Matrin-3 acts as a potential biomarker and promotes hepatocellular carcinoma progression by interacting with cell cycle-regulating genes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.

Prognostic value of neutrophil-to-lymphocyte ratio on proteinuria remission in patients with idiopathic membranous nephropathy.

BACKGROUND: As a novel marker of inflammation, the neutrophil-to-lymphocyte ratio (NLR) has been studied in various diseases. However, NLR in idiopathic membranous nephropathy (IMN) has been rarely studied. We sought to assess the role of NLR in predicting proteinuria remission in IMN. METHODS: This retrospective study involved 561 patients with IMN from January 2018 to December 2022 in Department of Nephrology of Wuhan Central Hospital. All baseline data were collected before the immunosuppressive regiment was administered. The Cox proportional hazards model and Kaplan-Meier curve were applied to assess the prognostic value of NLR for proteinuria remission. RESULTS: The area under the receiver operating characteristic curve revealed that the optimal cut-off NLR value for predicting proteinuria non-remission was 2.63, with a sensitivity and specificity of 58.2% and 72.7%, respectively. Kaplan-Meier curves showed a lower rate of proteinuria remission in patients with high NLR compared with low NLR (Log-rank = 5.04, p = 0.025). Multivariate Cox regression analysis showed that high NLR was an independent risk factor for proteinuria non-remission after adjustment (HR = 1.579, 95% CI 1.052-2.683, p = 0.023). Subgroup analysis indicated that high NLR was a risk factor for proteinuria non-remission especially in IMN patients with 24 h proteinuria ≥ 1 g (HR = 1.818, 95% CI 1.031-2.573, p = 0.012) and chronic kidney disease (CKD) stage 3-4 (HR = 1.935, 95% CI 1.084-2.495, p = 0.015). CONCLUSION: The current study shows that NLR is an independent risk factor for proteinuria non-remission in IMN. More attention should be paid to IMN patients with high NLR, especially for those patients with 24 h proteinuria ≥ 1 g and CKD stage 3-4.

Effect of preoperative arterial diameter on hospitalization and mortality in patients undergoing hemodialysis with forearm arteriovenous fistula access.

BACKGROUND: As pointed out by the recent Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for Vascular Access, the current quality of evidence supporting preoperative vascular anatomy and patient outcomes is suboptimal and insufficient to make recommendations. This study assessed arteriovenous fistulas (AVFs) created with different preoperative arterial diameters on hospitalization and mortality rates in patients undergoing hemodialysis at the authors' center. METHODS: Data from 261 patients who underwent HD between 2017 and 2019 were retrospectively examined. Differences in mortality and hospitalization rates between patients with different preoperative arterial diameters were compared, and risk factors for mortality and hospitalization were analyzed. RESULTS: Smaller preoperative artery diameter (<2 mm) was associated with all-cause mortality (risk ratio [RR] 1.61 [95% confidence interval (CI) 1.45-1.90]; p < 0.01), and access-related (RR 1.68 [95% CI 1.24-2.44]; p < 0.01), and congestive heart failure (CHF)-related (RR 0.67 [95% CI 0.38-1.01]; p = 0.04) hospitalization. Longer catheter-dependent duration (⩾60 days) was associated with access-related hospitalization (RR 1.48 [95% CI 1.07-2.11]; p = 0.03), and higher postoperative brachial artery blood flow (⩾1500 mL/min) was associated with CHF-related hospitalization (RR 1.58 [95% CI 1.02-2.29]; p < 0.01). Higher postoperative brachial artery blood flow (⩾1500 mL/min) was associated with all-cause mortality (hazard ratio [HR] 1.20 [95% CI 1.09-2.32]; p = 0.04), whereas preoperative artery diameter (HR 0.98 [95% CI 0.93-1.86]; p = 0.08) and catheter-dependent duration (HR 1.06 [95% CI 0.47-2.13]; p = 0.82) were not associated with all-cause mortality. CONCLUSION: In this cohort, smaller preoperative artery diameter was associated with all-cause and access-related hospitalizations, while a larger preoperative artery and higher postoperative brachial blood flow were associated with CHF-related hospitalization. However, only higher postoperative brachial blood flow was associated with all-cause mortality.

CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis.

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells, contributing to ∼ 20% of the total ALL cases, with a higher prevalence in adults than children. Despite the important role of human T-ALL cell lines in understanding the pathobiology of the disease, a detailed comparison of the tumorigenic potentials of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells, is still lacking. Methodology: In the present study, NOD-Prkdc scid IL2rgd ull (NTG) mice were intravenously injected with MOLT4, JURKAT cells, and PBS as a control. The leukemiac cell homing/infiltration into the bone marrow, blood, liver and spleen was investigated for bioluminescence imaging, flow cytometry, and immunohistochemistry staining. Gene expression profiling of the two cell lines was performed via RNA-seq to identify the differentially expressed genes (DEGs). CCR9 identified as a DEG, was further screened for its role in invasion and metastasis in both cell lines in vitro. Moreover, a JURKAT cell line with overexpressed CCR9 (Jurkat-OeCCR9) was investigated for T-ALL formation in the NTG mice as compared to the GFP control. Jurkat-OeCCR9 cells were then subjected to transcriptome analysis to identify the genes and pathways associated with the upregulation of CCR9 leading to enhanced tumirogenesis. The DEGs of the CCR9-associated upregulation were validated both at mRNA and protein levels. Simvastatin was used to assess the effect of cholesterol biosynthesis inhibition on the aggressiveness of T-ALL cells. Results: Comparison of the leukemogenic potentials of the two T-ALL cell lines showed the relatively higher leukemogenic potential of MOLT4 cells, characterized by their enhanced tissue infiltration in NOD-PrkdcscidIL2rgdull (NTG) mice. Transcriptmoe analysis of the two cell lines revealed numerous DEGs, including CCR9, enriched in vital signaling pathways associated with growth and proliferation. Notably, the upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in vitro and in NTG mice. Transcriptome analysis revealed that CCR9 overexpression facilitated cholesterol production by upregulating the expression of the transcriptional factor SREBF2, and the downstream genes: MSMO1, MVD, HMGCS1, and HMGCR, which was then corroborated at the protein levels. Notably, simvastatin treatment reduced the migration of the CCR9-overexpressing JURKAT cells, suggesting the importance of cholesterol in T-ALL progression. Conclusions: This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL.

The effect of early conversion from central venous catheter to arteriovenous fistula on hospitalization and mortality in incident haemodialysis patients.

BACKGROUND: Controversy remains as to whether initiating haemodialysis (HD) with a central venous catheter (CVC) and vascular access conversion are associated with the risk of morbidity and mortality in incident HD patients. METHODS: At our dialysis centre, the vascular access strategy is to create an arteriovenous fistula (AVF) early and use the AVF to initiate HD. In emergency situations, HD is initiated with a CVC and subsequent conversion from a CVC to an AVF as soon as possible. The effects of early AVF conversion on hospitalization and mortality were analysed. RESULTS: At HD initiation, 35.42% used AVF, 15.63% used CVC with immature AVF and 48.96% used CVC, and all patients were able to convert from CVC to AVF within approximately 3 months. Compared to starting HD using an AVF, using a CVC was associated with access-related hospitalizations at 2 years, regardless of whether an AVF was created before (incidence rate ratio (IRR) = 3.02, 95% CI 0.89-10.24, p = 0.03) or after (IRR = 4.10, 95% CI 1.55-10.85, p < 0.01) HD initiation. The Kaplan-Meier method showed that the 2-year survival probability was not statistically significant between the three groups (log-rank χ2 = 0.165, p = 0.921). Multivariate Cox proportional hazards regression showed that starting HD with a CVC was not associated with mortality at 2 years (p > 0.05). CONCLUSION: In this cohort, initiating HD with a CVC was associated with more access-related hospitalizations. Under the impact of an early AVF conversion strategy, despite initiating HD with a CVC, subsequent conversion from a CVC to an AVF within approximately 3 months had no impact on all-cause mortality in incident HD patients.

LncRNA15691 promotes T-ALL infiltration by upregulating CCR9 via increased MATR3 stability.

Our previous studies demonstrated that CCR9 plays an important role in several aspects of T-cell acute lymphoblastic leukemia progression and that CCR9 is a potential therapeutic target. However, the underlying mechanism that regulates CCR9 expression remains incompletely understood. In this study, bioinformatics analysis and validation in clinical samples revealed the lncRNA15691 to be positively correlated with CCR9 mRNA expression and significantly upregulated in T-cell acute lymphoblastic leukemia samples and CCR9high T-cell acute lymphoblastic leukemia cell lines. LncRNA15691, a previously uncharacterized lncRNA, was found to be located in both the cytoplasm and the nucleus via fluorescence in situ hybridization assay. In addition, lncRNA15691 upregulated the expression of CCR9 and was involved in T-cell acute lymphoblastic leukemia cell invasion. In vivo experiments showed that lncRNA15691 promoted leukemia cell homing/infiltration into the bone marrow, blood, and spleen, whereas the CCR9 ligand, CCL25, augmented the extramedullary infiltration of CCR9low leukemia cells overexpressing lncRNA15691 into blood, spleen, and liver. Subsequently, RNA protein pull-down assays, coupled with liquid chromatography-tandem mass spectrometry, were used to uncover potential lncRNA15691-interacting proteins, which were then validated by RNA immunoprecipitation. These mechanistic studies revealed that lncRNA15691 upregulated CCR9 expression via directly binding to and stabilizing MATR3 by inhibiting its nuclear degradation mediated by PKA. Collectively, our study revealed a novel mechanism of regulating CCR9 expression and implicated lncRNA15691 as a potential novel biomarker for T-cell acute lymphoblastic leukemia infiltration.

TTYH3, a potential prognosis biomarker associated with immune infiltration and immunotherapy response in lung cancer.

PURPOSE: The recognition of new diagnostic and prognostic biological markers for lung cancer is an essential and eager study. It's shown that ion channels play important roles in regulating various cellular processes and have been suggested to be associated with patient survival. However, tweety family member 3 (TTYH3), as a maxi-Cl- channel, its role in lung cancer remains elusive. METHODS: The expression, diagnostic and prognostic efficacy of TTYH3 were analyzed by public databases and clinical samples. Cell functional experiments were used to explore the effects of TTYH3 on cell viability. GO and KEGG enrichment analysis revealed underlying pathways that TTYH3 and its co-expressed genes were enriched in. TIMER, TIDE and R language analyses were used to detect the correlation between TTYH3 and immune infiltration cell and immunotherapy response. RESULTS: TTYH3 was up-regulated in lung cancer tissues compared to normal tissues and possessed a prominent diagnostic and prognostic value. TTYH3 knockdown significantly inhibited the proliferation of lung cancer cells. Enrichment analyses showed that TTYH3 and its co-expressed genes were mainly involved in immune related signaling pathways. Further investigation clarified that TTYH3 had a positive correlation with the infiltration of TAMs, Treg infiltration as well as T cell exhaustion and high TTYH3 expression indicated worse immunotherapy response and shorter survival after immune checkpoint blockade treatment. CONCLUSION: This study not only revealed the diagnostic and prognostic value of TTYH3 but also provided TTYH3-based estimation of immunotherapy response for lung cancer patients, which might provide new strategies like anti-TTYH3 combined with immune therapy for the treatment of lung cancer.

Insulin receptor substrate 1(IRS1) is related with lymph node metastases and prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related mortality globally with a high risk of lymph node metastasis (LNM). In this study, weighted gene co-expression network analysis (WGCNA) showed the identification of 10 modules among which the significant module (turquoise), including 1352 genes, was correlated with LNM. A group 52 overlapping differentially expressed genes (DEGs) was identified based on the comparison of turquoise module with GSE23400 and GSE20347 datasets. Using Ctyohubba plugin, we identified 7 hub genes (ACTG2, SORBS1, MYH11, CXCL12, CNN1, IRS1 and CXCL8). IRS1 displayed significant correlation with metastasis. The decreased expression of IRS1 was also a predictor of poor OS of ESCC patients whereas the hub genes namely ACTG2, MYH11, CXCL8, CXCL12, IRS1 and CNN1 were associated with RFS of ESCC patients. These findings suggest that the altered expression of these hub genes are associated with prognosis and thus can be used as potential biomarkers for ESCC. Moreover, immunohistochemical staining and cell functional experiments displayed that the overexpression of IRS1 was negatively associated with metastasis in ESCC. In general, our research revealed several novel genes in ESCC especially the association of IRS1 with LNM in ESCC, which could provide novel insights into the initiation and progression of ESCC.

The association between platelet-lymphocyte ratio and the risk of all-cause mortality in chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) patients have high levels of inflammatory mediators. These inflammatory mediators contribute to the increased risk of cardiovascular events and all-cause mortality. Platelet-lymphocyte ratio (PLR) has recently been recognized as a novel inflammatory marker and has been shown to be associated with the prognosis in CKD patients. However, the quality of these studies varies and their results are controversial. The purpose of this meta-analysis was to investigate the relationship between PLR and all-cause mortality in CKD patients. METHODS: A systematic literature search of PubMed, EMBASE, CENTRAL and ISI Web of Science was conducted. The databases were searched from their inception dates up to the latest issue (31 October 2021). Two reviewers independently searched the databases and screened studies. Data were extracted using a standardized collection form. Meta-analysis was performed to compare PLR values between CKD and non-CKD patients, and to investigate the association between PLR and all-cause mortality in CKD patients. This meta-analysis is reported in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: A total of 11 studies involving 4244 participants were selected. The pooled data indicated that PLR values were significantly higher in CKD patients than non-CKD controls (weighted mean difference = 21.6, 95% CI 17.39-25.81, p < 0.01), and PLR is associated with an increased risk of all-cause mortality in CKD patients (hazard ratio = 2.49, 95% CI 1.78-3.49, p < 0.01). CONCLUSIONS: Patients with CKD have higher PLR values compared to non-CKD patients. Meanwhile, PLR values were highly associated with all-cause mortality in CKD patients. PLR is a valid predictor as a clinically accessible indicator for patients with CKD.

The association between the locations of arteriovenous fistulas and patency rates: A systematic review and meta-analysis.

BACKGROUND: The arteriovenous fistulas (AVF) continue to be the most prevalent type of vascular access for hemodialysis (HD). However, the appropriate locations of AVF are controversial. We conducted the meta-analysis to investigate the differences in patency between upper-arm and forearm AVF. METHODS: PubMed, EMBASE, CENTRAL, and ISI Web of Science were searched to identify studies with differences in AVF patency at different locations. Reviewers searched the database, screened studies according to inclusion criteria, and conducted Meta-analysis. RESULTS: A total of 12 studies involving 3437 patients were selected. Pooled data showed that primary patency (PP) of AVF were higher in upper-arm than forearm at 1 and 2 years (odds ratio [OR] = 1.54, p = 0.0005; OR = 2.45, p = 0.001), but the differences in cumulative patency (CP) were not statistically significant at 1 and 2 years (OR = 2.10, p = 0.08; OR = 2.16, p = 0.1). The differences in PP and CP between upper-arm and forearm AVF in patients older than 65 years were not statistically significant at 1 (OR = 1.61, p = 0.05; OR = 2.05, p = 0.17) and 2 years (OR = 3.40, p = 0.13; OR = 1.38, p = 0.16). In Asian patients, the differences in PP and CP between upper-arm and forearm AVF were not statistically significant at 1 (OR = 1.17, p = 0.41; OR = 1.02, p = 0.94) and 2 years (OR = 2.95, p = 0.08; OR = 1.23, p = 0.41). CONCLUSIONS: In this study, the CP of upper-arm and forearm AVF was similar in overall population. There was no difference in PP and CP of AVF between upper-arm and forearm in Asian population or the elderly. The forearm AVF could be consider to be the first choice. for Asian patients or the elderly.

Circulating irisin level in chronic kidney disease patients: a systematic review and meta-analysis.

BACKGROUND: Irisin is not only a myokine but also an adipokine that is critical in many diseases including in the development of such diseases as obesity, diabetes mellitus, metabolic syndrome, coronary artery disease, and chronic inflammation. However, the association between irisin and chronic kidney disease (CKD) is unclear. This systematic review aimed to assess circulating irisin levels in patients with CKD and compare them with those in non-CKD patients. METHODS: PubMed, EMBASE, CENTRAL, ISI Web of Science, and CNKI were searched to identify observational studies of circulating irisin levels in patients with CKD. Two reviewers independently searched the databases and screened studies according to the inclusion criteria. Data were extracted using a standardized collection form. Meta-analysis was performed to compare the differences in circulating irisin levels between CKD and non-CKD patients. RESULTS: A total of 9 studies (6 cross-sectional and 3 case controls) involving 859 CKD patients and 393 non-CKD individuals were selected. The pooled data indicated that circulating irisin concentrations were significantly lower in CKD nondialysis patients (WMD = - 84.79, 95% CI - 170.23, 0.50; p < 0.05), peritoneal dialysis patients (WMD = - 235.81, 95% CI - 421.99, - 49.62; p = 0.01), and hemodialysis patients (WMD = - 217.46, 95% CI - 381.35, - 53.57; p = 0.009) than in healthy controls. CONCLUSIONS: This study confirmed that irisin levels were decreased in patients with CKD. Moreover, circulating irisin levels were lower in dialysis patients than in nondialysis patients.

Maturation and survival of arteriovenous fistula: The challenge starts from the preoperative assessment stage.

BACKGROUND: It is necessary to assess the association between the preoperative indicators and the maturation and survival of arteriovenous fistula (AVF). METHODS: We retrospectively identified 236 patients with a new AVF created between 2016 and 2018 in our Dialysis Center. RESULTS: Multivariate Logistic regression showed that preoperative arterial diameter (odds ratio [OR] = 1.452, 95% confidence interval [CI] [1.233, 1.710], p < 0.001), preoperative venous diameter (OR = 1.296, 95% CI [1.166, 1.477], p < 0.001), left ventricular ejection fraction (LVEF) (OR = 1.187, 95% CI [1.103, 1.277], p < 0.001), and diabetes mellitus (OR = 0.245, 95% CI [0.107, 0.560], p = 0.01) were independent influential factors for AVF maturation. Two years after the AVF surgery follow-up, multivariate Cox proportional-hazards model showed that the preoperative arterial diameter (OR = 0.510, 95% CI [0.320, 0.813], p = 0.005), preoperative venous diameter (OR = 0.940, 95% CI [0.897, 0.985], p = 0.010) and diabetes mellitus (OR = 1.785, 95% CI [1.117, 2.855], p = 0.016) was prognostic factors of AVF survival. The Kaplan-Meier method showed that the primary survival of AVF in patients with different preoperative arterial diameter was statistically significant (log-rank χ2 = 15.415, p < 0.001), while the secondary survival was not statistically significant (log-rank χ2 = 0.131, p = 0.717). CONCLUSION: In our cohort, the preoperative arterial and venous diameter and diabetes mellitus were independent influential factors for AVF maturation and prognostic factors of AVF survival. However, the preoperative LVEF only associated with the maturation of AVF. Meanwhile, smaller arterial diameter (≤2.15 mm) was associated with AVF maturation failure, but did not impact secondary survival of AVF.

MicroRNA-383 promotes reactive oxygen species-induced autophagy via downregulating peroxiredoxin 3 in human glioma U87 cells.

Peroxiredoxin 3 (PRDX3) is an abundant and effective enzyme, which aids in the removal of H2O2 in the mitochondria, thereby inhibiting cell autophagy. PRDX3 is a target protein of microRNA (miRNA/miR)-383, the overexpression of which has been found to inhibit the growth of glioma cells. We hypothesized that miR-383 serves an antitumor role by inhibiting oxidative stress during tumor growth. In the current study, human glioma U87 cells were transfected with pre-/short hairpin (sh)-PRDX3 vectors and miR-383 mimics/inhibitors. Apoptosis and reactive oxygen species (ROS) production were detected using flow cytometry. Autophagy was examined using acridine orange staining, and the expression of cytoplasmic autophagy-related proteins [autophagy-related protein 9 (ATG9), Ras-related protein Rab-1A (Rab1) and p62] was determined using western blot analysis. The interaction between miR-383 and PRDX3 was assessed using a dual-luciferase assay. The results indicated that both sh-PRDX3 and miR-383 mimics promoted apoptosis and increased the level of mitochondrial ROS, whilst acridine orange staining revealed that sh-PRDX3 promoted autophagy in U87 cells compared with that in the control cells. The detection of autophagic proteins indicated that sh-PRDX3 and miR-383 mimics increased the protein expression level of ATG9 and RAB1, and inhibited that of p62. On the contrary, the effect of miR-383 mimics was opposite to that of pre-PRDX3 in U87 cells. Reverse transcription-quantitative PCR and western blot assays revealed that miR-383 was negatively associated with PRDX3 in U87 cells. miR-383 was indicated to interact with PRDX3, as demonstrated using a dual-luciferase assay. In conclusion, the present study demonstrated that miR-383 induced cell apoptosis and mitochondrial ROS production by downregulating PRDX3 in U87 cells, thereby promoting oxidative stress-induced autophagy.

Clinical outcomes of dialysis patients with COVID-19 in the initial phase of the COVID-19 outbreak in Wuhan, China.

PURPOSE: Since the end of 2019, dialysis patients have been at risk of coronavirus disease 2019 (COVID-19) as well as other potential complications. Hence, we sought to describe the clinical characteristics of dialysis patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We reviewed clinical outcomes, which consisted of clinical data extracted from the medical records of 695 registered dialysis patients at the Dialysis Center of Central Hospital of Wuhan from January 13th, 2020, to February 29th, 2020, and performed statistical analysis. According to the results, there were 447, 227 and 21 hemodialysis (HD), peritoneal dialysis (PD) and combined HD and PD (HD&PD) cases, respectively. RESULTS: During the outbreak of COVID-19, 36 dialysis patients were infected by SARS-CoV-2. Among those 36 patients, 32 (7.2%) were on HD, and 4 (1.8%) were on PD. When comparing SARS-CoV-2 infection between HD and PD, the relative risk was 4.07 (RR = 4.07, 95% CI 1.46-11.35). We noted a median age of 66 years during the observation period, and the number of male patients was 23 (63.9%). There were 15 fatal cases tested positive for SARS-CoV-2 (13 cases on HD and 2 cases on PD). By comparing mortality in the same period of 2018, 2019 and 2020, the all-cause mortality of hemodialysis patients was significantly higher in 2020 (4.89%) than in either 2018 (2.55%) or 2019 (1.97%). There was no significant difference in mortality from all causes excluding COVID-19, during the same period among the 3-year period. However, during the COVID-19 outbreak, the mortality from all causes excluding COVID-19 was 2.73%, which was slightly higher than that from COVID-19 (2.16%). CONCLUSIONS: Although COVID-19 seriously threatens the health of people with uremia, deaths from all causes excluding COVID-19 during the epidemic cannot be ignored.

Clinical Characteristics and Immune Injury Mechanisms in 71 Patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a threat to global health. The mortality rate of severely ill patients in the early stage is 32.5%. The exacerbation of the condition and death of patients are closely associated with inflammatory cytokine storms, which are caused by excessive activation of the immune and complement systems as well as the coinfection of other pathogens. However, the immunological characteristics and the mechanisms underlying inflammatory storms have not been well elucidated. Here, we analyzed the clinical and immunological characteristics of 71 confirmed COVID-19 patients. Based on the National Health Commission of China (NHCC) guidelines, patients were stratified into mild and severe types. We compared the clinical and laboratory data obtained from electronic medical records between the two types. In regard to the hematological parameters, COVID-19 patients showed decreased erythrocyte count, hemoglobin, hematocrit, lymphocyte count, eosinophil count, and complement C1q, whereas neutrophils, C-reactive protein, and procalcitonin were significantly increased, especially in severe cases. We also found that CD3+ CD4+ T lymphocytes, CD3+ CD8+ T lymphocytes, CD19+ B lymphocytes, and CD16+ CD56+ NK cells in the peripheral blood of all patients were decreased. In addition, CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, and complement C1q in severely ill patients decreased more significantly. Additionally, interleukin 6 (IL-6) elevation was particularly prominent in all patients, especially in severe cases. These results suggest that CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6 may play critical roles in the inflammatory cytokine storm. The dysregulation of these aforementioned immune parameters, along with bacterial coinfection, were the important causes of exacerbation of the patients' condition and death. This study improves our understanding of the immune dysregulation of COVID-19 and provides potential immunotherapeutic strategies.IMPORTANCE The dysregulation of CD3+ CD8+ T lymphocytes, CD16+ CD56+ NK cells, C1q as well as IL-6, along with bacterial coinfection, were important causes of exacerbation of the patients' condition and death.

Uridine-cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer.

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine-cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor-associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.

ISO, via Upregulating MiR-137 Transcription, Inhibits GSK3ß-HSP70-MMP-2 Axis, Resulting in Attenuating Urothelial Cancer Invasion.

Our most recent studies demonstrate that miR-137 is downregulated in human bladder cancer (BC) tissues, while treatment of human BC cells with isorhapontigenin (ISO) elevates miR-137 abundance. Since ISO showed a strong inhibition of invasive BC formation in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced invasive BC mouse model, the elucidation of a potential biological effect of miR-137 on antagonizing BC invasion and molecular mechanisms underlying ISO upregulation of miR-137 are very important. Here we discovered that ectopic expression of miR-137 led to specific inhibition of BC invasion in human high-grade BC T24T and UMUC3 cells, while miR-137 deletion promoted the invasion of both cells, indicating the inhibitory effect of miR-137 on human BC invasion. Mechanistic studies revealed that ISO treatment induced miR-137 transcription by promoting c-Jun phosphorylation and, in turn, abolishing matrix metalloproteinase-2 (MMP-2) abundance and invasion in BC cells. Moreover, miR-137 was able to directly bind to the 3' UTR of Glycogen synthase kinase-3ß (GSK3ß) mRNA and inhibit GSK3ß protein translation, consequently leading to a reduction of heat shock protein-70 (HSP70) translation via targeting the mTOR/S6 axis. Collectively, our studies discover an unknown function of miR-137, directly targeting the 3' UTR of GSK3ß mRNA and, thereby, inhibiting GSK3ß protein translation, mTOR/S6 activation, and HSP70 protein translation and, consequently, attenuating HSP70-mediated MMP-2 expression and invasion in human BC cells. These novel discoveries provide a deep insight into understanding the biomedical significance of miR-137 downregulation in invasive human BCs and the anti-cancer effect of ISO treatment on mouse invasive BC formation.

XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell.

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP) is a well-known potent apoptosis suppressor and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. Anti-IAP therapy is reported to be closely related to epidermal growth factor receptor (EGFR) expression level. However, whether and how XIAP modulates EGFR expression remains largely unknown. METHODS: Human XIAP was knockdown with short-hairpin RNA in two different bladder cancer cell lines, T24T and UMUC3. Two XIAP mutants, XIAP ∆BIR (deletion of N-terminal three BIR domains) and XIAP ∆RING (deletion of C-terminal RING domain and keeping the function of BIR domains), were generated to determine which domain is involved in regulating EGFR. RESULTS: We found here that lacking of XIAP expression resulted in a remarkable suppression of EGFR expression, consequently leading to the deficiency of anchorage-independent cell growth. Further study demonstrated that BIR domain of XIAP was crucial for regulating the EGFR translation by suppressing the transcription and expression of miR-200a. Mechanistic studies indicated that BIR domain activated the protein phosphatase 2 (PP2A) activity by decreasing the phosphorylation of PP2A at Tyr307 in its catalytic subunit, PP2A-C. Such activated PP2A prevented the deviant phosphorylation and activation of MAPK kinases/MAPKs, their downstream effector c-Jun, and in turn inhibiting transcription of c-Jun-regulated the miR-200a. CONCLUSIONS: Our study uncovered a novel function of BIR domain of XIAP in regulating the EGFR translation, providing significant insight into the understanding of the XIAP overexpression in the cancer development and progression, further offering a new theoretical support for using XIAP BIR domain and EGFR as targets for cancer therapy.

Microsurgical Resection of Petroclival Tumors via the Subtemporal Transtentorial Approach.

AIM: To study and summarize our experience with the subtemporal transtentorial approach for resection of petroclival tumors. MATERIAL AND METHODS: Twenty-eight patients who suffered from petroclival tumors and underwent tumor resection via a subtemporal transtentorial approach between October 2010 and July 2013 were retrospectively reviewed. RESULTS: Total resection was performed in 22 cases, at a rate of 78.57%, subtotal resection in 5 cases, and large portion resection in 1 case. 13 patients who suffered from varying degrees of postoperative nerve dysfunction all improved or recovered, during the 6 to 24 month post-operative follow up. CONCLUSION: The subtemporal transtentorial approach is one of the best approaches for resection of petroclival tumors, especially for a tumor at the petrosal apex and upper-middle clival region, and has the advantages of less trauma, easy procedure of craniotomy, and also a good surgical exposure.

Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis.

Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1-FOXO1-MMP-2 axis. Cancer Prev Res; 9(7); 567-80. ©2016 AACR.