Stress granule activation attenuates lipopolysaccharide-induced cardiomyocyte dysfunction.

BACKGROUND: Sepsis is the leading cause of death in intensive care units. Sepsis-induced myocardial dysfunction, one of the most serious complications of sepsis, is associated with higher mortality rates. As the pathogenesis of sepsis-induced cardiomyopathy has not been fully elucidated, there is no specific therapeutic approach. Stress granules (SG) are cytoplasmic membrane-less compartments that form in response to cellular stress and play important roles in various cell signaling pathways. The role of SG in sepsis-induced myocardial dysfunction has not been determined. Therefore, this study aimed to determine the effects of SG activation in septic cardiomyocytes (CMs). METHODS: Neonatal CMs were treated with lipopolysaccharide (LPS). SG activation was visualized by immunofluorescence staining to detect the co-localization of GTPase-activating protein SH3 domain binding protein 1 (G3BP1) and T cell-restricted intracellular antigen 1 (TIA-1). Eukaryotic translation initiation factor alpha (eIF2α) phosphorylation, an indicator of SG formation, was assessed by western blotting. Tumor necrosis factor alpha (TNF-α) production was assessed by PCR and enzyme-linked immunosorbent assays. CMs function was evaluated by intracellular cyclic adenosine monophosphate (cAMP) levels in response to dobutamine. Pharmacological inhibition (ISRIB), a G3BP1 CRISPR activation plasmid, and a G3BP1 KO plasmid were employed to modulate SG activation. The fluorescence intensity of JC-1 was used to evaluate mitochondrial membrane potential. RESULTS: LPS challenge in CMs induced SG activation and resulted in eIF2α phosphorylation, increased TNF-α production, and decreased intracellular cAMP in response to dobutamine. The pharmacological inhibition of SG (ISRIB) increased TNF-α expression and decreased intracellular cAMP levels in CMs treated with LPS. The overexpression of G3BP1 increased SG activation, attenuated the LPS-induced increase in TNF-α expression, and improved CMs contractility (as evidenced by increased intracellular cAMP). Furthermore, SG prevented LPS-induced mitochondrial membrane potential dissipation in CMs. CONCLUSION: SG formation plays a protective role in CMs function in sepsis and is a candidate therapeutic target.

Perineural invasion confers poorer clinical outcomes in patients with T1/T2 intrahepatic cholangiocarcinoma: a single center, retrospective cohort study.

Background: Intrahepatic cholangiocarcinoma (ICC) poses a significant clinical challenge, demanding a thorough understanding of prognostic indicators for effective patient management. Despite reports suggesting the impact of perineural invasion (PNI) on the prognosis of early-stage ICC patients, there has been a dearth of comprehensive research specifically targeting this subgroup. This study seeks to investigate the influence of PNI on survival outcomes in early-stage ICC patients and aims to enhance the prognostic value of the American Joint Committee on Cancer (AJCC) T category. Methods: A cohort of 268 early-stage (T1-T2N0M0) ICC patients, who underwent curative-intent resection (R0) between 2011 and 2015 at the Eastern Hepatobiliary Surgery Hospital, were enrolled in this study. Lasso and Cox regression analyses were employed to explore differences in clinical and prognostic data. Kaplan-Meier curves were generated to illustrate the clinical significance of the combination of PNI and T category. Results: Among the 268 patients, 24.6% exhibited PNI. Patients with PNI demonstrated shorter recurrence-free survival (RFS) [median RFS: 16 months (interquartile range, 9.5-19 months)] and overall survival (OS) [median OS: 16.53 months (interquartile range, 10-25 months)]. PNI emerged as an independent risk factor for both RFS and OS in T1- and T2-stage patients (all P<0.05), whereas tumor size was only an independent risk factor for OS (P=0.004). PNI was associated with all prognostic markers for ICC patients, including gender, jaundice, cholangitis, hepatitis B virus (HBV) infection, cancer antigen 199 (CA199), preoperative serum albumin, and preoperative platelet count (all P<0.05). However, there was no significant difference in RFS (P=0.270) and OS (P=0.360) between T2 patients without PNI and T1 patients with PNI. Conclusions: This study underscores PNI as a robust prognostic factor in early-stage ICC, emphasizing the necessity of incorporating PNI into the AJCC T category for precise risk stratification. Clinically, understanding the impact of PNI on survival outcomes can guide tailored treatment strategies for early ICC patients.

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer.

Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.

Cytoreductive prostatectomy improves survival outcomes in patients with oligometastases: a systematic meta-analysis.

BACKGROUND: Whether cytoreductive prostatectomy (CRP) should be performed in patients with oligometastatic prostate cancer (OPC) remains controversial. The goal of this systematic meta-analysis was to assess the efficacy of CRP as a treatment for OPC. METHODS: This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Data sources included publications in the PubMed, Embase, the Cochrane Library, EBSCO, and Web of Science (SCI) databases as of May 2022. Eligible articles included prospective studies comparing the efficacy of CRP to a lack of CRP in patients with OPC. RESULTS: In total, 10 publications incorporating 888 patients were analyzed. Tumor-reducing prostatectomy was found to have no significant effect on long-term or short-term OS [OR = 2.26, 95% CI (0.97, 5.28), P = 0.06] and [OR = 1.73, 95% CI (0.83, 3.58), P = 0.14], but it significantly improved patient long-term or short-term CSS [OR = 1.77, 95% CI (1.01, 310), P = 0.04] and [OR = 2.71, 95% CI (1.72, 4.29), P < 0.0001] and PFS [OR = 1.93, 95% CI (1.25, 2.97), P = 0.003]. CONCLUSION: These results suggest that cytoreductive prostatectomy can confer survival benefits to OPC patients. TRIAL REGISTRATION: INPLASY protocol 202260017 https://doi.org/10.37766/inplasy2022.6.0017 .

[Comfort optimization of a new type of foot mechanism for lower extremity exoskeleton].

In order to reduce the impact caused by the contact between the foot and the ground when wearing the lower extremity exoskeleton under the condition of high load, this paper proposed an exoskeleton foot mechanism for improving the foot comfort, and optimized the key index of its influence on the comfort. Firstly, the physical model of foot mechanism was established based on the characteristics of foot stress in gait period, and then the mathematical model of vibration was abstracted. The correctness of the model was verified by the finite element analysis software ANSYS. Then, this paper analyzed the influence of vibration parameters on absolute transmissibility based on vibration mathematical model, and optimized vibration parameters with MATLAB genetic algorithm toolbox. Finally, this paper took white noise to simulate the road elevation as the vibration input, and used the visual simulation tool Simulink in MATLAB and the vibration equation to construct the acceleration simulation model, and then calculated the vibration weighted root mean square acceleration value of the foot. The results of this study show that this foot comfort mechanism can meet the comfort indexes of vibration absorption and plantar pressure, and this paper provides a relatively complete method for the design of exoskeleton foot mechanism, which has reference significance for the design of other exoskeleton foot and ankle joint rehabilitation mechanism.