Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

Background: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases.

Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes.

Background: Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer.

germline pathogenic variants in modern humans were likely originated during recent human history.

is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in damages its function, causing genome instability and increased cancer risk. Despite extensive study in , the evolutionary origin of the human germline pathogenic variants remains largely unclear.

Evolutionary Origin of Germline Pathogenic Variations in Modern Humans.

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between variation and cancer development.

Ethnic-specificity, evolution origin and deleteriousness of Asian BRCA variation revealed by over 7500 BRCA variants derived from Asian population.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization.

Plasminogen Activator Inhibitor-1-Positive Platelet-Derived Extracellular Vesicles Predicts MACE and the Proinflammatory SMC Phenotype.

Patients with established coronary artery disease remain at elevated risk of major adverse cardiac events. The goal of this study was to evaluate the utility of plasminogen activator inhibitor-1-positive platelet-derived extracellular vesicles as a biomarker for major adverse cardiac events and to explore potential underlying mechanisms. Our study suggests these extracellular vesicles as a potential biomarker to identify and a therapeutic target to ameliorate neointimal formation of high-risk patients.

Rhoifolin Alleviates Alcoholic Liver Disease and Inhibition of the TLR4/NF-κB Signaling Pathway.

Alcoholic liver disease (ALD) is a common chronic liver disorder worldwide, which is detrimental to human health. A preliminary study showed that the total flavonoids within "Tomentosa" exerted a remarkable effect on the treatment of experimental ALD. However, the active substances of "Tomentosa" were not elucidated.

Elevated β-catenin and C-myc promote malignancy, relapse, and indicate poor prognosis in patients with relapsed glioma.

Context: Extensive studies have shown that β-catenin and C-myc have been linked to a number of human cancers. However, the role of β-catenin and C-myc in relapse glioma remains unclear.

Aims: The aims of this study were to investigate the role of β-catenin and C-myc in relapsed glioma patients and to explore the possible impact of malignancy, relapse, and prognosis.

Extracellular Vesicles as an Index for Endothelial Injury and Cardiac Dysfunction in a Rodent Model of GDM.

Gestational diabetes mellitus (GDM) increases risk of adverse pregnancy outcomes and maternal cardiovascular complications. It is widely believed that maternal endothelial dysfunction is a critical determinant of these risks, however, connections to maternal cardiac dysfunction and mechanisms of pathogenesis are unclear. Circulating extracellular vesicles (EVs) are emerging biomarkers that may provide insights into the pathogenesis of GDM.

Urinary interleukin-9 in youth with type 1 diabetes mellitus.

Aims: Interleukin-9 (IL-9) attenuates podocyte injury in experimental kidney disease, but its role in diabetic nephropathy is unknown. We sought to relate urinary IL-9 levels to the release of podocyte-derived extracellular vesicles (EVs) in youth with type 1 diabetes. We related urinary IL-9 levels to clinical variables and studied interactions between urinary IL-9, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) on urinary albumin/creatinine ratio (ACR) a functional measure of podocyte injury.

Retraction: Overexpression of HDAC8 and down-regulation of CDKN2A is associated with worse prognosis of esophageal squamous cell carcinoma.

[This retracts the article DOI: 10.21037/tcr.2020.

Rhoifolin Alleviates Inflammation of Acute Inflammation Animal Models and LPS-Induced RAW264.7 Cells via IKKβ/NF-κB Signaling Pathway.

Rhoifolin (ROF) is a main effective component in Citrus grandis 'Tomentosa'. ROF has a potential anti-inflammatory activity, but its specific effects and mechanisms have not been studied. This study investigated the anti-inflammatory activity of ROF and searched for its possible molecular mechanisms.

Theoretical Study of Radical-Molecule Reactions with Negative Activation Energies in Combustion: Hydroxyl Radical Addition to Alkenes.

Many of the radical-molecule reactions are nonelementary reactions with negative activation energies, which usually proceed through two steps. They exist extensively in the atmospheric chemistry and hydrocarbon fuel combustion, so they are extensively studied both theoretically and experimentally. At the same time, various models, such as a two transition state model, a steady-state model, an equilibrium-state model, and a direct elementary dynamics model are proposed to get the kinetic parameters for the overall reaction.

Over-expression of HDAC8 down-regulate CDKN2A is associated with worse prognosis of esophageal squamous cell carcinoma.

Background: The epigenetic alteration has an impact on cancer cell cycle regulation. Expression of histone deacetylase 8 (HDAC8) ruled out the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) and this is linked with the prognosis of Esophageal cancer (EC) patients.

Methods: By the immunohistochemical staining, we examined the expression status of HDAC8 and CDKN2A protein of 110 esophageal squamous cell carcinoma (ESCC) patients in the tissue microarray.

Risk Factors for Cognitive Impairment in High-Grade Glioma Patients Treated with Postoperative Radiochemotherapy.

Purpose: Fractionated radiotherapy as well as concomitant and adjuvant chemotherapy such as temozolomide for postoperative high-grade glioma (HGG) patients improves progression-free survival and overall survival. Multiple factors such as chemotherapy, radiotherapy, tumor grade, residual tumor volume, and genetic modifications might play a role in the formation of cognitive impairment. The risk factors of cognitive impairment in postoperative patients with HGG receiving radiotherapy and chemotherapy remains a concern in this population.

Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice.

Prostaglandin E2 receptor EP1 (PGE/EP) promotes diabetic renal injury, and EP receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP receptors to HKD.

Effect of hemodialysis on extracellular vesicles and circulating submicron particles.

Background: Although hemodialysis is a highly effective treatment for diffusive clearance of low molecular weight uremic toxins, its effect on circulating extracellular vesicles and submicron particles is less clear. The purpose of this study was to examine the impact of hemodialysis on circulating levels of submicron particles.

Methods: Plasma samples from patients were collected immediately before and after the mid-week hemodialysis session.

Thyroid-Stimulating Hormone-Stimulated Human Adipocytes Express Thymic Stromal Lymphopoietin.

When recombinant human (rh) thyroid-stimulating hormone (TSH) is administered to thyroid cancer survivors, an acute extra-thyroidal effect raises pro-inflammatory cytokines and activates platelets. Thymic stromal lymphopoietin (TSLP) is a cytokine recently implicated in platelet activation. Our aim was to measure platelet microparticle levels after rhTSH stimulation in vivo, and to investigate TSLP expression in TSH-stimulated human adipocytes in culture.

Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36.

Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100-1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes.

High glucose increases the formation and pro-oxidative activity of endothelial microparticles.

Aims/hypothesis: Individuals with diabetes exhibit increases in circulating endothelial microparticles (eMPs, also referred to as endothelial microvesicles), which are associated with endothelial dysfunction and a heightened risk of cardiovascular complications. We have shown that eMPs are markers and mediators of vascular injury although their role in diabetes is unclear. We hypothesised that the composition and biological activity of eMPs are altered in response to high glucose exposure.

Measurement of Angiotensin Converting Enzyme 2 Activity in Biological Fluid (ACE2).

Angiotensin-converting enzyme 2 (ACE2) is a recently described member of the renin-angiotensin system that hydrolyzes angiotensin (Ang) II to Ang-(1-7), and may thereby protect against cardiovascular and renal diseases. ACE2 is a type 1 integral membrane protein and contains a catalytically active ectodomain that can be shed from the cell surface into the extracellular space, via cleavage by a disintegrin and metalloproteinase-17 (ADAM-17). ACE2 enzymatic activity and protein can be detected in biological fluids, including urine, plasma, and conditioned cell culture media.

Assessment of urinary microparticles in normotensive patients with type 1 diabetes.

Aims/hypothesis: Assessment of urinary extracellular vesicles including exosomes and microparticles (MPs) is an emerging approach for non-invasive detection of renal injury. We have previously reported that podocyte-derived MPs are increased in diabetic mice in advance of albuminuria. Here, we hypothesised that type 1 diabetes and acute hyperglycaemia would increase urinary podocyte MP levels in uncomplicated diabetes.