tbuckley/cabot-search huggingface dataset:
Error in Table
Authors: Neil Goldenberg, Leonardo Brandão, Christoph Male
Journal: JAMA (2022)

Also, additional surveillance imaging may have exposed patients to more procedural sedation, ionizing radiation, and cost and would have required patients to spend extra time undergoing additional testing.However, change in thrombus burden at 3 months will be evaluated in a subsequent exploratory analysis.Third, Abdelmonem and colleagues inquire as to why the period for adverse event collection in the study was from randomization through 94 days after diagnosis of index venous thromboembolism.Given that the trial was designed to evaluate duration of therapy using currently prescribed anticoagulants rather than investigational drugs, an adverse event collection time frame was selected to optimize relevance to the study intervention; accordingly, this was defined in the trial protocol and the safety plan as the time from randomization to completion of the longer of the 2 randomized durations of anticoagulation.Nevertheless, data on recurrent venous thromboembolism and bleeding events were collected through 2 years.Fourth, Abdelmonem and colleagues note that the secondary outcome was driven by occurrences of postthrombotic syndrome, which developed in approximately 25% of patients younger than 21 years of age with extremity deep venous thrombosis and is consistent with prior literature in pediatric and adult populations.We agree that further study of prognostic factors for postthrombotic syndrome in patients younger than 21 years of age is warranted.Through clinical and translational research, 4-6 including the use of banked plasma from the Kids-DOTT trial, investigators in the field of pediatric venous thromboembolism should continue to investigate this important issue.
MOZ and Menin–MLL Complexes Are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor
Authors: Matthew L. Hemming, Morgan R. Benson, Michael A. Loycano, Justin A. Anderson, Jessica L. Andersen, Madeleine L. Taddei, Andrei V. Krivtsov, Brandon J. Aubrey, Jevon A. Cutler, Charlie Hatton, Ewa Sicinska, Scott A. Armstrong
Journal: Cancer Discovery (2022)

Abstract Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin-modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin–MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin–MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique ﻿chromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application. Significance: Although many malignancies rely on oncogene amplification, GIST instead depends upon epigenetic regulation of KIT and other essential genes. Utilizing genome-scale CRISPR dependency screens, we identified complementary chromatin-modifying complexes essential to GIST and characterize the consequences of their disruption, elucidating a novel therapeutic approach to this disease. This article is highlighted in the In This Issue feature, p. 1599
Estimating the cost of achieving basic water, sanitation, hygiene, and waste management services in public health-care facilities in the 46 UN designated least-developed countries: a modelling study
Authors: Michael Chaitkin, Samantha McCormick, Jorge Alvarez-Sala Torreano, Irene Amongin, Silvia Gaya, Odd N Hanssen, Richard Johnston, Tom Slaymaker, Claire Chase, Guy Hutton, Maggie Montgomery
Journal: The Lancet Global Health (2022)

An alarming number of public health-care facilities in low-income and middle-income countries lack basic water, sanitation, hygiene (WASH), and waste management services. This study estimates the costs of achieving full coverage of basic WASH and waste services in existing public health facilities in the 46 UN designated least-developed countries (LDCs).In this modelling study, in-need facilities were quantified by combining published counts of public facilities with estimated basic WASH and waste service coverage. Country-specific per-facility capital and recurrent costs to deliver basic services were collected via survey of country WASH experts and officials between Sept 24 and Dec 24, 2020. Baseline cost estimates were modelled and discounted by 5% per year. Key assumptions were adjusted to produce lower and upper estimates, including adjusting the discount rate to 8% and 3% per year, respectively.An estimated US$6·5 billion to $9·6 billion from 2021 to 2030 is needed to achieve full coverage of basic WASH and waste services in public health facilities in LDCs. Capital costs are $2·9 billion to $4·8 billion and recurrent costs are $3·6 billion to $4·8 billion over this time period. A mean of $0·24-0·40 per capita in capital investment is needed each year, and annual operations and maintenance costs are expected to increase from $0·10 in 2021 to $0·39-0·60 in 2030. Waste management accounts for the greatest share of costs, requiring $3·7 billion (46·6% of the total) in the baseline estimates, followed by $1·8 billion (23·1%) for sanitation, $1·5 billion (19·5%) for water, and $845 million (10·7%) for hygiene. Needs are greatest for non-hospital facilities ($7·4 billion [94%] of $7·9 billion) and for facilities in rural areas ($5·3 billion [68%]).Investment will need to increase to reach full coverage of basic WASH and waste services in public health facilities. Financial needs are modest compared with current overall health and WASH spending, and better service coverage will yield substantial health benefits. To sustain services and prevent degradation and early replacement, countries will need to routinely budget for operations and maintenance of WASH and waste management assets.WHO (including underlying grants from the governments of Japan, the Netherlands, and the UK), World Bank (including an underlying grant from the Global Water Security and Sanitation Partnership), and UNICEF.For the Arabic, French and Portuguese translations of the abstract see Supplementary Materials section.
CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms
Authors: Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, Mark J. Smyth
Journal: Journal of Clinical Investigation (2022)
Naming Autism in the Right Context
Authors: Andres Roman-Urrestarazu, Guillaume Dumas, Varun Warrier
Journal: JAMA Pediatrics (2022)

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Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and Potential Predictive Markers for Response to Crizotinib
Authors: Che-Jui Lee, Patrick Schöffski, Elodie Modave, Tom van Wezel, Bram Boeckx, Jozef Sufliarsky, Hans Gelderblom, Jean-Yves Blay, Maria Debiec-Rychter, Raf Sciot, Judith V.M.G. Bovée, Diether Lambrechts, Agnieszka Wozniak
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The European Organization for Research and Treatment of Cancer (EORTC) clinical phase II trial 90101 “CREATE” showed high antitumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations that could play a role in the response to crizotinib. Experimental Design: Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy-number alterations (CNA), and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between molecular findings and clinical outcomes. Results: We found 12 ALK fusions with 11 different partners in ALK-positive IMFT cases by Archer analysis whereas we did not identify any ROS1-rearranged tumor. One ALK-negative patient responding to crizotinib was found to have an ETV6–NTRK fusion in the tumor specimen. The CNA profile and mutational landscape of IMFT revealed extensive molecular heterogeneity. Loss of chromosome 19 (25% of cases) and PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib. Conclusions: We identified multiple genetic alterations in archival IMFT material and provide further insight into the molecular profile of this ultra-rare, heterogeneous malignancy, which may potentially translate into novel treatment approaches for this orphan disease.
Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments
Authors: Lennart Kester, Danielle Seinstra, Annelot G.J. van Rossum, Claire Vennin, Marlous Hoogstraat, Daphne van der Velden, Mark Opdam, Erik van Werkhoven, Kerstin Hahn, Iris Nederlof, Ester H. Lips, Ingrid A.M. Mandjes, A. Elise van Leeuwen-Stok, Sander Canisius, Harm van Tinteren, Alex L.T. Imholz, Johanneke E.A. Portielje, Monique E.M.M. Bos, Sandra D. Bakker, Emiel J. Rutgers, Hugo M. Horlings, Jelle Wesseling, Emile E. Voest, Lodewyk F.A. Wessels, Marleen Kok, Hendrika M. Oosterkamp, Alexander van Oudenaarden, Sabine C. Linn, Jacco van Rheenen
Journal: Clinical Cancer Research (2021)

Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.
Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma
Authors: Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine Monestier, Laurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.
Interesting Manifestation of Autoimmune Encephalitis on FDG PET Scan
Authors: Abtin Doroudinia, Behnam Safarpour Lima, Mehrdad Bakhshayesh Karam, Niloufar Ghadimi, Farhad Yousefi
Journal: Clinical Nuclear Medicine (2021)

Abstract We are presenting a 22-year-old man with intractable seizures. Autoimmune epilepsy, vasculitis, and paraneoplastic disorder were among initial differential diagnoses. His initial laboratory tests and toxicology screen were unremarkable. His initial brain MRI demonstrated generalized cortical atrophy. Features such as progressive encephalopathy, neuropsychiatric symptoms, personality change, and autonomic dysfunction were in favor of autoimmune encephalitis. Autoantibody evaluations including anti-NMDA receptor (NR1) IgG were negative in both serum and CSF samples. FDG PET scan demonstrated intense FDG uptake in the basal ganglia, more prominent in the caudate nuclei and putamina, which is one of the known autoimmune encephalitis imaging features.
Abstract 10651: Identification of Allele-Specific Gene Expression in Association with Blood Pressure
Authors: Amena Keshawarz, Tianxiao Huan, Roby Joehanes, Chen Yao, Ching-Ti Liu, Cumhur Demirkale, Vasan S Ramachandran, L Adrienne Cupples, Daniel Levy
Journal: Circulation (2021)

Introduction: Risk of hypertension is explained by both behavioral and genetic factors that may act on transcriptomic mechanisms to affect blood pressure variability. Methods: Whole genome sequencing and RNA sequencing data were obtained on 1,671 Framingham Heart Study (FHS) participants (mean age 54±13 years). Allelic expression of heterozygous SNPs was measured and allelic imbalance was identified using a binomial test. SNPs with significant allelic imbalance were evaluated in linear regression to test the association between the reference/total allele count ratio and 1) systolic blood pressure (SBP), and 2) diastolic blood pressure (DBP). Models were adjusted for age, sex, BMI, and family structure. Results: At a Bonferroni-corrected p-value&lt;6.4E-8, we identified 20,890 SNPs with significant allelic imbalance at MAF&gt;0.01. Prior GWAS have identified &gt;2,000 SNPs associated with SBP, DBP, or hypertension; we identified allelic expression imbalance of 60 SNPs (in 44 genes) that were reported in GWAS to be associated with SBP, and of eight SNPs (in two genes) that are associated with DBP. These genes were significantly enriched for the immune effector process pathway (p=1.4E-7). Fifteen SNPs were located in promoter or promoter-flanking regions, while the remaining SNPs were located in protein-coding regions. Seventeen SNPs were also cis -eQTLs, of which four transcripts also were associated with SBP or DBP in the FHS cohort. Conclusion: We identified ASE linked to blood pressure. Our results suggested that novel transcriptomic regulatory mechanisms involving allelic imbalance at specific SNPs may play a role in blood pressure regulation.
Abstract EP67: Early Menopause Is Linked To Increased Risk Of Presenile Dementia Before Age 65 Years
Authors: Wenting Hao, Chunying Fu, Dongshan Zhu
Journal: Circulation (2022)

Introduction: Evidence on the association between age at menopause and risk of dementia has been inconsistent. Some studies observed that later menopause was related to lower risk of dementia, while others reported no association, or even came to the opposite. Estradiol plays an important role in a wide range of neurological functions in brain, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative diseases, and accelerate the progression of dementia. Hypothesis: Based on the neuroprotective effects of estrogen, we hypothesized that earlier menopause might be related to higher risk of and earlier onset of dementia, compared with menopause at normal age or later. Methods: We used cohort data from UK Biobank and a total of 153 291 postmenopausal women were included. Age at menopause was categorized as &lt;40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-55, and &gt;55 years. The main outcome was all-cause dementia, a comprehensive outcome including Alzheimer's disease (AD), vascular dementia (VD) and dementia classified elsewhere. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between menopausal age and all-cause dementia. We also stratified the age when dementia was diagnosed into ≤65 years and &gt;65 years to explore the association between age at menopause and timing of experiencing dementia. All HRs were adjusted for age at last follow-up, race, education level, BMI, cigarette smoking, alcohol drinking, cardiovascular disease status, diabetes status, income, leisure activities and physical activities. We also used restricted cubic splines to analyze the dose-response relationship between menopausal age and dementia. Results: Among the 153 291 women, there were 1688 woman suffering from all-cause dementia. The average follow-up time was 11.7 years. Compared with menopausal age of 50-51 years, the HRs (95% CI) with dementia in women with menopausal age &lt;40, 40-44, 45-49, 52-55 and &gt;55 years were 1.53 (1.22-1.91), 1.07 (0.89-1.28), 1.08 (0.94-1.25), 0.81 (0.70-0.94), and 0.91 (0.78-1.06) respectively. Restricted cubic spline also showed an inverse dose-response relationship between them. In addition, compared to women with menopausal age of 50-51 years, women with early menopause (&lt;45 years) had elevated risk of experiencing all-caused dementia before age 65 years (1.31, 1.07-1.72; P &lt;0.001). Conclusions: Compared to women with menopausal age of 50-51 years, women with premature menopause (&lt;40 years) had around 35% higher risk of having all-cause dementia, and women with early menopause (&lt;45 years) were 1.3 times more likely to experience presenile dementia before age 65 years. Women with early menopause may need a close monitoring of their cognitive decline in clinical practice.
SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells
Authors: Yuling Han, Jiajun Zhu, Liuliu Yang, Benjamin E. Nilsson-Payant, Romulo Hurtado, Lauretta A. Lacko, Xiaolu Sun, Aravind R. Gade, Christina A. Higgins, Whitney J. Sisso, Xue Dong, Maple Wang, Zhengming Chen, David D. Ho, Geoffrey S. Pitt, Robert E. Schwartz, Benjamin R. tenOever, Todd Evans, Shuibing Chen
Journal: Circulation Research (2022)

Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.
SARS-CoV-2 vaccine effectiveness in preventing confirmed infection in pregnant women
Authors: Adeel A. Butt, Hiam Chemaitelly, Abdullatif Al Khal, Peter V. Coyle, Huda Saleh, Anvar H. Kaleeckal, Ali Nizar Latif, Roberto Bertollini, Abdul-Badi Abou-Samra, Laith J. Abu-Raddad
Journal: Journal of Clinical Investigation (2021)

BackgroundSARS-CoV-2 infection in pregnancy is associated with a higher risk of pregnancy-related complications and neonatal respiratory distress and hospitalization. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known.MethodsAll women with confirmed pregnancy who presented to the national referral hospital in Qatar between December 20, 2020, and May 30, 2021, with at least 1 SARS-CoV-2 test and not testing prior to pregnancy were included. We determined the vaccine effectiveness of mRNA vaccines in preventing confirmed SARS-CoV-2 infection during pregnancy using both cohort and test-negative case-control designs. Analyses were adjusted for age group, nationality, and gestational age.ResultsAmong 4534 pregnant women, there were 407 vaccinated and 407 unvaccinated women in the matched cohort analysis. Vaccine effectiveness was 87.6% (95%CI 44.1%-97.2%) at least 14 days after the second dose. There were 386 test-positive and 834 matched women in the test-negative case control analysis. Vaccine effectiveness was 86.8% (95%CI 47.5%-98.5%) at least 14 days after the second dose. Adjustment for age, nationality, and gestational age yielded similar results for both designs. In the test-negative analysis, vaccine effectiveness at least 14 days after the first dose but before the second dose was 40.8% (95% CI 0.0%-80.4%). Of the 386 test-positive pregnant women, 74 cases were Alpha variant, 163 cases were Beta variant, and 156 cases were variants of unknown status. There were 9 severe or critical disease cases and no deaths in the test-positive pregnant women, all of whom were unvaccinated.ConclusionThe mRNA vaccines provide a high level of protection against documented SARS-CoV-2 infection, which supports the inclusion of pregnant women in vaccination campaigns.FUNDINGHamad Medical Corporation, Weill Cornell Medicine Qatar, and the Ministry of Public Health Qatar.