tbuckley/cabot-search huggingface dataset:
Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment
Authors: Jennifer H. Cox, Marc-Olivier Boily, Alexandre Caron, Tao Sheng, Joyce Wu, Jinyue Ding, Samuel Gaudreault, Oliver Chong, Jayakumar Surendradoss, Robert Gomez, Jeffrey Lester, Valerie Dumais, Xingsheng Li, Rajesh Gumpena, Matthew D. Hall, Alex G. Waterson, Gordon Stott, Andrew J. Flint, William J. Moore, W. Todd Lowther, John Knight, M. David Percival, Vincent Tong, Renata Oballa, David A. Powell, Andrew J. King
Journal: Journal of the American Society of Nephrology (2025)

Background: Primary hyperoxalurias 1-3 (PH1-3) are genetic diseases defined by elevated hepatic oxalate production and increased incidence of calcium oxalate kidney stones and potentially kidney failure. There are two approved agents available for PH1, and no approved therapies for PH2 or PH3. Lactate dehydrogenase A (LDHA) catalyzes the final step in hepatic oxalate synthesis and represents a potential therapeutic target for PH and other forms of hyperoxaluria associated with increased oxalate production. Methods: Potent and selective LDH inhibitors with liver-targeted tissue distribution were identified and characterized in enzymatic, cellular, and in vivo models. Results: We identified CHK-336, a novel oral small molecule that demonstrates potent and selective inhibition of the human LDH enzyme and its activity in hepatocyte assays across multiple species, including hepatocytes isolated from PH1 mice. CHK-336 demonstrated a favourable liver-distribution profile in mice, rats, and monkeys that was dependent on hepatic uptake by OATP transporters and target-mediated drug binding. In a rat pharmacodynamic model, CHK-336 inhibited conversion of 13 C2-glycolate to 13 C2-oxalate in a dose-dependent manner. In a PH1 mouse model, once-daily oral dosing of CHK-336 produced robust and dose-dependent reductions in urinary oxalate to the normal range. Seven days of treatment with CHK-336 also resulted in a significant reduction in urinary oxalate in a PH2 mouse model. Conclusions: In conclusion, CHK-336 is a potent, liver-targeted, small molecule LDH inhibitor that suppressed urinary oxalate production in a rat pharmacodynamic model and mouse models of PH1 and PH2.
Project EVOLVE: An international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia
Authors: Sara K Silbert, Alexander W Rankin, Chloe N Hoang, Alexandra Semchenkova, Regina M Myers, Elena Zerkalenkova, Hao-Wei Wang, Alexandra E Kovach, Constance M Yuan, Dana Delgado Colon, Loic Vasseur, Alex Bataller, Samuel John, Kaylyn Utley Lyons, Barbara D. Friedes, Anna Alonso-Saladrigues, Hisham Abdel-Azim, Estelle Balducci, Ahmed Aljudi, Marie Balsat, D. Nathan Biery, Aghiad Chamdin, Bill H Chang, Raymund S Cuevo, Barbara De Moerloose, David S. Dickens, Ulrich A Duffner, Nicolas Duployez, Firas El Chaer, Michelle Ann Elliott, Gabriele Escherich, Sneha Fernandes, Mandi R Fitzjohn, Zhubin J Gahvari, Stephan A. Grupp, Rui Rochelle He, Cynthia Harrison, Christopher Bruce Hergott, Emily M. Hsieh, Annette S Kim, Dennis John Kuo, Daniel P Larson, Benjamin J Lee, Thibaut TL Leguay, R. Coleman Lindsley, Abhishek A. Mangaonkar, Kerstin Mezger, Holly L Pacenta, Jing Pan, Marlie R. M. Provost, Latika Puri, Sunil Sudhir Raikar, Armando Jose Martinez, Isabella Quijada Bristol, Kyle Daniel Murphy, Lauren Reiman, Michele S Redell, Kelly Reed, Gabrielle Roth Guepin, Jeremy D Rubinstein, Süreyya Savaşan, Kristian T Schafernak, Alexandra McLean Stevens, Aimee C Talleur, Naomi Torres Carapia, Jacques Vargaftig, Anant Vatsayan, Matthias Wölfl, Lipng Zhao, Susana Rives, Vanessa A. Fabrizio, Koji Sasaki, Ibrahim Aldoss, Nicolas Boissel, Susan R Rheingold, Kara L Davis, Sara Ghorashian, Elad Jacoby, Alexander Popov, Adam Joseph Lamble, Nirali N Shah
Journal: Blood (2025)
Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma
Authors: Smith Giri, Binod Dhakal, Natalie S Callander, Eva Medvedova, Kelly Godby, Bhagirathbhai Dholaria, Susan Bal, Gayathri Ravi, Saurabh Chhabra, Rebecca Silbermann, Luciano J. Costa
Journal: Blood (2025)
Management of <i>Staphylococcus aureus</i> Bacteremia
Authors: Steven Y. C. Tong, Vance G. Fowler, Lesley Skalla, Thomas L. Holland
Journal: JAMA (2025)

Importance Staphylococcus aureus , a gram-positive bacterium, is the leading cause of death from bacteremia worldwide, with a case fatality rate of 15% to 30% and an estimated 300 000 deaths per year. Observations Staphylococcus aureus bacteremia causes metastatic infection in more than one-third of cases, including endocarditis (≈12%), septic arthritis (7%), vertebral osteomyelitis (≈4%), spinal epidural abscess, psoas abscess, splenic abscess, septic pulmonary emboli, and seeding of implantable medical devices. Patients with S aureus bacteremia commonly present with fever or symptoms from metastatic infection, such as pain in the back, joints, abdomen or extremities, and/or change in mental status. Risk factors include intravascular devices such as implantable cardiac devices and dialysis vascular catheters, recent surgical procedures, injection drug use, diabetes, and previous S aureus infection. Staphylococcus aureus bacteremia is detected with blood cultures. Prolonged S aureus bacteremia (≥48 hours) is associated with a 90-day mortality risk of 39%. All patients with S aureus bacteremia should undergo transthoracic echocardiography; transesophageal echocardiography should be performed in patients at high risk for endocarditis, such as those with persistent bacteremia, persistent fever, metastatic infection foci, or implantable cardiac devices. Other imaging modalities, such as computed tomography or magnetic resonance imaging, should be performed based on symptoms and localizing signs of metastatic infection. Staphylococcus aureus is categorized as methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) based on susceptibility to β-lactam antibiotics. Initial treatment for S aureus bacteremia typically includes antibiotics active against MRSA such as vancomycin or daptomycin. Once antibiotic susceptibility results are available, antibiotics should be adjusted. Cefazolin or antistaphylococcal penicillins should be used for MSSA and vancomycin, daptomycin, or ceftobiprole for MRSA. Phase 3 trials for S aureus bacteremia demonstrated noninferiority of daptomycin to standard of care (treatment success, 53/120 [44%] vs 48/115 [42%]) and noninferiority of ceftobiprole to daptomycin (treatment success, 132/189 [70%] vs 136/198 [69%]). Source control is a critical component of treating S aureus bacteremia and may include removal of infected intravascular or implanted devices, drainage of abscesses, and surgical debridement. Conclusions and relevance Staphylococcus aureus bacteremia has a case fatality rate of 15% to 30% and causes 300 000 deaths per year worldwide. Empirical antibiotic treatment should include vancomycin or daptomycin, which are active against MRSA. Once S aureus susceptibilities are known, MSSA should be treated with cefazolin or an antistaphylococcal penicillin. Additional clinical management consists of identifying sites of metastatic infection and pursuing source control for identified foci of infection.
Unveiling mechanisms underlying kidney function changes during sex hormone therapy
Authors: Sarah A van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R Parikh, Taryn G Vosters, Irene Gm van Valkengoed, Merle M Krebber, Daan J Touw, Martin den Heijer, Petter Bjornstad, Daniël Raalte, Natalie J Nokoff
Journal: Journal of Clinical Investigation (2025)

Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored. This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n=23) or masculinizing (testosterone; n=21) therapy. Baseline and three-month assessments included mGFR (Iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics. During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; p<0.05), without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, EGF, monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (-53%, -42%, -45%, and -58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma TNFR-1 increased (+134% and +8%, respectively; p<0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing, and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin). Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.
Developing Therapeutically Enhanced Extracellular Vesicles for Atherosclerosis Therapy
Authors: Neil Patel, Elijah Avery, Yi Huang, Eun Ji Chung
Journal: Advanced Healthcare Materials (2025)

Abstract Atherosclerosis is a chronic condition and the leading cause of death worldwide. While statin therapy is the clinical standard, many patients still experience acute cardiovascular events. To develop better therapies, the group previously delivered microRNA‐145 (miR‐145) via micellar nanoparticles to vascular smooth muscle cells (VSMCs) to inhibit atherosclerosis. However, for chronic diseases requiring repeat dosing, synthetic nanoparticles have drawbacks such as immunogenic response and low delivery efficiency. To meet this challenge, therapeutically enhanced extracellular vesicles (EVs) are engineered as a biologically‐derived nanoparticle modality to mitigate atherosclerosis. A novel strategy is employed to load miR‐145 into EVs using ExoMotifs—short miRNA sequences that facilitate miR cargo loading. EVs are further functionalized with a monocyte chemoattractant 1 (MCP‐1) peptide, which binds to C‐C chemokine receptor 2 upregulated in pathogenic VSMCs. Mouse aortic smooth muscle cell MCP‐1‐miR‐145 EVs restored VSMC gene expression and function in vitro. Moreover, compared to miR‐145‐loaded synthetic nanoparticles, MCP‐1‐miR‐145 EVs exerted similar therapeutic effects but with 25,000x less miR‐145 cargo. Lastly, MCP‐1‐miR‐145 EVs inhibited plaque growth in mid‐stage ApoE −/− atherosclerotic mice at a miR‐145 dose 5000x less than synthetic nanoparticles. Collectively, it is demonstrated that genetic engineering of VSMCs with miR‐145 produces therapeutically boosted EVs that reduce atherosclerosis plaque burden.
Paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN): a randomised, double-blind, phase 3 trial
Authors: Michael A Smyth, Hannah Noordali, Kath Starr, Joyce Yeung, Ranjit Lall, Felix Michelet, Gordon Fuller, Stavros Petrou, Alison Walker, Zoe Green, Rebecca McLaren, Elisha Miller, Duncan Buckley, Gavin D Perkins
Journal: The Lancet Regional Health - Europe (2025)
Volume Assessment in Patients Undergoing Long-Term Dialysis
Authors: Benjamin Lazarus, Simon J. Davies, Kevan R. Polkinghorne
Journal: Journal of the American Society of Nephrology (2025)

Abstract Accurate assessment of fluid status is a priority for patients with kidney failure undergoing long-term dialysis. There is wide variation in current volume-related practices between dialysis units and an urgent need to develop better evidence to guide practice. Clinical decisions relating to volume management are implicitly based on assessment of volume status, and there are numerous different but imperfect methods of assessment. Isotope-based dilutions are impractical for clinical use and may not be a gold-standard for patients with kidney failure. Individual trends in body weight and blood pressure have been used as a pragmatic surrogate marker for volume status. Probing the target weight based on blood pressure is still widely practiced but may pose risks related to volume depletion and accelerated loss of residual kidney function. Clinical signs such as elevated jugular venous pressure and leg edema are readily accessible but have poor diagnostic accuracy and wide interobserver variability that limit their reproducibility for volume assessment in clinical trials. Lung ultrasound and bioelectrical impedance analysis have a sound scientific rationale for the assessment of extracellular volume, and are appropriately associated with clinical outcomes, but neither approach has demonstrated convincingly favorable clinical outcomes in clinical trials. Other technologies for volume assessment exist but require further assessment in clinical trials. Advancements in clinical care can be made with existing technologies through comparative effectiveness trials of different fluid management strategies, routine and standardized measurement of volumetric parameters and individual patient preferences, and innovative integration of existing volume assessment methods. A systematic and globally coordinated approach to improving volume assessment and management is required to improve outcomes in patients receiving long-term dialysis.
Late Allograft Loss and Contemporary Cardio-Renal Metabolic Therapies
Authors: Amanda J. Vinson, Arthur Matas
Journal: Journal of the American Society of Nephrology (2025)

Abstract Late kidney allograft loss occurs through one of two mechanisms: a) deterioration of kidney function leading to re-transplantation or dialysis (death-censored graft loss) and b) premature death with a normally functioning transplant (death with graft function) –each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific endpoints (e.g., tubular atrophy, interstitial fibrosis and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in terms of reducing cardiovascular, infectious and malignancy endpoints (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or anti-fibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function, and discuss the potential roles of new cardio-renal metabolic agents including sodium-glucose cotransport 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (MRA), glucagon-like peptide 1 receptor agonists (GLP1-RA), and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.
Raffinose-metabolizing bacteria impair radiation-associated hematopoietic recovery <i>via</i> the bile acid/FXR/NF-κB signaling pathway
Authors: Yang Jiao, Jiawei Ren, Shichang Xie, Nan Yuan, Jiaqi Shen, Huafang Yin, Jian Wang, Hongjuan Guo, Jianping Cao, Xin Wang, Depei Wu, Zhemin Zhou, Xiaofei Qi
Journal: Gut Microbes (2025)

Radiation-associated hematopoietic recovery (RAHR) is critical for mitigating lethal complications of acute radiation syndrome (ARS), yet therapeutic strategies remain limited. Through integrated multi-omics analysis of a total body irradiation (TBI) mouse model, we identify Bacteroides acidifaciens-dominated gut microbiota as key mediators of RAHR impairment. 16S ribosomal rRNA sequencing revealed TBI-induced dysbiosis characterized by Bacteroidaceae enrichment, while functional metagenomics identified raffinose metabolism as the most significantly perturbed pathway. Notably, raffinose supplementation (10% w/v) recapitulated radiation-induced microbiota shifts and delayed bone marrow recovery. Fecal microbiota transplantation (FMT) revealed a causative role for raffinose-metabolizing microbiota, particularly Bacteroides acidifaciens, in delaying RAHR progression. Mechanistically, B. acidifaciens-mediated bile acid deconjugation activated FXR, subsequently suppressing NF-κB-dependent hematopoietic recovery. Therapeutic FXR inhibition via ursodeoxycholic acid (UDCA) had been shown to be a viable method for rescuing RAHR. Our results delineated a microbiome-bile acid-FXR axis as a master regulator of post-irradiation hematopoiesis. Targeting B. acidifaciens or its metabolic derivatives could represent a translatable strategy to mitigate radiation-induced hematopoietic injury.
Estimating heat-related mortality burden changes under type-specific green and blue space scenarios in China
Authors: Kejia Hu, Shiyi Wang, Fangrong Fei, Jingqiao Fu, Yujie Shen, Feng Chen, Yunquan Zhang, Jian Cheng, Xuchao Yang, Jieming Zhong, Yuming Guo, Jiayu Wu
Journal: Environmental Health Perspectives (2025)

Green and blue spaces (GBS) are assumed to mitigate heat-induced health risks. However, few studies have explored the impact of type-specific GBS changes on heat-related mortality burden. This study aimed to investigate the effect modifications of different GBS types on heat-related mortality risks, and to estimate the changes in mortality burden in multiple GBS scenarios. A case time-series study design was utilized based on the daily data on all-cause mortality and temperatures from 2009 to 2020 in 1,085 sub-districts in China. Mortality count data were obtained from the Zhejiang Center for Disease Control and Prevention. Meteorological data on temperature and relative humidity were acquired from the Zhejiang Meteorological Bureau. GBS exposure was assessed by integrating fine-scale population density, GBS boundary from Baidu and OpenStreetMap, and street-view image data from Baidu. Conditional Poisson regression analyses were conducted with the distributed lag non-linear model, incorporating modifiers of type-specific GBS exposure. Changes in heat-attributable mortality under different GBS scenarios were also assessed. Heat-related mortality risks were lower for populations with high exposure (95%) than for those with low exposure (5%) (1) to overall green spaces, forests, parks, nature reserves, and street greenery, rather than to grasses, farms, and scrubs; and (2) to overall blue spaces, lakes, and rivers, rather than reservoirs, wetlands, or coasts. An increase of 10%, 20%, and 30% exposure to overall green spaces are expected to avoid heat-related mortality burden by 1.6% (95% empirical confidence interval [eCI]: 1.4, 1.9), 3.2% (2.5, 3.9), and 4.8% (3.5, 6.2), respectively, whereas corresponding estimates for overall blue spaces are 5.4% (4.4, 6.4), 10.8% (8.5, 13.3), and 16.2% (12.3, 20.5), respectively. Conversely, a 30% decrease in overall green and blue space exposure will increase the heat-related mortality burden by 4.8% (4.3, 5.2) and 15.9% (15.2, 16.7), respectively. Our study revealed differences in the capacity of various GBS types to mitigate heat-related mortality risks. While the protective effects of GBS may be moderate, targeted planning strategies should prioritize their implementation for maximum benefits in mitigating heat-related health risks. The continuous shrinkage of the GBS would render other efforts futile, such as heat-health action plans. https://doi.org/10.1289/EHP14014.
Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans
Authors: Megan K. Proulx, Christine D. Wiggins, Charlotte J. Reames, Claire Wu, Michael C. Kiritsy, Ping Xu, Judith C. Gallant, Patricia S. Grace, Brooke A. Fenderson, Clare M. Smith, Cecilia S. Lindestam Arlehamn, Galit Alter, Douglas A. Lauffenburger, Christopher M. Sassetti
Journal: The Journal of Experimental Medicine (2025)

While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require Th1 cells and IFNγ, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNγ-dependent mouse model but with substantially lower lung IFNγ levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNγ signaling. Instead, noncanonical immune features such as Th17-like CD4 and γδT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.
Cross-feeding-based rational design of a probiotic combination of <i>Bacterides xylanisolvens</i> and <i>Clostridium butyricum</i> therapy for metabolic diseases
Authors: Shanshan Qiao, Tao Wang, Jingzu Sun, Junjie Han, Huanqin Dai, Mengxuan Du, Lan Yang, Chun-Jun Guo, Chang Liu, Shuang-Jiang Liu, Hongwei Liu
Journal: Gut Microbes (2025)

The human gut microbiota has gained interest as an environmental factor that contributes to health or disease. The development of next-generation live biotherapeutic products (LBPs) is a promising strategy to modulate the gut microbiota and improve human health. In this study, we identified a novel cross-feeding interaction between Bacteroides xylanisolvens and Clostridium butyricum and developed their combination into a novel LBP for treating metabolic syndrome. Using in-silico analysis and in vitro experiments, we demonstrated that B. xylanisolvens supported the growth and butyrate production of C. butyricum by supplying folate, while C. butyricum reciprocated by providing pABA for folate biosynthesis. Animal gavage experiments showed that the two-strain combination LBP exhibited superior therapeutic efficacy against metabolic disorders in high-fat diet-induced obese (DIO) mice compared to either single-strain treatment. Further omics-based analyses revealed that the single-strain treatments exhibited distinct taxonomic preferences in modulating the gut microbiota, whereas the combination LBP achieved more balanced modulation to preserve taxonomic diversity to a greater extent, thereby enhancing the stability and resilience of the gut microbiome. Moreover, the two-strain combinations more effectively restored gut microbial functions by reducing disease-associated pathways and opportunistic pathogen abundance. This work demonstrates the development of new LBP therapy for metabolic diseases from cross-feeding microbial pairs which exerted better self-stability and robust efficacy in complex intestinal environments compared to conventional single-strain LBPs.