tbuckley/cabot-search huggingface dataset:
Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival
Authors: Cornelia Volland, Peter Schott, Michael Didié, Jörg Männer, Bernhard Unsöld, Karl Toischer, Carla Schmidt, Henning Urlaub, Katrin Nickels, Ralph Knöll, Albrecht Schmidt, Kaomei Guan, Gerd Hasenfuß, Tim Seidler
Journal: Cardiovascular Research (2019)

Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation.General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis.By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.
Letter to the Editor: The Obsolescence of Sclerotherapy
Authors: Ulrich Thalheimer
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: I read with great interest the recent practice guidance on development of quality measures in cirrhosis.1 I commend the authors for producing a set of measures that will enable health care professionals and service providers to evaluate quality of care and drive improvement. I am, however, somewhat concerned by the inclusion of sclerotherapy in their process measure 11: “Patients with cirrhosis who are found to have bleeding esophageal varices should receive EVL or sclerotherapy at the time of index endoscopy.”1 Endoscopic band ligation was already shown many years ago to be associated with reduced mortality and fewer complications when compared with sclerotherapy. As far back as 1995, a meta‐analysis of seven trials comparing endoscopic band ligation with sclerotherapy in acute variceal bleeding showed a reduction of rebleeding from varices (odds ratio [OR] = 0.47, 95% confidence interval [CI] 0.29‐0.78), mortality (OR = 0.67, 95% CI 0.46‐0.98), and fewer esophageal strictures (OR = 0.10, 95% CI 0.03‐0.29). It has been stated that sclerotherapy for the treatment of variceal bleeding should be abandoned.2 The American Association for the Study of Liver Diseases guidelines clearly state that in variceal bleeding, endoscopic band ligation should be performed3 without any mention of sclerotherapy. Baveno VI guidelines state that band ligation is the recommended form of endoscopic therapy for acute esophageal variceal bleeding.4 The British Society of Gastroenterology guidelines very clearly state that sclerotherapy has been replaced by variceal band ligation and should no longer be offered as standard of care in acute variceal hemorrhage.5 Even if sclerotherapy may have a role in particular and unusual circumstances, as claimed by some, alternatives such as tissue adhesives and self‐expandable metal stents are likely to be of similar if not superior efficacy in such situations, without the risk of severe complications associated with the use of sclerotherapy. It certainly should have no role in the standard management of variceal bleeding. I believe this evidence should be reflected in any practice guidance, and sclerotherapy should not be included in any measures aimed at setting standards of care for patients with cirrhosis.
The Italian preparticipation evaluation programme: diagnostic yield, rate of disqualification and cost analysis
Authors: Teresina Vessella, Alessandro Zorzi, Laura Merlo, Cinzia Pegoraro, Flaviano Giorgiano, Michele Trevisanato, Mirella Viel, Pietro Formentini, Domenico Corrado, Patrizio Sarto
Journal: British Journal of Sports Medicine (2019)

Italian law mandates that every competitive athlete must undergo annual preparticipation evaluation (PPE) to identify cardiovascular (CV) diseases that pose a risk of sudden death (SD) during sport and other conditions that may threaten the athlete's health. We investigated the diagnostic yield, rate of disqualification and costs of our PPE.We included 5910 consecutive apparently healthy athletes (61% males, mean age 15±4 years) who underwent annual PPE performed by a sports medicine specialist. The PPE included history, physical examination, weight, height and blood pressure measurement, test of visual acuity, spirometry, urine chemistry, resting 12-lead ECG and exercise testing with ECG monitoring. In cases of abnormal findings, we carried out second-line investigations.During a 12-month study period, 5.326 (90.2%) athletes were cleared for competition after a normal first-line evaluation and 584 (9.8%) underwent one or more further examinations. Of those, 88 (1.5%) were diagnosed to have a CV disease (including 18 (0.3%) at-risk of SD) and 31 (0.5%) had a non-CV diagnosis. A total of 32 (0.5%) athletes were temporarily (n=15) or permanently (n=17) disqualified from competitive sports. The average cost per athlete was €79, which consisted of €64 (80%) for first-line evaluations and €15 (20%) for additional investigations.PPE according to the Italian model identified a range of diseases in 2.0% of apparently healthy athletes at an average cost of €79.
Neoadjuvant atezolizumab in resectable NSCLC patients: Updated clinical and immunophenotyping results from a multicenter trial.
Authors: Filiz Oezkan, Kai He, Dwight Hall Owen, Maciej Pietrzak, Valerie W. Rusch, Jamie E. Chaft, Rhonda Kitzler, Alan Nicholas, Katja Schulze, Ann Johnson, See Phan, Paul A. Bunn, Mark G. Kris, David J. Kwiatkowski, Bruce E. Johnson, Ignacio Ivan Wistuba, Jay M. Lee, Fred R. Hirsch, Gerard Lozanski, David Paul Carbone
Journal: Journal of Clinical Oncology (2019)

99 Background: Targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response and survival compared to chemo in NSCLC pts. We present a preliminary analysis of the clinical efficacy, safety and peripheral blood (PB) immunophenotyping from an ongoing multicenter atezolizumab (atezo) neoadjuvant immunotherapy study in resectable NSCLC. Methods: Pts received 2 cycles of atezo, 1200mg, days 1, 22 before resection. Tumor biopsies and PB were obtained pre-atezo & pre-surgery. The biomarker evaluable population (BEP) included pts with paired PB analyzed within 72 hrs by 10-color flow cytometry (IMMUNOME) and major pathological response (MPR) assessment (defined as ≤ 10% residual tumor). The primary endpoint was MPR. Secondary endpoints included safety, MPR by PD-L1, OS, and DFS. Immunophenotypic analyses were correlated with treatment, MPR and PD-L1 expression. Results: 116 patients have been enrolled as of October 31, 2018 and here we report on 54 of 180 planned pts with follow-up through surgery. 15 pts had Gr 3-4 AEs (3 treatment related), one Gr 5 AE (sudden death) was unrelated. By RECIST there were 3 PR, 49 SD, and 2 PD. 50/54 pts underwent the planned surgery, 47 pts had MPR assessment: 4 pts discontinued study preop (2 radiographic PD, 2 other reasons); 3 were unresectable. Excluding 5 pts with EGFR or ALK mutations, MPR rate was 10/45 (22%, 95% CI 11-37%). Baseline PD-L1 status was evaluable in 44/54 pts; BEP included 31 pts, 23 had tissue PD-L1 status: 16 PD-L1+. We observed significant increases in natural killer (NK) cells, CD8+ T-cells, Th1-response related dendritic cells (DC), and decreases in B-cells after atezo. Non-MPR pts showed significant increases in late activated NK cells, monocytic myeloid cells and Th2 and Th17-response–related DCs. PD-L1+ pts showed significant decreases of senescent T cells, monocytic myeloid cells, and increases of Th1-response–related DCs. We analyzed 22/54 tumor pairs, PD-L1+ cells increased in most pts after atezo treatment. Conclusions: Neoadjuvant atezo was well tolerated and the MPR rate is encouraging. Preliminary immunophenotyping data showed significant changes in PB with immunotherapy. Clinical trial information: NCT02927301.
Efficacy of platinum-pemetrexed combination chemotherapy in ALK<i>+</i> non-small cell lung cancer refractory to second-generation ALK TKIs.
Authors: Jessica Jiyeong Lin, Adam Jacob Schoenfeld, Viola Weijia Zhu, Beow Y. Yeap, Emily Chin, Marguerite Rooney, Andrew J. Plodkowski, Subba Digumarthy, Ibiayi Dagogo-Jack, Justin F. Gainor, Sai-Hong Ignatius Ou, Gregory J. Riely, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2019)

9067 Background: Second-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first- and second-line therapies in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). After progression on second-gen TKI(s), standard options include platinum (PT)-based chemotherapy (chemo) or the third-gen ALK TKI lorlatinib. The efficacy of PT-based chemo is established in treatment-naive pts but is undefined in pts who have failed prior ALK TKIs. Here we evaluate the efficacy of PT/pemetrexed (pem)-based chemo in pts with ALK+ NSCLC refractory to second-gen TKIs. Methods: A retrospective study was performed at three institutions. Pts were eligible if they had advanced ALK+ NSCLC refractory to ≥1 second-gen TKI, and received PT-pem-based chemo. Medical records and imaging were reviewed to determine outcomes. Results: Among 55 eligible pts, chemo regimens included: PT/pem (31/55, 56%), PT/pem/bevacizumab (bev) (6/55, 11%), PT/pem/PD-1 inhibitor (3/55, 5%), PT/pem with ALK TKI (8/55, 15%), PT/pem/bev with TKI (6/55, 11%), and PT/pem/PD-1 inhibitor with TKI (1/55, 2%). Pts had received one (6/55, 11%), two (38/55, 69%), or more (11/55, 20%) prior TKIs. Six pts (11%) previously received adjuvant or neoadjuvant chemo. Radiographic data for response evaluation was available for 39 pts. Among 36 pts with measurable baseline disease, confirmed ORR was 31% (11/36; 95% CI, 16-48%); 13 (36%) had stable disease. The median duration of response was 5.4 months (95% CI, 1.5-7.1 months). The median progression-free survival (PFS) for the entire cohort was 4.0 months (95% CI, 2.8-4.6 months). Chemo (PT/pem +/- bev or PD-1 inhibitor) plus ALK TKI (n = 15) was associated with a significant increase in PFS compared to chemo without TKI (n = 40) (median PFS 6.8 vs 3.2 months; HR 0.306; p = 0.002). Similarly, PT/pem plus ALK TKI (n = 8) was associated with increased PFS compared to PT/pem without TKI (n = 31) (median PFS 6.8 vs 2.9 months; HR 0.358; p = 0.036). Conclusions: The efficacy of PT-pem-based chemo is limited after failure of second-gen ALK TKIs but may be higher in pts who receive chemo plus ALK TKI, suggesting a potential role for ongoing ALK inhibition. The modest benefit of PT-pem-based chemo highlights the need for other therapeutic strategies for pts refractory to second-gen TKIs.
Analysis of colorectal cancer patients treated on ETCTN 10021: A multicenter randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation.
Authors: Arta Monjazeb, Anita Giobbie-Hurder, Ana Lako, Anteneh A. Tesfaye, Amanda Stroiney, Ryan D. Gentzler, Salma Jabbour, Olatunji B. Alese, Osama E. Rahma, James M. Cleary, Elad Sharon, David Raben, Harvey J. Mamon, Howard Streicher, Helen X. Chen, Mansoor Ahmed, Evisa Gjini, Scott Rodig, F. Stephen Hodi, Jonathan Daniel Schoenfeld
Journal: Journal of Clinical Oncology (2019)

49 Background: Pre-clinical and clinical evidence support immune effects of targeted radiation (RT) resulting in synergy with immune checkpoint therapy. However, prospective data are lacking in regards to safety, efficacy and immunologic impacts of different doses of RT given in conjunction with PD-L1 and CTLA-4 blockade. Methods: ETCTN 10021 is a multicenter randomized phase 2 study evaluating repeated low-dose fractionated RT (LDFRT) or hypofractionated RT (HFRT) in combination with PD-L1 and CTLA-4 inhibition in metastatic microsatellite-stable colorectal cancer (CRC) refractory to first-line chemotherapy, or non-small cell lung cancer progressive on prior PD-1 inhibition. The primary endpoint is objective response excluding irradiated lesions. Pre- and on-treatment biopsies were analyzed using multiplex immunofluorescence (IF) evaluating multiple immune markers. We report the prespecified analysis of the CRC cohort. Results: Twenty CRC patients were randomized, 19 of whom were treated with immunotherapy and RT, and 18 of whom were evaluable for response. Median lines of prior therapy were 4 (range 1-7). There were 16 patients with toxicity potentially related to treatment (84%), and 8 patients with possibly associated grade 3-5 toxicity (42%). Best response was stable disease in one patient with an abscopal out-of-field response who developed new lesions after HFRT and 4 cycles with decreasing overall disease burden. Correlative IF performed on 5 sample pairs revealed that HFRT, but not LDFRT, increased infiltration of CD8+, and CD8+/PD1+/Ki67+ T-cells in the RT field. Conclusions: We demonstrate the feasibility of a multicenter randomized study adding different RT regimens to PD-L1/CTLA-4 blockade. Toxicity was, in general, consistent with PD-L1/CTLA-4 inhibition with no significant RT-related toxicities noted. Although the best response of stable disease doesn’t support the use of PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population using these RT regimens and schedule, integrated biomarkers provide support that HFRT impacts the local immune microenvironment. Clinical trial information: NCT02888743.
Frontiers in positron emission tomography imaging of the vulnerable atherosclerotic plaque
Authors: Mark G MacAskill, David E Newby, Adriana A S Tavares
Journal: Cardiovascular Research (2019)

Rupture of vulnerable atherosclerotic plaques leading to an atherothrombotic event is the primary driver of myocardial infarction and stroke. The ability to detect non-invasively the presence and evolution of vulnerable plaques could have a huge impact on the future identification and management of atherosclerotic cardiovascular disease. Positron emission tomography (PET) imaging with an appropriate radiotracer has the potential to achieve this goal. This review will discuss the biological hallmarks of plaque vulnerability before going on to evaluate and to present PET imaging approaches which target these processes. The focus of this review will be on techniques beyond [18F]FDG imaging, some of which are clinically advanced, and others which are on the horizon. As inflammation is the primary driving force behind atherosclerotic plaque development, we will predominantly focus on approaches which either directly, or indirectly, target this process.
UK firm pays $1.4bn to settle US allegations over opioid marketing
Authors: Owen Dyer
Journal: BMJ (2019)

The UK conglomerate Reckitt Benckiser, maker of Durex and Lysol, will pay $1.4bn (£1.1bn; €1.2bn) to resolve civil litigation and criminal investigations launched by the US government over its marketing of Suboxone, an opioid addiction treatment. It is a record payout in litigation stemming from the US opioid epidemic and one of the biggest settlements ever paid by a drug company to the US government.12

The firm, which is based in Slough, Berkshire, and which also makes Dettol, Strepsils, Gaviscon, Nurofen, Clearasil, and Vanish, will pay $1.15bn to the federal government and $200m to states whose programs covered patients receiving Suboxone, to avoid criminal prosecution for fraudulent marketing.

The payment will also resolve civil allegations that the company used its “Here to help” patient advice service to “connect patients to doctors it knew were …
CheckMate 384: Phase IIIb/IV trial of nivolumab (nivo) 480 mg Q4W versus 240 mg Q2W after ≤ 12 months of nivo in previously treated advanced NSCLC.
Authors: Edward B. Garon, Niels Reinmuth, Lionel Falchero, Yolanda Garcia Garcia, José Hureaux, Ira Gore, Ronald P. Harris, Paolo Bidoli, Editta Baldini, Silverio Ros, Eckart Laack, Paul Mitchell, Martin Wolf, Kenneth John O'Byrne, Labib Zibdawi, Kevin Jao, David Spigel, Ang Li, Sridhar K. Rabindran, Eric Pichon
Journal: Journal of Clinical Oncology (2019)

100 Background: Nivo is approved as 240 mg Q2W in the EU and Japan and 240 mg Q2W or 480 mg Q4W in the US and Canada for second-line treatment (tx) of advanced NSCLC. Pharmacokinetic modeling in various tumors predicts that exposure, efficacy and safety can be maintained with less frequent Q4W dosing, which may provide a more convenient tx option. We present an interim analysis of efficacy and safety from CheckMate 384 (NCT02713867), an international, open-label, randomized phase 3b/4 trial evaluating less frequent nivo dosing (480 mg Q4W vs 240 mg Q2W) in patients (pts) with advanced NSCLC and prior Q2W nivo tx. Methods: Pts (N = 329) with previously treated histologically confirmed stage IIIB/IV or recurrent NSCLC, ECOG performance status 0–2, and prior tx with nivo 3 mg/kg or 240 mg Q2W for ≤12 mo, with ≥2 consecutive assessments of complete / partial response or stable disease, were randomized 1:1 to nivo 480 mg Q4W or 240 mg Q2W over a 30-min infusion. Co-primary endpoints: post-randomization (RND) progression-free survival rates (PFS) at 6 mo and 1 y. Secondary endpoints included safety. Due to tx landscape changes in NSCLC, statistical analyses were amended for a reduced sample size. One-sided 95% CIs were generated to compare PFS rates; presented data analyses are descriptive. Results: Of 166 and 163 pts randomized to 480 mg Q4W and 240 mg Q2W, 164 and 161 pts were treated, respectively. Median follow-up was 9.5 mo (480 mg Q4W) and 10.2 mo (240 mg Q2W). Baseline characteristics were balanced between tx arms. Stratified PFS rates post-RND were comparable between tx arms at 6 mo and 1 y (Table). Safety profiles were similar; any grade tx-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported in 48% vs 61% and 6% vs 9% of pts with 480 mg Q4W vs 240 mg Q2W. No tx-related deaths were reported. Conclusions: Nivo 480 mg Q4W showed similar efficacy and safety to 240 mg Q2W in pts with disease control on nivo, supporting the potential use of 480 mg Q4W as a more convenient dosing option for second-line NSCLC tx. Clinical trial information: NCT02713867. [Table: see text]
Resuscitation Strategies Using Peripheral Perfusion vs Serum Lactate Levels
Authors: Jayshil J. Patel, Paul A. Bergl
Journal: JAMA (2019)

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The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections
Authors: Alexandra M. Bender, Francesco R. Simonetti, Mithra R. Kumar, Emily J. Fray, Katherine M. Bruner, Andrew E. Timmons, Katherine Y. Tai, Katharine M. Jenike, Annukka A.R. Antar, Po-Ting Liu, Ya-Chi Ho, Dana N. Raugi, Moussa Seydi, Geoffrey S. Gottlieb, Afam A. Okoye, Gregory Q. Del Prete, Louis J. Picker, Joseph L. Mankowski, Jeffrey D. Lifson, Janet D. Siliciano, Greg M. Laird, Dan H. Barouch, Janice E. Clements, Robert F. Siliciano
Journal: Cell Host & Microbe (2019)
PTCH1 Mutation in a Patient With Metastatic Undifferentiated Carcinoma With Clear Cell Change
Authors: Katy K. Tsai, Neharika Khurana, Timothy McCalmont, Adil Daud, Boris Bastian, Iwei Yeh
Journal: Journal of the National Comprehensive Cancer Network (2019)

Abstract Clear cell basal cell carcinoma (BCC) is an unusual variant of BCC. Its pathogenesis, prognosis, and optimal management remain poorly described due to its rarity. This report presents a 51-year-old man with a history of excised BCC and cutaneous squamous cell carcinomas of the face, with multiple recurrent poorly differentiated carcinomas with clear cell changes of the shoulder for which further classification using conventional histologic means was not possible. His tumor tissue was sent to Foundation Medicine for testing, which revealed a high number of pathogenic genomic alterations, including a mutation in PTCH1 . He was diagnosed with dedifferentiated BCC and started on vismodegib. He developed lung metastases while receiving vismodegib, and his disease continued to progress while he was undergoing treatment in a phase I clinical trial. Given the high number of pathogenic alterations suggestive of high tumor mutational burden, immunotherapy was considered and off-label authorization was obtained for treatment with a PD-1 antibody (pembrolizumab). He had a dramatic disease response after 4 infusions of pembrolizumab. Molecular testing was instrumental in determining the correct diagnosis and formulating appropriate treatment options for this patient. Molecular profiling of metastatic BCCs and its subtypes is essential to the development of effective targeted therapies and combination approaches.