Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy.

PURPOSE: The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long-term survival in CRLM patients. METHODS: A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan-Meier plotter and compared using the log-rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. RESULTS: In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088-4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398-5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high-risk and low-risk groups. Notably, in the high-risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low-risk group. CONCLUSIONS: KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.

Advances in the Clinical Study of Nuclear Overhauser Enhancement.

Nuclear overhauser enhancement is a confounding factor arising from the in vivo application of a chemical exchange saturation transfer technique in which two nuclei in close proximity undergo dipole cross-relaxation. Several studies have shown applicability and efficacy of nuclear overhauser enhancement in observing tumors and other lesions in vivo. Thus, this effect could become an emerging molecular imaging research tool for many diseases. Moreover, nuclear overhauser enhancement has the advantages of simplicity, noninvasiveness, and high resolution and has become a major focus of current research. In this review, we summarize the principles and applications of nuclear overhauser enhancement. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Ecological management zone of Taiyuan City based on the supply and demand of ecosystem services.

Clarifying the matching degree and the trade-offs and synergies between supply and demand of ecosystem services is of significance for scientific division of management zoning and sustainable urban development. We calculated the supply and demand of ecosystem services at the sub-district (town) scale of Taiyuan based on multi-source data, explored the coldspots and hotspots area of the supply-demand ratio and the trade-offs and synergies of six ecosystem services using the Getis-Ord Gi* tool and correlation analysis, and proposed strategies based on the regional characteristics of natural-resource and socio-economy. Results showed the distribution of the supply and demand of ecosystem services had a spatial heterogeneity. In terms of supply, the area with high supply of carbon storage, air purification, thermal environment regulation and recreation service were located in the east and west parts, that of soil conservation in the west and water yield in the south part. In terms of demand, the demand distribution of carbon storage, thermal environment regulation, water yield and recreation service were characterized by high in the central and east-south area, and low in the periphery, and high demand of air purification in south and north parts, soil conservation in west part. There were substantial mismatches between the demand and supply of ecosystem services. The risk levels of the supply and demand of six ecosystem services showed a decreasing pattern from the Fenhe River to the eastern and western mountains. There were trade-offs between water yield and other five ecosystem services in their supply, while air purification and soil conservation had trade-offs with other four ecosystem services in demand. Based on the regional ecological management framework, we divided the study area into three primary zones and eight secondary zones, and proposed differentiated ecological management strategies to provide theoretical support for ecological zoning. The results could provide a basis for balancing the relationship of supply and demand of ecosystem services and promoting the sustainable development of the city.

METTL3/IGF2BP1 influences the development of non-small-cell lung cancer by mediating m6A methylation modification of TRPV1.

BACKGROUND: Methyltransferase 3 (METTL3) accelerates N6-methyladenosine (m6A) modifications and affects cancer progression, including non-small-cell lung cancer (NSCLC). In this study, we aimed to explore the regulatory mechanisms of METTL3 underling NSCLC. METHODS: Immunohistochemical assay, quantitative real-time polymerase chain reaction (qRT-PCR) assay, and western blot assay were conducted for gene expression. MTT assay and colony formation assay were performed to explore cell proliferation capacity. Cell apoptosis and THP-1 cell polarization were estimated by flow cytometry analysis. Cell migration and invasion capacities were evaluated by transwell assay. Methylated RNA immunoprecipitation assay, dual-luciferase reporter assay, actinomycin D treatment and RIP assay were performed to analyze the relationships of METTL3, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), and transient receptor potential cation channel subfamily V member 1 (TRPV1). The functions of METTL3 and TRPV1 in vivo were investigated through establishing the murine xenograft model. RESULTS: TRPV1 expression was upregulated in NSCLC and related poor prognosis. TRPV1 silencing inhibited NSCLC cell growth and metastasis, induced NSCLC cell apoptosis, and repressed M2 macrophage polarization. The results showed that METTL3 and IGF2BP1 could regulate TRPV1 expression through m6A methylation modification. Moreover, METTL3 deficiency inhibited NSCLC cell growth, metastasis, and M2 macrophage polarization and facilitated NSCLC cell apoptosis, while TRPV1 overexpression restored the impacts. In addition, METTL3 knockdown restrained tumor growth in vivo via regulating TRPV1 expression. CONCLUSION: METTL3 bound to IGF2BP1 and enhanced IGF2BP1's m6A recognition of TRPV1 mRNA, thereby promoting NSCLC cell growth and metastasis, and inhibiting M2 macrophage polarization.

Stratifying osteosarcoma patients using an epigenetic modification-related prognostic signature: implications for immunotherapy and chemotherapy selection.

Background: Osteosarcoma (OS) poses significant challenges in treatment and lacks reliable prognostic markers. Epigenetic alterations play a crucial role in disease progression. This study aimed to develop an accurate prognostic signature for OS using epigenetic modification genes (EMGs). Methods: The Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-OS cohort was analyzed. Univariate Cox analysis identified survival-associated EMGs. Based on least absolute shrinkage and selection operator (LASSO) regression and multivariate analysis, a 6-gene prognostic signature termed the epigenetic modification-related prognostic signature (EMRPS) was derived in the testing cohort. Kaplan-Meier and receiver operating characteristic (ROC) curve analysis confirmed predictive accuracy through internal and external validation (GEO accession GSE21257). A prognostic nomogram incorporating EMRPS and clinical features was constructed. Transcriptomic analysis including differential gene expression, Gene Ontology (GO), gene set enrichment analysis (GSEA), and immune infiltration analysis was conducted to explore mechanisms linking EMRPS to OS prognosis. Additionally, EMRPS impact on drug sensitivity was predicted. Results: A 6-gene EMRPS comprising DDX24, DNAJC1, HDAC4, SIRT7, SP140 and UHRF2 was successfully developed. The high-risk group showed significantly shorter survival, consistently observed in both internal and external validation. EMRPS demonstrated high predictive efficacy for 1-, 3-, and 5-year overall survival, with area under curve (AUC) >0.85 in training and ~0.7 in testing. The nomogram integrating age, gender, metastasis status, and EMRPS exhibited high predictive performance based on concordance index analysis. Mechanistic analysis indicated the low-risk group had increased immune infiltration and activity with higher immune checkpoint expression, reflecting an immune-activated tumor microenvironment (TME) suitable for immunotherapy. Drug sensitivity analysis revealed the low-risk group had increased sensitivity to cisplatin, a first-line OS chemotherapy. Conclusions: Our study successfully established an efficient EMRPS and nomogram, highlighting their potential as novel prognostic markers and indicators for selecting appropriate immunotherapy and chemotherapy candidates in OS treatment.

Robot-assisted internal fixation of calcaneal fractures versus conventional open reduction internal fixation: a systematic review and meta-analysis.

The aim of the study was to compare the efficacy and safety of robot-assisted (RA) percutaneous hollow screw fixation with traditional open reduction internal fixation (ORIF) for the treatment of calcaneal fractures through a systematic review and meta-analysis. An extensive search was conducted in the following databases-PubMed, CNKI, Embase, and the Cochrane Library-to gather research on patients with calcaneal fractures published up to July 2024. This search focuses on studies comparing the effectiveness of robot-assisted percutaneous cannulated screw fixation versus ORIF. We will include studies published in both English and Chinese. Our screening process adhered strictly to predefined inclusion and exclusion criteria, emphasizing randomized controlled trials (RCTs) and cohort studies. The ROBINS-I tool was utilized to evaluate the risk of bias in non-randomized studies. Meta-analysis was conducted using Review Manager 5.4.1. The final analysis incorporated six retrospective cohort studies comprising 247 patients-122 treated with robotic-assisted percutaneous cannulated screw fixation and 125 with conventional open reduction and internal fixation. The findings indicated that patients undergoing robotic-assisted percutaneous cannulated screw fixation experienced advantages over those receiving conventional treatment in terms of reduced hospital stay, lower estimated blood loss, and higher AOFAS scores at both 3 and 6 months. No statistically significant differences were observed between the two methods concerning operative time, fracture healing duration, or the frequency of intraoperative fluoroscopies. Robotic-assisted percutaneous cannulated screw fixation is a safe and viable treatment approach for patients with calcaneal fractures. When compared to ORIF methods, this robotic-assisted technique demonstrated significant benefits, including reduced hospital stay, lower estimated blood loss, and improved AOFAS scores at both 3 and 6 months.

Safety and feasibility of enhanced recovery after surgery-based management model for ambulatory pediatric surgical procedures.

BACKGROUND: There is still some room for optimizing ambulatory pediatric surgical procedures, and the preoperative and postoperative management quality for pediatric patients needs to be improved. AIM: To discuss the safety and feasibility of the enhanced recovery after surgery (ERAS)-based management model for ambulatory pediatric surgical procedures. METHODS: We selected 320 pediatric patients undergoing ambulatory surgery from June 2023 to January 2024 at The First People's Hospital of Liangshan Yi Autonomous Prefecture. Of these, 220 received ERAS-based management (research group) and 100 received routine management (control group). General information, postoperative ambulation activities, surgical outcomes (operation time, postoperative gastrointestinal ventilation time, and hospital stay), postoperative pain visual analogue scale, postoperative complications (incision infection, abdominal distension, fever, nausea, and vomiting), and family satisfaction were compared. RESULTS: The general information of the research group (sex, age, disease type, single parent, family history, etc.) was comparable to that of the control group (P > 0.05), but the rate of postoperative (2 h, 4 h, and 6 h after surgery) ambulation activities was statistically higher (P < 0.01), and operation time, postoperative gastrointestinal ventilation time, and hospital stay were markedly shorter (P < 0.05). The research group had lower visual analogue scale scores (P < 0.01) at 12 h and 24 h after surgery and a lower incidence of total postoperative complications than the control group (P = 0.001). The research group had higher family satisfaction than the control group (P = 0.007). CONCLUSION: The ERAS-based management model was safe and feasible in ambulatory pediatric surgical procedures and worthy of clinical promotion.

SIVA-1 interaction with PCBP1 serves as a predictive biomarker for cisplatin sensitivity in gastric cancer and its inhibitory effect on tumor growth in vivo.

Background: SIVA-1 has been reported to play a key role in cell apoptosis and gastric cancer (GC) chemoresistance in vitro. Nevertheless, the clinical significance of SIVA-1 in GC chemotherapy remains unclear. Methods and results: Immunohistochemistry and histoculture drug response assays were used to determine SIVA-1 expression and the inhibition rate (IR) of agents to GC and to further analyze the relationship between these two phenomena. Additionally, cisplatin (DDP)-resistant GC cells were used to elucidate the role and mechanism of SIVA-1 in vivo. The results demonstrated that SIVA-1 expression was positively correlated with the IR of DDP to GC but not with those of 5-fluorouracil (5-FU) or adriamycin (ADM). Furthermore, SIVA-1 overexpression with DDP treatment synergistically inhibited tumor growth in vivo by increasing PCBP1 and decreasing Bcl-2 and Bcl-xL expression. Conclusions: Our study demonstrated that SIVA-1 may serve as an indicator of the GC sensitivity to DDP, and the mechanism of SIVA-1 in GC resistance to DDP was preliminarily revealed.

Magnetic compression anastomosis to restore biliary tract continuity after obstruction following major abdominal trauma: A case report.

BACKGROUND: The combination of magnetic compression anastomosis (MCA) and endoscopy has been used to treat biliary stricture after liver transplantation. However, its use for the treatment of complex biliary obstruction after major abdominal trauma has not been reported. This case report describes the successful use of MCA for the treatment of biliary obstruction resulting from major abdominal trauma. CASE SUMMARY: A 23-year-old man underwent major abdominal surgery (repair of liver rupture, right half colon resection, and ileostomy) following a car accident one year ago. The abdominal drainage tube, positioned at the Winslow foramen, was draining approximately 600-800 mL of bile per day. During the two endoscopic retrograde cholangiopancreatography procedures, the guide wire was unable to enter the common bile duct, which prevented placement of a biliary stent. MCA combined with endoscopy was used to successfully achieve magnetic anastomosis of the peritoneal sinus tract and duodenum, and then a choledochoduodenal stent was placed. Finally, the external biliary drainage tube was removed. The patient achieved internal biliary drainage leading to the removal of the external biliary drainage tube, which improved the quality of life. CONCLUSION: Magnetic compression technique can be used for the treatment of complex biliary obstruction with minimal operative trauma.

Novel magnetic compression technique for the treatment of postoperative anastomotic stenosis in rectal cancer: A case report.

BACKGROUND: The treatment of postoperative anastomotic stenosis after excision of rectal cancer is challenging. Endoscopic balloon dilation and radial incision are not effective in all patients. We present a new endoscopy-assisted magnetic compression technique (MCT) for the treatment of rectal anastomotic stenosis. We successfully applied this MCT to a patient who developed an anastomotic stricture after radical resection of rectal cancer. CASE SUMMARY: A 50-year-old man had undergone laparoscopic radical rectal cancer surgery at a local hospital 5 months ago. A colonoscopy performed 2 months ago indicated that the rectal anastomosis was narrow due to which ileostomy closure could not be performed. The patient came to the Magnetic Surgery Clinic of the First Affiliated Hospital of Xi'an Jiaotong University after learning that we had successfully treated patients with colorectal stenosis using MCT. We performed endoscopy-assisted magnetic compression surgery for rectal stenosis. The magnets were removed 16 d later. A follow-up colonoscopy performed after 4 months showed good anastomotic patency, following which, ileostomy closure surgery was performed. CONCLUSION: MCT is a simple, non-invasive technique for the treatment of anastomotic stricture after radical resection of rectal cancer. The technique can be widely used in clinical settings.

Cancer stem cells: advances in knowledge and implications for cancer therapy.

Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/ß-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-ß, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.

Inhibition of SIRT1 relieves hepatocarcinogenesis via alleviating autophagy and inflammation.

Imbalanced Sirtuin 1 (SIRT1) levels may lead to liver diseases through abnormal regulation of autophagy, but the roles of SIRT1-regulated autophagy in hepatocellular carcinoma are still controversial. In this study, we found that SIRT1 mRNA and protein levels were upregulated in hepatocellular carcinoma, and high SIRT1 expression hinted an advanced stage and a poor prognosis. The differentially expressed proteins were significantly elevated in autophagy, cellular response to stress, and immune signaling pathways. In a thioacetamide-induced hepatocellular carcinoma mouse model, we found that SIRT1 expression was highly increased with increased autophagy and excessive macrophage inflammatory response. Next, we established a Hepa 1-6 cells and macrophage co-culture system in vitro to model the alteration of tumor microenvironment, and found that the medium from CCl4-treated or SIRT1-overexpressing Hepa 1-6 cells triggered the polarization of macrophage M1, and the culture medium derived from M1 macrophage promoted Hepa 1-6 cells growth and intracellular oxidative stress. The progression of liver fibrosis in the CCl4-induced liver fibrosis mouse model showed that inhibition of SIRT1 alleviated inflammatory response and ameliorated liver fibrosis. These findings suggest that SIRT1-regulated autophagy and inflammation are oncogenic in hepatocarcinogenesis.

MARCH1 negatively regulates TBK1-mTOR signaling pathway by ubiquitinating TBK1.

BACKGROUND: TBK1 positively regulates the growth factor-mediated mTOR signaling pathway by phosphorylating mTOR. However, it remains unclear how the TBK1-mTOR signaling pathway is regulated. Considering that STING not only interacts with TBK1 but also with MARCH1, we speculated that MARCH1 might regulate the mTOR signaling pathway by targeting TBK1. The aim of this study was to determine whether MARCH1 regulates the mTOR signaling pathway by targeting TBK1. METHODS: The co-immunoprecipitation (Co-IP) assay was used to verify the interaction between MARCH1 with STING or TBK1. The ubiquitination of STING or TBK1 was analyzed using denatured co-immunoprecipitation. The level of proteins detected in the co-immunoprecipitation or denatured co-immunoprecipitation samples were determined by Western blotting. Stable knocked-down cells were constructed by infecting lentivirus bearing the related shRNA sequences. Scratch wound healing and clonogenic cell survival assays were used to detect the migration and proliferation of breast cancer cells. RESULTS: We showed that MARCH1 played an important role in growth factor-induced the TBK1- mTOR signaling pathway. MARCH1 overexpression attenuated the growth factor-induced activation of mTOR signaling pathway, whereas its deficiency resulted in the opposite effect. Mechanistically, MARCH1 interacted with and promoted the K63-linked ubiquitination of TBK1. This ubiquitination of TBK1 then attenuated its interaction with mTOR, thereby inhibiting the growth factor-induced mTOR signaling pathway. Importantly, faster proliferation induced by MARCH1 deficiency was weakened by mTOR, STING, or TBK1 inhibition. CONCLUSION: MARCH1 suppressed growth factors mediated the mTOR signaling pathway by targeting the STING-TBK1-mTOR axis.

Tumor microenvironment characteristics association with clinical outcome in patients with resected intestinal-type gastric cancer.

BACKGROUND: Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. METHODS: TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. RESULTS: Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). CONCLUSIONS: Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.

Casual associations between blood metabolites and colon cancer.

BACKGROUND: Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer. AIM: To investigate causal associations between blood metabolites and colon cancer. METHODS: The study utilized a two-sample Mendelian randomization (MR) analysis to investigate the causal impact of 486 blood metabolites on colorectal cancer. The primary method of analysis used was the inverse variance weighted model. To further validate the results several sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, and MR robust adjusted profile score. These additional analyses were conducted to ensure the reliability and robustness of the findings. RESULTS: After rigorous selection for genetic variation, 486 blood metabolites were included in the MR analysis. We found Mannose [odds ratio (OR) = 2.09 (1.10-3.97), P = 0.024], N-acetylglycine [OR = 3.14 (1.78-5.53), P = 7.54 × 10-8], X-11593-O-methylascorbate [OR = 1.68 (1.04-2.72), P = 0.034], 1-arachidonoylglycerophosphocholine [OR = 4.23 (2.51-7.12), P = 6.35 × 10-8] and 1-arachidonoylglycerophosphoethanolamine 4 [OR = 3.99 (1.17-13.54), P = 0.027] were positively causally associated with colorectal cancer, and we also found a negative causal relationship between Tyrosine [OR = 0.08 (0.01-0.63), P = 0.014], Urate [OR = 0.25 (0.10-0.62), P = 0.003], N-acetylglycine [0.73 (0.54-0.98), P = 0.033], X-12092 [OR = 0.89 (0.81-0.99), P = 0.028], Succinylcarnitine [OR = 0.48 (0.27-0.84), P = 0.09] with colorectal cancer. A series of sensitivity analyses were performed to confirm the rigidity of the results. CONCLUSION: This study showed a causal relationship between 10 blood metabolites and colorectal cancer, of which 5 blood metabolites were found to be causal for the development of colorectal cancer and were confirmed as risk factors. The other five blood metabolites are protective factors.

The CfKOB1 gene related to cell apoptosis is required for pathogenicity and involved in mycovirus-induced hypovirulence in Colletotrichum fructicola.

Colletotrichum fructicola is a globally significant phytopathogenic fungus. Mycovirus-induced hypovirulence has great potential for biological control and study of fungal pathogenic mechanisms. We previously reported that the mycovirus Colletotrichum alienum partitivirus 1 (CaPV1) is associated with the hypovirulence of C. fructicola, and the present study aimed to further investigate a host factor and its roles in mycovirus-induced hypovirulence. A gene named CfKOB1, which encodes putative protein homologous to the ß-subunit of voltage-gated potassium channels and aldo-keto reductase, is downregulated upon CaPV1 infection and significantly upregulated during the early infection phase of Nicotiana benthamiana by C. fructicola. Deleting the CfKOB1 gene resulted in diminished vegetative growth, decreased production of asexual spores, hindered appressorium formation, reduced virulence, and altered tolerance to abiotic stresses. Transcriptome analysis revealed that CfKOB1 regulates many metabolic pathways as well as the cell cycle and apoptosis. Furthermore, enhanced apoptosis was observed in the ΔCfKOB1 mutants. Viral RNA accumulation was significantly increased in the CfKOB1 deletion mutant. Additionally, our findings demonstrated that CaPV1 infection in the WT strain also induced cell apoptosis. Collectively, these results highlight the diverse biological roles of the CfKOB1 gene in the fungus C. fructicola, while it also participates in mycovirus-induced hypovirulence by regulating apoptosis.

[Active secondary metabolites from an endophytic fungus Fusarium solani MBM-5 of Datura arborea].

This study investigated the chemical and biological activity of the secondary metabolites from an endophytic fungus Fusa-rium solani MBM-5 of Datura arborea. A total of six alkenoic acid compounds, including a new compound and five known ones, were isolated from the ethyl acetate extract of F. solani MBM-5 by using the chromatographic methods(open ODS column chromatography, silica gel column chromatography, Sephadex LH-20, and semi-preparative HPLC). The structures of the compounds were identified by using their physical and chemical data, spectroscopic methods(UV, IR, NMR, and HR-ESI-MS), and Mosher's reaction, which were fusaridioic acid E(1), fusaridioic acid C(2), fusaridioic acid A(3), L660282(4), hymeglusin(5), and hymeglnone(6). Compound 1 is new. MTT assay and Griss method were used to evaluate the growth inhibition of all the compounds against two tumor cells, as well as their influence and anti-inflammatory action on the release of NO from LPS-induced RAW264.7 cells. The results showed that compound 5 had strong growth inhibition activity against A549 and HepG2 cell lines, with IC_(50) values of 4.70 and 13.57 µmol·L~(-1), respectively. Compounds 1 and 6 significantly inhibited the release of NO from LPS-induced RAW264.7 cells, with IC_(50) values of 77.00 and 70.33 µmol·L~(-1), respectively.

Laparoscopic-assisted full-sized liver transplantation with magnetically fast portal vein anastomosis: an initial cohort study.

BACKGROUND: Some cases of laparoscopic-assisted liver transplantation (LA-LT) with utilization of reduced-size grafts has been reported. The authors here introduced successful utilization of LA-LT with whole liver grafts and magnetic portal vein anastomosis. METHODS: Eight patients with liver cirrhosis were included for LA-LT using donor organs after cardiac death. The surgical procedures included purely laparoscopic explant hepatectomy and whole-liver graft implantation via the midline incision. After explant removal, the whole-liver graft was then placed in situ, and a side-to-side cavo-caval anastomosis with 4-5 cm oval opening was performed. The magnetic rings were everted on the donor and recipient portal vein, respectively, and the instant attachment of the two magnets at the donor and recipient portal vein allowed fast blood reperfusion, followed by continuous suturing on the surface of the magnets. RESULTS: The median operation time was 495 (range 420-630). The median time of explant hepatectomy and inferior vena cava anastomosis was 239 (range 150-300) min and 14.5 (range 10-19) min, respectively. Of note, the median anhepatic time was 25 (range 20-35) min. All the patients were discharged home with no major complications after more than 12 months follow-up. CONCLUSION: LA-LT with full-size graft is feasible and utilization of magnetic anastomosis would further simplify the procedure.

Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation.

Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.