Construction and validation of a prognostic and therapeutic cuproptosis- and immune-related gene signature in hepatocellular carcinoma.

Background: Abnormal accumulation of copper could induce cell death and tumor growth, and affect tumor immune escape by regulating programmed cell death ligand 1 (PD-L1) expression. This study aims to establish and verify a risk signature based on cuproptosis- and immune-related genes (CIRGs) for hepatocellular carcinoma (HCC) management. Methods: HCC RNA-seq and clinical data were obtained from open databases. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were utilized to screen CIRGs and develop a risk signature. The signature's value for clinical applications, functional enrichment, tumor mutation burden (TMB), and immune profile analyses were investigated systematically. Results: A risk signature was developed utilizing seven CIRGs, and it performed well in predicting the prognosis of HCC patients in both the training and external validation cohorts. The model's risk score was discovered to be related to important clinical features. Top 15 mutated genes in HCC were significantly different among different risk groups. High-risk patients showed higher TMB, and high TMB was closely identified with a poorer prognosis. Immune profile analyses showed that immune infiltration level was higher in low-risk patients than high-risk patients, and the level of immune checkpoint genes expression varied significantly between patients in two different risk groups. Low-risk patients responded well to immunotherapy treatment, whereas high-risk patients were more sensitive to sorafenib, doxorubicin, gemcitabine and AKT (also known as protein kinase B) inhibitors. Conclusions: The established risk signature based on CIRGs can not only well predict the prognosis of HCC patients but is also promising in evaluating TMB and treatment response to immunotherapy, targeted therapy and chemotherapy, which has the potential to assist in the clinical management of HCC.

Exploring symptom clusters in Chinese patients with peritoneal dialysis: a network analysis.

BACKGROUND: In recent years, the research on symptom management in peritoneal dialysis (PD) patients has shifted from a single symptom to symptom clusters and network analysis. This study collected and evaluated unpleasant symptoms in PD patients and explored groups of symptoms that may affect PD patients with a view to higher symptom management. METHODS: The symptoms of PD patients were measured using the modified Dialysis Symptom Index. The symptom network and node characteristics were assessed by network analysis, and symptom clusters were explored by factor analysis. RESULTS: In this study of 602 PD patients (mean age 47.8 ± 16.8 years, 47.34% male), most had less than 2 years of dialysis experience. Five symptom clusters were obtained from factor analysis, which were body symptom cluster, gastrointestinal symptom cluster, mood symptom cluster, sexual disorder symptom cluster, and skin-sleep symptom cluster. Itching and decreased interest in sex may be sentinel symptoms, and being tired or lack of energy and feeling anxious are core symptoms in PD patients. CONCLUSIONS: This study emphasizes the importance of recognizing symptom clusters in PD patients for better symptom management. Five clusters were identified, with key symptoms including itching, decreased interest in sex, fatigue, and anxiety. Early intervention focused on these symptom clusters in PD patients holds promise for alleviating the burden of symptoms.

Higher N-terminal pro-brain natriuretic peptide level at onset of peritoneal dialysis-related peritonitis is a risk factor for technique failure.

BACKGROUND: Recent studies have suggested that the N-terminal fragment of B-type natriuretic peptide (NT-proBNP) level serve as a significant risk factor for mortality in patients with end-stage renal disease. However, the relationship between NT-proBNP levels and technique failure in peritoneal dialysis-associated peritonitis (PDAP) remains unclear. This study investigated the relationship between NT-proBNP levels at the onset of PDAP and the risk of technique failure in patients with PDAP. METHODS: A retrospective analysis was conducted on patients with PDAP from December 1, 2009, to December 31, 2021, at our peritoneal dialysis center. We recorded all demographic and baseline clinical data at the time of admission for each PDAP episode. Logistic and Cox regression analyses were performed to assess the association between NT-proBNP levels and technique failure. RESULTS: Of 485 PDAP episodes included in this study, 130 episodes of technique failure were observed. Multivariate logistic analysis revealed that hospital stay, Na and NT-proBNP levels, and peritoneal dialysate white blood cell counts on days 3 and 5 were independently associated with technique failure. The receiver operating characteristic curve demonstrated that the NT-proBNP level was a better indicator than the other four variables in indicating technique failure. In the multivariate Cox regression analysis, after adjusting for confounding factors, higher NT-proBNP levels (HR of 3.020, 95% CI 1.771, 5.150, P < 0.001) were associated with PDAP technique failure. CONCLUSIONS: This retrospective study identified the serum NT-proBNP level at the onset of PDAP as an independent risk factor for technique failure in these patients.

PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

Grey matter abnormalities in major depressive disorder patients with suicide attempts: A systematic review of age-specific differences.

Background: Previous studies have reported alterations in brain structure in major depressive disorder (MDD) patients with suicide attempts. However, age-related changes in suicidal MDD patients remain unclear. Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Embase, PubMed, and Web of Science were searched to identify relevant studies from inception to January 2023. All voxel-based and surface-based morphometry studies comparing suicidal MDD patients to MDD or healthy controls were included. Studies were then grouped by age range (old, middle-age, adolescent) and the commonalities and age-related structural brain alterations were summarized. The included studies were evaluated using the Newcastle-Ottawa Scale (NOS). Results: A total of 17 studies met the inclusion criteria, including 3 of late-life depression (LLD) patients, 11 of middle-aged depression (MAD) patients, and 3 of adolescent depression (AOD) patients. The majority of studies had moderate to high NOS scores, indicating good quality. Patients in all three age groups exhibited extensive alterations in the lateral, medial, and orbital regions of the frontal lobes. Furthermore, suicidal MAD patients showed a specific decrease in the gray matter volume of the dorsolateral prefrontal cortex compared to suicidal LLD patients. Cortical thickness and left angular gyrus volume were decreased in suicidal MAD and suicidal LLD patients, but increased in suicidal AOD patients. Conclusion: This systematic review summarizes structural brain changes in suicidal MDD patients at three age groups: elderly, middle-aged, and adolescent. These findings help elucidate the common circuitry of MDD related to suicide over the lifespan and highlight unique circuitry associated with different ages. These findings may help predict the risk of suicide in MDD patients at different ages.

COVID-19 and outcomes in Chinese peritoneal dialysis patients.

BACKGROUND: Reports on COVID-19 in peritoneal dialysis (PD) patients are scarce in China. This study aimed to describe the characteristics and outcomes of PD patients with COVID-19 after China abandoned the 'zero-COVID' policy. METHODS: This single-centre retrospective study included patients receiving PD who underwent testing for COVID-19 infections between 7 December 2022 and 7 January 2023. Outcomes of interest included factors associated with positive COVID-19 testing result and clinical outcomes including COVID-19-related hospitalisation and severe COVID-19, which were analysed using logistic regression analyses. RESULTS: A total of 349 PD patients (male 53.6%, age 49 ± 13 years old) were included, and 235 patients (67.3%) were infected. There were no significant differences between COVID-19 and non-COVID-19 patients other than higher proportion of vaccinated patients and slow transporters in the patients who tested positive for COVID-19 (44.7% vs. 28.1%, p = 0.003; 8.7% vs. 1.8%, p = 0.03, respectively). Multivariate analysis showed COVID-19 was associated with vaccination (odds ratio (OR): 1.71, 95% confidence interval (CI): 1.02-2.86) and slow transport type (compared with average transport type, OR: 4.52, 95% CI: 1.01-20.21). Among the patients with infection, 38 (16.2%) patients were hospitalised, 18 (7.7%) patients had severe disease and 9 (3.8%) patients died. In multivariate logistic analysis, both age (OR: 1.04, 95% CI: 1.01-1.07; OR: 1.06, 95% CI: 1.02-1.11) and hyponatremia (OR: 5.44, 95% CI: 1.63-18.13; OR: 6.50, 95% CI: 1.77-23.85) were independent risk factors for COVID-19-related hospitalisation and severe disease. CONCLUSIONS: Although vaccinated patients were more likely to have tested positive for COVID-19 infection, they appeared to have less severe infection and less need for hospitalisation. Patients who were older with a history of hyponatremia were more likely to experience adverse outcomes from COVID-19.

Re-emerging magnetic order in correlated van der Waals antiferromagnet NiPS3.

Van der Waals (vdW) gap is a significant feature that distinguishes vdW magnets from traditional magnets. Manipulating the magnetic properties by changing the vdW gap has been hot topic in condensed matter research. Here we report a re-emerging magnetic order induced by pressure in a correlated vdW antiferromagnetic insulator NiPS3. It is found that the interlayer magnetoresistance (MR) nearly vanishes at the critical pressure where the crystal structure transforms fromC2/mphase to the slidingC2/mphase. On further compression within the slidingC2/mphase, a substantially enhanced MR emerges from low temperature associated with an insulator-to-metal transition, indicating a metallic antiferromagnetic phase. The enhanced re-emerging MR in slidingC2/mphase can be ascribed to the increasing magnetic interaction between neighboring layers due to the vdW gap narrowing. Our results provide important experimental clues for understanding the pressure effects on magnetism in correlated layered materials.

Altered Proteomic Profile of Exosomes Secreted from Vero Cells Infected with Porcine Epidemic Diarrhea Virus.

Porcine epidemic diarrhea virus (PEDV) infection causes severe diarrhea in pigs and can be fatal in newborn piglets. Exosomes are extracellular vesicles secreted by cells that transfer biologically active proteins, lipids, and RNA to neighboring or distant cells. Herein, the morphology, particle size, and secretion of exosomes derived from a control and PEDV-infected group are examined, followed by a proteomic analysis of the exosomes. The results show that the exosomes secreted from the Vero cells had a typical cup-shaped structure. The average particle size of the exosomes from the PEDV-infected group was 112.4 nm, whereas that from the control group was 150.8 nm. The exosome density analysis and characteristic protein determination revealed that the content of exosomes in the PEDV-infected group was significantly higher than that in the control group. The quantitative proteomics assays revealed 544 differentially expressed proteins (DEPs) in the PEDV-infected group's exosomes compared with those in the controls, with 236 upregulated and 308 downregulated proteins. The DEPs were closely associated with cellular regulatory pathways, such as the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, extracellular matrix-receptor interaction, focal adhesion, and cytoskeletal regulation. These findings provide the basis for further investigation of the pathogenic mechanisms of PEDV and the discovery of novel antiviral targets.

Non-targeted metabolomics analysis reveals the mechanism of arbuscular mycorrhizal symbiosis regulating the cold-resistance of Elymus nutans.

Elymus nutans is a perennial grass of the Gramineae family. Due to its cold-resistance and nutrition deficiency tolerance, it has been applied to the ecological restoration of degraded alpine grassland on the Qinghai-Tibet Plateau. As an important symbiotic microorganism, arbuscular mycorrhizal fungi (AMF) have been proven to have great potential in promoting the growth and stress resistance of Gramineae grasses. However, the response mechanism of the AMF needs to be clarified. Therefore, in this study, Rhizophagus irregularis was used to explore the mechanism regulating cold resistance of E. nutans. Based on pot experiments and metabolomics, the effects of R. irregularis were investigated on the activities of antioxidant enzyme and metabolites in the roots of E. nutans under cold stress (15/10°C, 16/8 h, day/night). The results showed that lipids and lipid molecules are the highest proportion of metabolites, accounting for 14.26% of the total metabolites. The inoculation with R. irregularis had no significant effects on the activities of antioxidant enzyme in the roots of E. nutans at room temperature. However, it can significantly change the levels of some lipids and other metabolites in the roots. Under cold stress, the antioxidant enzyme activities and the levels of some metabolites in the roots of E. nutans were significantly changed. Meanwhile, most of these metabolites were enriched in the pathways related to plant metabolism. According to the correlation analysis, the activities of antioxidant enzyme were closely related to the levels of some metabolites, such as flavonoids and lipids. In conclusion, AMF may regulate the cold-resistance of Gramineae grasses by affecting plant metabolism, antioxidant enzyme activities and antioxidant-related metabolites like flavonoids and lipids. These results can provide some basis for studying the molecular mechanism of AMF regulating stress resistance of Gramineae grasses.

Genome-wide detection of CNV regions between Anqing six-end-white and Duroc pigs.

BACKGROUND: Anqing six-end-white pig is a native breed in Anhui Province. The pigs have the disadvantages of a slow growth rate, low proportion of lean meat, and thick back fat, but feature the advantages of strong stress resistance and excellent meat quality. Duroc pig is an introduced pig breed with a fast growth rate and high proportion of lean meat. With the latter breed featuring superior growth characteristics but inferior meat quality traits, the underlying molecular mechanism that causes these phenotypic differences between Chinese and foreign pigs is still unclear. RESULTS: In this study, copy number variation (CNV) detection was performed using the re-sequencing data of Anqing Six-end-white pigs and Duroc pigs, A total of 65,701 CNVs were obtained. After merging the CNVs with overlapping genomic positions, 881 CNV regions (CNVRs) were obtained. Based on the obtained CNVR information combined with their positions on the 18 chromosomes, a whole-genome map of the pig CNVs was drawn. GO analysis of the genes in the CNVRs showed that they were primarily involved in the cellular processes of proliferation, differentiation, and adhesion, and primarily involved in the biological processes of fat metabolism, reproductive traits, and immune processes. CONCLUSION: The difference analysis of the CNVs between the Chinese and foreign pig breeds showed that the CNV of the Anqing six-end-white pig genome was higher than that of the introduced pig breed Duroc. Six genes related to fat metabolism, reproductive performance, and stress resistance were found in genome-wide CNVRs (DPF3, LEPR, MAP2K6, PPARA, TRAF6, NLRP4).

[Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023)].

The awake prone position plays an important role in the treatment of hypoxemia and the improvement of respiratory distress symptoms in non-intubated patients. It is widely used in clinical practice because of its simple operation, safety, and economy. To enable clinical medical staff to scientifically and normatively implement prone position for awake patients without intubation, the committees of consensus formulation, guided by evidence-based methodology and Delphi method, conducted literature search, literature quality evaluation and evidence synthesis around seven topics, including indications and contraindications, evaluation, implementation, monitoring and safety management, termination time, complication prevention and health education of awake prone position. After two rounds of expert letter consultation, Expert consensus on implementation strategy of awake prone positioning for non-intubated patients in China (2023) was formulated, and provide guidance for clinical medical staff.

Grass-Legume Mixture with Rhizobium Inoculation Enhanced the Restoration Effects of Organic Fertilizer.

The establishment of artificial grassland is crucial in restoring degraded grassland and resolving the forage-livestock conflict, and the application of organic fertilizer and complementary seeding of grass-legume mixture are effective methods to enhance grass growth in practice. However, its mechanism behind the underground is largely unclear. Here, by utilizing organic fertilizer in the alpine region of the Qinghai-Tibet Plateau, this study assessed the potential of grass-legume mixtures with and without the inoculation of Rhizobium for the restoration of degraded grassland. The results demonstrated that the application of organic fertilizer can increase the forage yield and soil nutrient contents of degraded grassland, and they were 0.59 times and 0.28 times higher than that of the control check (CK), respectively. The community composition and structure of soil bacteria and fungi were also changed by applying organic fertilizer. Based on this, the grass-legume mixture inoculated with Rhizobium can further increase the contribution of organic fertilizer to soil nutrients and thus enhance the restoration effects for degraded artificial grassland. Moreover, the application of organic fertilizer significantly increased the colonization of gramineous plant by native mycorrhizal fungi, which was ~1.5-2.0 times higher than CK. This study offers a basis for the application of organic fertilizer and grass-legume mixture in the ecological restoration of degraded grassland.

A randomized controlled comparative study of different fluid exchange modes in urgent-start peritoneal dialysis in patients with end-stage renal disease: automated peritoneal dialysis combined with manual fluid exchange vs. manual fluid exchange alone.

During urgent-start peritoneal dialysis (USPD) in end-stage renal disease (ESRD) patients, both adequate dialysis and skill training for fluid exchange are essential. However, automated peritoneal dialysis (APD) alone or manual fluid exchange peritoneal dialysis (MPD) alone could meet the above demands. Therefore, our study combined APD with MPD (A-MPD), and compared A-MPD with MPD, aiming to find the most appropriate treatment mode. This was a single-center, prospective, randomized controlled study. All eligible patients were randomized into the MPD and A-MPD groups. All patients underwent a five-day USPD treatment 48 h after catheter implantation, and they were followed up for six months after discharge. Overall, 74 patients were enrolled in this study. Among these, 14 and 60 patients quit due to complications during USPD and completed the study (A-MPD = 31, MPD = 29), respectively. Compared with MPD, the A-MPD treatment mode had a better effect on removing serum creatinine, blood urea nitrogen, and potassium and improving serum carbon dioxide combining power levels; it had less time expenditure on the fluid exchange by nurses (p < 0.05). In addition, patients in the A-MPD group had higher scores on the skill tests than those in the MPD group (p = 0.002). However, no significant differences in short-term peritoneal dialysis (PD) complications, PD technical survival rate, or mortality were found between the two groups. Therefore, the A-MPD mode could be recommended as an adoptable and suitable PD modality for USPD in the future.

[Methylselenocysteine Promotes Etoposide Cytotoxicity by Enhancing Homotypic Gap Junctions Composed of Connexin 26].

Objective: To investigate the effect of methylselenocysteine (MSC) on the function of homotypic gap junction (GJ) composed of connexin (Cx) 26 and its regulation of chemotherapeutic drug cytotoxicity. Methods: The Tet-on HeLa cells transfected with and stably expressing Cx26 were used as the tool cells. Effects of MSC on cell growth, GJ function, and Cx26 protein expression were examined by MTT method, parachute assay, and Western blot analysis, respectively. The cytotoxicity of chemotherapeutic drugs was determined by standard colony-forming assay, and the relationship between MSC's effect on cytotoxicity of these chemotherapeutic drugs and its regulation of GJ was further analyzed. Results: In Tet-on HeLa cells, doxycycline (Dox) can induce the expression of Cx26, which could then form functional GJs. Within a concentration range of 50 µmol/L, MSC had no significant effect on HeLa cell growth. Non-toxic concentrations of MSC can enhance GJs in a concentration-dependent manner and exert its effect at the nanomolar level. This effect was associated with an induction of Cx26 protein expression by MSC. Among the three common chemotherapeutic agents with different mechanisms of action, etoposide (Eto) presented cytotoxicity differences between HeLa cells cultured at low density (nonconfluent, no GJ formed) and high density (confluent, GJ formed). What's more, the inhibitory effect of Eto combined with MSC on HeLa cell colony formation was stronger than that of Eto alone, and this effect occurred only in HeLa cells with GJ formation. Conclusion: MSC can potentiate the cytotoxicity of Eto by enhancing the GJs composed of Cx26, indicating that combined strategy of selenide and chemotherapy shows potential value in the treatment of malignant tumors.

[Current status and our consideration on clinical transformation of acupuncture research].

It has become one of the major strategic directions to develop translational medicine and realize the stride leap from basic research to clinical application in the national biomedical field. In recent years, both basic and clinical researches of acupuncture and moxibustion have made landmark progress. However, the transformation of acupuncture and moxibustion techniques still faced with many difficulties, such as low conversion rate and high difficulty of transformation. In this article, we mainly made a preliminary discussion on the current situations of acupuncture and moxibustion transformation from the aspects of basic research content, evidence-based medicine and clinical trials, evaluation criteria for the conclusion of scientific research projects and transformation mode, put forward some existing problems in the transformation process, and proposed some corresponding countermeasures to the problems.

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients.

BACKGROUND: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. METHODS: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). RESULTS: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment. CONCLUSIONS: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.

miR-141-3p Promotes the Cisplatin Sensitivity of Osteosarcoma Cell through Targeting the Glutaminase [GLS]-Mediated Glutamine Metabolism.

AIMS: This study aimed to evaluate the roles and molecular targets of miRNA-141-3p in the cisplatin sensitivity of osteosarcoma. BACKGROUND: Osteosarcoma is one of the most common-type bone tumors, occurring mainly in children and adolescents. Cancer cells display dysregulated cellular metabolism, such as the abnormally elevated glutamine metabolism. OBJECTIVE: Non-coding RNA miRNA-141-3p has been reported to act as a tumor suppressor in osteosarcoma. Currently, the precise molecular mechanisms for the miR- 141-3p-mediated chemosensitivity through regulating glutamine metabolism remain unclear. METHODS: We collected thirty paired OS tumors and their adjacent normal tissues. The osteosarcoma cell lines [Saos-2] and normal osteoblast cells, hFOB1.19, were used for in vitro experiments. RT-qPCR and Western blot were applied for gene expression detections. Targets of miR-141-3p were predicted from starBase. The MTT and flow cytometric assays were performed to determine cell growth and apoptosis rates. The cellular glutamine metabolism was monitored by glutamine uptake assay and the glutaminase [GLS] activity assay. RESULTS: We reported that miR-141-3p were significantly downregulated in osteosarcoma tissues and cells. Overexpression of miR-141-3p suppressed OS cell growth and sensitized OS cells to cisplatin. In addition, glutamine metabolism was significantly increased in osteosarcoma. We characterized that GLS played oncogenic roles in osteosarcoma and validated GLS was a direct target of miR-141-3p in OS cells. Rescue experiments consistently demonstrated that miR-141-3p-promoted cisplatin sensitivity was achieved by targeting GLS directly. CONCLUSION: Overall, our findings revealed new molecular mechanisms of the miR-141- 3p-modulated cisplatin sensitization through targeting the GLS-glutamine metabolism pathway. This study will contribute to developing new therapeutic approaches for the treatments of chemoresistant osteosarcoma.

Activation of the Akt/FoxO3 signaling pathway enhances oxidative stress-induced autophagy and alleviates brain damage in a rat model of ischemic stroke.

Autophagy has been implicated in stroke. Our previous study showed that the FoxO3 transcription factor promotes autophagy after transient cerebral ischemia/reperfusion (I/R). However, whether the Akt/FoxO3 signaling pathway plays a regulatory role in autophagy in cerebral I/R-induced oxidative stress injury is still unclear. The present study aims to investigate the effects of the Akt/FoxO3 signaling pathway on autophagy activation and neuronal injury in vitro and in vivo. By employing LY294002 or insulin to regulate the Akt/FoxO3 signaling pathway, we found that insulin pretreatment increased cell viability, decreased reactive oxygen species production, and enhanced the expression of antiapoptotic and autophagy-related proteins following H2O2 injury in HT22 cells. In addition, insulin significantly decreased neurological deficit scores and infarct volume and increased the expression of antiapoptotic and autophagy-related proteins following I/R injury in rats. However, LY294002 showed the opposite effects under these conditions. Altogether, these results indicate that Akt/FoxO3 signaling pathway activation inhibited oxidative stress-mediated cell death through activation of autophagy. Our study supports a critical role for the Akt/FoxO3 signaling pathway in autophagy activation in stroke.

Random forest can accurately predict the technique failure of peritoneal dialysis associated peritonitis patients.

Instructions: Peritoneal dialysis associated peritonitis (PDAP) is a major cause of technique failure in peritoneal dialysis (PD) patients. The purpose of this study is to construct risk prediction models by multiple machine learning (ML) algorithms and select the best one to predict technique failure in PDAP patients accurately. Methods: This retrospective cohort study included maintenance PD patients in our center from January 1, 2010 to December 31, 2021. The risk prediction models for technique failure were constructed based on five ML algorithms: random forest (RF), the least absolute shrinkage and selection operator (LASSO), decision tree, k nearest neighbor (KNN), and logistic regression (LR). The internal validation was conducted in the test cohort. Results: Five hundred and eight episodes of peritonitis were included in this study. The technique failure accounted for 26.38%, and the mortality rate was 4.53%. There were resignificant statistical differences between technique failure group and technique survival group in multiple baseline characteristics. The RF prediction model is the best able to predict the technique failure in PDAP patients, with the accuracy of 93.70% and area under curve (AUC) of 0.916. The sensitivity and specificity of this model was 96.67 and 86.49%, respectively. Conclusion: RF prediction model could accurately predict the technique failure of PDAP patients, which demonstrated excellent predictive performance and may assist in clinical decision making.