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Celiku, O., Tandle, A., Chung, J. - Y., Hewitt, S. M., Camphausen, K., & Shankavaram, U. (2017). Computational analysis of the mesenchymal signature landscape in gliomas. BMC Med Genomics, 10(1), 13.
Abstract: BACKGROUND: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting. RESULTS: Computational analysis of 275 glioma samples from “The Cancer Genome Atlas” was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway – Extracellular matrix organization – was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53-8.33), after controlling for known prognostic factors (age, and glioma grade). The signature's significance was validated in an independent data set. The putative stem cell marker CD44 was biologically validated in glioma cell lines and brain tissue samples. CONCLUSIONS: Our results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients.
Keywords: Cd44; Computational modeling; Epithelial to mesenchymal transition; Glioma
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Chae, S., Desai, S., Crowell, M., Sedgh, G., & Singh, S. (2017). Characteristics of women obtaining induced abortions in selected low- and middle-income countries. PLoS One, 12(3), e0172976.
Abstract: BACKGROUND: In 2010-2014, approximately 86% of abortions took place in low- and middle-income countries (LMICs). Although abortion incidence varies minimally across geographical regions, it varies widely by subregion and within countries by subgroups of women. Differential abortion levels stem from variation in the level of unintended pregnancies and in the likelihood that women with unintended pregnancies obtain abortions. OBJECTIVES: To examine the characteristics of women obtaining induced abortions in LMICs. METHODS: We use data from official statistics, population-based surveys, and abortion patient surveys to examine variation in the percentage distribution of abortions and abortion rates by age at abortion, marital status, parity, wealth, education, and residence. We analyze data from five countries in Africa, 13 in Asia, eight in Europe, and two in Latin America and the Caribbean (LAC). RESULTS: Women across all sociodemographic subgroups obtain abortions. In most countries, women aged 20-29 obtained the highest proportion of abortions, and while adolescents obtained a substantial fraction of abortions, they do not make up a disproportionate share. Region-specific patterns were observed in the distribution of abortions by parity. In many countries, a higher fraction of abortions occurred among women of high socioeconomic status, as measured by wealth status, educational attainment, and urban residence. Due to limited data on marital status, it is unknown whether married or unmarried women make up a larger share of abortions. CONCLUSIONS: These findings help to identify subgroups of women with disproportionate levels of abortion, and can inform policies and programs to reduce the incidence of unintended pregnancies; and in LMICs that have restrictive abortion laws, these findings can also inform policies to minimize the consequences of unsafe abortion and motivate liberalization of abortion laws. Program planners, policymakers, and advocates can use this information to improve access to safe abortion services, postabortion care, and contraceptive services.
Keywords: Abortion, Legal/*economics/psychology/*statistics & numerical data; Adolescent; Adult; Africa; Asia; Caribbean Region; Developing Countries/*economics; Educational Status; Europe; Female; Humans; Latin America; Marital Status/statistics & numerical data; Parity/physiology; Poverty/psychology/*statistics & numerical data; Pregnancy; *Pregnancy, Unplanned
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Chae, S., Desai, S., Crowell, M., Sedgh, G., & Singh, S. (2017). Characteristics of women obtaining induced abortions in selected low- and middle-income countries. PLoS One, 12(3), e0172976.
Abstract: BACKGROUND: In 2010-2014, approximately 86% of abortions took place in low- and middle-income countries (LMICs). Although abortion incidence varies minimally across geographical regions, it varies widely by subregion and within countries by subgroups of women. Differential abortion levels stem from variation in the level of unintended pregnancies and in the likelihood that women with unintended pregnancies obtain abortions. OBJECTIVES: To examine the characteristics of women obtaining induced abortions in LMICs. METHODS: We use data from official statistics, population-based surveys, and abortion patient surveys to examine variation in the percentage distribution of abortions and abortion rates by age at abortion, marital status, parity, wealth, education, and residence. We analyze data from five countries in Africa, 13 in Asia, eight in Europe, and two in Latin America and the Caribbean (LAC). RESULTS: Women across all sociodemographic subgroups obtain abortions. In most countries, women aged 20-29 obtained the highest proportion of abortions, and while adolescents obtained a substantial fraction of abortions, they do not make up a disproportionate share. Region-specific patterns were observed in the distribution of abortions by parity. In many countries, a higher fraction of abortions occurred among women of high socioeconomic status, as measured by wealth status, educational attainment, and urban residence. Due to limited data on marital status, it is unknown whether married or unmarried women make up a larger share of abortions. CONCLUSIONS: These findings help to identify subgroups of women with disproportionate levels of abortion, and can inform policies and programs to reduce the incidence of unintended pregnancies; and in LMICs that have restrictive abortion laws, these findings can also inform policies to minimize the consequences of unsafe abortion and motivate liberalization of abortion laws. Program planners, policymakers, and advocates can use this information to improve access to safe abortion services, postabortion care, and contraceptive services.
Keywords: Abortion, Legal/*economics/psychology/*statistics & numerical data; Adolescent; Adult; Africa; Asia; Caribbean Region; Developing Countries/*economics; Educational Status; Europe; Female; Humans; Latin America; Marital Status/statistics & numerical data; Parity/physiology; Poverty/psychology/*statistics & numerical data; Pregnancy; *Pregnancy, Unplanned
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Clark, P. A., Gaal, J. T., Strebe, J. K., Pasch, C. A., Deming, D. A., Kuo, J. S., et al. (2017). The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells. J Clin Neurosci, 36, 120–124.
Abstract: A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a 10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160muM; 22GSCs: IC50=44muM) compared to MGMT non-expressing (33GSCs: IC50=1.5muM; 114GSCs: IC50=5.2muM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74+/-2.9% and 38+/-3.2%, respectively; 22GSC: 61+/-11% and 38+/-2.6%, respectively; 33GSC: 56+/-9.5% and 60+/-7.1%, respectively; 114 GSC: 79+/-3.5% and 41+/-4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., +/- MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications.
Keywords: Antineoplastic Agents, Alkylating/*pharmacology; Cell Line, Tumor; Cell Proliferation/drug effects/radiation effects; Cell Survival/drug effects/radiation effects; Cells, Cultured; DNA Modification Methylases/genetics/*metabolism; DNA Repair Enzymes/genetics/*metabolism; Dacarbazine/*analogs & derivatives/pharmacology; *Electromagnetic Fields; Glioblastoma/genetics/*metabolism; Humans; Neoplastic Stem Cells/drug effects/radiation effects; Neurons/drug effects/radiation effects; Tumor Suppressor Proteins/genetics/*metabolism; Cancer stem cells; Glioblastoma; MGMT methylation; Temozolomide; Tumor treating fields
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Cole, D. C., Giordano, C. R., Vasilopoulos, T., & Fahy, B. G. (2017). Resident Physicians Improve Nontechnical Skills When on Operating Room Management and Leadership Rotation. Anesth Analg, 124(1), 300–307.
Abstract: BACKGROUND: Anesthesiology residency primarily emphasizes the development of medical knowledge and technical skills. Yet, nontechnical skills (NTS) are also vital to successful clinical practice. Elements of NTS are communication, teamwork, situational awareness, and decision making. METHODS: The first 10 consecutive senior residents who chose to participate in this 2-week elective rotation of operating room (OR) management and leadership training were enrolled in this study, which spanned from March 2013 to March 2015. Each resident served as the anesthesiology officer of the day (AOD) and was tasked with coordinating OR assignments, managing care for 2 to 4 ORs, and being on call for the trauma OR; all residents were supervised by an attending AOD. Leadership and NTS techniques were taught via a standardized curriculum consisting of leadership and team training articles, crisis management text, and daily debriefings. Resident self-ratings and attending AOD and charge nurse raters used the Anaesthetists' Non-Technical Skills (ANTS) scoring system, which involved task management, situational awareness, teamwork, and decision making. For each of the 10 residents in their third year of clinical anesthesiology training (CA-3) who participated in this elective rotation, there were 14 items that required feedback from resident self-assessment and OR raters, including the daily attending AOD and charge nurse. Results for each of the items on the questionnaire were compared between the beginning and the end of the rotation with the Wilcoxon signed-rank test for matched samples. Comparisons were run separately for attending AOD and charge nurse assessments and resident self-assessments. Scaled rankings were analyzed for the Kendall coefficient of concordance (omega) for rater agreement with associated chi and P value. RESULTS: Common themes identified by the residents during debriefings were recurrence of challenging situations and the skills residents needed to instruct and manage clinical teams. For attending AOD and charge nurse assessments, resident performance of NTS improved from the beginning to the end of the rotation on 12 of the 14 NTS items (P < .05), whereas resident self-assessment improved on 3 NTS items (P < .05). Interrater reliability (across the charge nurse, resident, and AOD raters) ranged from omega = .36 to .61 at the beginning of the rotation and omega = .27 to .70 at the end of the rotation. CONCLUSIONS: This rotation allowed for teaching and resident assessment to occur in a way that facilitated resident education in several of the skills required to meet specific milestones. Resident physicians are able to foster NTS and build a framework for clinical leadership when completing a 2-week senior elective as an OR manager.
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