tbuckley/cabot-search huggingface dataset:
Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer
Authors: Upasana Ray, Deok-Beom Jung, Ling Jin, Yinan Xiao, Subramanyam Dasari, Sayantani Sarkar Bhattacharya, Prabhu Thirusangu, Julie K. Staub, Debarshi Roy, Bhaskar Roy, S. John Weroha, Xiaonan Hou, James W. Purcell, Jamie N. Bakkum-Gamez, Scott H. Kaufmann, Nagarajan Kannan, Anirban K. Mitra, Viji Shridhar
Journal: Cancer Research (2021)

Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases.Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.
EPR22-113: Awareness, Utilization, and NCCN Guideline-Adherence to Breast Cancer Risk Management Behavior Among a Community-Based Sample of High-Risk Women
Authors: Rachel J Meadows, Anna Muraveva, Christina Bijou, Kate Shane-Carson, Coralia Balasca, Celia E Wills, Lisa D Yee, Electra D Paskett, Tasleem J Padamsee
Journal: Journal of the National Comprehensive Cancer Network (2022)

"EPR22-113: Awareness, Utilization, and NCCN Guideline-Adherence to Breast Cancer Risk Management Behavior Among a Community-Based Sample of High-Risk Women" published on 31 Mar 2022 by National Comprehensive Cancer Network.
Green Operating Room—Current Standards and Insights From a Large North American Medical Center
Authors: Sharath Kumar Anand, Lauren G. Culver, Joseph Maroon
Journal: JAMA Surgery (2022)

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Single-cell RNA sequencing reveals intrahepatic and peripheral immune characteristics related to disease phases in HBV-infected patients
Authors: Chao Zhang, Jiesheng Li, Yongqian Cheng, Fanping Meng, Jin-Wen Song, Xing Fan, Hongtao Fan, Jing Li, Yu-Long Fu, Ming-Ju Zhou, Wei Hu, Si-Yu Wang, Yuan-Jie Fu, Ji-Yuan Zhang, Ruo-Nan Xu, Ming Shi, Xueda Hu, Zemin Zhang, Xianwen Ren, Fu-Sheng Wang
Journal: Gut (2022)

Objective A comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure. Design We performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation. Results Both IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell–cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores. Conclusion Our study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.
Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Authors: Sylvain Garciaz, Andrew A. Guirguis, Sebastian Müller, Fiona C. Brown, Yih-Chih Chan, Ali Motazedian, Caitlin L. Rowe, James A. Kuzich, Kah Lok Chan, Kevin Tran, Lorey Smith, Laura MacPherson, Brian Liddicoat, Enid Y.N. Lam, Tatiana Cañeque, Marian L. Burr, Véronique Litalien, Giovanna Pomilio, Mathilde Poplineau, Estelle Duprez, Sarah-Jane Dawson, Georg Ramm, Andrew G. Cox, Kristin K. Brown, David C.S. Huang, Andrew H. Wei, Kate McArthur, Raphaël Rodriguez, Mark A. Dawson
Journal: Cancer Discovery (2021)

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.
ADULTS LIVING IN RURAL AREAS EXPERIENCE DISPARITIES IN HEALTH CARE ACCESS, AFFORDABILITY, AND CARDIOVASCULAR SCREENING COMPARED TO THOSE LIVING IN URBAN AREAS OF THE UNITED STATES
Authors: Ashley N. Kyalwazi, Yun Wang, Andrew S. Oseran, Robert W. Yeh, Rishi Wadhera
Journal: Journal of the American College of Cardiology (2022)
LEFT VENTRICULAR DYSFUNCTION DURING ACUTE PULMONARY EMBOLISM
Authors: Rafael Cires-Drouet, Allison LaRocco, Danielle Soldin, Thomas John, Shahab Toursavadkohi, Khanjan Nagarsheth, Brajesh K. Lal, Minerva Mayorga-Carlin, John Sorkin, Kevin Jones, Daniel Haase, Susie Nam Hong-Zohlman, Gautam V. Ramani, Bradley Taylor
Journal: Journal of the American College of Cardiology (2022)
Clinical Outcomes and Epidemiological Characteristics of Coronavirus-Infected Patients with Complete Immunization for Covid-19 Hospitalized In Intensive Care Unit
Authors: Tania Leme da Rocha Martinez, André Luis Valera Gasparoto, Thomaz Braga Ceglias, Anita L R Saldanha, Ana Paula Pantoja Margeotto, André Luiz Parrilha Panont, Otávio Castilho, Raoni Rego Godinho, Victor Hugo Parrilha Panont
Journal: Clinical Cardiology and Cardiovascular Interventions (2022)

The outcome of COVID-19 patients once admitted to the Intensive Care Unit can be compared as to their immunization status. As a stronger immune response is very important for recovery in all medical situations. From a total number of 181 patients with COVID-19 infection admitted to the ICU that had been fully vaccinated with two doses and at least 21 days before admission, all clinical and risk factors parameters were calculated. As it turned out there was a significant fall in all complications and the mortality rate was 10% less than that expected by the SAPS3 (43%). The authors emphasize the recommendation for complete vaccination for COVID-19 having had a very significant fall in the mortality rate. Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein.
Development of a peptide vaccine against hookworm infection: Immunogenicity, efficacy, and immune correlates of protection
Authors: Ahmed O. Shalash, Luke Becker, Jieru Yang, Paul Giacomin, Mark Pearson, Waleed M. Hussein, Alex Loukas, Istvan Toth, Mariusz Skwarczynski
Journal: Journal of Allergy and Clinical Immunology (2022)
Defining changes in physical limitation from the patient perspective: insights from the <scp>VITALITY‐HFpEF</scp> randomized trial
Authors: Javed Butler, John A. Spertus, Luke Bamber, Muhammad Shahzeb Khan, Lothar Roessig, Vanja Vlajnic, Josephine M. Norquist, Kevin J. Anstrom, Robert O. Blaustein, Carolyn S.P. Lam, Paul W. Armstrong
Journal: European Journal of Heart Failure (2022)

Clinically important thresholds in patient-reported outcomes measures like the Kansas City Cardiomyopathy Questionnaire (KCCQ) have not been defined for patients with heart failure and preserved ejection fraction (HFpEF). The aim of this study was to estimate meaningful thresholds for improvement or worsening in the KCCQ physical limitation score (PLS) in patients with HFpEF.In this pre-specified analysis from VITALITY-HFpEF, anchor- and distribution-based approaches were used to estimate thresholds for improvement or worsening in the KCCQ-PLS using Patient Global Impression of Change (PGIC) as an anchor. The KCCQ-PLS contains six elements, with each increment in response resulting in a change of 4.17 points when converted to a 0-100 scale. The mean change in KCCQ-PLS from baseline to week 12 was calculated for each PGIC group to estimate a meaningful within-patient change. Of 789 patients enrolled, 698 had complete KCCQ-PLS and PGIC data at week 12. The mean (± standard deviation) changes in KCCQ-PLS corresponding to PGIC changes of 'a little better', 'better', and 'much better' were 5.7 ± 18.6, 11.6 ± 19.3, and 18.4 ± 25.3 points, respectively. The scores of patients who responded 'a little better' (n = 177) overlapped substantially with those who reported 'no change' (n = 193; mean change 2.8 ± 18.9). The mean change in KCCQ-PLS for patients responding 'a little worse' (n = 32) was -2.6 ± 18.0 points. The threshold for meaningful within-patient change in KCCQ-PLS based on distribution-based analyses was 12.3 points. Using area under the curve (AUC) analyses of KCCQ-PLS, the sensitivity and specificity of a 4.17-point change were 0.61 and 0.57, for an 8.33-point change they were 0.49 and 0.64, and for a 12.5-point change they were 0.44 and 0.72 for being at least a little better on the PGIC (AUC = 0.54).In the VITALITY-HFpEF trial, a change in KCCQ-PLS of ≥8.33 points (corresponding to an improvement in ≥2 response categories of KCCQ-PLS) may represent the minimal clinically important difference for improvement and a change of ≤ -4.17 points (corresponding to a worsening in ≥1 response category of KCCQ-PLS) may suggest deterioration in patients with HFpEF.
The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies
Authors: Philip F. Halloran, Jeff Reeve, Katelynn S. Madill-Thomsen, Zachary Demko, Adam Prewett, Paul Billings
Journal: Journal of the American Society of Nephrology (2022)

The relationship between the donor-derived cell-free DNA fraction (dd-cfDNA[%]) in plasma in kidney transplant recipients at time of indication biopsy and gene expression in the biopsied allograft has not been defined.In the prospective, multicenter Trifecta study, we collected tissue from 300 biopsies from 289 kidney transplant recipients to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in corresponding plasma samples drawn just before biopsy. Rejection was assessed with the microarray-based Molecular Microscope Diagnostic System using automatically assigned rejection archetypes and molecular report sign-outs, and histology assessments that followed Banff guidelines.The median time of biopsy post-transplantation was 455 days (5 days to 32 years), with a case mix similar to that of previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probe sets correlating with dd-cfDNA(%) were previously annotated for association with ABMR and all types of rejection, either natural killer (NK) cell-expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-γ-inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, dd-cfDNA(%) correlated very strongly with ABMR and all types of rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury, and atrophy fibrosis. Active ABMR, mixed, and active TCMR had the highest dd-cfDNA(%), whereas dd-cfDNA(%) was lower in late-stage ABMR and less-active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted dd-cfDNA(%) better than histologic variables.The dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.NCT04239703.
LIBMAN-SACKS ENDOCARDITIS TREATMENT WITH WARFARIN AFTER RIVAROXABAN FAILURE: BREAKING THE CASCADE OF DELETERIOUS SEQUELAE
Authors: Yeraz Khachatoorian, Glenmore Lasam, Basera Sabharwal, Loba Alam, Karan Sud, Edgar Argulian, Soheila Talebi
Journal: Journal of the American College of Cardiology (2022)
Structural insights into collagen binding by platelet receptor glycoprotein VI
Authors: Louris J. Feitsma, Harma C. Brondijk, Gavin E. Jarvis, Dominique Hagemans, Dominique Bihan, Natasia Jerah, Marian Versteeg, Richard W. Farndale, Eric G. Huizinga
Journal: Blood (2022)
Malignant Syphilis
Authors: Richard Lueking, Susana Lazarte
Journal: New England Journal of Medicine (2022)

A 42-year-old man with untreated HIV infection presented with ulcerating skin lesions and systemic symptoms. The rapid plasma reagin titer was 1:512, and a skin-biopsy sample showed spirochetes. A diagnosis of malignant syphilis, an uncommon form of secondary syphilis, was made.
CLINICAL VALIDATION OF A NEW INTRAVASCULAR ULTRASOUND SYSTEM: A COMPARATIVE ANALYSIS ON LENGTH MEASUREMENTS
Authors: Chenguang Li, Junqing Yang, Xi Wang, Feng Zhang, Qinhua Jin, Chengwei Ju, Jun Guo, William Kongto Hau, Li Shen, Genshan Ma, Chunguang Qiu, Jiyan Chen, Juying Qian, Yundai Chen, Junbo Ge
Journal: Journal of the American College of Cardiology (2022)
Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis
Authors: Miranda P. Steenbeek, Majke H.D. van Bommel, Johan Bulten, Julia A. Hulsmann, Joep Bogaerts, Christine Garcia, Han T. Cun, Karen H. Lu, Heleen J. van Beekhuizen, Lucas Minig, Katja N. Gaarenstroom, Marielle Nobbenhuis, Mateja Krajc, Vilius Rudaitis, Barbara M. Norquist, Elizabeth M. Swisher, Marian J.E. Mourits, Leon F.A.G. Massuger, Nicoline Hoogerbrugge, Rosella P.M.G. Hermens, Joanna IntHout, Joanne A. de Hullu
Journal: Journal of Clinical Oncology (2022)

After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study.From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO.BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.
DeepCAGE: Incorporating Transcription Factors in Genome-Wide Prediction of Chromatin Accessibility
Authors: Qiao Liu, Kui Hua, Xuegong Zhang, Wing Hung Wong, Rui Jiang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Although computational approaches have been complementing high-throughput biological experiments for the identification of functional regions in the human genome, it remains a great challenge to systematically decipher interactions between transcription factors (TFs) and regulatory elements to achieve interpretable annotations of chromatin accessibility across diverse cellular contexts. To solve this problem, we propose DeepCAGE, a deep learning framework that integrates sequence information and binding statuses of TFs, for the accurate prediction of chromatin accessible regions at a genome-wide scale in a variety of cell types. DeepCAGE takes advantage of a densely connected deep convolutional neural network architecture to automatically learn sequence signatures of known chromatin accessible regions and then incorporates such features with expression levels and binding activities of human core TFs to predict novel chromatin accessible regions. In a series of systematic comparisons with existing methods, DeepCAGE exhibits superior performance in not only the classification but also the regression of chromatin accessibility signals. In a detailed analysis of TF activities, DeepCAGE successfully extracts novel binding motifs and measures the contribution of a TF to the regulation with respect to a specific locus in a certain cell type. When applied to whole-genome sequencing data analysis, our method successfully prioritizes putative deleterious variants underlying a human complex trait and thus provides insights into the understanding of disease-associated genetic variants. DeepCAGE can be downloaded from https://github.com/kimmo1019/DeepCAGE.
Primary Breast Lymphoma Detected by 18F-FDG and 68Ga-DOTA-FAPI-04 PET/CT
Authors: Yi Tao, Feifei Wang, Liming Chen, Zhanwen Huang
Journal: Clinical Nuclear Medicine (2022)

Abstract Primary breast lymphoma is a rare form of extranodal lymphoma. We report 18 F-FDG and 68 Ga-DOTA-FAPI-04 PET/CT findings of breast lymphoma in a 60-year-old woman. Both breast ultrasound and mammogram showed a mass in the right breast and suggested that the mass might be a malignant tumor. She was referred for an 18 F-FDG PET/CT scan and subsequently recruited in our 68 Ga-DOTA-FAPI-04 PET/CT trial. Both scans revealed the breast mass with intense tracer uptake. Biopsy and immunohistochemical examinations of the mass confirmed the diagnosis of diffuse large B-cell lymphoma.
Abstract P3-14-20: Racial and ethnic groups have different clustering of variants of uncertain significance
Authors: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel
Journal: Cancer Research (2022)

Abstract Background:Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS), likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results:Hispanic and African American patients had approximately twice as many uncertain results (VUS) compared to Caucasian patients for all cancer genes examined. Conclusions:Variant adjudication has disproportionately sorted out more uncertain results in Caucasians than Hispanics and African Americans. This leads to greater uncertainty in post-test counseling for these groups and should be a focus for lab testing companies going forward. Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of variants of uncertain significance [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 P3-14-20.
ACUTE MYOCARDITIS, CARDIOMYOPATHY AND PERICARDIAL TAMPONADE: A RARE CARDIAC TRINITY OF ACUTE MYELOID LEUKEMIA
Authors: Manasa Jasti, Parth Desai, Joanne Sutter, Thriveni Sanagala, Mushabbar A. Syed
Journal: Journal of the American College of Cardiology (2022)
SYSTEMATIC REVIEW AND META-ANALYSIS OF REMDESIVIR AND BRADYCARDIA IN PATIENTS WITH COVID-19
Authors: Daniel Jipescu, Aman Patel, Luna Liu, Daniel McMahan, Giridhar D. Mundluru, Kamala P. Tamirisa, Cezar Iliescu, Senthil Thambidorai
Journal: Journal of the American College of Cardiology (2022)