WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis.

BACKGROUND: Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed. METHODS: The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot. RESULTS: In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects. CONCLUSION: In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.

Establishment of a human induced pluripotent stem cell line from a patient with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in dozens of cardiac genes have been connected to the development of DCM including the Troponin T2 gene (TNNT2). Here, we generated a human induced pluripotent stem cells (hiPSCs) from a DCM patient with a familial history that carries a missense mutation in TNNT2. The hiPSCs show typical morphology of pluripotent stem cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.

Cryo-EM structure and functional analysis of the chromatin remodeler RSF.

The RSF complex belongs to the ISWI chromatin-remodeling family and is composed of two subunits: RSF1 (remodeling and spacing factor 1) and SNF2h (sucrose nonfermenting protein 2 homolog). The RSF complex participates in nucleosome spacing and assembly, and subsequently promotes nucleosome maturation. Although SNF2h has been extensively studied in the last few years, the structural and functional properties of the remodeler RSF1 still remain vague. Here, a cryo-EM structure of the RSF-nucleosome complex is reported. The 3D model shows a two-lobe architecture of RSF, and the structure of the RSF-nucleosome (flanked with linker DNA) complex shows that the RSF complex moves the DNA away from the histone octamer surface at the DNA-entry point. Additionally, a nucleosome-sliding assay and a restriction-enzyme accessibility assay show that the RSF1 subunit may cause changes in the chromatin-remodeling properties of SNF2h. As a `nucleosome ruler', the results of an RSF-dinucleosome binding affinity test led to the proposal that the critical distance that RSF `measures' between two nucleosomes is about 24 base pairs.

Proteomics and phosphoproteomics to study Tuina reverses capsule fibrosis in frozen shoulder: a research report based on rats.

Frozen shoulder (FS) is a common disorder often treated with Tuina, but the mechanisms involved remain unclear. We employed proteomics and phosphoproteomics to investigate the mechanisms associated with the treatment of capsule fibrosis in FS rats. We used a method composed of three weeks of cast immobilization to establish a model of FS. We then administered Tuina once daily for 14 days, evaluated glenohumeral range of motion (ROM), assessed histological changes, and identified differentially expressed proteins (DEPs) using proteomics and phosphoproteomics. This study demonstrated that Tuina could improve glenohumeral ROM and reserve capsule fibrosis in FS rats. Proteomics revealed proteins regulated by Tuina belonging to the PI3K-AKT and ECM receptor interaction signaling pathways. Phosphoproteomics detected differentially phosphorylated proteins regulated by Tuina to be enriched in the MAPK signaling pathway. The combination of proteomics and phosphoproteomics for Protein-Protein Interaction (PPI) network analysis revealed that the phosphorylation of Myh3 and Srsf1 with a node degree larger than the average degree were considered the central regulatory protein modulated by Tuina to reverse capsule fibrosis. Thbs1, Vtn, and Tenascin-W were significantly enriched in PI3K-AKT and ECM receptor interaction signaling pathways and highly expressed in model rats. Tuina resulted in reduced expression of these proteins. Our findings demonstrated some of mechanisms behind the reversal of FS capsule fibrosis following Tuina, a scientific medical therapy for FS patients.

Pro-osteogenic role of interleukin-22 in calcific aortic valve disease.

BACKGROUND AND AIMS: Although calcific aortic valve disease (CAVD) is a common valvular disease among elderly populations and its incidence has markedly increased in recent decades, the pathogenesis of CAVD remains unclear. In this study, we explored the potential role of interleukin (IL)-22 and the underlying molecular mechanism in CAVD. METHODS AND RESULTS: Our results showed that IL-22 was upregulated in calcific aortic valves from CAVD patients, and its main sources were CD3+ T cells and CD68+ macrophages. Human aortic valve interstitial cells (VICs) expressed the IL-22-specific receptor IL-22R1, and IL-22R1 expression also was elevated in calcified valves. Treatment of cultured human VICs with recombinant human IL-22 resulted in markedly increased expression of osteogenic proteins Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), as well as increased matrix calcium deposition. Moreover, siRNA silencing of IL-22R1 blocked the pro-osteogenic effect of IL-22 in VICs. In IL-22-treated VICs, we also observed increased phosphorylation of JAK3 and STAT3 and nuclear translocation of STAT3. Pretreatment with a specific JAK3 inhibitor, WHIP-154, or siRNA knockout of STAT3 effectively mitigated the IL-22-induced osteoblastic trans-differentiation of human VICs. CONCLUSIONS: Together, these data indicate that IL-22 promotes osteogenic differentiation of VICs by activating JAK3/STAT3 signaling. Based on our results demonstrating a pro-osteogenic role of IL-22 in human aortic valves, pharmacological inhibition of IL-22 signaling may represent a potential strategy for alleviating CAVD.

The creation and validation of predictive models to assess the risk of unfavorable outcomes following hybrid total arch repair for Stanford type A aortic dissection.

BACKGROUND: The objective of this study was to develop and validate a nomogram for the individualized prediction of adverse events in patients with Stanford type A aortic dissection (TAAD) undergoing hybrid total aortic arch repair. METHODS: From April 2019 to April 2022, we conducted a comprehensive review of the medical records of Stanford type A aortic dissection patients who underwent hybrid total aortic arch repair surgery at our hospital. Patients were separated into two groups based on whether or not a composite adverse event occurred following surgery. Using univariate and multivariate analyses of logistic regression, the prediction model was created. Construct risk prediction models utilizing nomograms and evaluate their precision, discrimination, and clinical utility. RESULTS: Age, platelets, serum blood urea nitrogen, and ascending aortic diameter were the variables included in the nomogram by univariate and multivariate analysis. The risk model performed well in internal validation, with an area under the curve (AUC) of 0.829. The calibration curve demonstrated good agreement between predicted and actual probabilities (Hosmer-Lemeshow test, P = 0.22). Clinical decision analysis curves demonstrate predictive nomograms' clinical utility. CONCLUSION: This study created and validated a nomogram for predicting the risk of composite endpoint events in TAAD patients undergoing hybrid total aortic arch repair. The nomogram can help determine the severity of a patient's condition and provide a more personalized diagnosis and treatment.

RNase H-Driven crRNA Switch Circuits for Rapid and Sensitive Detection of Various Analytical Targets.

The clustered regularly interspaced short palindromic repeats (CRISPR/Cas12a) system has exhibited great promise in the rapid and sensitive molecular diagnostics for its trans-cleavage property. However, most CRISPR/Cas system-based detection methods are designed for nucleic acids and require target preamplification to improve sensitivity and detection limits. Here, we propose a generic crRNA switch circuit-regulated CRISPR/Cas sensor for the sensitive detection of various targets. The crRNA switch is engineered and designed in a blocked state but can be activated in the presence of triggers, which are target-induced association DNA to initiate the trans-cleavage activity of Cas12a for signal reporting. Additionally, RNase H is introduced to specifically hydrolyze RNA duplexed with the DNA trigger, resulting in the regeneration of the trigger to activate more crRNA switches. Such a combination provides a generic and sensitive strategy for the effective sensing of the p53 sequence, thrombin, and adenosine triphosphate. The design is incorporated with nucleic acid nanotechnology and extensively broadens the application scope of the CRISPR technology in biosensing.

Universal DNA-Based Sensing Toolbox for Programming Cell Functions.

By recombining natural cell signaling systems and further reprogramming cell functions, use of genetically engineered cells and bacteria as therapies is an innovative emerging concept. However, the inherent properties and structures of the natural signal sensing and response pathways constrain further development. We present a universal DNA-based sensing toolbox on the cell surface to endow new signal sensing abilities for cells, control cell states, and reprogram multiple cell functions. The sensing toolbox contains a triangular-prismatic-shaped DNA origami framework and a sensing core anchored inside the internal confined space to enhance the specificity and efficacy of the toolbox. As a proof of principle, the sensing toolbox uses the customizable sensing core with signal sensing switches and converters to recognize unconventional signal inputs, deliver functional components to cells, and then control cell responses, including specific tumor cell death, immune cell disinhibition and adhesion, and bacterial expression. This work expands the diversity of cell sensing signals and reprograms biological functions by constructing nanomechanical-natural hybrid cells, providing new strategies for engineering cells and bacteria in diagnosis and treatment applications.

Structural genomics of the human dopamine receptor system.

The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration.

BACKGROUND: Copper homeostasis is associated with malignant biological behavior in various tumors. The excessive accumulation of copper can induce tumor death, which is named cuproptosis, and it is also closely related to tumor progression and the formation of the immune microenvironment. However, the associations of cuproptosis with glioblastoma (GBM) prognosis and microenvironment construction are poorly understood. METHOD: First, TCGA and GEO (GSE83300, GSE74187) merged datasets were used to analyze the association of cuproptosis-related genes (CRGs) with GBM. Then, we performed cluster analysis of CRGs in GBM from the GEO (GSE83300, GSE74187) and TCGA merged datasets. Subsequently, the prognostic risk model was constructed by least absolute shrinkage and selection operator (LASSO) according to gene expression features in CRG clusters. Next, we performed a series of in-depth analyses, including tumor mutational burden (TMB) analysis, cluster analysis, and GBM IDH status prediction. Finally, RARRES2 was identified as a target gene for GBM treatment, especially IDH wild-type GBM. In addition, we further analyzed the correlation of CRG clusters and RARRES2 expression with the GBM immune microenvironment by ESTIMATE and CIBERSORT analyses. In vitro experiments were conducted to demonstrate that targeting RARRES2 inhibits glioblastoma progression and macrophage infiltration, particularly IDH wild-type GBM. RESULTS: In the present study, we demonstrated that the CRG cluster was closely related to GBM prognosis and immune cell infiltration. Moreover, the prognostic risk model constructed with the three genes (MMP19, G0S2, RARRES2) associated with the CRG clusters could well evaluate the prognosis and immune cell infiltration in GBM. Subsequently, after further analyzing the tumor mutational burden (TMB) in GBM, we confirmed that RARRES2 in the prognostic risk model could be used as a crucial gene signature to predict the prognosis, immune cell infiltration and IDH status of GBM patients. CONCLUSION: This study fully revealed the potential clinical impact of CRGs on GBM prognosis and the microenvironment, and determined the effect of the crucial gene (RARRES2) on the prognosis and tumor microenvironment construction of GBM, meanwhile, our study also revealed over-expressed RARRES2 is related to the IDH satus of GBM, which provides a novel strategy for the treatment of GBM, particularly IDH wild-type GBM.

Sam68 promotes osteogenic differentiation of aortic valvular interstitial cells by TNF-α/STAT3/autophagy axis.

Calcified aortic valve disease (CAVD) is a major non-rheumatic heart valve disease in the world, with a high mortality rate and without suitable pharmaceutical therapy due to its complex mechanisms. Src-associated in mitosis 68-KD (Sam68), an RNA binding protein, has been reported as a signaling adaptor in numerous signaling pathways (Huot in Mol Cell Biol, 29(7), 1933-1943, 2009), particularly in inflammatory signaling pathways. The effects of Sam68 on the osteogenic differentiation process of hVICs and its regulation on signal transducer and activator of transcription 3 (STAT3) signaling pathway have been investigated in this study. Human aortic valve samples detection found that Sam68 expression was up-regulated in human calcific aortic valves. We used tumor necrosis factor α (TNF-α) as an activator for osteogenic differentiation in vitro and the result indicated that Sam68 was highly expressed after TNF-α stimulation. Overexpression of Sam68 promoted osteogenic differentiation of hVICs while Sam68 knockdown reversed this effect. Sam68 interaction with STAT3 was predicted by using String database and was verified in this study. Sam68 knockdown reduced phosphorylation of STAT3 activated by TNF-α and the downstream gene expression, which further influenced autophagy flux in hVICs. STAT3 knockdown alleviated the osteogenic differentiation and calcium deposition promoted by Sam68 overexpression. In conclusion, Sam68 interacts with STAT3 and participates in its phosphorylation to promote osteogenic differentiation of hVICs to induce valve calcification. Thus, Sam68 may be a new therapeutic target for CAVD. Regulatory of Sam68 in TNF-α/STAT3/Autophagy Axis in promoting osteogenesis of hVICs.

Adenovirus-IL-10 relieves chronic rejection after mouse heart transplantation by inhibiting miR-155 and activating SOCS5.

Objective: Chronic rejection remains the main factor that influence long-term survival of patients after heart transplantation. Interleukin-10 (IL-10) play critical role in macrophages-mediated transplant immune responses. We investigated the mechanism of IL-10 in macrophage related chronic rejection after mouse heart transplantation. Methods: Mouse heart transplant chronic rejection model was established to evaluate pathological changes in the allograft. Myocardial interstitial fibrosis, apoptosis, and inflammatory factor levels were detected in ad-IL-10-treated mice. The positive iNOS+ and Arg-1+ expressions, macrophage subset changes, and the proportion of regulatory T-cells (Tregs) and TIGIT+ Tregs were quantified by flow. In in vitro experiments, ad-IL-10 was transfected into macrophages followed by detection of apoptosis, phagocytosis, and CD163, CD16/32, and CD206 expression. The expression and relationships between IL-10, miR-155, and SOCS5 were also detected and verified. A rescue experiment was performed to evaluate macrophage function through the combined treatment of ad-IL-10 and overexpression of miR-155. Results: Significantly decreased IL-10 expression in chronic rejection during mouse heart transplantation was observed. Ad-IL-10-treated mice showed decreased pathological injury, perivascular fibrosis, apoptosis, inflammation, and iNOS+ and CD16/32+ expression, and increased Treg/TIGIT+ Treg cell, Arg-1+ and CD206+ cell proportion. Ad-IL-10-treated macrophages in vitro showed reduced apoptosis, improved phagocytosis, and M2 polarization. Mechanically, IL-10 negatively regulated miR-155 to activate SOCS5. Overexpression of miR-155 reversed IL-10 mediated-positive regulation of macrophage function. Conclusion: IL-10 downregulated miR-155 and activated SOCS5, thereby promoting macrophage M2 polarization to relieve chronic rejection after heart transplantation.

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation.

Intravascular transplantation of human-induced pluripotent stem cells (hiPSCs) demonstrated a significant therapeutic effect in the treatment of restenosis by the paracrine function of extracellular vesicles (EVs). However, the risk of tumorigenicity and poor cell survival limits its clinical applications. In this study, we for the first time applied a highly efficient and robust three-dimensional (3D) protocol for hiPSC differentiation into endothelial cells (ECs) with subsequent isolation of EVs from the derived hiPSC-EC (ECs differentiated from hiPSCs), and validated their therapeutic effect in intimal hyperplasia (IH) models. We found that intravenously (iv) injected EVs could accumulate on the carotid artery endothelium and significantly alleviate the intimal thickening induced by the carotid artery ligation. To elucidate the mechanism of this endothelial protection, we performed miRNA expression profiling and found out that among the most conserved endothelial miRNAs, miR-126 was the most abundant in hiPSC-EC-produced EVs (hiPSC-EC-EV). MiR-126 depletion from hiPSC-EC-EV can hinder its protective effect on human umbilical vein endothelial cells (HUVECs) in an inflammatory process. A variety of functional in vitro studies revealed that miR-126 was able to prevent endothelial apoptosis after inflammatory stimulation, as well as promote EC migration and tube formation through autophagy upregulation. The latter was supported by in vivo studies demonstrating that treatment with hiPSC-EC-EV can upregulate autophagy in mouse carotid artery ECs, thereby preventing IH and modulating vascular homeostasis via remodeling of the vascular intima. Our findings suggest a regulatory mechanism for the therapeutic effect on arterial restenosis by autophagy regulation, and provide a potential strategy for clinical treatment of the disease.

Nano-Biohybrid DNA Engager That Reprograms the T-Cell Receptor.

Although engineered T cells with transgenic chimeric antigen receptors (CARs) have made a breakthrough in cancer therapeutics, this approach still faces many challenges in the specificity, efficacy, and self-safety of genetic engineering. Here, we developed a nano-biohybrid DNA engager-reprogrammed T-cell receptor (EN-TCR) system to improve the specificity and efficacy, mitigate the excessive activation, and shield against risks from transgenesis, thus achieving a diversiform and precise control of the T-cell response. Utilizing modular assembly, the EN-TCR system can graft different specificities on T cells via antibody assembly. Besides, the designability of DNA hybridization enables precise target recognition by the library of multiantigen cell recognition circuits and allows gradual tuning of the T-cell activation level by the signaling switch and independent control over different types of T cells. Furthermore, we demonstrated the effectiveness of the system in tumor models. Together, this study provides a nongenetic T-cell engineering strategy to overcome major hindrances in T-cell therapy and may be extended to a general and convenient cell engineering strategy.

Prosthesis Selection for Aortic Valve Replacement With Concomitant Coronary Artery Bypass Grafting.

BACKGROUND: The optimal prosthesis for aortic valve replacement (AVR) with concomitant coronary artery bypass grafting (CABG) is controversial. We investigated postoperative outcomes in these patients with a biological prosthesis or mechanical prosthesis. METHODS: A retrospective cohort analysis was performed of 2485 patients aged 50 to 69 years who underwent AVR+CABG in Hubei province hospitals from 2002 to 2018. The median follow-up duration was 6.5 years (interquartile range, 0-15.8 years). Propensity score matching for 18 baseline characteristics yielded 346 patient pairs between bioprosthetic and mechanical prosthetic groups. End points were death, stroke, major bleeding event, and reoperation. RESULTS: No differences in survival, stroke, or overall reoperation rates were observed between the bioprosthetic and mechanical valve groups. The 15-year cumulative incidence of reoperation due to prosthesis failure/dysfunction was higher in the bioprosthetic group (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.26-5.88; P = .011), whereas the 15-year cumulative incidence of reoperation due to coronary artery disease progression/bypass failure was similar between 2 groups (HR, 0.76; 95% CI, 0.37-1.57; P = .459). Mechanical valves were associated with a higher 15-year cumulative incidence of major bleeding events compared with bioprosthetic valves (HR, 1.92; 95% CI, 1.16-3.19; P = .012). CONCLUSIONS: Long-term survival, overall reoperation, or stroke incidence was comparable among the 2 groups, while patients with a mechanical valve showed a greater likelihood of major bleeding events. Regarding the limited durability of bioprosthetic valves, a larger sample size monitored for 15 or more years will be necessary to determine the optimal aortic valve prosthesis for patients aged 50 to 69 years undergoing concurrent AVR and CABG.

The impact of particulate matter 2.5 on the risk of hepatocellular carcinoma: a meta-analysis.

OBJECTIVE: The convoluted element of PM2.5 may cause various biological reactions. Nowadays, few studies have indicated the long-term health effects of PM2.5 on HCC. Therefore, this meta-analysis first aims to obtain more precise estimates of the effects of PM2.5 exposure on HCC to assess the strength of the evidence. METHODS: A combination of computer and manual retrieval was used to search in Medline through PubMed, EMBASE and Web of Science. Review Manager 5.3 software was used to examine the heterogeneity among the studies. RESULTS: Finally, 8 qualified articles meet the inclusion criteria. The results were I2 = 0%, P > 0.1 indicating that there was no heterogeneity. The results showed that the concentration of PM2.5 increased by 10 µg/m3 was significantly correlated with liver cancer, and HR was 1.22 (95% CI 1.14-1.30, P < 0.05), indicating that maternal exposure to PM2.5 was positively correlated with liver cancer. CONCLUSIONS: Our meta-analysis showed that the patients with HCC significance related to PM2.5 exposure. However, more studies investigating the combined effects of different air pollutants on HCC incidence are warranted to provide more comprehensive evidence for assessing the different levels impacts of PM2.5 exposure on HCC incidence.

Integrated analysis about the effects of heat stress on physiological responses and energy metabolism in Gymnocypris chilianensis.

The temperature of the rivers in the Qilian Mountains, China varies widely from day to night, and Gymnocypris chilianensis living in these rivers may experience a change of 10 °C to 20 °C within a day. To explore the mechanisms underlying G. chilianensis responses to heat stress, we conducted an acute temperature stress experiment. In response to heat stress, levels of antioxidant enzymes (SOD\CAT\MDA) first increased and then decreased with time, but T-AOC levels only decreased. The activities of key glycolytic enzymes HK and PFK in the liver also first increased and then decreased and transaminase (AST/ALT) activity increased significantly. We obtained 5350 significantly different genes through transcriptome sequencing with enrichment pathways including primarily glycine, serine and threonine metabolism, cysteine and methionine metabolism, tryptophan metabolism, fructose and mannose metabolism, steroid hormone biosynthesis, and fatty acid degradation. A total of 457 differential metabolites were identified in the liver under thermal stress, most of which are involved in biochemical pathways of amino acid metabolism. Biosynthesis of amino acids indicated that G. chilianensis maintained physiological homeostasis by enhancing glucose metabolism and regulating lipid and amino acid metabolism pathways under thermal stress. We also randomly selected 12 key response genes for validation using qRT-PCR. This is the first study describing the mechanisms underlying responses to thermal stress in G. chilianensis, and may also provide reference data for the study of environmental mutations in indigenous fish in the Qinghai-Tibet Plateau and Qilian Mountains.

Successful Surgical Treatment of a Giant Left Coronary Artery Aneurysm with Fistula.

Coronary artery aneurysm (CAA) is an aortic catastrophe with low prevalence. Giant CAA is even more uncommon, requiring surgical intervention. Giant CAA usually originates from the proximal segments of the right coronary and the anterior descending arteries. Here we report a rare case of giant left CAA with fistula formation treated with successful surgery.

A Modified Hypothermic Circulatory Arrest Technique Improves Early and Near-Midterm Results in Patients with Acute Type A Aortic Dissection.

BACKGROUND: The hypothermic circulatory arrest (HCA) is an indispensable step in the surgical treatment of an acute type A aortic dissection (ATAAD), which could greatly affect the postoperative outcome. We modified the HCA technique and validated the feasibility and superiority of the new approach relative to the conventional method. METHODS AND RESULTS: Eighty-eight patients with ATAAD were enrolled in this study between May 2016 and April 2018. Of those, 36 patients in the Conventional treatment group had circulatory arrest at 25°C for about 16-28 minutes, while 52 patients in the Modification group underwent a circulatory arrest at 28°C for only 1-3 minutes. The preoperative clinical data and postoperative clinical outcomes were compared between the two groups. No intraoperative mortality occurred in any of the cases. No significant differences were observed in the aortic cross-clamp times during the cardiopulmonary bypass (CPB) between the two groups. In the Modification group, several indicators, such as mechanical ventilation time, postoperative 48-h drainage volume, blood transfusion volume, the ICU-stay time and postoperative hospital stay, were reduced significantly as compared with those in the Conventional group. Whereas three postoperative deaths in the hospital occurred in the Conventional treatment group, all the patients in the Modification group were cured. There is no difference in the incidence of postoperative complications between the two groups. The patients had a 100% follow up with a mean of 17 ± 6 months. CONCLUSIONS: A moderate hypothermia with a short circulatory arrest is a safe and effective HCA approach that provides satisfactory early and near-midterm results in the patients who received ATAAD treatment.

The role of ferroptosis in breast cancer patients: a comprehensive analysis.

Breast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygen species (ROS). We constructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes were extracted. KEGG function analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1, and TP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low-risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25, and IDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study. From the online database, we identified novel ferroptosis-related biomarkers for breast cancer prognosis. The findings of this study provide new insights into the development of new reliable and accurate cancer treatment options.