tbuckley/cabot-search huggingface dataset:
Abstract MP61: 1-year Prognosis By Coronary Artery And Extra-coronary Calcification In The 75-and-older Population
Authors: Yejin Mok, Yasuyuki Honda, Frances Wang, Candace Howard, Aaron R Folsom, Josef Coresh, Matthew Budoff, Michael J Blaha, Kuni Matsushita
Journal: Circulation (2022)

Background: Coronary artery calcium (CAC) is one of the most potent predictors of cardiovascular disease (CVD). Also, thoracic extra-coronary calcification (ECC) (e.g., aortic valve calcification) has provided additional prognostic information beyond CAC. However, data on CAC and ECC as predictors of CVD outcomes are limited in individuals aged ≥75 years and rarely report near-term prognosis despite its importance in the 75-and-older population given life expectancy. Methods: In 1,672 ARIC participants (age 75-94 years) without history of clinical coronary heart disease (CHD) at visit 7 (2018-2019), we assessed the associations of CAC and ECC with CVD (including CHD, stroke, and heart failure) over a median follow-up of 1.1 (IQI 0.7-1.5) years (46 CVD total cases), using adjusted Cox models. CAC and ECC were modeled categorically (Agatston scores 0-99 [reference], 100-299, and 300+) and continuously (log[Agatston score+1]). Results: Higher scores of CAC and calcium in the aortic valve (only when modeled continuously) and ascending aorta were significantly associated with elevated risk of CVD (e.g., adjusted hazard ratio [HR]: 2.79 [95% CI 1.21, 6.44] for CAC 300+ and 5.90 [2.42, 14.39] for ascending aorta calcium 300+ vs. 0-99.) ( Table ). We confirmed consistent results after excluding participants with prevalent stroke, and the association of aortic valve calcium 300+ with CVD became statistically significant (HR 2.31 [95% CI 1.02, 5.24]. When each CVD outcome was analyzed separately, significant associations with CHD and heart failure were shown in CAC (only when modeled continuously) and ascending aorta calcium (e.g., 4.98 [95% CI 1.10, 22.58] for CHD and 6.88 [2.14, 22.04] in ascending aorta calcium 300+). Conclusions: Coronary artery, ascending aorta, and aortic valve calcifications were positively associated with 1-year risk of CVD in 75+ year old. Our results support the prognostic value of CAC and ECC even in very old adults and suggest distinct prognostic implications of different vascular beds.
Clinically Tractable Outcome Prediction of Non-WNT/Non-SHH Medulloblastoma Based on TPD52 IHC in a Multicohort Study
Authors: Alberto Delaidelli, Christopher Dunham, Mariarita Santi, Gian Luca Negri, Joanna Triscott, Olga Zheludkova, Andrey Golanov, Marina Ryzhova, Konstantin Okonechnikov, Daniel Schrimpf, Damian Stichel, David W. Ellison, Andreas von Deimling, Marcel Kool, Stefan M. Pfister, Vijay Ramaswamy, Andrey Korshunov, Michael D. Taylor, Poul H. Sorensen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification. Experimental Design: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Results: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53–45.40; P &amp;lt; 0.0001], suggesting important implication for therapeutic choices. Conclusions: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
Retroperitoneal Chronic Expanding Hematoma Mimicking Malignancy on FDG PET/CT
Authors: Haruki Narita, Junki Takenaka, Shiro Watanabe, Takashige Abe, Kohsuke Kudo
Journal: Clinical Nuclear Medicine (2022)

Abstract A 49-year-old Japanese man had a chief complaint of left hypochondrium pain, and a CT scan revealed a mass in the left retroperitoneal space. CT and MRI scans revealed a hemorrhagic component and surrounding fibrous tissues. FDG PET/CT images showed increased uptake in the peripheral rim of the mass, indicating a malignant tumor. The SUV max was 7.6. We surgically resected the mass. The pathological examination confirmed the diagnosis of chronic expanding hematoma. It is difficult to differentiate CEH from malignant tumors on imaging; this should be recognized as a diagnostic pitfall.
Methods and indicators to validate country reductions in incidence of hepatitis C virus infection to elimination levels set by WHO
Authors: Adelina Artenie, Niklas Luhmann, Aaron G Lim, Hannah Fraser, Zoe Ward, Jack Stone, Louis MacGregor, Josephine G Walker, Adam Trickey, Lara K Marquez, Laith J Abu-Raddad, Houssein H Ayoub, Nick Walsh, Matthew Hickman, Natasha K Martin, Philippa Easterbrook, Peter Vickerman
Journal: The Lancet. Gastroenterology & hepatology (2022)
RTS,S: the first malaria vaccine
Authors: Fidel Zavala
Journal: Journal of Clinical Investigation (2022)

The long road to vaccine developmentAfter more than four decades of basic research and clinical trials, the World Health Organization (WHO) has recommended the malaria vaccine RTS,S for widespread use among children living in malaria endemic areas.Pioneering studies using rodent malaria models directed by Ruth S. Nussenzweig at the New York University School of Medicine demonstrated in the late 1960s that immunization with attenuated sporozoites -the infective stage of Plasmodium -induces immune responses that protect against parasite infection (1).These studies also identified the circumsporozoite protein (CSP), the sporozoite-specific molecule recognized by the protective immune responses that is the antigen incorporated in the RTS,S vaccine (2).The CSP is expressed on the surface of sporozoites of different Plasmodium species and contains a central domain of tandem repeats that represent approximately 30% of the entire sequence.Extensive experimental evidence indicates that binding of antibodies to these repeats immobilizes the sporozoites, preventing infection of hepatocytes, an obligatory stage of this infection (Figure 1).The RTS,S vaccine is a hepatitis B virus-like particle that contains a genetically fused portion of the repeat domain and the C-terminal region of the P. falciparum CSP (3).
Augmenting Adoptive T-cell Immunotherapy by Targeting the PD-1/PD-L1 Axis
Authors: Junyun Lai, Paul A. Beavis, Jasmine Li, Phillip K. Darcy
Journal: Cancer Research (2021)

Abstract Cancer immunotherapy utilizing checkpoint blockade antibodies or adoptive cellular therapy (ACT) with tumor-specific T cells has led to unprecedented clinical responses in patients with cancer and has been considered one of the most significant breakthroughs in cancer treatment in the past decade. Nevertheless, many cancers remain refractory to these therapies due to the presence of an immunosuppressive tumor microenvironment. This has led to the innovative idea of combining ACT with checkpoint inhibition. A landmark 2004 study by Blank and colleagues published in Cancer Research was one of the original demonstrations that adoptive transfer of T cells lacking the negative T-cell regulator, PD-1, was able to restore functional T-cell antitumor activity, resulting in rapid regression of established tumors in a preclinical model. This work was instrumental in not only driving clinical studies utilizing checkpoint inhibition but also a new wave of recent trials involving checkpoint blockade in the setting of ACT. See related article by Blank and colleagues, Cancer Res 2004;64:1140–1145.
FDG-Avid Sclerosing Adenosis of the Breast Mimicking Malignancy
Authors: Jian Zhang, Zhongfei Yu, Aisheng Dong, Yuzhao Zhu
Journal: Clinical Nuclear Medicine (2021)

Abstract Sclerosing adenosis is a common benign proliferative disorder of the breast. We describe FDG PET/CT findings in a case of sclerosing adenosis showing focal intense FDG uptake mimicking malignancy. This case indicates that sclerosing adenosis should be included in the differential diagnosis of focal breast FDG accumulation along with malignant and nonmalignant conditions.
Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes
Authors: Bertram Pitt, Gerasimos Filippatos, Rajiv Agarwal, Stefan D. Anker, George L. Bakris, Peter Rossing, Amer Joseph, Peter Kolkhof, Christina Nowack, Patrick Schloemer, Luis M. Ruilope
Journal: New England Journal of Medicine (2021)

Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear.
Deconvolving Clinically Relevant Cellular Immune Cross-talk from Bulk Gene Expression Using CODEFACS and LIRICS Stratifies Patients with Melanoma to Anti–PD-1 Therapy
Authors: Kun Wang, Sushant Patkar, Joo Sang Lee, E. Michael Gertz, Welles Robinson, Fiorella Schischlik, David R. Crawford, Alejandro A. Schäffer, Eytan Ruppin
Journal: Cancer Discovery (2022)

Abstract The tumor microenvironment (TME) is a complex mixture of cell types whose interactions affect tumor growth and clinical outcome. To discover such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a tool deconvolving cell type–specific gene expression in each sample from bulk expression, and LIRICS (Ligand–Receptor Interactions between Cell Subsets), a statistical framework prioritizing clinically relevant ligand–receptor interactions between cell types from the deconvolved data. We first demonstrate the superiority of CODEFACS versus the state-of-the-art deconvolution method CIBERSORTx. Second, analyzing The Cancer Genome Atlas, we uncover cell type–specific ligand–receptor interactions uniquely associated with mismatch-repair deficiency across different cancer types, providing additional insights into their enhanced sensitivity to anti–programmed cell death protein 1 (PD-1) therapy compared with other tumors with high neoantigen burden. Finally, we identify a subset of cell type–specific ligand–receptor interactions in the melanoma TME that stratify survival of patients receiving anti–PD-1 therapy better than some recently published bulk transcriptomics-based methods. Significance: This work presents two new computational methods that can deconvolve a large collection of bulk tumor gene expression profiles into their respective cell type–specific gene expression profiles and identify cell type–specific ligand–receptor interactions predictive of response to immune-checkpoint blockade therapy. This article is highlighted in the In This Issue feature, p. 873
A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature
Authors: Paul B. Dieffenbach, Christina Mallarino Haeger, Rakhshinda Rehman, Alexis M. Corcoran, Anna Maria F. Coronata, Shamsudheen K. Vellarikkal, Izabela Chrobak, Aaron B. Waxman, Sally H. Vitali, Lynette M. Sholl, Robert F. Padera, David Lagares, Francesca Polverino, Caroline A. Owen, Laura E. Fredenburgh
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Mechanical signaling through cell–matrix interactions plays a major role in progressive vascular remodeling in pulmonary arterial hypertension (PAH). MMP-8 (matrix metalloproteinase-8) is an interstitial collagenase involved in regulating inflammation and fibrosis of the lung and systemic vasculature, but its role in PAH pathogenesis remains unexplored. Objectives: To evaluate MMP-8 as a modulator of pathogenic mechanical signaling in PAH. Methods: MMP-8 levels were measured in plasma from patients with pulmonary hypertension (PH) and controls by ELISA. MMP-8 vascular expression was examined in lung tissue from patients with PAH and rodent models of PH. MMP-8–/– and MMP-8+/+ mice were exposed to normobaric hypoxia or normoxia for 4–8 weeks. PH severity was evaluated by right ventricular systolic pressure, echocardiography, pulmonary artery morphometry, and immunostaining. Proliferation, migration, matrix component expression, and mechanical signaling were assessed in MMP-8–/– and MMP-8+/+ pulmonary artery smooth muscle cells (PASMCs). Measurements and Main Results: MMP-8 expression was significantly increased in plasma and pulmonary arteries of patients with PH compared with controls and induced in the pulmonary vasculature in rodent PH models. Hypoxia-exposed MMP-8–/– mice had significant mortality, increased right ventricular systolic pressure, severe right ventricular dysfunction, and exaggerated vascular remodeling compared with MMP-8+/+ mice. MMP-8–/– PASMCs demonstrated exaggerated proliferation and migration mediated by altered matrix protein expression, elevated integrin-β3 levels, and induction of FAK (focal adhesion kinase) and downstream YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif) activity. Conclusions: MMP-8 is a novel protective factor upregulated in the pulmonary vasculature during PAH pathogenesis. MMP-8 opposes pathologic mechanobiological feedback by altering matrix composition and disrupting integrin-β3/FAK and YAP/TAZ-dependent mechanical signaling in PASMCs.
COVID-19 hospital admissions and deaths after BNT162b2 and ChAdOx1 nCoV-19 vaccinations in 2·57 million people in Scotland (EAVE II): a prospective cohort study
Authors: Utkarsh Agrawal, Srinivasa Vittal Katikireddi, Colin McCowan, Rachel H Mulholland, Amaya Azcoaga-Lorenzo, Sarah Amele, Adeniyi Francis Fagbamigbe, Eleftheria Vasileiou, Zoe Grange, Ting Shi, Steven Kerr, Emily Moore, Josephine L K Murray, Syed Ahmar Shah, Lewis Ritchie, Dermot O'Reilly, Sarah J Stock, Jillian Beggs, Antony Chuter, Fatemah Torabi, Ashley Akbari, Stuart Bedston, Jim McMenamin, Rachael Wood, Ruby S M Tang, Simon de Lusignan, F D Richard Hobbs, Mark Woolhouse, Colin R Simpson, Chris Robertson, Aziz Sheikh
Journal: The Lancet Respiratory Medicine (2021)
Comprehensive characterization of the epigenetic landscape in Multiple Myeloma
Authors: Elina Alaterre, Sara Ovejero, Laurie Herviou, Hugues de Boussac, Giorgio Papadopoulos, Marta Kulis, Stéphanie Boireau, Nicolas Robert, Guilhem Requirand, Angélique Bruyer, Guillaume Cartron, Laure Vincent, Anne Marie Martinez, José Ignacio Martin-Subero, Giacomo Cavalli, Jerome Moreaux
Journal: Theranostics (2022)

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2– Early Breast Cancer
Authors: Ulrike A. Nitz, Oleg Gluz, Sherko Kümmel, Matthias Christgen, Michael Braun, Bahriye Aktas, Kerstin Lüdtke-Heckenkamp, Helmut Forstbauer, Eva-Maria Grischke, Claudia Schumacher, Maren Darsow, Katja Krauss, Benno Nuding, Marc Thill, Jochem Potenberg, Christoph Uleer, Mathias Warm, Hans Holger Fischer, Wolfram Malter, Michael Hauptmann, Ronald E. Kates, Monika Gräser, Rachel Würstlein, Steven Shak, Frederick Baehner, Hans H. Kreipe, Nadia Harbeck
Journal: Journal of Clinical Oncology (2022)

To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer.Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental (v control) arm; secondary end points included distant DFS, overall survival, and translational research.Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority (P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% (P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001).WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.
Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial
Authors: Antoine Thiery-Vuillemin, Johann de Bono, Maha Hussain, Guilhem Roubaud, Giuseppe Procopio, Neal Shore, Karim Fizazi, Gabriel dos Anjos, Gwenaelle Gravis, Jae Young Joung, Nobuaki Matsubara, Daniel Castellano, Arnold Degboe, Chris Gresty, Jinyu Kang, Allison Allen, Christian Poehlein, Fred Saad
Journal: The Lancet Oncology (2022)
Ongoing rabies outbreak in dogs of unprecedented scale and human cases in Nelson Mandela Bay Municipality, South Africa, up to 13 February 2022
Authors: Matthijs F Ravensberg, Ewout B Fanoy, Jane Whelan, Carmen WE Embregts, Corine H GeurtsvanKessel, Jared B Strydom
Journal: Eurosurveillance (2022)

More than 430 cases of rabies have been confirmed in dogs in the Nelson Mandela Bay Metropolitan Municipality of South Africa since July 2021. We describe the ongoing outbreak, its geographical spread and six related human deaths that have occurred. Further investigation of the outbreak and vaccination of the dog population is required. Raising awareness among healthcare providers, the public, and among international travellers planning to visit the region, is key for action to protect human and animal health.
The barrier and beyond: Roles of intestinal mucus and mucin-type O-glycosylation in resistance and tolerance defense strategies guiding host-microbe symbiosis
Authors: Kirk Bergstrom, Lijun Xia
Journal: Gut Microbes (2022)

Over the past two decades, our appreciation of the gut mucus has moved from a static lubricant to a dynamic and essential component of the gut ecosystem that not only mediates the interface between host tissues and vast microbiota, but regulates how this ecosystem functions to promote mutualistic symbioses and protect from microbe-driven diseases. By delving into the complex chemistry and biology of the mucus, combined with innovative in vivo and ex vivo approaches, recent studies have revealed novel insights into the formation and function of the mucus system, the O-glycans that make up this system, and how they mediate two major host-defense strategies – resistance and tolerance – to reduce damage caused by indigenous microbes and opportunistic pathogens. This current review summarizes these findings by highlighting the emerging roles of mucus and mucin-type O-glycans in influencing host and microbial physiology with an emphasis on host defense strategies against bacteria in the gastrointestinal tract.
Targeting TGF-β for treatment of osteogenesis imperfecta
Authors: I-Wen Song, Sandesh C.S. Nagamani, Dianne Nguyen, Ingo Grafe, Vernon Reid Sutton, Francis H. Gannon, Elda Munivez, Ming-Ming Jiang, Alyssa Tran, Maegen Wallace, Paul Esposito, Salma Musaad, Elizabeth Strudthoff, Sharon McGuire, Michele Thornton, Vinitha Shenava, Scott Rosenfeld, Shixia Huang, Roman Shypailo, Eric Orwoll, Brendan Lee
Journal: Journal of Clinical Investigation (2022)

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-β signaling is a driver pathogenic mechanism in OI. Anti-TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.