Insights into the prognostic value and immunological role of CD74 in pan-cancer.

BACKGROUND: CD74 is a non-polymorphic type II transmembrane glycoprotein. It is involved in the regulation of T and B cell development, and dendritic cell (DC) motility. Numerous studies have found that CD74 exerts an essential role in tumor immunity, but the expression profile of CD74 is still not systematically reported, and its value in human pan-cancer analysis is unknown. In this study, we analyzed the expression pattern of CD74 in 33 cancers, and evaluated the significance of CD74 in prognosis prediction and cancer immunity. METHODS: Pan-cancer dataset from UCSC Xena.We used the Sangerbox website combined with R software' Timer, CIBERSORT method and IOBR package to analyze and plot the data. Survival was assessed using the Kaplan-Meier method and log-rank test for 33 cancer types (p < 0.05). In addition, to explore the relationship between CD74 expression and immune checkpoints, immune cell infiltration, tumor mutational burden (TMB) and microsatellite instability (MSI), Spearman correlation analysis was performed. RESULTS: This study comprehensively analyzed CD74 expression in 33 different tumor types, revealing that CD74 play an crucial role in cancer formation and development. CONCLUSIONS: CD74 gene expression in different cancers is associated with immune cell infiltration and immunomodulators and may provide a promising target for survival and immunotherapy. Our study shows that CD74 has an essential role as a biomarker of prognosis during tumor development, which highlights the possibility of new targeted therapies.

Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice. / 电针"四白"和"颧髎"æ¿€æ´»å°é¼ èº¯ä½“æ„Ÿè§‰è¿åŠ¨çš®å±‚çš„å ´å¥‹æ€§ç¥žç»å ƒ.

OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis.

Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.

Spatiotemporal observations of host-pathogen interactions in mucosa during SARS-CoV-2 infection indicate a protective role of ILC2s.

IMPORTANCE: Our study revealed the spatial interaction between humanized ACE2 and pseudovirus expressing Spike, emphasizing the role of type 2 innate lymphoid cells during the initial phase of viral infection. These findings provide a foundation for the development of mucosal vaccines and other treatment approaches for both pre- and post-infection management of coronavirus disease 2019.

CircularRNA Hsa_circ_0093335 promotes hepatocellular carcinoma progression via sponging miR-338-5p.

Circular RNAs play an important role in the development of various malignancies, including hepatocellular carcinoma (HCC). Nevertheless, the role of Hsa_circ_0093335 (circ0093335) in HCC has not yet been explored. To investigate the biological effects and molecular mechanisms of circ0093335 on HCC. Circ0093335 expression was detected in HCC cells and clinical specimens using qRT-PCR. The association between circ0093335 expression and HCC patients' clinical characteristics was determined using SPSS. The role of circ0093335 in HCC was estimated by overexpression and knockdown experiments in vitro and in vivo. qRT-PCR, nucleoplasma separation assay, FISH assay, RIP, dual luciferase reporter assay and rescue assay were used to validate the regulatory effect of circ0093335 on miR-338-5p. The study findings showed that circ0093335 was upregulated in HCC. High circ0093335 expression was linked with the tumour-node-metastasis stage and microvascular tumour invasion. circ0093335 is greatly involved in HCC cell proliferation, aggressive ability and mouse tumour growth, according to many in vitro and in vivo tests. Mechanistically, circ0093335 downregulated miR-338-5p expression by sponging, consequently promoting HCC progression. Our research indicated that circ0093335 might be a target for HCC therapy since it promotes tumour progression by acting as a miR-338-5p 'sponge'.

Comprehensive analysis of N1-methylandenosine regulators and m1A-related mRNAs and lncRNAs as prognostic factors in bladder cancer.

Bladder cancer (BC) is a lethal malignancy and recurs frequently. m1A plays a vital role in maintaining the biological functions of non-coding RNAs. The Cancer Genome Atlas (TCGA) is a free website from where transcriptome data of BC were obtained. We chose m1A methylation regulators for this study. Six m1A methylation regulator genes have a higher expression in BC tissue compared to normal tissue. The aberrant expression of those m1A regulator genes was remarkably related to BC prognosis and clinicopathological features. First, m1A-related mRNAs and long noncoding RNAs (lncRNAs) were identified. Next, univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were performed to get the optimum RNAs for the development of prognostic signatures. Also, a nomogram with T status, lncRNA risk scores and mRNA risk scores was constructed. It revealed an adequate capacity to predict the overall survival of BC cases in the training set as well as in the testing set and in the total TCGA cohort. In conclusion, m1A methylation regulator genes played an important role in predicting the overall survival of BC patients. In addition, m1A-related lncRNAs and mRNAs illustrated underlying mechanisms of tumorigenesis and development of BC.

microRNA-1-3p and T-synthase mRNA have high diagnostic efficacy on intestinal mucosal barrier dysfunction in patients with severe acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can be complicated by intestinal mucosal barrier dysfunction (SAP&IBD). The current study sought to examine the diagnostic efficacy of miR-1-3p and T-synthase mRNA in SAP&IBD patients. First, SAP patients were assigned to SAP&IBD and SAP groups. Serum miR-1-3p expression and T-synthase mRNA expression patterns in peripheral blood B lymphocytes were measured using RT-qPCR. Pearson tests, ROC curve analysis, and multivariate logistic regression were used to analyze the correlation between miR-1-3p/T-synthase mRNA and clinical data, their diagnostic efficiency, and independent risk factors for SAP&IBD patients, respectively. The results showed that serum miR-1-3p in the SAP&IBD group was elevated, and T-synthase mRNA expression in peripheral blood B lymphocytes was diminished. Additionally, serum miR-1-3p expression in SAP&IBD patients was negatively correlated with T-synthase mRNA expression, and positively correlated with their Ranson score, CRP, IL-6, DAO, and D-Lactate levels. Meanwhile, T-synthase mRNA level was negatively correlated with IL-6, DAO, and D-Lactate levels. Both, serum miR-1-3p, T-synthase mRNA, and their combination were found to exhibit diagnostic efficiency for SAP&IBD patients, and were independently associated with IBD in SAP patients. Collectively, our findings suggest that miR-1-3p and T-synthase serve as independent risk factors for SAP&IBD patients and can aid the diagnosis of IBD in SAP patients.

Secukinumab alleviates cognitive impairment by attenuating oxidative stress and neuronal apoptosis via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis.

BACKGROUND: Septic-associated encephalopathy (SAE) is a critical manifestation of sepsis that leads to long-term cognitive impairment. Interleukin (IL)-17A has been shown to mediate neuronal apoptosis in central nervous system diseases, while oxidative stress has been found to have a detrimental effect in SAE. However, the relationship between IL-17A and oxidative stress in SAE remains unclear. This study aimed to investigate the effects of secukinumab on alleviating cognitive impairment in a rat model of sepsis, as well as examine its underlying molecular mechanism of action. METHODS: A total of 282 male 8-week-old Sprague-Dawley rats were randomly subjected to cecal ligation and puncture (CLP) or sham treatment followed by volume resuscitation immediately after surgery. Secukinumab was administered intranasally 1 h post-CLP. Rats were given the p-ERK activator ceramide C6 intracerebroventricularly (i.c.v) 24 h before CLP surgery. Recombinant rIL-17A was administered i.c.v. at 0 h in naive rats, followed by intraperitoneal injection of the AKT inhibitor GDC0068 1 h post-rIL-17A injection. Clinical scores, body weight, and survival rate were assessed. In addition, immunofluorescence staining, neurobehavioral tests, Nissl staining, and western blotting were performed. Cognitive function was assessed 15-20 days post-CLP using the Morris water maze test. RESULTS: IL-17A and IL-17RA protein expression levels in the rat hippocampus increased and peaked 24 h post-CLP. Furthermore, IL-17RA was found to be expressed in neurons. The survival rate after CLP was 50%. Following CLP, an increased clinical score and significant decrease in body weight were observed. However, treatment with secukinumab led to a decrease in the clinical score of rats 24 h post-CLP. CLP resulted in spatial and memory impairment and anxiety-like behaviors in rats, while secukinumab treatment significantly alleviated cognitive impairment compared to the CLP group (p < 0.05). In addition, oxidative stress and neuronal apoptosis were found to be increased in the CLP group, while secukinumab significantly reduced oxidative stress and neuronal apoptosis in the hippocampus following CLP. Furthermore, secukinumab treatment led to a significant decrease in the protein expression levels of p-AKT, p-ERK1/2, Romo1, and Bax, together with increased Bcl-2 protein expression. Finally, treatment with ceramide C6 and GDC0068 abolished the neuroprotective effects of secukinumab post-CLP. CONCLUSION: Our results demonstrated that secukinumab attenuated oxidative stress and neuronal apoptosis and partially ameliorated cognitive impairment via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis. Thus, secukinumab may be a potential therapeutic strategy for septic patients.

The Association of Long-Term Use of Proton Pump Inhibitors and Histamine H2 Receptor Antagonists with Clinical Complications in Patients with Severe Sepsis.

Objective: Proton pump inhibitors (PPIs) are commonly used to treat gastric acidity, and their frequent use may trigger various malfunctioning, such as cardiac, renal, and liver function failure. In the current study, we evaluated the association between the excessive use of the PPIs and the clinical complications of intensive care unit (ICU) septic patients. Methods: A total of 208188 patients were analyzed from 2016 to 2017 through the China Critical Care Sepsis Trial (CCCST) database. The characteristics of the study group and outcome of events from the PPI- and H2 blocker-using groups were reported. To get unbiased results, the data from the target trials were randomly assigned for PPI and H2 blocker groups. Result: The data revealed 43.34 excess deaths (95% confidence intensive (CI) 25.12 to 62.02) per 1000 patients in patients extensively consuming PPI drugs. The sepsis with chronic kidney disease attributed to deaths 21.36; 95% CI (9.34 to 23.23). However, comorbidities, including circulatory diseases (16.34; 95% CI 5.78 to 23.45), nervous system (2.08; 95% CI 1.56 to 6.34), mental disorders (1.87; 95% CI 1.65 to 2.95), genitourinary system (5.23; 95% CI 3.69 to 8.89), and infectious and parasitic disease (4.17; 95% CI 1.44 to 7.49), were also reported. Extensive use of the PPIs and H2 blockers was associated with esophageal adenocarcinoma, Barrett's esophagus, neoplasms, and GI cancers. Conclusion: We conclude that the excessive use of PPI in sepsis patients triggers chronic kidney disease which has a higher clinical complication rate among others.

Cerebral venous sinus thrombosis in a patient with Klebsiella pneumoniae primary liver abscess: a case report.

BACKGROUND: Liver abscess is a common emergency in the emergency department. However, cerebral venous sinus thrombosis (CVST) is a rare and serious cerebrovascular disease. Cases of CVST in patients with Klebsiella pneumoniae primary liver abscess (KLA) have not been described in the literature. We report a case of CVST in patients with KLA. CASE PRESENTATION: A 54-year-old male patient came to our department with a fever for 2 days and altered mental status for 1 day. Abdominal computed tomography (CT) and liver magnetic resonance imaging (MRI) revealed multiple liver abscesses. The blood culture was identified as Klebsiella pneumoniae sepsis. Head contrast-enhanced MRI and magnetic resonance venography (MRV) imaging showed multiple thrombus formation in the right transverse sinus and sigmoid sinus. The patient's infection and thrombosis were controlled within one week of multidisciplinary comprehensive treatment such as antibiotic and antithrombotic therapy, and a good clinical recovery during the 1-month follow-up. CONCLUSION: CVST after liver abscess is rare, clinicians should be aware of this complication and vigilant for the possibility of bacterial meningitis. The underlying mechanisms need to be further studied.

Disseminated coccidioidomycosis in immunocompetent patients in non-endemic areas: a case series and literature review.

Coccidioidomycosis is caused by the dimorphic fungi Coccidioides species which is endemic in the Western hemisphere. Reports on the characteristics of travel-related disseminated coccidioidomycosis in immunocompetent patients are rare, especially in non-endemic regions. The multifaceted symptoms of this condition present a diagnostic challenge to clinicians. This study aimed to review immunocompetent patients diagnosed with disseminated coccidioidomycosis in a tertiary hospital in Eastern China and other non-endemic areas, and to emphasize the importance of combining travel history with clinical manifestations and proper diagnostic examinations. This study retrospectively reviewed a case series of disseminated coccidioidomycosis diagnosed in an academic hospital in Eastern China. We conducted a global literature review of disseminated coccidioidomycosis in immunocompetent patients with travel history. We identified six patients in our case series and reviewed 42 cases in the literature. Travel history included Mexico, Arizona, California, and regions of low endemicity. Extrapulmonary sites of infection, which presented with diverse signs and symptoms, involved the skin and soft tissue, musculoskeletal system, lymph nodes, and central nervous system. Misdiagnoses and diagnostic delays were common. Next-generation sequencing substantially promoted precise diagnosis in our series. The overall prognosis for immunocompetent individuals was positive, mainly benefited from long-term azole therapies. The patients that succumbed had either central nervous system involvement or multiorgan dissemination. Progressive pneumonia with varied symptoms and travel history should alert healthcare professionals in non-endemic areas to consider the possibility of Coccidioides species infection. We recommend detailed history-taking and hypothesis-free detection of pathogens for cases with diagnostic delay.

Clinical risk score for early prediction of recurring SARS-CoV-2 positivity in non-critical patients.

Introduction: Recurrent positive results in quantitative reverse transcriptase-PCR (qRT-PCR) tests have been commonly observed in COVID-19 patients. We aimed to construct and validate a reliable risk stratification tool for early predictions of non-critical COVID-19 survivors' risk of getting tested re-positive within 30 days. Methods: We enrolled and retrospectively analyzed the demographic data and clinical characters of 23,145 laboratory-confirmed cases with non-critical COVID-19. Participants were followed for 30 days and randomly allocated to either a training (60%) or a validation (40%) cohort. Multivariate logistic regression models were employed to identify possible risk factors with the SARS-CoV-2 recurrent positivity and then incorporated into the nomogram. Results: The study showed that the overall proportion of re-positive cases within 30 days of the last negative test was 24.1%. In the training cohort, significantly contributing variables associated with the 30-day re-positivity were clinical type, COVID-19 vaccination status, myalgia, headache, admission time, and first negative conversion, which were integrated to build a nomogram and subsequently translate these scores into an online publicly available risk calculator (https://anananan1.shinyapps.io/DynNomapp2/). The AUC in the training cohort was 0.719 [95% confidence interval (CI), 0.712-0.727] with a sensitivity of 66.52% (95% CI, 65.73-67.30) and a specificity of 67.74% (95% CI, 66.97-68.52). A significant AUC of 0.716 (95% CI, 0.706-0.725) was obtained for the validation cohort with a sensitivity of 62.29% (95% CI, 61.30-63.28) and a specificity of 71.26% (95% CI, 70.34-72.18). The calibration curve exhibited a good coherence between the actual observation and predicted outcomes. Conclusion: The risk model can help identify and take proper management in high-risk individuals toward the containment of the pandemic in the community.

Elevated Serum Tenascin-C Predicts Mortality in Critically Ill Patients With Multiple Organ Dysfunction.

Background: Multiple organ dysfunction is a complex and lethal clinical feature with heterogeneous causes and is usually characterized by tissue injury of multiple organs. Tenascin-C (TNC) is a matricellular protein that is rarely expressed in most of the adult tissues, but re-induced following injury. This study aimed to evaluate serum TNC in predicting mortality in critically ill patients with multiple organ dysfunction. Methods: Adult critically ill patients with at least two organs dysfunction and an increase of Sequential Organ Failure Assess (SOFA) score ≥ 2 points within 7 days were prospectively enrolled into two independent cohorts. The emergency (derivation) cohort was a consecutive series and the patients were from Emergency Department. The inpatient (validation) cohort was a convenience series and the patients were from medical wards. Their serum samples at the first 24 h after enrollment were collected and subjected to TNC measurement using ELISA. The association between serum TNC level and 28-day all-cause mortality was investigated, and then the predictive value of serum TNC was analyzed. Results: A total of 110 patients with a median age of 64 years (53, 73) were enrolled in the emergency cohort. Compared to the survivors, serum TNC in the non-survivors was significantly higher (467.7 vs. 197.5 ng/ml, p < 0.001). Multivariate logistic regression analysis revealed that the association between serum TNC and 28-day mortality was independent of sepsis or critical illness scores such as SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), and Simplified Acute Physiology Score (SAPS II), respectively (p < 0.001 for each). The area under receiver operating characteristic curve of serum TNC for predicting mortality was 0.803 (0.717-0.888) (p < 0.001), similar with SOFA 0.808 (0.725-0.891), APACHE II 0.762 (0.667-0.857), and SAPS II 0.779 (0.685-0.872). The optimal cut-off value of serum TNC was 298.2 ng/ml. Kaplan-Meier analysis showed that the survival of patients with serum TNC ≥ 300 ng/ml was significantly worse than that of patients with serum TNC < 300 ng/ml. This result was validated in the inpatient cohort. The sensitivity and specificity of serum TNC ≥ 300 ng/ml for predicting mortality were 74.3 and 74.7% in the emergency cohort, and 63.0 and 70.1% in the inpatient cohort, respectively. Conclusion: Serum TNC was associated with mortality in critically ill patients with multiple organ dysfunction, and would be used as a prognostic tool for predicting mortality in this population.

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma.

The burden of hepatocellular carcinoma (HCC) worldwide is increasing over time, while the underlying molecular mechanism of HCC development is still under exploration. Pseudogenes are classified as a special type of long non-coding RNAs (lncRNAs), and they played a vital role in regulating tumor-associated gene expression. Here, we report that a pseudogene peptidylprolyl isomerase A pseudogene 22 (PPIAP22) and its parental gene peptidylprolyl isomerase A (PPIA) were upregulated in HCC and were associated with the clinical outcomes of HCC. Further investigation revealed that PPIAP22 might upregulate the expression of PPIA through sponging microRNA (miR)-197-3p, behaving as competing endogenous RNA (ceRNA). PPIA could participate in the development of HCC by regulating mRNA metabolic process and tumor immunity based on the functional enrichment analysis. We also found a strong correlation between the expression levels of PPIA and the immune cell infiltration or the expression of chemokines, especially macrophage, C-C motif chemokine ligand 15 (CCL15), and C-X-C motif chemokine ligand 12 (CXCL12). Our findings demonstrate that the PPIAP22/miR-197-3p/PPIA axis plays a vital role in the progression of HCC by increasing the malignancy of tumor cells and regulating the immune cell infiltration, especially macrophage, through CCL15-CCR1 or CXCL12-CXCR4/CXCR7 pathways.

Association of coagulation dysfunction with cardiac injury among hospitalized patients with COVID-19.

Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46-65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.

STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib.

BACKGROUND: Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC. METHODS: STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo. RESULTS: Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy. CONCLUSIONS: Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.

Surface electrocardiographic characteristics in coronavirus disease 2019: repolarization abnormalities associated with cardiac involvement.

AIMS: The coronavirus disease 2019 (COVID-19) has spread rapidly around the globe, causing significant morbidity and mortality. This study aims to describe electrocardiographic (ECG) characteristics of COVID-19 patients and to identify ECG parameters that are associated with cardiac involvement. METHODS AND RESULTS: The study included patients who were hospitalized with COVID-19 diagnosis and had cardiac biomarker assessments and simultaneous 12-lead surface ECGs. Sixty-three hospitalized patients (median 53 [inter-quartile range, 43-65] years, 76.2% male) were enrolled, including patients with (n = 23) and without (n = 40) cardiac injury. Patients with cardiac injury were older, had more pre-existing co-morbidities, and had higher mortality than those without cardiac injury. They also had prolonged QTc intervals and more T wave changes. Logistic regression model identified that the number of abnormal T waves (odds ratio (OR), 2.36 [95% confidence interval (CI), 1.38-4.04], P = 0.002) and QTc interval (OR, 1.31 [95% CI, 1.03-1.66], P = 0.027) were independent indicators for cardiac injury. The combination model of these two parameters along with age could well discriminate cardiac injury (area the under curve 0.881, P < 0.001) by receiver operating characteristic analysis. Cox regression model identified that the presence of T wave changes was an independent predictor of mortality (hazard ratio, 3.57 [1.40, 9.11], P = 0.008) after adjustment for age. CONCLUSIONS: In COVID-19 patients, presence of cardiac injury at admission is associated with poor clinical outcomes. Repolarization abnormalities on surface ECG such as abnormal T waves and prolonged QTc intervals are more common in patients with cardiac involvement and can help in further risk stratification.

miR-155 facilitates calcium oxalate crystal-induced HK-2 cell injury via targeting PI3K associated autophagy.

Nephrolithiasis is one of the most common and highly recurrent diseases worldwide. Accumulating evidence revealed the elevated miR-155 levels both in serum and urine of nephrolithiasis patients. The aim of our research was to explore the role of miR-155 in CaOx-induced apoptosis in HK-2 cells. The expression levels of miR-155 in serum and renal tissues were quantified in 20 patients with nephrolithiasis using qRT-PCR assay. ELISA was performed to determine urinary levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha (TNF-α). Renal tubular cell model of CaOx nephrolithiasis was established to investigate the role and molelular mechanism of miR-155. Cell viability and apoptosis were assessed by MTT and flow cytometry, respectively. Immunofluoresent staining of LC3 autophagosome and western blotting were performed to evaluate the autophagic activity. Luciferase reporter assay was employed to verify the interaction between miR-155 and PI3KCA/Rheb. PI3K/Akt/mTOR signaling was further examined by western blotting. Serum and renal levels of miR-155 and inflammatory factors were significantly elevated in nephrolithiasis patients than in controls. CaOx treatment caused up-regulation of miR-155 and induced autophagy in renal tubular epithelial cells, while silencing miR-155 or inhibition of autophagy by 3-metheladenine (3-MA) ameliorated CaOx crystal-induced cell injury. PI3KCA and Rheb was identified as downstream targets of miR-155. Moreover, miR-155 activates autophagy and promotes cell injury through repressing PI3K/Akt/mTOR signaling pathway. Taken together, these findings demonstrated that miR-155 facilitates CaOx crystal-induced renal tubular epithelial cell injury via PI3K/Akt/mTOR-mediated autophagy, providing therapeutic targets for ameliorating cellular damage by CaOx crystals.

Single Percutaneous Tract Combined with Flexible Nephroscopy in the Management of Kidney Stones 2-4 cm: Better Options of Treatment Protocols.

PURPOSE: To investigate the safety and efficacy of single percutaneous tract combined with flexible nephroscopy in the Management of 2-4 cm renal calculi. MATERIALS AND METHODS: We retrospectively analysed the treatment data of patients with 2-4 cm renal calculi from June 2010 to June 2017. The data included 217 cases of percutaneous nephrolithotomy (PNL), 441 cases of retrograde intrarenal surgery (RIRS) and 217 cases of single-access percutaneous nephrolithotomy combined with flexible nephroscopy (PNCFN). The collected data were analyzed. RESULTS: A total of 875 cases were studied, with an average age of 42.35 ± 10.29 years. Group PNCFN showed the highest stone-free rates (SFRs)(73.7 vs 66.7 vs 80.2, P = .00), best patient satisfaction (89.84 vs 87.23 vs 92.29, P = .00). The length of stay was shorter in the RIRS group relative to the other two groups (5.22 vs 5.65 vs 3.72, P = .00). Haemoglobin decrease (> 10 g/L) was higher in group PNL than that in group RIRS and group PNCFN (P = .012). Hospitalization fees (RMB) were Increased in group PNCFN compared with that in group PNL and group RIRS (34563.45 vs 21334.69 vs 33343.16, P = .000). Treatment protocols of PNL decreased from 17.51% to 9.22%, those for RIRS from 5.22% to 17.69%, peaking at 2012, PNCFN from 8.29% to 15.67% showed a rapid growth trend. CONCLUSION: The percutaneous nephrolithotomy combined with flexible nephroscopy treatment on renal calculi of 2-4 cm was associated with higher stone-free rates and better patient satisfaction than RIRS and PNL.