tbuckley/cabot-search huggingface dataset:
Characterization of high TIL breast cancers reveals a prognostic and functionally distinct tissue-resident memory subpopulation
Authors: P Savas, B Virassamy, C Ye, A Salim, CP Mintoff, F Caramia, R Salgado, ZL Teo, S Dushyanthen, A Byrne, SJ Luen, SB Fox, TP Speed, LK Mackay, PJ Neeson, S Loi
Journal: Cancer Research (2019)
Abstract 11918: The Hispanic Paradox in County-level Obesity Prevalence
Authors: Areli Valencia, Bongeka Z Zuma, Gabriel M Knight, David Scheinker, Ashish Sarraju, Fatima Rodriguez
Journal: Circulation (2019)

Introduction: The Hispanic paradox refers to an epidemiological phenomenon where Hispanics experience better health outcomes than expected despite more adverse socioeconomic factors. Prior work has...
Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study
Authors: Wassim Abida, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog, Alan H. Bryce, Ray McDermott, Francesco Ricci, Julie Rowe, Jingsong Zhang, Josep Maria Piulats, Karim Fizazi, Axel S. Merseburger, Celestia S. Higano, Laurence E. Krieger, Charles J. Ryan, Felix Y. Feng, Andrew D. Simmons, Andrea Loehr, Darrin Despain, Melanie Dowson, Foad Green, Simon P. Watkins, Tony Golsorkhi, Simon Chowdhury
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. Patients and Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). Results: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition. See related commentary by Sokolova et al., p. 2439
Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease
Authors: Cheng-Kai Huang, Sabine Kafert-Kasting, Thomas Thum
Journal: Circulation Research (2020)

RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.
Comparison of iRECIST versus RECIST V.1.1 in patients treated with an anti-PD-1 or PD-L1 antibody: pooled FDA analysis
Authors: Flora Mulkey, Marc R Theoret, Patricia Keegan, Richard Pazdur, Rajeshwari Sridhara
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Response criteria developed when cytotoxic chemotherapy was the predominant therapeutic modality to treat patients with cancer, do not capture the full spectrum of tumor response patterns observed with anti-PD-1/PD-L1 antibody treatment. iRECIST was developed to capture both typical and atypical response patterns. Methods Target, non-target, and new lesion measurements for 7920 patients receiving anti-PD-1/PD-L1 antibody (n=4751) or anti-CTLA-4 antibody (n=613) or undergoing chemotherapy (n=2556) from 14 randomized controlled trials submitted to the U.S. Food and Drug Administration were used to calculate the best overall response, objective response rate and progression-free survival (PFS) per iRECIST (iPFS) and Response Evaluation Criteria in Solid Tumours (RECIST). Associations between either PFS or iPFS and overall survival (OS) were evaluated using the method adopted by Oba et al .1 Results Among 4751 anti-PD-1/PD-L1-antibody treated patients, 31.5% (95% CI 30.2% to 32.9%) and 30.5% (95% CI 29.2% to 31.8%) achieved an objective response per iRECIST or RECIST V.1.1, respectively. OS among the 48 patients with objective response by iRECIST only resembled that in patients with responses per RECIST V.1.1. The association between iPFS and OS was R 2 =0.277 and that between PFS and OS was R 2 =0.260. Conclusions Patients treated with anti-PD-1/PD-L1 antibodies with initial progressive disease per RECIST V.1.1 can experience prolonged stability or substantial reductions in tumor burden per iRECIST, atypical response patterns associated with prolonged OS. In the subgroup of patients with atypical responses, the application of iRECIST retrospectively in the evaluation of the objective response durations and the magnitude of PFS results in large differences compared with RECIST V.1.1. For the overall pooled population, the magnitude of these differences was modest, although a large proportion of patients had no further tumor assessments following RECIST V.1.1-defined progressive disease. Prospective studies employing iRECIST will be required to assess whether this response criteria more fully captures the benefit of immune checkpoint inhibitors.
Magnetic resonance (MR) safety and compatibility of a novel iron bioresorbable scaffold
Authors: Dong Bian, Li Qin, Wenjiao Lin, Danni Shen, Haiping Qi, Xiaoli Shi, Gui Zhang, Hongwei Liu, Han Yang, Jin Wang, Deyuan Zhang, Yufeng Zheng
Journal: Bioactive Materials (2020)

Fully bioresorbable scaffolds have been designed to overcome the limitations of traditional drug-eluting stents (DESs), which permanently cage the native vessel wall and pose possible complications. The ultrathin-strut designed sirolimus-eluting iron bioresorbable coronary scaffold system (IBS) shows comparable mechanical properties to traditional DESs and exhibits an adaptive degradation profile during target vessel healing, which makes it a promising candidate in all-comers patient population. For implanted medical devices, magnetic resonance (MR) imaging properties, including MR safety and compatibility, should be evaluated before its clinical use, especially for devices with intrinsic ferromagnetism. In this study, MR safety and compatibility of the IBS scaffold were evaluated based on a series of well-designed in-vitro, ex-vivo and in-vivo experiments, considering possible risks, including scaffold movement, over-heating, image artifact, and possible vessel injury, under typical MR condition. Traditional ASTM standards for MR safety and compatibility evaluation of intravascular devices were referred, but not only limited to that. The unique time-relevant MR properties of bioresorbable scaffolds were also discussed. Possible forces imposed on the scaffold during MR scanning and MR image artifacts gradually decreased along with scaffold degradation/absorption. Rigorous experiments designed based on a scientifically based rationale revealed that the IBS scaffold is MR conditional, though not MR compatible before complete absorption. The methodology used in the present study can give insight into the MR evaluation of magnetic scaffolds (bioresorbable) or stents (permanent).
Correction to: m6A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma
Authors: Li Liu, Jing Wang, Guifeng Sun, Qiong Wu, Ji Ma, Xin Zhang, Nan Huang, Zhixuan Bian, Song Gu, Min Xu, Minzhi Yin, Fenyong Sun, Qiuhui Pan
Journal: Molecular Cancer (2020)

After the publication of this work [1], the authors noticed that the affiliations were incorrectly provided. Updated affiliation section is provided in this paper.
Relationship between Symptoms, Exacerbations, and Treatment Response in Bronchiectasis
Authors: Yong-hua Gao, Hani Abo Leyah, Simon Finch, Mike Lonergan, Stefano Aliberti, Anthony De Soyza, Thomas C. Fardon, Gregory Tino, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives.Objectives: We hypothesized that patients with greater symptoms would be at higher risk of exacerbations and therefore that a treatment aimed at reducing daily symptoms would also reduce exacerbations in highly symptomatic patients.Methods: Our study comprised an observational cohort of 333 patients from the East of Scotland (2012–2016). Either symptoms were modeled as a continuous variable or patients were classified as having high, moderate, or low symptom burden (>70, 40–70, and <40 using the St. George’s Respiratory Questionnaire symptom score). The hypothesis that exacerbation reductions would only be evident in highly symptomatic patients was tested in a post hoc analysis of a randomized trial of inhaled dry powder mannitol (N = 461 patients).Measurements and Main Results: In the observational cohort, daily symptoms were a significant predictor of future exacerbations (rate ratio [RR], 1.10; 95% confidence interval [CI], 1.03–1.17; P = 0.005). Patients with higher symptom scores had higher exacerbation rates (RR, 1.74; 95% CI, 1.12–2.72; P = 0.01) over 12-month follow-up than those with lower symptoms. Inhaled mannitol treatment improved the time to first exacerbation (hazard ratio, 0.56; 95% CI, 0.40–0.77; P < 0.001), and the proportion of patients remaining exacerbation free for 12 months of treatment was higher in the mannitol group (32.7% vs. 14.6%; RR, 2.84; 95% CI, 1.40–5.76; P = 0.003), but only in highly symptomatic patients. In contrast, no benefit was evident in patients with lower symptom burden.Conclusions: Highly symptomatic patients have increased risk of exacerbations, and exacerbation benefit with inhaled mannitol was only evident in patients with high symptom burden.
Abstract 15799: Increased Oxidative Stress Marker During Acute Exercise Predicts the Poor Prognosis in Patients With Heart Failure
Authors: Atsushi Shibata, Akihisa Hanatani, Yumi Yamaguchi, Shinichi Iwata, Yasukatsu Izumi, Shoichi Ehara, Yasuhiro Izumiya, Minoru Yoshiyama
Journal: Circulation (2018)

Introduction: Reactive oxygen species (ROS) play important roles in the development and progression of heart failure (HF). Exercise therapy is established intervention for the patients with HF. How...
The effect of long-term exercise training on mortality and CVD-events in older adults - the Generation 100 study
Authors: Dorthe Stensvold, Hallgeir Viken, Jorunn Helbostad, Stian Lydersen, Asbjorn Stoylen, Jan Erik Ingebrigtsen, Sigmund Alfred Anderssen, Maria Fiatarone Singh, Havard Dalen, Jeff Coombes, Sigurd Loe Steinshamn, Oivind Rognmo, Ulrik Wisloff
Journal: Circulation (2019)
Type-2 Cannabinoid Receptors Maintain Epithelial Barrier in Aspirin-Exacerbated Respiratory Disease
Authors: Joshua Levy, Lionel Watkins, Sarah Mashburn, Lauren Roland, Monica Battle, Samuel Molina, Sarah Wise, John DelGaudio, Bob Moore, David Guidot, Michael Koval
Journal: Journal of Allergy and Clinical Immunology (2020)
The Anatomy and Physiology of Claustrum-Cortex Interactions
Authors: Jesse Jackson, Jared B. Smith, Albert K. Lee
Journal: Annual Review of Neuroscience (2020)

The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type–specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.
Association of Dual Decline in Memory and Gait Speed With Risk for Dementia Among Adults Older Than 60 Years
Authors: Qu Tian, Susan M. Resnick, Michelle M. Mielke, Kristine Yaffe, Lenore J. Launer, Palmi V. Jonsson, Giulia Grande, Anna-Karin Welmer, Erika J. Laukka, Stefania Bandinelli, Antonio Cherubini, Caterina Rosano, Stephen B. Kritchevsky, Eleanor M. Simonsick, Stephanie A. Studenski, Luigi Ferrucci
Journal: JAMA Network Open (2020)

Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia.
After PCI and 3 mo of DAPT, ticagrelor for 12 mo reduced bleeding vs continued DAPT and did not increase ischemic events
Authors: KoKo Aung, Thwe Htay
Journal: Annals of Internal Medicine (2020)

ACP Journal Club18 February 2020After PCI and 3 mo of DAPT, ticagrelor for 12 mo reduced bleeding vs continued DAPT and did not increase ischemic eventsKoKo Aung, MD, MPH, Thwe Htay, MDKoKo Aung, MD, MPHPaul L. Foster School of Medicine, El Paso, Texas, USA (K.A., T.H.)Search for more papers by this author, Thwe Htay, MDPaul L. Foster School of Medicine, El Paso, Texas, USA (K.A., T.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202002180-019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 2019;381:2032-42. https://pubmed.ncbi.nlm.nih.gov/31556978Clinical Impact RatingsGIM/FP/GP: Hospitalists: Cardiology: References1 Watanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial. JAMA. 2019;321:2414-27. [PMID: 31237644] Google Scholar2 Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA. 2019;321:2428-37. [PMID: 31237645] Google Scholar Author, Article, and Disclosure InformationAffiliations: Paul L. Foster School of Medicine, El Paso, Texas, USA (K.A., T.H.)Disclosures: The commentators have disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3039.This article was published at Annals.org on 4 February 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 February 2020Volume 172, Issue 4Page: JC19KeywordsAspirinHemorrhageHospitalistsHospitalizationsIschemiaMyocardial infarctionPercutaneous coronary interventionShockSt segment elevation myocardial infarctionStent implantation ePublished: 18 February 2020 Issue Published: 18 February 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Genomic alterations in visceral versus nonvisceral “metastatic” site tumor tissue in metastatic prostate cancer (mPC).
Authors: John Esther, Umang Swami, Jonathan Chipman, Taylor Ryan McFarland, Andrew W Hahn, Deepika Sirohi, Prayushi Sharma, Roberto Nussenzveig, Neeraj Agarwal, Benjamin Louis Maughan
Journal: Journal of Clinical Oncology (2020)

167 Background: Men with mPC with visceral metastasis, as compared to non-visceral disease have inferior outcomes regardless of therapy (PMID: 25403629). Herein, we hypothesize that visceral versus non-visceral metastasis sites differ with regards to underlying genomic alterations (GA). These GA possibly drive metastasis to visceral sites and mediate a more aggressive disease. Identifying these GA may guide future trial designs by better stratifying patients and predicting therapy responses. Methods: In this retrospective analysis, inclusion criteria were: diagnosis of mPC and comprehensive genomic profiling of metastatic tissue by CLIA certified lab. Liver and lung were defined as visceral while bone and lymph nodes were defined as non-visceral metastasis. Evaluated GA were p53, RB1, PTEN, AR, TMB, CDK12, SPOP, MYC, MET, BRCA genes, BRAF, ARID1A. Fisher’s Exact Test was used to compare GA in visceral and non-visceral tumor tissue. Results: Overall 54 men with mPC with visceral (n=8) and non-visceral (n=46) metastatic tissue biopsies were evaluated. Visceral biopsies included liver (3) and lung (5). Non-visceral biopsy sites included lymph nodes (33) and bone (13). Men with or without visceral metastasis had similar baseline characteristics (Fisher’s Exact Test and Wilcoxon Rank Test; Table). Visceral tumor tissue had a significantly greater odds of having RB1 mutation [OR = 12.09; 95% CI = (1.12, 178.21); p-value 0.02] as compared to non-visceral tumor tissue. Conclusions: RB1 GA were more common in visceral as compared to non-visceral metastatic sites in mPC. RB1 loss is associated with ineffectiveness to CDK4/6 inhibitors (PMID 26633733). These hypothesis-generating data suggest that men with mPC with visceral metastasis may not optimally benefit by enrollment on CDK4/6 inhibitor trials. BLM, NA: equal contribution.[Table: see text]
The role of small airways on persistent bronchial hyper-responsiveness in school children with asthma
Authors: Sun Hee Choi, Yeong-Ho Rha, Man Yong Han, Youn Ho Shin, Heysung Baek, Seong Cho, Richard Lockey
Journal: Journal of Allergy and Clinical Immunology (2020)

Bronchial hyperresponsiveness (BHR) is a key component of the pathophysiology of asthma. This is a retrospective study at Kyung Hee Hospital, Korea. Children with asthma and methacholine provocation challenge (MPC) at two times (mean, 18±6.5 months) were included. The second MPC was performed 3 months or more after no asthma or medications. Three groups included, according to methacholine PC20 FEV1 on two separate MPC occasions: persistent BHR (no change of BHR, ≤2.0 doubling MP concentration); improved BHR (significant change of BHR, ≥ 2.0 doubling MP concentration or resolution of BHR at the second MPC); no BHR group (no BHR at both MPC). MedCalc (Ostend, Belgium) was used for statistical analysis. 77 children (7.5-11.5 yr) were enrolled: 37 persistent, 25 improved and 15 no BHR. Total eosinophil count (EC) in BHR was higher in the persistent than other groups (252.4 vs 82.2 vs 172.4/uL, respectively, P=0.003). There were no differences in lung parameters at baseline among 3 groups. FEV1/FVC ratio and FEF25-75% at the second MPC were significantly lower in persistent versus other two groups (Z score FEV1/FVC ratio: 1.053 vs -0.249 vs 0.121, P=0.003; Z score FEF25-75%, 0.553 vs 0.354 vs 0.501, P=0.007, each group). Analysis of change between two measurements shows that the improved and no BHR groups lead improvement in FEF25-75%. There was no change in FEF25-75% in the persistent BHR over time (P=0.037). High EC and no improvement of FEF25-75%, a determinant of small airway function, are associated with persistent BHR.
A prospective study of fully covered metal stents for different types of refractory benign biliary strictures
Authors: Tatsuya Sato, Hirofumi Kogure, Yousuke Nakai, Kazunaga Ishigaki, Ryunosuke Hakuta, Kei Saito, Tomotaka Saito, Naminatsu Takahara, Tsuyoshi Hamada, Suguru Mizuno, Minoru Tada, Hiroyuki Isayama, Kazuhiko Koike
Journal: Endoscopy (2020)

While endoscopic management of benign biliary strictures (BBSs) is the standard of care, long-term treatment remains the issue in refractory cases, especially for anastomotic strictures after living-donor liver transplantation (LDLT) and hepaticojejunostomy anastomotic strictures (HJAS). The aim of this prospective study was to evaluate the safety and effectiveness of a fully covered self-expandable metal stent (FCSEMS) for patients with refractory BBSs.Patients with BBSs that were unamenable to endoscopic plastic stent placement with a treatment period of more than 6 months were eligible. An FCSEMS was placed endoscopically and removed after 90 days. In patients with surgically altered anatomy, an FCSEMS was placed using a double-balloon endoscope. The primary outcome was stricture resolution at FCSEMS removal. The secondary outcomes included stricture recurrence and adverse events.A total of 30 patients were enrolled: the causes of their BBSs were anastomotic stricture after LDLT in 13, HJAS in 12, post-cholecystectomy in two, chronic pancreatitis in two, and post-hepatectomy in one. The technical success rate of FCSEMS placement was 100 % and all FCSEMSs were successfully removed. The rate of stricture resolution at FCSEMS removal was 96.6 % (91.7 % in the post-LDLT group and 100 % in the HJAS group). Stricture recurrence occurred in three HJAS patients (10.7 %) during a median follow-up period of 15.6 months. Adverse events were observed in 12.1 %: five cholangitis, one pancreatitis, and one perforation.Temporary placement of an FCSEMS was a feasible and effective treatment option for refractory BBSs, especially for post-LDLT strictures and HJAS.