tbuckley/cabot-search huggingface dataset:
How to answer ethical questions at your medical school interview
Authors: Julian Sheather
Journal: BMJ (2015)

Medicine is about delivering health benefits to patients. Sometimes this means curing them of an illness. If they cannot be cured, it may entail trying to halt or slow the progression of a disease. In the end, it may mean providing the best possible end of life care. From outside, the role of doctors seems straightforward: they use their medical skills—and medical technology—to benefit their patients. The ability to do good for people is one of the attractions of a medical career: part of what makes it a vocation rather than just a job. However, there are times when it is not clear what we mean by “doing good.” Not necessarily because we are unsure about the diagnosis, or of whether a proposed treatment will be effective, but because there are real doubts about what “good” means. Is withdrawing life sustaining treatment from a patient in a persistent vegetative state good, or should he or she be kept alive indefinitely? Medicine entails the application of science to the healing of human beings. At times it can seem as if the human is swamped by the science. One of the reasons admissions tutors to medical schools might ask you how you would respond to ethical problems is because these questions can shed light on the human dimension of medicine. At an interview, admissions tutors will be exploring more than your scientific and analytic abilities. They will also be exploring emotional skills such as empathy. #### Box 1: Key points to consider when asked to discuss ethical dilemmas
Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression
Authors: Xiaoxu Huang, Zheng Li, Qiang Zhang, Weizhi Wang, Bowen Li, Lu Wang, Zhipeng Xu, Ailiang Zeng, Xing Zhang, Xuan Zhang, Zhongyuan He, Qiang Li, Guangli Sun, Sen Wang, Qing Li, Linjun Wang, Lu Zhang, Hao Xu, Zekuan Xu
Journal: Molecular Cancer (2019)

Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy.
Predicting complexation performance between cyclodextrins and guest molecules by integrated machine learning and molecular modeling techniques
Authors: Qianqian Zhao, Zhuyifan Ye, Yan Su, Defang Ouyang
Journal: Acta Pharmaceutica Sinica B (2019)

Most pharmaceutical formulation developments are complex and ideal formulations are generally obtained after extensive experimentation. Machine learning is increasingly advancing many aspects in modern society and has achieved significant success in multiple subjects. Current research demonstrated that machine learning can be adopted to build up high-accurate predictive models in drugs/cyclodextrins (CDs) systems. Molecular descriptors of compounds and experimental conditions were employed as inputs, while complexation free energy as outputs. Results showed that the light gradient boosting machine provided significantly improved predictive performance over random forest and deep learning. The mean absolute error was 1.38 kJ/mol and squared correlation coefficient was 0.86. The evaluation of relative importance of molecular descriptors further demonstrated the key factors affecting molecular interactions in drugs/CD systems. In the specific ketoprofen-CD systems, machine learning model showed better predictive performance than molecular modeling calculation, while molecular simulation could provide structural, dynamic and energetic information. The integration of machine learning and molecular simulation could produce synergistic effect for interpreting and predicting pharmaceutical formulations. In conclusion, the developed predictive models were able to quickly and accurately predict the solubilizing capacity of CD systems. Current research has taken an important step toward the application of machine learning in pharmaceutical formulation design.
Abstract CS1-3: Moderate penetrance mutations: What to do?
Authors: S Domchek
Journal: Cancer Research (2019)

Abstract Genetic testing for breast and ovarian cancer susceptibility has expanded beyond sequencing of BRCA1 and BRCA2. Panel testing has allowed for rapid, affordable, and routine testing of multiple genes simultaneously. There is no one standard “panel” – panels range in types and number of genes tested and panel composition is at the discretion of the ordering provider. Some of the genes commonly included have been long associated with specific genetic syndromes with high lifetime risks of the associated cancers, e.g. mutations in PTEN and Cowden's Syndrome, TP53 and Li Fraumeni Syndrome, STK11 and Peutz-Jeghers Syndrome, and CHD1 and Hereditary Diffuse Gastric Cancer. The inclusion of these “high penetrance genes” on broad cancer panels can lead to challenges regarding discussion and management when detected in families which are not syndromic (for example, the discussion of prophylactic gastrectomy in individuals with CDH1 mutations and no family history of gastric cancer). Mutations in other genes are clearly associated with breast cancer but with lower lifetime risks than for BRCA1 and BRCA2; for example, the lifetime risk of breast cancer for a PALB2 mutation is approximately 40-50%, whereas for ATM and truncating CHEK2 mutations this risk is 25-30%. Mutations in BRIP, RAD51C, and RAD51D are clearly associated with ovarian cancer with lifetime risks of approximately 10% (significantly lower than for BRCA1 mutations). This lecture will address the current understanding of associated cancer risks for mutations in genes included in hereditary cancer panels with a focus on implications for risk reduction and treatment. Citation Format: Domchek S. Moderate penetrance mutations: What to do? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr CS1-3.
Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial
Authors: David A Wohl, Yazdan Yazdanpanah, Axel Baumgarten, Amanda Clarke, Melanie A Thompson, Cynthia Brinson, Debbie Hagins, Moti N Ramgopal, Andrea Antinori, Xuelian Wei, Rima Acosta, Sean E Collins, Diana Brainard, Hal Martin
Journal: The Lancet HIV (2019)
Abstract P4-08-14: Invasive micropapillary carcinoma had no difference in prognosis compared with invasive ductal carcinoma: A propensity-matched analysis
Authors: S Hao, Y-Y Zhao, J-J Peng, W-T Yang, F Ren, K-D Yu, Z-M Shao
Journal: Cancer Research (2019)

Abstract Background: Invasive micropapillary carcinoma (IMPC) is a rare histopathological variant of breast carcinoma and usually performs poor clinical characteristics, such as high tendency of lymph nodes metastases. But whether it has worse prognosis than invasive ductal carcinoma (IDC) is still controversial nowadays. We conducted this retrospective study to figure out the prognostic difference between IMPC and IDC, then guide therapy of IMPC ultimately. Methods: In this study, we analyzed 327 cases of IMPC patients and 4979 cases of IDC who underwent primary resection in our institution during 2008 to 2012. By using propensity score matching, two groups were matched at a ratio of 1:1 by age, tumor size, nodal status, hormone and HER2 status to demonstrate the difference of prognosis assessed by Kaplan-Meier estimates and Cox regression analysis. Result: After a mean follow-up of 52 months, we established the IMPC group and figured out 324 IDC patients from the control group by propensity score matching (3 IMPC patients were canceled because of data missing). The result of survival analysis indicated that women diagnosed with IMPC had no significant reduced overall survival (OS) (p = 0.752) and disease-free survival (DFS) (p = 0.578) compared with women with IDC. Multivariate Cox regression analysis revealed that IMPC was not found as an independent prognostic factor for DFS (hazard ratio [HR] = 0.858; 95% confidential interval [CI], 0.419-1.757) or OS (HR = 0.720; 95%CI, 0.353-1.469). Conclusion: The consequence of survival analysis manifested that there was no statistically significant difference between 2 groups, and elucidated proactive or radical clinical therapy was unnecessary. Citation Format: Hao S, Zhao Y-Y, Peng J-J, Yang W-T, Ren F, Yu K-D, Shao Z-M. Invasive micropapillary carcinoma had no difference in prognosis compared with invasive ductal carcinoma: A propensity-matched analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-14.
Acquired generalized lipodystrophy under immune checkpoint inhibition
Authors: N. Haddad, T. Vidal‐Trecan, B. Baroudjian, A.‐M. Zagdanski, D. Arangalage, M. Battistella, J.‐F. Gautier, C. Lebbe, J. Delyon
Journal: British Journal of Dermatology (2019)

Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune‐related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47‐year‐old patient, treated with the anti‐programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti‐PD‐1‐induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow‐up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti‐programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune‐related adverse events (irAEs) are among the most frequent irAEs (14–30% and 30–40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti‐PD1 therapy and is associated with severe metabolic complications. With the increase in anti‐PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.
Abstract P4-06-27: LncRNA NKILA promotes tumour immune evasion by sensitizing tumour-specific t cells to activation-induced cell death
Authors: E Song, S Su, D Huang
Journal: Cancer Research (2019)

Abstract Activation induced cell death (AICD) of T lymphocytes is critical to maintain T-cell homeostasis, which is adopted by malignant tumors to convey immune evasion by eliminating tumor-reactive cytotoxic T cells. In this study, we demonstrated excessive apoptosis of tumor antigen-specific CTLs in breast and lung cancers. However, the mechanism involved in AICD of tumor-specific T cells remains obscure. Here, we demonstrated that NF-κB activity in tumor-specific T cells is high at the early phase of CTL activation induced by breast tumor antigens, but is suppressed at the later phase. This results in massive apoptosis of tumor-specific CTLs challenged by tumor cells. Interestingly, NKILA, an NFκB interacting lncRNA, sensitizes CTLs to AICD by inhibiting NF-κB activities after their activation, leading to tumor immune evasion. In vivo, administering CTLs with NKILA silencing into immunocompromised mice with breast cancer patient derived xenografts (PDXs) effectively inhibits PDX growth by increasing CTL infiltration. Clinically, NKILA was overexpressed in the tumor specific CTLs of breast and lung cancers, which was associated with less CTL infiltration in the tumors and shorter patient survival. Our findings present the first evidence that AICD in tumor-specific CTLs is crucial to cancer immune evasion, and targeting NKILA in CTLs emerges as a novel anti-tumor immunotherapy. Citation Format: Song E, Su S, Huang D. LncRNA NKILA promotes tumour immune evasion by sensitizing tumour-specific t cells to activation-induced cell death [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-27.
Assessment of Prescriber and Pharmacy Shopping Among the Family Members of Patients Prescribed Opioids
Authors: Kao-Ping Chua, Chad M. Brummett, Rena M. Conti, Rebecca L. Haffajee, Lisa A. Prosser, Amy S.B. Bohnert
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Most prescription opioid misuse involves opioids prescribed to others—a form of opioid diversion. However, few indicators of diversion risk exist. Because family members can often access patients’ opioids, one such indicator may be the frequency with which opioid prescriptions are filled by patients when their family members are engaged in opioid prescriber and pharmacy shopping (“doctor and pharmacy shopping”). To date, this frequency has not been estimated. <h3>Objective</h3> To estimate the proportion of opioid prescription fills for which family members meet prescriber and pharmacy shopping criteria. <h3>Design, Setting, and Participants</h3> A cross-sectional analysis of 2015-2016 claims from a national commercial insurer was conducted from August to October, 2018. The sample included patients without cancer who were covered by family insurance plans and had 1 or more opioid prescription fill in 2016, as measured by prescription drug claims. Fills were the unit of analysis. <h3>Main Outcomes and Measures</h3> For each fill in 2016 by the patient and each family member enrolled in the same plan (eg, spouse or child), the number of prescribers and number of pharmacies in the prior 12 months were counted. Prescriber and pharmacy shopping was defined as 4 or more prescribers and 4 or more pharmacies, following a National Quality Forum–endorsed measure. The proportion of fills for which 1 or more family member met criteria and the proportion for which the patient met criteria were calculated. <h3>Results</h3> Among 554 417 patients in the sample, 301 297 (54.3%) were female and 48 047 (8.7%) were children. Mean (SD) age was 41.4 (16.4) years. Patients were enrolled in 469 913 plans and, after exclusions, filled 1 471 971 opioid prescriptions in 2016. For 8485 fills (0.6%), 1 or more family member met prescriber and pharmacy shopping criteria. For 44 547 fills (3.0%), the patient met criteria. For 6947 of the 8485 fills (81.9%) for which 1 or more family member met criteria, patients did not meet criteria. When criteria were 3 or more prescribers at 3 or more pharmacies, the proportion of fills for which 1 or more family member met criteria increased to 1.9%. <h3>Conclusions and Relevance</h3> In this national study of US patients with private family insurance plans, 0.6% of opioid prescription fills occurred when at least 1 of the patient’s family members met prescriber and pharmacy shopping criteria. For most of these fills, patients did not meet criteria. Findings suggest the potential for opioid diversion within families.
Abstract P2-06-08: Withdrawn
Authors: F Vena, S Bayle, V Quereda, A Monastyrskyi, D Duckett
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Vena F, Bayle S, Quereda V, Monastyrskyi A, Duckett D. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-08.
Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia
Authors: Emmalee R. Adelman, Hsuan-Ting Huang, Alejandro Roisman, André Olsson, Antonio Colaprico, Tingting Qin, R. Coleman Lindsley, Rafael Bejar, Nathan Salomonis, H. Leighton Grimes, Maria E. Figueroa
Journal: Cancer Discovery (2019)

Abstract Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. Lineage−CD34+CD38− cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably, in vitro downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. Significance: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes. This article is highlighted in the In This Issue feature, p. 983
Abstract P4-09-02: Validation of iPrevent using the prospective family study cohort (ProF-SC)
Authors: K-A Phillips, Y Liao, IM Collins, R Buchsbaum, P Weideman, A Bickerstaffe, RJ MacInnis, J Cuzick, A Antoniou, IL Andrulis, EM John, MB Daly, SS Buys, JL Hopper, MB Terry
Journal: Cancer Research (2019)

Abstract Background: iPrevent (https://www.petermac.org/iprevent) provides women with highly-tailored risk management information after first estimating their breast cancer (BC) risk using the established risk prediction models, IBIS and BOADICEA. iPrevent has an internal switching algorithm that governs which model is used for each woman, depending on her risk factor data (i.e. LCIS/atypical hyperplasia status, BRCA status, and cancer family history). This study assessed the calibration and discriminatory accuracy of the 10-year BC risk estimates provided by iPrevent. Methods: Subjects were 16,574 women in the ProF-SC, aged 18-70 years and without BC or bilateral mastectomy at recruitment. After 10 years follow-up, 655 women (4%) were diagnosed with invasive BC. A “batch mode” for iPrevent is not available, so the iPrevent-assigned cumulative 10-year invasive BC risks were calculated by entering self-reported risk factors at cohort entry into either the IBIS (10,169 women) or BOADICEA (6,405 women) software packages (according to the iPrevent switching algorithm). To assess calibration, the mean iPrevent-assigned risk was compared with the mean 10-year observed invasive BC incidence, using a chi-squared goodness-of-fit statistic for the whole cohort, and by quartiles of risk. To evaluate discriminatory accuracy, the overall area under the receiver operating characteristic curve (AUC) for the development of invasive BC within 10 years was computed. Data were censored at date of invasive or in situ BC diagnosis, bilateral mastectomy, death, loss to follow-up, or at 10 years of follow-up. Results: For the whole cohort, iPrevent assigned risk was well-calibrated – 690 expected BCs (E) 655 observed (O) (E/O=1.05, 95% CI: 0.98-1.14), although for women in the highest risk quartile, i.e. &amp;gt;6% 10-year risk, E/O=1.19, 95% CI: 1.07-1.32. The AUC was 0.70, 95% CI: 0.68-0.72. Conclusions: iPrevent is well calibrated overall and has good discriminatory accuracy for predicting 10-year BC risk, thus justifying its clinical use. Citation Format: Phillips K-A, Liao Y, Collins IM, Buchsbaum R, Weideman P, Bickerstaffe A, MacInnis RJ, kConFab Investigators, Cuzick J, Antoniou A, Andrulis IL, John EM, Daly MB, Buys SS, Hopper JL, Terry MB. Validation of iPrevent using the prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-02.