NDC1 promotes hepatocellular carcinoma tumorigenesis by targeting BCAP31 to activate PI3K/AKT signaling.

Hepatocellular carcinoma (HCC) is among the world's worst malignancies. Nuclear division cycle 1 (NDC1) is an essential membrane-integral nucleoporin, found in this study to be significantly increased in primary HCC. A multivariate analysis revealed that higher NDC1 expression was linked to worse outcome in HCC patients. Mouse xenograft tumors overexpressing NDC1 grew rapidly, and HCC cells overexpressing NDC1 showed enhanced proliferation, invasion, and migration in vitro. In contrast, knocking down NDC1 had the opposite effects in vitro. Furthermore, co-immunoprecipitation and liquid chromatograph mass spectrometer analyses revealed that NDC1 activated PI3K/AKT signaling by interacting with BCAP31. In summary, NDC1 and BCAP31 cooperate to promote the PI3K/AKT pathway, which is essential for HCC carcinogenesis. This suggests that NDC1 is predictive of prognosis in HCC.

HBx Modulates Drug Resistance of Sorafenib-Resistant Hepatocellular Carcinoma Cells.

BACKGROUND: Approximately 50% of hepatocellular carcinoma (HCC) arises due to the infection by hepatitis B virus X protein (HBx). Sorafenib, a unique targeted oral kinase inhibitor, is the therapeutic agent of choice for advanced HCC. The mechanism of HBx in drug resistance of sorafenib-resistant HCC cells was evaluated in this study. METHODS: Employing a stepwise increase of the sorafenib content, Hep3B and HepG2 cells were iteratively induced to establish drug-resistant cell lines (Hep3B/R and HepG2/R). The survival rate of Hep3B, Hep3B/R, HepG2, and HepG2/R cells was estimated using the cell counting kit-8 (CCK-8) assay. The IC50 values of sorafenib were calculated, exploring its effects under varying concentrations. The HBx content was quantified via quantitative reverse transcription PCR (RT-qPCR) and Western Blot. HBx overexpression and interfering virus vectors were constructed and transfected into Hep3B/R and HepG2/R cells. Cell viability and metastasis were assessed by colony formation, wound healing, and transwell assays. E-cadherin, N-cadherin, Vimentin, Slug, and Snail content was evaluated via Western Blot. RESULTS: HBx content was significantly elevated in Hep3B/R and HepG2/R subgroups compared to Hep3B and HepG2 subgroups. The proliferation, clonogenicity, invasiveness, and migratory abilities of Hep3B/R and HepG2/R cells in the HBx subgroup were markedly enhanced; E-cadherin content was significantly reduced, whereas the content of N-cadherin, Vimentin, Slug, and Snail was significantly elevated in the HBx subgroup. Conversely, in the sh-HBx subgroup, the proliferation, clonogenicity, invasion, and migration of Hep3B/R and HepG2/R cells were significantly reduced, E-cadherin content was markedly increased, and N-cadherin, Vimentin, Slug, and Snail content was significantly reduced, compared to the sh-negative control (NC) subgroup. CONCLUSIONS: HBx knockout may affect the development of HCC by reducing the proliferation, invasion, and migration of Hep3B/R and HepG2/R cells through the inhibition of Epithelial-Mesenchymal Transition (EMT).

A dual-channel fluorescence probe for simultaneously visualizing cysteine and viscosity during drug-induced hepatotoxicity.

Cysteine (Cys), one of the important participants in protecting cells from oxidative stress, is closely associated with the occurrence and development of various diseases. Moreover, cell viscosity as a pivotal microenvironmental parameter has recently attracted increasing attention due to its dominant role in governing intracellular signal transduction and diffusion of reactive metabolites. Thus, simultaneous detection of Cys and viscosity is imperative for investigating their pathophysiological functions and cross-link. Herein we present a mitochondria-targetable dual-channel fluorescence probe ABDSP by grafting the acrylate modified pyridinium unit to dimethylaminobenzene. Whilst the probe is a seemingly simple, it could simultaneously discriminate Cys and viscosity in a fashion of distinguishable signals. Furthermore, the probe was successfully employed for visualizing mitochondrial Cys and viscosity, and probe into their cross-link during acetaminophen-induced hepatotoxicity.

Human FAM111A inhibits vaccinia virus replication by degrading viral protein I3 and is antagonized by poxvirus host range factor SPI-1.

Zoonotic poxviruses such as mpox virus (MPXV) continue to threaten public health safety since the eradication of smallpox. Vaccinia virus (VACV), the prototypic poxvirus used as the vaccine strain for smallpox eradication, is the best-characterized member of the poxvirus family. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified VACV Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A (family with sequence similarity 111 member A), a nuclear protein that regulates host DNA replication, was shown to restrict the replication of a VACV SPI-1 deletion mutant (VACV-ΔSPI-1) in human cells. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent restriction factor for VACV-ΔSPI-1 and MVA. Deletion of FAM111A rescued the replication of MVA and VACV-ΔSPI-1 and overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A necessitated its trypsin-like protease domain and DNA-binding domain but not the PCNA-interacting motif. We further identified that FAM111A translocated into the cytoplasm upon VACV infection by degrading the nuclear pore complex via its protease activity, interacted with VACV DNA-binding protein I3, and promoted I3 degradation through autophagy. Moreover, SPI-1 from VACV, MPXV, or lumpy skin disease virus was able to antagonize FAM111A by prohibiting its nuclear export. Our findings reveal the detailed mechanism by which FAM111A inhibits VACV and provide explanations for the immune evasive function of VACV SPI-1.

Exogenous hydrogen sulfide alleviates hepatic endoplasmic reticulum stress via SIRT1/FoxO1/PCSK9 pathway in NAFLD.

High-fat-induced endoplasmic reticulum (ER) stress has been the main reason for the occurrence and development of nonalcoholic fatty liver disease (NAFLD). Hydrogen sulfide (H2 S) produces a marked effect on regulating lipid metabolism and antioxidation, whose effects on ER stress of NAFLD are still unclear. Here, we studied the influence of exogenous H2 S on NAFLD and its potential mechanism. In vivo, NAFLD model was induced by high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of exogenous H2 S intervention for 4 weeks. HepG2 cells exposure to lipid mixture (LM) were used as vitro model to explore the potential mechanism. We found exogenous H2 S significantly inhibited the hepatic ER stress and improved the liver fat deposition of HFD-fed mice. These similar results were also observed in HepG2 cells dealt with LM after exogenous H2 S treatment. Further mechanism studies showed exogenous H2 S strengthened the combination of FoxO1 with the PCSK9 promoter gene through SIRT1-mediated deacetylation, thereby inhibiting the PCSK9 expression to relieve the hepatic ER stress. However, SIRT1 knockout eliminated the effects of exogenous H2 S on FoxO1 deacetylation, PCSK9 inhibition, and remission of hepatic ER stress and steatosis. In conclusion, exogenous H2 S improved NAFLD by inhibiting hepatic ER stress through SIRT1/FoxO1/PCSK9 pathway. Exogenous H2 S and ER stress may be potential drug and target for the treatment of NAFLD, respectively.

Identification of ferroptosis and drug resistance related hub genes to predict the prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Currently, overcoming the drug resistance in HCC is a critical challenge and ferroptosis has emerged as a promising therapeutic option for cancer. We aim to construct a new gene signature related to ferroptosis and drug resistance to predict the prognosis in HCC. The RNA-seq data of HCC patients was obtained from the Cancer Genome Atlas database. Using least absolute shrinkage and selection operator cox regression, Kaplan-Meier analysis, and differential analysis, we constructed a prognostic model consisting of six hub genes (TOP2A, BIRC5, VEGFA, HIF1A, FTH1, ACSL3) related to ferroptosis and drug resistance in HCC. Functional enrichment, pathway enrichment and GSEA analysis were performed to investigate the potential molecular mechanism, and construction of PPI, mRNA-miRNA, mRNA-RBP, mRNA-TF and mRNA-drugs interaction networks to predict its interaction with different molecules. Clinical prognostic characteristics were revealed by univariate, multivariate cox regression analysis and nomogram. We also analyzed the relationship between the signature, immune checkpoints, and drug sensitivity. The expression of the gene signature was detected in HCC cell lines and HPA database. Our prognostic model classified patients into high and low-risk groups based on the risk scores and found the expression level of the genes was higher in the high-risk group than the low-risk group, demonstrating that high expression of the hub genes was associated with poor prognosis in HCC. ROC analysis revealed its high diagnostic efficacy in both HCC and normal tissues. The proportional hazards model and calibration analysis confirmed that the model's prediction was most accurate for 1- and 3-years survival. QRT-PCR showed the high expression level of the gene signature in HCC. Our study built a novel gene signature with good potential to predict the prognosis of HCC, which may provide new therapeutic targets and molecular mechanism for HCC diagnosis and treatment.

RIPK2 promotes the progression of colon cancer by regulating BIRC3-mediated ubiquitination of IKBKG.

Colon cancer is a cancer with high morbidity and mortality worldwide. Receptor interacting serine/threonine kinase 2 (RIPK2) has been identified as a proto-oncogene, but its role in colon cancer is largely unknown. Herein, we found that RIPK2 interference could inhibit the proliferation and invasion of colon cancer cells, and promote apoptosis. Baculoviral IAP repeat containing 3 (BIRC3) is an E3 ubiquitin ligase, which was found highly expressed in colon cancer cells. Co-immunoprecipitation (Co-IP) experiments showed that RIPK2 could directly bind with BIRC3. Then, we demonstrated that RIPK2 overexpression promoted the expression of BIRC3, BIRC3 interference could eliminate RIPK2-dependent cell proliferation and invasion, and BIRC3 overexpression rescued the suppressive effect of RIPK2 interference on cell proliferation and invasion. We further identified IKBKG, an inhibitor of nuclear factor kappa B, as a ubiquitination substrate targeted by BIRC3. IKBKG interference could eliminate the inhibitory effect of BIRC3 interference on cell invasion. RIPK2 could promote BIRC3-mediated ubiquitination of IKBKG, inhibit the expression of IKBKG protein, and promote the expression of NF-κB subunits p50 and p65 proteins. In addition, DLD-1 cells transfected with sh-RIPK2 or/and sh-BIRC3 were injected into mice to establish a tumor xenograft model, and we found that administration of sh-RIPK2 or sh-BIRC3 impeded the growth of xenograft tumors in vivo, and co-administration displayed a better inhibitory effect. In general, RIPK2 promotes the progression of colon cancer by promoting BIRC3-mediated ubiquitination of IKBKG and activating the NF-κB signaling pathway.

NHC-catalyzed [3 + 3] cycloaddition of α-bromoenals with nitroketene aminals or nitroketene N,S-acetals: synthesis of nitro-containing dihydropyridin-2-ones.

An N-heterocyclic carbene (NHC)-catalyzed [3 + 3] cycloaddition of α-bromoenals with nitroketene aminals or nitroketene N,S-acetals has been developed. This methodology provides an efficient strategy for the construction of valuable nitro-containing heterocyclic compounds. This protocol features mild reaction conditions, easily available starting materials, broad substrate scope and easy scalability.

Effect of small nuclear ribonucleoprotein polypeptide A on the malignant biological behavior of hepatocellular carcinoma cells and its mechanism / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探究小核核糖核蛋白多肽A（SNRPA）在肝细胞癌（HCC）组织和细胞中的表达及其调控HCC细胞HepG2和Hep3B恶性生物学行为的作用及其机制。方法: 数据库分析SNRPA在泛癌组织中的表达及其与病理分期、HCC患者预后的相关性。常规培养HepG2和Hep3B细胞，将si-NC，si-SNRPA#1、si-SNRPA#2转染HepG2和Hep3B细胞，实验分为si-NC组、si-SNRPA#1组和si-SNRPA#2组；将SNRPA-vector和SNRPA-oe载体转染LO2细胞，分为SNRPA-vector组和SNRPA-oe组。qPCR法检测正常肝细胞和肝癌细胞以及转染各组HepG2和Hep3B细胞中SNRPA mRNA的表达，MTT法、Transwell法和WB法分别检测转染后各组HepG2和Hep3B细胞的增殖、迁移和侵袭能力以及EMT相关蛋白表达的变化。结果: 数据库分析显示，SNRPA mRNA在多数肿瘤组织中均呈高表达（均P<0.001）且与病理分期有关联（P<0.05或P<0.01）。SNRPA在HCC组织和细胞中均呈高表达（P<0.05或P<0.01），且与HCC患者的预后有关联（P<0.01）。敲减SNRPA表达明显抑制HepG2和Hep3B细胞增殖（P<0.05或P<0.01）而过表达SNRPA则能促进LO2细胞增殖（P<0.01），敲减SNRPA表达明显抑制HepG2和Hep3B细胞的迁移和侵袭能力（均P<0.01），明显促进E-cadherin的表达上调（P<0.01），而抑制N-cadherin、vimentin的表达（P<0.01）。结论: SNRPA在HCC组织及细胞中呈明显高表达，其可能通过调控上皮间质转化（EMT）进程进而促进HepG2和Hep3B细胞的增殖、迁移和侵袭。

Circ_0003570 Suppresses the progression of hepatocellular carcinoma through miR-182-5p/STARD13 regulatory axis.

BACKGROUND: Emerging evidence have revealed that circRNAs exert important biological effects in the development and progression of various diseases, including cancer. Our study aimed to elaborated the biological effects of hsa-circ_0003570 in hepatocellular carcinoma (HCC) development at the molecular level. RESULTS: The results of functional experiments showed that knockdown of circ_0003570 induced HCC cell growth, migration and invasion, whereas overexpression of circ_0003570 presented the opposite effects. In vivo experiments, xenograft tumors grown from circ-overexpressed cells had smaller tumor volume and weight than the control group. Further investigations suggested that circ_0003570 may function as a competing endogenous RNA via competitively binding miR-182-5p and thereby regulating the repression of downstream target gene STARD13, which were demonstrated by dual luciferase reporter assay and functional rescued experiments. CONCLUSIONS: Taken together, circ_0003570 suppresses the development of HCC by modulating miR-182-5p/STARD13 axis.

Role of H2 receptor blocker famotidine over the clinical recovery of COVID-19 patients: A randomized controlled trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic putting the population at a high risk of infection-related health hazards, mortality and a potential failure of proper medical therapies. Therefore, it is necessary to evaluate the potential use of the existing drugs that could be used as options for the medical management of COVID-19 patients. AIM: To evaluate the role of the H2 receptor blocker "famotidine" in COVID-19 illness. METHODS: This study was done on seriously ill COVID-19 patients admitted to the intensive care unit (ICU) from different institutes in Bangladesh. Patients were divided into famotidine treatment group "A" (famotidine 40 mg to 60 mg oral formulation every 8 h with other treatment as given), and control group "B" (treatment as given). National early warning score (NEWS)-2, and sequential organ failure assessment day-1 score was calculated to evaluate the outcome. Outcomes were evaluated by the time required for clinical improvement, characterized as duration required from enrollment to the achievement of NEWS-2 of ≤ 2 maintained for 24 h; time to symptomatic recovery, defined as the duration in days (from randomization) required for the recovery of the COVID-19 symptoms; mortality rate; duration of ICU and hospital stay; total period of hospitalization; the rate of supplementary oxygen requirement; the computed tomography (CT) chest recovery (%), the time required for the viral clearance and "NEWS-2" on discharge. RESULTS: A total of 208 patients were enrolled in this study with 104 patients in each group. The famotidine treatment group had comparatively better recovery of 75% and a low mortality of 25% than the control with a recovery of 70% and a mortality of 30%. Duration of clinical improvement (group A 9.53 d, group B 14.21 d); hospitalization period among the recovered patients (group A 13.04 d, group B 16.31 d), pulmonary improvement in chest CT (group A 21.7%, group B 13.2%), and the time for viral clearance (group A 20.7 d, group B 23.8 d) were found to be statistically significant P ≤ 0.05. However, the Kaplan Meier survival test was not significant among the two study groups, P = 0.989. CONCLUSION: According to our study, treatment with famotidine achieved a better clinical outcome compared to the control group in severe COVID-19 illness, although no significant survival benefit was found.

Global, Regional, and National Burden of Protein-Energy Malnutrition: A Systematic Analysis for the Global Burden of Disease Study.

BACKGROUND: Statistical data on the prevalence, mortality, and disability-adjusted life years (DALYs) of protein-energy malnutrition are valuable for health resource planning and policy-making. We aimed to estimate protein-energy malnutrition burdens worldwide according to gender, age, and sociodemographic index (SDI) between 1990 and 2019. METHODS: Detailed data on protein-energy malnutrition from 1990 to 2019 was extracted from the Global Burden of Disease (GBD) database. The global prevalence, deaths, and DALYs attributable to protein-energy malnutrition and the corresponding age-standardized rates (ASRs) were analyzed. RESULTS: In 2019, the global prevalence of protein-energy malnutrition increased to 14,767,275 cases. The age-standardized prevalence rate (ASPR) showed an increasing trend between 1990 and 2019, while the age-standardized deaths rate (ASDR) and age-standardized DALYs rate presented a significantly decreasing trend in the same period. Meanwhile, there was a clearly ASPR, ASDR, and age-standardized DALYs rate downtrend of the prediction curve when the SDI went up. CONCLUSIONS: PEM still has a relatively serious disease burden in the world, especially in children and the elderly. At the same time, this phenomenon will be more obvious due to the aging of the world's population. Effective prevention measures should be strengthened to continuously improve public health conditions.

The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin.

Hematological and neurological expressed 1 (HN1) is closely associated with the proliferation and metastasis of various tumors. However, the physiological functions and clinical significance of HN1 in hepatocellular carcinoma (HCC) remain indistinct. In this study, we investigated the role of HN1 in the pathogenesis of HCC and the underlying mechanism using clinical data from HCC patients, in vitro experiments utilizing HCC cell lines and in vivo animal models. We demonstrated that the overexpressed HN1 in HCC was correlated with patients' adverse outcomes. The gain and loss of function experiments indicated that HN1 could promote the proliferation, migration, and invasion of HCC cells in vitro. Furthermore, we found that HN1 knockdown sensitized HCC cells to oxaliplatin. Mechanically, HN1 prevented HMGB1 protein from ubiquitination and degradation via the autophagy-lysosome pathway, which was related to the interaction between HN1 protein and TRIM28 protein. In the nucleus, the downregulation of HMGB1 followed by HN1 knockdown resulted in increased DNA damage and cell death in the oxaliplatin-treated HCC cells. In the cytoplasm, HN1 regulated autophagy via HMGB1. Furthermore, HN1 knockdown in combination with HMGB1 overexpression restored the aggressive phenotypes of HCC cells and the sensitivity of these cells to oxaliplatin. HN1 knockdown inhibited the tumor growth and metastasis, and promoted the anticancer efficiency of oxaliplatin in vivo. In conclusion, our data suggest that the HN1/HMGB1 axis plays an important role in the development/progression and chemotherapy of HCC. Our findings indicate that the HN1/HMGB1 axis may be a promising therapeutic target for HCC treatment.

Efficacy and Outcome of Remdesivir and Tocilizumab Combination Against Dexamethasone for the Treatment of Severe COVID-19: A Randomized Controlled Trial.

Objective: In this study, we investigated the efficacy and safety of remdesivir and tocilizumab combination therapy against dexamethasone for the management of severe COVID-19 patients. Methods: This was a multicenter study. Cases were randomly chosen and divided into two groups using an odd-even ratio of 1:1 applied to the hospital registration number. Group A received remdesivir [5 mg/kg (<40 kg) or 200 mg (>40 kg) on day 1 and then 2.5 mg/kg (<40 kg) or 100 mg (>40 kg) daily] + tocilizumab [8 mg/kg up to 800 mg highest 12 h apart], and group B was the control and received dexamethasone 6 mg/day. In addition, a broad-spectrum antibiotic and other essential treatments were received by all patients. To evaluate the mortality risk, the sequential organ failure assessment (SOFA) score was calculated on day-1. Treatment outcomes were measured as time to clinical improvement; mortality rate; duration of ICU stay; total period of hospitalization; the rate of (Supplementary Material) oxygen use; time to clinical failure; National Early Warning Score-2 (NEWS), and the percentage of lung recovery on CT of chest on discharge. Clinical trial registration ID: NCT04678739. Results: Remdesivir-Tocilizumab group had a lower mortality rate (25.49%) than the control (30.77%). The time to clinical improvement (Group A-9.41; B-14.21 days), NEWS-2 on discharge (Group A-0.89; B-1.2), duration of ICU stay (Group A-7.68; B-10.58), and duration of hospitalization (Group A-9.91; B-14.68) were less in the treatment group. Group A had a better percentage of lung recovery on chest CT than the control (Group A-22.13; B-11.74). All these differences were statistically significant (p= <0.05) in a t-test. However, no significant survival benefit was found among the study groups in Kaplan-Meier survival analysis, p = 0.739. Conclusion: The remdesivir-tocilizumab combination had preferable outcomes compared to the dexamethasone therapy for the treatment of severe COVID-19 concerning mortality rate and clinical and pulmonary improvement, although it did not demonstrate a significant survival benefit. Clinical Trial Registration: https://clinicaltrials.gov, NCT04678739.

LncRNA SNHG5 promotes the proliferation and cancer stem cell-like properties of HCC by regulating UPF1 and Wnt-signaling pathway.

The role of long noncoding RNA (lncRNAs) had been demonstrated in different types of cancer, including hepatocellular carcinoma. This study was intended to investigate the role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in HCC proliferation and the liver CSC-like properties. Through functional experiments, we determined that knockdown of SNHG5 repressed HCC cell proliferation and CSC-like properties, while over-expression of SNHG5 promoted cell growth. At the same time, CSC markers (CD44, CD133, and ALDH1) and related transcription factors (OCT4, SOX2, and NANOG) were downregulated when SNHG5 was knocked down. Mechanically, RNA immunoprecipitation (RIP) and RNA pulldown assay showed that SNHG5 regulated the proliferation and CSC-like properties of HCC by binding UPF1. Further investigations showed that expression of critical components of Wnt/ß-catenin pathway (ß-catenin, TCF4, c-myc, cyclinD1, and c-Jun) were upregulated with depletion of UPF1 in liver CSCs, which were downregulated with depletion of SNHG5. After use of the inhibitor of Wnt/ß-catenin pathway, the formation of liver CSCs sphere decreased. Taken together, SNHG5 plays a critical role to promote HCC cell proliferation and cancer stem cell-like properties via UPF1 and Wnt/ß-catenin pathway.

Nomogram to predict cause-specific mortality of patients with rectal adenocarcinoma undergoing surgery: a competing risk analysis.

BACKGROUND: Rectal adenocarcinoma is one of major public health problems, severely threatening people's health and life. Cox proportional hazard models have been applied in previous studies widely to analyze survival data. However, such models ignore competing risks and treat them as censored, resulting in excessive statistical errors. Therefore, a competing-risk model was applied with the aim of decreasing risk of bias and thereby obtaining more-accurate results and establishing a competing-risk nomogram for better guiding clinical practice. METHODS: A total of 22,879 rectal adenocarcinoma cases who underwent primary-site surgical resection were collected from the SEER (Surveillance, Epidemiology, and End Results) database. Death due to rectal adenocarcinoma (DRA) and death due to other causes (DOC) were two competing endpoint events in the competing-risk regression analysis. The cumulative incidence function for DRA and DOC at each time point was calculated. Gray's test was applied in the univariate analysis and Gray's proportional subdistribution hazard model was adopted in the multivariable analysis to recognize significant differences among groups and obtain significant factors that could affect patients' prognosis. Next, A competing-risk nomogram was established predicting the cause-specific outcome of rectal adenocarcinoma cases. Finally, we plotted calibration curve and calculated concordance indexes (c-index) to evaluate the model performance. RESULTS: 22,879 patients were included finally. The results showed that age, race, marital status, chemotherapy, AJCC stage, tumor size, and number of metastasis lymph nodes were significant prognostic factors for postoperative rectal adenocarcinoma patients. We further successfully constructed a competing-risk nomogram to predict the 1-year, 3-year, and 5-year cause-specific mortality of rectal adenocarcinoma patients. The calibration curve and C-index indicated that the competing-risk nomogram model had satisfactory prognostic ability. CONCLUSION: Competing-risk analysis could help us obtain more-accurate results for rectal adenocarcinoma patients who had undergone surgery, which could definitely help clinicians obtain accurate prediction of the prognosis of patients and make better clinical decisions.

Colorectal Cancer Cell Differentiation Is Dependent on the Repression of Aerobic Glycolysis by NDRG2-TXNIP Axis.

BACKGROUND: Poorly differentiated colorectal cancers are more aggressive. Metabolism reprogramming is a significant hallmark in cancer, and aerobic glycolysis is common. However, how cancer cells reprogramming glucose metabolism contributes to cell differentiation was largely unknown. Previous studies have reported that tumor suppressor NDRG2 could promote colorectal cancers differentiation. AIMS: This study aims to demonstrate that NDRG2 promotes the differentiation of colorectal cancers, potentially through the inhibition of aerobic glycolysis via TXNIP induction. METHODS: Western blotting, qRT-PCR and immunohistochemical staining were used to detect the expression of related molecules. MTT assay was used to reflect cell viability and proliferation. Immunofluorescent assay was performed to identify the expression and distribution of molecules. Luciferase analysis and CHIP assays were used to investigate the mechanism. Bioinformatic analysis was performed to predict the relevance. RESULTS: In colorectal cancers, NDRG2 could inhibit cell proliferation, reduce glucose uptake and decrease expression of key glycolysis enzymes. Upregulated NDRG2 is associated with differentiated cancer. However, deletion of TXNIP, a classic glucose metabolism inhibitor, could obviously alter the function of NDRG2 in differentiation, glucose uptake, expression of key glycolysis enzymes and proliferation. Mechanistically, high glucose flux promotes the activity of TXNIP promoter. And NDRG2 promotes the occupancy of transcription factor Mondo A on TXNIP promoter, predominantly through the suppression of c-myc, which could complete with Mondo A binding to TXNIP promoter. In clinical samples, high expression of TXNIP indicates good prognosis and outcome. CONCLUSIONS: NDRG2-dependent induction of TXNIP is critical for the aerobic glycolysis during colorectal cancers differentiation.

NCF1/2/4 Are Prognostic Biomarkers Related to the Immune Infiltration of Kidney Renal Clear Cell Carcinoma.

Neutrophil cytoplasmic factor 1/2/4 (NCF1/2/4) belongs to the NADPH oxidase complex, which is a cytoplasmic component, and its polymorphism is the main factor related to autoimmune diseases, which is probably caused by the regulation of peroxide. They also play a role in tumor growth and metastasis. This research is aimed at evaluating the biological function and prognostic role of NCF1, NCF2, and NCF4 genes in kidney renal clear cell carcinoma (KIRC) by using multiple online bioinformatics website, including Oncomine, GEPIA, UALCAN, Kaplan-Meier Plotter, TIMER, TISIDB, cBioPortal, LinkedOmics, GeneMANIA, and DAVID databases. The mRNA levels of NCFs were higher in KIRC tissues than in normal tissues. The overexpression of NCFs was significantly correlated with advanced pathological grades and individual cancer stages in KIRC. Meanwhile, the expressions of NCFs played an important role in the tumorigenesis and progression of KIRC. Prognostic value analysis suggested that high transcription levels of NCF1/4 were associated with poor overall survival in KIRC patients. In addition, results from the LinkedOmics database showed that the KEGG pathway related to NCFs mainly focused on immune activation and immune regulation function. NCF genetic alterations, including copy number amplification, missense mutation, and deep deletion, could be found through the cBioPortal database. Further, NCF expression was significantly correlated with infiltration levels of various immune cells as well as immune signatures. Protein-protein interaction network and enrichment analysis of NCF1/2/4 in KIRC showed that NCF coexpressed genes mainly associated with diverse immune marker sets showed significance. Overall, these results indicated that NCFs could be prognostic biomarkers as well as effective targets for diagnosis in KIRC.

Clinical Characteristics and the Long-Term Post-recovery Manifestations of the COVID-19 Patients-A Prospective Multicenter Cross-Sectional Study.

Objective: Coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global issue. In addition to managing acute cases, post-COVID-19 persisting symptoms/complaints and different hematological values are of great concern. These have an impact on the patient's well-being and are yet to be evaluated. Therefore, clinical and primary diagnosis based on routine laboratory findings bears high importance during the initial period of COVID-19, especially in regions with fewer diagnostic facilities. Methods: Clinical information and associated complaints of the COVID-19 illness confirmed by reverse transcription-polymerase chain reaction (RT-PCR) were collected directly from the patients. Regular follow-ups were obtained on the phone every 2 weeks following recovery for 20 weeks. Initial hematological and radiology findings of the hospitalized patients except for intensive care unit (ICU) and high dependency units (HDUs) and a follow-up evaluation after 4 weeks following recovery were analyzed. Results: The post-COVID-19 persisting symptoms/complaints were found among 21.4% of symptomatic patients, which persisted for ≥20 weeks and had a significant relationship with the duration of COVID-19 illness and the existing comorbidity (p < 0.05). Post-COVID-19 primary type 2 diabetes mellitus (DM, 0.64%) and hypertension (HTN, 1.28%) and unstable DM (54.55%) and HTN (34.78%) to the pre-existing diabetic and hypertensive patients were observed. Post-recovery remarkable changes in the laboratory values included leukocytosis (16.1%), lymphocytosis (14.5%), and an increased prothrombin time (PT, 25.8%). Abnormalities in the D-dimer, serum ferritin, hemoglobin, and erythrocyte sedimentation rate (ESR) levels were present to an extent. Laboratory findings like chest X-ray, ESR, white blood cell (WBC) count, lymphocyte count, C-reactive protein (CRP), serum glutamic pyruvic transaminase (SGPT), serum ferritin, PT, D-dimer, and serum creatinine are important markers for the diagnosis and prognosis of COVID-19 illness (p < 0.05). Conclusion: Post-COVID-19 persisting symptoms and the changes in the laboratory values need to be considered with importance and as a routine clinical measure. Post-COVID-19 periodic follow-up for evaluating the patient's physical condition and the biochemical values should be scheduled with care and managed accordingly to prevent future comorbidity in patients with the post-COVID-19 syndrome.

miR-4677-3p participates proliferation and metastases of gastric cancer cell via CEMIP-PI3K/AKT signaling pathway.

Gastric cancer is one of the top three leading causes of cancer-related death in the world. Evidence indicated that miR-4677-3p was dysregulated and involved in modulating invasion and migration in multiple types of cancer cells. The aim of this research is to explore the function and mechanism of miR-4677-3p in the development of gastric cancer. In this study, we discovered that miR-4677-3p was down-regulated in gastric cancer tissues and cells. Over-expression of miR-4677-3p suppressed the proliferation, migration and invasion of gastric cancer cells. Furthermore, miR-4677-3p directly bond to CEMIP 3'UTR region and inhibited CEMIP expression. CEMIP promoted cell proliferation, migration and invasion of gastric cancer cells via accelerating PI3K/AKT signaling pathway. siCEMIP or PI3K/AKT signaling inhibitor (Akti-1/2 and LY294002) partly reversed the effects of miR-4677-3p on the cellular growth and metastasis of gastric cancer. In general, miR-4677-3p regulated the development of gastric cancer through CEMIP-PI3K/AKT signaling pathway axis. This study verified the function and molecular mechanism of miR-4677-3p in gastric cancer cells, and may provide a potential diagnosis/prognosis target for patients with gastric cancer.