tbuckley/cabot-search huggingface dataset:
PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon
Authors: Benoit Rousseau, Ivan Bieche, Eric Pasmant, Nadim Hamzaoui, Nicolas Leulliot, Lucas Michon, Aurelien de Reynies, Valerie Attignon, Michael B. Foote, Julien Masliah-Planchon, Magali Svrcek, Romain Cohen, Victor Simmet, Paule Augereau, David Malka, Antoine Hollebecque, Damien Pouessel, Carlos Gomez-Roca, Rosine Guimbaud, Amandine Bruyas, Marielle Guillet, Jean-Jacques Grob, Muriel Duluc, Sophie Cousin, Christelle de la Fouchardiere, Aude Flechon, Frederic Rolland, Sandrine Hiret, Esma Saada-Bouzid, Olivier Bouche, Thierry Andre, Diane Pannier, Farid El Hajbi, Stephane Oudard, Christophe Tournigand, Jean-Charles Soria, Stephane Champiat, Drew G. Gerber, Dennis Stephens, Michelle F. Lamendola-Essel, Steven B. Maron, Bill H. Diplas, Guillem Argiles, Asha R. Krishnan, Severine Tabone-Eglinger, Anthony Ferrari, Neil H. Segal, Andrea Cercek, Natalie Hoog-Labouret, Frederic Legrand, Clotilde Simon, Assia Lamrani-Ghaouti, Luis A. Diaz, Pierre Saintigny, Sylvie Chevret, Aurelien Marabelle
Journal: Cancer Discovery (2022)

Abstract Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. Significance: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. See related video: https://vimeo.com/720727355 This article is highlighted in the In This Issue feature, p. 1397
Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin
Authors: Christina B. Joseph, Marta Mariniello, Ayumi Yoshifuji, Guglielmo Schiano, Jennifer Lake, Jonathan Marten, Anne Richmond, Jennifer E. Huffman, Archie Campbell, Sarah E. Harris, Stephan Troyanov, Massimiliano Cocca, Antonietta Robino, Sébastien Thériault, Kai-Uwe Eckardt, Matthias Wuttke, Yurong Cheng, Tanguy Corre, Ivana Kolcic, Corrinda Black, Vanessa Bruat, Maria Pina Concas, Cinzia Sala, Stefanie Aeschbacher, Franz Schaefer, Sven Bergmann, Harry Campbell, Matthias Olden, Ozren Polasek, David J. Porteous, Ian J. Deary, Francois Madore, Philip Awadalla, Giorgia Girotto, Sheila Ulivi, David Conen, Elke Wuehl, Eric Olinger, James F. Wilson, Murielle Bochud, Anna Köttgen, Caroline Hayward, Olivier Devuyst
Journal: Journal of the American Society of Nephrology (2022)

Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
Highlights From the <i>Circulation</i> Family of Journals
Authors: Harry Crijns, Arif Elvan, Nadea Al-Windy, Ype Tuininga, Erik Badings, Ismail Aksoy, Isabelle Van Gelder, Prashanti Madhavapeddi, ; Camm, Peter Kowey, Jeremy Ruskin, Luiz Belardinelli, Xinxing Lai, Zhenyu Dong, Shengxian Wu, Xiaohua Zhou, Genming Zhang, Shangquan Xiong, Wei Wu, Rui Cao, Xiaolong Wang, Qi Hua, Jinhang Du, Jinying Fan, Jingyuan Mao, Weimin Jiang, Huishu Yuan, Yushan Chen, Yong Xu, Zhanquan Li, Jun Zhang, Guiying Dong, Hui Zhen, Ru Ding, Zonggui Wu, Ying Gao, Huamei He, Tomas Baka, James Balschi, Alykhan Motani, Kathy Nguyen, Qingxiang Liu, Rebecca Slater, Brooke Rock, Chen Wang, Christopher Hale, Georgios Karamanlidis, James Hartman, ; Fady, I Malik, Jeff Reagan, Ivan Luptak, Carlos Iribarren, Malini Chandra, Catherine Lee, Gabriela Sanchez, Danny Sam, ; Farima, Faith Azamian, Hyo-Min Cho, Huanjun Ding, Nathan Wong, Sabee Molloi, Suzanne Baron, Michael Ryan, Kimberly Moore, Seth Clancy, Candace Gunnarsson
Journal: Circulation (2022)

The highlights from the March subspecialty journals cover several fascinating topics.An open-label dose escalation study of oral inhaled flecainide solution for cardioversion of atrial fibrillation is described in Circulation Arrhythmia and Electrophysiology.A randomized trial comparing an herbal therapy with losartan for hypertension is presented in Circulation: Cardiovascular Quality and Outcomes.A novel small molecule that activates the sarcomere and increases contractility is described in a series of tissue models in Circulation: Heart Failure.The association of breast arterial calcification on mammography with cardiovascular disease in postmenopausal women is evaluated in Circulation: Cardiovascular Imaging.Finally, the costs associated with surgical versus transcatheter aortic valve replacement are compared in Circulation: Cardiovascular Interventions.
Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial
Authors: Gerda Trutnovsky, Olaf Reich, Elmar A Joura, Magdalena Holter, Alexandra Ciresa-König, Andreas Widschwendter, Christian Schauer, Gerhard Bogner, Ziga Jan, Angelika Boandl, Martin S Kalteis, Sigrid Regauer, Karl Tamussino
Journal: The Lancet (2022)
Risk of Guillain–Barré syndrome after vaccination against human papillomavirus: a systematic review and meta-analysis, 1 January 2000 to 4 April 2020
Authors: T Sonia Boender, Barbara Bartmeyer, Louise Coole, Ole Wichmann, Thomas Harder
Journal: Eurosurveillance (2022)

Background Guillain–Barré syndrome (GBS) is a rare autoimmune disease that can follow viral infections and has in a few cases been linked to vaccinations. Pre-licensure clinical trials did not observe an association between human papillomavirus (HPV) vaccination and GBS, a post-marketing study from 2017 reported an increased relative risk. Aim We assessed the risk of GBS after HPV vaccination through a systematic literature review and meta-analysis. Methods We searched Embase, MEDLINE and Cochrane for studies reporting on the risk of GBS after HPV vaccination in individuals aged ≥ 9 years, published between 1 January 2000 and 4 April 2020, excluding studies without a comparator group. Seven studies reporting relative effect sizes were pooled using random-effects meta-analysis. We assessed quality of evidence using the GRADE approach. Study protocol was registered (PROSPERO No. #CRD42019123533). Results Of 602 identified records, we included 25 studies. Based on over 10 million reports, cases of GBS were rare. In 22 studies no increased risk was observed, while in three studies a signal of increased risk of GBS after HPV vaccination was identified. Meta-analysis yielded a pooled random-effects ratio of 1.21 (95% CI: 0.60–2.43); I 2 = 72% (95% CI: 36–88). This translates to a number needed to harm of one million to be vaccinated to generate one GBS case. Quality of evidence was very low. Conclusions The absolute and relative risk of GBS after HPV vaccination is very low and lacks statistical significance. This is reassuring for the already implemented vaccination programmes and should be used in respective communication activities.
Response-Adapted Postinduction Strategy in Follicular Lymphoma
Authors: Motoharu Shibusawa, Eiji Kusumi, Jun Murakami, Tetsuya Tanimoto
Journal: Journal of Clinical Oncology (2022)

Luminari et al 1 conducted a randomized study among patients with untreated, advanced-stage, high-tumor burden follicular lymphoma in Italy.They compared standard rituximab maintenance (standard arm) with experimental rituximab maintenance (experimental arm), which was conducted by a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease.The authors observed superior progression-free survival (PFS) in the standard arm patients than in the experimental arm patients (3-year PFS 86% v 72%; P , .001).
Sotorasib's Benefits in Colorectal Cancer Modest
Journal: Cancer Discovery (2022)

Abstract The KRAS inhibitor sotorasib provides some clinical benefit in patients with advanced or metastatic KRASG12C-mutant colorectal cancer, according to results of a phase II clinical trial. The objective response rate was 9.7%, the disease control rate was 82.3%, and the progression-free survival was 4 months.
Primary stroke prevention worldwide: translating evidence into action
Authors: Mayowa O Owolabi, Amanda G Thrift, Ajay Mahal, Marie Ishida, Sheila Martins, Walter D Johnson, Jeyaraj Pandian, Foad Abd-Allah, Joseph Yaria, Hoang T Phan, Greg Roth, Seana L Gall, Richard Beare, Thanh G Phan, Robert Mikulik, Rufus O Akinyemi, Bo Norrving, Michael Brainin, Valery L Feigin
Journal: The Lancet Public Health (2021)
Vive la Résistance: T-cell Immunity in the Protection against SARS-CoV-2 Infection
Authors: Lisa H.F. McGary, Santosha A. Vardhana
Journal: Cancer Discovery (2022)

Summary Fahrner and colleagues investigated the immune response of patients with cancer and cancer-free individuals to SARS-CoV-2 and found that a propensity toward an IL5-predominant Th2/Tc2 response was predictive of susceptibility to infection. The results of this study also suggest that a cellular response against the Spike 1 protein receptor binding domain (S1-RBD) region of the SARS-CoV-2 proteome contributes to protection and that mutations in this region may drive viral evolution and immune escape. See related article by Fahrner et al., p. 958 (8).
Extramedullary Plasmacytoma
Authors: Fengyu Wu, Mingming Yu, Bin Shi, Qian Yu, Zhenguang Wang
Journal: Clinical Nuclear Medicine (2022)

Abstract A 66-year-old woman having intermittent abdominal distention for 2 months was referred to our hospital. An enhanced abdominal CT scan showed multiple hepatic lesions, suspected of metastases. An 18 F-FDG PET/CT scan, which was performed to seek primary tumor, showed multiple lesions with intense 18 F-FDG uptake in the liver and lymph nodes located in cardiophrenic angle, abdominal cavity, and retroperitoneal space. All 18 F-FDG–avid lesions were suspected of metastases. However, no suspected primary tumor was identified by the 18 F-FDG PET/CT scan, which prompted the liver biopsy. Pathologic analysis revealed the presence of plasmacytoma.
Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)
Authors: Erica L. Mayer, Christian Fesl, Dominik Hlauschek, Laura Garcia-Estevez, Harold J. Burstein, Nicholas Zdenkowski, Viktor Wette, Kathy D. Miller, Marija Balic, Ingrid A. Mayer, David Cameron, Eric P. Winer, José Juan Ponce Lorenzo, Diana Lake, Gunda Pristauz-Telsnigg, Tufia C. Haddad, Lois Shepherd, Hiroji Iwata, Matthew Goetz, Fatima Cardoso, Tiffany A. Traina, Dhanusha Sabanathan, Urs Breitenstein, Kerstin Ackerl, Otto Metzger Filho, Karin Zehetner, Kadine Solomon, Sarra El-Abed, Kathy Puyana Theall, Dongrui Ray Lu, Amylou Dueck, Michael Gnant, Angela DeMichele
Journal: Journal of Clinical Oncology (2022)

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.
Abstract P216: Association Of Heart Rate Variability With The Risk Of Heart Failure And Its Sub-types In Post-menopausal Women: A Longitudinal Cohort Study
Authors: Muhammad Baig, Moafi-Madani Miremad, Mary Roberts, Charles B Eaton
Journal: Circulation (2022)

Background: Previously our research findings revealed that low heart rate variability, a measure of autonomic imbalance, is associated with increased incidence of coronary heart disease (CHD) and heart failure (HF) in a cohort of post-menopausal women. Since CHD is strongly associated with HF, we investigated the effect of CHD on relationship of HRV and HF subtypes, i.e., heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), in post-menopausal women. Methods: Total of 28,603 post-menopausal women free of baseline CHD, HF and cardiac arrhythmias enrolled in Women’s Health Initiative (WHI) study, were followed for incident hospitalized CHD, HF and its subtypes (HFrEF vs HFpEF). Using multivariate cox proportional hazard model, we estimated the association of above outcomes with baseline quartiles of HRV measures; SDNN (standard deviation of normal-to-normal RR interval) and RMSSD (root mean square of successive difference of RR interval) produced by 10-second twelve-lead ECG on enrollment. We then evaluated the relationship between HRV and HF subtypes stratified by incident CHD. Results: A total of 2279 incident CHD and 1562 incident HF events occurred during a median follow-up duration of 17.5 years. After adjusting for incident CHD in a multivariate cox proportional model, association of low SDNN and RMSSD with incident HF remained significant (SDNN HR 1.19, CI 1.05 - 1.35; RMSSD HR 1.13 (1.00 - 1.29). However, in stratified analysis low SDNN was associated with increased incidence of HFpEF only among participants without incident CHD (HR 1.29, CI 1.05 - 1.58) and not in those with incident CHD (HR 1.06, CI 0.77 - 1.47). Whereas low SDNN was associated with increased incidence of HFrEF only among participants with incident CHD (HR 1.44. CI 1.05 - 1.98) and not in those without incident CHD (HR 1.18, CI 0.87 - 1.61). Conclusion: Post-menopausal women with low HRV who develop CHD have an increased risk of HFrEF while those who don’t develop CHD have an increased risk of HFpEF. The relationship between autonomic imbalance and HF subtypes is dependent on CHD status.
Evolutionary foundations of knowledge and belief attribution in nonhuman primates
Authors: Fumihiro Kano, Josep Call
Journal: Behavioral and Brain Sciences (2021)

Recent findings from anticipatory-looking false-belief tests have shown that nonhuman great apes and macaques anticipate that an agent will go to the location where the agent falsely believed an object to be. Phillips et al.'s claim that nonhuman primates attribute knowledge but not belief should thus be reconsidered. We propose that both knowledge and belief attributions are evolutionary old.
Respiratory Monitoring: Current State of the Art and Future Roads
Authors: Ian Costanzo, Devdip Sen, Lawrence Rhein, Ulkuhan Guler
Journal: IEEE Reviews in Biomedical Engineering (2020)

In this article, we present current methodologies, available technologies, and demands for monitoring various respiratory parameters. We discuss the importance of noninvasive techniques for remote and continuous monitoring and challenges involved in the current “smart and connected health” era. We conducted an extensive literature review on the medical significance of monitoring respiratory vital parameters, along with the current methods and solutions with their respective advantages and disadvantages. We discuss the challenges of developing a noninvasive, wearable, wireless system that continuously monitors respiration parameters and opportunities in the field and then determine the requirements of a state-of-the-art system. Noninvasive techniques provide a significant amount of medical information for a continuous patient monitoring system. Contact methods offer more advantages than non-contact methods; however, reducing the size and power of contact methods is critical for enabling a wearable, wireless medical monitoring system. Continuous and accurate remote monitoring, along with other physiological data, can help caregivers improve the quality of care and allow patients greater freedom outside the hospital. Such monitoring systems could lead to highly tailored treatment plans, shorten patient stays at medical facilities, and reduce the cost of treatment.
Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial
Authors: Qing Zhou, Ming Chen, Ou Jiang, Yi Pan, Desheng Hu, Qin Lin, Gang Wu, Jiuwei Cui, Jianhua Chang, Yufeng Cheng, Cheng Huang, Anwen Liu, Nong Yang, Youling Gong, Chuan Zhu, Zhiyong Ma, Jian Fang, Gongyan Chen, Jun Zhao, Anhui Shi, Yingcheng Lin, Guanghui Li, Yunpeng Liu, Dong Wang, Rong Wu, Xinhua Xu, Jianhua Shi, Zhihua Liu, Na Cui, Jingru Wang, Qiang Wang, Ran Zhang, Jason Yang, Yi-Long Wu
Journal: The Lancet Oncology (2022)
Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB
Authors: Anders U. Eliasen, Casper Emil T. Pedersen, Morten A. Rasmussen, Ni Wang, Matteo Soverini, Amelie Fritz, Jakob Stokholm, Bo L. Chawes, Andréanne Morin, Jette Bork-Jensen, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Preben B. Mortensen, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Ole Mors, Merete Nordentoft, Anders D. Børglum, Thomas Werge, Esben Agerbo, Cilla Söderhall, Matthew C. Altman, Anna H. Thysen, Chris G. McKennan, Susanne Brix, James E. Gern, Carole Ober, Tarunveer S. Ahluwalia, Hans Bisgaard, Anders G. Pedersen, Klaus Bønnelykke
Journal: Journal of Allergy and Clinical Immunology (2022)
Abstract MP31: Telehealth Versus Self-directed Lifestyle Intervention To Promote Healthy Blood Pressure: A Randomized Controlled Trial
Authors: Alex R Chang, Christina Yule, Heather Bonaparte, Charlotte Collins, Allison Naylor, Lawrence J Appel, Stephen P Juraschek, Lisa Bailey-Davis
Journal: Circulation (2022)

Introduction: Telehealth and web-based applications are increasingly available to promote healthy lifestyle behavior change. However, evidence that these approaches lower blood pressure is limited. Methods: We conducted a randomized controlled trial to compare the efficacy of a self-directed vs. a telehealth-delivered dietitian approach using web-based applications in 187 participants (mean age 54.6 y, 52% female) with 24-hour systolic blood pressure (BP) 120-160 mmHg. Participants were recruited in the Geisinger Health System from 1/2019 to 3/2021. Both study arms received personalized recommendations to improve dietary quality based on web-based food frequency questionnaire, and access to an online comprehensive weight management program. The telehealth arm additionally received weekly telephone calls with a dietitian who used motivational interviewing. The primary outcome was 3-month change in 24-hour systolic BP. Secondary outcomes included changes in awake and sleep BP, self-reported physical activity, healthy eating index (HEI)-2015 score, and weight. Results: Twenty-four hour systolic BP improved in both the telehealth-dietitian arm (-6.5 mmHg, 95% CI: -8.4, -4.6) and the self-directed arm (-4.9, 95% CI: -7.0, -2.8), with no difference between arms (p=0.3). Participants in the telehealth-dietitian arm had significantly greater decreases in sleep systolic BP (mean -6.9 mmHg vs. -1.5; p=0.004) and diastolic BP (-3.3 mmHg vs. 0.7; p=0.001). The telehealth-dietitian arm tended to have greater improvements in self-reported physical activity, weight loss, and HEI-2015 score (Figure). Participant satisfaction with the intervention was higher in the telehealth-dietitian arm (p=0.004). Conclusions: Among individuals with elevated BP, the telehealth-dietitian intervention did not lower 24-hour systolic BP compared to the self-directed arm over 3 months. However, there were encouraging changes in other outcomes, including reduced sleep systolic and diastolic BP and increased physical activity.