tbuckley/cabot-search huggingface dataset:
Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression
Authors: Tingjie Wang, Chuanrui Xu, Zhijing Zhang, Hua Wu, Xiujuan Li, Yu Zhang, Nan Deng, Ningxin Dang, Guangbo Tang, Xiaofei Yang, Bingyin Shi, Zihang Li, Lei Li, Kai Ye
Journal: Hepatology (2022)

Abstract Background and Aims Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. Approach and Results We performed single‐cell RNA sequencing (scRNA‐seq) using AKT/Notch intracellular domain–induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real‐time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress‐responding and proliferating subpopulations in late‐stage mouse ICC tissues and validated them using human scRNA‐seq data sets. By integrating weighted correlation network analysis and protein–protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ‐type containing 1 ( Zmiz1 ) and Y box protein 1 ( Ybx1 ) as core transcription factors required by stress‐responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA‐seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4‐Notch4‐Efnb2 signaling–dependent. Conclusions Stress‐responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast–endothelial cell interaction promotes ICC development.
Exclusive breast-feeding, the early-life microbiome and immune response, and common childhood respiratory illnesses
Authors: Christian Rosas-Salazar, Meghan H. Shilts, Zheng-Zheng Tang, Qilin Hong, Kedir N. Turi, Brittney M. Snyder, Derek A. Wiggins, Christian E. Lynch, Tebeb Gebretsadik, R. Stokes Peebles, Larry J. Anderson, Suman R. Das, Tina V. Hartert
Journal: Journal of Allergy and Clinical Immunology (2022)
Predicting Individual Changes in Terminal Half-Life After Switching to Extended Half-Life Concentrates in Patients With Severe Hemophilia
Authors: Olav Versloot, Emma Iserman, Pierre Chelle, Federico Germini, Andrea N. Edginton, Roger E. G. Schutgens, Alfonso Iorio, Kathelijn Fischer
Journal: HemaSphere (2022)

Predicting individual effects of switching from standard half-life (SHL) to extended half-life (EHL) FVIII/FIX concentrates is pivotal in clinical care, but large-scale individual data are scarce. The aim of this study was to assess individual changes in terminal half-life (THL) after switching to EHL concentrates and identifying determinants of a clinically relevant THL extension in people with severe hemophilia. Data from participants with pharmacokinetic studies on both SHL and EHL were extracted from the Web-Accessible Population Pharmacokinetics Service (WAPPS) database and stratified according to hemophilia type and age groups (children/adults). A 30% increase in THL was considered clinically relevant. Predictors of a relevant increase were identified using logistic regression. Data from 688 persons with severe hemophilia (2174 infusions) were included: 89% hemophilia A; median age: 21.7 (interquartile range [IQR]: 11.5-37.7); positive inhibitor history: 11.7%. THL increased by 38% (IQR: 17%-67%) and 212% (139%-367%) for hemophilia A and B, respectively. All EHL-FIX concentrate users showed clinically relevant THL extension. However, 40% (242/612) of people with hemophilia A showed limited extension or decrease in THL after switching. Relevant FVIII-THL extension was predicted by short baseline THL and blood group non-O in both children and adults. In conclusion, clinically relevant THL extension was observed in all 75/76 participants switching to EHL-FIX, and in 60% of 612 switching to EHL-FVIII. Short THL on SHL-FVIII and blood group non-O were identified as predictors for a relevant THL increase after switching to EHL-FVIII. Individualized pharmacokinetic assessment may guide clinical decision-making when switching from SHL to EHL-FVIII.
CORONARY STENT BALLOON INFLATION TECHNIQUE DURING PERCUTANEOUS CORONARY INTERVENTION IS IMPORTANT IN LIMITING MICROVASCULAR DYSFUNCTION: THE EMPIRE RANDOMISED CONTROLLED TRIAL
Authors: Stephen P. Hoole, Muhammad Aetesam-ur-Rahman, Yi-Da Chiu, Tian Zhao, Joana Oliveira, Clare East, Kitty Paques, Jo Steele, Melissa Duckworth, Sarah Fielding, Nick E. West
Journal: Journal of the American College of Cardiology (2022)
Extracellular vesicles and PD-L1 suppress macrophages, inducing therapy resistance in <i>TP53</i>-deficient B-cell malignancies
Authors: Elena Izquierdo, Daniela Vorholt, Stuart Blakemore, Benedict Sackey, Janica L. Nolte, Verena Barbarino, Jan Schmitz, Nadine Nickel, Daniel Bachurski, Liudmila Lobastova, Milos Nikolic, Michael Michalik, Reinhild Brinker, Olaf Merkel, Marek Franitza, Theodoros Georgomanolis, René Neuhaus, Maximilian Koch, Niklas Nasada, Gero Knittel, Björn Chapuy, Nicole Ludwig, Eckart Meese, Lukas Frenzel, Hans Christian Reinhardt, Martin Peifer, Rocio Rebollido-Rios, Heiko  Bruns, Marcus Krüger, Michael Hallek, Christian P. Pallasch
Journal: Blood (2022)
Project 2025: Proposals for the Continued Success of Drug Development in Acute Myeloid Leukemia
Authors: Daniel A. Pollyea, John Barrett, Courtney D. DiNardo, Laura C. Michaelis, Gail J. Roboz, Robert Q. Le, Kelly J. Norsworthy, R. Angelo de Claro, Marc R. Theoret, Richard Pazdur
Journal: Clinical Cancer Research (2021)

The Food and Drug Administration Oncology Center of Excellence initiated Project 2025 to develop 5-year goals in specific areas of oncology drug development. This meeting, in October 2020, brought together a panel of regulators and academic experts in acute myeloid leukemia (AML) to discuss opportunities to maximize the success that has recently occurred in AML drug development. The panel discussed challenges and opportunities in clinical trial design and novel endpoints, and outlined key considerations for drug development to facilitate continued growth in the field.
THE PROTECTIVE EFFECT OF TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR) ON RENAL FUNCTION
Authors: Deepa Soodi, Paul Yeung-Lai-Wah, Peter Umukoro, Somto Nwaedozie, Rachel Gabor, Eric DeJarlais, Romel Jose Garcia-Montilla
Journal: Journal of the American College of Cardiology (2022)
MYOCARDIAL PERFUSION IS ASSOCIATED WITH BIOMARKERS OF METABOLIC DISEASE AND CARDIAC REMODELING IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Jonathan A. Pan, Connor Siggins, Adrian Loffler, Sujith Kuruvilla, Frederick Epstein, Christopher M. Kramer, Ellen Keeley, Li-Ming Gan, Michael Salerno
Journal: Journal of the American College of Cardiology (2022)
Looking through the Lens of the Ribosome Biogenesis Evolutionary History: Possible Implications for Archaeal Phylogeny and Eukaryogenesis
Authors: Michael Jüttner, Sébastien Ferreira-Cerca
Journal: Molecular Biology and Evolution (2022)

Abstract Our understanding of microbial diversity and its evolutionary relationships has increased substantially over the last decade. Such an understanding has been greatly fueled by culture-independent metagenomics analyses. However, the outcome of some of these studies and their biological and evolutionary implications, such as the origin of the eukaryotic lineage from the recently discovered archaeal Asgard superphylum, is debated. The sequences of the ribosomal constituents are amongst the most used phylogenetic markers. However, the functional consequences underlying the analysed sequence diversity and their putative evolutionary implications are essentially not taken into consideration. Here, we propose to exploit additional functional hallmarks of ribosome biogenesis to help disentangle competing evolutionary hypotheses. Using selected examples, such as the multiple origins of halophily in archaea or the evolutionary relationship between the Asgard archaea and Eukaryotes, we illustrate and discuss how function-aware phylogenetic framework can contribute to refining our understanding of archaeal phylogeny and the origin of eukaryotic cells.
CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL IS ASSOCIATED WITH FUTURE CARDIOVASCULAR EVENTS IN PATIENTS WITH EARLY VASCULAR AGING
Authors: Nadia Akhiyat, Terra Lasho, Morsaleh Ganji, Takumi Toya, Chang-Xin Shi, Xianfeng Chen, Michel Corban, Esteban Braggio, Ali Ahmad, Stewart Keith, Lilach O. Lerman, Patnaik. Mrinal, Amir Lerman
Journal: Journal of the American College of Cardiology (2022)
IMPACT OF SACUBITRIL/VALSARTAN ON CARDIAC REMODELING IN HEART FAILURE WITH REDUCED EJECTION FRACTION USING REAL-WORLD DATA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Alaa Rahhal, Mohamed Kasem, Bassant Orabi, Safae Abuyousef, Fatima Hamou, Ahmed Mahfouz, Sumaya Alyafei, Emad Ahmed
Journal: Journal of the American College of Cardiology (2022)
The Application of Nanotechnology for Quantification of Circulating Tumour DNA in Liquid Biopsies: A Systematic Review
Authors: Nathan J. W. Wu, Matthew Aquilina, Bin-Zhi Qian, Remco Loos, Ines Gonzalez-Garcia, Cristina C. Santini, Katherine E. Dunn
Journal: IEEE Reviews in Biomedical Engineering (2022)

Technologies for quantifying circulating tumour DNA (ctDNA) in liquid biopsies could enable real-time measurements of cancer progression, profoundly impacting patient care. Sequencing methods can be too complex and time-consuming for regular point-of-care monitoring, but nanotechnology offers an alternative, harnessing the unique properties of objects tens to hundreds of nanometres in size. This systematic review was performed to identify all examples of nanotechnology-based ctDNA detection and assess their potential for clinical use. Google Scholar, PubMed, Web of Science, Google Patents, Espacenet and Embase/MEDLINE were searched up to 23rd March 2021. The review identified nanotechnology-based methods for ctDNA detection for which quantitative measures (e.g., limit of detection, LOD) were reported and biologically relevant samples were used. The pre-defined inclusion criteria were met by 66 records. LODs ranged from 10 zM to 50nM. 25 records presented an LOD of 10fM or below. Nanotechnology-based approaches could provide the basis for the next wave of advances in ctDNA diagnostics, enabling analysis at the point-of-care, but none are currently used clinically. Further work is needed in development and validation; trade-offs are expected between different performance measures e.g., number of sequences detected and time to result.
The spinach YY genome reveals sex chromosome evolution, domestication, and introgression history of the species
Authors: Xiaokai Ma, Li’ang Yu, Mahpara Fatima, William H. Wadlington, Amanda M. Hulse-Kemp, Xingtan Zhang, Shengcheng Zhang, Xindan Xu, Jingjing Wang, Huaxing Huang, Jing Lin, Ban Deng, Zhenyang Liao, Zhenhui Yang, Yanhong Ma, Haibao Tang, Allen Van Deynze, Ray Ming
Journal: Genome biology (2022)

Abstract Background Spinach ( Spinacia oleracea L.) is a dioecious species with an XY sex chromosome system, but its Y chromosome has not been fully characterized. Our knowledge about the history of its domestication and improvement remains limited. Results A high-quality YY genome of spinach is assembled into 952 Mb in six pseudo-chromosomes. By a combination of genetic mapping, Genome-Wide Association Studies, and genomic analysis, we characterize a 17.42-Mb sex determination region (SDR) on chromosome 1. The sex chromosomes of spinach evolved when an insertion containing sex determination genes occurred, followed by a large genomic inversion about 1.98 Mya. A subsequent burst of SDR-specific repeats (0.1–0.15 Mya) explains the large size of this SDR. We identify a Y-specific gene, NRT1/PTR 6.4 which resides in this insertion, as a strong candidate for the sex determination or differentiation factor. Resequencing of 112 spinach genomes reveals a severe domestication bottleneck approximately 10.87 Kya, which dates the domestication of spinach 7000 years earlier than the archeological record. We demonstrate that a strong selection signal associated with internode elongation and leaf area expansion is associated with domestication of edibility traits in spinach. We find that several strong genomic introgressions from the wild species Spinacia turkestanica and Spinacia tetrandra harbor desirable alleles of genes related to downy mildew resistance, frost resistance, leaf morphology, and flowering-time shift, which likely contribute to spinach improvement. Conclusions Analysis of the YY genome uncovers evolutionary forces shaping nascent sex chromosome evolution in spinach. Our findings provide novel insights about the domestication and improvement of spinach.
30P Comparative biochemical and cellular profiling of kinase inhibitors approved for clinical use from 2018 to 2020
Authors: J. Kooijman, W. Van Riel, M. Prinsen, J. Dylus, Y. Grobben, J. De Roos, J. Melis, T. De Bitter, Y. Narumi, Y. Kawase, N. Willemsen-Seegers, G. Zaman
Journal: Annals of Oncology (2022)
HEMODYNAMIC COMPLICATIONS IN PATIENTS WITH LIVER CIRRHOSIS ADMITTED FOR HEART FAILURE WITH REDUCED EJECTION FRACTION
Authors: Dennis Danso Kumi, Iriagbonse Asemota, Bharosa Sharma, Smirti Khanal, Raquel Soon-Shiong, Emmanuel Akuna, Muhammad U. Almani, Prajwal Shrestha
Journal: Journal of the American College of Cardiology (2022)
PREDICTING SUCCESS OF THE RETROGRADE APPROACH IN PERCUTANEOUS CORONARY INTERVENTION OF CHRONIC TOTAL CORONARY OCCLUSIONS WITH COLLATERAL GRADING SYSTEMS
Authors: Yvemarie Somsen, Rocco Giunta, Ruben Willem De Winter, Stefan Schumacher, Pepijn Van Diemen, Ruurt Jukema, Wynand Stuijfzand, Ibrahim Danad, Niels Verouden, Alexander Nap, Alfredo R. Galassi, Jose Henriques, Paul Knaapen
Journal: Journal of the American College of Cardiology (2022)
Acquired Immunotherapy Resistance in Gastrointestinal Cancers
Authors: Mojun Zhu, Tanios S. Bekaii-Saab
Journal: JAMA Network Open (2022)

Na Zhuo, MS; Chang Liu, PhD; Qi Zhang, PhD; Jian Li, MD; Xiaotian Zhang, MD; Jifang Gong, MD; Ming Lu, MD; Zhi Peng, MD, PhD; Jun Zhou, MD; Xicheng Wang, MD, PhD; Xi Jiao, PhD; Yujiao Wang, PhD; Yanni Wang, MS; Mengting Gao, MS; Lin Shen, MD; Zhihao Lu, MD
Abstract P3-20-08: Does contralateral prophylactic mastectomy improve survival in triple negative breast cancer?
Authors: Genevieve A Fasano, Solange Bayard, Yalei Chen, Jennifer Marti, Rache Simmons, Alexander Swistel, Jessica Bensenhaver, S David Nathanson, Lindsay Petersen, Erica Proctor, Melissa Davis, Lisa Newman
Journal: Cancer Research (2022)

Abstract Background: Despite increased incidence of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in women at average risk for breast cancer. In addition to BRCA1/2 mutation carriers, patients with estrogen-receptor negative tumors have been examined as a subgroup that may seek to benefit from CPM. In this study, we sought to investigate whether CPM improves survival in patients with triple negative breast cancer (TNBC).Study Design: Survival outcomes were evaluated for all TNBC patients from a multi-institutional database from 1999-2018 at New York Presbyterian - Weill Cornell Medical Center and Henry Ford Health System. Median follow-up time was 44.4 months.Results: 802 TNBC patients were evaluated. The median age was 57 years. 17% patients underwent CPM. Factors associated with CPM were White American race, younger age, presence of lymphovascular invasion (LVI), lack of mammography screen-detection, mastectomy surgery, postoperative adjuvant radiotherapy, and having had genetic testing. A borderline significant trend was observed in improved overall survival among patients undergoing CPM versus those not having CPM (5-year OS 95.1% vs. 85.0%; p = 0.05). Subset analysis of patients younger than 50 years of age at diagnosis demonstrated no improvement in overall survival for patients undergoing CPM versus those that declined CPM (94.3% v. 88.7%; p = 0.21). Conclusion: Our data demonstrate a trend in improved 5-year overall survival in TNBC patients undergoing CPM. However, in patients younger than 50 years at diagnosis, CPM did not confer a survival advantage. Citation Format: Genevieve A Fasano, Solange Bayard, Yalei Chen, Jennifer Marti, Rache Simmons, Alexander Swistel, Jessica Bensenhaver, S David Nathanson, Lindsay Petersen, Erica Proctor, Melissa Davis, Lisa Newman. Does contralateral prophylactic mastectomy improve survival in triple negative breast cancer? [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 P3-20-08.
Response to SARS-CoV-2 vaccination in systemic autoimmune rheumatic disease depends on immunosuppressive regimen: a matched, prospective cohort study
Authors: Peter Mandl, Selma Tobudic, Helmut Haslacher, Thomas Karonitsch, Daniel Mrak, Thomas Nothnagl, Thomas Perkmann, Helga Radner, Judith Sautner, Elisabeth Simader, Florian Winkler, Heinz Burgmann, Daniel Aletaha, Stefan Winkler, Stephan Blüml
Journal: Annals of the Rheumatic Diseases (2022)

To assess the humoral response to messenger RNA (mRNA) vaccine of patients with systemic autoimmune rheumatic disease (SARD) and the effect of immunosuppressive medication in a matched cohort study.Patients with SARD were enrolled and matched 1:1 for sex and age with healthy control (HC) subjects. Differences in humoral response to two doses of an mRNA vaccine in terms of seroconversion rate (SCR) and SARS-CoV-2 antibody level between the two groups and the impact of treatment within patients with SARD were assessed.We enrolled 82 patients with SARD and 82 matched HC. SCR after the first dose was lower among the patient group than that of HC (65% compared with 100% in HC, p<0.0001) but levelled up after the second dose (94% vs 100%). After the second dose, SCR was lower for patients on combination disease-modifying antirheumatic drug (DMARD) therapy compared with all other groups (81% compared with 95% for monotherapy, p=0.01; 100% for both no DMARD therapy and HC, both p<0.0001). In addition, antibody levels after both doses were lower in patients compared with HC. We found that vaccination response was determined primarily by the number of DMARDs and/or glucocorticoids received, with patients receiving combination therapy (dual and triple therapy) showing the poorest response.Patients with SARD showed a good response after the second vaccination with an mRNA vaccine. However, the choice of immunosuppressive medication has a marked effect on both SCR and overall antibody level, and the number of different immunomodulatory therapies determines vaccination response.
Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of <i>Ppp2r1b</i>
Authors: Suraj J. Patel, Nan Liu, Sam Piaker, Anton Gulko, Maynara L. Andrade, Frankie D. Heyward, Tyler Sermersheim, Nufar Edinger, Harini Srinivasan, Margo P. Emont, Gregory P. Westcott, Jay Luther, Raymond T. Chung, Shuai Yan, Manju Kumari, Reeby Thomas, Yann Deleye, André Tchernof, Phillip J. White, Guido A. Baselli, Marica Meroni, Dario F. De Jesus, Rasheed Ahmad, Rohit N. Kulkarni, Luca Valenti, Linus Tsai, Evan D. Rosen
Journal: Science Translational Medicine (2022)

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b , a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.