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Abstract Disulfidptosis, a novel form of regulated cell death, occurs due to the aberrant accumulation of intracellular cystine and other disulfides. Moreover, targeting disulfidptosis could identify promising approaches for cancer treatment. Long non-coding RNAs (lncRNAs) are known to be critically implicated in clear cell renal cell carcinoma (ccRCC) development. Currently, the involvement of disulfidptosis-related lncRNAs in ccRCC is yet to be elucidated. This study primarily dealt with identifying and validating a disulfidptosis-related lncRNAs-based signature for predicting the prognosis and immune landscape of individuals with ccRCC. Clinical and RNA sequencing data of ccRCC samples were accessed from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was conducted for the identification of the disulfidptosis-related lncRNAs. Additionally, univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator Cox regression, and stepwise multivariate Cox analysis were executed to develop a novel risk prognostic model. The prognosis-predictive capacity of the model was then assessed using an integrated method. Variation in biological function was noted using GO, KEGG, and GSEA. Additionally, immune cell infiltration, the tumor mutational burden (TMB), and tumor immune dysfunction and exclusion (TIDE) scores were calculated to investigate differences in the immune landscape. Finally, the expression of hub disulfidptosis-related lncRNAs was validated using qPCR. We established a novel signature comprised of eight lncRNAs that were associated with disulfidptosis (SPINT1-AS1, AL121944.1, AC131009.3, AC104088.3, AL035071.1, LINC00886, AL035587.2, and AC007743.1). Kaplan–Meier and receiver operating characteristic curves demonstrated the acceptable predictive potency of the model. The nomogram and C-index confirmed the strong correlation between the risk signature and clinical decision-making. Furthermore, immune cell infiltration analysis and ssGSEA revealed significantly different immune statuses among risk groups. TMB analysis revealed the link between the high-risk group and high TMB. It is worth noting that the cumulative effect of the patients belonging to the high-risk group and having elevated TMB led to decreased patient survival times. The high-risk group depicted greater TIDE scores in contrast with the low-risk group, indicating greater potential for immune escape. Finally, qPCR validated the hub disulfidptosis-related lncRNAs in cell lines. The established novel signature holds potential regarding the prognosis prediction of individuals with ccRCC as well as predicting their responses to immunotherapy.

Background: The Padua Prediction Score (PPS) recommended by the guidelines lacks effective external validation in a Chinese cohort. This study sought to assess the accuracy of the PPS to predict venous thromboembolism (VTE) risk in medical inpatients with acute respiratory conditions. Methods: This consecutive cohort study included 1,574 inpatients from January to August 2019. The occurrence rate of VTE in patients classified at high-risk and low-risk groups according to PPS and Caprini risk assessment model (RAM) was compared. The discriminatory capability of the RAMs was evaluated in all the patients and the subgroup without pharmacological prophylaxis. Reclassification parameters were also used to assess the clinical utility. Results: 170 (10.8%) patients were objectively confirmed as having VTE during hospitalization. The incidence rate of VTE in low-risk patients was 6.3% by PPS, which was significantly higher than that by Caprini RAM (2.6%, p

Background Sepsis-associated acute kidney injury (S-AKI) is a critical illness and is often associated with high morbidity and mortality rates. The soluble urokinase-type plasminogen activator receptor (suPAR) is an important immune mediator and is involved in kidney injury. However, its diagnostic value in S-AKI patients remains unclear. Therefore, we assessed the early predictive value of suPAR for S-AKI patients.Methods We prospectively enrolled adult patients, immediately after fulfilling the sepsis-3 criteria. Plasma suPAR levels at 0-, 12-, 24-, and 48-h post-sepsis diagnosis were measured. S-AKI development was the primary outcome. S-AKI risk factors were analyzed using logistic regression, and the value of plasma suPAR for early S-AKI diagnosis was assessed using receiver operating characteristic (ROC) curves.Results Of 179 sepsis patients, 63 (35.2%) developed AKI during hospitalization. At 12-, 24-, and 48-h post-sepsis diagnosis, plasma suPAR levels were significantly higher in patients with S-AKI than in patients without S-AKI (p

AimThis study aimed to investigate the relationship between a new metric—metabolic score for insulin resistance (METS-IR)—and estimated glomerular filtration rate (eGFR) among Japanese participants who underwent health check-ups.MethodsWe conducted a cross-sectional study that involved participants in a medical health screening program, which was conducted at the Medical Health Check-up Center in Japan. This retrospective study examined the relationship between METS-IR and eGFR among 881 individuals that joined the program between March 1, 2004, and December 31, 2012. Covariates consisted of serum laboratory tests and lifestyle questionnaires. Multivariate linear regression analysis was used to explore the association between METS-IR and eGFR. In addition, subgroup and interaction analyses were done based on age, sex, body mass index (BMI), alcohol use, smoking status, and hyperuricemia.ResultsA total of 881 individuals participated in this study. High METS-IR was highly linked with reduced eGFR (adjusted β = -5.04, 95% confidence interval (CI): -7.65 to -2.43), while METS-IR was utilized as a categorical variable inside the multiple regression analysis. A decrease in eGFR of 2.54 units was reported for every 10-unit rise in METS-IR (adjusted β = -2.54, 95% CI: -4.04 to -1.05, P-value = 0.001). Stratified analysis suggested no marked interaction between METS-IR and eGFR across age, sex, BMI, and alcohol consumption groups. However, there was an indication of interaction between METS-IR level, smoking status (P-value = 0.001), and uric level (P-value = 0.011) on eGFR decrease.ConclusionsMETS-IR is remarkably associated with eGFR among the participants who underwent health check-ups in Gifu, Japan. Although more studies are required to prove it, METS-IR could be applied as a monitoring index for early screening, primary prevention, and diagnostic and treatment management strategies for chronic kidney disease.

Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.

Clear cell renal cell carcinoma (ccRCC) is one of the most frequent pathological subtypes of kidney cancer, accounting for ~70–75%, and the major cause of mortality is metastatic disease. The difference in gene expression profiles between primary ccRCC tumors and metastatic tumors has not been determined. Thus, we report integrated genomic and transcriptomic analysis for identifying differentially expressed genes (DEGs) between primary and metastatic ccRCC tumors to understand the molecular mechanisms underlying the development of metastases. The microarray datasets GSE105261 and GSE85258 were obtained from the Gene Expression Omnibus (GEO) database, and the R package limma was used for DEG analyses. In summary, the results described herein provide important molecular evidence that metastatic ccRCC tumors are different from primary tumors. Enrichment analysis indicated that the DEGs were mainly enriched in ECM–receptor interaction, platelet activation, protein digestion, absorption, focal adhesion, and the PI3K–Akt signaling pathway. Moreover, we found that DEGs associated with a higher level of tumor immune infiltrates and tumor mutation burden were more susceptible to poor prognosis of ccRCC. Specifically, our study indicates that seven core genes, namely the collagen family (COL1A2, COL1A1, COL6A3, and COL5A1), DCN, FBLN1, and POSTN, were significantly upregulated in metastatic tumors compared with those in primary tumors and, thus, potentially offer insight into novel therapeutic and early diagnostic biomarkers of ccRCC.

Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction. [ABSTRACT FROM AUTHOR]