Case Report: Talaromyces marneffei Infection in a Chinese Child With a Complex Heterozygous CARD9 Mutation

Talaromyces marneffei (TM) infection is rarely seen in clinical practice, and its pathogenesis may be related to deficiency in antifungal immune function. Human caspase recruitment domain-containing protein 9 (CARD9) is a key molecule in fungal immune surveillance. There have been no previous case reports of TM infection in individuals with CARD9 gene mutations. Herein, we report the case of a 7-month-old Chinese boy who was admitted to our hospital with recurring cough and fever with a papular rash. A blood culture produced TM growth, which was confirmed by metagenomic next-generation sequencing. One of the patient’s sisters had died of TM septicaemia at 9 months of age. Whole exome sequencing revealed that the patient had a complex heterozygous CARD9 gene mutation with a c.1118G>C p.R373P variation in exon 8 and a c.610C>T p.R204C variation in exon 4. Based on the culture results, voriconazole antifungal therapy was administered. On the third day of antifungal administration, his temperature dropped to within normal range, the rash gradually subsided, and the enlargement of his lymph nodes, liver, and spleen improved. Two months after discharge, he returned to the hospital for a follow-up examination. His general condition was good, and no specific abnormalities were detected. Oral voriconazole treatment was continued. Unexplained TM infection in HIV-negative individuals warrants investigation for immune deficiencies

Rare Copy Number Variants Identify Novel Genes in Sporadic Total Anomalous Pulmonary Vein Connection

Total anomalous pulmonary venous connection (TAPVC) is a rare congenital heart anomaly. Several genes have been associated TAPVC but the mechanisms remain elusive. To search novel CNVs and candidate genes, we screened a cohort of 78 TAPVC cases and 100 healthy controls for rare copy number variants (CNVs) using whole exome sequencing (WES). Then we identified pathogenic CNVs by statistical comparisons between case and control groups. After that, we identified altogether eight pathogenic CNVs of seven candidate genes (PCSK7, RRP7A, SERHL, TARP, TTN, SERHL2, and NBPF3). All these seven genes have not been described previously to be related to TAPVC. After network analysis of these candidate genes and 27 known pathogenic genes derived from the literature and publicly database, PCSK7 and TTN were the most important genes for TAPVC than other genes. Our study provides novel candidate genes potentially related to this rare congenital birth defect (CHD) which should be further fundamentally researched and discloses the possible molecular pathogenesis of TAPVC

The Expression of Notch/Notch Ligand, IL-35, IL-17, and Th17/Treg in Preeclampsia

The aim of this study was to examine the interaction of Notch/Notch ligand with Th17/Treg, cytokines IL-35 and IL-17 in cases of preeclampsia (PE). Methods. Peripheral blood was obtained from 42 PE patients and 22 health pregnant women. The mRNA expressions of Notch/Notch ligand, Treg transcription factor FoxP3 and Th17 transcription factor RORγt, EBI3 and P35 (IL-35 two subunits), and IL-17 were determined by qPCR. The serum levels of IL-17 and IL-35 were measured by ELISA. Results. It was observed that the expressions of Foxp3, EBI3, and P35 in PE patients were lower compared with normal pregnancy, whereas the RORγt expression was significantly increased. The results also demonstrated that PE patients exhibited decreased levels of Treg-related cytokine IL-35, whereas IL-17 was significantly increased. PE patients expressed higher levels of Notch receptor (1–4) and Notch ligand of DLL4, whereas Notch ligand of Jagged-1, -2 was much lower. Furthermore, the levels of FoxP3 T cells correlated positively with Jagged-2. In addition, there were positive correlations between the mRNA level of IL-17 and DLL4. Conclusion. Our results indicated that maternal immunological changes may reverse maternal tolerance in PE, and this phenomenon may due to the Th17/Treg imbalance affected by Notch/Notch ligand

Muscle-Specific Histone H3K36 Dimethyltransferase SET-18 Shortens Lifespan of Caenorhabditis elegans by Repressing daf-16a Expression

Summary: Mounting evidence shows that histone methylation, a typical epigenetic mark, is crucial for gene expression regulation during aging. Decreased trimethylation of Lys 36 on histone H3 (H3K36me3) in worms and yeast is reported to shorten lifespan. The function of H3K36me2 in aging remains unclear. In this study, we identified Caenorhabditis elegans SET-18 as a histone H3K36 dimethyltransferase. SET-18 deletion extended lifespan and increased oxidative stress resistance, dependent on daf-16 activity in the insulin/IGF pathway. In set-18 mutants, transcription of daf-16 isoform a (daf-16a) was specifically upregulated. Accordingly, a decrease in H3K36me2 on daf-16a promoter was observed. Muscle-specific expression of SET-18 increased in aged worms (day 7 and day 11), attributable to elevation of global H3K36me2 and inhibition of daf-16a expression. Consequently, longevity was shortened. These findings suggested that chromatic repression mediated by tissue-specific H3K36 dimethyltransferase might be detrimental to lifespan and may have implications in human age-related diseases. : Su et al. report that a muscle-specific H3K36 dimethyltransferase SET-18 is activated in aged worm. SET-18 shortens lifespan by repressing daf-16a promoter via H3K36me2 modification. Activation of SET-18 in old age (days 7 and 11) is responsible for increased global H3K36me2 in chromatin and then represses daf-16a transcription and promotes aging of worms. Keywords: SET-18, H3K36me2 modification, lifespan, daf-16a, insulin/IGF-1-like pathwa

Cancer associated fibroblast derived gene signature determines cancer subtypes and prognostic model construction in head and neck squamous cell carcinomas

Abstract Background Head and neck squamous cell carcinomas (HNSCC) are the most common type of head and neck cancer with an unimproved prognosis over the past decades. Although the role of cancer‐associated‐fibroblast (CAF) has been demonstrated in HNSCC, the correlation between CAF‐derived gene expression and patient prognosis remains unknown. Methods A total of 528 patients from TCGA database and 270 patients from GSE65858 database were contained in this study. After extracting 66 CAF‐related gene expression data from TCGA database, consensus clustering was performed to identify different HNSCC subtypes. Limma package was used to distinguish the differentially expression genes (DEGs) between these subtypes, followed by Lasso regression analysis to construct a prognostic model. The model was validated by performing Kaplan‐Meier survival, ROC and risk curve, univariate and multivariate COX regression analysis. GO, KEGG, GSEA, ESTIMATE and ssGSEA analyses was performed to explort the potential mechanism leading to different prognosis. Results Based on the 66 CAF‐related gene expression pattern we stratitied HNSCC patients into two previously unreported subtypes with different clinical outcomes. A prognostic model composed of 15 DEGs was constructed and validated. In addition, bioinformatics analysis showed that the prognostic risk of HNSCC patients was also negatively correlated to immune infiltration, implying the role of tumor immune escape in HNSCC prognosis and treatment option. Conclusions The study develops a reliable prognostic prediction tool and provides a theoretical treatment guidance for HNSCC patients

Laparoscopic Roux-en-Y gastric bypass for excess weight and diabetes: a multicenter retrospective cohort study in China

Aim: The aims of this study were to better understand the outcomes of Roux-en-Y gastric bypass (RYGB) surgery in patients across multiple hospitals in China along with patients with type 2 diabetes mellitus (T2DM) and to explore the potential preoperative predictors of diabetes outcomes after RYGB.Methods: This was a retrospective cohort study in Chinese patients who underwent laparoscopic RYGB at five Chinese hospitals from April 2009 to December 2014 and returned for follow-up approximately one-year post-surgery. The STROCSS guideline checklist was applied.Results: In total, 130 patients underwent RYGB: 85 males and 45 females; age, 43.4 ± 11.3 years; and preoperative body mass index (BMI), 33.1 ± 9.0 kg/m2. Of those, 103 (79.2%) had T2DM duration of 6.6 ± 4.7 years and pre-RYGB HbA1c of 8.1 ± 1.9%. Among the patients with T2DM, glycemic control (HbA1c < 7.0%) increased from 28.7% before surgery to 79.3% at 12 months post-procedure, with a concurrent reduction in the use of anti-hyperglycemic agents, including a reduction in insulin requirement from 55.4% to 27.0%. The percentage of excess weight loss was -42.8 ± 44.2%. Among 71 patients with T2DM and data about remission status, 14 (19.7%) achieved T2DM remission at 12 months post-surgery. Age and duration of T2DM were lower in the remission group, while baseline BMI and weight were higher compared with the non-remission group.Conclusion: RYGB may be effective for weight loss and T2DM control in Chinese patients, and outcomes are consistent with the literature in Western populations. Younger patients with T2DM and with a higher BMI pre-surgery and shorter duration of T2DM were more likely to achieve T2DM remission

Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation

Abstract Bile duct tumor thrombosis (BDTT) is a complication mostly observed in patients with advanced hepatocellular carcinoma (HCC), causing jaundice and associated with poor clinical outcome. However, its underlying molecular mechanism is unclear. Here, we develop spontaneous preclinical HCC animal models with BDTT to identify the role of BMI1 expressing tumor initiating cells (BMI1high TICs) in inducing BDTT. BMI1 overexpression transforms liver progenitor cells into BMI1high TICs, which possess strong tumorigenicity and increased trans-intrahepatic biliary epithelial migration ability by secreting lysosomal cathepsin B (CTSB). Orthotopic liver implantation of BMI1high TICs into mice generates tumors and triggers CTSB mediated bile duct invasion to form tumor thrombus, while CTSB inhibitor treatment prohibits BDTT and extends mouse survival. Clinically, the elevated serum CTSB level determines BDTT incidence in HCC patients. Mechanistically, BMI1 epigenetically up-regulates CTSB secretion in TICs by repressing miR-218-1-3p expression. These findings identify a potential diagnostic and therapeutic target for HCC patients with BDTT