The mechanism and clinical application of farnesyl diphosphate farnesyltransferase 1 in cancer metabolism.

Cancer poses a significant risk to human well-being. Among the crucial characteristics of cancer is metabolic reprogramming. To meet the relentless metabolic needs, cancer cells enhance cholesterol metabolism within the adverse tumor microenvironment. Reprograming cholesterol metabolism includes a series of modifications in the synthesis, absorption, esterification, and metabolites associated with cholesterol. These adjustments have a strong correlation with the proliferation, invasion, metastasis, and other characteristics of malignant tumors. FDFT1, also known as farnesyl diphosphate farnesyltransferase 1, is an enzyme crucial in the process of cholesterol biosynthesis. Its significant involvement in tumor metabolism has garnered considerable interest. The significance of FDFT1 in cancer metabolism cannot be overstated, as it actively interacts with cancer cells. This paper aims to analyze and consolidate the mechanism of FDFT1 in cancer metabolism and explore its clinical application. The goal is to contribute new strategies and targets for the prevention and treatment of cancer metabolism.

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China.

BACKGROUND: Relapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready process developed in China, demonstrated remarkable efficacy and manageable safety in the pivotal RELIANCE study. However, no published data are available on the "real-world" use of relma-cel, especially for patients with CNS involvement. PATIENTS AND METHODS: Retrospective analyses were conducted for commercial relma-cel used in patients with R/R CNSL at 12 clinics. The primary endpoint was to evaluate the proportion of patients who achieved complete response (CR) at 3 months. Secondary endpoints included best complete response (BCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and the incidence of adverse events. RESULTS: Among the 22 CNSL patients (12 primary CNSLs; 10 secondary CNSLs), the best overall response rate was 90.9% and the BCR rate was 68.2%. With median follow-up of 316 days (range, 55-618 days), the estimated 1-year PFS rate, DOR, and OS rate were 64.4%, 71.5%, and 79.2%, respectively. Significant clinical benefits were observed in patients who were in durable CR or partial response to the most recent prior therapy preleukapheresis and received relma-cel as consolidation therapy (n=8), with 1-year PFS rate of 100.0% versus 41.7% (p=0.02). In addition, in terms of primary endpoint, non-CR at 3 months postinfusion seemed to be predictive of a worse prognosis, with an estimated 1-year PFS of 83.3% versus 37.0% (p=0.03), respectively. CRS occurred in 72.9% of patients (grade 3: 4.5%) and immune effector cell-associated neurotoxicity syndrome in 36.4% of patients (grade 3: 4.5%). With the add-on agent PD-1 inhibitor (tislelizumab) to the ongoing BTKi, significant re-expansions of CAR T-cell were detected by quantitative PCR or flow cytometry after a median of 2 weeks (range, 12-32 days). CONCLUSIONS: This study was the first and largest real-world study of commercial relma-cel for R/R CNSL, demonstrating promising efficacy and acceptable safety. We reaffirmed the benefit of immuno-agents such as BTKi or PD-1 inhibitor on CAR T-cell re-expansion and hypothesized a dual-agent CAR-T related combinatorial therapies, which warrants further validation. Most importantly, we highlighted the earlier use of CAR T-cell therapy as a consolidative therapy for patients sensitive to salvage therapy, which provided an impetus and inspired-future strategy.

Du-moxibustion ameliorates depression-like behavior and neuroinflammation in chronic unpredictable mild stress-induced mice.

BACKGROUND: Neuroinflammation is involved in the advancement of depression. Du-moxibustion can treat depression. Here, we explored whether Du-moxibustion could alleviate neuroglia-associated neuro-inflammatory process in chronic unpredictable mild stress (CUMS) mice. METHODS: C57BL/6J mice were distributed into five groups. Except for the CON group, other four groups underwent CUMS for four consecutive weeks, and Du-moxibustion was given simultaneously after modeling. Behavioral tests were then carried out. Additionally, Western blot was conducted to measure the relative expression levels of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). Immunofluorescence was employed to evaluate the positive cells of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were analyzed using an ELISA assay. RESULTS: We found that CUMS induced depression-like behaviors, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, decreased the time in open arms and prolonged immobility. Furthermore, versus the CON group, the expression of HMGB1, TLR4, MyD88, NF-κB, positive cells of Iba-1, IL-1ß and TNF-α were increased but positive cells of GFAP were decreased in CUMS group. However, the detrimental effects were ameliorated by treatment with CUMS+FLU and CUMS+DM. LIMITATIONS: A shortage of this study is that only CUMS model of depression were used, while other depression model were not included. CONCLUSIONS: Du-moxibustion alleviates depression-like behaviors in CUMS mice mainly by reducing neuroinflammation, which offers novel insights into the potential treatment of depression.

Neutrophil hitchhiking nanoparticles enhance bacteria-mediated cancer therapy via NETosis reprogramming.

Bacteria have shown great potential in anti-tumor treatment, and an attenuated strain of Salmonella named VNP20009 has been shown to be safe in clinical trials. However, colonized bacteria recruit neutrophils into the tumor, which release NETs to capture and eliminate bacteria, compromising bacterial-based tumor treatment. In this study, we report a neutrophil hitchhiking nanoparticles (SPPS) that block the formation of NET to enhance bacteria-mediated tumor therapy. In the 4 T1 tumor-bearing mouse model, following 24 h of bacterial therapy, there was an approximately 3.0-fold increase in the number of neutrophils in the bloodstream, while the amount of SPPS homing to tumor tissue through neutrophil hitchhiking increased approximately 2.0-fold. It is worth noting that the NETs in tumors significantly decreased by approximately 2.0-fold through an intracellular ROS scavenging-mediated NETosis reprogramming, thereby increasing bacterial vitality by 1.9-fold in tumors. More importantly, the gene drug (siBcl-2) loaded in SPPS can be re-encapsulated in apoptotic bodies by reprogramming neutrophils from NETosis to apoptosis, and enable the redelivery of drugs to tumor cells, further boosting the antitumor efficacy with a synergistic effect, resulting in about 98% tumor inhibition rate and 90% survival rate.

Frontiers in chronic fatigue syndrome research: An analysis of the top 100 most influential articles in the field.

Chronic fatigue syndrome (CFS) is a complex constellation of symptoms that significantly reduces the quality of life among affected individuals and increases public health expenditures. We conducted a search on the Web of Science Core Collection database and selected the top 100 cited articles in the field of CFS. Several literature analysis tools, including CiteSpace 6.1.R6, VOSviewer 1.6.19, and Scimago Graphica 1.0.30, were utilized to integrate the most influential research papers and academic journals in order to obtain a comprehensive understanding of the CFS field. The top 100 highly-cited publications were published in 67 reputable journals, with contributions from 250 institutions across 26 countries/regions involved in CFS research. This demonstrates the extensive attention and coverage of CFS research by high-quality academic journals and institutions, highlighting the interdisciplinary and multidisciplinary nature of CFS studies. The journal with the highest publication volume and total citations was Lancet. The top 5 co-occurring keywords were chronic fatigue syndrome, cognitive behavior therapy, epidemiology, definition, and disorders, indicating the ongoing attention researchers have devoted to the diagnostic criteria and clinical studies of CFS. Cluster analysis results suggested that primary care, infectious retrovirus, gene expression, and metabolomics may become the focal points and trends in future CFS research. The prospective research directions in this field include the search for biological markers, with a particular focus on immunology; the advancement of diagnostic techniques; the screening of risk genes associated with CFS; and the conduct of epidemiological investigations.

The activation of SIRT1 by resveratrol reduces breast cancer metastasis to lung through inhibiting neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) play a crucial role in breast cancer metastasis. However, the therapeutic target of NETs in breast cancer metastasis is still unknown. Using a natural metabolite library and single-cell sequencing data analysis, we identified resveratrol (RES), a polyphenolic natural phytoalexin, and agonist of silent information regulator-1 (SIRT1) that suppressed NETs formation after cathepsin C (CTSC) treatment. In vivo, RES significantly hindered breast cancer metastasis in a murine orthotopic 4T1 breast cancer model. Serum levels of myeloperoxidase-DNA and neutrophil elastase-DNA in mouse breast cancer model were significantly lower after RES treatment. Correspondingly, the tumour infiltrated CD8+T cells in the lungs increased after the treatment. Mechanistically, RES targets SIRT1 in neutrophils and significantly inhibits the citrullination of histones H3, which is essential for chromatin decondensation and NETs formation. Furthermore, we identified that the NETs were suppressed by RES in bone marrow neutrophils after CTSC treatment, while specific deficiency of SIRT1 in neutrophils promoted NETs formation and breast cancer to lung metastasis. Thus, our results revealed that RES could be potentially identified as a viable therapeutic drug to prevent neutrophil cell death and breast cancer metastasis.

Partial response to RC-48 as palliative treatment in a patient with locallocally advanced carcinoma ex pleomorphic adenoma harboring a HER2 mutation: a case report.

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.

Metagenomic insights into the mechanisms of triphenyl phosphate degradation by bioaugmentation with Sphingopyxis sp. GY.

Biodegradation of triphenyl phosphate (TPHP) by Sphingopyxis sp. GY was investigated, and results demonstrated that TPHP could be completely degraded in 36 h with intracellular enzymes playing a leading role. This study, for the first time, systematically explores the effects of the typical brominated flame retardants, organophosphorus flame retardants, and heavy metals on TPHP degradation. Our findings reveal that TCPs, BDE-47, HBCD, Cd and Cu exhibit inhibitory effects on TPHP degradation. The hydrolysis-, hydroxylated-, monoglucosylated-, methylated products and glutathione (GSH) conjugated derivative were identified and new degradation pathway of TPHP mediated by microorganism was proposed. Moreover, toxicity evaluation experiments indicate a significant reduction in toxicity following treatment with Sphingopyxis sp. GY. To evaluate its potential for environmental remediation, we conducted bioaugmentation experiments using Sphingopyxis sp. GY in a TPHP contaminated water-sediment system, which resulted in excellent remediation efficacy. Twelve intermediate products were detected in the water-sediment system, including the observation of the glutathione (GSH) conjugated derivative, monoglucosylated product, (OH)2-DPHP and CH3-O-DPHP for the first time in microorganism-mediated TPHP transformation. We further identify the active microbial members involved in TPHP degradation within the water-sediment system using metagenomic analysis. Notably, most of these members were found to possess genes related to TPHP degradation. These findings highlight the significant reduction of TPHP achieved through beneficial interactions and cooperation established between the introduced Sphingopyxis sp. GY and the indigenous microbial populations stimulated by the introduced bacteria. Thus, our study provides valuable insights into the mechanisms, co-existed pollutants, transformation pathways, and remediation potential associated with TPHP biodegradation, paving the way for future research and applications in environmental remediation strategies.

AURKA Identified as Potential Lung Cancer Marker through Comprehensive Bioinformatic Analysis and Experimental Verification.

Non-small-cell lung cancer (NSCLC) is a malignancy with high overall morbidity and mortality due to a lack of reliable methods for early diagnosis and successful treatment of the condition. We identified genes that would be valuable for the diagnosis and prognosis of lung cancer. Common DEGs (DEGs) in three GEO datasets were selected for KEGG and GO enrichment analysis. A protein-protein interaction (PPI) network was constructed using the STRING database, and molecular complex detection (MCODE) identified hub genes. Gene expression profiling interactive analysis (GEPIA) and the Kaplan-Meier method analyzed hub genes expression and prognostic value. Quantitative PCR and western blotting were used to test for differences in hub gene expression in multiple cell lines. The CCK-8 assay was used to determine the IC50 of the AURKA inhibitor CCT137690 in H1993 cells. Transwell and clonogenic assays validated the function of AURKA in lung cancer, and cell cycle experiments explored its possible mechanism of action. Overall, 239 DEGs were identified from three datasets. AURKA, BIRC5, CCNB1, DLGAP5, KIF11, and KIF15 had shown great potential for lung cancer diagnosis and prognosis. In vitro experiments suggested that AURKA significantly influenced the proliferation and migration of lung cancer cells and activities related to the dysregulation of the cell cycle. AURKA, BIRC5, CCNB1, DLGAP5, KIF11, and KIF15 may be critical genes that influence the occurrence, development, and prognosis of NSCLC. AURKA significantly affects the proliferation and migration of lung cancer cells by disrupting the cell cycle.

Integrative bioinformatics approaches to establish potential prognostic immune-related genes signature and drugs in the non-small cell lung cancer microenvironment.

Introduction: Research has revealed that the tumor microenvironment (TME) is associated with the progression of malignancy. The combination of meaningful prognostic biomarkers related to the TME is expected to be a reliable direction for improving the diagnosis and treatment of non-small cell lung cancer (NSCLC). Method and Result: Therefore, to better understand the connection between the TME and survival outcomes of NSCLC, we used the "DESeq2" R package to mine the differentially expressed genes (DEGs) of two groups of NSCLC samples according to the optimal cutoff value of the immune score through the ESTIMATE algorithm. A total of 978 up-DEGs and 828 down-DEGs were eventually identified. A fifteen-gene prognostic signature was established via LASSO and Cox regression analysis and further divided the patients into two risk sets. The survival outcome of high-risk patients was significantly worse than that of low-risk patients in both the TCGA and two external validation sets (p-value < 0.05). The gene signature showed high predictive accuracy in TCGA (1-year area under the time-dependent ROC curve (AUC) = 0.722, 2-year AUC = 0.708, 3-year AUC = 0.686). The nomogram comprised of the risk score and related clinicopathological information was constructed, and calibration plots and ROC curves were applied, KEGG and GSEA analyses showed that the epithelial-mesenchymal transition (EMT) pathway, E2F target pathway and immune-associated pathway were mainly involved in the high-risk group. Further somatic mutation and immune analyses were conducted to compare the differences between the two groups. Drug sensitivity provides a potential treatment basis for clinical treatment. Finally, EREG and ADH1C were selected as the key prognostic genes of the two overlapping results from PPI and multiple Cox analyses. They were verified by comparing the mRNA expression in cell lines and protein expression in the HPA database, and clinical validation further confirmed the effectiveness of key genes. Conclusion: In conclusion, we obtained an immune-related fifteen-gene prognostic signature and potential mechanism and sensitive drugs underling the prognosis model, which may provide accurate prognosis prediction and available strategies for NSCLC.

Real-World Experience of PD-1 Inhibitors for Relapsed and Refractory Hodgkin Lymphoma: A Multicenter Retrospective Analysis of Patients in China.

INTRODUCTION: Despite the promising clinical trial data regarding programmed death 1 (PD-1) inhibitors in relapsed/refractory classical Hodgkin lymphoma (R/R cHL), there remains a paucity of studies describing the outcomes of patients in a real-world setting, especially for Asian cohort. METHODS: We present a multicenter retrospective analysis of patients with R/R cHL who had failed ≥2 prior lines of therapies and received sintilimab or tislelizumab developed in China (sintilimab or tislelizumab monotherapy) at 3 medical centers from January 2019 to September 2021. Efficacy was evaluated with progression-free survival (PFS), overall survival, duration of response (DOR), best overall response (BOR) including objective response rate (ORR), complete response rate (CRR). Safety data were also recorded. RESULTS: 74 patients were reviewed. The median age was 38 years (range, 14-85 years). The ORR, CRR, and disease control rate were 78.3%, 52.7%, and 91.9%, respectively. The median duration of follow-up was 22 (4-36) months. Four patients (5.4%) died of disease progression. The median PFS and DOR was 22.1 and 23.5 months. BOR as a new emergent endpoint was found to be the only independent prognostic factor for PFS in our study (HR = 6.234, p = 0.005), suggesting this endpoint carries stronger prognostic value over traditional endpoints in the immunotherapy era. 66 (89.2%) patients reported adverse event (AE) with any grade, with the majority of AEs being grade 1 or 2. CONCLUSION: We presented a unique real-life experience and conducted a relatively long follow-up of PD-1 antibodies developed in China for R/R HL patients which confirmed their promising effectiveness and manageable side effects given in real world in an Asian cohort. Even for those who would usually be excluded in most of clinical trials such as elderly or minor patients, anti-PD-1 monotherapy also showed a significant improvement of outcomes. Furthermore, the depth of response seemed to be a more powerful predictive tool in new era, which might serve as a basis for future immune risk-adapted strategies.

The Development of Drug Delivery Systems for Efficient Intracranial Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) is the most devastating form of stroke, which accounts for 10-15% of cases and causes high morbidity and mortality. With the continuous exploration of the pathological mechanism of ICH, extensive research focusing on ICH therapy has been conducted. However, the traditional treatment methods, such as surgery for removing the hematoma and pharmacotherapy for improving the clearance of the hematoma and neuroprotection, are greatly limited due to their poor practicality and treatment efficiency. The rapid development of drug delivery systems offers an important prospect for treating ICH as they exhibit great versatility, which can improve the pharmacokinetic behavior of drugs in vivo, increase the drug accumulation in specific cell types or tissues, and enhance the therapeutic effect with diminished toxic effect. In this review, the main molecular pathological mechanisms of ICH are comprehensively described and the limitation of traditional pharmacotherapy are also discussed. Then the development based on drug delivery systems for treating ICH is highlighted. Finally, based on these discussions the challenges of drug delivery systems with a view to providing a new feasible path for the treatment of ICH are summarized.

FBP1 induced by ß-elemene enhances the sensitivity of gefitinib in lung cancer.

BACKGROUND: ß-elemene is known to play a critical role in tumorigenesis as well as tyrosine kinase inhibitor (TKI) resistance in lung cancer. However, the biological function and molecular mechanism remain largely unknown. METHODS: In this study, the common genes involved in gefitinib resistance and ß-elemene were identified using bioinformatic analysis. The expression of FBP1 was examined by qRT-PCR and Western blot analysis. Cell proliferation, flow cytometry, clone formation and IC50 assays were performed to assess the effects of ß-elemene and FBP1. Western blot analysis was used to evaluate apoptosis-related gene expression. Finally, in vivo experiments were conducted to assess the crucial role of FBP1 in gefitinib-resistant HCC827/GR cells in nude mice. RESULTS: Screening analysis demonstrated that fructose-1,6-bisphosphatase (FBP1) was induced by ß-elemene and downregulated in gefitinib-resistant lung cells. Functionally, overexpression of FBP1 inhibited proliferation and gefitinib resistance and promoted apoptosis of PC9/GR and HCC827/GR cells in vitro. Mechanistically, FBP1 impeded the nuclear translocation of p-STAT3. The FBP1/STAT3 axis was required for FBP1-mediated apoptosis-related gene expression. In vivo experiments further confirmed the enhanced effects of FBP1 on lung cancer cell sensitivity to gefitinib. CONCLUSION: Our research indicated that ß-elemene suppressed proliferation and enhanced sensitivity to gefitinib by inducing apoptosis through the FBP1/STAT3 axis in gefitinib-resistant lung cancer cells.

Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy.

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2'-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Transcription factor FoxM1 promotes cyst growth in PKD1 mutant ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.

Identification of pyroptosis-related gene signature for predicting prognosis of patients with pancreatic cancer using bioinformatics.

Pancreatic cancer, a common digestive system malignancy, is dubbed the "king of cancers". The role of pyrophosis-related genes (PRGs) in pancreatic cancer prognosis is yet unknown. In pancreatic cancer and normal tissue, we discovered 9 PRGs that are expressed differently in pancreatic cancer and healthy tissue. Based on the differential expression of PRGs, 2 clusters of pancreatic cancer cases could be identified. The 2 groups had significant disparities in total survival time. The prognostic model of a 5-PRGs signature was created using least absolute shrinkage and selection operator (LASSO) method. The median risk score was used to split pancreatic cancer patients in The Cancer Genome Atlas (TCGA) cohort into 2 groups: low risk and high risk. Patients classified as low-risk had significantly higher survival rates than those classified as high-risk (P < .01). The same results were obtained by validating them against the Gene Expression Omnibus database (P = .030). Cox regression statistical analysis showed that risk score was an independent predictor of overall survival in pancreatic cancer patients. Functional enrichment analysis revealed that apoptosis, cell proliferation, and cell cycle-related biological processes and signaling pathways were enriched. Additionally, the immunological status of the high-risk group worsened. In conclusion, a novel pyroptosis-related gene signature can be used to predict pancreatic cancer patient prognosis.

X-box Binding Protein 1 is a Potential Immunotherapy Target in Ovarian Cancer.

The allure of potentially dramatic and durable responses to immunotherapy has driven the study of several immune checkpoint inhibitor (ICI) agents in ovarian cancer. However, the results of ICI therapy in ovarian cancer have been rather disappointing. It is important to understand the reasons for the poor efficacy of ICI in ovarian cancer and to look for new targets for immunotherapy. To solve this problem, ovarian cancer-associated datasets were individually collected from The Cancer Genome Atlas (TCGA)、International Cancer Genome Consortium (ICGC)、Genotype-Tissue Expression (GTEx), and comprehensively performed to expression, prognostic, pathological correlation, genomic and immunologic analyses of reported all immune checkpoints by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Tumor and Immune System Interaction Database (TISIDB), cBio Cancer Genomics Portal (cBioPortal), and Kaplan-Meier Plotter. We concluded that those well-identified immune checkpoints might not be ideal targets for ovarian cancer immunotherapy. Intriguingly, the genomic alteration of X-box binding protein 1 (XBP1), the important mediator of chemotherapy-induced cancer immunogenic cell death, was found to be a potential coregulator of immune checkpoints in ovarian cancer. Importantly, XBP1 was detected to be highly expressed in ovarian cancer compared with normal ovarian tissue, and high XBP1 expression significantly benefits both overall survival (OS) and disease-free survival (DFS) of ovarian cancer patients. More importantly, XBP1 was further observed to be closely related to anti-tumor immunity in ovarian cancer, including multiple T-cell signatures and immunity-killing molecules. In conclusion, upregulating XBP1 rather than targeting immune checkpoints represents a potentially more efficient approach for ovarian cancer therapy.

LINC00116 Is a Novel Prognostic Biomarker of Nonsmall Cell Lung Cancer.

Purpose: Lung cancer is the most malignant respiratory cancer with an undesirable prognosis. Emerging evidence shows that long noncoding RNAs (lncRNAs) can regulate lung cancer development. Currently, the role of LINC00116, a novel lncRNA, in lung cancer is unknown. This study was designed to evaluate the association and clinical significance between the level of LINC00116 and lung cancer. Materials and Methods: In the present study, 19 paired lung cancer and non-cancerous adjacent tissues were collected from lung cancer patients to measure the expression of LINC00116 by quantitative reverse transcription-polymerase chain reaction and Microarray analysis (Oncomine and CCLE). Clinicopathological features of patients were obtained to analyze their relationships with LINC00116 expression levels. Kaplan-Meier survival analysis was used to analyze the prognosis. Results: LINC00116 expression was upregulated in lung cancer. Furthermore, we found that LINC00116 expression was correlated with pT factor, pN factor, pTNM stage, smoking history, differentiation, and Ki-67 labeling index (p < 0.05). In addition, Kaplan-Meier survival analysis showed that high levels of LINC00116 expression were associated with poorer overall survival (OS), progression-free survival (PFS) and first progression (FP) (p < 0.05) of lung cancer patients. Conclusions: Our study provided evidence that LINC00116 is upregulated in lung cancer tissues and can predict poor survival. It might also be able to serve as a therapeutic target. The Clinical Trial Registration number 2022-020.

Protective Effects of Ferulic Acid on Deoxynivalenol-Induced Toxicity in IPEC-J2 Cells.

Deoxynivalenol (DON), a mycotoxin that contaminates crops such as wheat and corn, can cause severe acute or chronic injury when ingested by animals or humans. This study investigated the protective effect of ferulic acid (FA), a polyphenolic substance, on alleviating the toxicity induced by DON (40 µM) in IPEC-J2 cells. The experiments results showed that FA not only alleviated the decrease in cell viability caused by DON (p < 0.05), but increased the level of superoxide dismutase (SOD) (p < 0.01), glutathione peroxidase (GSH-Px), (catalase) CAT and glutathione (GSH) (p < 0.05) through the nuclear factor erythroid 2-related factor 2 (Nrf2)-epoxy chloropropane Kelch sample related protein-1 (keap1) pathway, and then decreased the levels of intracellular oxidative stress. Additionally, FA could alleviate DON-induced inflammation through mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-κB) pathways, down-regulated the secretion of interleukin-6 (IL-6) (p < 0.0001), interleukin-8 (IL-8) (p < 0.05), interleukin-1ß (IL-1ß), interferon-γ (IFN-γ) and further attenuated the DON-induced intracellular apoptosis (10.7% to 6.84%) by regulating the expression of Bcl2-associated X protein (Bax) (p < 0.0001), B-cell lymphoma-2 (Bcl-2) (p < 0.0001), and caspase-3 (p < 0.0001). All these results indicate that FA exhibits a significantly protective effect against DON-induced toxicity.

[Study on the central mechanism of acupuncture for post-stroke spasticity based on the Na+/K+-ATPase-EAATs-Glu pathway].

OBJECTIVE: To observe the effect of acupuncture at "Yanglingquan" (GB34) and "Baihui" (GV20) on Na+/K+-ATPase, excitatory amino acid transporters (EAATs) and glutamate (Glu) in hippocampus of post-stroke spasticity rats, so as to explore the central mechanism in anti-spasticity. METHODS: In a total of 48 healthy SD rats, 12 rats were randomly selected to be included into sham operation group, and the remaining rats were used to make a middle cerebral artery occlusion (MCAO) model using a suture method. On the 3rd day after modeling, MCAO limb spasticity rats were screened by neurological deficit symptoms and muscle tension scores, and randomly divided into the model, GB34 (Hui-puncture at GB34) and GB34+GV20 (Hui-puncture at GB34 and horizontal insertion at GV20) groups (n=12 rats in each group), and the treatment was lasted for 7 conse-cutive days. The neurological symptoms and muscle tension score were observed with the Zea Longa score and modified Ashworth scale (MAS). The levels of Glu, EAAT1 (GLAST) and EAAT2 (GLT-1) in the ischemic area of cerebral hippocampus were detected by ELISA, the expression of Na+/K+-ATPase α1 (ATP1α1) was detected by Western blot, the expression of ATP1α1 mRNA was detected by real-time PCR, and the expression of GLAST, GLT-1 and ATP1α1 was detected by immunofluorescence. RESULTS: After modeling, Zea Longa score and MAS score were increased (P<0.01), the level of Glu in the ischemic area of cerebral hippocampus was increased (P<0.01), while the expression levels of GLAST, GLT-1, ATP1α1 protein and mRNA were all decreased (P<0.01) in the model group relevant to the sham operation group. After 7 days' treatment, all the increased and decreased levels of the indexes mentioned above were reversed in the two acupuncture groups relevant to the model group (P<0.01, P<0.05), and the effects of acupuncture at GB34+GV20 were obviously superior to that of acupuncture at GB34 (P<0.05, P<0.01). CONCLUSION: Acupuncture can alleviate post-stroke spasticity effectively, which may be related to its effect in up-regulating the expressions of Na+/K+-ATPase and EAATs in hippocampus. The anti-spastic effect of acupuncture at GB34+GV20 is superior to GB34 alone.