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Chen X, Ren C, Wang Q, Liu X. Bidirectional influence between benign prostatic hyperplasia, prostate cancer, and prostatitis and mental disorders: two-sample and multivariate mendelian randomization analyses. Aging Male 2024; 27:2419853. [PMID: 39460452 DOI: 10.1080/13685538.2024.2419853] [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: 04/04/2024] [Revised: 10/06/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND We aimed to use Mendelian randomization (MR) to determine the causality between fifteen major mental disorders (MDs) and benign prostatic hyperplasia (BPH), prostate cancer (PCa), and prostatitis. METHODS The main MR analysis was performed using the inverse variance-weighted (IVW) method. RESULTS The study found that insomnia (odds ratio [OR], 1.6190; p = .0017) was significantly associated with an increased risk of BPH, and mood disorders (OR, 1.1590; p = .0221) was nominally associated with an increased risk of BPH. Conversely, BPH was suggestively associated with a low epilepsy risk (OR, 0.9988; p = .0043), and was nominally associated with an increased risk of insomnia (OR, 1.0061; p = .0291). Furthermore, attention deficit hyperactivity disorder (ADHD) was suggestively associated with a low PCa risk (OR = 0.9474; p = .0058). However, no causal relationship was observed between PCa and MDs. Finally, anorexia nervosa (OR, 1.1686; p = .0248) and depression (OR, 336.5383; p = .0308) were nominally positively correlated with prostatitis. Prostatitis was suggestively associated with increased risk of ADHD (OR, 1.0868; p = .0413). CONCLUSION Our findings provide clinicians with a basis for developing programs to prevent or treat MDs and prostatic diseases.
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Affiliation(s)
- Xiangyu Chen
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Congzhe Ren
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Qihua Wang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoqiang Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
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2
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Casanovas F, Dinamarca F, Posso M, Mané A, Oller S, Córcoles D, Macià F, Sala M, Pérez-Sola V, Ruiz AI. Cancer characteristics in patients with schizophrenia: a 25-year retrospective analysis. Psychiatry Res 2024; 342:116206. [PMID: 39321636 DOI: 10.1016/j.psychres.2024.116206] [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: 03/03/2024] [Revised: 09/15/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
Schizophrenia is associated with higher cancer-related mortality, perhaps due to delayed diagnosis and limited access to treatment. The study aimed to compare patients diagnosed with cancer with and without schizophrenia to determine whether these groups differ in terms of oncological variables and survival outcomes. This was a retrospective, observational cohort study that included 30.990 patients diagnosed with cancer between 1997 and 2021. We performed univariate and bivariate analyses for the sociodemographic and clinical variables, and constructed Kaplan-Meier survival curves and used the log-rank test to perform the comparisons. All variables were compared for each cancer type. One hundred and sixty-two (0.52 %) patients had a confirmed diagnosis of schizophrenia (ICD-9 criteria). The mean age at diagnosis was significantly lower in the schizophrenia group. A significantly higher proportion of the schizophrenia group was diagnosed with cancer through the emergency department and a lower percentage through scheduled appointments. A smaller percentage of patients in the schizophrenia group received radical treatment for cancer. The mortality rate was higher in the schizophrenia group and median survival was lower. These findings suggest that cancer patients with schizophrenia have worse outcomes than patients without schizophrenia in terms of oncological variables and survival.
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Affiliation(s)
- Francesc Casanovas
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red, Área de Salud Mental (CIBERSAM), Madrid, Spain.
| | - Fernando Dinamarca
- Department of Psychiatry at Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Margarita Posso
- Department of Epidemiology and Evaluation, Hospital del Mar Research Institute, Barcelona, Spain; Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), Madrid, Spain
| | - Anna Mané
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red, Área de Salud Mental (CIBERSAM), Madrid, Spain; Department of Medicine and Life Sciences (MELIS), Pompeu Fabra University, Barcelona, Spain
| | - Sílvia Oller
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red, Área de Salud Mental (CIBERSAM), Madrid, Spain
| | - David Córcoles
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red, Área de Salud Mental (CIBERSAM), Madrid, Spain
| | - Francesc Macià
- Department of Epidemiology and Evaluation, Hospital del Mar Research Institute, Barcelona, Spain; Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), Madrid, Spain
| | - Maria Sala
- Department of Epidemiology and Evaluation, Hospital del Mar Research Institute, Barcelona, Spain; Research Network on Chronicity, Primary Care and Health Promotion (RICAPPS), Madrid, Spain
| | - Víctor Pérez-Sola
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red, Área de Salud Mental (CIBERSAM), Madrid, Spain; Department of Medicine and Life Sciences (MELIS), Pompeu Fabra University, Barcelona, Spain
| | - Ada I Ruiz
- Mental Health Institute, Hospital del Mar Research Institute, Barcelona, Spain
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Bhoir S, De Benedetti A. Targeting Prostate Cancer, the 'Tousled Way'. Int J Mol Sci 2023; 24:11100. [PMID: 37446279 DOI: 10.3390/ijms241311100] [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: 06/13/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
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Affiliation(s)
- Siddhant Bhoir
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA
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Wootten JC, Wiener JC, Blanchette PS, Anderson KK. Cancer incidence and stage at diagnosis among people with psychotic disorders: Systematic review and meta-analysis. Cancer Epidemiol 2022; 80:102233. [PMID: 35952461 DOI: 10.1016/j.canep.2022.102233] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 12/16/2022]
Abstract
Research regarding the incidence of cancer among people with psychotic disorders relative to the general population is equivocal, although the evidence suggests that they have more advanced stage cancer at diagnosis. We conducted a systematic review and meta-analysis to examine the incidence and stage at diagnosis of cancer among people with, relative to those without, psychotic disorders. We searched the MEDLINE, EMBASE, PsycINFO, and CINAHL databases. Articles were included if they reported the incidence and/or stage at diagnosis of cancer in people with psychotic disorders. Random effects meta-analyses were used to determine risk of cancer and odds of advanced stage cancer at diagnosis in people with psychosis, relative to those without psychotic disorders. A total of 40 articles were included in the review, of which, 31 were included in the meta-analyses. The pooled age-adjusted risk ratio for all cancers in people with psychotic disorders was 1.08 (95% CI: 1.01-1.15), relative to those without psychotic disorders, with significant heterogeneity by cancer site. People with psychotic disorders had a higher incidence of breast, oesophageal, colorectal, testicular, uterine, and cervical cancer, and a lower incidence of skin, prostate, and thyroid cancer. People with psychotic disorders also had 22% higher (95% CI: 2-46%) odds of metastases at diagnosis, compared to those without psychotic disorders. Our systematic review found a significant difference in overall cancer incidence among people diagnosed with psychotic disorders and people with psychotic disorders were more likely to present with advanced stage cancer at diagnosis. This finding may reflect a need for improved access to and uptake of cancer screening for patients diagnosed with psychotic disorders.
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Affiliation(s)
- Jared C Wootten
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
| | - Joshua C Wiener
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Phillip S Blanchette
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; ICES Western, London, Ontario, Canada; Division of Medical Oncology, London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada
| | - Kelly K Anderson
- Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; ICES Western, London, Ontario, Canada; Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Association between schizophrenia and prostate cancer risk: Results from a pool of cohort studies and Mendelian randomization analysis. Compr Psychiatry 2022; 115:152308. [PMID: 35303584 DOI: 10.1016/j.comppsych.2022.152308] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 03/07/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Observational studies analyzing the risk of prostate cancer in schizophrenia patients have generated mixed results. We performed a meta-analysis and a Mendelian randomization (MR) analysis to evaluate the relationship and causality between schizophrenia and the risk of prostate cancer. METHODS A comprehensive and systematic search of cohort studies was conducted, and a random-effects model meta-analysis was performed to calculate the standardized incidence ratios (SIRs) for prostate cancer incidence among schizophrenia patients versus the general population. To investigate the correlation between genetically-predicted schizophrenia and prostate cancer risk, we used summary statistics from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium (61,106 controls and 79,148 cases), and 75 schizophrenia-associated single nucleotide polymorphisms (SNP) from European descent as the instrumental variable. RESULTS In the meta-analysis of 13 cohort studies with 218,076 men involved, a decreased risk of prostate cancer was observed among schizophrenia patients [SIR 0.610; 95% confidence interval (CI) 0.500-0.740; p < 0.001] with significant heterogeneity (I2 = 83.3%; p < 0.001). However, MR analysis did not sustain the link between genetically-predicted schizophrenia and prostate cancer [odds ratio (OR) 1.033; 95% CI 0.998-1.069; p = 0.065]. The result was robust against extensive sensitivity analyses. CONCLUSIONS Our study indicated a decreased risk of prostate cancer in schizophrenia patients through meta-analysis, while MR analysis did not support the connection between schizophrenia and prostate cancer. Due to the interaction of genetic variants between binary exposures, we need to be cautious in interpreting and presenting causal associations. Moreover, further research is needed to investigate underlying factors that might link schizophrenia to the risk of prostate cancer.
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Predicting the risk of prostate cancer in asymptomatic men: a cohort study to develop and validate a novel algorithm. Br J Gen Pract 2021; 71:e364-e371. [PMID: 33875417 PMCID: PMC8087311 DOI: 10.3399/bjgp20x714137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 09/08/2020] [Indexed: 12/02/2022] Open
Abstract
Background Diagnosis of prostate cancer at an early stage can potentially identify tumours when intervention may improve treatment options and survival. Aim To develop and validate an equation to predict absolute risk of prostate cancer in asymptomatic men with prostate specific antigen (PSA) tests in primary care. Design and setting Cohort study using data from English general practices, held in the QResearch database. Method Routine data were collected from 1098 QResearch English general practices linked to mortality, hospital, and cancer records for model development. Two separate sets of practices were used for validation. In total, there were 844 455 men aged 25–84 years with PSA tests recorded who were free of prostate cancer at baseline in the derivation cohort; the validation cohorts comprised 292 084 and 316 583 men. The primary outcome was incident prostate cancer. Cox proportional hazards models were used to derive 10-year risk equations. Measures of performance were determined in both validation cohorts. Results There were 40 821 incident cases of prostate cancer in the derivation cohort. The risk equation included PSA level, age, deprivation, ethnicity, smoking status, serious mental illness, diabetes, BMI, and family history of prostate cancer. The risk equation explained 70.4% (95% CI = 69.2 to 71.6) of the variation in time to diagnosis of prostate cancer (R2) (D statistic 3.15, 95% CI = 3.06 to 3.25; Harrell’s C-index 0.917, 95% CI = 0.915 to 0.919). Two-step approach had higher sensitivity than a fixed PSA threshold at identifying prostate cancer cases (identifying 68.2% versus 43.9% of cases), high-grade cancers (49.2% versus 40.3%), and deaths (67.0% versus 31.5%). Conclusion The risk equation provided valid measures of absolute risk and had higher sensitivity for incident prostate cancer, high-grade cancers, and prostate cancer mortality than a simple approach based on age and PSA threshold.
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Zharinov GM, Khalchitsky SE, Loktionov A, Sogoyan MV, Khutoryanskaya YV, Neklasova NY, Bogomolov OA, Smirnov IV, Samoilovich MP, Skakun VN, Vissarionov SV, Anisimov VN. The presence of polymorphisms in genes controlling neurotransmitter metabolism and disease prognosis in patients with prostate cancer: a possible link with schizophrenia. Oncotarget 2021; 12:698-707. [PMID: 33868590 PMCID: PMC8021032 DOI: 10.18632/oncotarget.27921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/08/2021] [Indexed: 01/08/2023] Open
Abstract
Polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time (PSADT) corresponding to unfavorable and favorable disease prognosis respectively. The ‘unfavorable prognosis’ group (40 cases) was defined by PSADT ≤ 2 months, whereas patients in the ‘favorable prognosis’ group (67 cases) had PSADT ≥ 30 months. The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated: a) the STin2 VNTR in the serotonin transporter SLC6A4 gene; b) the 30-bp VNTR in the monoamine oxidase A MAOA gene; c) the Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene; d) the promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene. The STin2 12R/10R variant of the SLC6A4 gene (OR = 2.278; 95% CI = 0.953–5.444) and the -521T/T homozygosity of the DRD4 gene (OR = 1.579; 95% CI = 0.663–3.761) tended to be overrepresented in PC patients with unfavorable disease prognosis. These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients. These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.
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Affiliation(s)
- Gennady M Zharinov
- A.M. Granov Russian Research Center for Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation, Pesochny, St. Petersburg, 197758, Russia.,These authors contributed equally to this work
| | - Sergei E Khalchitsky
- H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Ministry of Health of the Russian Federation, Pushkin, St. Petersburg, 196603, Russia.,These authors contributed equally to this work
| | - Alexandre Loktionov
- DiagNodus Ltd, Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom
| | - Marina V Sogoyan
- H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Ministry of Health of the Russian Federation, Pushkin, St. Petersburg, 196603, Russia
| | - Yulia V Khutoryanskaya
- St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation, St. Petersburg, 194100, Russia
| | - Natalia Yu Neklasova
- A.M. Granov Russian Research Center for Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation, Pesochny, St. Petersburg, 197758, Russia
| | - Oleg A Bogomolov
- A.M. Granov Russian Research Center for Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation, Pesochny, St. Petersburg, 197758, Russia
| | - Ilya V Smirnov
- A.M. Granov Russian Research Center for Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation, Pesochny, St. Petersburg, 197758, Russia
| | - Marina P Samoilovich
- A.M. Granov Russian Research Center for Radiology and Surgical Technologies of the Ministry of Health of the Russian Federation, Pesochny, St. Petersburg, 197758, Russia
| | - Vladimir N Skakun
- Yaroslav-the-Wise Novgorod State University of the Ministry of Science and Higher Education of the Russian Federation, Veliky Novgorod, 173003, Russia
| | - Sergei V Vissarionov
- H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Ministry of Health of the Russian Federation, Pushkin, St. Petersburg, 196603, Russia
| | - Vladimir N Anisimov
- N.N. Petrov National Medical Research Center of Oncology, Pesochny, St. Petersburg, 197758, Russia
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Singh V, Bhoir S, Chikhale RV, Hussain J, Dwyer D, Bryce RA, Kirubakaran S, De Benedetti A. Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy. iScience 2020; 23:101474. [PMID: 32905878 PMCID: PMC7486443 DOI: 10.1016/j.isci.2020.101474] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/15/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022] Open
Abstract
Through in vitro kinase assays and docking studies, we report the synthesis and biological evaluation of a phenothiazine analog J54 with potent TLK1 inhibitory activity for prostate cancer (PCa) therapy. Most PCa deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa. Treatments that can suppress the conversion to mCRPC have high potential to be rapidly implemented in the clinics. ADT results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DNA damage response that typically results in temporary cell-cycle arrest of androgen-responsive PCa cells, whereas its abrogation leads to apoptosis. We studied J54 as a potent inhibitor of this axis and as a mediator of apoptosis in vitro and in LNCaP xenografts, which has potential for clinical investigation in combination with ADT. J54 has low affinity for the dopamine receptor in modeling and competition studies and weak detrimental behavioral effects in mice and C. elegans.
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Affiliation(s)
- Vibha Singh
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, USA
| | - Siddhant Bhoir
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, USA
- Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, India
| | - Rupesh V. Chikhale
- Division of Pharmacy & Optometry, University of Manchester, Manchester, UK
| | - Javeena Hussain
- Department of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, India
| | - Donard Dwyer
- Department of Psychiatry and Behavioral Medicine, LSU Health Sciences Center, Shreveport, USA
| | - Richard A. Bryce
- Division of Pharmacy & Optometry, University of Manchester, Manchester, UK
| | - Sivapriya Kirubakaran
- Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, India
- Department of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, India
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, USA
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Ni L, Wu J, Long Y, Tao J, Xu J, Yuan X, Yu N, Wu R, Zhang Y. Mortality of site-specific cancer in patients with schizophrenia: a systematic review and meta-analysis. BMC Psychiatry 2019; 19:323. [PMID: 31660909 PMCID: PMC6816203 DOI: 10.1186/s12888-019-2332-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Numerous studies have reported contradicting results on the relationship between cancer mortality and schizophrenia. Our aim is to quantify the mortality rate of common site-specific cancers among patients with schizophrenia and to synthesize the available research evidence. METHODS We performed a systemic search of the PubMed, EMBASE and Web of Science databases. Studies reporting the mortality rate of different cancer in patients with schizophrenia were included. A random-effects model was applied to calculate the pooled relative risks (RRs) with 95% confidence intervals (95%CIs). RESULTS Seven studies consisting of 1,162,971 participants with schizophrenia were included in this meta-analysis. Data regarding mortality risk of breast, colon, lung and prostate cancer among schizophrenia patients were subjected to quantitative analysis. Pooled results showed significant increases in mortality risk of breast cancer (RR = 1.97, 95%CI 1.38-2.83), lung cancer (RR = 1.93, 95%CI 1.46-2.54) and colon cancer (RR = 1.69, 95%CI 1.60-1.80) in patients with schizophrenia compared with those in the general population or control group. The mortality risk of prostate cancer increased in male patients, although no significant difference was detected (RR = 1.58, 95% CI 0.79-3.15). Increased risks of mortality from lung and colon cancer were observed in female patients (RR = 2.49, 95%CI 2.40-2.59 and RR = 2.42, 95%CI 1.39-4.22, respectively) and elevated risks of mortality from lung and colon cancer in male patients (RR = 2.40, 95%CI 2.30-2.50 and RR = 1.90, 95%CI 1.71-2.11, respectively) were detected. CONCLUSIONS Individuals with schizophrenia have a significantly high risk of mortality from breast, colon, and lung cancer.
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Affiliation(s)
- Liwei Ni
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Jian Wu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Yuming Long
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Jialong Tao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Jianhao Xu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Xuya Yuan
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Na Yu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Runhong Wu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
| | - Yusong Zhang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004 People’s Republic of China
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Singh V, Jaiswal PK, Ghosh I, Koul HK, Yu X, De Benedetti A. Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors. Int J Cancer 2019; 145:1055-1067. [PMID: 30737777 PMCID: PMC6617729 DOI: 10.1002/ijc.32200] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/29/2018] [Accepted: 01/29/2019] [Indexed: 01/01/2023]
Abstract
Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen‐independent (AI) colonies of LNCaP and TRAMP‐C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long‐term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1‐T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT). What's new? Standard therapy for advanced Prostate Cancer (PCa) consists of anti‐androgens, which only provide temporary respite from disease progression to metastatic castrate‐resistant prostate cancer (mCRPC). Here, the authors show in the LNCaP cell model that the increased expression with ADT of TLK1B, a prosurvival checkpoint pathway that is enacted before conversion to androgen‐independent growth, offers a unique target for attacking more specifically PCa cells before their conversion to CRPC. Moreover, they suggest to re‐purpose thioridazine or other phenothiazine antipsychotic drugs as inhibitors of the TLK1 > Nek1 > ATR > Chk1 DNA Damage Response (DDR) axis for the early treatment of advanced PCa still responsive to ADT.
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Affiliation(s)
- Vibha Singh
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA
| | - Praveen Kumar Jaiswal
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA
| | - Ishita Ghosh
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA
| | - Hari K Koul
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA.,Feist Weiller Cancer Center, LSUHSC, Shreveport, LA.,Overton Brooks VA Medical center, Shreveport, LA
| | - Xiuping Yu
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA
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Seeman MV. Women who suffer from schizophrenia: Critical issues. World J Psychiatry 2018; 8:125-136. [PMID: 30425943 PMCID: PMC6230925 DOI: 10.5498/wjp.v8.i5.125] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/24/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Many brain diseases, including schizophrenia, affect men and women unequally - either more or less frequently, or at different times in the life cycle, or to varied degrees of severity. With updates from recent findings, this paper reviews the work of my research group over the last 40 years and underscores issues that remain critical to the optimal care of women with schizophrenia, issues that overlap with, but are not identical to, the cares and concerns of men with the same diagnosis. Clinicians need to be alert not only to the overarching needs of diagnostic groups, but also to the often unique needs of women and men.
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Affiliation(s)
- Mary V Seeman
- Department of Psychiatry, University of Toronto, Institute of Medical Science, Toronto, ON M5P 3L6, Canada
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12
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The incidence rate of cancer in patients with schizophrenia: A meta-analysis of cohort studies. Schizophr Res 2018; 195:519-528. [PMID: 28943096 DOI: 10.1016/j.schres.2017.08.065] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 08/22/2017] [Accepted: 08/31/2017] [Indexed: 11/22/2022]
Abstract
BACKGROUND Numerous studies report that cancer prevalence in patients with schizophrenia might be different from the general population, but findings remain controversial. AIM Our updated meta-analysis of cohort studies aims to analyze the data from cohort studies concerning the incidence risk of overall cancer and some site-specific cancers in patients with schizophrenia. METHOD We performed a systemic search through electronic databases. Cohort studies evaluating and describing the cancer incidence among patients with schizophrenia were included. Pooled risk ratios (RRs) were calculated for assessing the incidence risk of cancer. RESULTS There were 16 cohort studies included in this meta-analysis, which combined a total of 480,356 participants with schizophrenia and 41,999 cases of cancer. Results showed that there was a slight significant decreased overall risk ratio of cancer incidence among patients with schizophrenia (RR=0.90, 95% CI 0.81-0.99). When stratified by cancer site and gender, there were significant decreased incidence risk rates of colorectal cancer (RR=0.82, 95% CI 0.69-0.98) and prostate cancer (RR=0.55, 95% CI 0.42-0.71) in those patients, moreover, the incidence rate of colorectal cancer decreased significantly in male patients (RR=0.89, 95% CI 0.81-0.98), and the incidence rate of lung cancer increased significantly in female patients (RR=1.12, 95% CI 1.01-1.25). CONCLUSIONS The incidence risk of some cancers was reduced in patients with schizophrenia. Gender and type of cancer were two important confounding factors contributed to the heterogeneity that required adjustment in our cancer incidence meta-analysis.
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Roney MSI, Park SK. Antipsychotic dopamine receptor antagonists, cancer, and cancer stem cells. Arch Pharm Res 2018; 41:384-408. [PMID: 29556831 DOI: 10.1007/s12272-018-1017-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 02/27/2018] [Indexed: 12/12/2022]
Abstract
Cancer is one of the deadliest diseases in the world. Despite extensive studies, treating metastatic cancers remains challenging. Years of research have linked a rare set of cells known as cancer stem cells (CSCs) to drug resistance, leading to the suggestion that eradication of CSCs might be an effective therapeutic strategy. However, few drug candidates are active against CSCs. New drug discovery is often a lengthy process. Drug screening has been advantageous in identifying drug candidates. Current understanding of cancer biology has revealed various clues to target cancer from different points of view. Many studies have found dopamine receptors (DRs) in various cancers. Therefore, DR antagonists have attracted a lot of attention in cancer research. Recently, a group of antipsychotic DR antagonists has been demonstrated to possess remarkable abilities to restrain and sensitize CSCs to existing chemotherapeutics by a process called differentiation approach. In this review, we will describe current aspects of CSC-targeting therapeutics, antipsychotic DR antagonists, and their extraordinary abilities to fight cancer.
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Affiliation(s)
- Md Saiful Islam Roney
- College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea
| | - Song-Kyu Park
- College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea.
- Research Driven Hospital, Korea University Guro Hospital, Biomedical Research Center, Seoul, 08308, Republic of Korea.
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Agay N, Flaks-Manov N, Nitzan U, Hoshen MB, Levkovitz Y, Munitz H. Cancer prevalence in Israeli men and women with schizophrenia. Psychiatry Res 2017; 258:262-267. [PMID: 28844558 DOI: 10.1016/j.psychres.2017.07.082] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 06/08/2017] [Accepted: 07/29/2017] [Indexed: 01/13/2023]
Abstract
The aim of this cross-sectional study was to compare cancer prevalence rates among patients with schizophrenia to those of the non-schizophrenia population. The study population included members of Clalit Health Services aged 25 to 74 years and all data was taken from patients' electronic health records. Of the 2,060,314 members who were included in the study, 32,748 had a diagnosis of schizophrenia. Cancer prevalence rates in women with and without schizophrenia were 491 per 10,000 and 439 per 10,000, respectively; in men, cancer prevalence rates were 226 per 10,000 and 296 per 10,000, respectively. The age-adjusted prevalence rate of all-type cancer was significantly lower among men with schizophrenia, compared to men without schizophrenia; specifically, men with schizophrenia had a lower rate of prostate cancer, and of cancers in the "other" category, compared to men without schizophrenia. Reduced cancer rates in men with schizophrenia may reflect under-diagnosis of some cancer types, likely due to insufficient medical attention. An effort to improve screening regimes should be made.
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Affiliation(s)
- Nirit Agay
- The Academic College of Tel Aviv-Yaffo, Rabenu Yeruham St., Tel-Aviv Yaffo 86162, Israel.
| | | | - Uri Nitzan
- Shalvata Mental Health Center, Hod-Hasharon, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
| | | | - Yeheal Levkovitz
- Shalvata Mental Health Center, Hod-Hasharon, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
| | - Hanan Munitz
- Public Health Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
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O'Brien MT, Oakhill JS, Ling NXY, Langendorf CG, Hoque A, Dite TA, Means AR, Kemp BE, Scott JW. Impact of Genetic Variation on Human CaMKK2 Regulation by Ca 2+-Calmodulin and Multisite Phosphorylation. Sci Rep 2017; 7:43264. [PMID: 28230171 PMCID: PMC5322397 DOI: 10.1038/srep43264] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/23/2017] [Indexed: 12/18/2022] Open
Abstract
The Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity is strongly associated with prostate and hepatic cancers, whereas reduced CaMKK2 activity has been linked to schizophrenia and bipolar disease in humans. Here we report the functional effects of nine rare-variant point mutations that were detected in large-scale human genetic studies and cancer tissues, all of which occur close to two regulatory phosphorylation sites and the catalytic site on human CaMKK2. Four mutations (G87R, R139W, R142W and E268K) cause a marked decrease in Ca2+-independent autonomous activity, however S137L and P138S mutants displayed increased autonomous and Ca2+-CaM stimulated activities. Furthermore, the G87R mutant is defective in Thr85-autophosphorylation dependent autonomous activity, whereas the A329T mutation rendered CaMKK2 virtually insensitive to Ca2+-CaM stimulation. The G87R and R139W mutants behave as dominant-negative inhibitors of CaMKK2 signaling in cells as they block phosphorylation of the downstream substrate AMP-activated protein kinase (AMPK) in response to ionomycin. Our study provides insight into functionally disruptive, rare-variant mutations in human CaMKK2, which have the potential to influence risk and burden of disease associated with aberrant CaMKK2 activity in human populations carrying these variants.
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Affiliation(s)
- Matthew T O'Brien
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia
| | - Jonathan S Oakhill
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne, 3000, Australia
| | - Naomi X Y Ling
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia
| | - Christopher G Langendorf
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia
| | - Ashfaqul Hoque
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia
| | - Toby A Dite
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia
| | - Anthony R Means
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Bruce E Kemp
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne, 3000, Australia
| | - John W Scott
- St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, 3065, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne, 3000, Australia
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Weinstein LC, Stefancic A, Cunningham AT, Hurley KE, Cabassa LJ, Wender RC. Cancer screening, prevention, and treatment in people with mental illness. CA Cancer J Clin 2016; 66:134-51. [PMID: 26663383 PMCID: PMC4783271 DOI: 10.3322/caac.21334] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
People with mental illness die decades earlier in the United States compared with the general population. Most of this disparity is related to preventable and treatable chronic conditions, with many studies finding cancer as the second leading cause of death. Individual lifestyle factors, such as smoking or limited adherence to treatment, are often cited as highly significant issues in shaping risk among persons with mental illness. However, many contextual or systems-level factors exacerbate these individual factors and may fundamentally drive health disparities among people with mental illness. The authors conducted an integrative review to summarize the empirical literature on cancer prevention, screening, and treatment for people with mental illness. Although multiple interventions are being developed and tested to address tobacco dependence and obesity in these populations, the evidence for effectiveness is quite limited, and essentially all prevention interventions focus at the individual level. This review identified only one published article describing evidence-based interventions to promote cancer screening and improve cancer treatment in people with mental illness. On the basis of a literature review and the experience and expertise of the authors, each section in this article concludes with suggestions at the individual, interpersonal, organizational, community, and policy levels that may improve cancer prevention, screening, and treatment in people with mental illness.
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Affiliation(s)
- Lara C Weinstein
- Associate Professor, Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia, PA
| | - Ana Stefancic
- Staff Research Associate, Columbia University-School of Social Work, New York, NY
| | - Amy T Cunningham
- Clinical Research Coordinator III, Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia, PA
| | - Katelyn E Hurley
- Clinical Research Specialist, Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia, PA
| | | | - Richard C Wender
- Chief Cancer Control Officer, American Cancer Society, Atlanta, GA and Professor, Department of Family and Community Medicine, Thomas Jefferson University, Philadelphia, PA
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Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithms to estimate future risk of common cancers in men and women: prospective cohort study. BMJ Open 2015; 5:e007825. [PMID: 25783428 PMCID: PMC4368998 DOI: 10.1136/bmjopen-2015-007825] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To derive and validate a set of clinical risk prediction algorithm to estimate the 10-year risk of 11 common cancers. DESIGN Prospective open cohort study using routinely collected data from 753 QResearch general practices in England. We used 565 practices to develop the scores and 188 for validation. SUBJECTS 4.96 million patients aged 25-84 years in the derivation cohort; 1.64 million in the validation cohort. Patients were free of the relevant cancer at baseline. METHODS Cox proportional hazards models in the derivation cohort to derive 10-year risk algorithms. Risk factors considered included age, ethnicity, deprivation, body mass index, smoking, alcohol, previous cancer diagnoses, family history of cancer, relevant comorbidities and medication. Measures of calibration and discrimination in the validation cohort. OUTCOMES Incident cases of blood, breast, bowel, gastro-oesophageal, lung, oral, ovarian, pancreas, prostate, renal tract and uterine cancers. Cancers were recorded on any one of four linked data sources (general practitioner (GP), mortality, hospital or cancer records). RESULTS We identified 228,241 incident cases during follow-up of the 11 types of cancer. Of these 25,444 were blood; 41,315 breast; 32,626 bowel, 12,808 gastro-oesophageal; 32,187 lung; 4811 oral; 6635 ovarian; 7119 pancreatic; 35,256 prostate; 23,091 renal tract; 6949 uterine cancers. The lung cancer algorithm had the best performance with an R(2) of 64.2%; D statistic of 2.74; receiver operating characteristic curve statistic of 0.91 in women. The sensitivity for the top 10% of women at highest risk of lung cancer was 67%. Performance of the algorithms in men was very similar to that for women. CONCLUSIONS We have developed and validated a prediction models to quantify absolute risk of 11 common cancers. They can be used to identify patients at high risk of cancers for prevention or further assessment. The algorithms could be integrated into clinical computer systems and used to identify high-risk patients. WEB CALCULATOR There is a simple web calculator to implement the Qcancer 10 year risk algorithm together with the open source software for download (available at http://qcancer.org/10yr/).
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Affiliation(s)
| | - Carol Coupland
- Division of Primary Care, University Park, Nottingham, UK
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18
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Raviv G, Laufer M, Baruch Y, Barak Y. Risk of prostate cancer in patients with schizophrenia. Compr Psychiatry 2014; 55:1639-42. [PMID: 24957959 DOI: 10.1016/j.comppsych.2014.05.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 05/15/2014] [Accepted: 05/15/2014] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVES To examine the rate of prostate cancer in a cohort of schizophrenia in-patients in the PSA-era as compared to expected rates. There is conflicting evidence on the relative risk of prostate cancer in men with schizophrenia. METHODS the study sample was comprised of schizophrenia patients who had been admitted to a tertiary care mental health center between 1990 and 2011. The data for the sample was cross-referenced with the National Cancer Registry. Analyses of Standardized Incidence Rates (SIR) for prostate cancer and for lung cancer (representing an organ system not sensitive to sex hormones) were performed. RESULTS Of 4,326 schizophrenia patients included in the present study, 181 (4.2%) were diagnosed with cancer at any site. Only 10 of these patients were diagnosed with prostate cancer. This reflects a reduced risk; SIR of 0.56 (95% CI 0.27-1.03). In the same cohort, 33 schizophrenia patients were diagnosed with lung cancer presenting a SIR of 1.43 (95% CI 0.98-2.01) in this sample. CONCLUSIONS The present study suggests a reduced rate of prostate cancer in patients admitted for schizophrenia. There are several possible explanations for this finding including chronic state of hyperprolactinemia induced by antipsychotic drugs.
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Affiliation(s)
- Gil Raviv
- Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Menachem Laufer
- Department of Urology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Yehuda Baruch
- Abarbanel Mental Health Center, Bat-Yam, Israel; Sackler School of Medicine, Tel-Aviv University, Israel
| | - Yoram Barak
- Abarbanel Mental Health Center, Bat-Yam, Israel; Sackler School of Medicine, Tel-Aviv University, Israel.
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19
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Ronald S, Awate S, Rath A, Carroll J, Galiano F, Dwyer D, Kleiner-Hancock H, Mathis JM, Vigod S, De Benedetti A. Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy. Genes Cancer 2013; 4:39-53. [PMID: 23946870 DOI: 10.1177/1947601913479020] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 01/25/2013] [Indexed: 11/16/2022] Open
Abstract
The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.
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Affiliation(s)
- Sharon Ronald
- Department of Biochemistry and Molecular Biology and the Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
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Fond G, Macgregor A, Attal J, Larue A, Brittner M, Ducasse D, Capdevielle D. Antipsychotic drugs: pro-cancer or anti-cancer? A systematic review. Med Hypotheses 2012; 79:38-42. [PMID: 22543071 DOI: 10.1016/j.mehy.2012.03.026] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 03/04/2012] [Accepted: 03/22/2012] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Important data was recently published on the potential genotoxic or carcinogenic effects of antipsychotics, as well as on their cytotoxic properties on cancer cells, that must be considered by psychiatrists in the benefit/risk ratio of their prescriptions. AIM OF THE STUDY To answer whether or not antipsychotics, as a class or only some specific molecules, may influence cancer risk among treated patients. METHODS ELIGIBILITY CRITERIA: All studies (in vitro, animal studies and human studies) concerning effects of antipsychotic drugs on cancer development were included. The search paradigm [neoplasms AND (antipsychotic agents OR neuroleptic OR phenothiazine)] was applied to Medline (1966-present) and Web of Science (1975-present). RESULTS Ninety-three studies were included in the qualitative synthesis. Results can be summarized as follows: (1) patients with schizophrenia may be less likely to develop cancer than the general population, (2) antipsychotics as a class cannot be considered at the moment as at risk for cancer, even if some antipsychotics have shown carcinogenic properties among rodents, (3) phenothiazines seem to have antiproliferative properties that may be useful in multidrug augmentation strategies in various cancer treatments, but their bad tolerance may decrease usage amongst non-psychotic patients, and (4) clozapine appears to have a separate status given that this molecule shows antiproliferative effects implied in agranulocytosis as well as a potential increased risk for leukemia. CONCLUSION Benefit/risk ratio regarding cancer risk is in favor of treating patients with schizophrenia with antipsychotic drugs. The practicing clinician should be reassuring on the subject of cancer risk due to antipsychotic drugs.
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Affiliation(s)
- G Fond
- Université Montpellier 1, Montpellier F-34000, France.
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Bespalova IN, Angelo GW, Ritter BP, Hunter J, Reyes-Rabanillo ML, Siever LJ, Silverman JM. Genetic variations in the ADAMTS12 gene are associated with schizophrenia in Puerto Rican patients of Spanish descent. Neuromolecular Med 2012; 14:53-64. [PMID: 22322903 DOI: 10.1007/s12017-012-8169-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Accepted: 01/20/2012] [Indexed: 02/07/2023]
Abstract
ADAMTS12 belongs to the family of metalloproteinases that mediate a communication between specific cell types and play a key role in the regulation of normal tissue development, remodeling, and degradation. Members of this family have been implicated in neurodegenerative and neuroinflammatory, as well as in muscular-skeletal, cardiovascular, respiratory and renal diseases, and cancer. Several metalloproteinases have been associated with schizophrenia. In our previous study of the pedigree from a genetic isolate of Spanish origin in Puerto Rico, we identified a schizophrenia susceptibility locus on chromosome 5p13 containing ADAMTS12. This gene, therefore, is not only a functional but also a positional candidate gene for susceptibility to the disorder. In order to examine possible involvement of ADAMTS12 in schizophrenia, we performed mutation analysis of the coding, 5'- and 3'-untranslated, and putative promoter regions of the gene in affected members of the pedigree and identified 18 sequence variants segregated with schizophrenia. We then tested these variants in 135 unrelated Puerto Rican schizophrenia patients of Spanish origin and 203 controls and identified the intronic variant rs256792 (P = 0.0035; OR = 1.59; 95% CI = 1.16-2.17) and the two-SNP haplotype rs256603-rs256792 (P = 0.0023; OR = 1.62; 95% CI = 1.19-2.21) associated with the disorder. The association remained significant after correction for multiple testing. Our data support the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia.
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Affiliation(s)
- Irina N Bespalova
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Abstract
The U.S. National Institutes of Health's new National Center for Advancing Translational Sciences (NCATS) should be refocused to spur innovation and renamed in a way that doesn't further polarize the scientific community. This Commentary offers some suggestions for both types of transformations.
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Preti A, Wilson DR. Schizophrenia, cancer and obstetric complications in an evolutionary perspective-an empirically based hypothesis. Psychiatry Investig 2011; 8:77-88. [PMID: 21852982 PMCID: PMC3149115 DOI: 10.4306/pi.2011.8.2.77] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Accepted: 10/12/2010] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Patients diagnosed with schizophrenia have reduced fecundity and premature mortality (both accidental and violent) with no obvious compensatory advantages among kin. The prevalence of the disorder is around 0.7/1%, higher than the expected prevalence of spontaneous mutations. Genes favoring schizophrenia may have been positively selected in the environment of evolutionary adaptation. Literature on potential adaptive genes is reviewed within an evolutionary framework. METHODS Literature search on major scientific search engine (PubMed/Medline, Ovid/PsychInfo) on papers aimed at investigating potential pathways justifying a mutation-selection balanced model. Findings are presented with a narrative touch to favor readability and understanding. RESULTS Reduced incidence of cancer in both patients diagnosed with schizophrenia and their siblings was reported worldwide. Such findings are notable given higher cancer risk factors in schizophrenia, i.e., smoking, alcohol abuse, obesity, poor diet, and poor adherence to therapy. Some genes involved in cancer proliferation might as well confer protective advantage in immune-surveillance, inflammation, vascular proliferation or apoptosis that otherwise will adversely affect early neurodevelopment. CONCLUSION Evidence that reduced risk of certain somatic diseases is associated with schizophrenia is quite significant to progress in the evolutionary epidemiological analysis of psychopathology.
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Affiliation(s)
- Antonio Preti
- Centro Medico Genneruxi, via Costantinopoli 42, Cagliari, Italy
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Abstract
In this review, I describe how evolutionary genomics is uniquely suited to spearhead advances in understanding human disease risk, owing to the privileged position of genes as fundamental causes of phenotypic variation, and the ability of population genetic and phylogenetic methods to robustly infer processes of natural selection, drift, and mutation from genetic variation at the levels of family, population, species, and clade. I first provide an overview of models for the origins and maintenance of genetically based disease risk in humans. I then discuss how analyses of genetic disease risk can be dovetailed with studies of positive and balancing selection, to evaluate the degree to which the 'genes that make us human' also represent the genes that mediate risk of polygenic disease. Finally, I present four basic principles for the nascent field of human evolutionary medical genomics, each of which represents a process that is nonintuitive from a proximate perspective. Joint consideration of these principles compels novel forms of interdisciplinary analyses, most notably studies that (i) analyze tradeoffs at the level of molecular genetics, and (ii) identify genetic variants that are derived in the human lineage or in specific populations, and then compare individuals with derived versus ancestral alleles.
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Affiliation(s)
- Bernard J Crespi
- Department of Biosciences, Simon Fraser University Burnaby, BC, Canada
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25
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Bespalova IN, Durner M, Ritter BP, Angelo GW, Rossy-Fullana E, Carrion-Baralt J, Schmeidler J, Silverman JM. Non-synonymous variants in the AMACR gene are associated with schizophrenia. Schizophr Res 2010; 124:208-15. [PMID: 20875727 PMCID: PMC2981684 DOI: 10.1016/j.schres.2010.08.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 08/24/2010] [Accepted: 08/31/2010] [Indexed: 11/15/2022]
Abstract
BACKGROUND The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia. METHODS The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent. RESULTS AND CONCLUSION We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.
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Affiliation(s)
- Irina N Bespalova
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Tabarés-Seisdedos R, Rubenstein JLR. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry 2009; 14:563-89. [PMID: 19204725 DOI: 10.1038/mp.2009.2] [Citation(s) in RCA: 184] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.
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Affiliation(s)
- R Tabarés-Seisdedos
- Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, CIBER-SAM, University of Valencia, Valencia, Spain.
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Koga M, Ishiguro H, Yazaki S, Horiuchi Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Muchardt C, Yaniv M, Arinami T. Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. Hum Mol Genet 2009; 18:2483-94. [DOI: 10.1093/hmg/ddp166] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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