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1
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Antwi GO, Rhodes DL. Association between e-cigarette use and depression in US cancer survivors: a cross-sectional study. J Cancer Surviv 2023; 17:1452-1460. [PMID: 35169981 DOI: 10.1007/s11764-022-01176-1] [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: 12/31/2020] [Accepted: 01/16/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Though prior studies have observed significant association between e-cigarette use and mental health outcomes including depression in the general population, the relationship between e-cigarette use and clinical depression in the cancer survivor subpopulation is unknown. The purpose of this study was to examine the cross-sectional association between e-cigarette use and self-reported clinical depression among cancer survivors. METHODS Pooled data from the 2017 and 2018 Behavioral Risk Factor Surveillance Survey were used. Multivariable logistic regression was used to analyze the independent association between e-cigarette use and self-reported clinical depression in a sample of 7,498 cancer survivors. RESULTS Among cancer survivors in this study, 22.1% reported a history of clinical diagnosis of depression. The overall prevalence rates for current and former e-cigarette use were 2.6% and 10.5%, respectively. Analysis showed 51.3% of current users, 40% of former users, and 19.1% of those who had never used e-cigarettes self-reported a history of clinical depression. In the multivariable analysis, the odds of self-reported clinical depression were significantly higher for survivors who were current users (OR = 2.85; 95% CI: 1.38-5.90) and former users (OR = 1.63; 95% CI: 1.05-2.55) compared to never e-cigarette users. CONCLUSION Findings from this study suggest a statistically significant association between e-cigarette use and depression in cancer survivors. Future studies should focus on examining the longitudinal association between e-cigarette use and depression in cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS Study findings reemphasized the need for interventions to support cancer survivors with evidence-based treatments for depression as well as the need for clinicians to screen for psychological distress and/or e-cigarette use and make appropriate recommendations.
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Affiliation(s)
- Godfred O Antwi
- Department of Public Health and Health Education, SUNY Brockport, 350 New Campus Drive, NY, 14420, Brockport, USA.
| | - Darson L Rhodes
- Department of Public Health and Health Education, SUNY Brockport, 350 New Campus Drive, NY, 14420, Brockport, USA
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2
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Mori Y, Nishikawa SG, Fratiloiu AR, Tsutsui M, Kataoka H, Joh T, Johnston RN. Modulation of Reoviral Cytolysis (I): Combination Therapeutics. Viruses 2023; 15:1472. [PMID: 37515160 PMCID: PMC10385176 DOI: 10.3390/v15071472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.
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Affiliation(s)
- Yoshinori Mori
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Sandra G Nishikawa
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Andreea R Fratiloiu
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Mio Tsutsui
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hiromi Kataoka
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Takashi Joh
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Randal N Johnston
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
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3
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Serine/Threonine Phosphatase Calcineurin Orchestrates the Intrinsic Resistance to Micafungin in the Human-Pathogenic Fungus Mucor circinelloides. Antimicrob Agents Chemother 2023; 67:e0068622. [PMID: 36688672 PMCID: PMC9933632 DOI: 10.1128/aac.00686-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Procedures such as solid-organ transplants and cancer treatments can leave many patients in an immunocompromised state. This leads to their increased susceptibility to opportunistic diseases such as fungal infections. Mucormycosis infections are continually emerging and pose a serious threat to immunocompromised patients. Recently there has been a sharp increase in mucormycosis cases as a secondary infection in patients battling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Mucorales fungi are notorious for presenting resistance to most antifungal drugs. The absence of effective means to treat these infections results in mortality rates approaching 100% in cases of disseminated infection. One of the most effective antifungal drug classes currently available is the echinocandins. Echinocandins seem to be efficacious in the treatment of many other fungal infections. Unfortunately, susceptibility testing has found that echinocandins have little to no effect on Mucorales fungi. In this study, we found that the model Mucorales Mucor circinelloides genome carries three copies of the genes encoding the echinocandin target protein β-(1,3)-d-glucan synthase (fksA, fksB, and fksC). Interestingly, we found that exposing M. circinelloides to micafungin significantly increased the expression of the fksA and fksB genes, resulting in an increased accumulation of β-(1,3)-d-glucan on the cell walls. However, this overexpression of the fks genes is not directly connected to the intrinsic resistance. Subsequent investigation discovered that the serine/threonine phosphatase calcineurin regulates the expression of fksA and fksB, and the deletion of calcineurin results in a decrease in expression of all three fks genes. Deletion of calcineurin also results in a lower minimum effective concentration (MEC) of micafungin. In addition, we found that duplication of the fks gene is also responsible for the intrinsic resistance, in which lack of either fksA or fksB led a lower MEC of micafungin. Together, these findings demonstrate that calcineurin and fks gene duplication contribute to the intrinsic resistance to micafungin we observe in M. circinelloides.
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Yang ZY, Chen WL, Wu WT, Lai CH, Ho CL, Wang CC. Return to Work and Mortality in Breast Cancer Survivors: A 11-Year Longitudinal Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:14418. [PMID: 36361291 PMCID: PMC9655987 DOI: 10.3390/ijerph192114418] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/23/2022] [Accepted: 10/29/2022] [Indexed: 06/16/2023]
Abstract
Breast cancer is the most commonly occurring cancer in women, and it is a major cause of cancer death around the world. With the development of diagnostic methods and improvements in treatment methods, the incidence rate of breast cancer and the number of breast cancer survivors continue to simultaneously increase. We used national registry database to analyze the features that affect employment and return to work among breast cancer survivors. A total of 23,220 employees, who were newly diagnosed with breast cancer were recruited based on the Labor Insurance Database (LID), the Taiwan Cancer Registry (TCR), and National Health Insurance Research Database (NHIRD) during the period 2004-2015. The correlations between return to work (RTW) and independent confounding factors were examined using Cox proportional hazards model. Survival probability was analyzed using the Kaplan-Meir method. After adjusting for confounding variables, cancer stage, chemotherapy and higher income were significantly negatively correlated with RTW. Among breast cancer survivors, RTW was found to be related to a lower risk of all-cause mortality in both the unadjusted and fully adjusted model. Patients who had RTW exhibited better survival in all stages. Work-, disease- and treatment-related factors influenced RTW among employees with breast cancer. RTW was associated with better breast cancer survival. Our study demonstrates the impact of RTW and the associated factors on breast cancer survivorship.
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Affiliation(s)
- Zhe-Yu Yang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Wei-Liang Chen
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Division of Occupational Medicine, Department of Family & Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Wei-Te Wu
- National Institute of Environmental Health Science, National Health Research Institutes, Miaoli 350, Taiwan
| | - Ching-Huang Lai
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Ching-Liang Ho
- Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Chung-Ching Wang
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Division of Occupational Medicine, Department of Family & Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
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5
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Munari FF, Dos Santos W, Evangelista AF, Carvalho AC, Pastrez PA, Bugatti D, Wohnrath DR, Scapulatempo-Neto C, Guimarães DP, Longatto-Filho A, Reis RM. Profile of esophageal squamous cell carcinoma mutations in Brazilian patients. Sci Rep 2021; 11:20596. [PMID: 34663841 PMCID: PMC8523676 DOI: 10.1038/s41598-021-00208-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022] Open
Abstract
Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 (7/46, 15.2%), NFE2L2 (5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 (EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
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Affiliation(s)
- Fernanda Franco Munari
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Wellington Dos Santos
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Adriane Feijó Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Ana Carolina Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Paula Aguiar Pastrez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Diego Bugatti
- Department of Upper Digestive, Barretos Cancer Hospital, Barretos, Brazil
| | - Durval R Wohnrath
- Department of Upper Digestive, Barretos Cancer Hospital, Barretos, Brazil
| | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil
| | - Denise Peixoto Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Department of Endoscopy, Barretos Cancer Hospital, Barretos, Brazil
| | - Adhemar Longatto-Filho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Medical Laboratory of Medical Investigation (LIM) 14, Department of Pathology, Medical School, University of São Paulo, São Paulo, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil. .,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. .,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
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6
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Yu JL, Liao HY. Piezo-type mechanosensitive ion channel component 1 (Piezo1) in human cancer. Biomed Pharmacother 2021; 140:111692. [PMID: 34004511 DOI: 10.1016/j.biopha.2021.111692] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/21/2021] [Accepted: 04/29/2021] [Indexed: 02/09/2023] Open
Abstract
Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanosensitive ion channel protein that is evolutionarily conserved and multifunctional. It plays an important role as an oncogenic mediator in several malignant tumors. It mediates the proliferation, migration, and invasion of a variety of cancer cells through various mechanisms. Multiple studies have shown that the expression of Piezo1 is related to the clinical characteristics of senescence and cancer patients, making Piezo1 useful as a new biomarker for the diagnosis and prognosis of a variety of human cancers. Manipulating the expression or function of Piezo1 is a potential therapeutic strategy for different diseases. Piezo1 may be a promising tumor biomarker and therapeutic target. Here we review the biological function, mechanism of action, and potential clinical significance of Piezo1 in oncogenesis and progression.
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Affiliation(s)
- Jia-Lin Yu
- The 947th Army Hospital of the Chinese People's Liberation Army, 13 Kuona Bazha Road, XinJiang 844200, PR China
| | - Hai-Yang Liao
- The Fist Affiliated Hospital of Gannan Medical College, 23 Youth Road, Jiangxi 342800, PR China
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7
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Liao HY, Da CM, Liao B, Zhang HH. Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem 2021; 92:9-18. [PMID: 33713636 DOI: 10.1016/j.clinbiochem.2021.03.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/13/2021] [Accepted: 03/03/2021] [Indexed: 12/19/2022]
Abstract
Matrix metalloproteinase-7 (MMP-7) is a small proteolytic enzyme that secretes zinc and calcium endopeptidases. It can degrade a variety of extracellular matrix substrates and other substrates and plays important regulatory roles in many human pathophysiological processes. Since its discovery, MMP-7 has been recognized as a regulatory protein in wound healing, bone growth, and remodeling. Later, MMP-7 was reported to regulate the occurrence and development of cancers and mediate the proliferation, differentiation, metastasis, and invasion of several types of cancer cells via various mechanisms. Thus, matrix metalloproteinase-7 may be a promising tumor biomarker and therapeutic target. The expression of MMP-7 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-7 may be a potential treatment strategy for different diseases including cancers. This review summarizes the role played by MMP-7 in carcinogenesis of several human cancers, underlying mechanisms, and its clinical significance of the occurrence and development of cancers.
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Affiliation(s)
- Hai-Yang Liao
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Chao-Ming Da
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Bei Liao
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China; The First Clinical Medical College of Lanzhou University, 1 Donggang Road, Lanzhou 730000, PR China
| | - Hai-Hong Zhang
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
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8
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Nishioka T, Tada H, Ibaragi S, Chen C, Sasano T. Nicotine exposure induces the proliferation of oral cancer cells through the α7 subunit of the nicotinic acetylcholine receptor. Biochem Biophys Res Commun 2018; 509:514-520. [PMID: 30598264 DOI: 10.1016/j.bbrc.2018.12.154] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 12/21/2018] [Indexed: 02/08/2023]
Abstract
Oral cancer and smoking are closely related, because the oral cavity, which is the route of ingestion of tobacco smoke, is in direct contact with the oral mucosa. Nicotine, one of the components of tobacco, can diffuse rapidly to the central nervous system and is responsible for tobacco addiction. Nicotine is present in high concentrations in the bloodstream of smokers; while the addictive effects of this alkaloid have extensively been studied, its effect on tumorigenesis is not clear yet. Therefore, in this study, we examined the effect of nicotine on cell proliferation and the signaling pathways it activates. The human oral squamous cell carcinoma cell line HSC-2 was used as a model system. We demonstrated the correlation between nicotine and epidermal growth factor receptor (EGFR) signaling. Nicotine treatment induced HSC-2 cell proliferation and migration and the phosphorylation of EGFR. Furthermore, nicotine treatment activated the EGFR downstream effectors phosphatidylinositol-3 kinase/AKT and p44/42 mitogen-activated protein kinases (ERK), which, in turn, promoted cell proliferation. Overall, our study suggests that nicotine promotes cell growth and migration through epidermal growth factor (EGF) signaling and plays an important role in oral cancer progression.
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Affiliation(s)
- Takashi Nishioka
- Division of Oral Diagnosis, Tohoku University Graduate School of Dentistry, Sendai, Japan.
| | - Hiroyuki Tada
- Division of Oral Immunology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Soichiro Ibaragi
- Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Changyan Chen
- Center for Drug Discovery, Northeastern University, Boston, MA, USA
| | - Takashi Sasano
- Division of Oral Diagnosis, Tohoku University Graduate School of Dentistry, Sendai, Japan
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9
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Roskoski R. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res 2018; 139:395-411. [PMID: 30500458 DOI: 10.1016/j.phrs.2018.11.014] [Citation(s) in RCA: 325] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 11/07/2018] [Indexed: 02/07/2023]
Abstract
The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ErbB3 is kinase impaired. Surprisingly, the ErbB2-ErbB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (746ELREA750) or the exon-21 L858R substitution. Gefitinib and erlotinib are orally effective type I reversible EGFR mutant inhibitors; type I inhibitors bind to an active enzyme conformation. Unfortunately, secondary resistance to these drugs occurs within about one year owing to a T790M gatekeeper mutation. Osimertinib is an irreversible type VI inhibitor that forms a covalent bond with C797 of EGFR and is FDA-approved for the treatment of patients with this mutation; type VI inhibitors generally form a covalent adduct with their target protein. Resistance also develops to this and related type VI inhibitory drugs owing to a C797S mutation; the serine residue is unable to react with the drugs to form a covalent bond. Approximately 20% of breast cancer patients exhibit ErbB2/HER2 gene amplification on chromosome 17q. One of the earliest targeted treatments in cancer involved the development of trastuzumab, a monoclonal antibody that interacts with the extracellular domain ErbB2/HER2 causing its down regulation. Surgery, radiation therapy, chemotherapy with cytotoxic drugs, and hormonal modulation are the mainstays in the treatment of breast cancer. Moreover, lapatinib and neratinib are FDA-approved small molecule ErbB2/HER2 antagonists used in the treatment of selected breast cancer patients. Of the approximate three dozen FDA-approved small molecule protein kinase inhibitors, five are type VI irreversible inhibitors and four of them including afatinib, osimertinib, dacomitinib, and neratinib are directed against the ErbB family of receptors (ibrutinib is the fifth and it targets Bruton tyrosine kinase). Avitinib, olmutinib, and pelitinib are additional type VI inhibitors in clinical trials for non-small cell lung cancer that target EGFR. Secondary resistance to both targeted and cytotoxic drugs is the norm, and devising and implementing strategies for minimizing or overcoming resistance is an important goal in cancer therapeutics.
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Affiliation(s)
- Robert Roskoski
- Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States.
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10
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Khandelwal S, Boylan M, Spallholz JE, Gollahon L. Cytotoxicity of Selenium Immunoconjugates against Triple Negative Breast Cancer Cells. Int J Mol Sci 2018; 19:E3352. [PMID: 30373175 PMCID: PMC6274915 DOI: 10.3390/ijms19113352] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/19/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023] Open
Abstract
Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10⁻20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2•-) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium.
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Affiliation(s)
- Soni Khandelwal
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| | - Mallory Boylan
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| | - Julian E Spallholz
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| | - Lauren Gollahon
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA.
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
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11
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Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res 2018; 135:239-258. [DOI: 10.1016/j.phrs.2018.08.013] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/13/2018] [Indexed: 02/07/2023]
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12
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Zhang Y, Ge Y, Ping X, Yu M, Lou D, Shi W. Synergistic apoptotic effects of silibinin in enhancing paclitaxel toxicity in human gastric cancer cell lines. Mol Med Rep 2018; 18:1835-1841. [PMID: 29901126 DOI: 10.3892/mmr.2018.9129] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/23/2018] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer (GC) is the 3rd leading cause of tumor‑associated mortality worldwide. The efficacy of paclitaxel, a frequently used GC chemotherapeutic agent, is hindered due to drug resistance, dose‑induced toxicity and adverse side effects. Silibinin, an active compound of a widely consumed dietary supplement, milk thistle extract, has recently been demonstrated to have strong antitumor efficacy in a human GC cell model. Thus, to enhance the efficacy of GC treatment, the present study evaluated whether silibinin exerted a synergistic therapeutic effect with paclitaxel. It was observed that the combination of silibinin‑paclitaxel was able to trigger cell cycle arrest and apoptosis. The cell cycle arrest assay indicated that silibinin and paclitaxel alone induced a G2/M phase arrest, and the silibinin‑paclitaxel combination strongly inhibited G2/M cells from entering the S phase. The apoptosis assay and western blot analysis of poly‑ADP‑ribose polymerase, pro‑caspase 3 and pro‑caspase 8 demonstrated that silibinin synergized with paclitaxel in promoting SGC‑7901 GC cell apoptosis. Furthermore, upregulation of the ratio of apoptosis regulator Bcl‑2/apoptosis regulator BAX and tumor necrosis factor receptor superfamily member 6 (Fas)/Fas ligand indicated that the silibinin‑paclitaxel combination activated the death receptor‑mediated pathway in SGC‑7901 cells. The results of the present study suggested that silibinin enhanced the therapeutic potential of paclitaxel against human GC SGC‑7901 cells.
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Affiliation(s)
- Yuanxin Zhang
- College of Biology and Food Engineering, Jilin Institute of Chemical Technology, Jilin City, Jilin 132022, P.R. China
| | - Yakun Ge
- College of Biology and Food Engineering, Jilin Institute of Chemical Technology, Jilin City, Jilin 132022, P.R. China
| | - Xie Ping
- Jilin Entry‑Exit Inspection and Quarantine Bureau, Changchun, Jilin 130062, P.R. China
| | - Ming Yu
- College of Biology and Food Engineering, Jilin Institute of Chemical Technology, Jilin City, Jilin 132022, P.R. China
| | - Dawei Lou
- School of Chemistry and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin City, Jilin 132022, P.R. China
| | - Wei Shi
- Key Laboratory for Molecular Enzymology and Engineering of The Ministry of Education, School of Life Science, Jilin University, Changchun, Jilin 130012, P.R. China
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13
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A Systematic Review and Narrative Synthesis to Explore the Effectiveness of Exercise-Based Interventions in Improving Fatigue, Dyspnea, and Depression in Lung Cancer Survivors. Cancer Nurs 2018; 42:295-306. [DOI: 10.1097/ncc.0000000000000605] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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14
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Clinical outcomes based on multigene profiling in metastatic breast cancer patients. Oncotarget 2018; 7:76362-76373. [PMID: 27806348 PMCID: PMC5363515 DOI: 10.18632/oncotarget.12987] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 10/13/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.
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15
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Pardo J, Peng Z, Leblanc RM. Cancer Targeting and Drug Delivery Using Carbon-Based Quantum Dots and Nanotubes. Molecules 2018; 23:E378. [PMID: 29439409 PMCID: PMC6017112 DOI: 10.3390/molecules23020378] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 02/07/2018] [Accepted: 02/09/2018] [Indexed: 12/14/2022] Open
Abstract
Currently cancer treatment is in large part non-specific with respect to treatment. Medication is often harsh on patients, whereby they suffer several undesired side effects as a result. Carbon-based nanoparticles have attracted attention in recent years due to their ability to act as a platform for the attachment of several drugs and/or ligands. Relatively simple models are often used in cancer research, wherein carbon nanoparticles are conjugated to a ligand that is specific to an overexpressed receptor for imaging and drug delivery in cancer treatment. These carbon nanoparticles confer unique properties to the imaging or delivery vehicle due to their nontoxic nature and their high fluorescence qualities. Chief among the ongoing research within carbon-based nanoparticles emerge carbon dots (C-dots) and carbon nanotubes (CNTs). In this review, the aforementioned carbon nanoparticles will be discussed in their use within doxorubicin and gemcitabine based drug delivery vehicles, as well as the ligand-mediated receptor specific targeted therapy. Further directions of research in current field are also discussed.
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Affiliation(s)
- Joel Pardo
- Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
| | - Zhili Peng
- Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
- College of Pharmacy and Chemistry, Dali University, Dali 671000, Yunnan, China.
| | - Roger M Leblanc
- Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
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16
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Downregulation of liver-intestine cadherin enhances cisplatin-induced apoptosis in human gastric cancer BGC823 cells. Cancer Gene Ther 2017; 25:1-9. [PMID: 29203930 DOI: 10.1038/s41417-017-0001-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 08/28/2017] [Accepted: 09/12/2017] [Indexed: 12/27/2022]
Abstract
Gastric cancer is the fourth most common type of cancer. Liver-intestine cadherin (CDH17) has been found to be involved in the proliferation and apoptosis of gastric cancer cells. Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumor and hematological malignancies. However, the mechanism of enhancing cisplatin-inducing effects on human gastric cancer BGC823 cells by blocking CDH17 gene, both in vitro and in vivo, remains to be clarified. In this study, we investigated the signaling pathway by which cisplatin induces apoptosis by blocking CDH17 gene in gastric cancer BGC823 cells. Our results indicate that down-expression of CDH17 gene can enhance apoptosis-inducing effects of cisplatin on human gastric cancer BGC823 cells. The expression levels of Bax and Cyt-c proteins were upregulated, but the expression levels of Bcl-2 and Bcl-xL proteins were downregulated by blocking CDH17 gene in gastric cancer BGC823 cells after treatment with cisplatin. Moreover, down-expression of CDH17 enhanced the efficacy of cisplatin-induced inhibition of tumor growth in nude mice via apoptosis induction. Down-expression of CDH17 gene can significantly improve apoptosis-inducing effects of cisplatin in vitro and in vivo, which is a new strategy to improve chemotherapeutic effects on gastric cancer.
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17
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Mao XY, Jin MZ, Chen JF, Zhou HH, Jin WL. Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants. Pharmacol Ther 2017; 183:137-151. [PMID: 29055715 DOI: 10.1016/j.pharmthera.2017.10.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric disorders and cancers, in addition to inherited factors. Currently, natural products or nutraceuticals (commonly called medical foods) are increasingly employed for adjunctive therapy of these patients. However, the potential molecular mechanisms of the nutrient efficacy remain elusive. In this review, we summarized the neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly through the differential modulations of redox homeostasis. In addition, the balance between reactive oxygen species (ROS) production and ROS elimination was manipulated by multiple molecular mechanisms, including cell signaling pathways, inflammation, transcriptional regulation and epigenetic modulation, which were involved in the therapeutic potential of nutraceutical antioxidants against neurological diseases and cancers. We specifically proposed that ROS scavenging was integral in the neuroprotective potential of nutraceuticals, while alternation of ROS level (either increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted the anti-cancer property of these compounds. We also hypothesized that ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death, was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting ferroptosis is advantageous to develop new nutraceuticals with more effective and lower adverse reactions for curing patients with neuropsychiatric diseases or carcinomas.
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Affiliation(s)
- Xiao-Yuan Mao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China.
| | - Ming-Zhu Jin
- Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Jin-Fei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR China.
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China; National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, PR China; Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, PR China.
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18
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Tian X, Liu M, Zhu Q, Tan J, Liu W, Wang Y, Chen W, Zou Y, Cai Y, Han Z, Huang X. Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells. Expert Rev Anticancer Ther 2017. [PMID: 28622054 DOI: 10.1080/14737140.2017.1344097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Xia Tian
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Meng Liu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Qingxi Zhu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Jie Tan
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Weijie Liu
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yanfen Wang
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Wei Chen
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yanli Zou
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Yishan Cai
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Zheng Han
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
| | - Xiaodong Huang
- Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, China
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19
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ALETAHA M, MANSOORI B, MOHAMMADI A, FAZELI M, BARADARAN B. The Effect of Snail1 Gene Silencing by siRNA in Metastatic Breast Cancer Cell Lines. IRANIAN JOURNAL OF PUBLIC HEALTH 2017; 46:659-670. [PMID: 28560197 PMCID: PMC5442279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Breast cancer is the most common diagnosed cancer among women in the world. Snail1 plays a role in the development of the invasive phenotypes of cancer, neural cell differentiation, cell division and apoptosis in tumor cells. Traces of snail1 in metastasis of breast cancer to bone are observed. The aim of this study was to investigate the effect of specific snail1 siRNAs on the proliferation, migration, induction of apoptosis and cell cycle arrest of MDA-MB-468 cells. METHODS In 2015, this experimental study was performed on the MDA-MB-468 cell lines in Immunology Research Center, Tabriz University of Medical Sciences. After the design and construction of siRNA, transfection was performed with transfection reagent. The expression levels of mRNA and protein were measured by qRT-PCR and western blot analysis, respectively. The survival of cells was determined by using MTT assay cells, apoptosis using Tunel assay, Cell migration using scratch assay, Cell cycle analysis by Propidium Iodide (PI) DNA staining method using flow cytometry on the MDA-MB-468. RESULTS Transfection with siRNA significantly suppressed the expression of snail1 gene in dose-dependent manner after 48 h (P<0.0001). Surprisingly, treatment with snail1 siRNA arrested cell cycle in S phases (P<0.0001). Moreover, siRNA transfection had effects on breast adenocarcinoma cells and inhibited the migration (P<0.0001), proliferation (P<0.0001) and induced apoptosis (P<0.0016). CONCLUSION The snail1 can be considered as a potent adjuvant in breast cancer therapy.
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Affiliation(s)
- Mansoor ALETAHA
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, Dept. of Pathobiology, Shiraz University, Shiraz, Iran
| | - Behzad MANSOORI
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali MOHAMMADI
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi FAZELI
- Dept. of Pharmacology and Toxicology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Behzad BARADARAN
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Corresponding Author:
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20
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Therapeutic effects of bach1 siRNA on human breast adenocarcinoma cell line. Biomed Pharmacother 2017; 88:34-42. [DOI: 10.1016/j.biopha.2017.01.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 01/05/2017] [Indexed: 11/23/2022] Open
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21
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Roskoski R. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol Res 2017; 120:116-132. [PMID: 28330784 DOI: 10.1016/j.phrs.2017.03.010] [Citation(s) in RCA: 188] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 03/15/2017] [Indexed: 12/12/2022]
Abstract
One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and VEGFR1-3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways. VEGFR1-3 contain an extracellular segment with seven immunoglobulin-like domains, a transmembrane segment, a juxtamembrane segment, a protein kinase domain with an insert of about 70 amino acid residues, and a C-terminal tail. VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways. VEGFR1 modulates the activity of VEGFR2, which is the chief pathway in vasculogenesis and angiogenesis. VEGFR3 and its ligands (VEGF-C and VEGF-D) are involved primarily in lymphangiogenesis. Small molecule VEGFR1/2/3 inhibitors including axitinib, cabozantinib, lenvatinib, sorafenib, sunitinib, and pazopanib are approved by the FDA for the treatment of renal cell carcinomas. Most of these agents are type II inhibitors of VEGFR2 and inhibit the so-called DFG-Aspout inactive enzyme conformation. These drugs are steady-state competitive inhibitors with respect to ATP and like ATP they form hydrogen bonds with the hinge residues that connect the small and large protein kinase lobes. Bevacizumab, a monoclonal antibody that binds to VEGF-A, is also approved for the treatment of renal cell carcinomas. Resistance to these agents invariably occurs within one year of treatment and clinical studies are underway to determine the optimal sequence of treatment with these anti-angiogenic agents. The nivolumab immune checkpoint inhibitor is also approved for the second-line treatment of renal cell carcinomas. Owing to the resistance of renal cell carcinomas to cytotoxic drugs and radiation therapy, the development of these agents has greatly improved the therapeutic options in the treatment of these malignancies.
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Affiliation(s)
- Robert Roskoski
- Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States.
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22
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Burridge L, Mitchell G, Jiwa M, Girgis A. Helping lay carers of people with advanced cancer and their GPs to talk: an exploration of Australian users' views of a simple carer health checklist. HEALTH & SOCIAL CARE IN THE COMMUNITY 2017; 25:357-365. [PMID: 26694537 DOI: 10.1111/hsc.12312] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/21/2015] [Indexed: 06/05/2023]
Abstract
The lay caregiving role is integral to advanced cancer care but places carers' health at risk. A supportive General Practitioner (GP) can help primary lay carers manage their health, if they disclose their concerns. A Needs Assessment Tool for Caregivers (NAT-C) was developed for carers to self-complete and use as the basis of a GP consultation, then tested in a randomised controlled trial. This paper reports a qualitative research study to determine the usefulness and acceptability of the NAT-C in the Australian primary care setting. Convenience samples of 11 carers and 5 GPs were interviewed between September 2010 and December 2011 regarding their experiences with and perceptions of the NAT-C. Open-ended questions were used, and the transcripts were analysed qualitatively to identify themes and patterns. Three major themes were identified: (a) Acceptability of the intervention; (b) Impact of the intervention on the GP-patient relationship; and (c) Place of the intervention in advanced cancer care. This simple checklist was acceptable to carers, although some were uncertain about the legitimacy of discussing their own needs with their GP. Carer-patients could not be certain whether a GP would be willing or equipped to conduct a NAT-C-based consultation. Such consultations were acceptable to most GPs, although some already used a holistic approach while others preferred brief symptom-based consultations. Although the NAT-C was acceptable to most carers and GPs, supportive consultations take time. This raises organisational issues to be addressed so carers can seek and benefit from their GP's support.
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Affiliation(s)
- Letitia Burridge
- School of Medicine, The University of Queensland, Royal Brisbane and Women's Hospitals, Herston, Queensland, Australia
| | - Geoffrey Mitchell
- School of Medicine, The University of Queensland, Royal Brisbane and Women's Hospitals, Herston, Queensland, Australia
| | - Moyez Jiwa
- School of Medicine Sydney, Melbourne Clinical School, University of Notre Dame, Australia
| | - Afaf Girgis
- Centre for Oncology Education and Research Translation (CONCERT), Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia
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23
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Roskoski R. Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers. Pharmacol Res 2017; 117:343-356. [DOI: 10.1016/j.phrs.2017.01.007] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 01/06/2017] [Indexed: 12/24/2022]
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24
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Martin E, Pourtau L, Di Palma M, Delaloge S. New oral targeted therapies for metastatic breast cancer disrupt the traditional patients' management-A healthcare providers' view. Eur J Cancer Care (Engl) 2016; 26. [PMID: 28026083 DOI: 10.1111/ecc.12624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2016] [Indexed: 01/18/2023]
Abstract
Although a cure still cannot be expected for metastatic breast cancer, thanks to progressive advances in treatments, life expectancy has been increasing over the past 15 years. This study aims to present the impact on the organisation of patients' management of newly released oral targeted therapies dedicated to metastatic breast cancer and the obstacles to their diffusion. Our work is based on the analysis of 40 semi-structured interviews, conducted with oncology healthcare professionals in three regions of France (2015-2016). It shows three main results. First, the prescription of an oral targeted therapy requires greater collaboration between healthcare professionals than traditional intravenous oncology drugs, which may be challenging. Second, there remain many barriers to the dissemination of oral targeted therapies. Third, taking an oral targeted therapy keeps the patient away from the hospital facility and asks for a strong therapeutic alliance. The management of oral targeted therapies is time-consuming for medical oncologists and disrupts the traditional care pathway. The multiplication of actors involved in patients' management reinforces the slowdown in the deployment and acceptance of therapeutic innovations. More players equal a higher risk of slowdown. Questioning and re-designing hospital organisation and management modalities towards this type of care are critical.
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Affiliation(s)
- E Martin
- Université Paris-Sud/Paris Saclay, Le Kremlin-Bicêtre, France.,Laboratoire EA 1610, Faculté des sciences d'Orsay, Orsay, France
| | - L Pourtau
- Université Paris-Sud/Paris Saclay, Le Kremlin-Bicêtre, France.,Laboratoire EA 1610, Faculté des sciences d'Orsay, Orsay, France
| | - M Di Palma
- Département Ambulatoire, Gustave Roussy, Villejuif, France
| | - S Delaloge
- Département de Médecine Oncologique, Gustave Roussy, Villejuif, France
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25
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Patel HK, Gajbhiye V, Kesharwani P, Jain NK. Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment. J Colloid Interface Sci 2016; 482:142-150. [DOI: 10.1016/j.jcis.2016.07.047] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 07/19/2016] [Accepted: 07/19/2016] [Indexed: 11/16/2022]
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26
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Aran V, Victorino AP, Thuler LC, Ferreira CG. Colorectal Cancer: Epidemiology, Disease Mechanisms and Interventions to Reduce Onset and Mortality. Clin Colorectal Cancer 2016; 15:195-203. [DOI: 10.1016/j.clcc.2016.02.008] [Citation(s) in RCA: 229] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/03/2016] [Indexed: 02/07/2023]
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27
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Musavi Shenas SMH, Mansoori B, Mohammadi A, Salehi S, Kaffash B, Talebi B, Babaloo Z, Shanehbandi D, Baradaran B. SiRNA-mediated silencing of Snail-1 induces apoptosis and alters micro RNA expression in human urinary bladder cancer cell line. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2016; 45:969-974. [DOI: 10.1080/21691401.2016.1198361] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Seyed Mohammad Hossein Musavi Shenas
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- International Branch (Aras), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shima Salehi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Kaffash
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Talebi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Mowls DS, Brame LS, Martinez SA, Beebe LA. Lifestyle behaviors among US cancer survivors. J Cancer Surviv 2016; 10:692-8. [DOI: 10.1007/s11764-016-0515-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 01/16/2016] [Indexed: 11/29/2022]
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29
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Grunes D, Yankelevitz D, Beasley MB, Burstein D, Zhang D, Ye F, Szporn A, Si Q, Zhang Z, El Salem F, Wu M. Fine-needle aspiration of small pulmonary nodules yields material for reliable molecular analysis of adenocarcinomas. J Am Soc Cytopathol 2016; 5:57-63. [PMID: 31042492 DOI: 10.1016/j.jasc.2015.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Revised: 10/30/2015] [Accepted: 11/03/2015] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Early molecular characterization with Kirsten rat sarcoma factor, epidermal growth factor, and anaplastic lymphoma kinase are critical to manage pulmonary adenocarcinoma. Fine-needle aspiration (FNA) of lesions <2 cm are routine in our institution and are used in molecular analysis. We report our experience. MATERIALS AND METHODS We searched our databank for primary pulmonary adenocarcinomas diagnosed by FNA between January 2009 and April 2013. Size of the lesion aspirated, molecular results, and sample source (FNA versus surgical specimen) were recorded. We compared the frequency of mutations identified by FNA versus surgical specimens and the frequency of mutations in lesions by size (<1 cm, 1-2 cm, >2 cm). RESULTS We identified 397 primary pulmonary adenocarcinomas. Molecular studies were requested by the clinician in 89 (22%) of primary adenocarcinomas. FNAs were used in 55 cases; 51 (93%) yielded sufficient material for molecular studies; surgical tissue were used in 34 cases; 33 (97%) yielded sufficient material for molecular studies. The insufficient specimens came from 2 FNAs of 0.6 cm nodules, an FNA of a 2 cm nodule, and a core biopsy. CONCLUSIONS FNA was adequate for molecular analysis of small nodules. In nodules greater than 0.6 cm, the adequacy is comparable to surgical tissue. There was no statistically significant change in mutation rate by size (53%-58%). Importantly, FNA of small lesions for cytological diagnosis and molecular analysis is encouraged by our data and experience in order to provide early treatment.
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Affiliation(s)
- Dianne Grunes
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York.
| | - David Yankelevitz
- Department of Radiology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mary Beth Beasley
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - David Burstein
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - David Zhang
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Molecular Diagnostics, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Fei Ye
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Molecular Diagnostics, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Arnold Szporn
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Qiusheng Si
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Zesong Zhang
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Fadi El Salem
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Maoxin Wu
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cytopathology, The Icahn School of Medicine at Mount Sinai, New York, New York.
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An F, Zhao WJ, Tang L, Qiu RG. Concentration-dependent differential effects of an epothilone analog on cell cycle and p53 signaling. Oncol Rep 2015; 34:1361-8. [PMID: 26177745 DOI: 10.3892/or.2015.4128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 06/22/2015] [Indexed: 11/06/2022] Open
Abstract
The tumor-suppressor protein p53 is considered to be one of the most important transport hubs of cell signal transduction, playing critical roles in the control of cell cycle arrest, apoptosis and many other processes as a nuclear transcription factor. p53 also acts in the cytoplasm to trigger apoptosis. Paclitaxel and other microtubule inhibitors can inhibit the growth of different types of cancer cells and induce apoptosis which is believed to be p53-independent. In the present study, we demonstrated that UTD1, a genetically engineered epothilone analog and a new microtubule inhibitor, activated p53 as a transcription factor at low concentrations demonstrated by its enhanced transcriptional activity and accumulation of p21, which led to cell cycle arrest. However, at high concentrations of UTD1, p53 was accumulated in the cytoplasm which contributed to induction of apoptosis. These observations indicate that the epothilone analog has differential effects on intracellular signaling and implies that p53 plays different roles in cells exposed to different concentrations of the anticancer agent.
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Affiliation(s)
- Fan An
- Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China
| | - Wei-Jie Zhao
- Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China
| | - Li Tang
- Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China
| | - Rong-Guo Qiu
- Research Center for Molecular Medicine, Dalian University of Technology, Dalian, Liaoning 116023, P.R. China
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Xu J, Liu Y, Wang X, Huang J, Zhu H, Hu Z, Wang D. Association between KIAA1199 overexpression and tumor invasion, TNM stage, and poor prognosis in colorectal cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:2909-2918. [PMID: 26045799 PMCID: PMC4440108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 02/25/2015] [Indexed: 06/04/2023]
Abstract
To investigate the expression of KIAA1199 in tumor tissue and its potential value as a prognostic indicator of survival in patients with colorectal cancer (CRC). The expression of KIAA1199 mRNA in CRC was characterized using real-time PCR and 20 pairs of fresh-frozen CRC tissues and corresponding non-cancerous tissues. KIAA1199 protein expression was confirmed using immunohistochemistry on a tissue microarray chip from 202 patients with CRC. Then, we correlated KIAA1199 protein expression to CRC conventional clinicopathological features and patient's outcome. The expression of KIAA1199 mRNA and protein were up-regulated in CRC compared to normal tissues (P=0.015 and P<0.001, individually). KIAA1199 protein expression was related to tumor invasion depth (P=0.013) and lymph node metastasis (P=0.003). Kaplan-Meier survival and Cox regression analyses revealed that high KIAA1199 expression (P<0.001) and serum carcinoembryonic antigen (CEA) level post operation (P=0.005) were independent factors predicting poor prognosis of patients with CRC. We present evidence that high expression of KIAA1199 is associated with tumor invasion depth, TNM stage, and poor prognosis in CRC. Our findings suggest KIAA1199 could be used as a prognostic factor and novel therapeutic target for CRC.
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Affiliation(s)
- Jian Xu
- Department of General Surgery, Changzheng Hospital, Second Military Medical UniversityShanghai, China
| | - Ying Liu
- Department of Pathology, Nantong University Affiliated HospitalJiangsu, China
| | - Xudong Wang
- Department of Laboratory Medicine, Nantong University Affiliated HospitalJiangsu, China
| | - Jianfei Huang
- Department of Pathology, Nantong University Affiliated HospitalJiangsu, China
| | - Huijun Zhu
- Department of Pathology, Nantong University Affiliated HospitalJiangsu, China
| | - Zhiqian Hu
- Department of General Surgery, Changzheng Hospital, Second Military Medical UniversityShanghai, China
| | - Defeng Wang
- Department of Science and Technology Branch, Nantong University Affiliated HospitalJiangsu, China
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Lopes JR, Maschio LB, Jardim-Perassi BV, Moschetta MG, Ferreira LC, Martins GR, Gelaleti GB, De Campos Zuccari DAP. Evaluation of melatonin treatment in primary culture of canine mammary tumors. Oncol Rep 2014; 33:311-9. [PMID: 25384569 DOI: 10.3892/or.2014.3596] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 09/22/2014] [Indexed: 11/06/2022] Open
Abstract
Mammary neoplasias are the most common tumors observed in female dogs. Identification of these tumors is valuable in order to identify beneficial therapeutic agents as alternative treatments for this tumor type. Oral administration of melatonin appears to exert an oncostatic effect on mammary neoplasia and may have a possible mechanism of action through its interaction with estrogen receptors on epithelial cells. Hence, we analyzed the potential therapeutic value of melatonin in tumors that are estrogen-dependent or -independent, and established a relationship of its action with the expression of the melatonin receptors MT1 and MT2. Furthermore, we analyzed the rate of cell proliferation and apoptosis after treatment with melatonin. Cell cultures were performed using 10 canine mammary tumor fragments and were divided into estrogen receptor (ER)-positive and ER-negative tumors. The results showed that both ER-positive and ER-negative tumors had decreased cell viability and proliferation after treatment with melatonin (p<0.05), although treatment was more effective in the ER-positive tumors. Analysis of the relative expression of the MT1 and MT2 genes by quantitative PCR was performed and the data were compared with the expression of ER in 24 canine mammary tumors and the cellular response to melatonin in 10 samples. MT1 was overexpressed in ER-positive tumors (p<0.05), whereas MT2 was not expressed. Furthermore, melatonin treatment in ER-positive tumors showed an efficient oncostatic effect by inhibiting cell viability and proliferation and inducing apoptosis. These results suggest that melatonin decreased neoplastic mammary cell proliferation and viability and induced apoptosis, with greater efficacy in ER-positive tumors that have a high expression of melatonin receptor MT1. This is a strong evidence for the use of melatonin as a therapeutic agent for estrogen-dependent canine mammary tumors.
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Affiliation(s)
- Juliana Ramos Lopes
- Post-graduate Program in Genetics, São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil
| | - Larissa Bazela Maschio
- Post-graduate Program in Genetics, São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil
| | | | | | - Lívia Carvalho Ferreira
- Post-graduate Program in Genetics, São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil
| | | | - Gabriela Bottaro Gelaleti
- Post-graduate Program in Genetics, São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil
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Luo HY, Xu RH. Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer. World J Gastroenterol 2014; 20:3858-3874. [PMID: 24744578 PMCID: PMC3983442 DOI: 10.3748/wjg.v20.i14.3858] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/11/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide. The treatment of advanced CRC has improved significantly in recent years. With the emergence of two targeted antibodies, cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab (Avastin), a vascular endothelial growth factor monoclonal antibody, the treatment of metastatic CRC has entered the era of personalized therapy. Predictive and prognostic biomarkers have, and will continue to, facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC (mCRC). In this review, we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
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Gil Ferreira C, Aran V, Zalcberg-Renault I, Victorino AP, Salem JH, Bonamino MH, Vieira FM, Zalis M. KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients. BMC Gastroenterol 2014; 14:73. [PMID: 24720724 PMCID: PMC3997472 DOI: 10.1186/1471-230x-14-73] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 04/02/2014] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND KRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. METHODS The profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age. RESULTS The median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found. CONCLUSIONS To the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.
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Affiliation(s)
- Carlos Gil Ferreira
- Progenética Diagnósticos Moleculares, Av, Presidente Vargas, 962 3 Andar, Cep: 20071-002 Rio de Janeiro, RJ, Brazil.
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Wu X, Wang Y, Wang H, Wang Q, Wang L, Miao J, Cui F, Wang J. Quinacrine Inhibits Cell Growth and Induces Apoptosis in Human Gastric Cancer Cell Line SGC-7901. Curr Ther Res Clin Exp 2014; 73:52-64. [PMID: 24653512 DOI: 10.1016/j.curtheres.2012.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2012] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Quinacrine (QC), an antimalarial drug, has been shown to possess anticancer effect both in vitro (cancer cell lines) and in vivo (mouse models). In the cancer cells, QC can simultaneously suppress nuclear factor-κB and activate p53 signaling, which results in the induction of the apoptosis in these cells. However, the experimental results come from a few limited cancer cell lines, and the detailed mechanisms remain unknown. OBJECTIVE This study investigated the tumor-killing effects of QC on gastric cancer cells as well as underlying molecular pathways. METHODS SGC-7901 cells were treated with or without QC at different concentrations for 24 hours. The effect of QC on the inhibition of SGC-7901 cell proliferation was assessed by Cell Counting Kit-8 assay. Apoptosis was detected by examining nuclear morphology and quantifying phosphatidylserine externalization. Alterations in cellular morphology were analyzed by laser scanning confocal microscopy for fluorescent analysis. Cell cycle analysis was performed by propidium iodide (PI) staining and flow cytometry. The enzyme activity changes of caspase-3 were detected by colorimetry expression method. Western blot analysis was used to detect the changes in the protein level of Bax, Bc1-2, p53, and cytochrome c in cytosol of SGC-7901 cells. RESULTS Our results showed that QC could significantly inhibit the growth of SGC-7901 cells in a dose-dependent manner, with the IC50 mean (SD) value of 16.18 (0.64) μM, compared with nontreated controls. QC treatment (15 μM) could also induce apoptosis in SGC-7901 cells (26.30% [5.31%], compared with control group of 3.37% [0.81%]; P < 0.01), and the increasing phosphatidylserine level and the accumulation of chromatin nucleation in QC-treated cells provided further evidence. In addition, cell cycle analysis with PI staining showed that a significant S enriches, increasing from 12.00% (1.24%) (control) to 20.94% (2.40%) (QC treatment) (P < 0.01). Furthermore, increased activities of caspase-3 (increasing from 0.108 [0.019] to 0.628 [0.068]; P < 0.01) were observed in SGC-7901 cells treated with 15 μM QC. Western blot analysis showed that QC treatment significantly increased the levels of proapoptotic proteins, including cytochrome c, Bax, and p53, and decreased the levels of antiapoptotic protein Bcl-2, thus shifting the ratio of Bax/Bcl-2 in favor of apoptosis. CONCLUSIONS Our findings suggest that QC can significantly inhibit cell growth and induce apoptosis in SGC-7901 cells, which involves p53 upregulation and caspase-3 activation pathway.
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Affiliation(s)
- Xiaoyang Wu
- The First Affiliated Hospital of Soochow University, Suzhou, China ; Department of Surgery, the First People's Hospital of Kunshan City, Kunshan, China
| | - Yunliang Wang
- Department of Neurology, the 148 Hospital of PLA, Zibo, Shandong, China
| | - Hongwei Wang
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Qiang Wang
- Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois
| | - Lin Wang
- Department of Medicine, Shangqiu Medical College, Shangqiu, China
| | - Jingcheng Miao
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, China
| | - Fengmei Cui
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, China
| | - Jinzhi Wang
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, China
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Martinelli F, Quinten C, Maringwa JT, Coens C, Vercauteren J, Cleeland CS, Flechtner H, Gotay C, Greimel E, King M, Mendoza T, Osoba D, Reeve BB, Ringash J, Koch JSV, Shi Q, Taphoorn MJ, Weis J, Bottomley A. Examining the relationships among health-related quality-of-life indicators in cancer patients participating in clinical trials: a pooled study of baseline EORTC QLQ-C30 data. Expert Rev Pharmacoecon Outcomes Res 2014; 11:587-99. [DOI: 10.1586/erp.11.51] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Roskoski R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 2013; 79:34-74. [PMID: 24269963 DOI: 10.1016/j.phrs.2013.11.002] [Citation(s) in RCA: 970] [Impact Index Per Article: 80.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 11/08/2013] [Indexed: 10/26/2022]
Abstract
The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). These receptors consist of a glycosylated extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of ErbB2, which lacks a ligand, and ErbB3, which is kinase impaired, is surprisingly the most robust signaling complex of the ErbB family. Growth factor binding to EGFR induces a large conformational change in the extracellular domain, which leads to the exposure of a dimerization arm in domain II of the extracellular segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them. The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies.
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Affiliation(s)
- Robert Roskoski
- Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA.
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Hong S, Cagle J. Factors associated with perceptions of the cancer care system: a multilevel modeling approach. J Psychosoc Oncol 2013; 31:642-58. [PMID: 24175900 DOI: 10.1080/07347332.2013.835020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Perceptions about the health care system are a key driver of disparities and utilization. This study examined individual and contextual factors related to care and noncare dimensions and their relationship to perceptions of the cancer care system. A national sample of 877 cases was modeled using a multilevel modeling approach. Insurance complaints, number of treatments, and advocacy impact were negatively associated with satisfaction with the cancer care system at the individual level. Also, respondents in states where more Christians resided and lower hospital capacity were more likely to indicate satisfaction. Findings suggest implications for practitioners and health policy makers.
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Affiliation(s)
- Seokho Hong
- a School of Social Work , University of Maryland , Baltimore , MD , USA
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Lunenfeld B, Stratton P. The clinical consequences of an ageing world and preventive strategies. Best Pract Res Clin Obstet Gynaecol 2013; 27:643-59. [PMID: 23541823 PMCID: PMC3776003 DOI: 10.1016/j.bpobgyn.2013.02.005] [Citation(s) in RCA: 148] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Accepted: 02/10/2013] [Indexed: 12/21/2022]
Abstract
Over the past century, the world has seen unprecedented declines in mortality rates, leading to an accelerated increase in the world population. This century will realise falling fertility rates alongside ageing populations. The 20th century was the century of population growth; the 21st century will be remembered as the century of ageing. Increase in life expectancy is one of the highest achievements of humankind; however, ageing and age-related disease is a mounting challenge for individuals, families, and for social, economic, and healthcare systems. Since healthy life expectancy has lagged behind the increase in life expectancy, the rise in morbidity will increase the burden on healthcare systems. Implementation of preventive health strategies to decrease, delay or prevent frailty, lung, breast and colon cancer, cardiovascular disease, metabolic syndrome, osteoporosis and osteopaenia, may increase health expectancy, and permit women to age gracefully and maintain independent living, without disability, for as long as possible.
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Affiliation(s)
- Bruno Lunenfeld
- Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.
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Kang EJ, Im SA, Oh DY, Han SW, Kim JS, Choi IS, Kim JW, Kim YJ, Kim JH, Kim TY, Lee JS, Bang YJ, Lee KW. Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival. Gastric Cancer 2013; 16:581-589. [PMID: 23266882 DOI: 10.1007/s10120-012-0227-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 11/27/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival. METHODS Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1. RESULTS A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS. CONCLUSIONS The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.
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Affiliation(s)
- Eun Joo Kang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea
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Kumar N, Kale RK, Tiku AB. Chemopreventive effect of Lagenaria siceraria in two stages DMBA plus croton oil induced skin papillomagenesis. Nutr Cancer 2013; 65:991-1001. [PMID: 23914728 DOI: 10.1080/01635581.2013.814800] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Cancer chemoprevention is a dietary or therapeutic strategy to prevent, suppress, or delay carcinogenesis either at initiation or progression level with nontoxic agents. Use of natural dietary compounds has been a major chemopreventive approach to modulate tumorigenic pathways. In the present study, we have evaluated Lagenaria siceraria (bottle gourd), a common vegetable of Indian household for its chemomodulatory potential. The fruit has been used in traditional medicine for a very long time for health benefits and to cure pain, ulcers, fever, cough, asthma, and other bronchial disorders. However, despite its reported beneficial effect the chemo modulatory potential of this plant has not been reported. Therefore chemopreventive effect of bottle gourd juice (BGJ) was studied against 7,12-dimethylbenz(a)anthracene (DMBA) plus croton oil induced skin papillomagenesis in Swiss albino mice. The effect was studied both at antiinitiation and antiinitiation/promotion level followed by histopathological study. A dose of 2.5% and 5% given in drinking water showed significant decrease in papilloma number, papilloma incidence, papilloma multiplicity, papilloma latency, papilloma volume, and papilloma size in different size range. Histopathological study showed chemopreventive effect by minimizing loss of stratification, a decrease in number of epithelial layers, reducing dermal infiltration and protection for various cytoplasmic changes. Higher dose of BGJ was found to be more effective than lower dose and the chemopreventive effect was maximum for antiinitiation/promotion treatment. Altogether, this study reports the chemopreventive effect of Lagenaria siceraria on skin papillomagenesis for the first time and suggests that its consumption may help in suppression of skin cancer.
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Affiliation(s)
- Navneet Kumar
- a School of Life Sciences , Jawaharlal Nehru University , New Delhi , India
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Roskoski R. The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders. Expert Opin Drug Discov 2013; 8:1165-79. [DOI: 10.1517/17460441.2013.813015] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Dacic S. Molecular genetic testing for lung adenocarcinomas: a practical approach to clinically relevant mutations and translocations. J Clin Pathol 2013; 66:870-4. [PMID: 23801495 DOI: 10.1136/jclinpath-2012-201336] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
There is a consensus that molecular testing of the lung carcinoma should be the standard of care in the clinical management of patients with lung carcinoma. Recent practice guidelines in oncology and pathology recommend that all advanced and metastatic non-small-cell lung carcinoma with adenocarcinoma histology undergo biomarker testing for epidermal growth factor receptor gene (EGFR) mutations and anaplastic lymphoma kinase gene (ALK) rearrangements. Other types of non-small-cell carcinoma may be considered for such testing if they occur in never-smokers. The landscape of targetable biomarkers in non-small-cell carcinoma is changing rapidly, and demand for clinical testing beyond EGFR mutations and ALK gene rearrangements is increasing. Many patients may test positive for other 'drivers'. As a result, they may be treated with approved biomarker-driven therapies or may be eligible to receive investigational agents in clinical trials. This creates challenges for treating physicians and pathologists such as obtaining sufficient tissue for molecular testing and standardisation of molecular testing in clinical laboratories. This review will focus on the most important lung carcinoma biomarkers predictive of response and will discuss proposed routine molecular testing in clinical practice.
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Sha S, Gu Y, Xu B, Hu H, Yang Y, Kong X, Wu K. Decreased expression of HOXB9 is related to poor overall survival in patients with gastric carcinoma. Dig Liver Dis 2013; 45:422-9. [PMID: 23332081 DOI: 10.1016/j.dld.2012.12.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 11/26/2012] [Accepted: 12/06/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Studies have demonstrated the implication of HOXB9 in tumorigenesis, but its role in gastric carcinoma remains unknown. AIMS To investigate the expression and prognostic value of HOXB9 in patients with gastric carcinoma. METHODS The localization and expression of HOXB9 in gastric cancer cells lines were detected by immunofluorescence and western blot. The mRNA and protein expression level of HOXB9 was detected in subjects with gastric carcinoma and paired non-cancerous tissues. Correlation between HOXB9 expression and clinicopathological parameters, the association of HOXB9 expression with the patients' survival rate was also assessed. RESULTS HOXB9 was predominantly localized in the cell nucleus. A significant decrease in HOXB9 intensity in poorly differentiated gastric cancer cells is evident (P<0.01). A lower mRNA and protein expression level of HOXB9 was detected in gastric carcinoma (P<0.01). Decreased expression of HOXB9, poorly differentiation status and the presence of lymph node metastasis predict shorter overall survival (P<0.05). Patients without HOXB9 expression had a lower overall survival rate (P<0.01). Multivariate Cox regression analysis showed HOXB9 was an independent prognostic factor in gastric carcinoma (P<0.01). CONCLUSIONS HOXB9 is down-regulation in gastric carcinoma and may be a novel prognostic marker for poorer clinical outcome for patients with gastric carcinoma.
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Affiliation(s)
- Sumei Sha
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
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Gotoh A, Nagaya H, Kanno T, Tagawa M, Nishizaki T. Fiber-substituted conditionally replicating adenovirus Ad5F35 induces oncolysis of human bladder cancer cells in in vitro analysis. Urology 2013; 81:920.e7-11. [PMID: 23394881 DOI: 10.1016/j.urology.2012.12.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Revised: 11/08/2012] [Accepted: 12/12/2012] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To assess the oncolytic effect of fiber-substituted conditionally replicating adenovirus type 5 (Ad5) F35 vector on human bladder cancer cell lines such as 253J, 5637, KK-47, T24, TCCSUP, and UMUC-3 cells. MATERIALS AND METHODS Ad5F35 and Ad5 conditionally replicating adenovirus vectors containing the E1 gene controlled by the human midkine promoter (Ad5F35/MKp-E1 and Ad5/MKp-E1, respectively) were constructed. Reverse transcriptase-polymerase chain reaction and cell viability assay were performed in cells transfected with Ad5F35/MKp-E1 or Ad5/MKp-E1. RESULTS Of the bladder cancer cells used, considerably lower expression of mRNA for Coxsackie and adenovirus receptor, an Ad5 receptor, was found with T24 and TCCSUP cells. However, the mRNA for CD46, an Ad35 receptor, was abundantly expressed in all the cell types. Ad5F35/MKp-E1 induced oncolysis in a plaque formation unit-dependent manner for all the bladder cancer cells used, with greater efficacy than Ad5/MKp-E1 for T24, TCCSUP, and 253J cells. CONCLUSION The results of the present study have shown that Ad5F35/MKp-E1 is more useful for the gene therapy of bladder cancer than Ad5/MKp-E1 is for some cell lines.
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Affiliation(s)
- Akinobu Gotoh
- Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan
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Li Q, Zhai H, Deleger L, Lingren T, Kaiser M, Stoutenborough L, Solti I. A sequence labeling approach to link medications and their attributes in clinical notes and clinical trial announcements for information extraction. J Am Med Inform Assoc 2012; 20:915-21. [PMID: 23268488 PMCID: PMC3756265 DOI: 10.1136/amiajnl-2012-001487] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective The goal of this work was to evaluate machine learning methods, binary classification and sequence labeling, for medication–attribute linkage detection in two clinical corpora. Data and methods We double annotated 3000 clinical trial announcements (CTA) and 1655 clinical notes (CN) for medication named entities and their attributes. A binary support vector machine (SVM) classification method with parsimonious feature sets, and a conditional random fields (CRF)-based multi-layered sequence labeling (MLSL) model were proposed to identify the linkages between the entities and their corresponding attributes. We evaluated the system's performance against the human-generated gold standard. Results The experiments showed that the two machine learning approaches performed statistically significantly better than the baseline rule-based approach. The binary SVM classification achieved 0.94 F-measure with individual tokens as features. The SVM model trained on a parsimonious feature set achieved 0.81 F-measure for CN and 0.87 for CTA. The CRF MLSL method achieved 0.80 F-measure on both corpora. Discussion and conclusions We compared the novel MLSL method with a binary classification and a rule-based method. The MLSL method performed statistically significantly better than the rule-based method. However, the SVM-based binary classification method was statistically significantly better than the MLSL method for both the CTA and CN corpora. Using parsimonious feature sets both the SVM-based binary classification and CRF-based MLSL methods achieved high performance in detecting medication name and attribute linkages in CTA and CN.
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Affiliation(s)
- Qi Li
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Brantley-Sieders DM, Fan KH, Deming-Halverson SL, Shyr Y, Cook RS. Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. PLoS One 2012; 7:e45238. [PMID: 23028869 PMCID: PMC3460936 DOI: 10.1371/journal.pone.0045238] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 08/20/2012] [Indexed: 11/19/2022] Open
Abstract
Despite available demographic data on the factors that contribute to breast cancer mortality in large population datasets, local patterns are often overlooked. Such local information could provide a valuable metric by which regional community health resources can be allocated to reduce breast cancer mortality. We used national and statewide datasets to assess geographical distribution of breast cancer mortality rates and known risk factors influencing breast cancer mortality in middle Tennessee. Each county in middle Tennessee, and each ZIP code within metropolitan Davidson County, was scored for risk factor prevalence and assigned quartile scores that were used as a metric to identify geographic areas of need. While breast cancer mortality often correlated with age and incidence, geographic areas were identified in which breast cancer mortality rates did not correlate with age and incidence, but correlated with additional risk factors, such as mammography screening and socioeconomic status. Geographical variability in specific risk factors was evident, demonstrating the utility of this approach to identify local areas of risk. This method revealed local patterns in breast cancer mortality that might otherwise be overlooked in a more broadly based analysis. Our data suggest that understanding the geographic distribution of breast cancer mortality, and the distribution of risk factors that contribute to breast cancer mortality, will not only identify communities with the greatest need of support, but will identify the types of resources that would provide the most benefit to reduce breast cancer mortality in the community.
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Affiliation(s)
- Dana M. Brantley-Sieders
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Kang-Hsien Fan
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Sandra L. Deming-Halverson
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Social & Scientific Systems, Inc., Durham, North Carolina, United States of America
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Rebecca S. Cook
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
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