Identification of 4 autophagy-related genes in heart failure by bioinformatics analysis and machine learning.

Introduction: Autophagy refers to the process of breaking down and recycling damaged or unnecessary components within a cell to maintain cellular homeostasis. Heart failure (HF) is a severe medical condition that poses a serious threat to the patient's life. Autophagy is known to play a pivotal role in the pathogenesis of HF. However, our understanding of the specific mechanisms involved remains incomplete. Here, we identify autophagy-related genes (ARGs) associated with HF, which we believe will contribute to further comprehending the pathogenesis of HF. Methods: By searching the GEO (Gene Expression Omnibus) database, we found the GSE57338 dataset, which was related to HF. ARGs were obtained from the HADb and HAMdb databases. Annotation of GO and enrichment analysis of KEGG pathway were carried out on the differentially expressed ARGs (AR-DEGs). We employed machine learning algorithms to conduct a thorough screening of significant genes and validated these genes by analyzing external dataset GSE76701 and conducting mouse models experimentation. At last, immune infiltration analysis was conducted, target drugs were screened and a TF regulatory network was constructed. Results: Through processing the dataset with R language, we obtained a total of 442 DEGs. Additionally, we retrieved 803 ARGs from the database. The intersection of these two sets resulted in 15 AR-DEGs. Upon performing functional enrichment analysis, it was discovered that these genes exhibited significant enrichment in domains related to "regulation of cell growth", "icosatetraenoic acid binding", and "IL-17 signaling pathway". After screening and verification, we ultimately identified 4 key genes. Finally, an analysis of immune infiltration illustrated significant discrepancies in 16 distinct types of immune cells between the HF and control group and up to 194 potential drugs and 16 TFs were identified based on the key genes. Discussion: In this study, TPCN1, MAP2K1, S100A9, and CD38 were considered as key autophagy-related genes in HF. With these relevant data, further exploration of the molecular mechanisms of autophagy in HF can be carried out.

Short- and long-term outcomes of laparoscopic versus open gastrectomy after neoadjuvant chemotherapy: A case-control study using a propensity score matching method.

Background: Neoadjuvant chemotherapy (NACT) is increasingly becoming the recommended treatment for locally advanced gastric cancer (LAGC) with promising results. According to previous reports, few studies have evaluated the benefits of laparoscopic gastrectomy (LG) after NACT. Methods: 135 patients from our center who underwent gastrectomy with NACT were available, including 41 patients of LG and 94 OG between July 2018 and July 2022. To reduce selection bias, we used the nearest neighbor method and set caliper = 0.2 for 3:1 matching between LG and OG groups for propensity score matching method (PSM). After PSM, the matched 41 patients with LG and 80 patients with OG formed the cohort, respectively. Univariate and multivariate Cox analyses were performed on all variables to determine independent risk factors associated with survival. Results: LG had a longer operating time compared to OG [260.00 min (220.00 min, 300.00 min) vs. 200.00 min (160.00 min, 260 min), P < 0.001]. The estimated blood loss, metastatic lymph nodes (LN), total LN examined, postoperative hospital stays, blood transfusion (P>0.05) and the incidence of postoperative complications did not show statistical differences from the OG group (P = 0.084). The type of surgery (LG vs. OG) did not show a significant risk propensity in the univariate and multivariate Cox analysis (HR = 0.69, P = 0.36, 95 % CI: 0.31-1.53). Through the Kaplan-Meier curves, a certain trend showed that the LG group had a better long-term survival outcomes than the OG group, although there was no statistical difference between two groups (P>0.05). Conclusion: LG is a promising treatment option for LAGC patients receiving NACT and had an acceptable safety and efficacy compared to OG.

Multidrug-resistant Klebsiella Pneumoniae Infection Led to Resection of the Graft in a Small Bowel Transplant Recipient: A Case Report and Review of the Literature.

BACKGROUND: Infection due to multidrug-resistant Klebsiella pneumoniae is a common cause of graft resection after small bowel transplantation. We report a failed case in which the intestinal graft was resected 18 days after the operation due to postoperative infection with multidrug-resistant K pneumoniae and a literature review of other common causes of small bowel transplantation failure have been reported. METHODS: A female, 29 years of age, underwent partial living small bowel transplantation for short bowel syndrome. After the operation, the patient was infected with multidrug-resistant K pneumoniae, even though various anti-infective regimens were employed. It further developed into sepsis and disseminated into intravascular coagulation, leading to exfoliation and necrosis of the intestinal mucosa. Finally, the intestinal graft had to be resected to save the patient's life. RESULTS: Multidrug-resistant K pneumoniae infection often affects the biological function of intestinal grafts and can even lead to necrosis. Other common causes of failure, including postoperative infection, rejection, post-transplantation lymphoproliferative disorder, graft-vs-host disease, surgical complications, and other related diseases, were also discussed throughout the literature review. CONCLUSIONS: Pathogenesis due to diverse and interrelated factors makes the survival of intestinal allografts a great challenge. Therefore, only by fully understanding and mastering the common causes of surgical failure can the success rate of small bowel transplantation be effectively improved.

Comparison of thoracoabdominal versus abdominal-transhiatal surgical approaches in Siewert type II adenocarcinoma at the esophagogastric junction: Protocol for a prospective multicenter randomized controlled trial.

Background: Siewert type II adenocarcinoma of the esophagogastric junction (Siewert II AEG) can be resected by the right thoracoabdominal surgical approach (RTA) or abdominal-transhiatal surgical approach (TH) under minimally invasive conditions. Although both surgical methods achieve complete tumor resection, there is a debate as to whether the former method is superior to or at least noninferior to the latter in terms of surgical safety. Currently, a small number of retrospective studies have compared the two surgical approaches, with inconclusive results. As such, a prospective multicenter randomized controlled trial is necessary to validate the value of RTA (Ivor-Lewis) compared to TH. Methods: The planned study is a prospective, multicenter, randomized clinical trial. Patients (n=212) with Siewert II AEG that could be resected by either of the above two surgical approaches will be included in this trial and randomized to the RTA group (n=106) or the TH group (n=106). The primary outcome will be 3-year disease-free survival (DFS). The secondary outcomes will include 5-year overall survival (OS), incidence of postoperative complications, postoperative mortality, local recurrence rate, number and location of removed lymph nodes, quality of life (QOL), surgical Apgar score, and duration of the operation. Follow-ups are scheduled every three months for the first 3 years after the surgery and every six months for the next 2 years. Discussion: Among Siewert II AEG patients with resectable tumors, this is the first prospective, randomized clinical trial comparing the surgical safety of minimally invasive RTA and TH. RTA is hypothesized to provide better digestive tract reconstruction and dissection of mediastinal lymph nodes while maintaining a high quality of life and good postoperative outcome. Moreover, this trial will provide a high level of evidence for the choice of surgical procedures for Siewert II AEG. Clinical trial registration: Chinese Ethics Committee of Registering Clinical Trials, identifier (ChiECRCT20210635); Clinical Trial.gov, identifier (NCT05356520).

Prognostic model based on m6A-associated lncRNAs in esophageal cancer.

Background: This research aimed to build an m6A-associated lncRNA prognostic model of esophageal cancer that can be used to predict outcome in esophageal cancer patients. Methods: RNA sequencing transcriptome data and clinical information about patients with esophageal cancer were obtained according to TCGA. Twenty-four m6A-associated genes were selected based on previous studies. m6A-associated lncRNAs were determined through Pearson correlation analysis. Three m6A-associated lncRNA prognostic signatures were built through analysis of the training set using univariate, LASSO, and multivariate Cox regression. To validate the stabilization of the risk signature, Kaplan-Meier and ROC curve analyses were performed on the testing and complete sets. The prognoses of EC patients were predicted quantitatively by building a nomogram. GSEA was conducted to analyze the underlying signaling pathways and biological processes. To identify the underlying mechanisms through which the lncRNAs act, we constructed a PPI network and a ceRNA network and conducted GO and KEGG pathway analyses. EC samples were evaluated using the ESTIMATE algorithm to compute stromal, immune, and estimate scores. The ssGSEA algorithm was used to quantitatively infer immune cell infiltration and immune functions. The TIDE algorithm was performed to simulate immune evasion and predict the response to immunotherapy. Results: We identified and validated an m6A-associated lncRNA risk model in EC that could correctly and reliably predict the OS of EC patients. The ceRNA network, PPI network, and GO and KEGG pathway analyses confirmed and the underlying mechanisms and functions provided enlightenment regarding therapeutic strategies for EC. Immunotherapy responses were better in the low-risk subgroup, and PD-1 and CTLA4 checkpoint immunotherapy benefited the patients in the low-risk subgroup. Conclusions: We constructed a new m6A-related lncRNA prognostic risk model of EC, based on three m6A-related lncRNAs: LINC01612, AC025166.1 and AC016876.2, that can predict the prognoses of EC patients.

Study protocol for feasibility and safety of adopting early oral feeding in post total laparoscopic total gastrectomy (overlap esophagojejunostomy): A multicentre randomized controlled trial.

Background: Total laparoscopic total gastrectomy (TLTG) for gastric cancer, especially with overlap esophagojejunostomy, has been verified that it has advantages of minimally invasion, less intraoperative bleeding, and faster recovery. Meanwhile, early oral feeding (EOF) after the operation has been demonstrated to significantly promote early rehabilitation in patients, particularly with distal gastrectomy. However, due to the limited application of TLTG, there is few related research proving whether it is credible or safe to adopt EOF after TLTG (overlap esophagojejunostomy). So, it is urgent to start a prospective, multicenter, randomized clinical trials to supply high level evidence. Methods/design: This study is a prospective, multicenter, randomized controlled trial with 200 patients (100 in each group). These eligible participants are randomly allocated into two different groups, including EOF group and delay oral feeding (DOF) group after TLTG (overlap esophagojejunostomy). Anastomotic leakage will be carefully observed and recorded as the primary endpoints; the period of the first defecation and exhaust, postoperative length of stay and hospitalization expenses will be recorded as secondary endpoints to ascertain the feasibility and safety of adopting EOF after TLTG (overlap esophagojejunostomy). Discussion: Recently, the adoption of TLTG was limited due to its difficult anastomotic procedure, especially in vivo esophagojejunostomy. With the innovation and improvement of operating techniques, overlap esophagojejunostomy with linear staplers simplified the anastomotic steps and reduced operational difficulties after TLTG. Meanwhile, EOF had received increasing attention from surgical clinicians as a nutrition part of enhanced recovery after surgery (ERAS), which had shown better results in patients after distal gastrectomy. Considering the above factors, we implemented EOF protocol to evaluate the feasibility and safety of adopting EOF after TLTG (overlap esophagojejunostomy), which provided additional evidence for the development of clinical nutrition guidelines. Clinical trial registration: [www.chictr.org.cn], identifier [ChiECRCT20200440 and ChiCTR2000040692].

20(s)-ginsenoside Rh2 promotes TRAIL-induced apoptosis by upregulating DR5 in human hepatocellular carcinoma cells.

Tumor necrosis factor-related apoptosis-inducing ligand is a potential therapeutic anti-cancer drug with selective cytotoxicity in cancer cells. However, in multiple clinical trials, the therapeutic effect of TRAIL is limited owing to tumor resistance. The combination of small molecules or other drugs may represent a suitable strategy to overcome TRAIL resistance. This study found that 20(s)-ginsenoside Rh2 sensitized non-sensitive human hepatocellular carcinoma cells to TRAIL-induced apoptosis. The combination of TRAIL and Rh2 decreased cell viability and increased caspase cascade-induced apoptosis in several liver cancer cell lines. Moreover, we found that Rh2 reduced the apoptosis-related protein XIAP and Survivin, a negative regulator of the apoptosis pathway. At the same time, Rh2 can further enhance TRAIL-induced apoptosis by upregulating the death receptor 5, thereby significantly enhancing its anti-tumor effect. Furthermore, Rh2 enhanced the therapeutic efficacy of TRAIL in mouse xenograft models, suggesting that Rh2 also sensitizes TRAIL in vivo. Taken together, our study indicates that Rh2 may act as a sensitizer in combination with TRAIL to increase the efficacy of its anti-tumor activity.

Effects of Associated Minerals on the Co-Current Oxidizing Pyrolysis of Oil Shale in a Low-Temperature Stage.

Low-temperature co-current oxidizing pyrolysis, which can achieve high recovery of hydrocarbons without significant oil loss, has great potential to reduce the huge external energy required for oil shale conversion. However, this promising method is far from being fully understood, especially the unknown competing mechanism of different types of inorganic minerals in promoting or inhibiting hydrocarbon generation. In this study, the raw Huadian oil shale (HD-R), its carbonate-free (HD-C-F), and carbonate-silicate-free (HD-CS-F) samples obtained through acid treatment are used to investigate the effects of associated minerals on the oil shale co-current oxidizing pyrolysis. The results of shale oil yields of HD-R, HD-C-F, and HD-CS-F were 41.53, 22.38, and 33.97%, respectively, indicating that silicates inhibited, while carbonates catalyzed the formation of shale oil during the co-current oxidizing pyrolysis. Meanwhile, silicates increase the alkane content and decrease the alkene content in shale oil via promoting the combination of hydrogen radicals and alkyl radicals. On the contrary, alkali metals and alkaline earth metals in carbonates inhibit the binding activity of hydrogen radicals and alkyl radicals, concurrently enhancing the release of hydrogen-free radicals of alkyl radicals to form more alkenes. The removal of carbonates could enhance the conversion of organic carbon into hydrocarbons, and the silicates will strengthen the conversion process. It is hoped that this experiment can further enrich and perfect the basic theory of oil shale pyrolysis and provide a reliable reference for the pretreatment of oil shale conversion.

Thermal Behavior of Oil Shale Pyrolysis under Low-Temperature Co-Current Oxidizing Conditions.

The thermal behavior of the Huadian oil shale during low-temperature co-current oxidizing pyrolysis was studied by lab-scale experiments under different basic pyrolysis temperatures and input gas flow rates. The results showed that, in the process of oil shale co-current oxidizing pyrolysis, the increasing input gas flow rates under the same basic pyrolysis temperatures can significantly enhance the heat generation of oil shale. Meanwhile, it can be seen from the temperature variation characteristics of oil shale that the heat released by the oxidation reaction of semicoke and oxygen is enough to support the thermal decomposition of organic matter without supplemental heating. Moreover, it can be concluded from the 92.06% effective recovery of shale oil that a high yield of oil without a significant loss can be achieved. Finally, compared with increasing basic pyrolysis temperatures, the increased input gas flow rates have a more obvious effect on improving the effective recovery of shale oil.

miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice.

Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO) and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl), was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs) into intermediate neural progenitors (INPs) in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment.