Human milk-derived MANF, as an immuno-nutritional factor, maintains the intestinal epithelial barrier and protects against necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a leading cause of death in preterm infants. Compared to formula milk, breastfeeding protects against NEC. However, the composition of breast milk is quite complicated, and many immunological compositions remain unknown. In this study, we aimed to investigate the concentration of a secreted protein, Mesencephalic astrocyte-derived neurotrophic factor (MANF), in breastmilk and evaluate its immune-regulatory function in protecting the intestinal epithelial barrier. Our data indicated that MANF was secreted in human milk but could not be detected in infant formulas. More importantly, the amount of MANF in colostrum was higher than that in mature milk. We also clarified that MANF was mainly expressed in intestinal macrophages and was capable of inducing apoptosis and decreasing the inflammation of pro-inflammatory macrophages in both NEC intestinal tissues and BMDMs. Mechanismly, MANF protein significantly inhibited the apoptosis of intestinal epithelial cells and protected epithelial tight junctions through downregulation of the NF-κB pathway in pro-inflammatory macrophages. These results reveal the crucial function of human milk-derived MANF in intestinal macrophages, which contributes to downregulating the intestinal inflammatory response and protecting the homeostasis of intestinal epithelial cells. Our study not only demonstrates a potential mechanism underlying breastfeeding protective effects in NEC but also, more importantly, enables clinical translation, facilitating new strategies for the development of nutritional interventions in the prevention of NEC.

Analysis of living habit risk factors for esophageal cancer in central China: A bi-center case-control study.

Background: Esophageal cancer remains a public health problem in many countries, especially developing countries. The early lifestyle preventive measures mentioned in the treatment guidelines for esophageal cancer are very limited. We aimed to evaluate the risk factors for esophageal cancer in a high-incidence area in China and to provide evidence for clinical intervention in esophageal cancer prevention. Methods: Symptom and lifestyle/habit questionnaires including 19 items were designed. The correlation between the occurrence of esophageal cancer and living habits was analyzed retrospectively through questionnaire survey. A total of 708 subjects (365 esophageal cancer, 343 non-esophageal cancer) enrolled from two hospitals in central China (Linzhou Esophageal Cancer Hospital and The Third Xiangya Hospital of Central South University) completed symptom and lifestyle/habit questionnaires. We used conditional logistic regression to estimate the odds ratio (OR) with consideration of 95% confidence interval (CI). Results: The composition ratio analysis showed that the top five lifestyle factors related to esophageal cancer were eating too fast, drinking, hot drinks, smoking and overeating. Univariate analysis showed that 15 factors, including male sex, smoking, drinking, eating too fast, overeating, hot drinks, greasy food, acidic food, hard food, strong tea, coffee, bedtime immediately after meals, eating food before bedtime, difficult defecation, and an overtight belt, were associated with esophageal cancer (all P <0.05). Logistic multivariate regression analysis showed, drinking (OR 3.609, 95%CI 2.223-5.859; P=0.000); hot drinks (OR 2.672, 95%CI 1.786-3.997; P=0.000); overeating (OR 2.110, 95%CI 1.411-3.154; P=0.000); eating too fast (OR 1.879, 95%CI 1.274-2.772; P=0.001); strong tea (OR 1.882, 95%CI 1.171~3.023; P=0.009); hard food (OR 1.723, 95%CI 1.113-2.667; P=0.015); smoking (OR 1.686, 95%CI 1.045-2.720; P=0.032), which were significantly associated with the development of esophageal cancer. Conclusion: The unhealthy lifestyles of patients in high-incidence areas of esophageal cancer in central China are significantly associated with the incidence of esophageal cancer. Lifestyle changes that address these factors, especially overeating and eating too fast, which are rarely studied or discussed despite being common, may improve esophageal cancer management and treatment outcomes. The present results may be used as a reference for preventive education and treatment.

Prognostic value and immune characteristics of RUNX gene family in human cancers: a pan-cancer analysis.

BACKGROUND: Runt-related transcription factors (RUNX) are involved in numerous fundamental biological processes and play crucial parts in tumorigenesis and metastasis both directly and indirectly. However, the pan-cancer evidence of the RUNX gene family is not available. METHODS: In this study, we analyzed the potential association between RUNX gene family expression and patient's prognosis, immune cell infiltration, drug response, and genetic mutation data across different types of tumors using based on The Cancer Genome Atlas, Gene Expression Omnibus, and Oncomine database. RESULTS: The results showed that the expression of the RUNX gene family varied among different cancer types, revealing its heterogeneity in cancers and that expression of RUNX2 was lower than that of RUNX1 and RUNX3 across all cancer types. RUNX gene family gene expression was related to prognosis in several cancers. Furthermore, our study revealed a clear association between RUNX gene family expression and ESTIMATE score, RNA stemness, and DNA stemness scores. Compared with RUNX1 and RUNX2, RUNX3 showed relatively low levels of genetic alterations. RUNX gene family genes had clear associations with immune infiltrate subtypes, and their expression was positively related to immune checkpoint genes and drug sensitivity in most cases. Two immunotherapy cohorts confirm that the expression of RUNX was correlated with the clinical response of immunotherapy. CONCLUSIONS: These findings will help to elucidate the potential oncogenic roles of RUNX gene family genes in different types of cancer and it can function as a prognostic marker in various malignant tumors.

Construction and validation of a novel prognostic signature for uveal melanoma based on five metabolism-related genes.

BACKGROUND: Uveal melanoma (UM) is the most aggressive intraocular tumor worldwide. Accurate prognostic models are urgently needed. The present research aimed to construct and validate a prognostic signature is associated with overall survival (OS) for UM patients based on metabolism-related genes (MRGs). METHODS: MRGs were obtained from molecular signature database (MSigDB). The gene expression profiles and patient clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. In the training datasets, MRGs were analyzed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO) Cox analyses to build a prognostic model. The GSE84976 was treated as the validation cohort. In addition, time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses the reliability of the developed model. Then, gene set enrichment analysis (GSEA) was used for gene enrichment analysis. Nomogram that combined the five-gene signature was used to evaluate the predictive OS value of UM patients. RESULTS: Five MRGs were identified and used to establish the prognostic model for UM patients. The model was successfully validated using the testing cohort. Moreover, ROC analysis demonstrated a strong predictive ability that our prognostic signature had for UM prognosis. Multivariable Cox regression analysis revealed that the risk model was an independent predictor of prognosis. UM patients with a high-risk score showed a higher level of immune checkpoint molecules. CONCLUSION: We established a novel metabolism-related signature that could predict survival and might be therapeutic targets for the treatment of UM patients.

Identification of Immune Cell Infiltration Landscape and Their Prognostic Significance in Uveal Melanoma.

Uveal melanoma (UVM) is the most common primary intraocular cancer in adults. Increasing evidence has demonstrated that immune cell infiltration (ICI) is crucial in predicting patient outcomes and therapeutic efficacy. Thus, describing the immune cell infiltrative landscape of UVM tumors may yield a novel prognostic marker and provide direction for immunotherapeutic selection. In this study, the gene expression data and clinical information of UVM patients were obtained from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. The ICI landscape of UVM was analyzed using the CIBERSORT and ESTIMATE algorithms. Two ICI phenotypes were defined, and the ICI scores were calculated by using principal component analysis algorithms. We found that a subtype with high ICI scores had poorer prognosis and increased expression levels of immune checkpoint-related genes. This study demonstrates that ICI scores are an independent prognostic biomarker and highlights their value in predicting immunotherapeutic outcomes.

Pan-cancer analysis reveals an immunological role and prognostic potential of PXN in human cancer.

Paxillin (PXN) is a protein involved in numerous physiological processes, and its presence is closely related to the occurrence and development of many types of tumors. However, no studies have analyzed PXN from a pan-cancer perspective. We analyzed PXN expression, immune cell infiltration, prognosis, and biological function across different types of tumors included in The Cancer Genome Atlas and Gene Expression Omnibus datasets. The results showed that expression of PXN varies in different tumors. Expression of PXN strongly correlated with prognosis in patients with tumors; higher PXN expression usually was linked to poor overall and disease-free survival. Expression of PXN in breast invasive carcinoma and lymphoid neoplasm diffuse large B-cell lymphoma was related to the degree of CD8+ T-cell infiltration, and infiltration of cancer-associated fibroblasts, such as kidney renal papillary cell carcinoma and brain lower-grade glioma, was also observed in other tumors. The results of pan-cancer analysis showed that abnormal PXN expression was related to poor prognosis, immune infiltration, and protein phosphorylation in different tumor types. Therefore, the PXN gene may become a potential biomarker of clinical tumor prognosis.

Anti-angiogenic therapy in ovarian cancer: current situation & prospects.

Ovarian cancer (OC) is one of five leading causes of cancer related death among women worldwide. Although treatment has been improving, the survival rate has barely improved over the past 30 years. The fatality rate is due to asymptomatic early signs and the lack of long-term effective treatment strategies for advanced disease. Angiogenesis is an important process in tumour growth and metastasis and is the creation of new blood vessels from existing blood vessels. It is a dynamic and complex process involving various molecular regulatory pathways and multiple mechanisms. The inhibition of angiogenesis has become a recognized therapeutic strategy for many solid tumours. While benefits in progression-free survival have been observed, the OS is far from satisfactory for OC patients who receive antiangiogenic therapy. In this article, the present research status of angiogenesis in OC was reviewed and the reasons for poor antiangiogenic therapeutic effects was explored with the aim to identify potential therapeutic targets that may improve the effect of antiangiogenic therapies.

Protective effect of astaxanthin against SnS2 nanoflowers induced testes toxicity by suppressing RIPK1-RIPK3-MLKL signaling in mice.

The reproductive toxicity of SnS2 nanoflowers (SnS2 NFs) has been studied in our previous experiment, but the underlying mechanism is still not clear. Astaxanthin (ASX) is a red carotenoid pigment with antioxidant, anticancer and anti-inflammatory properties, showing neuroprotective properties via its antioxidant capacity. To examine the ASX effect on sub-chronic testis injury induced by SnS2 NFs, we randomly and equally divided 40 Kunming male mice into four groups (control, ASX control, NF and NF + ASX groups). Then, ASX dissolved in olive oil was administered intragastrically for 30 consecutive days. Results showed that ASX treatment improved the sperm parameters in mice. Meanwhile, the ASX treatment significantly attenuated testis histopathological injury and ultrastructure alterations induced by SnS2 NFs. It also alleviated testicular oxidative stress, inflammation, apoptosis and necroptosis in mice. Furthermore, ASX markedly upregulated the expression of Bcl-2 and downregulated the expressions of Fas, FasL, RIPK1, FADD, Bax, Cytochrome C, Caspase-9, Cleaved Caspase-8, Cleaved Caspase-3, RIPK3, MLKL and FLIP in the testis tissues compared with the NF group. Therefore, ASX had a markedly protective effect against SnS2 NFs in mice, and the potential mechanism is associated with its ability to inhibit the oxidative stress, inflammatory response, testicular apoptosis and necroptosis, as well as downregulating in the expression of the RIPK1-RIPK3-MLKL signaling and mitochondrial related apoptosis genes.

Hepatic, Metabolic, and Toxicity Evaluation of Repeated Oral Administration of SnS2 Nanoflowers in Mice.

Tin sulfide (SnS2) nanoflowers (NFs) with highly photocatalytic activity for wastewater treatment may lead to potential health hazards via oral routes of human exposure. No studies have reported the hepatic effects of SnS2 NFs on the metabolic function and hepatotoxicity. In this study, we examined the hepatic effects of the oral administration of SnS2 NFs (250-1000 mg/kg) to ICR mice for 14 days, with the particle size ranging from 50 to 200 nm. Serum and liver tissue samples were assayed using biochemical analysis, liver histopathology and metabolic gene expression. The different sizes of SnS2 NFs (250 mg/kg dose), such as 50, 80, and 200 nm, did not induce any adverse hepatic effect related to biochemical parameters or histopathology in the treated mice compared with controls. The oral administration of 50-nm SnS2 NFs at doses of 250, 500, and 1000 mg/kg for 14 days produced dose-dependent hepatotoxicity and inflammatory responses in treated mice. Furthermore, the expression of metabolic genes in the liver tissues was altered, supporting the SnS2 NF-related hepatotoxic phenotype. The oral administration of SnS2 NFs also produced abnormal microstructures in the livers of the treated mice. Taken together, these data indicate that the increased risk of hepatotoxicity in SnS2 NF-treated mice was independent of the particle size but was dependent on their dose. The no-observed-adverse effect level was <250 mg/kg for the 50-nm SnS2 NFs. Our study provides an experimental basis for the safe application of SnS2 NFs.

Editor's Highlight: Effects of Intraperitoneal Injection of SnS2 Flowers on Mouse Testicle.

SnS2 nanoflowers (SnS2 NFs) have been widely used in photoelectric and catalytic applications. However, its explosure and reproductive toxicity is unknown. The aim of this study was to investigate the effect of exposure to 3 different sized-SnS2 flowers (dose: 38 mg/kg; size: 50, 80, and 200 nm) in testes of mice for 4 weeks by intraperitoneal injection. Though the body weight of mice treated or not with SnS2 NFs was not different, and SnS2 NFs were distributed to the organs including liver, kidney, spleen, heart, brain, and testis, more distribution SnS2 NFs (50 and 80 nm) were found in testicle tissues compared with SnS2 flowers (200 nm) in those tissues. The results of sperm count and survival analysis, histopathological evaluation, and qRT-PCR detection showed that there was moderate reproductive toxicity induced by the small-sized SnS2 NFs in testicle tissues. Furthermore, elevated malondialdehyde level and decreased superoxide dismutase activity were also observed in the SnS2 NFs (dose: 38 mg/kg; size: 50 and 80 nm) treated groups. Likewise, the qRT-PCR data indicated that SnS2 NFs can induce apoptosis and inflammation responses. Although the pro-inflammation marker of TNF-α, IL-1ß, iNOS, and COX-2 at the mRNA levels were higher expression in 50 and 80 nm groups than that in control and 200 nm group, no statistical significance existed between 50 and 80 nm groups. Accordingly, the repeated-dose toxicity of SnS2 NFs in testicle tissues was also observed in a dose-dependent manner by intraperitoneal injection of SnS2 NFs (size: 50 nm; 0.38, 3.8, and 38 mg/kg) for 4 weeks, when determined by sperm count, survival rate, and qRT-PCR analysis. In addition, transmission electron microscopy showed that the ultrastructural abnormalities formed by the small-sized SnS2 NFs in testes were more severe than those formed by the large-sized SnS2 in testes. Taken together, these findings implied that the SnS2 NFs activated inflammation responses that signified apoptosis in murine testes. This study provided useful information for risk analysis and regulation of SnS2 NFs by administration agencies.

Clinical correlation between serum YKL-40 protein level and recurrence of non-muscle invasive bladder cancer.

BACKGROUND: To explore the clinical correlation between serum YKL-40 protein level and recurrence of non-muscle invasive bladder cancer (NMIBC). METHODS: Totally 76 NMIBC patients (including 34 patients with confirmed recurrence and 42 patients without recurrence during the 2-year post-operative follow-up) and 31 healthy volunteers were recruited in this study. Blood samples were collected early in the morning, and serum YKL-40 protein levels of all these patients were analysed by using enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum YKL-40 protein levels were significantly higher in NMIBC patients than in healthy controls (P<0.001). Meanwhile, serum YKL-40 protein levels were found to be significantly higher in patients with recurrent NMIBC than those without tumor recurrence (P=0.001). CONCLUSIONS: Serum YKL-40 protein can be a reliable molecular marker for the clinical diagnosis of NMIBC recurrence. In particular, it can inform the post-operative management.