tbuckley/cabot-search huggingface dataset:
Leukemia Cutis
Authors: Denise Barry, Astrid Schmieder
Journal: New England Journal of Medicine (2021)

A 65-year-old man presented with a 5-day history of a painful, symmetric rash on his hands and elbows. Skin biopsy revealed leukemia cutis. Findings on bone marrow biopsy were consistent with chronic myelomonocytic leukemia.
Distinct gene expression profiles between human preterm-derived and adult-derived intestinal organoids exposed to<i>Enterococcus faecalis</i>: a pilot study
Authors: Andrea C Masi, Tatiana Y Fofanova, Christopher A Lamb, Jennifer M Auchtung, Robert A Britton, Mary K Estes, Sasirekha Ramani, Simon J Cockell, Jonathan Coxhead, Nicholas D Embleton, Janet E Berrington, Joseph F Petrosino, Christopher J Stewart
Journal: Gut (2021)
Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapies
Authors: Masatoshi Kudo, Robert Montal, Richard S. Finn, Florian Castet, Kazuomi Ueshima, Naoshi Nishida, Philipp K. Haber, Youyou Hu, Yasutaka Chiba, Myron Schwartz, Tim Meyer, Riccardo Lencioni, Josep M. Llovet
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS. Patients and Methods: A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis. Results: Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27–0.70; P &amp;lt; 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses. Conclusions: OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies.
Long non-coding RNA ACTA2-AS1 promotes ductular reaction by interacting with the p300/ELK1 complex
Authors: Amaia Navarro-Corcuera, Tejasav S. Sehrawat, Nidhi Jalan-Sakrikar, Hunter R. Gibbons, Nicholas E. Pirius, Shalil Khanal, Feda H. Hamdan, Sayed Obaidullah Aseem, Sheng Cao, Jesus M. Banales, Ningling Kang, William A. Faubion, Nicholas F. LaRusso, Vijay H. Shah, Robert C. Huebert
Journal: Journal of Hepatology (2021)
Association of Total Thyroidectomy or Thyroid Lobectomy With the Quality of Life in Patients With Differentiated Thyroid Cancer With Low to Intermediate Risk of Recurrence
Authors: Wanna Chen, Jie Li, Sui Peng, Shubin Hong, Heyang Xu, Bo Lin, Xiaoli Liang, Yihao Liu, Jiadong Liang, Zhaoxi Zhang, Yingnan Ye, Fang Liu, Cuiyu Lin, Haipeng Xiao, Weiming Lv
Journal: JAMA Surgery (2021)

<h3>Importance</h3> Owing to the good prognosis of differentiated thyroid cancer (DTC), guidelines recommend total thyroidectomy (TT) or thyroid lobectomy (TL) as surgical treatment for DTC with low to intermediate risk of recurrence. However, the association of these surgeries with the health-related quality of life (HRQOL) of patients with DTC with low to intermediate risk of recurrence is unclear. <h3>Objective</h3> To longitudinally compare the HRQOL of patients with DTC undergoing different surgeries. <h3>Design, Setting, and Participants</h3> This prospective observational longitudinal cohort study enrolled patients diagnosed with DTC with low to intermediate risk of recurrence at the First Affiliated Hospital, Sun Yat-sen University, China, from October 1, 2018, to September 31, 2019. Eligible patients were categorized into TL and TT groups according to the surgery they underwent. They were evaluated preoperatively and followed up at 1, 3, 6, and 12 months postoperatively using 3 HRQOL-related questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0; Hospital Anxiety and Depression Scale; and Thyroid Cancer–Specific Quality of Life Questionnaire); serum thyrotropin levels, complications, and patient satisfaction were also monitored. Data were analyzed to compare the HRQOL of patients undergoing different surgeries at different time points. <h3>Exposures</h3> Total thyroidectomy or TL. <h3>Main Outcomes and Measures</h3> The primary end point was HRQOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0; Hospital Anxiety and Depression Scale; and Thyroid Cancer–Specific Quality of Life Questionnaire) at different time points, and the secondary end points were postoperative complications, thyrotropin level, and patient satisfaction. <h3>Results</h3> Of the 1060 eligible patients, 563 underwent TL (438 women [77.8%]; median [IQR] age, 38 [31-45] years), and 497 underwent TT (390 women [78.5%]; median [IQR] age, 38 [32-48] years). Compared with the TL group, including the 1- to 4-cm tumor subgroup, the TT group experienced more postoperative HRQOL problems at 1 and 3 months postoperatively. However, nearly all the differences disappeared at 6 and 12 months postoperatively. <h3>Conclusions and Relevance</h3> Results of this study suggest that HRQOL of patients with DTC with low to intermediate risk of recurrence is not associated with the extent of surgery, and HRQOL may not be an important consideration when making surgical decisions. If better HRQOL is requested in the short term, TL may be preferred.
Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial
Authors: Caron A Jacobson, Julio C Chavez, Alison R Sehgal, Basem M William, Javier Munoz, Gilles Salles, Pashna N Munshi, Carla Casulo, David G Maloney, Sven de Vos, Ran Reshef, Lori A Leslie, Ibrahim Yakoub-Agha, Olalekan O Oluwole, Henry Chi Hang Fung, Joseph Rosenblatt, John M Rossi, Lovely Goyal, Vicki Plaks, Yin Yang, Remus Vezan, Mauro P Avanzi, Sattva S Neelapu
Journal: The Lancet Oncology (2021)
Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with <i>MYD88</i> and <i>CXCR4</i> Mutations
Authors: Steven P. Treon, Christian Buske, Sheeba K Thomas, Jorge J. Castillo, Andrew R. Branagan, Meletios A. Dimopoulos, Maria Gavriatopoulou, Diego Cadavid, Felix T Garzon, Weihua Tang, Sean Seyffert, Varun Garg, Shariq Ali, Arthur G. Taveras, Kelly Chen, Jeffrey V. Matous
Journal: Blood (2021)
Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging
Authors: Di Ren, Julia Fedorova, Kayla Davitt, Tran Ngoc Van Le, John H. Griffin, Patricia C. Liaw, Charles T. Esmon, Alireza R. Rezaie, Ji Li
Journal: Circulation Research (2021)

APC (activated protein C) is a plasma serine protease with anticoagulant and anti-inflammatory activities. EPCR (Endothelial protein C receptor) is associated with APC's activity and mediates its downstream signaling events. APC exerts cardioprotective effects during ischemia and reperfusion (I/R). This study aims to characterize the role of the APC-EPCR axis in ischemic insults in aging.Young (3-4 months) and aged (24-26 months) wild-type C57BL/6J mice, as well as EPCR point mutation (EPCRR84A/R84A) knockin C57BL/6J mice incapable of interaction with APC and its wild type of littermate C57BL/6J mice, were subjected to I/R. Wild-type APC, signaling-selective APC-2Cys, or anticoagulant-selective APC-E170A were administrated before reperfusion.The results demonstrated that cardiac I/R reduces APC activity, and the APC activity was impaired in the aged versus young hearts possibly attributable to the declined EPCR level with aging. Serum EPCR measurement showed that I/R triggered the shedding of membrane EPCR into circulation, while administration of APC attenuated the I/R-induced EPCR shedding in both young and aged hearts. Subsequent echocardiography showed that APC and APC-2Cys but not APC-E170A ameliorated cardiac dysfunction during I/R in both young and aged mice. Importantly, APC elevated the resistance of the aged heart to ischemic insults through stabilizing EPCR. However, all these cardioprotective effects of APC were blunted in the EPCRR84A/R84A mice versus its wild-type littermates. The ex vivo working heart and metabolomics results demonstrated that AMPK (AMP-activated protein kinase) mediates acute adaptive response while AKT (protein kinase B) is involved in chronic metabolic programming in the hearts with APC treatment.I/R stress causes shedding of the membrane EPCR in the heart, and administration of APC prevents I/R-induced cardiac EPCR shedding that is critical for limiting cardiac damage in aging.
Tetrahedral DNA nanostructures synergize with MnO2 to enhance antitumor immunity via promoting STING activation and M1 polarization
Authors: Siping Liang, Jiaying Li, Zhengyu Zou, Miao Mao, Siqi Ming, Fan Lin, Ziyan Zhang, Can Cao, Jinyu Zhou, Yuanqing Zhang, Jiaping Li, Minhao Wu
Journal: Acta Pharmaceutica Sinica B (2021)

Stimulator of interferon genes (STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here, we showed that tetrahedral DNA nanostructures (TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn2+ to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn2+, we constructed a TDN-MnO2 complex and found that it displayed a much higher efficacy than TDN plus Mn2+ to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO2. These findings provide new therapeutic opportunities for cancer therapy.
Stem Cells and Organs-on-chips: New Promising Technologies for Human Infertility Treatment
Authors: Eisa Tahmasbpour Marzouni, Catharyn Stern, Andrew Henrik Sinclair, Elena Jane Tucker
Journal: Endocrine Reviews (2021)

Abstract Having biological children remains an unattainable dream for most couples with reproductive failure or gonadal dysgenesis. The combination of stem cells with gene editing technology and organ-on-a-chip models provides a unique opportunity for infertile patients with impaired gametogenesis caused by congenital disorders in sex development or cancer survivors. But how will these technologies overcome human infertility? This review discusses the regenerative mechanisms, applications, and advantages of different types of stem cells for restoring gametogenesis in infertile patients, as well as major challenges that must be overcome before clinical application. The importance and limitations of in vitro generation of gametes from patient-specific human-induced pluripotent stem cells (hiPSCs) will be discussed in the context of human reproduction. The potential role of organ-on-a-chip models that can direct differentiation of hiPSC-derived primordial germ cell-like cells to gametes and other reproductive organoids is also explored. These rapidly evolving technologies provide prospects for improving fertility to individuals and couples who experience reproductive failure.
TAMI-69. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION
Authors: Yuan Pan, Jared Hysinger, Tara Barron, Nicki Schindler, Olivia Cobb, Xiaofan Guo, Belgin Yalçın, Corina Anastasaki, Sara Mulinyawe, Anitha Ponnuswami, Suzanne Scheaffer, Yu Ma, Kun-Che Chang, Xin Xia, Joseph Toonen, James Lennon, Erin Gibson, John Huguenard, Linda Liau, Jeffrey Goldberg, Michelle Monje, David Gutmann
Journal: Neuro-Oncology (2021)

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.
Spatial discordances between mRNAs and proteins in the intestinal epithelium
Authors: Yotam Harnik, Lisa Buchauer, Shani Ben-Moshe, Inna Averbukh, Yishai Levin, Alon Savidor, Raya Eilam, Andreas E. Moor, Shalev Itzkovitz
Journal: Nature Metabolism (2021)
Differences in estimates for 10-year risk of cardiovascular disease in Black versus White individuals with identical risk factor profiles using pooled cohort equations: an in silico cohort study
Authors: Ramachandran S Vasan, Edwin van den Heuvel
Journal: The Lancet Digital Health (2021)

Sex-specific and race-specific pooled cohort equations (PCEs) are recommended for estimating the 10-year risk of cardiovascular disease, with an absolute risk of more than 7·5% indicating a clinical decision threshold. We compared differences between Black and White individuals in PCE-estimated absolute cardiovascular disease risk across various plausible risk factor combinations with the aim of evaluating if using the PCE might result in different clinical decisions in Black versus White individuals with identical risk profiles.
The ancestral stringent response potentiator, DksA has been adapted throughout <i>Salmonella</i> evolution to orchestrate the expression of metabolic, motility, and virulence pathways
Authors: Helit Cohen, Boaz Adani, Emiliano Cohen, Bar Piscon, Shalhevet Azriel, Prerak Desai, Heike Bähre, Michael McClelland, Galia Rahav, Ohad Gal-Mor
Journal: Gut Microbes (2021)

DksA is a conserved RNA polymerase-binding protein known to play a key role in the stringent response of proteobacteria species, including many gastrointestinal pathogens. Here, we used RNA-sequencing of Escherichia coli, Salmonella bongori and Salmonella enterica serovar Typhimurium, together with phenotypic comparison to study changes in the DksA regulon, during Salmonella evolution. Comparative RNA-sequencing showed that under non-starved conditions, DksA controls the expression of 25%, 15%, and 20% of the E. coli, S. bongori, and S. enterica genes, respectively, indicating that DksA is a pleiotropic regulator, expanding its role beyond the canonical stringent response. We demonstrate that DksA is required for the growth of these three enteric bacteria species in minimal medium and controls the expression of the TCA cycle, glycolysis, pyrimidine biosynthesis, and quorum sensing. Interestingly, at multiple steps during Salmonella evolution, the type I fimbriae and various virulence genes encoded within SPIs 1, 2, 4, 5, and 11 have been transcriptionally integrated under the ancestral DksA regulon. Consequently, we show that DksA is necessary for host cells invasion by S. Typhimurium and S. bongori and for intracellular survival of S. Typhimurium in bone marrow-derived macrophages (BMDM). Moreover, we demonstrate regulatory inversion of the conserved motility-chemotaxis regulon by DksA, which acts as a negative regulator in E. coli, but activates this pathway in S. bongori and S. enterica. Overall, this study demonstrates the regulatory assimilation of multiple horizontally acquired virulence genes under the DksA regulon and provides new insights into the evolution of virulence genes regulation in Salmonella spp.
Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader–Willi Syndrome
Authors: Laeya Baldini, Anne Robert, Bruno Charpentier, Stéphane Labialle
Journal: Molecular Biology and Evolution (2021)

The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader-Willi syndrome (PWS), yet its molecular function remains poorly understood. Here, we combined phylogenetic and molecular analyses to identify candidate RNA targets. Based on the analysis of several eutherian orthologs, we found evidence of extensive birth-and-death and conversion events during SNORD116 gene history. However, the consequences for phylogenetic conservation were heterogeneous along the gene sequence. The standard snoRNA elements necessary for RNA stability and association with dedicated core proteins were the most conserved, in agreement with the hypothesis that SNORD116 generate genuine snoRNAs. In addition, one of the two antisense elements typically involved in RNA target recognition was largely dominated by a unique sequence present in at least one subset of gene paralogs in most species, likely the result of a selective effect. In agreement with a functional role, this ASE exhibited a hybridization capacity with putative mRNA targets that was strongly conserved in eutherians. Moreover, transient downregulation experiments in human cells showed that Snord116 controls the expression and splicing levels of these mRNAs. The functions of two of them, diacylglycerol kinase kappa and Neuroligin 3, extend the description of the molecular bases of PWS and reveal unexpected molecular links with the Fragile X syndrome and autism spectrum disorders.
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine)
Authors: Mical Paul, Elena Carrara, Pilar Retamar, Thomas Tängdén, Roni Bitterman, Robert A. Bonomo, Jan de Waele, George L. Daikos, Murat Akova, Stephan Harbarth, Celine Pulcini, José Garnacho-Montero, Katja Seme, Mario Tumbarello, Paul Christoffer Lindemann, Sumanth Gandra, Yunsong Yu, Matteo Bassetti, Johan W. Mouton, Evelina Tacconelli, Jesús Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2021)

ScopeThese ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy.MethodsAn expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak).RecommendationsThe guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary
Authors: Jennifer S. Lawton, Jacqueline E. Tamis-Holland, Sripal Bangalore, Eric R. Bates, Theresa M. Beckie, James M. Bischoff, John A. Bittl, Mauricio G. Cohen, J. Michael DiMaio, Creighton W. Don, Stephen E. Fremes, Mario F. Gaudino, Zachary D. Goldberger, Michael C. Grant, Jang B. Jaswal, Paul A. Kurlansky, Roxana Mehran, Thomas S. Metkus, Lorraine C. Nnacheta, Sunil V. Rao, Frank W. Sellke, Garima Sharma, Celina M. Yong, Brittany A. Zwischenberger
Journal: Journal of the American College of Cardiology (2021)
Endoscopic ultrasound combined with ERCP to treat cystic-duct-remnant stone
Authors: Rungsun Rerknimitr, Panida Piyachaturawat, Wiriyaporn Ridtitid, Natee Faknak
Journal: Endoscopy (2021)

A 68-year-old man who had undergone complicated cholecystectomy 18 years ago presented with right upper quadrant abdominal pain and a high-grade fever. His complete blood count, liver function tests, and pancreatic enzyme levels were within normal limits. The broad-spectrum antibiotic combination of piperacillin and tazobactam was administered intravenously for 5 days until pain and fever subsided. A magnetic resonance cholangiopancreatogram ([Fig. 1]) revealed a few 1–1.5 cm gallstones in the cystic duct remnant and none in common bile duct. The patient declined another cholecystectomy and chose an endoscopic treatment.
Safety and Efficacy of Subcutaneous (SC) Blinatumomab for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)
Authors: Pilar Martínez Sánchez, Paul Gordon, Stefan Schwartz, Giuseppe Rossi, Francoise Huguet, Jesus Maria Hernández-Rivas, Priti Kadu, Hansen L. Wong, Ana Markovic, Yuliya Katlinskaya, Bharat Panwar, Gerhard Zugmaier
Journal: Blood (2021)