tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults
Authors: Eleanor Wilson, Jaya Goswami, Abdullah H. Baqui, Pablo A. Doreski, Gonzalo Perez-Marc, Khalequ Zaman, Jorge Monroy, Christopher J.A. Duncan, Mugen Ujiie, Mika Rämet, Lina Pérez-Breva, Ann R. Falsey, Edward E. Walsh, Rakesh Dhar, Lauren Wilson, Jiejun Du, Parinaz Ghaswalla, Archana Kapoor, Lan Lan, Shraddha Mehta, Runa Mithani, Catherine A. Panozzo, Alana K. Simorellis, Barbara J. Kuter, Florian Schödel, Wenmei Huang, Caroline Reuter, Karen Slobod, Sonia K. Stoszek, Christine A. Shaw, Jacqueline M. Miller, Rituparna Das, Grace L. Chen
Journal: New England Journal of Medicine (2023)

Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. Download a PDF of the Research Summary. In this ongoing, randomized, double-blind, placebo-controlled, phase 2–3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 μg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.) QUICK TAKE VIDEO SUMMARYAn mRNA-Based RSV PreF Vaccine in Older Adults 02:14
Recombinant or Standard-Dose Influenza Vaccine in Adults under 65 Years of Age
Authors: Amber Hsiao, Arnold Yee, Bruce Fireman, John Hansen, Ned Lewis, Nicola P. Klein
Journal: New England Journal of Medicine (2023)

Quadrivalent recombinant influenza vaccines contain three times the amount of hemagglutinin protein as standard-dose egg-based vaccines, and the recombinant formulation is not susceptible to antigenic drift during manufacturing. Data are needed on the relative effectiveness of recombinant vaccines as compared with standard-dose vaccines against influenza-related outcomes in adults under the age of 65 years.
Continued Progress in the Development of Safe and Effective RSV Immunizations
Authors: Amanda C. Cohn, Aron J. Hall
Journal: New England Journal of Medicine (2023)

Before 2023, there were no immunizing tools to protect older adults and all infants from illness and death due to respiratory syncytial virus (RSV). In 2023, two RSV vaccines for older adults, one of which is also approved for use in pregnant persons, and a long-acting monoclonal antibody to protect infants and some toddlers up to 19 months of age were approved by the Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.1-3 These major developments occurred nearly 60 years after a formalin-inactivated RSV vaccine that had been . . .
Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD
Authors: Josh Bilson, Carolina J. Oquendo, James Read, Eleonora Scorletti, Paul R. Afolabi, Jenny Lord, Laure B. Bindels, Giovanni Targher, Sumeet Mahajan, Diana Baralle, Philip C. Calder, Christopher D. Byrne, Jaswinder K. Sethi
Journal: Metabolism (2023)

Background and aims Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome. Methods Sixty-two patients with NAFLD (60 % men) were studied before and after 12 months of treatment with synbiotic or placebo and provided SAT samples. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. RNA-sequencing and histological analysis of SAT were performed to determine differential gene expression, CCGE and the presence of collagen fibres. Regression modelling and receiver operator characteristic curve analysis were used to test associations with, and risk prediction for, ≥F2 liver fibrosis. Results Patients with ≥F2 liver fibrosis (n = 24) had altered markers of AT dysfunction and a SAT gene expression signature characterised by enrichment of inflammatory and extracellular matrix-associated genes, compared to those with <F2 fibrosis (n = 38). Differences in transcript profiles between patients with vs without ≥F2 liver fibrosis were largely explained by adjusting for differences in HOMA-IR. Gut microbiome-modifying synbiotic treatment did not change SAT transcriptomic profiles or circulating inflammatory/adipokine markers. SAT CCGE values were independently associated with (8.38 (1.72–40.88), p = 0.009), and were a good predictor of, ≥F2 fibrosis (AUROC 0.79, 95 % CI 0.69–0.90). Associations between SAT transcriptomic profiles and ≥F2 fibrosis were reproduced using end-of-trial data. Conclusion A differential gene expression signature in SAT associates with ≥F2 liver fibrosis is explained by a measure of systemic insulin resistance and is not changed by synbiotic treatment. SAT CCGE values are a good predictor of ≥F2 liver fibrosis in NAFLD.
Diphthamide – a conserved modification of eEF2 with clinical relevance
Authors: Raffael Schaffrath, Ulrich Brinkmann
Journal: Trends in Molecular Medicine (2023)

Diphthamide, a complex modification on eukaryotic translation elongation factor 2 (eEF2), assures reading-frame fidelity during translation. Diphthamide and enzymes for its synthesis are conserved in eukaryotes and archaea. Originally identified as target for diphtheria toxin (DT) in humans, its clinical relevance now proves to be broader than the link to pathogenic bacteria. Diphthamide synthesis enzymes (DPH1 and DPH3) are associated with cancer, and DPH gene mutations can cause diphthamide deficiency syndrome (DDS). Finally, new analyses provide evidence that diphthamide may restrict propagation of viruses including SARS-CoV-2 and HIV-1, and that DPH enzymes are targeted by viruses for degradation to overcome this restriction. This review describes how diphthamide is synthesized and functions in translation, and covers its clinical relevance in human development, cancer, and infectious diseases.
Why birds are smart
Authors: Onur Güntürkün, Roland Pusch, Jonas Rose
Journal: Trends in Cognitive Sciences (2023)

Many cognitive neuroscientists believe that both a large brain and an isocortex are crucial for complex cognition. Yet corvids and parrots possess non-cortical brains of just 1-25 g, and these birds exhibit cognitive abilities comparable with those of great apes such as chimpanzees, which have brains of about 400 g. This opinion explores how this cognitive equivalence is possible. We propose four features that may be required for complex cognition: a large number of associative pallial neurons, a prefrontal cortex (PFC)-like area, a dense dopaminergic innervation of association areas, and dynamic neurophysiological fundaments for working memory. These four neural features have convergently evolved and may therefore represent 'hard to replace' mechanisms enabling complex cognition.
Auto-HCT May Be Best after Chemo in DLBCL
Journal: Cancer Discovery (2023)

Abstract Some patients with diffuse large B-cell lymphoma eligible for chimeric antigen receptor T-cell therapy end up receiving chemotherapy due to a lack of timely access to treatment. In this situation, those who achieve a complete remission with bridging chemotherapy may do better with autologous hematopoietic cell transplantation, a registry analysis suggests.
Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort
Authors: Stephanie B. Dixon, Fang Wang, Lu Lu, Carmen L. Wilson, Daniel M. Green, Thomas E. Merchant, Deo Kumar Srivastava, Angela Delaney, Rebecca M. Howell, John L. Jefferies, Leslie L. Robison, Kirsten K. Ness, Melissa M. Hudson, Wassim Chemaitilly, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2023)

Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors.
The Translational Value of Rodent Models of Sepsis
Authors: Michael A. Matthay, Eric P. Schmidt, Julie A. Bastarache, Carolyn S. Calfee, Charles W. Frevert, Thomas R. Martin
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"The Translational Value of Rodent Models of Sepsis." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
1,5-Anhydroglucitol: A Novel Biomarker of Adherence to Sodium–Glucose Cotransporter 2 Inhibitors
Authors: Natalie R. Daya, Michael Fang, Mahesh Mathew, Jung-Im Shin, James Pankow, Pamela L. Lutsey, Arielle Valint, Justin B. Echouffo-Tcheugui, Elizabeth Selvin
Journal: Diabetes Care (2023)
Serum Low C-Peptide Levels Correlate With Low Muscle Mass in Patients With Type 2 Diabetes Mellitus
Authors: Xiulin Shi, Weijuan Su, Jinyang Wang, Peiying Huang, Caoxin Huang, Wenhui Zeng, Wei Liu, Yuxian Zhang, Mingzhu Lin, Xuejun Li
Journal: Diabetes Care (2023)
Low Awareness of Diabetes as a Major Risk Factor for Cardiovascular Disease in Middle- and High-Income Countries
Authors: Richard S. Chaudhary, Melanie B. Turner, Laxmi S. Mehta, Nora M. Al-Roub, Sidney C. Smith, Dhruv S. Kazi
Journal: Diabetes Care (2023)

OBJECTIVE Awareness of diabetes as a major risk factor for cardiovascular disease (CVD) may enhance uptake of screening for diabetes and primary prevention of CVD. RESEARCH DESIGN AND METHODS The American Heart Association conducted an online survey in 50 countries. The main outcome of this study was the proportion of individuals in each country who recognized diabetes as a CVD risk factor. We also examined variation by sex, age, geographic region, and country-level economic development. RESULTS Among 48,988 respondents, 15,747 (32.1%) identified diabetes as a major CVD risk factor. Awareness was similar among men and women, but increased with age, and was greater in high-income than in middle-income countries. CONCLUSIONS Two-thirds of adults in surveyed countries did not recognize diabetes as a major CVD risk factor. Given the increasing global burden of diabetes and CVD, this finding underscores the need for concerted efforts to raise public health awareness.
A therapeutic strategy to target distinct sources of IgE and durably reverse allergy
Authors: Andre Limnander, Navneet Kaur, Seblewongel Asrat, Carley Tasker, Anita Boyapati, Li-Hong Ben, John Janczy, Paulina Pedraza, Pablo Abreu, Wen-Chi Chen, Stephen Godin, Benjamin J. Daniel, Harvey Chin, Michelle DeVeaux, Karen Rodriguez Lorenc, Andres Sirulnik, Olivier Harari, Neil Stahl, Matthew A. Sleeman, Andrew J. Murphy, George D. Yancopoulos, Jamie M. Orengo
Journal: Science Translational Medicine (2023)

Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE + plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell–targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE + memory B cells that require class switching and long-lived IgE + plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.
Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury
Authors: Yumeng Wen, Emily Su, Leyuan Xu, Steven Menez, Dennis G. Moledina, Wassim Obeid, Paul M. Palevsky, Sherry G. Mansour, Prasad Devarajan, Lloyd G. Cantley, Patrick Cahan, Chirag R. Parikh
Journal: Science Translational Medicine (2023)

Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor–β2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.
Short-course combination treatment for experimental chronic Chagas disease
Authors: Silvia González, Richard J. Wall, John Thomas, Stephanie Braillard, Gino Brunori, Isabel Camino Díaz, Juan Cantizani, Sandra Carvalho, Pablo Castañeda Casado, Eric Chatelain, Ignacio Cotillo, Jose M. Fiandor, Amanda Fortes Francisco, David Grimsditch, Martine Keenan, John M. Kelly, Albane Kessler, Chiara Luise, Jon J. Lyon, Lorna MacLean, Maria Marco, J. Julio Martin, Maria S. Martinez Martinez, Christy Paterson, Kevin D. Read, Angel Santos-Villarejo, Fabio Zuccotto, Susan Wyllie, Tim J. Miles, Manu De Rycker
Journal: Science Translational Medicine (2023)

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi , affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Q i active site of T. cruzi cytochrome b, part of the cytochrome bc 1 complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears T. cruzi parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.
Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway
Authors: Cheng Zhang, Jiao-jiao Yu, Chen Yang, Zhen-long Yuan, Hui Zeng, Jun-jian Wang, Shuang Shang, Xiao-xi Lv, Xiao-tong Liu, Jing Liu, Qi Xue, Bing Cui, Feng-wei Tan, Fang Hua
Journal: Science Translational Medicine (2023)

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1 WT ) as a potential diagnostic and prognostic biomarker for non–small cell lung cancer (NSCLC), but how IDH1 WT modulates NSCLC progression remains elusive. Here, we report that IDH1 WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1 WT interacts with and stabilizes PHGDH and fragile X–related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1 WT -PHGDH and IDH1 WT -FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine–depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1 WT in serine metabolism, highlighting IDH1 WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.
Lymphoid tissues contribute to plasma viral clonotypes early after antiretroviral therapy interruption in SIV-infected rhesus macaques
Authors: Antonio Solis-Leal, Nongthombam Boby, Suvadip Mallick, Yilun Cheng, Fei Wu, Grey De La Torre, Jason Dufour, Xavier Alvarez, Vinay Shivanna, Yaozhong Liu, Christine M. Fennessey, Jeffrey D. Lifson, Qingsheng Li, Brandon F. Keele, Binhua Ling
Journal: Science Translational Medicine (2023)

The rebound-competent viral reservoir, composed of a virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after ART interruption (ATI), remains the biggest obstacle to treating HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop therapeutic strategies for reducing the rebound-competent viral reservoir. In this study, barcoded simian immunodeficiency virus (SIV), SIVmac239M, was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood and tissues from secondary lymphoid organs (spleen, mesenteric lymph nodes, and inguinal lymph nodes) and from the colon, ileum, lung, liver, and brain were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX and RNAscope in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy, although plasma viral RNA remained below 22 copies per milliliter. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. CD4 + T cells were the main cell type harboring viral RNA after ATI. Furthermore, T cell zones in lymphoid tissues showed higher viral RNA abundance than B cell zones for most animals. These findings are consistent with lymphoid tissues contributing to the virus present in plasma early after ATI.