👤 Maggie H Bui

Metabolic syndrome (MetS) is a multifactorial disorder associated with increased cardiometabolic risk. This exploratory study aimed to investigate the associations between five candidate single nucleotide polymorphisms (SNPs) and their haplotypes with MetS in children aged 6-11 years from Northern Vietnam. A total of 547 children aged 6-11 years were included, comprising 39 children with MetS and 508 controls. MetS was defined using age-specific criteria based on modified International Diabetes Federation and National Cholesterol Education Program definitions. Genotyping of These findings suggest that Show less

The Rare Gynecologic Sarcoma study involved 23 institutions from 10 countries focusing on myxoid leiomyosarcoma and non-smooth muscle uterine sarcomas. Here, we present the main results of the study, including the comparison between the original and final diagnosis, the frequency and type of molecular aberrations, and the clinicopathologic outcomes. A total of 379 cases were included, with available results for next-generation sequencing (NGS) RNA in 338 of 379 cases and NGS DNA in 335 of 379 cases. According to the original diagnoses, the study included 204 cases of low-grade endometrial stromal sarcoma (LG-ESS), 75 cases of high-grade endometrial stromal sarcoma (HG-ESS), 74 cases of undifferentiated uterine sarcoma (UUS), 17 cases of myxoid leiomyosarcoma, and 9 cases of unclassifiable sarcoma. The results of our second reading showed that 29% (110/379) of all the tumors had been originally misdiagnosed. After the reclassification, the final diagnoses were 147 cases of LG-ESS, 69 cases of HG-ESS, 58 cases of UUS, 3 cases of LG-ESS with high-grade transformation, 7 cases of perivascular epithelioid cell tumor, 9 cases of uterine tumor resembling ovarian sex cord tumor, 8 cases of tumors with a KAT6B/A::KANSL1 fusion, 2 cases of tumors with an NTRK fusion, 29 cases of undifferentiated carcinoma, and 47 tumors with smooth muscle differentiation. The molecular testing showed that LG-ESS harbor a recurrent fusion in 75.9% and HG-ESS in 43.7% of cases. The results of our study emphasize the diagnostic, prognostic, and predictive significance of molecular testing in mesenchymal uterine tumors. Show less

Genetic tests are important in the classification, treatment, and prognosis of acute myeloid leukemia (AML). The present study aimed to detect genetic abnormalities and investigate the correlation between gene abnormalities and the treatment results of childhood AML. A descriptive cross-sectional study of 35 children with de novo AML was established between 2017 and 2022 at Hue Central Hospital, Vietnam. Parameters of age, gender, gene fusions, remission, relapse rate, and survival rates were investigated. The male-to-female ratio was 1.92:1. The mean age was 7.3±4.9 years. The multiplex reverse transcription polymerase chain reaction (RT-PCR) using the HemaVision 28N kit test results showed that 12 (34.3%) patients had genetic abnormalities, of which five (14.2%) patients had AML1/ETO fusion, three (8.6%) had PML/RARA fusion, two (5.7%) had MLL/AF6 fusion, one (2.9%) had KMT2A/MLLT10 fusion, and one (2.9%) had AML1/ETO and BCR/ABL1 fusion. Prognostic grouping according to genetic mutation showed eight (22.9%) patients with a favorable prognosis, 23 (65.7%) patients with an intermediate prognosis, and four (11.4%) patients with a poor prognosis. There were significant relationships between the remission rate and the genetic risk group. The remission rates for poor, intermediate, and good prognosis groups were 25%, 43.5%, and 100%, respectively. However, there were no statistical correlations between the relapse rate, the overall survival rate, and the event-free survival rate with the genetic risk group. Genetic abnormalities have a role in the classification, prognosis, and treatment of AML patients. However, treatment outcomes in AML are influenced by multiple factors beyond genetics, including infection-related complications, nutritional status, socioeconomic conditions, supportive care infrastructure, and access to intensive chemotherapy and transplant services. Supportive care plays an important role in the treatment outcome of childhood AML. Show less

Genetic cardiomyopathies (CMs) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. However, genetic testing practices are understudied in patients with ESHF. This single-center, retrospective study included consecutive patients with ESHF who underwent heart transplantation (HT) or left ventricular assist device (LVAD) implantation between 2018 and 2023. Data, including genetic testing and pathology reports, were collected from the electronic medical records. Analyses of demographic and clinical characteristics were stratified by genetic-testing completion and the presence of clinically actionable variants. Logistic regression was performed to evaluate for associations between histology findings and genetic variants. A total of 529 adult patients (mean age 57 years) were included in the study and were predominantly male (79%, 422/529) and non-white (61%, 322/529). Genetic testing was performed in 54% (196/360) of patients with either nonischemic or mixed CMs. A clinically actionable result was identified in 36% (70/196) of patients, of whom only 43% (30/70) had genetic counselor referrals. The most common genetic variants were TTN (32%, 24/75), MYBPC3 (13%, 10/75) and TTR (11%, 8/75). Clinically actionable variants were identified in patients with known heart failure precipitators such as alcohol use. In multivariable analysis, the presence of interstitial fibrosis, specifically diffuse, on pathology was significantly associated with a clinically actionable variant (aOR 2.29, 95% CI [1.08-4.86]; P = 0.03). Patients with ESHF and with nonischemic or mixed CM who were undergoing advanced therapies had low uptakes of genetic services, including testing and counselors, despite high burdens of genetic disease. Pathology findings such as interstitial fibrosis may provide insight into genetic etiology. The underuse of services suggests a need for implementation strategies to improve uptake. Show less

Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, β-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity. Show less

IL-17D is a cytokine that belongs to the IL-17 family and is conserved in vertebrates and invertebrates. In contrast to IL-17A and IL-17F, which are expressed in Th17 cells, IL-17D is expressed broadly in nonimmune cells. IL-17D can promote immune responses to cancer and viruses in part by inducing chemokines and recruiting innate immune cells such as NK cells. Although bacterial infection can induce IL-17D in fish and invertebrates, the role of mammalian IL-17D in antibacterial immunity has not been established. To determine whether IL-17D has a role in mediating host defense against bacterial infections, we studied i.p. infection by group A Show less

YAP is a transcriptional coactivator that controls organ expansion and differentiation and is inhibited by the Hippo pathway in cells in interphase. Here, we demonstrated that, during mitosis, YAP localized to the midbody and spindle, subcellular structures that are involved in cytokinesis, the process by which contraction of the cytoskeleton produces two daughter cells. Furthermore, YAP was phosphorylated by CDK1, a kinase that promotes cell cycle progression. Knockdown of YAP by shRNA or expression of a nonphosphorylatable form of YAP delayed the separation of daughter cells (called abscission) and induced a cytokinesis phenotype associated with increased contractile force, membrane blebbing and bulges, and abnormal spindle orientation. Consequently, these defects led to an increased frequency of multinucleation, micronuclei, and aneuploidy. YAP was required for proper localization of proteins that regulate contraction during cytokinesis, including ECT2, MgcRacGap, Anillin, and RHOA. In addition, depletion of YAP increased the phosphorylation of myosin light chain, which would be expected to activate the contractile activity of myosin II, the molecular motor involved in cytokinesis. The polarity scaffold protein PATJ coprecipitated with YAP and colocalized with YAP at the cytokinesis midbody, and knockdown of PATJ phenocopied the cytokinetic defects and spindle orientation alterations induced by either YAP depletion or expression of a nonphosphorylatable YAP mutant. Together, these results reveal an unanticipated role for YAP in the proper organization of the cytokinesis machinery during mitosis through interaction with the polarity protein PATJ. Show less