The immune regulation and therapeutic potential of the SMAD gene family in breast cancer.

Breast cancer is a serious threat to human health. The transforming growth factor-ß signaling pathway is an important pathway involved in the occurrence and development of cancer. The SMAD family genes are responsible for the TGF-ß signaling pathway. However, the mechanism by which genes of the SMAD family are involved in breast cancer is still unclear. Therefore, it is necessary to investigate the biological roles of the SMAD family genes in breast cancer. We downloaded the gene expression data, gene mutation data, and clinical pathological data of breast cancer patients from the UCSC Xena database. We used the Wilcox test to estimate the expression of genes of the SMAD family in cancers. And the biological functions of SMAD family genes using the DAVID website. The Pearson correlation method was used to explore the immune cell infiltration and drug response of SMAD family genes. We conducted in biological experiments vitro and vivo. In this study, we integrated the multi-omics data from TCGA breast cancer patients for analysis. The expression of genes of SMAD family was significantly dysregulated in patients with breast cancer. Except for SMAD6, the expression of other SMAD family genes was positively correlated. We also found that genes of the SMAD family were significantly enriched in the TGF-ß signaling pathway, Hippo signaling pathway, cell cycle, and cancer-related pathways. In addition, SMAD3, SMAD6, and SMAD7 were lowly expressed in stage II breast cancer, while SMAD4 and SMAD2 were lowly expressed in stage III cancer. Furthermore, the expression of genes of the SMAD family was significantly correlated with immune cell infiltration scores. Constructing a xenograft tumor mouse model, we found that SMAD3 knockdown significantly inhibited tumorigenesis. Finally, we analyzed the association between these genes and the IC50 value of drugs. Interestingly, patients with high expression of SMAD3 exhibited significant resistance to dasatinib and staurosporine, while high sensitivity to tamoxifen and auranofin. In addition, SMAD3 knockdown promoted the apoptosis of BT-549 cells and decreased cell activity, and BAY-1161909 and XK-469 increased drug efficacy. In conclusion, genes of the SMAD family play a crucial role in the development of breast cancer.

Single-cell RNA sequencing combined with whole exome sequencing reveals the landscape of the immune pathogenic response to chronic mucocutaneous candidiasis with STAT1 GOF mutation.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membranes (e.g., mouth, esophagus, and vagina). Compared with that of other infectious diseases, the immune pathogenic mechanism of CMC is still poorly understood. We identified a signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutation in a CMC patient. Single-cell transcriptional profiling on peripheral blood mononuclear cells from this patient revealed decreases in immature B cells and monocytes. Further analysis revealed several differentially expressed genes related to immune regulation, including RGS1, TNFAIP3, S100A8/A9, and CTSS. In our review of the literature on signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutations, we identified seven cases in total. The median age of onset for CMC (n=4, data lacking for three cases) was 10.5 years (range: birth to 11 years), with an average onset age of 8 years. There were no reports linking tumors to the c.Y289C mutation, and the incidence of pre-existing clinical disease in patients with the c.Y289C mutation was similar to previous data.

Effect of hydrolyzed formulas on gastrointestinal tolerance in preterm infants: a systematic review and meta-analysis.

OBJECTIVE: Hydrolyzed formulas (HFs) have been increasingly used in early enteral feeding in preterm infants. The current study aimed to compare the effect of HFs with standard preterm formula (SPF) on gastrointestinal tolerance in preterm infants by systematically reviewing the randomized controlled trials (RCTs) related. METHODS: Relevant studies published until August 2021 were searched in English and Chinese databases, including PubMed, Embase, Cochrane Library, CNKI, WanFang Data, and VIP. Three outcomes, including the incidence of feed intolerance (FI), necrotizing enterocolitis (NEC), and the time to full enteral feeding, were chosen to evaluate the effect on gastrointestinal tolerance comprehensively. RESULTS: Ten eligible studies with 886 participants were included in the final analysis. Infants who received HFs showed a lower risk of FI (RR = 0.61, 95% CI = 0.42-0.90; p < .05) and shorter time to full enteral feeding (MD = -0.56, 95% CI = -1.03 to -0.10; p < .05) compared with those fed with SPF. There was no significant difference in risk of NEC (RR = 0.48, 95%CI = 0.21 - 1.08; p > .05) between the two groups. CONCLUSIONS: The results showed that HFs may have benefits in improving gastrointestinal tolerance in preterm infants, including reducing the risk of FI and shortening the time to full enteral feeding.

Anaesthesia provision, infrastructure and resources in the Heilongjiang Province, China: a cross-sectional observational study.

OBJECTIVE: The aim of this study was to explore the current status of the anaesthesia provision, infrastructure and resources in the Heilongjiang Province, China. DESIGN: A cross-sectional observational study of hospitals, anaesthesiologists, assistant anaesthesiologists and anaesthetic nurses in the Heilongjiang Province. SETTING: All hospitals in the Heilongjiang Province. PARTICIPANTS: The hospitals, anaesthesiologists (attending physicians, associate chief physicians and chief physicians), assistant anaesthesiologists (licenced assistant physicians, resident physicians and other trainees) and anaesthetic nurses. MAIN OUTCOME MEASURES: Standard descriptive statistics (percentages and numbers) were used to summarise the data. RESULTS: The investigation involved 1123 hospitals, 405 of these hospitals had anaesthesiology departments (36.06%). There were 2406 anaesthesiologists, 175 assistant anaesthesiologists and 409 anaesthetic nurses. The proportion of anaesthesiologists was 56.60% in tertiary hospitals, 40.15% in secondary hospitals and 3.25% in primary hospitals and ungraded hospitals, respectively. Anaesthesiologists were present in 91.20% of public hospitals and 8.80% of private hospitals. Anaesthesiologists were present in 83.55% general hospitals and 16.45% of specialised hospitals. The Heilongjiang Province has a total of 2041 operating rooms and 543 beds in recovery rooms. The number of anaesthesia cases per capita per year was 326.86. The percentages of anaesthesiologists' age ≥46, 36-45, 25-35 and <25 are 24.03%, 41.80%, 33.91% and 0.27%, respectively. The proportions of resident physicians and attending physicians were 60.87%, and the proportions of associate chief physicians and chief physicians were 39.13%. The proportions of anaesthesiologists working >12 hours, 10 hours≤time≤12 hours, 8 hours≤time<10 hours and <8 hours were 0.55%, 22.04%, 64.30% and 13.11%, respectively. CONCLUSIONS: The present study demonstrated for the first time that the proportion of anaesthesiologists in the Heilongjiang Province, China, is still insufficient. The structure of anaesthesiologists needs to be optimised.

[Main food intake prediction of Chinese residents based on grey model].

OBJECTIVE: To predict the main food intake trend of the China's urban and rural residents from 2022 to 2030. METHODS: Data was collected from the China Health and Nutrition Survey(CHNS), which was carried out on a stratified, multistage, clustered, and random sampling method. And the average daily food intake in the survey was continuously collected by a 24-hour dietary review method for 3 consecutive days. The sample sizes aged 20 years or older of seven rounds survey were 9794, 9425, 9313, 9726, 12 760, 15 446 and 15 051, respectively. Based on the seven rounds of average food intake, the main food intake of urban and rural residents in China from 2022 to 2030 was predicted by the Grey model. RESULTS: (1)The mean absolute percentage error of average food intake prediction in urban and rural ranged from 1.6% to 38.4%. (2)In terms of the trends of food intake from 2022 to 2030, the grain and vegetable average intake of plant food in urban and rural residents showed a decreasing trend, while the average intake of fruits showed an increasing trend. The average intake of animal food, such as poultry and aquatic products in urban, livestock, poultry, eggs in rural areas showed an upward trend. Meanwhile, the average intake of animal food, such as livestock and eggs in urban and aquatic products in rural showed a downward trend. (3)Compared with the 2018, the fruits, poultry and aquatic product intake of urban and rural residents in 2030 will increase by 60.7%, 29.4% and 6.6%, the intake of grain, vegetables, livestock and eggs in urban areas will decrease by 36.9%, 19.4%, 8.7% and 12.4%, respectively. In 2030, the intake of fruits, livestock, poultry and eggs of rural residents will increase by 88.9%, 31.8%, 71.9% and 9.2%, respectively. While the intake of grain, vegetables and aquatic products of rural residents will decrease by 32.5%, 24.8% and 2.2%, respectively. (4)By 2030, the average intake of poultry in urban and rural areas will be within the recommended range of dietary guidelines. But the average intake of grain, vegetables, fruits, eggs and aquatic products in urban and rural areas will remain below dietary recommendations. While the livestock average intake will be far higher than the recommendations. CONCLUSION: The model accuracy is different when applied to different kinds of food. According to the prediction result of the grey model, residents should be guided to maintain the current grain intake level and increase the intake of vegetables, fruits, poultry, eggs and aquatic products in order to get balanced diet, while reducing the intake of livestock.

Gut microbiota associated with cryptococcal meningitis and dysbiosis caused by anti-fungal treatment.

The gut microbiota is a dynamic and highly diverse microbial ecosystem that affects many aspects of the host's physiology. An improved understanding of the gut microbiota could lead to better strategies for the diagnosis and therapy of cryptococcal meningitis (CM), but the impact of Cryptococcus infection and anti-fungal treatment on the gut microbiota has rarely been studied. We characterized the diversity and composition of the gut microbiota in CM patients at diagnosis and healthy controls (HCs) using metagenomic sequencing and determined the effects of anti-fungal drugs. We found that CM patients had distinct bacterial and fungal compositions compared with HCs, with eight differentially abundant fungal and 72 differentially abundant bacterial species identified between the two groups. CM patients showed an increased abundance of Enterococcus avium, Leuconostoc mesenteroides, and Weissella cibaria, and a decreased abundance of Prevotella spp. compared with HCs. However, anti-fungal treatment only led to minor changes in the intestinal microbiota. Moreover, both positive and negative correlations existed in fungal, bacterial, and clinical indicators. Our study suggests that the Cryptococcus neoformans infection caused a distinct dysbiosis of the gut microbiota and contributes valuable information implying potential links between the CM and gut microbiota.

Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer's-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model.

An increasing number of studies have suggested that traumatic brain injury (TBI) is associated with some neurodegenerative diseases, including Alzheimer's disease (AD). Various aspects of the mechanism of TBI-induced AD have been elucidated. However, there are also studies opposing the view that TBI is one of the causes of AD. In the present study, we demonstrated that TBI exacerbated the disruption of hippocampal-dependent learning and memory, worsened the reductions in neuronal cell density and synapse formation, and aggravated the deposition of Aß plaques in the hippocampi of APP/PS1 mice. We also found that TBI rapidly activated microglia in the central nervous system (CNS) and that this effect lasted for at least for 3 weeks. Furthermore, TBI boosted Aß-related microglia-mediated neuroinflammation in the hippocampi of APP/PS1 mice and the transformation of microglia toward the proinflammatory phenotype. Therefore, our experiments suggest that TBI accelerates the onset of cognitive dysfunction and Alzheimer-like pathology in the APP/PS1 mouse model, at least partly by altering microglial reactions and polarization.

PARP-1 promotes autophagy via the AMPK/mTOR pathway in CNE-2 human nasopharyngeal carcinoma cells following ionizing radiation, while inhibition of autophagy contributes to the radiation sensitization of CNE-2 cells.

It was previously reported that poly-(adenosine diphosphate-ribose) polymerase-1 (PARP-1) regulated ionizing radiation (IR)-induced autophagy in CNE-2 human nasopharyngeal carcinoma cells. The present study aimed to investigate whether PARP-1-mediated IR-induced autophagy occurred via activation of the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway in CNE-2 cells. In addition, the effect of PARP-1 and AMPK inhibition on the radiation sensitization of CNE-2 cells was investigated. CNE-2 cells were treated with 10 Gy IR in the presence or absence of the AMPK activator 5-amino-1-ß-D-ribofuranosyl-1H-imid-azole-4-carboxamide (AICAR). In addition, IR-treated CNE-2 cells were transfected with lentivirus-delivered small-hairpin RNA or treated with the AMPK inhibitor Compound C. Western blot analysis was used to assess the protein expression of PARP-1, phosphorylated (p)-AMPK, microtubule-associated protein 1 light chain 3 (LC3)-II and p-P70S6K. Cell viability and clone formation assays were performed to determine the effect of PARP-1 silencing and AMPK inhibition on the radiation sensitization of CNE-2 cells. The results showed that IR promoted PARP-1, p-AMPK and LC3-II protein expression as well as decreased p-P70S6K expression compared with that of the untreated cells. In addition, AICAR increased the expression of p-AMPK and LC3-II as well as decreased p-P70S6K expression compared with that of the IR-only group; however, AICAR did not increase PARP-1 expression. Furthermore, PARP-1 gene silencing decreased the expression of PARP-1, p-AMPK and LC3-II as well as increased p-P70S6K expression. Compound C decreased p-AMPK and LC3-Ⅱ expression as well as increased p-P70S6K expression; however, Compound C did not increase PARP-1 expression. Western blot analysis detected limited expression of p-LKB1 in all treatment groups. Cell viability and clone formation assays revealed that PARP-1 or AMPK inhibition reduced the proliferation of CNE-2 cells following IR. In conclusion, the present study demonstrated that PARP-1 promoted autophagy via the AMPK/mTOR pathway; in addition, PARP-1 or AMPK inhibition contributed to the radiation sensitization of CNE-2 cells following IR. However, it remains to be elucidated whether PARP-1 is an upstream mediator of the LKB1 pathway in CNE­2 cells following IR.