tbuckley/cabot-search huggingface dataset:
Important Concerns Over SARS-CoV-2 Infection in Children With Cancer—Reply
Authors: Andrew L. Kung, Audrey Mauguen, Farid Boulad
Journal: JAMA Oncology (2020)

targeting agents because of potential false responses owing to their effect on contrast uptake. 2 Therefore, further value is added if the response is maintained for a meaningful duration.Longer DOR has been consistently noted following antiprogrammed cell death 1 (PD-1) therapy across tumor types, explained by generation of polyclonal and memory-adaptive tumor immunity. 3Therefore, DOR is an increasingly important end point, in addition to ORR, for evaluating the efficacy and long-term clinical benefit of immunotherapy.Given the above rationale, we presented a descriptive summary of DOR. 4 We agree with McCaw et al that the differing response rates between arms and the small number of responders may cause a potential bias in case of imbalance in baseline disease burden in responding patients.Although our study 4 did not collect overall baseline disease burden, we conducted a post hoc evaluation of tumor location and the number of sites with lesions at baseline (data not presented).While there was no difference in the tumor location distribution between the arms, all responders in the nivolumab arm (n = 12) had only 1 site involved, while 78% (n = 28) of responders in the bevacizumab arm had 1 site involved and 22% (n = 8) had 2 sites involved.However, the median DOR in the bevacizumab arm was similar between patients with 1 and 2 sites involved. 4Additionally, the median DOR for responders to nivolumab in CA209-143 is longer than that typically observed with salvage agents, such as lomustine 5,6 or temozolomide rechallenge (NCT00392171), and surpassed that achieved by bevacizumab, suggesting that PD-1 inhibition may offer longer-term clinical benefit among glioblastoma responders.We also acknowledge the concerns of dependent censoring.However, in the current study, 4 because of the length of follow-up, there were very few censored participants remaining.Thus, dependent censoring may have minimal influence on this descriptive analysis.We also evaluated the median DOR while including both responders and nonresponders. 4However, given the high numbers of nonresponders, this method only yields the value of zero for both treatment arms, which may be less informative to clinicians.Given the totality of the clinical, mechanistic, and statistical rationales presented above, we conclude that there is value to reporting median DOR in a descriptive manner, while acknowledging the caveats discussed here and by McCaw et al.Additional research in a larger patient population may be needed to further evaluate the value of the DOR benefit in patients with glioblastoma treated with immunotherapy.Better understanding of patient and treatment characteristics among those who achieve a durable DOR may help guide improvement of the efficacy of immunotherapy in a patient population with an urgent need for better treatments.
SGLT2 inhibitors increase risk for diabetic ketoacidosis in type 2 diabetes
Authors: Tomás P. Griffin, Sean F. Dinneen
Journal: Annals of Internal Medicine (2020)

Source Citation Liu J, Li L, Li S, et al. Sodium–glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2020;22:1619-27. 32364674
FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer
Authors: Mirat Shah, Suparna Wedam, Joyce Cheng, Mallorie H. Fiero, Huiming Xia, Fang Li, Jianghong Fan, Xinyuan Zhang, Jingyu Yu, Pengfei Song, Wei Chen, Tiffany K. Ricks, Xiao Hong Chen, Kirsten B. Goldberg, Yutao Gong, William F. Pierce, Shenghui Tang, Marc R. Theoret, Richard Pazdur, Laleh Amiri-Kordestani, Julia A. Beaver
Journal: Clinical Cancer Research (2020)

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.
Maternal Antenatal Corticosteroid Treatment and Childhood Mental and Behavioral Disorders—Reply
Authors: Katri Räikkönen, Mika Gissler, Eero Kajantie
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Author Correction: A stochastic agent-based model of the SARS-CoV-2 epidemic in France
Authors: Nicolas Hoertel, Martin Blachier, Carlos Blanco, Mark Olfson, Marc Massetti, Marina Sánchez Rico, Frédéric Limosin, Henri Leleu
Journal: Nature Medicine (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Abstract 18911: Histone Acetylation Domain by p300 are Changed During the Transition From Cardiac Hypertrophy to Heart Failure
Authors: Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2017)

Background: A histone acetyltransferase (HAT), p300, is required for acetylation and the transcriptional activity of GATA4, as well as for pathological left ventricular hypertrophy (LVH) and the de...
A 3D, Dynamically Loaded Hydrogel Model of the Osteochondral Unit to Study Osteocyte Mechanobiology
Authors: Rachel L. Wilmoth, Virginia L. Ferguson, Stephanie J. Bryant
Journal: Advanced Healthcare Materials (2020)

Osteocytes are mechanosensitive cells that orchestrate signaling in bone and cartilage across the osteochondral unit. The mechanisms by which osteocytes regulate osteochondral homeostasis and degeneration in response to mechanical cues remain unclear. This study introduces a novel 3D hydrogel bilayer composite designed to support osteocyte differentiation and bone matrix deposition in a bone-like layer and to recapitulate key aspects of the osteochondral unit's complex loading environment. The bilayer hydrogel is fabricated with a soft cartilage-like layer overlaying a stiff bone-like layer. The bone-like layer contains a stiff 3D-printed hydrogel structure infilled with a soft, degradable, cellular hydrogel. The IDG-SW3 cells embedded within the soft hydrogel mature into osteocytes and produce a mineralized collagen matrix. Under dynamic compressive strains, near-physiological levels of strain are achieved in the bone layer (≤ 0.08%), while the cartilage layer bears the majority of the strains (>99%). Under loading, the model induces an osteocyte response, measured by prostaglandin E2, that is frequency, but not strain, dependent: a finding attributed to altered fluid flow within the composite. Overall, this new hydrogel platform provides a novel approach to study osteocyte mechanobiology in vitro in an osteochondral tissue-mimetic environment.
Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer
Authors: Munisha Smalley, Siva Kumar Natarajan, Jayanta Mondal, Douglas Best, David Goldman, Basavaraja Shanthappa, Moriah Pellowe, Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Nithya Ramadurai, Elliot O. Eton, Joshua L. Smalley, Andrew Brown, Allen Thayakumar, Mamunur Rahman, Kazuya Arai, Mohammad Kohandel, Shiladitya Sengupta, Aaron Goldman
Journal: Cancer Research (2020)

Abstract Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate “disabled” NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a “chimeric” nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy. Significance: This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.
5P Hormonal biomarkers can improve prediction of response to hormonal therapy in advanced and recurrent endometrial cancer: Results of the PROMOTE-R study
Authors: W.J. Van Weelden, R. Lalisang, J. Bulten, K. Lindemann, H. Van Beekhuizen, H. Trum, D. Boll, H. Werner, L. Van Lonckhuijzen, R. Yigit, D. Forsse, E. Witteveen, K. Galaal, A. Van Ginkel, V. Weinberger, M.A. Inda, C. Krakstad, A. Romano, A. van de Stolpe, J. Pijnenborg
Journal: Annals of Oncology (2020)
42P Imatinib mesylate (IM) promotes malignant behaviour of IM-resistant gastrointestinal stromal tumours (GISTs) via activation of FGF-signaling
Authors: S. Boichuk, E. Mikheeva, A. Sabirov, S. Petrov, M. Novikova, P. Kopnin, E. Valeeva
Journal: Annals of Oncology (2020)
Multimorbidity in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: Results From a Longitudinal, Multicenter Data Linkage Study
Authors: Shifa H. Sarica, Peter J. Gallacher, Neeraj Dhaun, Jan Sznajd, John Harvie, John McLaren, Lucy McGeoch, Vinod Kumar, Nicole Amft, Lars Erwig, Angharad Marks, Laura Bruno, York Zöllner, Corri Black, Neil Basu
Journal: Arthritis & Rheumatology (2020)

Objective Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) is considered a chronic, relapsing condition. To date, no studies have investigated multimorbidity in AAV nationally. This study was undertaken to characterize temporal trends in multimorbidity and report excess health care expenditures associated with multimorbidities in a national AAV cohort from Scotland. Methods Eligible patients with AAV were diagnosed between 1997 and 2017. Each patient was matched with up to 5 general population controls. Linked morbidity and health care expenditure data were retrieved from a Scottish national hospitalization repository and from published national cost data. Multimorbidity was defined as the development of ≥2 disorders. Prespecified morbidities, individually and together, were analyzed for risks and associations over time using modified Poisson regression, discrete interval analysis, and chi‐square test for trend. The relationship between multimorbidities and health care expenditure was investigated using multivariate linear regression. Results In total, 543 patients with AAV (median age 58.7 years [range 48.9–68.0 years]; 53.6% male) and 2,672 general population controls (median age 58.7 years [range 48.9–68.0 years]; 53.7% male) were matched and followed up for a median of 5.1 years. AAV patients were more likely to develop individual morbidities at all time points, but especially &lt;2 years after diagnosis. The highest proportional risk observed was for osteoporosis (adjusted incidence rate ratio 8.0, 95% confidence interval [95% CI] 4.5–14.2). After 1 year, 23.0% of AAV patients and 9.3% of controls had developed multimorbidity ( P &lt; 0.0001). After 10 years, 37.0% of AAV patients and 17.3% of controls were reported to have multimorbidity ( P &lt; 0.0001). Multimorbidity was associated with disproportionate increases in health care expenditures in AAV patients. Health care expenditure was highest for AAV patients with ≥3 morbidities (3.89‐fold increase in costs, 95% CI 2.83–5.31; P &lt; 0.001 versus no morbidities). Conclusion These findings emphasize the importance of holistic care in patients with AAV, and may identify a potentially critical opportunity to consider early screening.
Clinical response to immune checkpoint inhibition in patients with advanced skin cancers receiving concurrent ruxolitinib therapy for haematological malignancy
Authors: N. Haddad, J. Delyon, S. Trabelsi Messai, F. Herms, M.T. Leccia, C. Lebbe, J. Whitney, S. Bhatia, N. Basset‐Seguin
Journal: British Journal of Dermatology (2020)
Abstract NT-120: KNOCKOUT OF MTF1 RESULTS IN THE INHIBITION OF EMT IN OVARIAN CANCER CELLS
Authors: Guannan Zhao, Lawrence M Pfeffer Junming Yue
Journal: Clinical Cancer Research (2019)

Abstract Due to peritoneal metastasis and frequent recurrence, ovarian cancer has the highest mortality among gynecological cancers. Epithelial to mesenchymal transition (EMT) contributes to ovarian tumor metastasis. In this study, we report for the first time that metal regulatory transcription factor 1 (MTF1) was upregulated in ovarian cancer, and its high expression was associated with poor patient survival and disease relapse. Knockout of MTF1 using lentiviral CRISPR/Cas9 nickase vector-mediated gene editing inhibited EMT by upregulating epithelial cell markers E-cadherin and cytokeratin 7, and downregulating mesenchymal markers Snai2 and β-catenin in ovarian cancer SKOV3 and OVCAR3 cells. Loss of MTF1 reduced cell proliferation, migration, and invasion in both SKOV3 and OVCAR3 cells. Knockout of MTF1 upregulated the expression of the KLF4 transcription factor, and attenuated two cellular survival pathways, ERK1/2 and AKT. Our studies demonstrated that MTF1 plays an oncogenic role and contributes to ovarian tumor metastasis by promoting EMT. MTF1 may be a novel biomarker for early diagnosis as well as a drug target for clinical therapy. Citation Format: Guannan Zhao, Lawrence M Pfeffer Junming Yue. KNOCKOUT OF MTF1 RESULTS IN THE INHIBITION OF EMT IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-120.
Haploinsufficiency of<i>Tmem43</i>in cardiac myocytes activates the DNA damage response pathway leading to a late-onset senescence-associated pro-fibrotic cardiomyopathy
Authors: Leila Rouhi, Sirisha M Cheedipudi, Suet Nee Chen, Siyang Fan, Raffaella Lombardi, Xiaofan Chen, Cristian Coarfa, Matthew J Robertson, Priyatansh Gurha, Ali J Marian
Journal: Cardiovascular Research (2020)

Arrhythmogenic cardiomyopathy (ACM) encompasses a genetically heterogeneous group of myocardial diseases whose manifestations are sudden cardiac death, cardiac arrhythmias, heart failure, and in a subset fibro-adipogenic infiltration of the myocardium. Mutations in the TMEM43 gene, encoding transmembrane protein 43 (TMEM43) are known to cause ACM. The purpose of the study was to gain insights into the molecular pathogenesis of ACM caused by TMEM43 haploinsufficiency.
Association between Kawasaki Disease and Prenatal Exposure to Ambient and Industrial Air Pollution: A Population-Based Cohort Study
Authors: Stephane Buteau, Sabrina Belkaibech, Marianne Bilodeau-Bertrand, Marianne Hatzopoulou, Audrey Smargiassi, Nathalie Auger
Journal: Environmental Health Perspectives (2020)

Environmental factors may contribute to the development of Kawasaki disease in children, but prenatal environmental exposures are understudied.We used a population-based cohort to investigate whether prenatal exposure to outdoor air pollution is associated with the incidence of Kawasaki disease in childhood.We performed a longitudinal cohort study of all children born in Quebec, Canada, between 2006 and 2012. Children were followed for Kawasaki disease from birth until 31 March 2018. We assigned prenatal air pollutant exposure according to the residential postal code at birth. The main exposure was annual average concentration of ambient fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2) from satellite-based estimates and land-use regression models. As secondary exposures, we considered industrial PM2.5, NO2, and sulfur dioxide (SO2) emissions estimated from dispersion models. We estimated hazard ratios (HRs) using Cox proportional hazards models, adjusted for maternal age, parity, sex, multiple birth, maternal smoking during pregnancy, socioeconomic status, birth year, and rural residence. We considered single and multipollutant models. We performed several sensitivity analyses, including assessing modifying effects of maternal comorbidities (e.g., diabetes, preeclampsia).The cohort comprised 505,336 children, including 539 with Kawasaki disease. HRs for each interquartile range increase in ambient air pollution were 1.16 (95% CI: 0.96, 1.39) for PM2.5 and 1.12 (95% CI: 0.96, 1.31) for NO2. For industrial air pollution, HRs were 1.07 (95% CI: 1.01, 1.13) for SO2, 1.09 (95% CI: 0.99, 1.20) for NO2, and 1.01 (95% CI: 0.97, 1.05) for PM2.5. In multipollutant models, associations for ambient PM2.5 and NO2 (i.e., from all sources) were robust to adjustment for industrial pollution, and vice versa.In this population-based cohort study, both prenatal exposure to ambient and industrial air pollution were associated with the incidence of Kawasaki disease in childhood. Further studies are needed to consolidate the observed associations. https://doi.org/10.1289/EHP6920.
Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern
Authors: Mariola Olkowicz, Marta Tomczyk, Janusz Debski, Urszula Tyrankiewicz, Kamil Przyborowski, Tomasz Borkowski, Magdalena Zabielska-Kaczorowska, Natalia Szupryczynska, Zdzislaw Kochan, Marta Smeda, Michal Dadlez, Stefan Chlopicki, Ryszard T. Smolenski
Journal: Metabolism (2020)
Epidermal growth factor receptor (EGFR) gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation
Authors: Wu Zhang, Jim Yun, Oliver Press, Michael Gordon, Nalin Mallik, Dongyun Yang, Susan Groshen, Heinz-Josef Lenz
Journal: Cancer Research (2004)

4747  An association between epidermal growth factor receptor (EGFR) signaling pathway and response of cancer cells to ionizing radiation has been reported. Recently, a variant EGFR gene that has an arginine-to-lysine substitution in the extracellular domain at codon 497 within subdomain IV of EGFR has been identified. In vitro studies show that the variant EGFR (HER1-497K) has attenuated functions in ligand binding, growth stimulation, tyrosine kinase activation and induction of protooncogenes MYC, FOS and JUN. A (CA)n repeat polymorphism in intron 1 of the EGFR gene that alters EGFR expression in-vitro and in-vivo has also been described. Lower EGFR levels are associated with a higher number of CA repeats. In this study we determined both polymorphisms in 92 stage II or III rectal cancer patients treated with adjuvant or neo-adjuvant chemoradiation therapy using PCR-RFLP and a 5’-end 33P-γATP labeled PCR protocol and tested whether both polymorphisms will predict local recurrence in rectal cancer patients treated with chemoradiation. We found patients with EGFR (HER1-497K) AA genotype have a decreased relative risk of local recurrence compared with those with AG genotype or wild type (HER1-497R) GG genotype. Furthermore, Patients with HER1-497 AG or GG genotype combined with CA repeats