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Review Article
| Open AccessNext-generation rapid phenotypic antimicrobial susceptibility testing
Authors present a scoping review synthesizing new and upcoming technologies providing rapid phenotypic antimicrobial susceptibility testing (AST).
- Grace Reszetnik
- , Keely Hammond
- & Cedric P. Yansouni
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Article
| Open AccessNon-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial
Oncolytic viruses have been tested in patients with malignant glioma, however clinical efficacy remains limited. Here the authors report the results of a phase I trial of Ad-TD-nsIL12, an oncolytic adenovirus expressing a mutant (non-secreting) form of IL12, in patients with high-grade glioma.
- Weihai Ning
- , Xiao Qian
- & Hongwei Zhang
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Article
| Open AccessA molecular video-derived foundation model for scientific drug discovery
Accurate molecular representation of compounds is a fundamental challenge for drug discovery. Here, the authors present a molecular video-based foundation model pretrained on 120 million frames of 2 million molecular videos, and apply it to molecular targets and properties prediction.
- Hongxin Xiang
- , Li Zeng
- & Feixiong Cheng
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Article
| Open AccessPreoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice
Utilizing short-term dietary interventions for surgical preconditioning stands as an emerging approach to enhance surgical outcomes. Here, the authors show the potential of short-term preoperative methionine restriction as a simple intervention to ameliorate postinterventional vascular remodelling.
- Peter Kip
- , Thijs J. Sluiter
- & Margreet R. de Vries
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Article
| Open AccessGenome-wide meta-analysis conducted in three large biobanks expands the genetic landscape of lumbar disc herniations
A genome-wide association study suggests 41 previously unreported loci on top of the 23 known loci that influence the disease risk for lumbar disc herniations. Many of these loci harbour genes implicated in disc structure and inflammation, as well as genes related to the nervous system and nerve function.
- Ville Salo
- , Juhani Määttä
- & Johannes Kettunen
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Article
| Open AccessCohort studies on 71 outcomes among people with atopic eczema in UK primary care data
Eczema may be associated with atopic as well as non-atopic diseases. Here the authors studied associations between atopic eczema and 71 subsequent adverse health outcomes in a large (>20 million) UK primary care data, enabling comparison between outcomes and judging relevance for clinical practice and guidelines.
- Julian Matthewman
- , Anna Schultze
- & Sinéad M. Langan
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Article
| Open AccessElectron-donable heterojunctions with synergetic Ru-Cu pair sites for biocatalytic microenvironment modulations in inflammatory mandible defects
Mandible defect is a global health challenge. This study proposes an electron-donable heterojunction with synergetic catalytic sites and switchable anti-inflammatory and antibacterial activities for the repair of mandible defects.
- Mingru Bai
- , Ting Wang
- & Chong Cheng
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Article
| Open AccessEfficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone: a multicenter, phase Ib/II study
Giant cell tumor of bone (GCTB) is a rare primary osteolytic bone tumor with high local recurrence rate after surgical resection. Here the authors conduct a phase Ib/II trial, evaluating the efficacy and safety of JMT103 (RANK-RANKL inhibitor) in patients with unresectable or surgically-challenging GCTB.
- Hairong Xu
- , Yong Zhou
- & Xiaohui Niu
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Article
| Open AccessEffectiveness of BNT162b2 XBB vaccine in the US Veterans Affairs Healthcare System
This study evaluates the effectiveness of the BNT162b2 XBB.1.5-adapted vaccine against COVID-19 outcomes within the US Veterans Affairs Healthcare System, finding 50–61% during XBB predominance and 24–35% effectiveness during JN.1 predominance, emphasizing the importance of strain match.
- Aisling R. Caffrey
- , Haley J. Appaneal
- & John M. McLaughlin
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Article
| Open AccessIntersecting social and environmental determinants of multidrug-resistant urinary tract infections in East Africa beyond antibiotic use
Antibiotic resistance is biologically driven by antibiotic use but other social, environmental, demographic, economic and behavioural factors also contribute. Here, the authors conduct a cross-sectional study to identify risk factors jointly associated with multidrug resistant urinary tract infection in East Africa.
- Katherine Keenan
- , Michail Papathomas
- & John Stelling
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Article
| Open AccessInflammasome-targeted therapy might prevent adverse perinatal outcomes of recurrent chronic intervillositis of unknown etiology
Chronic histiocytic intervillositis of unknown origin is a rare but serious and hard-to-prevent condition, leading to repeated pregnancy losses. Here authors show that high-grade cases are associated with inflammasome activation in placental samples, and they report the birth of healthy full-term infants following sustained inflammasome inhibition in three high-risk pregnancies.
- Aurélien Mattuizzi
- , Fanny Sauvestre
- & Estibaliz Lazaro
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Article
| Open AccessRisk-stratified treatment for drug-susceptible pulmonary tuberculosis
Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.
- Vincent K. Chang
- , Marjorie Z. Imperial
- & Elizabeth Guy
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Article
| Open AccessThe regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials
Impaired interleukin-2 production and regulatory T cell dysfunction is implicated in multiple autoimmune diseases. Here, in two phase lb trials, the authors show that rezpegaldesleukin, a Treg-selective pegylated IL-2, is safe and improves symptoms in patients with atopic dermatitis or psoriasis.
- Jonathan I. Silverberg
- , David Rosmarin
- & Jonathan Zalevsky
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Article
| Open AccessSkeletal muscle reprogramming enhances reinnervation after peripheral nerve injury
Peripheral nerves slowly regrow after injury, but often fail to form functional synapses. Here, authors use NANOG, a pluripotency factor, to induce denervated muscle to a pro-regenerative state improving muscle reinnervation after nerve transection.
- Pihu Mehrotra
- , James Jablonski
- & Kirkwood E. Personius
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Article
| Open AccessSocio-demographic and genetic risk factors for drug adherence and persistence across 5 common medication classes
This study examines socio-demographic and genetic factors for adherence and persistence to five medication classes, identifying lower socio-economic and immigration status as major predictors of lower adherence, while genetic factors show minimal impact.
- Mattia Cordioli
- , Andrea Corbetta
- & Andrea Ganna
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Article
| Open AccessDuctal lavage followed by observation versus oral corticosteroids in idiopathic granulomatous mastitis: A randomized trial
Ductal lavage represents a treatment option for idiopathic granulomatous mastitis. Here, the authors report the results of a randomized clinical trial, indicating that ductal lavage followed by observation is non-inferior to oral corticosteroids
- Xiaolin Chen
- , Heng Huang
- & Kai Chen
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Article
| Open AccessUncovering genetic loci and biological pathways associated with age-related cataracts through GWAS meta-analysis
Here, the authors expand knowledge of the genetic architecture of age-related cataracts, exploring associated pathways and drug-gene interactions, and clarify the roles of type 1 diabetes and UV exposure in cataract etiology.
- Santiago Diaz-Torres
- , Samantha Sze-Yee Lee
- & Miguel E. Rentería
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Article
| Open AccessMicrobiome-based correction for random errors in nutrient profiles derived from self-reported dietary assessments
Here, the authors introduce METRIC, a deep-learning method that corrects measurement errors in self-reported dietary nutrient profiles using assessed data and microbial composition, effectively enhancing dietary accuracy.
- Tong Wang
- , Yuanqing Fu
- & Yang-Yu Liu
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Article
| Open AccessPlasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer
Non-invasive approaches for risk stratification and screening remain crucial for colorectal cancer (CRC). Here, the authors develop a model for CRC risk stratification by integrating plasma proteomics data with polygenic risk score and QCancer-15 risk score, which could guide recommendations for earlier screening of high-risk populations.
- Jing Sun
- , Yue Liu
- & Xue Li
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Article
| Open AccessHEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status
It’s poorly understood how renal manifestations develop in HEV infection in patients. Here, the authors observe glomerular accumulation of the viral protein ORF2 in complex with host IgG in immunocompromised patients with chronic or acute HEV infection who developed glomerulonephritis.
- Anne-Laure Leblond
- , Birgit Helmchen
- & Achim Weber
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Article
| Open AccessApatinib plus hepatic arterial infusion of oxaliplatin and raltitrexed for hepatocellular carcinoma with extrahepatic metastasis: phase II trial
Locoregional treatment of hepatocellular carcinoma (HCC) using hepatic arterial infusion chemotherapy (HAIC) has been shown to be effective. Here the authors conduct a phase II clinical trial evaluating the efficacy and safety of combining apatinib (VEGFR2 inhibitor) and HAIC (oxaliplatin plus raltitrexed) in patients with advanced HCC with extrahepatic metastasis.
- Shiguang Chen
- , Xiangdong Wang
- & Chuanben Chen
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Article
| Open AccessDisparities in high fasting plasma glucose-related cardiovascular disease burden in China
Evidence for comprehensive assessment of cardiovascular disease (CVD) burden attributable to high fasting plasma glucose (FPG) in China is limited. Here, the authors show CVD deaths attributable to high FPG varied substantially across China. Exposure to high FPG and population aging were the primary drivers of increased CVD burden.
- Xue Cao
- , Yixin Tian
- & Zengwu Wang
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Article
| Open AccessGenome-wide association studies of COVID-19 vaccine seroconversion and breakthrough outcomes in UK Biobank
Here, the authors use a large cohort to corroborate a link between genetic variants in the HLA region and COVID−19 vaccine responses, and locate 10 independent genetic loci significantly associated with breakthrough infection phenotypes after the vaccination. These findings support the notion that genetics play important roles in COVID−19 response and effectiveness.
- Marta Alcalde-Herraiz
- , Martí Català
- & Daniel Prieto-Alhambra
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Article
| Open AccessEnhanced Staphylococcus aureus protection by uncoupling of the α-toxin-ADAM10 interaction during murine neonatal vaccination
Staphylococcus aureus infection results in robust induction of immunity but the development of efficacious vaccines remains challenging. Here the authors present a vaccine that amplifies T cell immunity early in life by targeting the S. aureus α-toxin-ADAM10 interaction in a murine model.
- Kelly L. Tomaszewski
- , Meagan Blanchard
- & Juliane Bubeck Wardenburg
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Comment
| Open AccessStrengthening and expanding capacities in clinical trials: advancing pandemic prevention, preparedness and response in Africa
Enhancing the clinical trial capabilities within Africa is essential to augment the continent’s pandemic prevention, preparedness and response efforts. Here, we describe the critical challenges of clinical trials in Africa and draw upon the lessons learnt from the
Con sortium forC OVID-19Va ccineC linicalT rials (CONCVACT) experience, such as the importance of regional collaboration, capacity building and establishing standardized protocols.- Nicaise Ndembi
- , Tadesse T. Mekonen
- & John Nkengasong
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Article
| Open AccessXenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation
SBS leads to severe morbidity and mortality. Here, using a xenotransplantation model, the authors uncover the role of zinc transport pathways in intestinal adaptation in SBS, highlighting the potential of zinc supplementation as a therapeutic approach.
- Maame Efua S. Sampah
- , Hannah Moore
- & David J. Hackam
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Article
| Open AccessA fair individualized polysocial risk score for identifying increased social risk in type 2 diabetes
Racial and ethnic minorities bear a disproportionate burden of type 2 diabetes (T2D) and its complications, with social determinants of health (SDoH) recognized as key drivers of these disparities. Here, the authors developed an individualized polysocial risk score (iPsRS) to screen for unmet social needs essential to hospitalization risk in patients with Type 2 Diabetes, incorporating fairness optimization and explainable AI.
- Yu Huang
- , Jingchuan Guo
- & Jiang Bian
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Article
| Open AccessEffects of iron supplements and iron-containing micronutrient powders on the gut microbiome in Bangladeshi infants: a randomized controlled trial
As part of a large placebo-controlled randomized controlled trial of iron or micronutrient powders given to 923 children in rural Bangladesh for 3 months, the authors evaluated changes to the gut microbiome and identified no changes in diversity or composition. However, potentially pathogenic changes were seen in unadjusted analysis.
- Andrew Baldi
- , Sabine Braat
- & Sant-Rayn Pasricha
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Article
| Open AccessTargeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity
Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Here the authors show that elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local bone GC activation, is associated with bone loss and obesity mice.
- Chuanxin Zhong
- , Nanxi Li
- & Ge Zhang
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Article
| Open AccessImmune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage
The SARS-CoV-2 JN.1 lineage spread rapidly in winter 2023-24 with high estimated levels of transmission but limited increase in severe disease burden. Here, the authors use electronic health record data from the United States to investigate the immune history and clinical outcomes of patients infected with this strain.
- Joseph A. Lewnard
- , Parag Mahale
- & Sara Y. Tartof
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Article
| Open AccessThe genetic landscape of basal ganglia and implications for common brain disorders
Here the authors identify 72 genetic loci, including 50 novel loci, linked to basal ganglia volume with links to neurodevelopment and brain disorders.
- Shahram Bahrami
- , Kaja Nordengen
- & Ole A. Andreassen
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Article
| Open AccessPost-COVID-19 condition symptoms among emergency department patients tested for SARS-CoV-2 infection
In this study of more than 6500 emergency department patients, symptoms consistent with Long COVID are reported by 38.9% of SARS-CoV-2 test-positive and 20.7% of test-negative patients three months after their visit. A documented SARS-CoV-2 infection increased the risk fourfold of reporting Long COVID symptoms.
- Patrick M. Archambault
- , Rhonda J. Rosychuk
- & Sébastien Robert
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Article
| Open AccessCRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells
NK cell-based therapy can kill acute myeloid leukemia (AML), but immune suppression may occur. Here the authors overcome the immunosuppression of AML-targeted CAR33-NK cells via non-viral CRISPR-editing of the immune checkpoint NKG2A, leading to an enhanced potency of the CAR-NK cell product with sustained anti-tumor efficacy.
- Tobias Bexte
- , Nawid Albinger
- & Evelyn Ullrich
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Article
| Open AccessAir pollution below US regulatory standards and cardiovascular diseases using a double negative control approach
The health impacts of air pollution at low concentrations are unclear. Here, using a double negative control approach to capture omitted confounders, the authors show increased cardiovascular risk associated with long-term air pollution exposure below US regulatory standards, suggesting the need to tighten the current standards.
- Yichen Wang
- , Mahdieh Danesh Yazdi
- & Joel D. Schwartz
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Article
| Open AccessThe co-occurrence of genetic variants in the TYR and OCA2 genes confers susceptibility to albinism
This study demonstrates that the co-occurrence of two specific variants in the TYR and OCA2 genes significantly increases the likelihood of having albinism. The outlined approach could help to elucidate digenic/oligogenic patterns in other rare conditions.
- David J. Green
- , Vincent Michaud
- & Panagiotis I. Sergouniotis
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Article
| Open AccessEffect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial
Evidence for the treatment of patients with mild-to-moderate COPD is limited. Here, the authors show that long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improve lung function in patients with mild-tomoderate COPD.
- Yumin Zhou
- , Fan Wu
- & Li Chen
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Article
| Open AccessHistone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion
Transcriptomics is widely used to identify functional and developmental states of T cells and their genetically engineered therapeutic counterparts, such as CAR-T cells. Here authors show that by looking at epigenetic markers in human CD8 + T cells and CAR-T cells, properties and quality of these cells, which are not obvious from gene expression analysis, could be accurately described.
- S. Fiorenza
- , Y. Zheng
- & C. J. Turtle
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Article
| Open AccessImpact of pneumococcal conjugate vaccines on invasive pneumococcal disease-causing lineages among South African children
Introduction of pneumococcal conjugate vaccines in South Africa has led to reductions in vaccine serotype-related invasive disease. Here, the authors perform a genomic surveillance study to evaluate the impact of vaccines on the population structure of S. pneumoniae.
- Cebile Lekhuleni
- , Kedibone Ndlangisa
- & Mignon du Plessis
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Article
| Open AccessGV-971 prevents severe acute pancreatitis by remodeling the microbiota-metabolic-immune axis
Severe acute pancreatitis (SAP) is a profoundly lethal inflammatory condition with limited therapeutic options. Here, the authors present GV-971, an anti-Alzheimer's medication, as a promising candidate for SAP by effectively restoring intestinal microbiota homeostasis and metabolite profiles.
- Xi Chen
- , Xin Chen
- & Jinbao Liu
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Article
| Open AccessEfficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial
A Phase 2, randomized, placebo-controlled study evaluated novel GLP-1 analog ecnoglutide in adults with type 2 diabetes. Here we show that ecnoglutide significantly reduced HbA1c from baseline up to -2.39% compared to -0.55% for placebo (P<0.0001), with a safety profile similar to approved GLP-1 analogs.
- Dalong Zhu
- , Weimin Wang
- & Hai Pan
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Article
| Open AccessParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants
Interpreting the significance of putative splice-altering variants outside canonical splice sites remains challenging. Here, the authors describe ParSE-seq, a high-throughput assay to annotate the effect of germline variants on RNA-splicing. They calibrate the assay and deploy it to study hundreds of variants in the arrhythmia-associated gene SCN5A.
- Matthew J. O’Neill
- , Tao Yang
- & Andrew M. Glazer
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Article
| Open AccessGeneralizability assessment of AI models across hospitals in a low-middle and high income country
The integration of AI into healthcare systems in low-middle income countries faces significant challenges. Here, authors show that AI models developed in high income countries can be adapted for LMICs using methods like missing feature imputation and transfer learning.
- Jenny Yang
- , Nguyen Thanh Dung
- & David A. Clifton
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Article
| Open AccessHeteroduplex oligonucleotide technology boosts oligonucleotide splice switching activity of morpholino oligomers in a Duchenne muscular dystrophy mouse model
Here, the authors develop a PMO-based heteroduplex oligonucleotide technology that enhances PMO delivery to tissues and normalizes motor/cardiac function and CNS symptoms in a mouse model of Duchenne muscular dystrophy.
- Juri Hasegawa
- , Tetsuya Nagata
- & Takanori Yokota
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Article
| Open AccessEmergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections
Here, the authors isolate a SARS-CoV-2 mutant that has developed decreased sensitivity to Paxlovid and remdesivir from an immunocompromised patient, show that drug resistance can be overcome by simultaneous treatment with both drugs in vitro, and demonstrate that the drug resistant virus can efficiently transmit in the hamster model.
- Mohammed Nooruzzaman
- , Katherine E. E. Johnson
- & Mirella Salvatore
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Article
| Open AccessLongitudinal deep neural networks for assessing metastatic brain cancer on a large open benchmark
Cancer is a dynamic disease, with one of its deadly complications being metastatic brain tumors. Here, the authors present a large, multimodal, longitudinal dataset of metastatic cancer, assembled from real world data for cancer research and artificial intelligence (AI) model development. They train time-dependent AI models, and find that novel, dynamic biomarkers exist that are predictive of systemic disease control and overall survival.
- Katherine E. Link
- , Zane Schnurman
- & Eric Karl Oermann
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Article
| Open AccessNormothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39
The authors previously reported that normothermic ex vivo kidney perfusion is superior to static cold storage in terms of organ protection, but the detailed mechanism was unclear. Here the authors show that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by administration of AP39, a mitochondria-targeted hydrogen sulfide donor.
- Masataka Kawamura
- , Catherine Parmentier
- & Lisa A. Robinson
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Article
| Open AccessPro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis
Systemic blockade of CD47 showed promising results for treating atherosclerosis but induces anemia. Here, the authors show that macrophage-specific nanoparticles promoting efferocytosis reduce apoptotic cell accumulation and inflammation in a porcine model of atherosclerosis without causing anemia.
- Sharika Bamezai
- , Yapei Zhang
- & Nicholas J. Leeper
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Article
| Open AccessIL-4 drives exhaustion of CD8+ CART cells
The application and therapeutic success of CAR-T cell approaches are limited by the development of T cell exhaustion. Here, Stewart et al discover a role for IL-4 in driving CD8+ CAR-T cell exhaustion and demonstrate the improvement of CAR-T cell effectivity with interruption of IL-4 signalling.
- Carli M. Stewart
- , Elizabeth L. Siegler
- & Saad S. Kenderian
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Article
| Open AccessThe global geography of artificial intelligence in life science research
AI promises to transform medicine, but geographic concentration may hinder its equitable application. Here, authors map a global atlas of medical AI research and show that greater integration of global expertize could help AI deliver on its promise.
- Leo Schmallenbach
- , Till W. Bärnighausen
- & Marc J. Lerchenmueller