tbuckley/cabot-search huggingface dataset:
Abstract OT2-28-01: A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704
Authors: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis
Journal: Cancer Research (2022)

Abstract Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.
Comment on Dawed et al. Genome-Wide Meta-Analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas. Diabetes Care 2021;44:2673–2682
Authors: Ke Wang, Mai Shi, Aimin Yang, Brian Tomlinson, Juliana C.N. Chan, Elaine Chow
Journal: Diabetes Care (2022)

We read with interest the article by Dawed et al. ( 1) reporting genetic variants associated with sulfonylurea response in a genome-wide meta-analysis of White Europeans.The C allele of rs10770791 in the intronic region of solute carrier organic anion transporter family member 1B1 (SLCO1B1) was identified as one of two loci associated with improved HbA 1c response.Interestingly, two wellestablished nonsynonymous variants of SLCO1B1, rs4149056 (*5, c.521T>C, p.V174A) and rs2306283 (*37; c.388A>G, p.N130D), in partial link disequilibrium with rs10770791, were not significantly associated with sulfonylurea response based on individual-level data (n 5 3,557).Although in vitro data implicate sulfonylureas as substrates of organic anion transporting polypeptide 1B1 (OATP1B1) transporter, there is a lack of in vivo data supporting an effect of SLCO1B1 variants on sulfonylurea pharmacokinetics.This contrasts with statins, where the rs4149056 c.521T>C allele is well known to be associated with a 4.6-fold increase in risk of statin-induced myopathy.This is supported by both in vitro evidence of reduced OATP1B1 transporter activity and in vivo pharmacokinetic studies showing higher statin exposure among CC homozygotes (2).Further, Dawed et al. (1) only investigated the role of
Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer
Authors: Joline S.J. Lim, Andrea L.A. Wong, Samuel G.W. Ow, Natalie Y.L. Ngoi, Gloria H.J. Chan, Yvonne L.E. Ang, Wan Qin Chong, Siew Eng Lim, Yi Wan Lim, Matilda Lee, Joan R.E. Choo, Hon Lyn Tan, Wei Peng Yong, Ross A. Soo, David S.P. Tan, Cheng Ean Chee, Raghav Sundar, Kritika Yadav, Supriya Jain, Lingzhi Wang, Bee Choo Tai, Boon Cher Goh, Soo-Chin Lee
Journal: Clinical Cancer Research (2022)

Abstract Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. Patients and Methods: Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.
Somatic mutational profiles and germline polygenic risk scores in human cancer
Authors: Yuxi Liu, Alexander Gusev, Yujing J. Heng, Ludmil B. Alexandrov, Peter Kraft
Journal: Genome Medicine (2022)

Abstract Background The mutational profile of cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-base substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures. Methods We used polygenic risk scores (PRS) to summarize common germline variation associated with cancer risk and other cancer-related traits and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas. Somatic mutational profiles were constructed from whole-exome sequencing data of primary tumors. PRS were calculated for the 12 selected cancer types and 9 non-cancer traits, including cancer risk determinants, hormonal factors, and immune-mediated inflammatory diseases, using germline genetic data and published summary statistics from genome-wide association studies. Results We found 17 statistically significant associations between somatic mutational profiles and germline PRS after Bonferroni correction ( p &lt; 3.15 × 10 −5 ), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations attributed to signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. Positive associations were also found between age at menarche PRS and mutation counts of SBS1 in overall and estrogen receptor-positive breast cancer. Consistent with prior studies that found an inverse association between the pubertal development PRS and risk of prostate cancer, likely reflecting hormone-related mechanisms, we found an inverse association between age at menarche PRS and mutation counts of SBS1 in prostate cancer. Inverse associations were also found between several cancer PRS and tumor mutation counts. Conclusions Our analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect the mechanisms through hormone regulation and immune responses that contribute to cancer etiology and drive cancer progression.
Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST)
Authors: Johnathan K. Joffe, Fay H. Cafferty, Laura Murphy, Gordon J.S. Rustin, Syed A. Sohaib, Rhian Gabe, Sally P. Stenning, Elizabeth James, Dipa Noor, Simona Wade, Francesca Schiavone, Sarah Swift, Elaine Dunwoodie, Marcia Hall, Anand Sharma, Jeremy Braybrooke, Jonathan Shamash, John Logue, Henry H. Taylor, Ivo Hennig, Jeff White, Sarah Rudman, Jane Worlding, David Bloomfield, Guy Faust, Hilary Glen, Rachel Jones, Michael Seckl, Graham MacDonald, Thiagarajan Sreenivasan, Satish Kumar, Andrew Protheroe, Ramachandran Venkitaraman, Danish Mazhar, Victoria Coyle, Martin Highley, Tom Geldart, Robert Laing, Richard S. Kaplan, Robert A. Huddart
Journal: Journal of Clinical Oncology (2022)

Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses.A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed.Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths.Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.
ASSOCIATION OF NPC1L1 GENE POLYMORPHISMS WITH CORONARY ARTERY CALCIUM IN PATIENTS WITH PREMATURE TRIPLE-VESSEL DISEASE
Authors: Yulong Li, Jiawen Li, Xiao-Fang Tang, Jingjing Xu, Ru Liu, Lei Song, Jinqing Yuan, Xueyan Zhao
Journal: Journal of the American College of Cardiology (2022)
Molecular consequences of SARS-CoV-2 liver tropism
Authors: Nicola Wanner, Geoffroy Andrieux, Pau Badia-i-Mompel, Carolin Edler, Susanne Pfefferle, Maja T. Lindenmeyer, Christian Schmidt-Lauber, Jan Czogalla, Milagros N. Wong, Yusuke Okabayashi, Fabian Braun, Marc Lütgehetmann, Elisabeth Meister, Shun Lu, Maria L. M. Noriega, Thomas Günther, Adam Grundhoff, Nicole Fischer, Hanna Bräuninger, Diana Lindner, Dirk Westermann, Fabian Haas, Kevin Roedl, Stefan Kluge, Marylyn M. Addo, Samuel Huber, Ansgar W. Lohse, Jochen Reiser, Benjamin Ondruschka, Jan P. Sperhake, Julio Saez-Rodriguez, Melanie Boerries, Salim S. Hayek, Martin Aepfelbacher, Pietro Scaturro, Victor G. Puelles, Tobias B. Huber
Journal: Nature Metabolism (2022)

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.
PROGNOSTIC SIGNIFICANCE OF NEW-ONSET ATRIAL FIBRILLATION IN COVID-19
Authors: Darae Ko, Timothy Treu, Laura Tarko, Yuk-Lam Ho, Ashley Galloway, Sarah Preis, Ludovic Trinquart, David Gagnon, Kevin M. Monahan, Robert Helm, Ariela R. Orkaby, Steven Lubitz, Allan Walkey, Kelly Cho, Peter W. Wilson, Emelia J. Benjamin
Journal: Journal of the American College of Cardiology (2022)
LEFT ATRIAL APPENDAGE OCCLUSION IN PATIENTS WITH LEFT VENTRICULAR ASSIST DEVICE
Authors: Jakrin Kewcharoen, Kuldeep Shah, Rahul Bhardwaj, Tahmeed Contractor, Mohit Turagam, Ravi Mandapati, Dhanunjaya R. Lakkireddy, Jalaj Garg
Journal: Journal of the American College of Cardiology (2022)
EUSTACHIAN VALVE ENDOCARDITIS: RARELY SOUGHT, OFTEN OVERLOOKED
Authors: George Horani, Kunwar Kaur, Prem Patel, Kalpeshkumar Shah, Dilesha Kumanayaka, Habib A. Habib, Joaquim Correia, Irvin D. Goldfarb, Fayez E. Shamoon
Journal: Journal of the American College of Cardiology (2022)
PREDICTION OF RISK FOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH ATRIAL FIBRILLATION INCREMENTAL VALUE OF DIASTOLIC WALL STRAIN
Authors: Yoshinobu Suwa, Yoko Miyasaka, Naoki Taniguchi, Shoko Harada, Eri Nakai, Ichiro Shiojima
Journal: Journal of the American College of Cardiology (2022)
Human autoantibodies underlying infectious diseases
Authors: Anne Puel, Paul Bastard, Jacinta Bustamante, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2022)

The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.
Immediate and Sustained Outcomes and Moderators Associated With Metacognitive Training for Psychosis
Authors: Danielle Penney, Geneviève Sauvé, Daniel Mendelson, Élisabeth Thibaudeau, Steffen Moritz, Martin Lepage
Journal: JAMA Psychiatry (2022)

<h3>Importance</h3> A substantial increase in the number of trials examining metacognitive training (MCT) for psychosis necessitates an updated examination of the outcomes associated with MCT. <h3>Objectives</h3> To review the immediate and sustained associations of MCT with proximal (directly targeted) and distal (indirectly influenced) outcomes and assess treatment- and participant-related moderators to identify the potential factors associated with the expected heterogeneity of effect sizes. <h3>Data Sources</h3> Eleven electronic databases were searched from 2007 to June 3, 2021 (alert until September 10, 2021). Reference lists of earlier meta-analyses and included reports were screened. <h3>Study Selection</h3> Reports examined MCT and included participants with schizophrenia spectrum and related psychotic disorders (1045 reports identified; 281 assessed). There were no age, sex, gender, race and ethnicity, language, or study design restrictions. Two reviewers performed the selection of studies to be analyzed. <h3>Data Extraction and Synthesis</h3> The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Data were extracted by 3 reviewers and pooled using random effects models. Hedges<i>g</i>effect sizes were computed. The Mixed-Methods Appraisal tool was used to assess study quality. <h3>Main Outcomes and Measures</h3> Proximal outcomes were global positive symptoms, delusions, hallucinations, and cognitive biases. Distal outcomes were self-esteem, negative symptoms, quality of life, well-being, and functioning. Immediate and sustained outcomes were examined. Meta-regressions, subgroup, and sensitivity analyses assessed moderators. <h3>Results</h3> This systematic review and meta-analysis included 43 studies (46 reports). Forty reports were synthesized in meta-analysis (N=1816 participants) and 6 reports were included in narrative review. In the studies examined, MCT was associated with positive symptoms (<i>g</i> = 0.50; 95% CI, 0.34-0.67), delusions (<i>g</i> = 0.69; 95% CI, 0.45-0.93), hallucinations (<i>g</i> = 0.26; 95% CI, 0.11-0.40), cognitive biases (<i>g</i> = 0.16; 95% CI, 0.03-0.29), self-esteem (<i>g</i> = 0.17; 95% CI, 0.03-0.31), negative symptoms (<i>g</i> = 0.23; 95% CI, 0.10-0.37), and functioning (<i>g</i> = 0.41; 95% CI, 0.12-0.69). These associations were maintained up to 1 year. The quality of life effect size was nonsignificant (<i>g</i> = 0.20; 95% CI, −0.07 to 0.47); only 1 study assessed well-being. Publication year was associated with moderated hallucinations (β = 0.04; 95% CI, 0.00-0.07). Overall, narrative review results corroborated meta-analytic findings. <h3>Conclusions and Relevance</h3> In this meta-analysis, MCT for psychosis was associated with benefits up to 1 year postintervention in several treatment contexts. These findings suggest that MCT may merit integration in treatment guidelines for schizophrenia.
Patients with presumed tuberculosis in sub-Saharan Africa that are not diagnosed with tuberculosis: a systematic review and meta-analysis
Authors: Shamanthi Jayasooriya, Francesca Dimambro-Denson, Claire Beecroft, Julie Balen, Babatunde Awokola, Caroline Mitchell, Beate Kampmann, Fiona Campbell, Pete Dodd, Kevin Mortimer
Journal: Thorax (2022)

Background Many patients in sub-Saharan Africa whom a diagnosis of tuberculosis is considered are subsequently not diagnosed with tuberculosis. The proportion of patients this represents, and their alternative diagnoses, have not previously been systematically reviewed. Methods We searched four databases from inception to 27 April 2020, without language restrictions. We included all adult pulmonary tuberculosis diagnostic studies from sub-Saharan Africa, excluding case series and inpatient studies. We extracted the proportion of patients with presumed tuberculosis subsequently not diagnosed with tuberculosis and any alternative diagnoses received. We conducted a random effects meta-analysis to obtain pooled estimates stratified by passive and active case finding. Results Our search identified 1799 studies, of which 18 studies (2002–2019) with 14 527 participants from 10 African countries were included. The proportion of patients with presumed tuberculosis subsequently not diagnosed with tuberculosis was 48.5% (95% CI 39.0 to 58.0) in passive and 92.8% (95% CI 85.0 to 96.7) in active case-finding studies. This proportion increased with declining numbers of clinically diagnosed tuberculosis cases. A history of tuberculosis was documented in 55% of studies, with just five out of 18 reporting any alternative diagnoses. Discussion Nearly half of all patients with presumed tuberculosis in sub-Saharan Africa do not have a final diagnosis of active tuberculosis. This proportion may be higher when active case-finding strategies are used. Little is known about the healthcare needs of these patients. Research is required to better characterise these patient populations and plan health system solutions that meet their needs. PROSPERO registration number CRD42018100004.
High-Flow Oxygen vs Conventional Oxygen and Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19—Reply
Authors: Gustavo A. Ospina-Tascón, Diana Martínez, Andrés Gempeler
Journal: JAMA (2022)

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