Integrated multi-omics analysis identifies CD73 as a prognostic biomarker and immunotherapy response predictor in head and neck squamous cell carcinoma.

Background: Advances in tumor immunotherapy have been developed for patients with advanced recurrent or metastatic (R/M) HNSCC. However, the response of most HNSCC patients to immune checkpoint inhibitors (ICI) remains unsatisfactory. CD73 is a promising target for tumor immunotherapy, but its role in HNSCC remains insufficient. In this study, we aim to explore the function of CD73 in HNSCC. Methods: Transcriptomic and clinical data of TCGA-HNSC were downloaded from UCSC Xena for analysis of CD73 mRNA expression and prognosis. Immunohistochemical assay were performed to validate the expression of CD73 in tumor tissues and its relationship with CD8+ T cells. GSEA analysis was performed with the "clusterProfiler" R package. Immune infiltration analysis was calculated with ESTIMATE, CIBERSORT and MCP-counter algorithms. Single-cell transcriptomic data was originated from GSE103322. Cell clustering, annotation and CD73 expression were from the TISCH database. Correlation data between CD73 and tumor signatures were obtained from the CancerSEA database. Somatic mutation data were obtained from TCGA-HNSC and analyzed by "maftools" R package. Immune efficacy prediction was performed using TIDE algorithm and validated with the IMvigor210 cohort. Results: Compared with normal tissues, both mRNA and protein expressions of CD73 were elevated in tumor tissues (P = 9.7×10-10, P = 7.6×10-5, respectively). Kaplan-Meier analysis revealed that patients with high expression of CD73 had worse overall survival (log-rank P = 0.0094), and CD73 could be used as a diagnostic factor for HNSCC (AUC = 0.778). Both bulk RNA-seq and single-cell RNA-seq analysis showed that high CD73 expression can promote EMT and metastasis, samples with high CD73 expression had reduced CD8+ T cells. Furthermore, it was found that CD73-high group was more prone to have mutations in TP53, HRAS and CDKN2A, and were negatively correlated with TMB (P = 0.0055) and MSI (P = 0.00034). Mutational signature analysis found that CD73 was associated with APOBEC signature. Immunotherapy efficacy analysis showed that CD73-high group was less sensitive to immune efficacy. Conclusions: Our results demonstrate that CD73 has an inhibitory effect on the tumor microenvironment, and is more likely to be unresponsive to ICI therapy. Collectively, targeting CD73 may provide new insights for tumor targeted therapy and/or immunotherapy.

Sex-specific differences in bone mineral density loss after sleeve gastrectomy.

Background: Sleeve gastrectomy is an effective bariatric procedure; however, sleeve gastrectomy-related adverse skeletal outcomes have been increasingly reported. High levels of sex hormone-binding globulin (SHBG) have been documented to be a risk factor of bone mineral density (BMD) loss with different effects observed between sexes. The aim of this study was to identify sex-specific changes in BMD following sleeve gastrectomy and to evaluate the role of SHBG in this process. Methods: This retrospective study included 19 middle-aged men and 30 non-menopausal women with obesity who underwent sleeve gastrectomy in China. Anthropometrics, bone turnover markers, calciotropic hormones, BMD, SHBG, and gonadal steroids were measured preoperatively and at 6 and 12 months postoperatively. Longitudinal changes in BMD, bone turnover markers and SHBG were compared between sexes by linear mixed models. Multiple stepwise regression analysis was used to identify the predictors of BMD loss at the investigated bone sites. Results: Over the 12-month study period, total hip and femoral neck BMD decreased, while lumbar spine BMD remained largely unchanged in both sexes. Linear mixed models revealed significant sex × time interaction effects in total hip BMD and SHBG, showing that men had a significantly greater reduction in total hip BMD and less increase in SHBG after sleeve gastrectomy than women. In the multivariate model, SHBG was significantly associated with total hip BMD loss in men (adjusted ß = -0.533, P = 0.019) but not women while total estrogen was significantly associated with total hip BMD loss in women (adjusted ß = 0.508, P = 0.01) but not men. Conclusion: Significant sex-specific BMD changes were observed after sleeve gastrectomy in the current study. Sleeve gastrectomy-related increase in SHBG may be a specific risk factor for total hip BMD loss in men. Our results indicate that sex-specific screening may be warranted to facilitate personalized postoperative bone care in this population.

PARP12 is required for mitochondrial function maintenance in thermogenic adipocytes.

PARP12 is a member of poly-ADP-ribosyl polymerase (PARPs), which has been characterized for its antiviral function. Yet its physiological implication in adipocytes remains unknown. Here, we report a central function of PARP12 in thermogenic adipocytes. We show that PARP12 is highly expressed in brown adipose tissue and is mainly localized to the mitochondria. Knockdown of PARP12 in vitro reduced UCP1 expression. In parallel, the deficiency of PARP12 reduced mitochondrial respiration in adipocytes, while overexpression of PARP12 reversed these effects.

Serum Creatinine-to-Cystatin C Ratio in the Progression Monitoring of Non-alcoholic Fatty Liver Disease.

BACKGROUND: The simultaneous assessment of visceral adiposity and muscle mass might be useful to monitor the risk of non-alcoholic fatty liver disease (NAFLD) progression in large population. We aimed to investigate the value of serum creatinine-to-cystatin C ratio (CCR) in evaluating these two parameters and predicting liver steatosis and fibrosis. METHODS: 154 overweight/obese inpatients (49 males, 105 females) scheduled for bariatric surgery and 49 non-overweight/obese volunteers (18 males, 31 females) responded to the hospital advertisement were involved in the cross-sectional study. Liver steatosis and fibrosis were diagnosed with transient elastography (TE). The psoas muscle area (PMA) and visceral fat area (VFA) were measured using magnetic resonance imaging. RESULTS: The body mass index, insulin resistance, and lipid profiles showed significant differences between the CCR tertiles. Multiple regression analyses revealed that the CCR was significantly associated with the controlled attenuation parameter (ß = -0.30, P = 0.006 in males; ß = -0.19, P = 0.017 in females) and liver stiffness measurements in males (ß = -0.246, P = 0.044). A low CCR was associated with moderate-to-severe steatosis (P < 0.001), significant liver fibrosis (P < 0.01), and excellent predictive power for these two conditions (P < 0.01). The CCR had a negative correlation with the VFA/PMA ratio (r = -0.584, P < 0.001 in males; r = -0.569, P < 0.001 in females). CONCLUSIONS: The CCR is a serum marker for muscle-adjusted visceral fat mass, and a low CCR is associated with an increased risk of progressive NAFLD.

Maternal exposure to tributyltin during early gestation increases adverse pregnancy outcomes by impairing placental development.

Tributyltin (TBT) is a persistent organotin pollutant widely used as agricultural and wood biocides, exhibiting well-documented toxicity to reproductive functions in aquatic organisms. However, the effect of TBT on early pregnancy and placental development has been rarely studied in mice. Pregnant mice were fed with 0, 0.2, and 2 mg/kg/day TBT from gravid day 1 to day 8 or 13. TBT exposure led to an increase in the number of resorbed embryo and a reduction in the weight of fetus at gestational days 13. Further study showed that TBT significantly decreased placental weight and area, lowered laminin immunoreactivity and the expressions of placental development-related molecules including Fra1, Eomes, Hand1, and Ascl2. Moreover, TBT treatment markedly inhibited the placental proliferation and induced up-regulation of p53 and cleaved caspase-3 proteins, and down-regulation of Bcl-2 protein. In addition, TBT administration increased levels of malondialdehyde and H2 O2 and decreased activities of catalase and superoxide dismutase. Collectively, these results suggested TBT-induced adverse pregnancy outcomes during early pregnancy might be involved in developmental disorders of the placenta via dysregulation of key molecules, proliferation, apoptosis, and oxidative stress.

Long non-coding RNA H19 and cancer: A competing endogenous RNA.

Long non-coding RNA (lncRNA) is a class of non-coding RNA with a length of more than 200 nucleotides, which has become a hotspot in the research of tumorigenesis and development in recent years. Accumulating studies have indicated that H19 is abnormally expressed in human malignant tumors, and regulates cell proliferation, migration, invasion, anti-apoptosis and epithelial-mesenchymal transition through various mechanisms, thus playing a carcinogenic or anti-cancer role. H19 has been found to act as a microRNA sponge to indirectly regulate the expression of microRNA downstream target genes thus mediating cancer progression in several cancer types. Even in the same cancer, H19 also sponges various microRNAs to mediate diverse regulatory mechanisms. Tissue-specific expression of H19 suggests that it may be an early diagnostic marker or prognostic indicator of cancers. In this review, we summarize the latest original researches, mainly focusing on the role of H19 sponging microRNAs in cancers. We hope this article can facilitate readers obtain the molecular mechanisms of H19 sponging miRNAs in cancers and provide a broad perspective for further research on cancer diagnosis and therapy.

2,4-Dibromo-6-{(E)-[(R)-1-phenyl-ethyl]imino-meth-yl}phenol.

In the title Schiff base, C(15)H(13)Br(2)NO, the benzene and phenyl rings form a dihedral angle of 75.18 (13)°. The N=C bond length of 1.263 (6) Šis shorter than of the N-C bond [1.476 (5) Å], indicating a double bond. In the crystal, there is some pseudosymmetry. This occurs because most of the two mol-ecules are centrosymmetrically related. The mol-ecular structure is stabilized by intra-molecular O-H⋯N hydrogen bonds.