tbuckley/cabot-search huggingface dataset:
Pulmonary vascular system: A vulnerable target for COVID‐19
Authors: Jiayuan Ai, Weiqi Hong, Min Wu, Xiawei Wei
Journal: MedComm (2021)

Abstract The number of coronavirus disease 2019 (COVID‐19) cases has been increasing significantly, and the disease has evolved into a global pandemic, posing an unprecedented challenge to the healthcare community. Angiotensin‐converting enzyme 2, the binding and entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in hosts, is also expressed on pulmonary vascular endothelium; thus, pulmonary vasculature is a potential target in COVID‐19. Indeed, pulmonary vascular thickening is observed by early clinical imaging, implying a tropism of SARS‐CoV‐2 for pulmonary vasculature. Recent studies reported that COVID‐19 is associated with vascular endothelial damage and dysfunction along with inflammation, coagulopathy, and microthrombosis; all of these pathologic changes are the hallmarks of pulmonary vascular diseases. Notwithstanding the not fully elucidated effects of COVID‐19 on pulmonary vasculature, the vascular endotheliopathy that occurs after infection is attributed to direct infection and indirect damage mainly caused by renin‐angiotensin‐aldosterone system imbalance, coagulation cascade, oxidative stress, immune dysregulation, and intussusceptive angiogenesis. Degradation of endothelial glycocalyx exposes endothelial cell (EC) surface receptors to the vascular lumen, which renders pulmonary ECs more susceptible to SARS‐CoV‐2 infection. The present article reviews the potential pulmonary vascular pathophysiology and clinical presentations in COVID‐19 to provide a basis for clinicians and scientists, providing insights into the development of therapeutic strategies targeting pulmonary vasculature.
FP12.02 Pembrolizumab as a Monotherapy or in Combination With Platinum-Based Chemotherapy in NSCLC: Correlation With Blood Biomarkers
Authors: L. Holtzman, M. Moskovitz, D. Urban, M. Wollner, H. Nechushtan, D. Rainhorn, A. Zer, T. Shochat, J. Bar, Y. Rottenberg, E. Dudnik
Journal: Journal of Thoracic Oncology (2021)
Microfluidic Arrays of Breast Tumor Spheroids for Drug Screening and Personalized Cancer Therapies
Authors: Elisabeth Prince, Sina Kheiri, Yihe Wang, Fei Xu, Jennifer Cruickshank, Valentina Topolskaia, Huachen Tao, Edmond W. K. Young, Alison. P. McGuigan, David W. Cescon, Eugenia Kumacheva
Journal: Advanced Healthcare Materials (2021)

One of the obstacles limiting progress in the development of effective cancer therapies is the shortage of preclinical models that capture the dynamic nature of tumor microenvironments. Interstitial flow strongly impacts tumor response to chemotherapy; however, conventional in vitro cancer models largely disregard this key feature. Here, a proof of principle microfluidic platform for the generation of large arrays of breast tumor spheroids that are grown under close-to-physiological flow in a biomimetic hydrogel is reported. This cancer spheroids-on-a-chip model is used for time- and labor-efficient studies of the effects of drug dose and supply rate on the chemosensitivity of breast tumor spheroids. The capability to grow large arrays of tumor spheroids from patient-derived cells of different breast cancer subtypes is shown, and the correlation between in vivo drug efficacy and on-chip spheroid drug response is demonstrated. The proposed platform can serve as an in vitro preclinical model for the development of personalized cancer therapies and effective screening of new anticancer drugs.
Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial
Authors: Courtney D DiNardo, Andre C Schuh, Eytan M Stein, Pau Montesinos, Andrew H Wei, Stéphane de Botton, Amer M Zeidan, Amir T Fathi, Hagop M Kantarjian, John M Bennett, Mark G Frattini, Patricia Martin-Regueira, Frederik Lersch, Jing Gong, Maroof Hasan, Paresh Vyas, Hartmut Döhner
Journal: The Lancet Oncology (2021)
Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease
Authors: Alice Taubes, Phil Nova, Kelly A. Zalocusky, Idit Kosti, Mesude Bicak, Misha Y. Zilberter, Yanxia Hao, Seo Yeon Yoon, Tomiko Oskotsky, Silvia Pineda, Bin Chen, Emily A. Aery Jones, Krishna Choudhary, Brian Grone, Maureen E. Balestra, Fayzan Chaudhry, Ishan Paranjpe, Jessica De Freitas, Nicole Koutsodendris, Nuo Chen, Celine Wang, William Chang, Alice An, Benjamin S. Glicksberg, Marina Sirota, Yadong Huang
Journal: Nature Aging (2021)
MA09.07 Genomic Landscape and Clinical Outcomes With Immune Checkpoint Inhibitors in NF1-Mutant NSCLC
Authors: M. Negrao, S. Schmidt, D. Sui, R. Sharaf, H. Kemp, W. Lewis, C. Bristow, G. Frampton, J. Lee, J. Heymach, D. Gibbons, L. Albacker, F. Skoulidis
Journal: Journal of Thoracic Oncology (2021)
Mechanisms of resistance to docetaxel in human breast cancer cell lines
Authors: George E. Duran, Yan C. Wang, Brian Francisco, Branimir I. Sikic
Journal: Cancer Research (2004)

1214  We derived taxane-resistant variants from four human breast cancer cell lines (MCF-7, BT-549, MDA-MB-231 and T-47D) by continuous exposure to docetaxel. Rt-PCR assays indicated that 4/4 of these variants were positive for the multidrug resistance gene MDR1. Expression of its gene product, P-glycoprotein (P-gp), was confirmed in each by immunoblotting with the monoclonal antibody C219 and by FACS analysis using UIC2/Texas Red staining. MDR1-positive variants accumulated less rhodamine 123 (Rh123) by FACS, but incubation with the P-gp inhibitor PSC 833 (PSC) corrected these to wild-type levels. Further, PSC co-incubation completely restored the sensitivity to known P-gp substrates using the MTT colorimetric cell proliferation assay. In order to study non-MDR1 mechanisms of taxane resistance, we derived another set of variants by co-selecting with docetaxel in the presence of PSC. Rt-PCR assays indicated that all of these docetaxel-PSC variants were negative for MDR1 following 35 cycles of amplification. These variants were negative for P-gp by immunoblotting, and they accumulated equivalent levels of Rh123 relative to wild-type cell lines by FACS. We screened all docetaxel variants and found no mutations in the taxane cellular target, the Class I β-tubulin isoform (M40), by sequencing PCR-amplified products. PSC suppresses the MDR1 resistance phenotype following taxane selection, and the resistance observed is unlikely to be due to transporter-mediated mechanisms. Genomic profiling of all taxane variants by high-density microarrays is on-going to identify candidate genes which may determine docetaxel sensitivity in breast cancer cell lines. Supported by a grant from Aventis Pharmaceuticals.
Conjunctivitis in adult patients with moderate‐to‐severe atopic dermatitis: results from five tralokinumab clinical trials
Authors: A. Wollenberg, L.A. Beck, M. de Bruin Weller, E.L. Simpson, S. Imafuku, M. Boguniewicz, R. Zachariae, C.K. Olsen, J.P. Thyssen
Journal: British Journal of Dermatology (2021)

Tralokinumab, a fully human IgG4 monoclonal antibody that specifically binds with high affinity to interleukin‐13, effectively reduces moderate‐to‐severe atopic dermatitis (AD) when given every 2 weeks. The incidence of conjunctivitis is elevated vs. placebo, but severity and aetiology have not been examined. To analyse conjunctivitis data recorded in five randomized, placebo‐controlled trials of tralokinumab in adult patients with moderate‐to‐severe AD. Overall, 2285 adults with AD were studied up to 16 weeks. Cochran–Mantel–Haenszel weights were applied to calculate the adjusted incidence of adverse events. The incidence of conjunctivitis was higher (7·5%) with tralokinumab than with placebo (3·2%). Most events were mild or moderate in severity, and 78·6% and 73·9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1·4%) events led to the permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline AD, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. This analysis reports events up to week 16 only, with limited confirmation of conjunctivitis and its aetiology by an ophthalmologist, and insufficient reporting of ophthalmic treatments. Treatment with tralokinumab was associated with an increased incidence of conjunctivitis vs. placebo, but these cases were mostly mild and transient.
Requirement of the estrogen receptor-α and aromatic hydrocarbon receptor in transcriptional regulation of BRCA-1
Authors: Chi-Fan Ku, Sherif Morgan, Donato F. Romagnolo
Journal: Cancer Research (2005)

6123  Of the hereditary breast cancers, only 40-45% can be attributed to mutations in the BRCA-1 coding sequence. While the coding sequence is rarely mutated in sporadic breast cancer, reduced levels of wild-type BRCA-1 protein are often found in these tumors suggesting that non-mutational events, such as environmental insults may lower the expression of BRCA-1. Our investigations of the BRCA-1 promoter revealed consensus sequences for activator protein-1 (AP-1 = 5’-CTGAG-3’) and xenobiotic responsive element (XRE = 5’-GCGTG-3’). In transient transfection studies, we found that estrogen induced transcription activity of a 1.7 kb BRCA-1 promoter fragment containing the transcriptional start sites for exon 1A and 1B. Using chromatin immunoprecipitation (ChIP) assays, we found that estrogen stimulated the recruitment of c-Jun, FosB, Fra-2 and the estrogen receptor-α (ERα) and the cofactor p300 at a 237 bp promoter fragment upstream of exon 1B comprising the AP-1 element. The cotreatment with tamoxifen antagonized the recruitment of p300 and ERα to this region. Results of electromobility shift assays mapped the binding site for the ERα to a 32 bp region (-46 to -14) comprising the candidate AP-1 motif. These results support a model in which estrogen activation of BRCA-1 transcription requires the formation of an AP-1/ERα complex containing the cofactor p300. In addition, site-directed mutagenesis of the XRE site resulted in loss of estrogen stimulation of BRCA-1 expression suggesting that the XRE may act as a positive regulator of estrogen regulation of BRCA-1. ChIP assays confirmed the recruitment of the aromatic hydrocarbon receptor (AhR) to a promoter fragment containing the XRE. The recruitment of the ERα and AhR respectively to the AP-1 and XRE sites is time dependent and follows a cyclical pattern. We propose that the unliganded AhR is required for estrogen induction of BRCA-1 transcription. Conversely, ligands of the AhR may repress BRCA-1 transcription possibly by stimulating competition of the AhR with the ERα for common transcription factors. A potential contribution of these findings is an increased understanding of the mechanistic pathway in which ligands of the AhR can influence BRCA-1 expression and contribute to the etiology of sporadic breast cancer.
Analysis of Respiratory Fluoroquinolones and the Risk of Sudden Cardiac Death Among Patients Receiving Hemodialysis
Authors: Magdalene M. Assimon, Patrick H. Pun, Lily (Chin-Hua) Wang, Sana M. Al-Khatib, M. Alan Brookhart, David J. Weber, Wolfgang C. Winkelmayer, Jennifer E. Flythe
Journal: JAMA Cardiology (2021)

Respiratory fluoroquinolone antibiotics are some of the most common medications with QT interval-prolonging potential prescribed to patients with hemodialysis-dependent kidney failure-individuals who have a very high risk of sudden cardiac death (SCD). To date, there have been no large-scale, population-specific studies evaluating the cardiac safety of respiratory fluoroquinolones in the hemodialysis population.To investigate the cardiac safety of respiratory fluoroquinolones among individuals with hemodialysis-dependent kidney failure.A retrospective cohort study examining safety using an active comparator new-user design was conducted using administrative claims data from a US-wide kidney failure registry from January 1, 2007, to December 31, 2016, including 264 968 Medicare beneficiaries receiving in-center maintenance hemodialysis. Data analysis was performed from January 4 to August 16, 2021.Respiratory fluoroquinolone (levofloxacin or moxifloxacin) vs amoxicillin-based (amoxicillin or amoxicillin with clavulanic acid) antibiotic treatment.Sudden cardiac death within 5 days of outpatient initiation of a study antibiotic. Inverse probability of treatment-weighted survival models to estimate hazard ratios (HRs), risk differences (RDs), and corresponding 95% CIs. Death due to a cause other than SCD was treated as a competing event. Fracture was considered as a negative control outcome.The study cohort included 264 968 unique in-center hemodialysis patients and 626 322 study antibiotic treatment episodes: 251 726 respiratory fluoroquinolone treatment episodes (40.2%) and 374 596 amoxicillin-based treatment episodes (59.8%). Of the 264 968 patients, 135 236 (51.0%) were men, and the mean (SD) age was 61 (15) years. Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was associated with a higher relative and absolute 5-day risk of SCD (weighted HR, 1.95; 95% CI, 1.57-2.41; and weighted RD per 100 000 treatment episodes, 44.0; 95% CI, 31.0-59.2). Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was not associated with the 5-day risk of fracture.In this study, compared with amoxicillin-based antibiotic treatment, respiratory fluoroquinolone treatment was associated with a higher short-term risk of SCD among patients with hemodialysis-dependent kidney failure. This finding suggests that decisions between the use of respiratory fluoroquinolones and amoxicillin-based antibiotics should be individualized, with prescribers considering both the clinical benefits and potential cardiac risks.
Perceptions and experiences of individuals at-risk of rheumatoid arthritis (RA) knowing about their risk of developing RA and being offered preventive treatment: systematic review and thematic synthesis of qualitative studies
Authors: Heidi J Siddle, Lara S Chapman, Kulveer Mankia, Codruța Zăbălan, Marios Kouloumas, Karim Raza, Marie Falahee, Joel Kerry, Andreas Kerschbaumer, Daniel Aletaha, Paul Emery, Suzanne H Richards
Journal: Annals of the Rheumatic Diseases (2021)

Objectives There is increasing interest in identifying individuals at-risk of rheumatoid arthritis (RA) and initiating early treatment to prevent or delay the onset of arthritis. We aimed to describe the perceptions and experiences of at-risk individuals and to inform the conduct of clinical trials and studies, and clinical practice. Methods A systematic review and thematic synthesis of qualitative studies was conducted. Two review authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist and assessed confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation–Confidence in Evidence from Reviews of Qualitative Research approach. Results Seven studies involving 115 individuals at-risk of developing RA were included. Three major themes (seven subthemes) were identified: understanding the risk of developing RA (knowledge of RA and identification of potential risk factors); preventive interventions to reduce the risk of developing RA (understanding the value and role of preventive interventions, and engagement with preventive interventions); and perceptions of predictive testing for RA (benefits of predictive testing, decision to undertake predictive testing and concerns about predictive testing). Moderate confidence in most review findings was evident. Conclusion While there are clear benefits in informing individuals at-risk of RA about their risk following predictive testing and offering preventive treatment, there are potential barriers to engagement, intensified by the burden of uncertainty. Identification of the optimum approaches for presenting risk information, including the risks and benefits of engaging with preventive interventions, is urgently needed to support individuals at-risk of RA in their decision making. PROSPERO registration number CRD42021236034.
Non-obese non-alcoholic fatty liver disease (NAFLD) in Asia: an international registry study
Authors: Eunice Xiang-Xuan Tan, Jonathan Wei-Jie Lee, Nur Halisah Jumat, Wah-Kheong Chan, Sombat Treeprasertsuk, George Boon-Bee Goh, Jian-Gao Fan, Myeong Jun Song, Phunchai Charatcharoenwitthaya, Ajay Duseja, Kento Imajo, Atsushi Nakajima, Yosuke Seki, Kazunori Kasama, Satoru Kakizaki, Laurentius A. Lesmana, Kenneth I. Zheng, Ming-Hua Zheng, Calvin J. Koh, Khek-Yu Ho, Khean-Lee Goh, Vincent Wai-Sun Wong, Yock-Young Dan
Journal: Metabolism (2021)

A significant proportion of the non-alcoholic fatty liver disease (NAFLD) population is non-obese. Prior studies reporting the severity of NAFLD amongst non-obese patients were heterogenous. Our study, using data from the largest biopsy-proven NAFLD international registry within Asia, aims to characterize the demographic, metabolic and histological differences between non-obese and obese NAFLD patients.1812 biopsy-proven NAFLD patients across nine countries in Asia assessed between 2006 and 2019 were pooled into a curated clinical registry. Demographic, metabolic and histological differences between non-obese and obese NAFLD patients were evaluated. The performance of Fibrosis-4 index for liver fibrosis (FIB-4) and NAFLD fibrosis score (NFS) to identify advanced liver disease across the varying obesity subgroups was compared. A random forest analysis was performed to identify novel predictors of fibrosis and steatohepatitis in non-obese patients.One-fifth (21.6%) of NAFLD patients were non-obese. Non-obese NAFLD patients had lower proportions of NASH (50.5% vs 56.5%, p = 0.033) and advanced fibrosis (14.0% vs 18.7%, p = 0.033). Metabolic syndrome in non-obese individuals was associated with NASH (OR 1.59, 95% CI 1.01-2.54, p = 0.047) and advanced fibrosis (OR 1.88, 95% CI 0.99-3.54, p = 0.051). FIB-4 performed better than the NFS score (AUROC 81.5% vs 73.7%, p < 0.001) when classifying patients with F2-4 fibrosis amongst non-obese NAFLD patients. Haemoglobin, GGT, waist circumference and cholesterol are additional variables found on random forest analysis useful for identifying non-obese NAFLD patients with advanced liver disease.A substantial proportion of non-obese NAFLD patients has NASH or advanced fibrosis. FIB-4, compared to NFS better identifies non-obese NAFLD patients with advanced liver disease. Serum GGT, cholesterol, haemoglobin and waist circumference, which are neither components of NFS nor FIB-4, are important biomarkers for advanced liver disease in non-obese patients.
P14.03 Vibostolimab Plus Pembrolizumab With/Without Docetaxel vs Docetaxel in NSCLC After Platinum Chemotherapy and Immunotherapy
Authors: S. Peters, D.H. Lee, R. Ramlau, B. Halmos, C. Schumann, D. Planchard, N. Bhagwati, Q. Chen, D. Kush, S. Novello
Journal: Journal of Thoracic Oncology (2021)
FP03.04 Dasatinib Improves the Antitumor Activity of Anti-PD-1 in NSCLC Models by Inhibiting Treg Conversion and Proliferation
Authors: E. Redin, I. Garmendia, T. Lozano, D. Serrano, Y. Senent, M. Redrado, M. Villalba, C.E. De Andrea, F. Exposito, D. Ajona, S. Ortiz-Espinosa, A. Remirez, C. Bertolo, C. Sainz, J.M. García-Pedrero, R. Pio, J.J. Lasarte, J. Agorreta, L. Montuenga, A. Calvo
Journal: Journal of Thoracic Oncology (2021)
A Novel Treatment Strategy for Patients with Intermediate-Stage HCC Who Are Not Suitable for TACE: Upfront Systemic Therapy Followed by Curative Conversion
Authors: Masatoshi Kudo
Journal: Liver Cancer (2021)

achievement of marked tumor shrinkage," which differs from the treatment concept for other types of advanced cancer or advanced HCC.Upfront Systemic Therapy with Subsequent Locoregional Therapy/Resection in Intermediate-Stage HCC
P10.04 Immunotherapy-Treated Non-Small Cell Lung Cancer Patients With Sensitizing Gene Alterations: A Real World Survival Analysis
Authors: L. Khaddour, C. Zhang, F. Ali, S. Gadgeel, E. Tadesse, M. Thompson, D. Reding, J. Treisman, A. Berry, M. Izano, C. Sweetnam, A. Stafford, F. Wolf, T. Brown, I. Rybkin
Journal: Journal of Thoracic Oncology (2021)
SARS-CoV-2 Infection among Nursing Home Residents
Authors: Elizabeth M White, Vincent Mor
Journal: New England Journal of Medicine (2021)

Infection among Nursing Home ResidentsTo the Editor: White et al. (July 29 issue) 1 provided interesting data on the effectiveness of messenger RNA vaccines in reducing the incidence of SARS-CoV-2 infection in a vulnerable nursing home population.The study showed that there were similar decreases in SARS-CoV-2 infection (asymptomatic and symptomatic) in the vaccinated population and in the unvaccinated population.The authors attributed the decrease in infection in the vaccinated group to vaccine protection and attributed the similar decrease in the unvaccinated group to robust vaccine coverage among residents and staff, together with the use of masks and infection-control measures.This appears to be in contradiction to the authors' description of Table S3 in the Supplementary Appendix of their letter (available at NEJM .org),which indicated that they found no consistent relationship between the incidence of infection among residents and vaccination rates among the staff (a finding also acknowledged in the text of their letter).The fact that the residents in the vaccinated group were also using masks and following infection-control measures and the fact that the decline in infection was similar in the two groups raise the question of how much added protective effect was provided by vaccines in this study.The efficacy of masks in providing protection against infection and death is well documented. 2-4It is of note that both hospitalizations mentioned in the footnote of Table 1 in their letter were in the vaccinated group.