Background Guidelines recommend using high-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) to risk stratify hemodynamically stable patients with acute pulmonary embolism (PE). However, there are no evidence-based cutoff values defined for this clinical application. Methods We performed a single-center, retrospective cohort study of patients with imaging-confirmed

Background Increased cardiac troponin (cTn) concentrations occur in acute myocardial injury and chronic diseases. Characterization of cTn composition in the circulation may assist in differentiating etiologies of myocardial injury. Our goal was to study cTn composition and kinetics in patients following type 1 myocardial infraction (T1MI), cardiac procedures, and chronic heart diseases to establish

BACKGROUND Current studies suggest that cardiac troponin (cTn) forms in the circulation may vary in different clinical scenarios. Our aim was to design a combination of cTn assays specific to the main cTn forms and to evaluate their analytical performance. METHODS We developed immunoassays specific for measuring (1) long-cTnT cTnI-cTnT-TnC (ITC) ternary complex, with cTnT in long form without cleavage

BACKGROUND. Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.

Myocardial infarction (MI) is characterized by massive cardiomyocyte (CM) death and cardiac dysfunction, and effective therapies to achieve cardioprotection are greatly needed. Here, we report that flavin-containing monooxygenase 2 (FMO2) levels were markedly increased in CMs in both ex vivo and in vivo models of ischemic injury. Genetic deletion of FMO2 resulted in reduced CM survival and enhanced

To the Editor: Frameshift neoantigen-based cancer prevention vaccines (e.g., Nous-209, NCT05078866) are being tested in clinical trials for patients with Lynch syndrome (LS) caused by monoallelic mismatch repair (MMR) gene pathogenic variants (PVs). A liquid biopsy biomarker panel has been developed for profiling frameshift mutations (FSMs) in tumors and plasma cell-free DNA (cfDNA) for disease surveillance

Acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality, and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain–containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary

Effective antitumor T cell activity relies on the expression and MHC presentation of tumor neoantigens. Tumor cells can evade T cell detection by silencing the transcription of antigens or by altering MHC machinery, resulting in inadequate neoantigen-specific T cell activation. We identified the DNA–protein kinase inhibitor (DNA-PKi) NU7441 as a promising immunomodulator that reduced immunosuppressive

BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor high-content

BRAFV600E-mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis. The combination of anti-BRAF/anti-EGFR (encorafenib/cetuximab) treatment for patients with BRAFV600E-mutant mCRC improves clinical benefits; unfortunately, inevitable acquired resistance limits the treatment outcome, and the mechanism has not been validated. Here, we discovered that monoacylglycerol O-acyltransferase

Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L and K cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity

Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor–based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid–binding immunoglobulin-like lectins) are expressed on immune cells and regulate their function. Siglec-7 and Siglec-9 contribute to

Heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) represent starkly diverging clinical phenotypes, yet may be caused by mutations to the same sarcomeric protein. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective was to develop a mechanistic explanation of diverging phenotypes in two

mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB,

Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to intestinal inflammatory diseases (IBDs) and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally down-regulated 4-like protein, NEDD4L (NEDD4-2)

Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs)

Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here

In the era of precision medicine, pharmacogenetics has substantial potential for addressing inter-individual variability in drug responses. Although pharmacogenetics has been a research focus for many years, resulting in the establishment of several formal guidelines, its clinical implementation remains limited to several gene-drug combinations in most countries, including Korea. The main causes of

Background Urinalysis, an essential diagnostic tool, faces challenges in terms of standardization and accuracy. The use of artificial intelligence (AI) with mobile technology can potentially solve these challenges. Therefore, we investigated the effectiveness and accuracy of an AI-based program in automatically interpreting urine test strips using mobile phone cameras, an approach that may revolutionize

Background In 2022, the revised WHO classification and International Consensus Classification (ICC) for myeloid neoplasms were published. We examined the impact of these guidelines on AML diagnoses alongside the 2022 European LeukemiaNet (ELN) recommendations on risk stratification. Methods We included 450 adult patients with newly diagnosed AML (non-acute promyelocytic leukemia) from the cBioPortal

Background Immunoglobulin (Ig) measurements in the clinical laboratory have been traditionally performed by nephelometry, turbidimetry, electrophoresis, and ELISA assays. Mass spectrometry (MS) measurements have the potential to provide deeper insights on the nature of these markers. Content Different approaches—top-down, middle-down, or bottom-up—have been described for measuring specific Igs for

Background Predicting in-hospital cardiac arrest (IHCA) is crucial for potentially reducing mortality and improving patient outcomes. However, most models, which rely solely on vital signs, may not comprehensively capture the patients' risk profiles. We aimed to improve IHCA predictions by combining vital sign indicators with laboratory test results and, optionally, International Classification of

BACKGROUND Partial protective immunity to schistosomiasis develops over time, following repeated praziquantel treatment. Moreover, animals develop protective immunity after repeated immunisation with irradiated cercariae. Here, we evaluated development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni (Sm) in healthy, Schistosoma-naïve participants using single-sex

BACKGROUND Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease. METHODS To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software

The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among

Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and

Background Serum total 25-hydroxyvitamin D [25(OH)D] concentration is the most widely used clinical biomarker for vitamin D status. Under certain physiological and pathological conditions, however, total 25(OH)D may not always be the best index for vitamin D status. Instead, the nonprotein-bound (free) fraction of total 25(OH)D has been suggested as a more appropriate marker in certain clinical situations

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental

Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum (F. nucleatum) is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both human

Antagonists (e.g., Ziconotide, Gabapentin) of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2

The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint

Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells’ survival during BTK inhibitor–induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment

The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role

Metabolic dysfunction–associated steatotic hepatitis (MASH) is a chronic progressive liver disease that is highly prevalent worldwide. MASH is characterized by hepatic steatosis, inflammation, fibrosis, and liver damage, which eventually result in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying MASH progression remain largely

Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), catagen (regression), and telogen (quiescence). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous

Female individuals have an increased prevalence of many Th17 cell–mediated diseases, including asthma. Androgen signaling decreases Th17 cell–mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell–mediated airway inflammation. We show that Th17 cells from male humans

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol, the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased

Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted nonclassical functions of Ku70 in cellular processes. However, its function in immune homeostasis and antitumor immunity remains unknown. Here, we discovered a marked

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occurred in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia

Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease (CVD). Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain-containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle

BACKGROUND Antiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of HIV-1 reservoir size. METHODS We used a complete statistical approach to outline parameters underlying diversity in HIV-1 reservoir size in a cohort of 892 people with HIV-1 (PWH) on suppressive ART for >3 years

Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused

BACKGROUND Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but the existence of NPC protective antibody against EBV-associated antigens remains inconclusive. METHODS NPC cases and matched controls were identified from prospective cohorts comprising 75,481 participants in southern China. ELISA and conditional logistic regression were applied to assess effects of gp42-IgG

The SLC6A1 gene encodes the gamma-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed two AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1 KO mice at different developmental ages and various routes of administration