RCOR1 improves neurobehaviors and neuron injury in rat cerebral palsy by Endothelin-1 targeting-induced Akt/GSK-3ß pathway upregulation.

BACKGROUND: RE1 Silencing Transcription factor (REST) corepressor 1 (RCOR1) has been reported to orchestrate neurogenesis, while its role in cerebral palsy (CP) remains elusive. Besides, RCOR1 can interact with Endothelin-1 (EDN1), and EDN1 expression is related to brain damage. Therefore, this study aimed to explore the effects of RCOR1/EDN1 on brain damage during the progression of CP. METHODS: CP rats were established via hypoxia-ischemia insult, and injected with lentivirus-RCOR1, followed by examination of brain pathological conditions. The RCOR1 and EDN1 interaction was recognized using hTFtarget. Healthy rat cortical neuron cells received interference of RCOR1/EDN1 expression, and underwent oxygen-glucose deprivation/reoxygenation (OGD/R) treatment, after which phenotypic and molecular assays were conducted through the biochemical method, qRT-PCR and/or western blot. RESULTS: RCOR1 was low-expressed but EDN1 was high-expressed in CP model rats and OGD/R-treated neurons. RCOR1 overexpression ameliorated rat neurobehaviors, alleviated brain pathological conditions, reduced TUNEL-positive cells, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) level and repressed EDN1 expression in the brains of CP model rats. In neurons, RCOR1 overexpression counteracted OGD/R-induced viability decrease, reduction of the levels of RCOR1, SOD, Bcl-2, caspase-3, p-Akt/Akt and p-GSK-3ß/GSK-3ß, and elevation of the levels of EDN1, ROS, Bax, and cleaved caspase-3, while EDN1 overexpression did contrarily on these events. Moreover, there was a negative interplay between RCOR1 overexpression and EDN1 overexpression in OGD/R-induced neurons. CONCLUSION: RCOR1 ameliorates neurobehaviors and suppresses neuronal apoptosis and oxidative stress in CP through EDN1 targeting-mediated upregulation of Akt/GSK-3ß.

Pneumatosis intestinalis and hepatic portal venous gas in patient with Amanita exitialis poisoning: A case report from Shenzhen, China.

A 57-year-old male admitted as an emergency for mushroom poisoning with hypovolemic shock, acute renal injury (Cr 213 µmol/L) and metabolic acidosis (pH 7.1). Twenty-six hours ago, he consumed 4 caps of wild mushrooms and presented with acute gastroenteritis, generalized malaise and lower limbs jerk. On ICU admission, he developed ventricular defibrillation and was resuscitated with intubation and ventilation. In addition to plasma exchange and hemoperfusion therapy, the patient was managed with massive fluid and potassium replacement, vasopressors, activated charcoal, silymarin, penicillin G and piperacillin tazobactam. On ICU Day 2, the patient's general condition improved with vasopressor ceased, renal function normalized except large amount of diarrhea. On ICU Day 3, the patient deteriorated again with worsening abdominal distension leading to intra-abdominal hypertension (IAH). Toxic liver injury by mushroom became significant. Repeated acute renal injury, deranged clotting and compromised hemodynamics were also noted which indicated acute abdominal compartment syndrome. Emergent computed tomography (CT) of abdomen revealed Pneumatosis intestinalis (PI) in the small intestines and hepatic portal venous gas (HPVG) in the left liver lobe. Water assisted colonoscopy decompression was performed emergently for IAH relief. Thereafter, the patient improved rapidly with organ dysfunction recovered next day. Acute liver failure gradually subsided. On ICU Day 8, the patient was discharged to general ward. The mushroom was later morphologically identified as Amanita exitialis (A. exitialis) by at least two specialists from Chinese Centre for Disease Control and Prevention (CDC). A. exitialis is a lethal mushroom that mainly affect liver and gastrointestinal (GI) tract. The current case and literature review suggest that the severity of GI injury caused by lethal A. exitialis may be underestimated.

An outbreak of Amanita exitialis poisoning.

BACKGROUND: The mushroom Amanita exitialis is reported to cause acute liver injury. It is found in Southern China, and has been previously associated with a high incidence of mortality. METHODS: We described a series of 10 patients with Amanita exitialis poisoning admitted to The Second Affiliated Hospital of the Chinese University of Hong Kong (Shenzhen) in April 2022. Patient demographics, clinical features, laboratory results, therapeutic interventions, and outcome data were collected. RESULTS: Among the 10 patients, 9 survived, while 1 died. Gastrointestinal symptoms were the first to appear (average latency period, 11 ± 4.2 h). Diarrhea was the most common clinical symptom (average duration, 4.4 days). Abdominal distention was an important sign, especially in severely-ill patients. Thrombocytopenia occurred on day 2 after mushroom ingestion and persisted for 3-4 days. Alanine aminotransferase and total bilirubin peaked on days 2-3. CONCLUSION: Amanita exitialis poisoning is characterized by gastrointestinal symptoms and liver injury. In the patient who died, acute hepatic failure led to hepatic encephalopathy and cerebral edema. Abdominal distension accompanied by thrombocytopenia was common in critically ill patients in this outbreak.

Statistical characteristics of the spatial distribution of wind and snowfall in the Beijing-Tianjin-Hebei Region.

In the current design specification of building structure, the basic wind pressure and basic snow pressure are two independent values, and it is impossible to acquire both of these values when snow and wind occur at the same time. Taking parameters such as snowfall intensity, snowfall amount, wind speed, and wind direction as indicators, the value of the combined distribution of wind and snowfall in the Beijing-Tianjin-Hebei region of China was extracted. A joint distribution map of the daily average snowfall among the top-ten largest consecutive snowfall events and the daily average wind scale from the first day of snowfall to the fifth day after the snowfall were obtained. The study found that after a heavy snowfall in the Zhangjiakou area, the accumulated wind power was large and, although the wind speed was favorable for the occurrence of snowdrifts, the snowfall was light. After a heavy snowfall in the Shijiazhuang area, the accumulated wind power was small, and the probability of snowdrift formation was low. In the eastern regions of Cangzhou, Beijing, Tianjin, Tangshan, and Qinhuangdao, the accumulated wind force was relatively large after a heavy snowfall, and the probability of windblown snow was relatively high.

Intrinsic ß-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer.

Colorectal cancer is the third most common cancer worldwide and shows resistance to immune checkpoint inhibitors which have been demonstrated to be effective in many other types of cancers. Pre-existing T-cell response in tumor microenvironment often determines the therapeutic benefit of immune checkpoint blockade. Tumor-infiltrating CD8+ T-cells are considered as the major effector immune cells in antitumor immunity. In this study, we aimed to identify the intrinsic oncogenic pathway that contributes to a reduction of CD8+ T-cell infiltration in colorectal cancer. To achieve this, human colon adenocarcinoma samples derived from The Cancer Genome Altas (TCGA) were stratified into low T-cell-inflamed and high T-cell-inflamed groups based on the expression of T-cell signature genes. Gene set enrichment analysis of revealed a close correlation between activation of the Wnt/ß-catenin signaling pathway and absence of T-cell infiltration. By immunohistochemical analysis of 155 colorectal cancer tissues, we found that tumors with high ß-catenin expression showed a significant reduction of CD8+ T-cell infiltration. Mechanistically, ß-catenin can regulate CCL4 expression to recruit CD103+ dendritic cells to enable CD8+ T cell activation. Collectively, our data indicate that oncogenic ß-catenin signal may mediate colorectal cancer resistance to immunotherapies, pointing to the combined PD-1-immunotherapy with targeting ß-catenin in colorectal cancer.

Proinflammatory follicular helper T cells promote immunoglobulin G secretion, suppress regulatory B cell development, and correlate with worse clinical outcomes in gastric cancer.

Gastric cancer is one of the most common and aggressive malignancies. Both bacterial virulence factors and host chronic inflammation are thought to promote gastric cancer development. In this study, we investigated the potential involvement of follicular helper T cells in gastric cancer. Functions of follicular helper T subsets were examined in Helicobacter pylori-infected gastric cancer patients and H. pylori-infected but asymptomatic individuals. We found that the follicular helper T cells in gastric cancer individuals were skewed toward the Th1 and Th17 subsets compared to those in H. pylori-infected but asymptomatic individuals. In a naive B cell-follicular helper T cell coculture, the Th1-follicular helper T cells by themselves were ineffective at stimulating a robust antibody response, unlike the Th2-follicular helper T and Th17-follicular helper T cells. However, Th1-follicular helper T cells significantly promoted the immunoglobulin G response in collaboration with other follicular helper T subsets, through the secretion of interferon gamma. We also found that Th1-follicular helper T cells suppressed the development of interleukin-10+ regulatory B cells, a cell type previously thought to protect H. pylori-infected individuals from tissue damage. In addition, the frequency of Th1-follicular helper T cells in gastric cancer patients was negatively correlated with the disease-free survival of gastric cancer patients after tumor resection. These results suggested that dysregulation of follicular helper T subsets in gastric cancer patients, characterized by increased Th1-follicular helper T cells, contributed to inflammation and tumor development.

A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer.

BACKGROUND: Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC. OBJECTIVES: This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC. DATA SOURCES: Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science. SYNTHESIS METHODS: Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies. RESULTS: Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61-0.75) and 0.83 (95% CI 0.75-0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41-2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69-1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57-0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28-0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14-0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of PD-1/PD-L1 inhibitors. CONCLUSION: The PD-1/PD-L1 therapy significantly prolonged the OS and improved the ORR, simultaneously lowering the treatment-related adverse effect events versus docetaxel.

Decreased TUSC3 Promotes Pancreatic Cancer Proliferation, Invasion and Metastasis.

Pancreatic cancer is an aggressive disease with dismal prognosis. It is of paramount importance to understand the underlying etiological mechanisms and identify novel, consistent, and easy-to-apply prognostic factors for precision therapy. TUSC3 (tumor suppressor candidate 3) was identified as a potential tumor suppressor gene and previous study showed TUSC3 is decreased in pancreatic cancer at mRNA level, but its putative tumor suppressor function remains to be verified. In this study, TUSC3 expression was found to be suppressed both at mRNA and protein levels in cell line models as well as in clinical samples; decreased TUSC3 expression was associated with higher pathological TNM staging and poorer outcome. In three pairs of cell lines with different NF-κB activity, TUSC3 expression was found to be reversely correlated with NF-κB activity. TUSC3-silenced pancreatic cancer cell line exhibited enhanced potential of proliferation, migration and invasion. In an orthotopic implanted mice model, TUSC3 silenced cells exhibited more aggressive phenotype with more liver metastasis. In conclusion, the current study shows that decreased immunological TUSC3 staining is a factor prognostic of poor survival in pancreatic cancer patients and decreased TUSC3 promotes pancreatic cancer cell proliferation, invasion and metastasis. The reverse correlation between NF-κB activity and TUSC3 expression may suggest a novel regulation pattern for this molecule.

Effects of leptin on the expression of alpha1 (I) collagen gene in human osteoblast-like MG63 cells.

The objective of this study was to examine the effects of leptin on alpha (alpha) 1 (I) collagen gene expression in a human osteoblast-like MG63 cell line. MG63 cells were incubated with different doses of leptin (10(-8), 10(-7), and 10(-6) mol x L(-1)) for 24, 48, and 72 h. alpha1 (I) collagen gene expression in MG63 cells was detected by real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), with 17beta-estradiol (17beta-E2) as the positive control. Expression of the alpha1 (I) collagen gene, regulated by leptin, was dose and time dependent, with maximal expression in the 10(-7) mol x L(-1) group at 72 h of incubation. As a positive control, 17beta-E2 reached its maximal effect in the 10(-7) mol x L(-1) group at 24 h. We conclude that leptin has the ability to up-regulate alpha1 (I) collagen gene expression in MG63 cells, with a more potent effect but a less rapid response than 17beta- E2.