This study explored the mechanistic basis for nonsmall cell lung cancer (NSCLC) cisplatin (DDP) treatment resistance in an effort to define effective approaches to abrogating the emergence of such chemoresistance. Analyses of NSCLC expression of hsa_circ_0000190, miR-1253, and interleukin 6 (IL-6) were conducted via a quantitative real-time polymerase chain reaction (qPCR) approach, while the ability of these tumor cells to resist DDP treatment was evaluated with a CCK-8 assay. Interactions between different RNA molecules were assessed using both RNA immunoprecipitation and dual-luciferase reporter assays. NSCLC cell lines and tissues resistant to DDP were found to express higher levels of hsa_circ_0000190, and knocking down this circRNA in NSCLC cells was associated with greater sensitivity to DDP exposure. Further research identified miR-1253 as a hsa_circ_0000190 target, with the ability of hsa_circ_0000190 knockdown to restore DDP sensitivity being largely attributable to the ability of this circRNA to suppress miR-1253 activity. IL-6 was identified as a major miR-1253 target in this context, with miR-1253 regulating chemoresistance in NSCLC cells in part by preventing IL-6 upregulation. Together, these data suggest that hsa_circ_0000190 can promote DDP chemoresistance in NSCLC cells through its ability to modulate miR-1253/IL-6 axis activity, highlighting a novel pathway that can be targeted in an effort to guide the more effective diagnosis and management of DDP-resistant tumors.

Background. Diffuse large B‐cell lymphoma (DLBCL) is one of the largest lymphoma subcategories. Usually, 50%–70% of DLBCL patients can be cured by the standard treatment. But, at least one third have bad prognosis. Based on this situation, the research on DLBCL therapy strategy is still indispensable. Methods. A prognostic signature was built according to the public data and bioinformatics methods, the stability and reliability was assessed and validated. GSEA was performed to explore the difference in different groups. Consensus clustering and immune infiltration analysis were conducted comprehensively. Results. In this work, a signature based on multiple metabolism‐associated genes (MTGs) was established, containing 16 MTGs, to predict the prognosis of DLBCL patients. The accuracy and effectiveness of this signature have been verified by three external validation sets. According to the risk formula, DLBCL patients were divided into high‐ and low‐risk groups, and the survival rate of the low‐risk group was significantly higher than that of the high‐risk group. Furthermore, gene set enrichment analysis (GSEA) demonstrated that beta‐alanine metabolism and regulation of actin cytoskeleton signal pathways were enriched in the low‐risk group. The actual survival and nomogram‐predicted survival matched well both in the training cohort and verification cohorts. Conclusion. In general, our prognostic signature can provide reliable and valuable information for medical workers in predicting the prognosis of DLBCL. A preprint was made available by the research square in the following link: “https://www.researchsquare.com/article/rs-1468741/v2.”

Intraoperative cytological examination of central nervous system (CNS) lesions was first introduced in 1920 by Eisenhardt and Cushing for rapid evaluation of neurosurgical specimens and to guide surgical treatment. It is recognized that this method not only confirms the adequacy of biopsy in CNS samples but also indicates the presence and preliminary diagnosis of lesional tissue. A total of 93 patients who underwent touch imprint cytology (TIC) for CNS tumors or lesions between 2018 and 2023 were included in the study. All cases were correlated with the final histopathological diagnosis, and pitfalls and difficulties encountered with discrepancies were noted. The most common primary CNS tumors were gliomas and meningiomas, while secondary (metastatic) tumors were predominantly lung, breast, and gastrointestinal system carcinomas. Sensitivity, specificity, positive predictive value, and negative predictive value for diagnosis with TIC were 94.1%, 100%, and 61.5%, respectively. Final histopathological diagnosis by TIC was made in 88 cases (94.6%) and the discrepancy was found in 5 cases (5.37%). Three of the five discrepancies (3.2%) were haematolymphoid malignancies (two lymphomas and one plasma cell neoplasia), one glioblastoma, and one hemangioblastoma case. TIC is a fast, safe, and inexpensive diagnostic tool used during intraoperative neuropathology consultation. Awareness of the pitfalls of using this method during intraoperative consultation will enable high-diagnostic accuracy.

Phospholipase D (PLD) is an enzyme that consists of six isoforms (PLD1-PLD6) and has been discovered in different organisms including bacteria, viruses, plants, and mammals. PLD is involved in regulating a wide range of nerve cells' physiological processes, such as cytoskeleton modulation, proliferation/growth, vesicle trafficking, morphogenesis, and development. Simultaneously, PLD, which also plays an essential role in the pathogenesis of neurodegenerative and neuroimmune diseases. In this review, family members, characterizations, structure, functions and related signaling pathways, and therapeutic values of PLD was summarized, then five representative diseases including Alzheimer disease (AD), Parkinson's disease (PD), etc. were selected as examples to tell the involvement of PLD in these neurological diseases. Notably, recent advances in the development of tools for studying PLD therapy envisaged novel therapeutic interventions. Furthermore, the limitations of PLD based therapy were also analyzed and discussed. The content of this review provided a thorough and reasonable basis for further studies to exploit the potential of PLD in the treatment of neurodegenerative and neuroimmune diseases.

To investigate the clinical and pathological effects of serum C3 level, mesangial C3 deposition intensity and blood lipid on IgA nephropathy. According to the deposition intensity of immunofluorescence (IF) complement C3 in mesangial region, a total of 151 patients were divided into: (1) negative group (65 cases), (2) weak positive group (51 cases), and (3) strong positive group (35 cases). According to the level of serum C3, the patients were divided into two groups: (1) 33 patients with decreased serum C3 (<85 mg/dL); (2) 118 patients with normal serum C3. The clinicopathological data of the patients were analyzed retrospectively according to the groups. (1) With the increase of C3 deposition in mesangial region, the mean value of serum C3 level decreased, and the difference was statistically significant (P=0.001). (2) Compared with the normal serum C3 group, the blood urea nitrogen (BUN), serum creatinine (Scr), and albumin (Alb) in the serum C3 decreased group were higher, and the differences were statistically significant (P < 0.05), while the fasting blood glucose (FBG), low-density lipoprotein (LDL), triglyceride and 24-hr urinary protein (24hUTP) were lower, which difference was statistically significant (P < 0.05). (3) Compared with negative group and weak positive group, BUN, uric acid (UA), and Scr were higher in the strong positive group with C3 deposition, while eGFR was lower, with statistical significance (P < 0.05). However, C3 deposition in the mesangial region was related to T and enhanced mesangial C3 deposition was associated with more severe tubular atrophy and/or interstitial fibrosis, with statistically significant differences (P=0.001). Patients with strong mesangial C3 deposition and elevated lipid levels had more severe tubule atrophy and/or interstitial fibrosis, as well as more severe pathological lesions, suggesting that activation of the complement system is involved in the pathogenesis of IgA nephropathy and increases the metabolic burden of the kidney.

Glioma is a devastating type of brain tumor with high morbidity and mortality rates. Despite current treatment options, the prognosis for glioma patients remains poor. Metabolic reprograming has emerged as a crucial aspect of tumorigenesis, and the oxidative phosphorylation pathway has received increasing attention as a promising target for cancer treatment. In this study, we conducted a comprehensive analysis of transcriptome data to identify differentially expressed genes related to oxidative phosphorylation in glioma. Based on these findings, we developed the first oxidative phosphorylation‐based prognostic and diagnostic signatures and investigated the methylation level of oxidative phosphorylation‐related genes, constructed miRNA–mRNA regulatory networks, and screened potential oxidative phosphorylation pathway inhibitors. Moreover, we analyzed the immune cell infiltration pattern based on oxidative phosphorylation‐related genes’ expression and found that the high‐oxidative phosphorylation group had more inhibitory immune cell infiltration. Overall, this study provides novel insights into the possible molecular mechanisms of oxidative phosphorylation in glioma progression and identifies potential targets for future glioma therapy.

Premature rupture of membrane (PROM) refers to the rupture of membranes before the onset of labor which increases the risk of perinatal morbidity and mortality. Recently, circular RNAs (circRNAs) have emerged as promising regulators of diverse diseases. However, the circRNA expression profiles and potential circRNA-miRNA-mRNA regulatory mechanisms in PROM remain enigmatic. In this study, we displayed the expression profiles of circRNAs and mRNAs in plasma and fetal membranes of PROM and normal control (NC) groups based on circRNA microarray, the Gene Expression Omnibus database, and NCBI's Sequence Read Archive. A total of 1,459 differentially expressed circRNAs (DECs) in PROM were identified, with 406 upregulated and 1,053 downregulated. Then, we constructed the circRNA-miRNA-mRNA network in PROM, encompassing 22 circRNA-miRNA pairs and 128 miRNA-mRNA pairs. Based on the analysis of gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene set enrichment analysis (GSEA), DECs were implicated in immune-related pathways, with certain alterations persisting even postpartum. Notably, 11 host genes shared by DECs of fetal membrane tissue and prenatal plasma in PROM were significantly implicated in inflammatory processes and extracellular matrix regulation. Our results suggest that structurally stable circRNAs may predispose to PROM by mediating systemic immune imbalances, including peripheral leukocyte disorganization, local immune imbalance at the maternal-fetal interface, and local collagen disruption. This is the first time to decipher a landscape on circRNAs of PROM, reveals the pathogenic cause of PROM from the perspective of circRNA, and opens up a new direction for the diagnosis and treatment of PROM.

Background: As an important downstream effector of various signaling pathways, mTOR plays critical roles in regulating many physiological processes including erythropoiesis. It is composed of two distinct complexes, mTORC1 and mTORC2, which differ in their components and downstream signaling effects. Our previous study revealed that the inhibition of mTORC1 by rapamycin significantly repressed the erythroid progenitor expansion in the early stage but promoted enucleation and mitochondria clearance in the late stage of erythroid differentiation. However, the particular roles and differences of mTORC1 and mTORC2 in the regulation of erythropoiesis still remain largely unknown. In the present study, we investigated the comparative effects of dual mTORC1/mTORC2 mTOR kinase inhibitor AZD8055 and mTORC1 inhibitor rapamycin on erythroid differentiation in K562 cells induced by hemin and erythropoiesis in β‐thalassemia mouse model.Materials and Methods: In vitro erythroid differentiation model of hemin‐induced K562 cells and β‐thalassemia mouse model were treated with AZD8055 and rapamycin. Cell Counting Kit‐8 was used to detect cell viability. The cell proliferation, cell cycle, erythroid surface marker expression, mitochondrial content, and membrane potential were determined and analyzed by flow cytometry and laser scanning confocal microscopy. Globin gene expression during erythroid differentiation was measured by RT‐qPCR. The mTORC2/mTORC1 and autophagy pathway was evaluated using western blotting.Results: Both AZD8055 and rapamycin treatments increased the expression levels of the erythroid differentiation‐specific markers, CD235a, α‐globin, γ‐globin, and ε‐globin. Notably, AZD8055 suppressed the cell proliferation and promoted the mitochondrial clearance of hemin‐induced K562 cells more effectively than rapamycin. In a mouse model of β‐thalassemia, both rapamycin and AZD8055 remarkably improve erythroid cell maturation and anemia. Moreover, AZD8055 and rapamycin treatment inhibited the mTORC1 pathway and enhanced autophagy, whereas AZD8055 enhanced autophagy more effectively than rapamycin. Indeed, AZD8055 treatment inhibited both mTORC2 and mTORC1 pathway in hemin‐induced K562 cells.Conclusion: AZD8055 is more effective than rapamycin in inhibiting proliferation and promoting mitochondrial clearance in erythroid differentiation, which might provide us one more therapeutic option other than rapamycin for ineffective erythropoiesis treatment in the future. These findings also provide some preliminary information indicating the roles of mTORC1 and mTORC2 in erythropoiesis, and further studies are necessary to dissect the underlying mechanisms.