tbuckley/cabot-search huggingface dataset:
Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment
Authors: Sumit K Subudhi, Bilal A Siddiqui, Ana M Aparicio, Shalini S Yadav, Sreyashi Basu, Hong Chen, Sonali Jindal, Rebecca S S Tidwell, Ashwin Varma, Christopher J Logothetis, James P Allison, Paul G Corn, Padmanee Sharma
Journal: Journal for ImmunoTherapy of Cancer (2021)

Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.In this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.Twenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.Tremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.NCT03204812.
Abstract 11953: Nanoscale Movement of L-Type Calcium Channels in the Cardiomyocyte Membrane Can Contribute to Arrhythmia During Heart Failure
Authors: Anamika Bhargava, Tom O'Hara, Markus B Sikkel, Alexander R Lyon, Natalia A Trayanova, Julia Gorelik
Journal: Circulation (2012)

Cardiac L-Type calcium channels (LTCCs) are crucial for normal excitation-contraction coupling and are located predominantly in T-tubules. In heart failure T-tubules lose their organisation, howeve...
Long-term immunogenicity of BNT162b2 vaccination in older people and younger health-care workers
Authors: Pinkus Tober-Lau, Tatjana Schwarz, Kanika Vanshylla, David Hillus, Henning Gruell, Norbert Suttorp, Irmgard Landgraf, Kai Kappert, Joachim Seybold, Christian Drosten, Florian Klein, Florian Kurth, Leif Erik Sander, Victor Max Corman
Journal: The Lancet Respiratory Medicine (2021)
Changes in Cigarette Sales in the United States During the COVID-19 Pandemic
Authors: Samuel Asare, Anuja Majmundar, Farhad Islami, Priti Bandi, Stacey Fedewa, Lee J. Westmaas, Nigar Nargis
Journal: Annals of Internal Medicine (2021)

Background:The COVID-19 pandemic may have been associated with changes in smoking behaviors.Objective: To estimate changes in cigarette sales in the United States during the COVID-19 pandemic after accounting for the long-term declining trend in sales.Methods: Data on cigarettes released for consumption based on monthly filings by the tobacco companies from January 2007 to June 2021 were obtained from the Alcohol and Tobacco Tax and Trade Bureau of the U.S.
Campaign highlights families caught on climate crisis frontline
Authors: Alison Shepherd
Journal: BMJ (2021)

Peter Caton

As government representatives from across the world prepare to travel to Glasgow to attend next month’s COP26 climate emergency summit, the charity Action Against Hunger has launched a Mothers on the Frontline campaign to highlight the effects that climate change is already having on families.

The charity commissioned the photographer Peter Caton to visit Ethiopia …
Abstract 19494: 3D Volumetric Assessment of Coronary Plaque Change in Asymptomatic Subjects in Response to Therapy Using CT Angiography
Authors: Veit Sandfort, Mark Ahlman, Marissa Mallek, Alexander Broersen, Andrew Sams, David A Bluemke
Journal: Circulation (2015)

Introduction: Studies using intravascular ultrasound have demonstrated that plaque can regress after statin treatment. However, due to the invasive nature of this method data on asymptomatic individuals is scarce. CT angiography (CTA) data on change in plaque volume has shown variable success and has been evaluated mainly in high risk individuals. The aim of this study was to determine the change in coronary plaque in asymptomatic subjects undergoing statin treatment. Methods: Study subjects were recruited from an ongoing study (‘Randomized Trial of Imaging Versus Risk Factor-Based Therapy for Plaque Regression’). CTA (320-slice) was performed at baseline and after 2 years using a consistent protocol (kVp 120 or 100 kVp, iodine dose base on body weight). Plaque lesions (n = 100) were measured at baseline and follow up using customized tools to align coronary datasets based on anatomic landmarks. Plaque components were assessed by stratification of change in plaque volume by age. Results: The mean subject age was 64 years (81 % male). The mean Framingham risk was 11%. The median statin dose was 40 mg simvastatin or equivalent. Plaque characterization showed that younger subjects had a significantly higher proportion of non-calcified plaque subcomponents compared with older subjects (86% vs 62% respectively, p ≤ 0.01). The median change in total and non-calcified plaque volume was +2.9% and -5.9% respectively (not statistically significant from 0). Overall 36% of the lesions showed progression of non-calcified plaque while 64% showed regression. Of note, older subjects (over 65y) showed progression of total plaque volume while younger subjects showed no significant change. Younger subjects experienced more reduction in non-calcified plaque volume compared with older subjects (median -12.1% vs -2% respectively, p=0.02). Conclusions: Approximately 2/3 of the lesions showed plaque regression with 40 mg equivalent simvastatin dose over two years. Younger subjects (≤ 65 years) had larger percentages of soft plaque than older subjects, and showed significantly more regression of non-calcified plaque in relationship to statin therapy. Change in plaque using 3D volumetric registration of CTA data appears feasible and may help determine response to therapy.
Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey
Authors: Jose Nativi-Nicolau, Alfonso Siu, Angela Dispenzieri, Mathew S. Maurer, Claudio Rapezzi, Arnt V. Kristen, Pablo Garcia-Pavia, Samantha LoRusso, Márcia Waddington-Cruz, Olivier Lairez, Ronald Witteles, Doug Chapman, Leslie Amass, Martha Grogan, Fabio Adrian Barroso, Johan Van Cleemput, Nowell Fine, Hartmut Schmidt, Burkhard Gess, Henning Moelgaard, Violaine Planté-Bordeneuve, David Adams, Jocelyn Inamo, Giuseppe Vita, Calogero Lino Cirami, Marco Luigetti, Michele Emdin, Yoshiki Sekijima, Taro Yamashita, Eun-Seok Jeon, Maria Alejandra Gonzalez Duarte Briseno, Hans Nienhuis, Olga Azevedo, Josep Maria Campistol Plana, Juan Gonzalez Moreno, Jose Gonzalez Costello, Jonas Wixner, Yesim Parman, Sanjiv Shah, Dianna Quan, Tessa Marburger, Michael Polydefkis, Stephen Gottlieb, Jeffrey Ralph, Nitasha Sarswat, Jin Luo, Srinivas Murali, William Cotts, Brian Drachman, David Steidley, Scott Hummel, David Slosky, Hector Ventura, Daniel Jacoby, James Hoffman, James Tauras, Sasa Zivkovic, Jose Tallaj, Daniel Lenihan, Christopher Mueller
Journal: JACC CardioOncology (2021)

Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745)
Humoral and cellular responses after COVID-19 vaccination in anti-CD20-treated lymphoma patients
Authors: Nora Liebers, Claudius Speer, Louise Benning, Peter-Martin Bruch, Isabelle Kraemer, Julia Meissner, Paul Schnitzler, Hans-Georg Kräusslich, Peter Dreger, Carsten Mueller-Tidow, Isabel Poschke, Sascha Dietrich
Journal: Blood (2021)
骨粗鬆症の閉経後女性において骨折と骨密度に対する副甲状腺ホルモン(1-34)の効果
Authors: Neer R M, Arnaud C D, Zanchetta J R, Prince R, Gaich G A, Reginster J-Y, Hodsman A B, Eriksen E F, Mitlak B H
Journal: New England Journal of Medicine (2001)
Feasibility and efficacy of transcatheter interatrial shunt devices for chronic heart failure: a systematic review and meta‐analysis
Authors: Lucas Lauder, Tiago V. Pereira, Markus C. Degenhardt, Sebastian Ewen, Saarraaken Kulenthiran, Andrew J.S. Coats, Michael Böhm, Stefan D. Anker, Bruno R. da Costa, Felix Mahfoud
Journal: European Journal of Heart Failure (2021)
Pathophysiological pathways in patients with heart failure and atrial fibrillation
Authors: Bernadet T Santema, Vicente Artola Arita, Iziah E Sama, Mariëlle Kloosterman, Maarten P van den Berg, Hans L A Nienhuis, Isabelle C Van Gelder, Peter van der Meer, Faiez Zannad, Marco Metra, Jozine M Ter Maaten, John G Cleland, Leong L Ng, Stefan D Anker, Chim C Lang, Nilesh J Samani, Kenneth Dickstein, Gerasimos Filippatos, Dirk J van Veldhuisen, Carolyn S P Lam, Michiel Rienstra, Adriaan A Voors
Journal: Cardiovascular Research (2021)

Abstract Aims Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. Methods and results From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10−12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10−8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10−18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. Conclusion In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies.
P24.01 Turnaround Time and Variant Prevalence of a Blood-based KRAS Test in Patients With NSCLC
Authors: E. Santos, P. Rich, P. Walker, E. Schaefer, J. Tan, N. Nagajothi, J. Dubay, R. Mitchell, J. Boyd, D. Oubre, N. Ikhlaque, R. Page, M. Khalil, S. Sinha, H. Halawani, S. Boniol, J. Orsini, E. Pauli, W. Akerley
Journal: Journal of Thoracic Oncology (2021)
Lysyl hydroxylase 1 (LH1) deficiency promotes angiotensin II (Ang II)-induced dissecting abdominal aortic aneurysm
Authors: Hao Li, Haochen Xu, Hongyan Wen, Hongyue Wang, Ranxu Zhao, Yingying Sun, Congxia Bai, Jiedan Ping, Li Song, Mingyao Luo, Jingzhou Chen
Journal: Theranostics (2021)

Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.
P29.04 Treatment Plan Parameters and Toxicity Following Chemoradiotherapy and High-Dose Radiotherapy in Stage III Non-Small Cell Lung Cancer
Authors: I. Remmerts De Vries, M. Ronden, I. Bahce, M. Dahele, F. Spoelstra, P. De Haan, C. Haasbeek, B. Lissenberg-Witte, B. Slotman, W. Verbakel
Journal: Journal of Thoracic Oncology (2021)
Under-reporting of deaths limits our understanding of true burden of covid-19
Authors: Charles Whittaker, Patrick G T Walker, Mervat Alhaffar, Arran Hamlet, Bimandra A Djaafara, Azra Ghani, Neil Ferguson, Maysoon Dahab, Francesco Checchi, Oliver J Watson
Journal: BMJ (2021)

Estimating mortality attributable to different diseases, risk factors, or events is pivotal to inform resource allocation and evaluate public health interventions.Information on death rates and burden also supports wider aims of societal governance, public accountability, and memorialisation.Recent examples of mortality estimation include the true toll of hurricane Maria in Puerto Rico, 1 mortality during famine in Somalia, 2 and the war in South Sudan. 3 Mortality data have also been essential in understanding the spread of covid-19.However, under-reporting in official death records has greatly obscured this understanding.We explore why under-reporting of deaths should have been expected, examine how use of alternative mortality sources can help advocate for a more equitable pandemic response, and highlight the crucial need for increased investment into civil registration and vital statistics systems before the next pandemic.
Would You Recommend Aspirin to This Patient for Primary Prevention of Atherosclerotic Cardiovascular Disease?
Authors: Risa B. Burns, Michael Pignone, Erin D. Michos, Zahir Kanjee
Journal: Annals of Internal Medicine (2021)

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. Reducing ASCVD risk through primary prevention strategies has been shown to be effective; however, the role of aspirin in primary prevention remains unclear. The decision to recommend aspirin has been limited by the difficulty clinicians and patients face when trying to balance benefits and harms. In 2016, the U.S. Preventive Services Task Force addressed this issue by determining the risk level at which prophylactic aspirin generally becomes more favorable, recommending aspirin above a risk cut point (>10% estimated ASCVD risk). In 2019, the American College of Cardiology and the American Heart Association issued a guideline on the primary prevention of CVD that recommends low-dose aspirin might be considered for the primary prevention of ASCVD among select adults aged 40 to 70 years who are at higher ASCVD risk but not at increased risk for bleeding. Here, 2 experts discuss how to apply this guideline in general and to a patient in particular while answering the following questions: How do you assess ASCVD risk, and what is the role, if any, of the coronary artery calcium score?; At what risk threshold of benefits and harms would you recommend aspirin or not?; and How do you help a patient come to a decision about starting or stopping aspirin therapy?
Estimated Cost-effectiveness of Genetic Testing in Siblings of Newborns With Cancer Susceptibility Gene Variants
Authors: Grace O’Brien, Kurt D. Christensen, Haley K. Sullivan, Natasha K. Stout, Lisa Diller, Jennifer M. Yeh, Ann Chen Wu
Journal: JAMA Network Open (2021)

Newborn population-based genetic screening may reduce pediatric cancer deaths and could be cost-effective.1 Testing siblings of newborns with variants (ie, cascade testing) could further improve population health.2 Economic studies of cascade testing have focused on adults, although evidence suggests that cost-effectiveness improves for some cancer syndromes when surveillance is initiated in younger individuals.3 Our objective was to estimate the benefits and costs of cascade testing of siblings of newborns with cancer susceptibility gene variants.
Genetically identified amygdala–striatal circuits for valence-specific behaviors
Authors: Xian Zhang, Wuqiang Guan, Tao Yang, Alessandro Furlan, Xiong Xiao, Kai Yu, Xu An, William Galbavy, Charu Ramakrishnan, Karl Deisseroth, Kimberly Ritola, Adam Hantman, Miao He, Z. Josh Huang, Bo Li
Journal: Nature Neuroscience (2021)
Abstract 11972: Epicardial Adipose Tissue is Associated With Measures of Diastolic Dysfunction in Type 2 Diabetes
Authors: Regitse H Christensen, Christian S Hansen, Bernt Johan von Scholten, Magnus T Jensen, Bente K Pedersen, Tina Vilsbøll, Peter Rossing, Jan S Jensen, Peter G Jørgensen
Journal: Circulation (2018)

Introduction: Patients with type 2 diabetes (T2D) have high levels of epicardial (EAT) and pericardial (PAT) adipose tissue, which due to their intimate proximities to the myocardium, are believed ...
Pyruvate kinase M2 regulates fibrosis development and progression by controlling glycine auxotrophy in myofibroblasts
Authors: Ganesh Satyanarayana, Ravi Chakra Turaga, Malvika Sharma, Siming Wang, Falguni Mishra, Guangda Peng, Xiaonan Deng, Jenny Yang, Zhi-Ren Liu
Journal: Theranostics (2021)

Rationale: Fibrosis is a pathologic condition of abnormal accumulation of collagen fibrils. Collagen is a major extracellular matrix (ECM) protein synthesized and secreted by myofibroblasts, composing mainly (Gly-X-Y)n triplet repeats with >30% Gly residue. During fibrosis progression, myofibroblasts must upregulate glycine metabolism to meet the high demands of amino acids for collagen synthesis. Method: Expression of PKM2 in myofibroblasts was analyzed in cultured fibroblasts and fibrosis disease tissues. Functional roles of PKM2 and PKM2 activator in biosynthesis of serine → glycine and production of collagen from glycolysis intermediates were assayed in cultured activated LX-2 and human primary lung fibroblast cells. Mouse models of Liver, lung, and pancreas fibrosis were employed to analyze treatment effects of PKM2 activator in organ tissue fibrosis. Results: We report here that myofibroblast differentiation upregulates pyruvate kinase M2 (PKM2) and promotes dimerization of PKM2. Dimer PKM2 slows the flow rate of glycolysis and channels glycolytic intermediates to de novo glycine synthesis, which facilitates collagen synthesis and secretion in myofibroblasts. Our results show that PKM2 activator that converts PKM2 dimer to tetramer, inhibits fibrosis progression in mouse models of liver, lung, and pancreatic fibrosis. Furthermore, metabolism alteration by dimer PKM2 increases NADPH production, which consequently protects myofibroblasts from apoptosis. Conclusion: Our study uncovers a novel role of PKM2 in tissue/organ fibrosis, suggesting a possible strategy for treatment of fibrotic diseases using PKM2 activator.
P48.01 Anlotinib Plus Docetaxel vs Docetaxel for 2nd-Line Treatment of EGFR negative NSCLC (ALTER-L018): A Randomized Phase II Trial
Authors: L. Wu, Z. Wu, Z. Xiao, Z. Ma, J. Weng, Y. Chen, Y. Cao, P. Cao, M. Xiao, H. Zhang, H. Duan, Q. Wang, J. Li, Y. Xu, X. Pu, K. Li
Journal: Journal of Thoracic Oncology (2021)
P08.04 Comparative Clinical Outcomes Between EGFR Exon20ins and Wildtype NSCLC Treated with Immune Checkpoint Inhibitors
Authors: L. Bazhenova, N. Girard, A. Minchom, S. Ou, S. Gadgeel, J.M. Trigo, S. Viteri, A. Londhe, P. Mahadevia, J. Bauml
Journal: Journal of Thoracic Oncology (2021)