tbuckley/cabot-search huggingface dataset:
Cytotoxic T-Cells Drive Outcome in Inflammatory Dilated Cardiomyopathy
Authors: Maurits A. Sikking, Daniel Harding, Michiel T.H.M. Henkens, Sophie L.V.M. Stroeks, Max F.G.H.M. Venner, Bastien Nihant, Rick E.W. van Leeuwen, Silvia Fanti, Xiaofei Li, Pieter van Paassen, Christian Knackstedt, Hans-Peter Brunner-la Rocca, Vanessa P.M. van Empel, Job A.J. Verdonschot, Federica M. Marelli-Berg, Stephane R.B. Heymans
Journal: Circulation Research (2024)
Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF
Authors: Li Shen, Pooja Dewan, João Pedro Ferreira, Jonathan W. Cunningham, Pardeep S. Jhund, Inder S. Anand, Alvin Chandra, Lu-May Chiang, Brian Claggett, Akshay S. Desai, Jianjian Gong, Carolyn S. P. Lam, Martin P. Lefkowitz, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Margaret M. Redfield, Jean L. Rouleau, Dirk J. van Veldhuisen, Faiez Zannad, Michael R. Zile, Scott D. Solomon, John J. V. McMurray
Journal: Circulation (2024)

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28–30) in 1809 of 2895 patients (62.5%), borderline (score 24–27) in 794 (27.4%), and impaired (score &lt;24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06–1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21–2.06) for those with scores &lt;24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.
Early‐life exposure to residential greenness and risk of asthma in a U.S. bronchiolitis cohort
Authors: Wojciech Feleszko, Heidi Makrinioti, Marta Nalej, Tadao Ooka, Zhaozhong Zhu, Ashley F. Sullivan, Tuomas Jartti, Kohei Hasegawa, Carlos A. Camargo
Journal: Allergy (2024)

Severe bronchiolitis (i.e., bronchiolitis requiring hospitalization) is linked to childhood asthma development. Despite a growing understanding of risk factors for developing post-bronchiolitis asthma, protective factors remain unclear. In this study, we aimed to investigate whether exposure to residential greenness between birth and bronchiolitis hospitalization is associated with asthma and atopic asthma development by age 6 years.
Dietary salt, vascular dysfunction, and cognitive impairment
Authors: Giuseppe Faraco
Journal: Cardiovascular Research (2024)

Abstract Excessive salt consumption is a major health problem worldwide leading to serious cardiovascular events including hypertension, heart disease, and stroke. Additionally, high-salt diet has been increasingly associated with cognitive impairment in animal models and late-life dementia in humans. High-salt consumption is harmful for the cerebral vasculature, disrupts blood supply to the brain, and could contribute to Alzheimer’s disease pathology. Although animal models have advanced our understanding of the cellular and molecular mechanisms, additional studies are needed to further elucidate the effects of salt on brain function. Furthermore, the association between excessive salt intake and cognitive impairment will have to be more thoroughly investigated in humans. Since the harmful effects of salt on the brain are independent by its effect on blood pressure, in this review, I will specifically discuss the evidence, available in experimental models and humans, on the effects of salt on vascular and cognitive function in the absence of changes in blood pressure. Given the strong effects of salt on the function of immune cells, I will also discuss the evidence linking salt consumption to gut immunity dysregulation with particular attention to the ability of salt to disrupt T helper 17 (Th17) cell homeostasis. Lastly, I will briefly discuss the data implicating IL-17A, the major cytokine produced by Th17 cells, in vascular dysfunction and cognitive impairment.
Bioactive metabolites: a clue to the link between MASLD and CKD?
Authors: Wen-Ying Chen, Jia-Hui Zhang, Li-Li Chen, Christopher D Byrne, Giovanni Targher, Liang Luo, Yan Ni, Ming-Hua Zheng, Dan-Qin Sun
Journal: Clinical and Molecular Hepatology (2024)

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules [such as bile acids (BAs), trimethylamine-N-oxide, and short-chain fatty acids], or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.
Inflammasome activation links enteric <i>Salmonella</i> Typhimurium infection to a rapid, cytokine-dependent increase in intestinal mucin release
Authors: Xiao Han, Joannie M. Allaire, Shauna M. Crowley, Jocelyn J. Chan, Kelly Lau, Conghao Zhang, Simon A. Hirota, Kirk Bergstrom, Leigh A. Knodler, Bruce A. Vallance
Journal: Gut Microbes (2024)

The host restricts Salmonella enterica serovar Typhimurium infection of the gut via inflammasome-dependent sloughing of infected epithelial cells. Here we determined that concurrent caspase 1/11-dependent release of the goblet cell-derived mucin, Muc2, into the intestinal lumen also controls Salmonella burdens in infected mice. The increased release of mucins from goblet cells in the cecum and nearby proximal colon, and the subsequent thickening of the protective mucus barrier layer in the distal colon, were all dependent on the cytokines interleukin (IL)-18 and IL-22, as deficiencies in either cytokine resulted in reduced mucin secretion. Supplementation of IL-18 into IL-22 deficient mice restored mucin secretion, indicating that IL-22 acted upstream of IL-18 secretion during infection. In contrast, IL-18 and IL-22 independent signaling through Nlrp6 underlies only a modest, infection-induced increase in mucin secretion from goblet cells in the distal colon. These findings reveal that inflammasome signaling orchestrates multiple levels of protection centered on the intestinal epithelium, including pyroptosis and expulsion of infected enterocytes, as well as the release of mucins by goblet cells in the cecum and along the length of the colon. Our studies underscore the pivotal, multi-faceted role of inflammasome signaling in promoting host defense at the intestinal mucosal surface.
Structural insights into the mechanotransducing mechanism of FtsEX in cell division
Authors: Yuejia Chen, Du Guo, Xin Wang, Changbin Zhang, Yatian Chen, Qinghua Luo, Yujiao Chen, Lili Yang, Zhibo Zhang, Tian Hong, Zhengyu Zhang, Haohao Dong, Shenghai Chang, Jianping Hu, Xiaodi Tang
Journal: MedComm (2024)

Abstract The filamentous temperature‐sensitive (Fts) protein FtsEX plays a pivotal role in Escherichia coli ( E. coli ) cell division by facilitating the activation of peptidoglycan hydrolysis through the adaptor EnvC. FtsEX belongs to the type VII ATP‐binding cassette (ABC) transporter superfamily, which harnesses ATP energy to induce mechanical force, triggering a cascade of conformational changes that activate the pathway. However, the precise mechanism by which FtsEX initiates mechanotransmission remains elusive. Due to the inherent instability of this type of ABC transporter protein in vitro, the conformation of FtsEX has solely been determined in the stabilized ATP‐bound state. To elucidate the dynamics of FtsEX, we characterized FtsEX and EnvC of various functional structures through cryo‐electron microscopy (cryo‐EM) and homology modeling. We validated the structures by molecular dynamics simulations. By site‐directed mutagenesis and phenotype screening, we also identified the functional residues involved in allosteric communication between FtsE and FtsX as well as FtsX and EnvC. Additionally, we discovered a potential role of phospholipids in stabilizing the complex conformation during mechanotransmission. This comprehensive exploration significantly enhances our understanding of the intricate mechanisms governing bacterial cell division and unveils potential molecular targets for developing innovative antimicrobial drugs to combat antibiotic resistance.
Species- and subspecies-level characterization of health-associated bacterial consortia that colonize the human gut during infancy
Authors: Samuel S. Minot, Koshlan Mayer-Blackwell, Andrew Fiore-Gartland, Andrew Johnson, Steven Self, Parveen Bhatti, Lena Yao, Lili Liu, Xin Sun, Yi Jinfa, James Kublin
Journal: Gut Microbes (2024)

Background The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.
Nanomedicine for cancer patient‐centered care
Authors: Carlo Sorrentino, Stefania Livia Ciummo, Cristiano Fieni, Emma Di Carlo
Journal: MedComm (2024)

Abstract Cancer is a leading cause of morbidity and mortality worldwide, and an increase in incidence is estimated in the next future, due to population aging, which requires the development of highly tolerable and low‐toxicity cancer treatment strategies. The use of nanotechnology to tailor treatments according to the genetic and immunophenotypic characteristics of a patient's tumor, and to allow its targeted release, can meet this need, improving the efficacy of treatment and minimizing side effects. Nanomedicine‐based approach for the diagnosis and treatment of cancer is a rapidly evolving field. Several nanoformulations are currently in clinical trials, and some have been approved and marketed. However, their large‐scale production and use are still hindered by an in‐depth debate involving ethics, intellectual property, safety and health concerns, technical issues, and costs. Here, we survey the key approaches, with specific reference to organ‐on chip technology, and cutting‐edge tools, such as CRISPR/Cas9 genome editing, through which nanosystems can meet the needs for personalized diagnostics and therapy in cancer patients. An update is provided on the nanopharmaceuticals approved and marketed for cancer therapy and those currently undergoing clinical trials. Finally, we discuss the emerging avenues in the field and the challenges to be overcome for the transfer of nano‐based precision oncology into clinical daily life.
Progressive cancer targeting by programmable aptamer‐tethered nanostructures
Authors: Fatemeh Mohammadi, Hamed Zahraee, Farkhonde Zibadi, Zahra Khoshbin, Mohammad Ramezani, Mona Alibolandi, Khalil Abnous, Seyed Mohammad Taghdisi
Journal: MedComm (2024)

Abstract Scientific research in recent decades has affirmed an increase in cancer incidence as a cause of death globally. Cancer can be considered a plurality of various diseases rather than a single disease, which can be a multifaceted problem. Hence, cancer therapy techniques acquired more accelerated and urgent approvals compared to other therapeutic approaches. Radiotherapy, chemotherapy, immunotherapy, and surgery have been widely adopted as routine cancer treatment strategies to suppress disease progression and metastasis. These therapeutic approaches have lengthened the longevity of countless cancer patients. Nonetheless, some inherent limitations have restricted their application, including insignificant therapeutic efficacy, toxicity, negligible targeting, non‐specific distribution, and multidrug resistance. The development of therapeutic oligomer nanoconstructs with the advantages of chemical solid‐phase synthesis, programmable design, and precise adjustment is crucial for advancing smart targeted drug nanocarriers. This review focuses on the significance of the different aptamer‐assembled nanoconstructs as multifunctional nucleic acid oligomeric nanoskeletons in efficient drug delivery. We discuss recent advancements in the design and utilization of aptamer‐tethered nanostructures to enhance the efficacy of cancer treatment. Valuably, this comprehensive review highlights self‐assembled aptamers as the exceptionally intelligent nano‐biomaterials for targeted drug delivery based on their superior stability, high specificity, excellent recoverability, inherent biocompatibility, and versatile functions.
A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease
Authors: Tom Thomas, Matthias Friedrich, Charlotte Rich-Griffin, Mathilde Pohin, Devika Agarwal, Julia Pakpoor, Carl Lee, Ruchi Tandon, Aniko Rendek, Dominik Aschenbrenner, Ashwin Jainarayanan, Alexandru Voda, Jacqueline H. Y. Siu, Raphael Sanches-Peres, Eloise Nee, Dharshan Sathananthan, Dylan Kotliar, Peter Todd, Maria Kiourlappou, Lisa Gartner, Nicholas Ilott, Fadi Issa, Joanna Hester, Jason Turner, Saba Nayar, Jonas Mackerodt, Fan Zhang, Anna Jonsson, Michael Brenner, Soumya Raychaudhuri, Ruth Kulicke, Danielle Ramsdell, Nicolas Stransky, Ray Pagliarini, Piotr Bielecki, Noah Spies, Brian Marsden, Stephen Taylor, Allon Wagner, Paul Klenerman, Alissa Walsh, Mark Coles, Luke Jostins-Dean, Fiona M. Powrie, Andrew Filer, Simon Travis, Holm H. Uhlig, Calliope A. Dendrou, Christopher D. Buckley
Journal: Nature Immunology (2024)

Abstract Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn’s disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.
Detecting clinical medication errors with AI enabled wearable cameras
Authors: Justin Chan, Solomon Nsumba, Mitchell Wortsman, Achal Dave, Ludwig Schmidt, Shyamnath Gollakota, Kelly Michaelsen
Journal: npj Digital Medicine (2024)

Drug-related errors are a leading cause of preventable patient harm in the clinical setting. We present the first wearable camera system to automatically detect potential errors, prior to medication delivery. We demonstrate that using deep learning algorithms, our system can detect and classify drug labels on syringes and vials in drug preparation events recorded in real-world operating rooms. We created a first-of-its-kind large-scale video dataset from head-mounted cameras comprising 4K footage across 13 anesthesiology providers, 2 hospitals and 17 operating rooms over 55 days. The system was evaluated on 418 drug draw events in routine patient care and a controlled environment and achieved 99.6% sensitivity and 98.8% specificity at detecting vial swap errors. These results suggest that our wearable camera system has the potential to provide a secondary check when a medication is selected for a patient, and a chance to intervene before a potential medical error.
Safety principles for medical summarization using generative AI
Authors: Dillon Obika, Christopher Kelly, Nicola Ding, Chris Farrance, Jonathan Krause, Praney Mittal, Donny Cheung, Heather Cole-Lewis, Madeleine Elish, Alan Karthikesalingam, Dale Webster, Bakul Patel, Michael Howell
Journal: Nature Medicine (2024)
Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis
Authors: Xin Liu, Mengjie Yang, Ping Xu, Mingwei Du, Shanshan Li, Jin Shi, Qiang Li, Jinfeng Yuan, Yu Pang
Journal: Cellular and Molecular Immunology (2024)

Abstract Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue that is complicated by the ability of the pathogen to delay the host’s T-cell immune response. This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb, allowing it to establish a persistent chronic infection. To investigate the underlying mechanisms, this study focused on Mtb’s exploitation of host tryptophan metabolism. Mtb upregulates indoleamine 2,3-dioxygenase 1 (IDO1) in inflammatory macrophages, thereby increasing kynurenine (Kyn) production. Kyn then activates the aryl hydrocarbon receptor (AhR), leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of the chemokines CXCL9 and CXCL10, which are crucial for T-cell recruitment to the lungs. Supported by in vivo mouse models, our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity, thereby undermining Mtb-induced immunosuppression. In contrast, additional Kyn injection obviously inhibited T-cell infiltration and activity. These results highlight potential therapeutic targets of AhR and IDO1, offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.
The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies
Authors: Mengge Yu, Giselle Sek Suan Nah, Vaidehi Krishnan, Fatin Nasha Bte Sulaimi, King Pan Ng, Chuqi Wang, Shruti Bhatt, Charles Chuah, David E. Bergstrom, S. Tiong Ong
Journal: Leukemia (2024)
Retraction Note: SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide
Authors: H. Jiang, C. Acharya, G. An, M. Zhong, X. Feng, L. Wang, N. Dasilva, Z. Song, G. Yang, F. Adrian, L. Qiu, P. Richardson, N. C. Munshi, Y. -T. Tai, K. C. Anderson
Journal: Leukemia (2024)
Choline geranate (CAGE): A multifaceted ionic liquid for drug delivery
Authors: Samir Mitragotri
Journal: Journal of Controlled Release (2024)

Ionic liquids, organic salts in a liquid state below 100 °C, have traditionally been associated with industrial applications. Recent research has introduced a new generation of ionic liquids, designed from biocompatible ions, to enable applications in drug delivery. Here, I provide a historical perspective, development status and applications of a leading example of biocompatible ionic liquids, a salt of Choline And Geranic acid (CAGE). Since its first report in 2014, CAGE has opened multiple drug delivery applications including transdermal, oral, buccal, sustained release, tissue ablation, periodontitis and hand hygiene, among others. CAGE-based products have been tested in more than 200 patients through multiple Phase 1 and Phase 2 clinical studies, including successful use in a Phase 2 clinical study in Atopic Dermatitis patients. CAGE became the first 'drug delivery ionic liquid' to enter into clinical trials. This article summarizes the key fundamental and translational aspects of CAGE as pertained to its use in drug delivery.
Tumor therapy utilizing dual-responsive nanoparticles: A multifaceted approach integrating calcium-overload and PTT/CDT/chemotherapy
Authors: Xiaorong Yang, Hong Zhang, Zehua Wu, Qin Chen, Wei Zheng, Qiying Shen, Qiaolin Wei, Jia-Wei Shen, Yong Guo
Journal: Journal of Controlled Release (2024)
Prolonged release and antiviral efficacy of HIV fusion inhibitor LP-98-loaded microspheres in rhesus macaques
Authors: Zhe Cong, Yi Wei, Huihui Chong, Dong Zhang, Ling Tong, Jingjing Zhang, Yuanmei Zhu, Zejing Gao, Huijuan Jin, Jiahan Lu, Qiuhan Lu, Ting Chen, Qiang Wei, Guanghui Ma, Yuxian He, Fangling Gong, Jing Xue
Journal: Journal of Controlled Release (2024)

Non-adherence to antiretroviral treatment is a critical obstacle to effectively managing the progression of AIDS and reducing transmission and mortality rates. A promising strategy to address the clinical disadvantages of user-dependent dosing and decrease medication frequency is the development of long-acting antiretrovirals. In this study, we fabricated PLGA microspheres (MS) incorporating the lipopeptide LP-98 (LP-98-MS), which has previously exhibited potent anti-HIV efficacy. Our findings demonstrate that a single-dose injection of LP-98-MS in SHIV-infected rhesus macaques resulted in sustained and gradual release, maintaining antiviral effects at least 28 days. Notably, a single administration of LP-98-MS provided more than 28 days of sustained release, resulting in high-level pre-exposure prophylaxis (PrEP) for rhesus macaques, even providing complete protection when exposed to repeated intravaginal and intrarectal SHIV challenges. Overall, LP-98-MS holds significant potential in reducing medication frequency and shows promising prospects for further development.