tbuckley/cabot-search huggingface dataset:
Abstract 13312: Impaired Executive Function in Adults With a Repaired Atrial Septal Defect
Authors: Benjamin Asschenfeldt, Lars Evald, Simon F Eskildsen, Johan Heiberg, Leif Østergaard, Vibeke E Hjortdal
Journal: Circulation (2019)

Introduction: The paradigm of a benign neurodevelopmental outcome in septal congenital heart defects is challenged. We have previously shown, that a repaired atrial septal defect (ASD) is associate...
Abstract P552: The Role of Traditional Risk Factors in Mediating the Influence of Cumulative Social Risk Exposure on Cardiovascular Death
Authors: Wei Zhang, Muhammad Imtiaz Ahmad, Elsayed Z SOLIMAN
Journal: Circulation (2020)

Introduction: Cumulative social risk exposure, defined as experiencing more than one social risk factor and captured through an index of cumulative social risk, is associated with a significant increase in cardiovascular disease (CVD) mortality. However, the role of CVD risk factors in explaining this association is unclear. Methods: This analysis included 15,906 participants (45.6±19.5 years, 53.4% women, 57.7% minority race) from the Third National Health and Nutrition Examination Survey (NHANES-III) who were CVD-free at enrollment. Baseline social risk factors (minority race, poverty-income ratio&lt;1, education&lt;12 grade, and living single) were used to create a cumulative social risk score (0 to ≥3). The mediation by each CVD risk factor was assessed by estimating the magnitude of attenuation in the hazard ratio for the association between social risk score and CVD death adjusted by demographics and risk factors. Results: During a median follow up of 14 years, 1,309 CVD deaths occurred. Participants with more than one social risk factor were at increased risk of CVD death (Table) . The risk of CVD death in demographic adjusted models was attenuated by 31%, 21% and 36% in people with social risk score 1, 2, and ≥3 versus 0, respectively, after further adjustment for traditional CVD risk factors. Among all CVD risk factors included in the analysis, current smoking was the most powerful mediating effect, accounting for approximately one half of the combined risk factor effect, followed by obesity and diabetes ( Table ). Conclusions: Traditional CVD risk factors explain about one third of the association between cumulative social risk exposure and CVD death. While these findings underscore the importance of management of traditional CVD risk factors, particularly smoking, in socially disadvantaged population, they call for further studies to identify other pathways that explain the link between social risk exposure and CVD.
Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects
Authors: Tomi Rantamäki, Samuel Kohtala
Journal: Pharmacological Reviews (2020)

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. <h3>Significance Statement</h3> Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as <i>N</i>-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.
Additional Considerations for Screening and Treatment of Depression in Patients With Acute Coronary Syndrome
Authors: Montika Bush, Bradley N. Gaynes, Sidney C. Smith
Journal: JAMA Internal Medicine (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
A prospective phase II study of gefitinib in non-small cell cancer patients with epidermal growth factor receptor gene (EGFR) mutations
Authors: K. Sugio, H. Uramoto, T. Oyama, T. Onizuka, Y. Ichiki, M. Yasuda, M. Sugaya, T. Nozoe, M. Takenoyama, T. Hanagiri, K. Yasumoto
Journal: Journal of Clinical Oncology (2007)

18081 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to gefitinib, a tyrosine kinase inhibitor that targets EGFR, especially in patients with adenocarcinoma, females, and/or never/light smokers. In our retrospective study, cases with EGFR mutations (exon19del or L858R) showed a high sensitivity to gefitinib, and the patients with sensitive EGFR mutations also tended to have a more favorable prognosis than those with wild-type after gefitinib treatment (Uramoto, et al. Lung Cancer 2006;51:71). In the present study, we prospectively assessed the efficacy of gefitinib and the survival benefit for patients with EGFR mutations. Methods: Patients with either recurrent disease after undergoing surgery or advanced disease (IIIB or IV) of NSCLC which demonstrated EGFR mutations were eligible for this study. EGFR mutations in exons 19–21 were examined by our previously described screening method (Sugio, et al. Br J Cancer 2006;94:896) and confirmed by direct sequencing after informed consent was obtained from all patients. The patients with EGFR mutations were enrolled in this study after obtaining informed consent a second time, and they were thereafter treated with gefitinib. Results: Between 2005 and 2006, 16 patients (10 males/6 females, all adenocarcinoma) who had EGFR mutations were enrolled onto this study. Six pts had a deletion in exon 19, 8 pts had a missense mutation in exon 21 (L858R), 1 pt had both an exon 19 del and L858R, and 1 pts had an exon19 del and missense mutation in exon 20 (G796A). The overall response rate was 50%, and the disease control rate was 88%. In patients with exon19 del and L858R, the response rates were 83% and 25%, respectively. A case with a deletion in exon19 and a missense mutation in exon20 (G796A) showed resistance to gefitinib. The median progression-free survival time was 8.8 months, and the median survival time was 15.4 months. No life-threatening toxicity was observed. Conclusions: EGFR mutations in exons 19 or 21 are therefore considered to a good predictor of the efficacy of gefitinib, and the treatment with gefitinib was also found to achieve a prolonged survival. No significant financial relationships to disclose.
Abstract P3-01-14: N-Myc and STAT interactor regulates STAT5a in mammary development and metastasis
Authors: Rajeev Sharad Samant, Heba A Alsheikh, Brandon J Metge, Dongquan Chen, Shi Wei, Lalita A Shevde
Journal: Cancer Research (2020)

Abstract Delicate balance between cellular plasticity and differentiation is critically maintained during mammary development. Disruption of this balance leads to breast cancer initiation and metastatic progression. Recent findings from our lab have revealed that N-Myc and STAT Interactor (NMI) protein is decreased in 70% of primary patient specimens with metastatic breast cancer. Mammary specific Nmi knock out mouse model revealed that conditional Nmi loss disrupts luminal differentiation in the mammary gland affecting alveologenesis and prompted the progression of tumors with aggressive metastatic characteristics. Our studies showed that Nmi is induced at the onset of pregnancy and its expression remains throughout lactation. Furthermore, prolactin stimulation and differentiation of HC11 murine mammary epithelial cells is accompanied by up-regulation of Nmi. STAT5a is one of the downstream effector of prolactin and is essential for differentiation of secretory alveolar epithelium. However, functional relationship of NMI and STAT5a was not known. Here we present our finding that NMI and STAT5a expression has a direct relationship in normal mammary development as well as in breast primary and metastatic tumor specimens. We demonstrate that loss of Nmi in vivo caused a decrease in STAT5a activity and a subsequent transcriptomic shift in mammary epithelial and breast cancer cells. Detailed examination of STAT5a mammary specific controlled genetic program in the context of transcription profiles of NMI knockout and overexpressing cell lines as well as mammary tumors revealed ISG20, interferon stimulated exonuclease gene 20, as a unique negatively regulated transcript. Here we show that expression of ISG20 is kept in check by NMI by miR17-92 cluster and that ISG20 has a positive influence on tumor progression and metastasis. Citation Format: Rajeev Sharad Samant, Heba A Alsheikh, Brandon J Metge, Dongquan Chen, Shi Wei, Lalita A Shevde. N-Myc and STAT interactor regulates STAT5a in mammary development and metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-14.
Epidermal growth factor receptor (EGFR) as a potential new target in the treatment of patients with adrenocortical carcinoma: Results of pre-clinical studies
Authors: M. Fassnacht, S. Hahner, P. Adam, B. Heinrich, M. Quinkler, P. Stroebel, B. Allolio
Journal: Journal of Clinical Oncology (2007)

21025 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with incompletely understood pathogenesis and poor prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been demonstrated in several tumors and is partly associated with a more aggressive phenotype and a worse prognosis. In addition, targeting the EGFR tyrosine kinase represents a successful new therapeutic strategy, e.g. in non-small cell lung cancer. Therefore, we investigated the role of EGFR in ACC as a potential therapeutic target. Methods: EGFR expression was analyzed by immunohistochemistry in 115 ACCs and 5 normal adrenals using paraffin sections and tissue arrays (scoring of expression: 0–3). Utilizing the clinical data from the German ACC registry, Kaplan Meier survival analyses were performed. In 30 patients the tumor DNA was sequenced for mutations of the “hot spot” exons 19–21 of the EGFR gene. In addition, cells of the ACC cell line NCI-h295 were incubated with the EGFR antibody cetuximab (1–100 μg/ml) and cell proliferation was measured by MTT tests. Results: Immunohistochemistry revealed EGFR expression in 78% of ACCs. In 67/115 (58%) of the ACCs and 0/5 of the normal adrenals the expression level was judged as moderate-to-high (score 2 or 3). However, the expression level did not correlate with the clinical outcome in these patients. In addition, none of the sequenced tumor DNA samples showed a mutation in exons 19–21. Cetuximab exhibited a dose dependent antiproliferative effect in NCI-H295 cells (cell viability: 1μg/ml: 95±2%; 10μg/ml 90±3%*; 100 μg/ml 85±4%* vs untreated control cells: 100±3%; * = p&lt;0.01). Conclusion: EGFR is overexpressed in the majority of ACC. Moreover, in vitro experiments demonstrated that inhibition of EGFR signalling lead to moderate growth inhibition in ACC cells. Therefore, in patients with ACC refractory to established cytotoxic therapies the experimental use of EGFR inhibitors (combined with cytotoxic therapy) seems to be justified. No significant financial relationships to disclose.
Omission of radiotherapy after breast conserving surgery among elderly women with favorable prognosis tumors
Authors: W. T. Swenson, M. Hoffman, A. Hoffman
Journal: Journal of Clinical Oncology (2007)

9034 Background: Adjuvant radiotherapy after breast-conserving surgery is a standard therapy for invasive breast carcinoma. Controversy exists regarding the benefit of adjuvant radiotherapy for elderly women with favorable prognosis tumors. Methods: Using data from the Surveillance Epidemiology and End Results (SEER) registry, data were analyzed for 28,808 women ages = 65 years, with stage I and II, who underwent breast conservation therapy between 1998 and 2002. Relative survival rates (observed survival/expected survival) were calculated using Kaplan-Meier method for women who underwent radiotherapy and those for whom radiotherapy was omitted. Results: Among women = 65 years with stage I breast cancer who underwent breast conserving surgery (n = 20,400), 71.7% received adjuvant radiotherapy. Among those with stage II breast cancer (n = 8,408), 66.0% received adjuvant radiotherapy. Five-year relative survival rates among stage I patients were 1.000 (95% CI: 0.990, 1.010) for those receiving adjuvant radiotherapy, and 0.959 (95% CI: 0.932, 0.986) for those without adjuvant radiotherapy. Among stage II patients, the 5-year survival rates were 0.998 (95% CI: 0.978, 1.018) for those receiving adjuvant radiotherapy, and 0.832 (95% CI: 0.791, 0.873) for those without adjuvant radiotherapy. Conclusions: Adjuvant radiotherapy following breast conserving surgery may be safely omitted for elderly women with stage I breast carcinoma, especially for women ages 85–94 years. [Table: see text] No significant financial relationships to disclose.
Abstract MP59: Serum Sphingolipids and Incident Diabetes in US Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Jin Choul Chai, Guochong Chen, Bing Yu, Megan Grove, Amanda M Fretts, Martha L DAVIGLUS, Olga L Garcia-Bedoya, Bharat Thyagarajan, Neil Schneiderman, Jianwen Cai, Robert Kaplan, Eric Boerwinkle, Qibin Qi
Journal: Circulation (2020)

Introduction: Genetic or pharmacological inhibition of sphingolipid synthases prevented diabetes in animal studies. Scanty of cohort studies that examined circulating sphingolipids and incident diabetes yielded disparate findings. Hypothesis: Specific sphingolipids are associated with elevated risk of diabetes beyond traditional risk factors. Methods: Untargeted metabolomics profiling was performed using fasting serum samples collected from 2010 adult participants of the Hispanic Community Health Study/Study of Latinos, who were free of diabetes and other major chronic diseases at baseline (2008 to 2011). A total of 43 sphingolipids were quantified and 6 sphingolipid scores were derived considering subclasses and chemical structures. Survey Poisson regressions were applied to estimate relative risk (RR) and 95% confidence interval (CI) of incident diabetes associated with individual sphingolipids and the scores. Results: Over ~6 years of follow-up, 224 incident diabetes cases were identified using the ADA criteria. After adjustment for socioeconomic and lifestyle factors, 8 sphingolipids were associated with higher risk of diabetes significantly at the FDR-adjusted level ( Figure ). After further adjusting for general and central adiposity, blood pressure, CRP, HDL cholesterol, and triglycerides, only associations for three saturated sphingomyelins (SMs),36:0 (RR =1.41 [95% CI 1.17-1.69]), 38:0 (RR =1.32 [1.11-1.56]), and d18:0/22:0 (RR =1.45 [1.24-1.71]) remained. Of the 6 scores, only a score comprising 5 saturated SMs was associated with higher risk of diabetes (RR =1.31 [1.12-1.53]) after the full adjustment. An addition of the saturated SM score to the full model including traditional risk factor lead to a modest improvement in diabetes risk classification (net reclassification improvement = 22.0%; 95% CI: 7.8%-36.1%). Conclusions: Our findings suggest that a cluster of saturated SMs may be associated with higher risk of diabetes beyond traditional risk factors in US Hispanics/Latinos.
Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the Vγ9Vδ2 TCR and Is Essential for Phosphoantigen Sensing
Authors: Mohindar M. Karunakaran, Carrie R. Willcox, Mahboob Salim, Daniel Paletta, Alina S. Fichtner, Angela Noll, Lisa Starick, Anna Nöhren, Charlotte R. Begley, Katie A. Berwick, Raphaël A.G. Chaleil, Vincent Pitard, Julie Déchanet-Merville, Paul A. Bates, Brigitte Kimmel, Timothy J. Knowles, Volker Kunzmann, Lutz Walter, Mark Jeeves, Fiyaz Mohammed, Benjamin E. Willcox, Thomas Herrmann
Journal: Immunity (2020)
A phase I study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer
Authors: D. Rischin, K. Narayan, A. Oza, L. Mileshkin, D. Bernshaw, K. Hanlon, B. McClure, A. Fyles
Journal: Journal of Clinical Oncology (2007)

5543 Background and Purpose: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. GOG are currently studying the hypoxic cytotoxin, tirapazamine (TPZ) in combination with biweekly intermediate dose cisplatin (CIS) and radiation in a large phase III trial. The aim of this phase I study was to develop a better tolerated regimen that added TPZ to the standard regimen of radiation and weekly low dose CIS. Methods: Eligible patients had previously untreated carcinoma of the cervix, Stages IB2 - IVA. The starting schedule was radiotherapy (45 to 50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly CIS 40 mg/m 2 weeks 1–6 and weekly TPZ 290 mg/m 2 (prior to CIS) in weeks 1–5. Results: Between 3/05 and 7/06 eleven patients were enrolled, median age (range) 52 (31–65), squamous cell carcinoma 10, adenocarcinoma 1, 1B2–5, IIA-1, IIB-3, IIIB- 1, IVA-1. The first 2 patients on dose level 1 experienced a dose limiting toxicity (DLT), one grade 3 ALT (SGPT) elevation and grade 4 pulmonary embolism and one grade 3 ototoxicity. Doses were decreased to dose level -1 CIS 30 mg/m 2 and TPZ 260 mg/m 2 . Three patients were treated without any DLTs. Six patients were then treated on dose level -1a, CIS 35 mg/m 2 and TPZ 260 mg/m 2 , with 2 DLTs: grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. The sixth patient on dose level -1a withdrew from the trial in week 2 after being advised about the DLTs observed on this dose level. 3 additional patients will be accrued on dose level -1 to confirm safety of this dose level. One patient has relapsed in pelvic nodes, all other patients remain disease-free with a median followup of 10 months (range 5 - 21) Conclusions: The combination of weekly TPZ and CIS with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being TPZ 260 mg/m 2 , CIS 30 mg/m 2 . No significant financial relationships to disclose.
Medically assisted dying: Canada tables legislation to broaden accessibility criteria
Authors: Owen Dyer
Journal: BMJ (2020)

Canada’s government has tabled new legislation that would remove some of the restrictions placed on medical aid in dying, most notably the requirement that applicants suffer from a terminal condition which makes their death “reasonably foreseeable.”

The new bill will also permit eligible patients to ask for a medically assisted death in advance directives—and to have that wish respected even if they are no longer mentally able to give informed consent at time of death.

But it explicitly rules out assisting the death of people whose only condition is a mental illness. To be eligible, patients must experience intolerable suffering from an incurable condition, said Canada’s justice minister David …
Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial
Authors: Julien Mazieres, Fabrice Barlesi, Isabelle Rouquette, Olivier Molinier, Benjamin Besse, Isabelle Monnet, Clarisse Audigier-Valette, Anne-Claire Toffart, Patrick Aldo Renault, Séverine Fraboulet, Sandrine Hiret, Bertrand Mennecier, Didier Debieuvre, Virginie Westeel, Philippe Masson, Anne Madroszyk-Flandin, Eric Pichon, Alexis B. Cortot, Elodie Amour, Franck Morin, Gérard Zalcman, Denis Moro-Sibilot, Pierre-Jean Souquet
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR–tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. Patients and Methods: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI–naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. Results: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. Conclusions: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.