Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience.

Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

Tumefactive Demyelination Lesions: Report on three cases.

PURPOSE: Tumefactive demyelination (TD) lesion and its subtype Balo's concentric sclerosis (BCS), are rare manifestations of central nervous system demyelinating disease. Because of its rarity, physicians might hesitate in reaching a diagnosis or initiating steroid pulse therapy. This study aims at pinpointing the key neuroimaging features to distinguish TD lesions from surgical conditions, and illustrating the clinical outcomes of patients with TD lesions. CASE REPORT: Two of the three patients had solitary TD lesions, one 47-year-old man presenting with newly onset seizure and another 54-year-old women suffering from progressive hemiparesis. The male patient underwent craniotomy for mass excision without further steroid therapy, while the female patient received methylprednisolone pulse therapy only. Both patients remained free of clinical and radiological relapses over the past 6-7 years, leading to the diagnosis of clinically isolated syndrome. The third case is a 30-year-old woman with subacute onset of dysarthria and hemiparesis. She had two BCS lesions along with other demyelinating lesions in the juxtacortical and periventricular regions, cerebellar peduncles, and spinal cord, fulfilling dissemination in time and space. Her neurological deficits resolved after pulse therapy, and she received long-term disease modifying therapy for multiple sclerosis. CONCLUSION: This study underscores the diverse neuroimaging and clinical presentations of patients with TD lesions, and emphasizes the importance of clinical vigilance regarding this rare condition.

Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis.

Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

Histone Lysine Methylation Modification and Its Role in Vascular Calcification.

Histone methylation is an epigenetic change mediated by histone methyltransferase, and has been connected to the beginning and progression of several diseases. The most common ailments that affect the elderly are cardiovascular and cerebrovascular disorders. They are the leading causes of death, and their incidence is linked to vascular calcification (VC). The key mechanism of VC is the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes, which is a highly adjustable process involving a variety of complex pathophysiological processes, such as metabolic abnormalities, apoptosis, oxidative stress and signalling pathways. Many researchers have investigated the mechanism of VC and related targets for the prevention and treatment of cardiovascular and cerebrovascular diseases. Their findings revealed that histone lysine methylation modification may play a key role in the various stages of VC. As a result, a thorough examination of the role and mechanism of lysine methylation modification in physiological and pathological states is critical, not only for identifying specific molecular markers of VC and new therapeutic targets, but also for directing the development of new related drugs. Finally, we provide this review to discover the association between histone methylation modification and VC, as well as diverse approaches with which to investigate the pathophysiology of VC and prospective treatment possibilities.

The crosstalk between endothelial cells and vascular smooth muscle cells aggravates high phosphorus-induced arterial calcification.

Arterial calcification is highly prevalent, particularly in patients with end-stage renal disease (ESRD). The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is the critical process for the development of arterial calcification. However, the detailed mechanism of VSMCs calcification remains to be elucidated. Here, we investigated the role of exosomes (Exos) derived from endothelial cells (ECs) in arterial calcification and its potential mechanisms in ESRD. Accelerated VSMCs calcification was observed when VSMCs were exposed to ECs culture media stimulated by uremic serum or high concentration of inorganic phosphate (3.5 mM Pi). and the pro-calcification effect of the ECs culture media was attenuated by exosome depletion. Exosomes derived from high concentrations of inorganic phosphate-induced ECs (ECsHPi-Exos) could be uptaken by VSMCs and promoted VSMCs calcification. Microarray analysis showed that miR-670-3p was dramatically increased in ECsHPi-Exos compared with exosomes derived from normal concentrations of inorganic phosphate (0.9 mM Pi) induced ECs (ECsNPi-Exos). Mechanistically, insulin-like growth factor 1 (IGF-1) was identified as the downstream target of miR-670-3p in regulating VSMCs calcification. Notably, ECs-specific knock-in of miR-670-3p of the 5/6 nephrectomy with a high-phosphate diet (miR-670-3pEC-KI + NTP) mice that upregulated the level of miR-670-3p in artery tissues and significantly increased artery calcification. Finally, we validated that the level of circulation of plasma exosomal miR-670-3p was much higher in patients with ESRD compared with healthy controls. Elevated levels of plasma exosomal miR-670-3p were associated with a decline in IGF-1 and more severe artery calcification in patients with ESRD. Collectively, these findings suggested that ECs-derived exosomal miR-670-3p could promote arterial calcification by targeting IGF-1, which may serve as a potential therapeutic target for arterial calcification in ESRD patients.

Cellular Crosstalk in the Vascular Wall Microenvironment: The Role of Exosomes in Vascular Calcification.

Vascular calcification is prevalent in aging, diabetes, chronic kidney disease, cardiovascular disease, and certain genetic disorders. However, the pathogenesis of vascular calcification is not well-understood. It has been progressively recognized that vascular calcification depends on the bidirectional interactions between vascular cells and their microenvironment. Exosomes are an essential bridge to mediate crosstalk between cells and organisms, and thus they have attracted increased research attention in recent years. Accumulating evidence has indicated that exosomes play an important role in cardiovascular disease, especially in vascular calcification. In this review, we introduce vascular biology and focus on the crosstalk between the different vessel layers and how their interplay controls the process of vascular calcification.

Efficacy and safety of AnluoHuaxian pills on chronic hepatitis B with normal or minimally elevated alanine transaminase and early liver fibrosis: A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: The AnluoHuaxian pill (AHP) is a widely used patented medicine for chronic hepatitis B (CHB) patients with advanced fibrosis or cirrhosis that has been used in China for more than 15 years. However, data are lacking on whether monotherapy with AHP can be effective in CHB patients with alanine aminotransferase (ALT) levels less than 2 times the upper limit of normal (ALT<2ULN) and early liver fibrosis (F ≤ 2). AIM OF THE STUDY: We aimed to investigate whether monotherapy with AHP improves liver histology in these patients. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 270 CHB patients with ALT<2ULN and F ≤ 2 were treated in 12 hospitals in China. The patients were randomly assigned to an intervention (AHP) group and a placebo group at a ratio of 2:1. Of these 270 enrolled patients, 147 had paired liver biopsies. The primary end point was histological change after 48 weeks of treatment. RESULTS: Per-protocol analysis revealed that the rate of histologic improvement in liver fibrosis patients in the AHP group was significantly higher than that in the placebo group (37.7% vs. 19.5%, P = 0.035) after 48 weeks of treatment, which was consistent with results from intention-to-treat and sensitivity analyses. Moreover, after adjusting for baseline characteristics, AHP was superior to placebo with respect to improving liver fibrosis (odds ratio [OR] = 2.58, 95% confidence interval [CI]: (1.01, 6.63),P = 0.049) and liver histology (OR = 3.62, 95% CI: (1.42, 9.20),P = 0.007). In noninvasive measurement of liver fibrosis (FibroScan®), the level of liver stiffness measurement (LSM) had decreased significantly at 48 weeks (5.1 kPa) compared with that at baseline (5.7 kPa) (P = 0.008) in the AHP group, whereas it did not decrease significantly in the placebo group. Cirrhosis developed in one patient in the placebo group but in no patients in the AHP group. No serious side effects occurred in the AHP-treated patients. CONCLUSIONS: Treatment of CHB patients who had ALT<2ULN and F ≤ 2 with the traditional Chinese medicine AHP for 48 weeks improves liver fibrosis. However, due to the short duration of treatment and the limited sample size of liver pathology, the long-term benefits of AHP in reducing fibrosis and the risk of cirrhosis and hepatocellular carcinoma in these patients need to be further studied in the future.

Propensity-matched comparison of balloon-expandable and self-expanding valves for transcatheter aortic valve replacement in a Chinese population.

Background: Balloon-expandable valves (BEV) and self-expanding valves (SEV) for transcatheter aortic valve replacement (TAVR) have shown promising results in Western populations. Herein, we comparatively evaluated their hemodynamics and early clinical outcomes in a Chinese population. Methods: One hundred seventy-eight patients with symptomatic aortic stenosis who had undergone transfemoral TAVR using SEV (n=153; Venus-A, 97; VitaFlow, 56) or BEV (n=25; Sapien3) from September 2020 to April 2021 were retrospectively enrolled, and 25 pairs were propensity-score matched for 10 baseline variables. The primary study outcomes were aortic valve hemodynamics and postoperative complications at discharge and 3-month follow-up. Results: TAVR was successful in all patients. Compared with SEV group, the BEV group had similarly distributed baseline characteristics, procedural time, hospital stay, new pacemaker implantation, and paravalvular regurgitation grade. We also observed that the BEV group had lower rates of balloon pre-dilation (60% vs. 92%, P=0.018), post-dilation (0 vs. 20%, P=0.050) and second valve implantation (0 vs. 24%, P=0.022); higher mean transaortic gradient (14.3±6.1 vs. 10.8±4.9, P=0.030) and proportion of patients with elevated gradients (20% vs. 0, P=0.050) at discharge; and similar rehospitalization, mean transaortic gradient, new pacemaker implantation, and paravalvular regurgitation grade than the SEV group at the 3-month follow-up. There were no deaths in either group. However, the proportion of patients with elevated gradients in SEV group was higher at 3 months than before discharge (24% vs. 0, P=0.022). Conclusions: BEV and SEV for transfemoral TAVR appear comparably safe and effective, with high device success and favorable 3-month clinical outcomes. However, the transaortic gradient and new pacemaker implantation in the SEV group increased during follow-up, warranting larger studies with longer-term follow-up.

MiR-125b enhances autophagic flux to improve septic cardiomyopathy via targeting STAT3/HMGB1.

We explore the role of miR-125b in septic cardiomyopathy, focusing on miR-125b/STAT3/HMGB1 axis. CLP mouse model and LPS-stimulated primary rat cardiomyocytes (CMs) and H9C2 cell were used as in vivo and in vitro models of septic cardiomyopathy, respectively. qRT-PCR and western blot were performed to measure expression levels of miR-125b, STAT3, HMGB1, and autophagy-related proteins. MTT assay was employed to examine LPS toxicity. Dual luciferase activity assay and CHIP were performed to validate interactions of miR-125b/STAT3 and STAT3/HMGB1 promoter. Immunostaining was used to assess the level of autophagic flux. ROS level was measured by fluorescence assay. Heart functions were examined via intracoronary Doppler ultrasound. miR-125b was diminished while STAT3 and HMGB1 were elevated in the heart tissue following CLP surgery and in LPS-treated H9C2 cells. LPS treatment up-regulated ROS generation and suppressed autophagic flux. Overexpression of miR-125b mimics or knockdown of STAT3 or HMGB1 alleviated LPS-induced hindrance of autophagic flux and ROS production. miR-125b directly targeted STAT3 mRNA and STAT3 bound with HMGB1 promoter. Overexpression of miR-125b mitigated myocardial dysfunction induced by CLP in vivo. Hyperactivation of STAT3/HMGB1 caused by reduced miR-125b contributes to ROS generation and the hindrance of autophagic flux during septic cardiomyopathy, leading to myocardial dysfunction.

The Controversial Role of Irisin in Clinical Management of Coronary Heart Disease.

Irisin, a PGC1α-dependent myokine, was once believed to have beneficial effects induced by exercise. Since its first discovery of adipose browning in 2012, multiple studies have been trying to explore the metabolic functions of irisin, such as glucose and lipid metabolism. However, recently many studies with irisin concentration measuring were doubt for methodological problems, which may account for the continuous inconsistencies. New tools like recombinant irisin and gene-knockout mice are required to reconfirm the questioned functions of irisin. In this paper, we make a critical introduction to the latest researches concerning the relationship between irisin and coronary heart disease, which includes atherosclerosis, stable angina pectoris and acute coronary syndromes. These studies provided various controversial evidence of short and long-term monitoring and therapeutic effect from molecular cellular mechanisms, in vivo experiments and epidemiological investigation. But with ambiguities, irisin still has a long way to go to identify its functions in the clinical management.

Development of Machine Learning Models for Prediction of Osteoporosis from Clinical Health Examination Data.

Osteoporosis is treatable but often overlooked in clinical practice. We aimed to construct prediction models with machine learning algorithms to serve as screening tools for osteoporosis in adults over fifty years old. Additionally, we also compared the performance of newly developed models with traditional prediction models. Data were acquired from community-dwelling participants enrolled in health checkup programs at a medical center in Taiwan. A total of 3053 men and 2929 women were included. Models were constructed for men and women separately with artificial neural network (ANN), support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), and logistic regression (LoR) to predict the presence of osteoporosis. Area under receiver operating characteristic curve (AUROC) was used to compare the performance of the models. We achieved AUROC of 0.837, 0.840, 0.843, 0.821, 0.827 in men, and 0.781, 0.807, 0.811, 0.767, 0.772 in women, for ANN, SVM, RF, KNN, and LoR models, respectively. The ANN, SVM, RF, and LoR models in men, and the ANN, SVM, and RF models in women performed significantly better than the traditional Osteoporosis Self-Assessment Tool for Asians (OSTA) model. We have demonstrated that machine learning algorithms improve the performance of screening for osteoporosis. By incorporating the models in clinical practice, patients could potentially benefit from earlier diagnosis and treatment of osteoporosis.

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

Ferroptosis is classified as an iron-dependent form of regulated cell death (RCD) attributed to the accumulation of lipid hydroperoxides and redox imbalance. In recent years, accumulating researches have suggested that ferroptosis may play a vital role in the development of diverse metabolic diseases, for example, diabetes and its complications (e.g., diabetic nephropathy, diabetic cardiomyopathy, diabetic myocardial ischemia/reperfusion injury and atherosclerosis [AS]), metabolic bone disease and adrenal injury. However, the specific physiopathological mechanism and precise therapeutic effect is still not clear. In this review, we summarized recent advances about the development of ferroptosis, focused on its potential character as the therapeutic target in metabolic diseases, and put forward our insights on this topic, largely to offer some help to forecast further directions.

PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks.

The unfolded protein response (UPR) plays important roles in various cells that have a high demand for protein folding, which are involved in the process of cell differentiation and development. Here, we separately knocked down the three sensors of the UPR in myoblasts and found that PERK knockdown led to a marked transformation in myoblasts from a fusiform to a rounded morphology, which suggests that PERK is required for early myoblast differentiation. Interestingly, knocking down PERK induced reprogramming of C2C12 myoblasts into stem-like cells by altering the miRNA networks associated with differentiation and stemness maintenance, and the PERK-ATF4 signaling pathway transactivated muscle differentiation-associated miRNAs in the early stage of myoblast differentiation. Furthermore, we identified Ppp1cc as a direct target gene of miR-128 regulated by the PERK signaling pathway and showed that its repression is critical for a feedback loop that regulates the activity of UPR-associated signaling pathways, leading to cell migration, cell fusion, endoplasmic reticulum expansion, and myotube formation during myoblast differentiation. Subsequently, we found that the RNA-binding protein ARPP21, encoded by the host gene of miR-128-2, antagonized miR-128 activity by competing with it to bind to the 3' untranslated region (UTR) of Ppp1cc to maintain the balance of the differentiation state. Together, these results reveal the crucial role of PERK signaling in myoblast maintenance and differentiation and identify the mechanism underlying the role of UPR signaling as a major regulator of miRNA networks during early differentiation of myoblasts.

A novel double-balloon catheter for percutaneous balloon pulmonary valvuloplasty under echocardiographic guidance only.

BACKGROUND: Percutaneous balloon pulmonary valvuloplasty (PBPV) is the procedure of choice for uncomplicated severe or symptomatic pulmonary stenosis. Echocardiography (echo)-guided PBPV can completely avoid the use of radiation and contrast agents compared to fluoroscopy-guided PBPV. Although we have confirmed that echo-guided PBPV is feasible in humans, the poor visibility of the traditional catheter under echo greatly limits the promotion of this new technology. METHODS: We produced a novel double-balloon catheter to make the catheter easy to be detected by echo through adding a guiding balloon at the distal end of the catheter. Echo-guided PBPV was performed on thirty healthy swine using either a novel catheter or a traditional catheter to evaluate the feasibility and safety of the novel double-balloon catheter. The feasibility was evaluated by the success rate of balloon inflation at the pulmonary valve annulus and the operating time. The safety was evaluated by the frequency of balloon slippage and the incidence of complications. RESULTS: There were no significant between-group differences in terms of weight and the ratio of balloon diameter to pulmonary annulus diameter. The success rate was 93.3% and 60% in the novel and traditional groups, respectively. The novel group had significantly (p<0.05) lower mean procedure time (6.33±6.86min vs 24.8±9.79min) and lower frequency of balloon slippage (0.07±0.26 vs 0.53±0.52), arrhythmia (0.07±0.26 vs 0.47±0.52), and tricuspid regurgitation (6.7% vs 40%) than the traditional group. No myocardial hematoma or pericardial tamponade occurred in the novel catheter group. CONCLUSION: Although further studies and improvements are required, the study results indicate that the novel double-balloon catheter for echo-guided PBPV is feasible and safe.

Decreased Expression of NUSAP1 Predicts Poor Overall Survival in Cervical Cancer.

Background: Nucleolar and spindle-associated protein 1 (NUSAP1) was previously reported to be associated with poor prognosis in multiple cancers. In the present study, we comprehensively investigated the clinicopathological features and potential prognostic value of NUSAP1 in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods: The expression profiles of the genes were extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Cancer Cell Line Encyclopedia (CCLE), Gene Expression Profiling Interactive Analysis (GEPIA), and The Human Protein Atlas databases. The association between clinicopathological characteristics and NUSAP1 was analyzed using logistic regression in TCGA patients and receiver operating characteristic (ROC) curve analysis for GSE7803, GSE9750, and GSE63514 datasets. The prognostic value of NUSAP1 in TCGA patients was evaluated using the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. Results: A total of 68 differentially expressed genes (DEGs) were identified in CESC. ROC analysis of NUSAP1 suggested that the area under the ROC curve was 0.968. Kaplan-Meier survival analysis indicated that CESC with low expression of NUSAP1 has a worse prognosis than CESC with high NUSAP1 expression (P = 0.005). The logistic regression revealed that low NUSAP1 expression in CESC was related to advanced tumor stage in TCGA database. Moreover, Cox regression analysis showed that NUSAP1 expression correlated significantly with prognosis in the case of patients in TCGA database. GSEA demonstrated that CESC patients with high expression of NUSAP1 were enriched in the G2M checkpoint, MYC targets, and breast cancer ZNF217. Conclusion: The results suggest that identification of DEGs might enhance our understanding of the causes and molecular mechanisms underlying the development of CESC. Moreover, NUSAP1 may play an important role in CESC progression and prognosis and may serve as a valuable indicator of poor survival in CESC.

Multicenter Comparison of Percutaneous and Surgical Pulmonary Valve Replacement in Large RVOT.

BACKGROUND: A percutaneous approach for pulmonary valve replacement (PVR) is a feasible alternative to surgical PVR in selected patients with severe pulmonary regurgitation after repair of tetralogy of Fallot. However, large right ventricular outflow tract (diameter ≥ 25 mm) remains challenging. METHODS: This retrospective multicenter study enrolled consecutive patients with large right ventricular outflow tract who underwent percutaneous PVR (Venus P-valve, Venus MedTech Inc, Hangzhou, China) (n = 35) or surgical PVR (homograft valve; n = 30) between May 2014 and April 2017. Patients were followed up at 1, 3, 6, and 12 months, and yearly thereafter. Main study outcomes were pulmonary valve function and right ventricular function at discharge and midterm follow-up. RESULTS: PVR was successful in all patients. Percutaneous compared with surgical PVR group had: similarly distributed baseline characteristics; shorter hospitalization, intensive care unit stay, and endotracheal intubation duration; lower cost; lower pulmonary valve gradient before discharge; lower pulmonary valve regurgitant grade (mean difference, -0.63; 95% CI -1.11 to -0.20, P = .022), pulmonary valve gradient (mean difference, -5.7 mm Hg; 95% CI -9.4 to -2.2 mm Hg, P = .005), and right ventricular end-diastolic volume index (mean difference, -9.5 mL/m2; 95% CI -16.9 to -3.1 mL/m2, P = .022); and greater right ventricular ejection fraction (mean difference, 5.4%; 95% CI 2.4%-8.3%, P = .002) at median 36 months follow-up, without deaths in either group. CONCLUSIONS: Percutaneous PVR using Venus P-valve appeared to be a safe, efficacious and minimally invasive alternative to surgical PVR in selected patients with large right ventricular outflow tract yielding better right ventricular and pulmonary valve function at midterm follow-up.

Low dose of flurbiprofen axetil decrease the rate of acute kidney injury after operation: a retrospective clinical data analysis of 9915 cases.

BACKGROUND: Flurbiprofen axetil (FA) is a commonly prescribed agent to relieve perioperative pain, but the relationship between FA and postoperative acute kidney injury (AKI) remains unclear. This study attempted to evaluate the effects of different dose of perioperative FA on postoperative AKI. METHODS: A total of 9915 patients were enrolled for this retrospective study. The clinical characteristics and the prevalence of postoperative AKI among patients non-using, using low dose (50-100 mg), middle dose (100-250 mg) and large dose (≧250 mg) of FA were analyzed respectively. The impact of different dose of FA on postoperative AKI was analyzed using univariable and multivariate logistic regression analysis. RESULTS: The prevalence of postoperative AKI was 6.7% in the overall subjects and 5.1% in 2446 cases who used FA. The incidence of AKI in low dose group was significantly less than that of non use group (4.5% vs 7.2%, P < 0.001), but the incidence of AKI in large dose group was significantly higher than that in the non-use group (18.8% vs 7.2%, P < 0.001). However, there was no significant difference between patients without using FA and subjects using middle dose of FA (7.2% vs 5.6%, p = 0.355). Multivariate logistic regression analysis showed that low dose of FA was a protective factor for postoperative AKI (OR = 0.75, p = 0.0188), and large dose of FA was a risk factor for postoperative AKI (OR = 4.8, p < 0.0001). CONCLUSIONS: The impact of FA on postoperative AKI was dose-dependent, using of low dose FA (50-100 mg) perioperatively may effectively reduce the incidence of postoperative AKI.

Multi-omics Analysis of Microenvironment Characteristics and Immune Escape Mechanisms of Hepatocellular Carcinoma.

The immune environment in primary tumor has a profound impact on immunotherapy. However, the clinical relevance of immune environment in hepatocellular carcinoma (HCC) is largely unknown. Here, the immune profile and its clinical response in HCC were investigated. The gene expression profiles of 569 HCCs from three cohorts (The Cancer Genome Atlas, TCGA, n = 257; Gene Expression Omnibus, GEO, n = 170; International Cancer Genome Consortium, ICGC, n = 142) were used in the current study. Five gene expression subtypes (C1-C5) responsible for global immune genes were identified in HCCs at stage I/II. It was found that subtype C4 was associated with upregulation and subtype C5 was associated with downregulation of immune profiles in most metagenes. Immune-correlation analysis of the five subtypes demonstrated that C3 and C4 had higher immune score and better prognostic outcome, as compared with other subtypes. Moreover, the mutation frequencies of TP53, CTNNB1, and AXIN1 had significant difference in the five subgroups. Further, the expression of PDCD1, CD274, PDCD1LG2, CTLA4, CD86, and CD80 was higher in subtype C4 in comparison with the other subtypes. The WGCNA of immune-related genes in the five subtypes revealed that blue and turquoise modules were positively correlated with subtype C4 and were associated with 12 common pathways in the KEGG database. These results were validated in external cohorts from the NCI (National Cancer Institute) cohort (GSE14520) and the ICGC (International Cancer Genome Consortium) cohort. In summary, one immune-enhanced subtype and one immune-decreased subtype having different immune and clinical characteristics may provide guidance for developing novel treatment strategies for immune system malfunction-related cancer.

Clinical Prognostic Significance of HOXC9 Expression in Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) involves the abnormal expression of a set of genetic and epigenetic genes, which may be useful for predicting prognosis. The transcription factor homeobox C9 (HOXC9) is a member of the homeobox family and participates in diverse cellular metabolic processes. In the current study, the prognostic value of HOXC9 in CRC was evaluated by analyzing public data from The Cancer Genome Atlas. METHODS: The correlation between clinical features and HOXC9 expression levels was evaluated by logistic regression. Kaplan-Meier and Cox regression was performed to determine the association between HOXC9 expression and patient prognosis. Gene set enrichment analysis was conducted to explore the function of HOXC9 in CRC. RESULTS: HOXC9 showed higher expression in tumor tissue than in normal tissue. An increased level of HOXC9 in CRC was notably associated with an advanced tumor stage (OR = 1.58, for stage I/II vs. stage III/IV, p = 0.037), increased risk of distant metastasis (odds ratio = 1.84, for T1/T2 vs. T3/T4, p = 0.025), and tendency for venous invasion (OR = 2.25, p = 0.003). Kaplan-Meier analysis revealed that higher HOXC9 levels were predictive of poor overall (p = 0.0083) and progression-free survival (p = 0.0014). Multivariate COX regression model analysis proved that HOXC9 was independently associated with overall survival (hazard ratio = 2.88, 95% confidence interval: 1.14 - 7.29, p = 0.025). Gene set enrichment analysis showed that several biological function symbols were particularly enriched in the increased HOXC9 phenotype. CONCLUSIONS: HOXC9 may play a critical role in CRC progression and serve as a novel potential marker of poor prognosis in CRC.

Percutaneous closure of patent foramen ovale under transthoracic echocardiography guidance-midterm results.

BACKGROUND: Conventional percutaneous closure of patent foramen ovale (PFO) is usually performed under the guidance of fluoroscopy. Whether closure of PFO under transthoracic echocardiography (TTE) guidance only is safe and effective is unknown. The present study therefore aimed to assess the safety and efficacy of percutaneous closure of PFO under TTE guidance only. METHODS: This study retrospectively enrolled a total of 52 consecutive patients (55.8% male, mean age 34.0±13.0 years, range, 10-59 years) with PFO treated at our institution from June 2015 to September 2017 by percutaneous closure under echocardiographic guidance only. The patients mean body weight was 58.7±10.8 kg. Patients underwent follow-up by TTE immediately post procedure by electrocardiogram and TTE at 1, 3, 6 and 12 months after discharge and annually thereafter, and by clinical evaluation at all time points. RESULTS: Of the 52 patients, 47 (90.4%) were successfully treated by percutaneous closure under TTE guidance. The mean procedure duration (from puncture to sheath removal) was 21.0±6.2 (range, 11-33) minutes. A trivial residual shunt which disappeared 24 hours later was observed in only 1 (1.9%) patient immediately post procedure. Median hospital stay was 3.0 days without severe complications such as peripheral vascular injury or cardiac perforation at discharge. At median 15.5 (11.3, 18.0) months follow-up, there were no complications such as death, stroke, transient ischemic attack (TIA) and residual shunt. CONCLUSIONS: In this single center study of mostly lean patients, percutaneous closure of PFO under TTE guidance as the only imaging tool appeared effective at midterm follow-up, while avoiding radiation exposure, endotracheal intubation and contrast agent use.