du
- Hebei Hospital of Traditional Chinese Medicine, Hebei, China
- Hebei Key Laboratory of Turbidity and Toxicology, Hebei, China
- Hebei Provincial Key Laboratory of Integrated Traditional and Western Medicine Research on Gastroenterology, Hebei, China
| | - Xue-zhong Zhou
- School of Computer and Information Technology, Beijing Jiaotong University, Beijing, China
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段 世, 郑 谦, 石 冰, 冯 帆. [Distribution of ABO and Rh Blood Groups in Tibetan and Han Populations With Cleft Lip and Palate in a Tertiary Hospital in Western China]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:932-938. [PMID: 39170012 PMCID: PMC11334283 DOI: 10.12182/20240760101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Indexed: 08/23/2024]
Abstract
Objective Congenital cleft lip and palate is a common birth defect that seriously affects the lives of the afflicted children and their families. Previously, no research has been done to investigate the pathogenic characteristics of cleft lip and palate among ethnic minorities, for example, Tibetans, a minority ethnic group with a large population in China. This study aims to investigate the relationship between the occurrence of cleft lip and palate in Tibetans and Han Chinese in western China and the distribution of ABO blood groups and Rh blood groups to provide a theoretical basis for the precise prevention and treatment of cleft lip and palate. Methods In this study, statistics on Tibetan patients with cleft lip and palate, some Han patients with cleft lip and palate, and normal controls from western China were retrospectively collected. All participants were patients from West China Stomatology Hospital, Sichuan University. All patients with cleft lip and palate received treatment at the hospital between January 2016 and September 2023. The normal controls were outpatients or inpatients who did not have cleft lip and palate, and who received treatment at the hospital between January 2020 and October 2023. Information on the A, B, O, and AB blood groups and Rh positive and negative blood groups of the patients was collected and compared with that of the normal controls. The incidence of different phenotypes, including cleft lip alone, cleft palate alone, and cleft lip with cleft palate, in patients of blood groups A, B, O and AB were statistically analyzed by Chi-square test. Results A total of 1227 Tibetan patients with cleft lip and palate, 4064 Han patients with cleft lip and palate, and 5360 normal controls were included in the study. Among all the patients with cleft lip and palate, 1863 had cleft lip alone, 1425 had cleft palate alone, and 2003 had cleft lip with cleft palate. The ABO blood group distribution of Tibetan patients with cleft lip and palate was characterized as O>B>A>AB, with Rh positive blood group accounting for 100%, blood type O accounting for 41.15%, and blood type B accounting for 30.64%. The blood group distribution of the Han patients with cleft lip and palate was characterized as O>A>B>AB, with Rh positive blood group accounting for 99.58%, blood type O accounting for 35.78%, and type A accounting for 30.54%. There was a significant difference in ABO blood groups between Tibetan and Han patients with cleft lip and palate (P<0.005), but no significant difference in Rh blood groups. The ABO blood group distribution of the Tibetan patients with cleft lip and palate showed an obvious difference from that of the control group, while those of the Han patients with cleft lip and cleft palate and the control group did not show obvious differences. In the analysis of the subtypes, it was found that the blood group distribution in the subtypes of cleft lip alone, cleft palate alone, and cleft lip with cleft palate in the Tibetan population was O>B>A>AB, while that in the Han Chinese population was O>A>B>AB. There were differences in blood group distribution between Tibetans and Hans of the subtypes of cleft lip alone and cleft lip with cleft palate (P<0.001), but there was no difference in blood group distribution in the population of cleft palate-only subtype. The proportion of blood type O in Tibetan patients with cleft lip and palate was significantly higher than that in the Han patients with cleft lip and palate. The blood group distribution of Tibetan patients with cleft lip and palate in Sichuan Province, Xizang Autonomous Region, and Qinghai Province was always O>B>A>AB. Tibetan patients from Shiqu County and Baiyu County, Ganzi Tibetan Autonomous Prefecture and Chaya County, Qamdo City were predominantly of blood type B, and those from other regions were mainly of blood type O. Conclusion There were significant differences in the phenotype composition and ABO blood group distribution between the Tibetan and Han populations with cleft lip and palate in western China. The distribution of blood group O in the population with cleft lip and palate was higher than that in the normal population, and the same trend was observed for different phenotypes. However, differences between Tibetan and Han populations in ABO blood group distribution were only found in the phenotypes of cleft lip only and cleft lip with palate. Tibetans with blood type O are more prone to cleft lip deformity than Han people, and the effect in the phenotype of cleft lip with palate is less pronounced than that in the phenotype of cleft lip only.
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Affiliation(s)
- 世均 段
- 口腔疾病防治全国重点实验室 国家口腔医学中心 国家口腔疾病临床医学研究中心 四川大学华西口腔医院 （成都 610041）State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - 谦 郑
- 口腔疾病防治全国重点实验室 国家口腔医学中心 国家口腔疾病临床医学研究中心 四川大学华西口腔医院 （成都 610041）State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - 冰 石
- 口腔疾病防治全国重点实验室 国家口腔医学中心 国家口腔疾病临床医学研究中心 四川大学华西口腔医院 （成都 610041）State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - 帆 冯
- 口腔疾病防治全国重点实验室 国家口腔医学中心 国家口腔疾病临床医学研究中心 四川大学华西口腔医院 （成都 610041）State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Chen YS, Jin E, Day PJ. Use of Drug Sensitisers to Improve Therapeutic Index in Cancer. Pharmaceutics 2024; 16:928. [PMID: 39065625 PMCID: PMC11279903 DOI: 10.3390/pharmaceutics16070928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.
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Affiliation(s)
- Yu-Shan Chen
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
| | - Enhui Jin
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
| | - Philip J. Day
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
- Department of Medicine, University of Cape Town, Cape Town 7925, South Africa
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Suleiman Khoury Z, Sohail F, Wang J, Mendoza M, Raake M, Tahoor Silat M, Reddy Bathinapatta M, Sadeghzadegan A, Meghana P, Paul J. Neuroinflammation: A Critical Factor in Neurodegenerative Disorders. Cureus 2024; 16:e62310. [PMID: 39006715 PMCID: PMC11246070 DOI: 10.7759/cureus.62310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.
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Affiliation(s)
| | - Fatima Sohail
- Department of Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, USA
| | - Jada Wang
- Department of Medicine, St. George's University, Brooklyn, USA
| | - Moises Mendoza
- Department of Health Sciences, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, VEN
| | - Mohammed Raake
- Department of Medicine, Annamalai University, Chennai, IND
| | | | | | - Amirali Sadeghzadegan
- Department of General Practice, Marmara University School of Medicine, Istanbul, TUR
| | - Patel Meghana
- Department of Medicine, Ramaiah University of Applied Sciences, Bengaluru, IND
| | - Janisha Paul
- Department of Medicine, Punjab Institute of Medical Sciences, Jalandhar, IND
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25
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Jiang D, Zheng S, Xu X, Yue H, Liang W, Wu Z. Uncovering Druggable Targets in Aortic Dissection: An Association Study Integrating Mendelian Randomization, pQTL, and Protein-Protein Interaction Network. Biomedicines 2024; 12:1204. [PMID: 38927411 PMCID: PMC11200553 DOI: 10.3390/biomedicines12061204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/16/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Aortic dissection (AD) is a life-threatening acute aortic syndrome. There are limitations and challenges in the discovery and application of biomarkers and drug targets for AD. Mendelian randomization (MR) analysis is a reliable analytical method to identify effective therapeutic targets. We aimed to identify novel therapeutic targets for AD and investigate their potential side-effects based on MR analysis. Data from protein quantitative trait loci (pQTLs) were used for MR analyses to identify potential therapeutic targets. We probed druggable proteins involved in the pathogenesis of aortic dissection from deCODE. In this study, a two-sample MR analysis was conducted, with druggable proteins as the exposure factor and data on genome-wide association studies (GWAS) of AD as the outcome. After conducting a two-sample MR, summary data-based Mendelian randomization (SMR) analysis and colocalization analysis were performed. A protein-protein interaction (PPI) network was also constructed to delve into the interactions between identified proteins. After MR analysis and the Steiger test, we identified five proteins as potential therapeutic targets for AD. SMR analysis and colocalization analysis also confirmed our findings. Finally, we identified ASPN (OR = 1.36, 95% CI: 1.20, 1.54, p = 4.22 × 10-5) and SPOCK2 (OR = 0.57, 95% CI: 0.41, 0.78, p = 4.52 × 10-4) as the core therapeutic targets. Through PPI network analysis, we identified six druggable targets, enabling the subsequent identification of six promising drugs from DrugBank for treating AD. This discovery of specific proteins as novel therapeutic targets represents a significant advancement in AD treatment. These findings provide more effective treatment options for AD.
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Affiliation(s)
| | | | | | | | | | - Zhong Wu
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, No. 37 Guoxue Road, Wuhou District, Chengdu 610041, China; (D.J.)
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Chen Q, Yang Z, Liu H, Man J, Oladejo AO, Ibrahim S, Wang S, Hao B. Novel Drug Delivery Systems: An Important Direction for Drug Innovation Research and Development. Pharmaceutics 2024; 16:674. [PMID: 38794336 PMCID: PMC11124876 DOI: 10.3390/pharmaceutics16050674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The escalating demand for enhanced therapeutic efficacy and reduced adverse effects in the pharmaceutical domain has catalyzed a new frontier of innovation and research in the field of pharmacy: novel drug delivery systems. These systems are designed to address the limitations of conventional drug administration, such as abbreviated half-life, inadequate targeting, low solubility, and bioavailability. As the disciplines of pharmacy, materials science, and biomedicine continue to advance and converge, the development of efficient and safe drug delivery systems, including biopharmaceutical formulations, has garnered significant attention both domestically and internationally. This article presents an overview of the latest advancements in drug delivery systems, categorized into four primary areas: carrier-based and coupling-based targeted drug delivery systems, intelligent drug delivery systems, and drug delivery devices, based on their main objectives and methodologies. Additionally, it critically analyzes the technological bottlenecks, current research challenges, and future trends in the application of novel drug delivery systems.
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Affiliation(s)
- Qian Chen
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
| | - Zhen Yang
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
| | - Haoyu Liu
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
| | - Jingyuan Man
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
| | - Ayodele Olaolu Oladejo
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
- Department of Animal Health Technology, Oyo State College of Agriculture and Technology, Igboora 201003, Nigeria
| | - Sally Ibrahim
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
- Department of Animal Reproduction and AI, Veterinary Research Institute, National Research Centre, Dokki 12622, Egypt
| | - Shengyi Wang
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
| | - Baocheng Hao
- Key Laboratory of New Animal Drug Project, Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agriculture Sciences, Lanzhou 730050, China; (Q.C.); (Z.Y.); (H.L.); (J.M.); (A.O.O.); (S.I.)
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Mosca I, Freri E, Ambrosino P, Belperio G, Granata T, Canafoglia L, Ragona F, Solazzi R, Filareto I, Castellotti B, Messina G, Gellera C, DiFrancesco JC, Soldovieri MV, Taglialatela M. Case report: Marked electroclinical improvement by fluoxetine treatment in a patient with KCNT1-related drug-resistant focal epilepsy. Front Cell Neurosci 2024; 18:1367838. [PMID: 38644974 PMCID: PMC11027738 DOI: 10.3389/fncel.2024.1367838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/11/2024] [Indexed: 04/23/2024] Open
Abstract
Variants in KCNT1 are associated with a wide spectrum of epileptic phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), non-EIMFS developmental and epileptic encephalopathies, autosomal dominant or sporadic sleep-related hypermotor epilepsy, and focal epilepsy. Here, we describe a girl affected by drug-resistant focal seizures, developmental delay and behavior disorders, caused by a novel, de novo heterozygous missense KCNT1 variant (c.2809A > G, p.S937G). Functional characterization in transiently transfected Chinese Hamster Ovary (CHO) cells revealed a strong gain-of-function effect determined by the KCNT1 p.S937G variant compared to wild-type, consisting in an increased maximal current density and a hyperpolarizing shift in current activation threshold. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant KCNT1 channels. Treatment of the proband with fluoxetine led to a prolonged electroclinical amelioration, with disappearance of seizures and better EEG background organization, together with an improvement in behavior and mood. Altogether, these results suggest that, based on the proband's genetic and functional characteristics, the antidepressant drug fluoxetine may be repurposed for the treatment of focal epilepsy caused by gain-of-function variants in KCNT1. Further studies are needed to verify whether this approach could be also applied to other phenotypes of the KCNT1-related epilepsies spectrum.
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Affiliation(s)
- Ilaria Mosca
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
| | - Elena Freri
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Paolo Ambrosino
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Giorgio Belperio
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Tiziana Granata
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Laura Canafoglia
- Department of Diagnostic and Technology, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Francesca Ragona
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Roberta Solazzi
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Ilaria Filareto
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Barbara Castellotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Giuliana Messina
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Cinzia Gellera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | | | - Maria Virginia Soldovieri
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, Italy
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Frankot MA, Young ME, Vonder Haar C. Understanding Individual Subject Differences through Large Behavioral Datasets: Analytical and Statistical Considerations. Perspect Behav Sci 2024; 47:225-250. [PMID: 38660505 PMCID: PMC11035513 DOI: 10.1007/s40614-023-00388-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2023] [Indexed: 04/26/2024] Open
Abstract
A core feature of behavior analysis is the single-subject design, in which each subject serves as its own control. This approach is powerful for identifying manipulations that are causal to behavioral changes but often fails to account for individual differences, particularly when coupled with a small sample size. It is more common for other subfields of psychology to use larger-N approaches; however, these designs also often fail to account for the individual by focusing on aggregate-level data only. Moving forward, it is important to study individual differences to identify subgroups of the population that may respond differently to interventions and to improve the generalizability and reproducibility of behavioral science. We propose that large-N datasets should be used in behavior analysis to better understand individual subject variability. First, we describe how individual differences have been historically treated and then outline practical reasons to study individual subject variability. Then, we describe various methods for analyzing large-N datasets while accounting for the individual, including correlational analyses, machine learning, mixed-effects models, clustering, and simulation. We provide relevant examples of these techniques from published behavioral literature and from a publicly available dataset compiled from five different rat experiments, which illustrates both group-level effects and heterogeneity across individual subjects. We encourage other behavior analysts to make use of the substantial advancements in online data sharing to compile large-N datasets and use statistical approaches to explore individual differences.
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Affiliation(s)
- Michelle A. Frankot
- Injury and Recovery Laboratory, Department of Psychology, West Virginia University, Morgantown, WV USA
- Injury and Recovery Laboratory, Department of Neuroscience, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210 USA
| | - Michael E. Young
- Department of Psychological Sciences, Kansas State University, Manhattan, KS USA
| | - Cole Vonder Haar
- Injury and Recovery Laboratory, Department of Psychology, West Virginia University, Morgantown, WV USA
- Injury and Recovery Laboratory, Department of Neuroscience, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210 USA
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Wang S, Wu X, Wu X, Cheng J, Chen Q, Qi Z. Systematic analysis of the role of LDHs subtype in pan-cancer demonstrates the importance of LDHD in the prognosis of hepatocellular carcinoma patients. BMC Cancer 2024; 24:156. [PMID: 38291366 PMCID: PMC10829303 DOI: 10.1186/s12885-024-11920-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Lactate dehydrogenase (LDHs) is an enzyme involved in anaerobic glycolysis, including LDHA, LDHB, LDHC and LDHD. Given the regulatory role in the biological progression of certain tumors, we analyzed the role of LDHs in pan-cancers. METHODS Cox regression, Kaplan-Meier curves, Receiver Operating Characteristic (ROC) curves, and correlation of clinical indicators in tumor patients were used to assess the prognostic significance of LDHs in pan-cancer. The TCGA, HPA, TIMER, UALCAN, TISIDB, and Cellminer databases were used to investigate the correlation between the expression of LDHs and immune subtypes, immune checkpoint genes, methylation levels, tumor mutational load, microsatellite instability, tumor-infiltrating immune cells and drug sensitivity. The cBioPortal database was also used to identify genomic abnormalities of LDHs in pan-cancer. A comprehensive assessment of the biological functions of LDHs was performed using GSEA. In vitro, HepG2 and Huh7 cells were transfected with LDHD siRNA and GFP-LDHD, the proliferation capacity of cells was examined using CCK-8, EdU, and colony formation assays; the migration and invasion of cells was detected by wound healing and transwell assays; western blotting was used to detect the levels of MMP-2, MMP-9, E-cadherin, N-cadherin and Akt phosphorylation. RESULTS LDHs were differentially expressed in a variety of human tumor tissues. LDHs subtypes can act as pro-oncogenes or anti-oncogenes in different types of cancer and have an impact on the prognosis of patients with tumors by influencing their clinicopathological characteristics. LDHs were differentially expressed in tumor immune subtypes and molecular subtypes. In addition, LDHs expression correlated with immune checkpoint genes, tumor mutational load, and microsatellite instability. LDHD was identified to play an important role in the prognosis of HCC patients, according to a comprehensive analysis of LDHs in pan-cancer. In HepG2 and Huh7 cells, knockdown of LDHD promoted cell proliferation, migration, and invasion, promoted the protein expression levels of MMP-2, MMP-9, N-cadherin, and Akt phosphorylation, but inhibited the protein expression level of E-cadherin. In addition, LDHD overexpression showed the opposite changes. CONCLUSION LDHs subtypes can be used as potential prognostic markers for certain cancers. Prognostic and immunotherapeutic analysis indicated that LDHD plays an important role in the prognosis of HCC patients. In vitro experiments revealed that LDHD can affect HCC proliferation, migration, and invasion by regulating MMPs expression and EMT via Akt signaling pathway, which provides a new perspective on the anti-cancer molecular mechanism of LDHD in HCC.
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Affiliation(s)
- Shengnan Wang
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
- Department of Pathology, Fuyang People's Hospital, Anhui Medical University, Fuyang, Anhui, 236000, P.R. China
| | - Xingwei Wu
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
- Clinical Laboratory, Traditional Chinese Hospital of Lu'an, Anhui University of Chinese Medicine, Lu'an 237000, Anhui, P.R. China
| | - Xiaoming Wu
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
- Department of Thyroid and Breast Surgery, Yijishan Hospital, First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
| | - Jin Cheng
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
- Department of Gastroenterology, Yijishan Hospital, First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
| | - Qianyi Chen
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China
| | - Zhilin Qi
- Department of Biochemistry and Molecular Biology, Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241002, P.R. China.
- Anhui Province Key Laboratory of Active Biological Macro-Molecules, Wannan Medical College, Wuhu, Anhui, 241002, P.R. China.
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Zhou R, Wu Q, Yang Z, Cai Y, Wang D, Wu D. The Role of the Gut Microbiome in the Development of Acute Pancreatitis. Int J Mol Sci 2024; 25:1159. [PMID: 38256232 PMCID: PMC10816839 DOI: 10.3390/ijms25021159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
With the explosion research on the gut microbiome in the recent years, much insight has been accumulated in comprehending the crosstalk between the gut microbiota community and host health. Acute pancreatitis (AP) is one of the gastrointestinal diseases associated with significant morbidity and subsequent mortality. Studies have elucidated that gut microbiota are engaged in the pathological process of AP. Herein, we summarize the major roles of the gut microbiome in the development of AP. We then portray the association between dysbiosis of the gut microbiota and the severity of AP. Finally, we illustrate the promises and challenges that arise when seeking to incorporate the microbiome in acute pancreatitis treatment.
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Affiliation(s)
- Ruilin Zhou
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (R.Z.); (Z.Y.); (Y.C.)
| | - Qingyang Wu
- Eight-Year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Q.W.); (D.W.)
| | - Zihan Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (R.Z.); (Z.Y.); (Y.C.)
| | - Yanna Cai
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (R.Z.); (Z.Y.); (Y.C.)
| | - Duan Wang
- Eight-Year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Q.W.); (D.W.)
| | - Dong Wu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (R.Z.); (Z.Y.); (Y.C.)
- Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Falsaperla R, Sortino V, Vitaliti G, Ruggieri M. Comment on: "Steps to Improve Precision Medicine in Epilepsy": Are we all Agreed on the Definition? Mol Diagn Ther 2024; 28:129-130. [PMID: 38070054 DOI: 10.1007/s40291-023-00688-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 01/14/2024]
Affiliation(s)
- Raffaele Falsaperla
- Neonatal Intensive Care Unit and Neonatal Accompaniment Unit, Azienda Ospedaliero-Universitaria Policlinico "Podolico-San Marco", San Marco Hospital, University of Catania, Catania, Italy.
- Unit of Pediatrics and Pediatric Emergency, Azienda Ospedaliero-Universitaria Policlinico, "Rodolico-San Marco", San Marco Hospital, Catania, Italy.
| | - Vincenzo Sortino
- Unit of Pediatrics and Pediatric Emergency, Azienda Ospedaliero-Universitaria Policlinico, "Rodolico-San Marco", San Marco Hospital, Catania, Italy
| | - Giovanna Vitaliti
- Unit of Pediatrics and Pediatric Emergency, Azienda Ospedaliero-Universitaria Policlinico, "Rodolico-San Marco", San Marco Hospital, Catania, Italy
| | - Martino Ruggieri
- Unit of Clinical Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, AOU "Policlinico", PO "G. Rodolico", Via S. Sofia, 78, 95124, Catania, Italy
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Carrera I, Corzo L, Martínez-Iglesias O, Naidoo V, Cacabelos R. Neuroprotective Effect of Nosustrophine in a 3xTg Mouse Model of Alzheimer's Disease. Pharmaceuticals (Basel) 2023; 16:1306. [PMID: 37765114 PMCID: PMC10535028 DOI: 10.3390/ph16091306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer's disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by a cocktail of neurotrophic factors and derived peptides named Nosustrophine, a nootropic supplement made by a peptide complex extracted from the young porcine brain, ensuring neuroprotection and improving neuro-functional recovery. Experimental 3xTg-APP/Bin1/COPS5 transgenic mice models of AD were treated with Nosustrophine at two different early ages, and their neuropathological hallmark and behavior response were analyzed. Results showed that Nosustrophine increased the activity of the immune system and reduced pathological changes in the hippocampus and cortex by halting the development of amyloid plaques, mainly seen in mice of 3-4 months of age, indicating that its effect is more preventive than therapeutic. Taken together, the results indicate the potent neuroprotective activity of Nosustrophine and its stimulating effects on neuronal plasticity. This study shows for the first time an effective therapy using nootropic supplements against degenerative diseases, although further investigation is needed to understand their molecular pathways.
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Affiliation(s)
- Iván Carrera
- EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165 Bergondo, Corunna, Spain; (L.C.); (O.M.-I.); (V.N.); (R.C.)
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Tunde Aborode A, Jesutofunmi Idowu N, Tundealao S, Jaiyeola J, Constance Chinyere E, Charles Ogunleye S, Olorunshola M, Adedayo Emmanuel O. Integrative Precision Medicine for Dementia and Alzheimer's Diseases in Africa. AGING BRAIN 2023; 4:100095. [PMID: 38098965 PMCID: PMC10719563 DOI: 10.1016/j.nbas.2023.100095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 12/17/2023] Open
Affiliation(s)
| | | | - Samuel Tundealao
- School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Joseph Jaiyeola
- Department of Demography, College for Health, Community and Policy, University of Texas at San Antonio
| | | | - Seto Charles Ogunleye
- Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, 39760, MS, USA
| | - Mercy Olorunshola
- Department of Biological Sciences, State University of New York at Binghamton, NewYork, USA
| | - Ogunware Adedayo Emmanuel
- Department of Neuroscience, Developmental, and Regenerative Biology, University of Texas at San Antonio, USA
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Zhang Y, Tao J, Wang R, Xuan H, Chen Z, Xiao L, Ding H, Sun Z. Prognostic value of E‑26 transformation‑specific‑related gene in prostate cancer based on immunohistochemistry analysis. Oncol Lett 2023; 26:296. [PMID: 37274473 PMCID: PMC10236269 DOI: 10.3892/ol.2023.13882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/05/2023] [Indexed: 06/06/2023] Open
Abstract
E-26 transformation-specific-related gene (ERG) has been implicated in prostate cancer; however, its prognostic role remains unclear. Therefore, the present study aimed to investigate the association of ERG with the prognosis after radical prostatectomy in patients with prostate cancer. Patient data were collected at the Huadong Hospital, affiliated with Fudan University, between January 2016 and March 2020. ERG protein expression was detected using immunohistochemistry. Independent-sample t-tests and χ2 tests were used to evaluate prostate cancer prognosis depending on ERG levels. The Kaplan-Meier method was used to estimate biochemical failure-free survival (BFFS) and the log-rank test was used to test the distribution. Prognostic factors were determined using Cox regression analysis. The median patient age was 69 years (range, 47-82 years). The median prostate-specific antigen (PSA) and free-PSA levels before treatment were 9.58 ng/ml (range, 0.003-187.400 ng/ml) and 1.13 ng/ml (range, 0.0059-30.6100 ng/ml), respectively. ERG protein expression was positive in 43 (16.6%) and negative in 216 (83.4%) cases. The median follow-up period and BFFS were 30 and 28 months, respectively. There was a significant difference in biochemical recurrence (P=0.017) between patients with positive and negative ERG expression. Patients with positive ERG expression had significantly worse BFFS curves compared with those with negative ERG expression (P=0.0038). In the multivariate Cox regression analysis, positive ERG expression was found to be an independent prognostic factor in patients with prostate cancer who underwent radical prostatectomy (hazard ratio, 4.08; 95% confidence interval, 2.03-8.17; P=0.000074). In conclusion, positive ERG expression is an independent prognostic risk factor for prostate cancer. These findings may be valuable for improvements in the clinical application of ERG immunohistochemistry.
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Affiliation(s)
- Yang Zhang
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jing Tao
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Rangrang Wang
- Department of Surgery, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Haojie Xuan
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Zhihao Chen
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Li Xiao
- Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Haiyong Ding
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Zhongquan Sun
- Department of Urology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
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Sun T, Wang J, Suo M, Liu X, Huang H, Zhang J, Zhang W, Li Z. The Digital Twin: A Potential Solution for the Personalized Diagnosis and Treatment of Musculoskeletal System Diseases. Bioengineering (Basel) 2023; 10:627. [PMID: 37370558 DOI: 10.3390/bioengineering10060627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/12/2023] [Accepted: 05/20/2023] [Indexed: 06/29/2023] Open
Abstract
Due to the high prevalence and rates of disability associated with musculoskeletal system diseases, more thorough research into diagnosis, pathogenesis, and treatments is required. One of the key contributors to the emergence of diseases of the musculoskeletal system is thought to be changes in the biomechanics of the human musculoskeletal system. However, there are some defects concerning personal analysis or dynamic responses in current biomechanical research methodologies. Digital twin (DT) was initially an engineering concept that reflected the mirror image of a physical entity. With the application of medical image analysis and artificial intelligence (AI), it entered our lives and showed its potential to be further applied in the medical field. Consequently, we believe that DT can take a step towards personalized healthcare by guiding the design of industrial personalized healthcare systems. In this perspective article, we discuss the limitations of traditional biomechanical methods and the initial exploration of DT in musculoskeletal system diseases. We provide a new opinion that DT could be an effective solution for musculoskeletal system diseases in the future, which will help us analyze the real-time biomechanical properties of the musculoskeletal system and achieve personalized medicine.
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Affiliation(s)
- Tianze Sun
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Jinzuo Wang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Moran Suo
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Xin Liu
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Huagui Huang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Jing Zhang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Wentao Zhang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
| | - Zhonghai Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian 116600, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian 116000, China
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Liao CC, Wu KH, Chen G. Application of Preoperative Multimodal Image Fusion Technique in Microvascular Decompression Surgery via Suboccipital Retrosigmoid Approach. World Neurosurg 2023; 173:e37-e47. [PMID: 36716853 DOI: 10.1016/j.wneu.2023.01.088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 01/29/2023]
Abstract
OBJECTIVE To explore the application value of preoperative multimodal image fusion technique in microvascular decompression (MVD) surgery via the suboccipital retrosigmoid approach. METHODS Comprehensive data of 13 patients with primary trigeminal neuralgia (TN) and 13 patients with hemifacial spasm (HFS) treated by MVD surgery via the suboccipital retrosigmoid approach at the Department of Neurosurgery in Zhuhai People's Hospital from January 2021 to December 2021 were retrospectively analyzed. Preoperatively, all patients underwent cranial thin-section computed tomography and magnetic resonance examinations. Three-dimensional (3D) digital images of the skull, brainstem, nerves, and blood vessels were constructed by the 3D-slicer software or RadiAnt DICOM Viewer, which were then applied to design the surgical approach and surgical plan. The multimodal image fusion results, clinical characteristics, intraoperative data, surgical outcomes, and complications of all patients were summarized. RESULTS The 3D digital images after fusion reconstruction can vividly show the anatomical relationship between the skull, brainstem, nerves, and blood vessels and was helpful to tailor the surgical strategy. All 26 patients underwent a smooth surgery. During the surgery, the key points were accurately located, the corners of the transverse sinus and sigmoid sinus were completely exposed, and no venous sinus injury occurred in all 26 patients. The key point was approximately located at the top point of the digastric groove, 12.3 ± 0.46 mm vertically above and 6.3 ± 0.6 mm laterally to the Frankfurt horizontal plane. The average cranial opening time was 30.4 (±3.6) min, and the mean operating time was 104.7 (±12.1) min. The diameter of the bone window was about 2.0 cm-3.0 cm, and the bone flap was restored. Among the 13 patients with primary TN, 12 (92.3%) exhibited complete relief of pain and 1 had significant relief. Complications of surgery included facial sensory numbness in 1 case, vertigo in 2 cases, and herpes at the corners of the mouth in 1 case. Of the 13 patients with HFS, 12 (92.3%) had complete relief of facial twitching symptoms and 1 had significant relief, and the complications included mild facial palsy in 2 (15.4%) cases and facial sensory numbness in another 2 (15.4%) cases. The mean follow-up time after surgery ranged from 6-16 months, and 1 of 26 patients experienced recurrence of HFS during the follow-up period. CONCLUSIONS Preoperative multimodal image fusion technology can provide adequate preoperative assessment for patients and assistance in designing surgical approaches, which is an important guideline for MVD surgery via the suboccipital retrosigmoid approach for primary TN and facial muscle spasm.
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Affiliation(s)
- Chang-Chun Liao
- Department of Neurosurgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University,China), Zhuhai, China
| | - Kai-Hua Wu
- Department of Neurosurgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University,China), Zhuhai, China
| | - Gang Chen
- Department of Neurosurgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University,China), Zhuhai, China.
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Long X, Yuan X, Du J. Single-cell and spatial transcriptomics: Advances in heart development and disease applications. Comput Struct Biotechnol J 2023; 21:2717-2731. [PMID: 37181659 PMCID: PMC10173363 DOI: 10.1016/j.csbj.2023.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/11/2023] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
Current transcriptomics technologies, including bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), single-nucleus RNA-sequencing (snRNA-seq), and spatial transcriptomics (ST), provide novel insights into the spatial and temporal dynamics of gene expression during cardiac development and disease processes. Cardiac development is a highly sophisticated process involving the regulation of numerous key genes and signaling pathways at specific anatomical sites and developmental stages. Exploring the cell biological mechanisms involved in cardiogenesis also contributes to congenital heart disease research. Meanwhile, the severity of distinct heart diseases, such as coronary heart disease, valvular disease, cardiomyopathy, and heart failure, is associated with cellular transcriptional heterogeneity and phenotypic alteration. Integrating transcriptomic technologies in the clinical diagnosis and treatment of heart diseases will aid in advancing precision medicine. In this review, we summarize applications of scRNA-seq and ST in the cardiac field, including organogenesis and clinical diseases, and provide insights into the promise of single-cell and spatial transcriptomics in translational research and precision medicine.
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Affiliation(s)
- Xianglin Long
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Xin Yuan
- Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Jianlin Du
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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Shaaban S, Ji Y. Pharmacogenomics and health disparities, are we helping? Front Genet 2023; 14:1099541. [PMID: 36755573 PMCID: PMC9900000 DOI: 10.3389/fgene.2023.1099541] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/10/2023] [Indexed: 01/24/2023] Open
Abstract
Pharmacogenomics has been at the forefront of precision medicine during the last few decades. Precision medicine carries the potential of improving health outcomes at both the individual as well as population levels. To harness the benefits of its initiatives, careful dissection of existing health disparities as they relate to precision medicine is of paramount importance. Attempting to address the existing disparities at the early stages of design and implementation of these efforts is the only guarantee of a successful just outcome. In this review, we glance at a few determinants of existing health disparities as they intersect with pharmacogenomics research and implementation. In our opinion, highlighting these disparities is imperative for the purpose of researching meaningful solutions. Failing to identify, and hence address, these disparities in the context of the current and future precision medicine initiatives would leave an already strained health system, even more inundated with inequality.
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Affiliation(s)
- Sherin Shaaban
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States,ARUP Laboratories, Salt Lake City, Utah, United States,*Correspondence: Sherin Shaaban,
| | - Yuan Ji
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States,ARUP Laboratories, Salt Lake City, Utah, United States
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Roman-Belmonte JM, De la Corte-Rodriguez H, Rodriguez-Merchan EC, Vazquez-Sasot A, Rodriguez-Damiani BA, Resino-Luís C, Sanchez-Laguna F. The three horizons model applied to medical science. Postgrad Med 2022; 134:776-783. [PMID: 36093684 DOI: 10.1080/00325481.2022.2124086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 08/18/2022] [Indexed: 10/14/2022]
Abstract
The three horizons model is a framework that helps manage an organization's innovation strategy. This model considers three aspects (horizons) that should be present in the institution and guide the development of new systems. Applied to medical science, the horizons are considered as paradigms that set the guidelines for clinical knowledge. New technologies can influence this model by causing disruptive changes. Horizon 1 (evidence-based medicine) reflects the current paradigm and emphasizes the aspect of continuous improvement needed to strengthen it, such as with the introduction of the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) methodology. Evidence-based medicine has made it possible to stop performing harmful interventions like autologous bone marrow or stem cell transplantation in cancer treatment for women with early poor prognosis breast cancer or to discontinue the erroneous belief that children should not sleep on their backs to prevent sudden infant death syndrome. Horizon 2 (real-world evidence) refers to a new model in which innovation has generated new capabilities. This change makes it possible to correct weaknesses of the previous paradigm, as in the case of pragmatic clinical trials. Real-world evidence has been used to show that drugs such as tofacitinib are effective without using methotrexate as background or to demonstrate the efficacy of chemotherapy in older patients with stage II colon cancer. Horizon 3 (precision medicine) involves a disruptive innovation, leading to the abandonment of the traditional mechanistic model of medical science and is made possible by the appearance of major advances such as artificial intelligence. Precision medicine has been used to assess the use of retigabine for the treatment of refractory epilepsy or to define a genome-adjusted radiation dose using a biological model to simulate the response to radiotherapy, facilitate dose adjustment and predict outcome in breast cancer.
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Affiliation(s)
- Juan M Roman-Belmonte
- Department of Physical Medicine and Rehabilitation, Cruz Roja San José y Santa Adela University Hospital, Madrid, Spain
| | | | - E Carlos Rodriguez-Merchan
- Department of Orthopedic Surgery, La Paz University Hospital, Madrid, Spain
- Department of Orthopedic Surgery, Osteoarticular Surgery Research, Hospital La Paz Institute for Health Research - IdiPAZ (La Paz University Hospital - Autonomous University of Madrid), Madrid, Spain
| | - Aranzazu Vazquez-Sasot
- Department of Physical Medicine and Rehabilitation, Cruz Roja San José y Santa Adela University Hospital, Madrid, Spain
| | - Beatriz A Rodriguez-Damiani
- Department of Physical Medicine and Rehabilitation, Cruz Roja San José y Santa Adela University Hospital, Madrid, Spain
| | - Cristina Resino-Luís
- Department of Physical Medicine and Rehabilitation, Cruz Roja San José y Santa Adela University Hospital, Madrid, Spain
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Syrbe S. Developmental and epileptic encephalopathies - therapeutic consequences of genetic testing. MED GENET-BERLIN 2022; 34:215-224. [PMID: 38835873 PMCID: PMC11006352 DOI: 10.1515/medgen-2022-2145] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
Developmental and epileptic encephalopathies comprise a heterogeneous group of monogenic neurodevelopmental disorders characterized by early-onset seizures, marked epileptic activity and abnormal neurocognitive development. The identification of an increasing number of underlying genetic alterations and their pathophysiological roles in cellular signaling drives the way toward novel precision therapies. The implementation of novel treatments that target the underlying mechanisms gives hope for disease modification that will improve not only the seizure burden but also the neurodevelopmental outcome of affected children. So far, beneficial effects are mostly reported in individual trials and small numbers of patients. There is a need for international collaborative studies to define the natural history and relevant outcome measures and to test novel pharmacological approaches.
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Affiliation(s)
- Steffen Syrbe
- Division of Paediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
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41
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Liu Z, Lin G, Yan Z, Li L, Wu X, Shi J, He J, Zhao L, Liang H, Wang W. Predictive mutation signature of immunotherapy benefits in NSCLC based on machine learning algorithms. Front Immunol 2022; 13:989275. [PMID: 36238300 PMCID: PMC9552174 DOI: 10.3389/fimmu.2022.989275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Background Developing prediction tools for immunotherapy approaches is a clinically important and rapidly emerging field. The routinely used prediction biomarker is inaccurate and may not adequately utilize large amounts of medical data. Machine learning is a promising way to predict the benefit of immunotherapy from individual data by individuating the most important features from genomic data and clinical characteristics. Methods Machine learning was applied to identify a list of candidate genes that may predict immunotherapy benefits using data from the published cohort of 853 patients with NSCLC. We used XGBoost to capture nonlinear relations among many mutation genes and ICI benefits. The value of the derived machine learning-based mutation signature (ML-signature) on immunotherapy efficacy was evaluated and compared with the tumor mutational burden (TMB) and other clinical characteristics. The predictive power of ML-signature was also evaluated in independent cohorts of patients with NSCLC treated with ICI. Results We constructed the ML-signature based on 429 (training/validation = 8/2) patients who received immunotherapy and extracted 88 eligible predictive genes. Additionally, we conducted internal and external validation with the utility of the OAK+POPLAR dataset and independent cohorts, respectively. This ML-signature showed the enrichment in immune-related signaling pathways and compared to TMB, ML-signature was equipped with favorable predictive value and stratification. Conclusion Previous studies proposed no predictive difference between original TMB and modified TMB, and original TMB contains some genes with no predictive value. To demonstrate that fewer genetic tests are sufficient to predict immunotherapy efficacy, we used machine learning to screen out gene panels, which are used to calculate TMB. Therefore, we obtained the 88-gene panel, which showed the favorable prediction performance and stratification effect compared to the original TMB.
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Affiliation(s)
- Zhichao Liu
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guo Lin
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zeping Yan
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Linduo Li
- College of Engineering, Northeastern University, Boston, MA, United States
| | - Xingchen Wu
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | | | - Jianxing He
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Lei Zhao
- Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Lei Zhao, ; Hengrui Liang, ; Wei Wang,
| | - Hengrui Liang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
- *Correspondence: Lei Zhao, ; Hengrui Liang, ; Wei Wang,
| | - Wei Wang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
- *Correspondence: Lei Zhao, ; Hengrui Liang, ; Wei Wang,
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Kim DW, Kim JH, Lee SK, Lee SA, Lee JW, Kim MY, Seo DW. Perampanel as First Adjunctive Treatment in Patients with Focal-Onset Seizures in the FAME Study: <i>Post hoc</i> Analyses of Dose-Related Efficacy, Safety and Clinical Factors Associated with Response. J Epilepsy Res 2022; 12:6-12. [PMID: 35910330 PMCID: PMC9289380 DOI: 10.14581/jer.22002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/02/2022] [Accepted: 05/10/2022] [Indexed: 11/03/2022] Open
Abstract
Background and Purpose: Perampanel is approved for the adjunctive treatment of focal-onset seizures (FOS) with or without secondary generalized seizures. The FAME (Fycompa<sup>®</sup> as first Add-on to Monotherapy in patients with Epilepsy; NCT02726074) study evaluated the efficacy and safety of perampanel added to monotherapy in patients with FOS with or without secondary generalized seizures (SGS). <i>Post hoc</i> analyses of the FAME study assessed potential predictors of response and an in-depth evaluation of the safety and efficacy of perampanel.Methods: Efficacy was assessed by reduction of total seizure frequency by ≥50%, ≥75% or 100%, and safety by incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Univariate and multivariate logistic regression analyses for treatment response were performed.Results: Most patients (82/85) received perampanel doses of 4-8 mg/day during maintenance therapy and the highest efficacy rates were achieved with 4 mg/day, irrespective of efficacy outcome. Doses of 4 or 6 mg/day in patients with FOS with SGS (n=16) produced comparable efficacy outcomes. In multivariate analysis, total perampanel dose was predictive of 50% and 75% response rates; longer total perampanel administration period with 50% response; and concomitant non-anti-seizure medication with a 100% response. Patients developed a TEAE more frequently during the 12-week titration period (60.2%) than the 24-week maintenance period (28.4%), including dizziness (45.5% vs. 9.1%), somnolence (10.2% vs. 0%), and headache (4.5% vs. 3.4%).Conclusions: <i>Post hoc</i> analyses show that even low doses of perampanel may be effective and TEAEs are usually self-limited or well-tolerated.
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Affiliation(s)
- Dong Wook Kim
- Department of Neurology, Konkuk University School of Medicine, Seoul, Korea
| | - Ji Hyun Kim
- Department of Neurology, Korea University Guro Hospital, Seoul, Korea
| | - Sang Kun Lee
- Department of Neurology, Seoul National University Hospital, Seoul, Korea
| | - Sang Ahm Lee
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | | | - Dae-Won Seo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Abstract
Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as in humans, status epilepticus is one of the more common neurological emergencies in dogs with epilepsy. In both species, epilepsy is not a single disease but a group of disorders characterized by a broad array of clinical signs, age of onset, and underlying causes. Brain imaging suggests that the limbic system, including the hippocampus and cingulate gyrus, is often affected in canine epilepsy, which could explain the high incidence of comorbid behavioral problems such as anxiety and cognitive alterations. Resistance to antiseizure medications is a significant problem in both canine and human epilepsy, so dogs can be used to study mechanisms of drug resistance and develop novel therapeutic strategies to benefit both species. Importantly, dogs are large enough to accommodate intracranial EEG and responsive neurostimulation devices designed for humans. Studies in epileptic dogs with such devices have reported ictal and interictal events that are remarkably similar to those occurring in human epilepsy. Continuous (24/7) EEG recordings in a select group of epileptic dogs for >1 year have provided a rich dataset of unprecedented length for studying seizure periodicities and developing new methods for seizure forecasting. The data presented in this review substantiate that canine epilepsy is an excellent translational model for several facets of epilepsy research. Furthermore, several techniques of inducing seizures in laboratory dogs are discussed as related to therapeutic advances. Importantly, the development of vagus nerve stimulation as a novel therapy for drug-resistant epilepsy in people was based on a series of studies in dogs with induced seizures. Dogs with naturally occurring or induced seizures provide excellent large-animal models to bridge the translational gap between rodents and humans in the development of novel therapies. Furthermore, because the dog is not only a preclinical species for human medicine but also a potential patient and pet, research on this species serves both veterinary and human medicine.
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Affiliation(s)
- Wolfgang Löscher
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
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Beltrán-Corbellini Á, Aledo-Serrano Á, Møller RS, Pérez-Palma E, García-Morales I, Toledano R, Gil-Nagel A. Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies. Front Neurol 2022; 13:777115. [PMID: 35250806 PMCID: PMC8891166 DOI: 10.3389/fneur.2022.777115] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/27/2022] [Indexed: 12/14/2022] Open
Abstract
This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.
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Affiliation(s)
| | - Ángel Aledo-Serrano
- Epilepsy Program, Neurology Department, Hospital Ruber Internacional, Madrid, Spain
- *Correspondence: Ángel Aledo-Serrano
| | - Rikke S. Møller
- Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark
| | - Eduardo Pérez-Palma
- Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago, Chile
| | - Irene García-Morales
- Epilepsy Program, Neurology Department, Hospital Ruber Internacional, Madrid, Spain
- Epilepsy Unit, Neurology Department, Clínico San Carlos University Hospital, Madrid, Spain
| | - Rafael Toledano
- Epilepsy Program, Neurology Department, Hospital Ruber Internacional, Madrid, Spain
- Epilepsy Unit, Neurology Department, Ramón y Cajal University Hospital, Madrid, Spain
| | - Antonio Gil-Nagel
- Epilepsy Program, Neurology Department, Hospital Ruber Internacional, Madrid, Spain
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45
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Zimmern V, Minassian B, Korff C. A Review of Targeted Therapies for Monogenic Epilepsy Syndromes. Front Neurol 2022; 13:829116. [PMID: 35250833 PMCID: PMC8891748 DOI: 10.3389/fneur.2022.829116] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 01/13/2022] [Indexed: 11/15/2022] Open
Abstract
Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing “precision therapies” based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.
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Affiliation(s)
- Vincent Zimmern
- Division of Child Neurology, University of Texas Southwestern, Dallas, TX, United States
- *Correspondence: Vincent Zimmern
| | - Berge Minassian
- Division of Child Neurology, University of Texas Southwestern, Dallas, TX, United States
| | - Christian Korff
- Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland
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Saini L, Singanamalla B, Natarajan R, Madaan P. Role of genotype–phenotype correlation in prognostication of a child with a novel potassium channelopathy. J Pediatr Neurosci 2022. [DOI: 10.4103/jpn.jpn_294_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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47
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Riva A, Golda A, Balagura G, Amadori E, Vari MS, Piccolo G, Iacomino M, Lattanzi S, Salpietro V, Minetti C, Striano P. New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment. Front Neurol 2021; 12:753753. [PMID: 34950099 PMCID: PMC8690245 DOI: 10.3389/fneur.2021.753753] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/28/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Despite the wide availability of novel anti-seizure medications (ASMs), 30% of patients with epilepsy retain persistent seizures with a significant burden in comorbidity and an increased risk of premature death. This review aims to discuss the therapeutic strategies, both pharmacological and non-, which are currently in the pipeline. Methods: PubMed, Scopus, and EMBASE databases were screened for experimental and clinical studies, meta-analysis, and structured reviews published between January 2018 and September 2021. The terms “epilepsy,” “treatment” or “therapy,” and “novel” were used to filter the results. Conclusions: The common feature linking all the novel therapeutic approaches is the spasmodic rush toward precision medicine, aiming at holistically evaluating patients, and treating them accordingly as a whole. Toward this goal, different forms of intervention may be embraced, starting from the choice of the most suitable drug according to the type of epilepsy of an individual or expected adverse effects, to the outstanding field of gene therapy. Moreover, innovative insights come from in-vitro and in-vivo studies on the role of inflammation and stem cells in the brain. Further studies on both efficacy and safety are needed, with the challenge to mature evidence into reliable assets, ameliorating the symptoms of patients, and answering the challenges of this disease.
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Affiliation(s)
- Antonella Riva
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Alice Golda
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Ganna Balagura
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, Netherlands
| | - Elisabetta Amadori
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Maria Stella Vari
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Gianluca Piccolo
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Michele Iacomino
- Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Simona Lattanzi
- Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Ancona, Italy
| | - Vincenzo Salpietro
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Carlo Minetti
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Pasquale Striano
- Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
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Balestrini S, Guerrini R, Sisodiya SM. Rare and Complex Epilepsies from Childhood to Adulthood: Requirements for Separate Management or Scope for a Lifespan Holistic Approach? Curr Neurol Neurosci Rep 2021; 21:65. [PMID: 34817708 PMCID: PMC8613076 DOI: 10.1007/s11910-021-01154-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE In this descriptive review, we describe current models of transition in rare and complex epilepsy syndromes and propose alternative approaches for more holistic management based on disease biology. RECENT FINDINGS Previously published guidance and recommendations on transition strategies in individuals with epilepsy have not been systematically and uniformly applied. There is significant heterogeneity in models of transition/transfer of care across countries and even within the same country. We provide examples of the most severe epilepsy and related syndromes and emphasise the limited data on their outcome in adulthood. Rare and complex epilepsy syndromes have unique presentations and require high levels of expertise and multidisciplinary approach. Lifespan clinics, with no transition, but instead continuity of care from childhood to adulthood with highly specialised input from healthcare providers, may represent an alternative effective approach. Effectiveness should be measured by evaluation of quality of life for both patients and their families/caregivers.
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Affiliation(s)
- Simona Balestrini
- Department of Clinical and Experimental Epilepsy, University College of London (UCL) Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, London, Bucks, UK.
- Neuroscience Department, Meyer Children's Hospital, European Reference Network ERN EpiCARE, 50139, Florence, Italy.
| | - Renzo Guerrini
- Neuroscience Department, Meyer Children's Hospital, European Reference Network ERN EpiCARE, 50139, Florence, Italy
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, University College of London (UCL) Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, London, Bucks, UK
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Löscher W. Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy. Front Pharmacol 2021; 12:730257. [PMID: 34776956 PMCID: PMC8580162 DOI: 10.3389/fphar.2021.730257] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/04/2021] [Indexed: 01/09/2023] Open
Abstract
Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10-20 years, as potential therapeutic solutions for diseases of complex etiology and diseases with significant drug-resistance problems. Such agents that modulate multiple targets simultaneously are developed with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target or to combinations of single-target drugs. Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms. This novel drug exhibited promising effects in numerous preclinical models of difficult-to-treat seizures. However, in a recent randomized placebo-controlled phase IIb add-on trial in treatment-resistant focal epilepsy patients, padsevonil did not separate from placebo in its primary endpoints. At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening and its presumed dual mechanism of action was only described recently. In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy.
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Affiliation(s)
- Wolfgang Löscher
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany, and Center for Systems Neuroscience Hannover, Hannover, Germany
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Distinct gene-set burden patterns underlie common generalized and focal epilepsies. EBioMedicine 2021; 72:103588. [PMID: 34571366 PMCID: PMC8479647 DOI: 10.1016/j.ebiom.2021.103588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/04/2021] [Accepted: 09/06/2021] [Indexed: 01/02/2023] Open
Abstract
Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. Funding DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
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