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High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

Summary: Hydrochlorothiazide (HCTZ) is reported to impair glucose tolerance and may induce new onset of diabetes, but the pharmacomicrobiomics of the adverse effect for HCTZ remains unknown. Mice-fed HCTZ exhibited insulin resistance and impaired glucose tolerance. By using FMT and antibiotic cocktail models, we found that HCTZ-induced metabolic disorder was mediated by commensal microbiota. HCTZ consumption disturbed the structure of the intestinal microbiota, causing abnormal elevation of Gram-negative Enterobacteriaceae and lipopolysaccharide (LPS) then leading to intestinal barrier dysfunction. Additionally, HCTZ activated TLR4 signaling and induced macrophage polarization and inflammation in the liver. Furthermore, HCTZ-induced macrophage polarization and metabolic disorder were abrogated by blocking TLR4 signaling. HCTZ consumption caused a significant increase in Gram-negative Enterobacteriaceae, which elevated the levels of LPS, thereby activating LPS/TLR4 pathway, promoting inflammation and macrophage polarization, and resulting in metabolic disorders. These findings revealed that the gut microbiome is the key medium underlying HCTZ-induced metabolic disorder.

Introduction: Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states. Objectives: In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting. Methods: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed. Results: The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol. Conclusion: Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.

Background: Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. Objective: The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. Patients and Methods: We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. Results: We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. Conclusion: The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

Abstract Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

Abstract Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients’ survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT–DNA–PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN–ATM–CHK2 signal and ATR–CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.

Background and AimsAlthough the manual crude fecal microbiota transplantation (FMT) reduces blood lipids in animal models of hyperlipidemia, its clinical effect on blood lipid metabolism in patients with hyperlipidemia and hypolipidemia remains unclear, especially in the Chinese population. It was reported that washed microbiota transplantation (WMT) was safer, more precise, and more quality-controllable than the crude FMT by manual. This study aimed to investigate the feasibility and effectiveness of WMT on lipid metabolism in the Chinese population.MethodsClinical data of patients with various indications who received WMT for 1–3 treatment procedures were collected. Changes in blood lipids before and after WMT, namely, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), liver fat attenuation, and liver stiffness measurement, were compared.ResultsA total of 177 patients (40 cases of hyperlipidemia, 87 cases with normal blood lipids, and 50 cases of hypolipidemia) were enrolled in the First Affiliated Hospital of Guangdong Pharmaceutical University. WMT has a significant therapeutic effect in reducing blood lipid levels (TC and TG) in the short- and medium term in patients with hyperlipidemia (p

Mice are the most frequently used animals in pharmacokinetic studies; however, collecting series of blood samples from mice is difficult because of their small sizes and tiny vessels. In addition, due to the small sample size, it is problematic to perform high required quantification. Thus, present work aims to find an effective strategy for overcoming these challenges using trans-resveratrol as a tool drug. Based on the idea of a joint technology, the capillary microsampling (CMS) was chosen for blood sample collection from mice after delivery of trans-resveratrol (150 mg/kg) by gavage, and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of trans-resveratrol and its main metabolites. All the mouse blood samples were exactly collected by CMS without obvious deviation. This provided credible samples for subsequent quantitative analysis. The HPLC-MS/MS method was found to be sensitive, accurate, and repeatable, and the pharmacokinetic parameters for all analytes were comparable with those reported in previous studies. However, the present joint technology offers the advantages of less animal damage, easy for sample preparation, and improved reliability. It has overcome some of the major limitations revealed in previous pharmacokinetic studies in mice and therefore provides a more effective option for future studies.

Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach.

Purpose: Lung cancer is the largest cause of cancer deaths in the world. Platinum-based chemotherapy is a foundation of first-line chemotherapy. However, the prognosis of lung cancer treated with platinum-based chemotherapy is still a challenge. Single nucleotide polymorphism of non-coding RNA has the potential to be a biomarker, but its effectiveness has yet to be comprehensively assessed. In this study, we explored the association between polymorphisms of non-coding RNA and prognosis of lung cancer patients receiving platinum-based chemotherapy.Materials and Methods: For 446 lung cancer patients receiving platinum-based chemotherapy, 22 single nucleotide polymorphisms of microRNA and long noncoding RNA were genotyped by MALDI-TOF mass spectrometry. Cox regression analysis, Kaplan-Meier method, and long-rank test have been performed to assess the association of overall and progression-free survival with polymorphisms.Results: In the additive and dominant models, genetic polymorphism of ANRIL rs1333049 (G > C) was significantly associated with progression-free survival. Additive model: CC vs GC vs GG [HR = 0.84, p = 0.021, 95% CI (0.73–0.97)]; Recessive model: CC vs GG + GC [HR = 0.77, p = 0.026, 95% CI (0.61–0.97)]. In the dominant model, compared with the CC genotype patients, lower risk of death [HR = 0.81, p = 0.036, 95% CI (0.66–0.99)] and lower risk of progression [HR = 0.81, p = 0.040, 95% CI (0.67–0.99)] have been observed on the patients with CG or GG genotype in miR-146A rs2910164.Conclusion: Our research demonstrated the potential of using ANRIL rs1333049 (G > C) and miR-146A rs2910164 (C > G) as biomarkers to support the prediction of a better prognosis for lung cancer patients receiving platinum-based chemotherapy.

Essential Hypertension (EH) results in the burden of cardiovascular disease (CVD) such as Heart Failure (HF) and Ischemic Stroke (IS). A rapidly emerging field involving the role of Wnt/β-catenin signaling pathway in cardiovascular development and dysfunction has recently drawn extensive attention. In the present study, we conducted a genetic association between genomic variants in Wnt/β-catenin signaling pathway and EH, HF, IS. A total of 95 SNPs in 12 Wnt signaling genes (WNT3A, WNT3, WNT4, DKK1, DKK2, LRP5, LRP6, CTNNB1, APC, FZD1, FRZB, SFRP1) were genotyped in 1,860 participants (440 patients with EH, 535 patients with HF, 421 patients with IS and 464 normal control subjects) using Sequenom MassArray technology. WNT3A rs752107(C > T) was strongly associated with an increased risk of EH, HF and IS. Compared with WNT3A rs752107 CC genotype, the CT genotype carriers had a 48% increased risk of EH (OR = 1.48, 95% CI = 1.12–1.96, P = 0.006), the TT genotype conferred a 139% increased risk of EH (OR = 2.39, 95% CI = 1.32–4.34, P = 0.003). Regarding HF and IS, the risk of HF in the T allele carriers (CT + TT) was nearly increased by 58% (OR = 1.58, 95% CI = 1.22–2.04, P = 4.40 × 10−4) and the risk of IS was increased by 37% (OR = 1.37, 95% CI = 1.04–1.79, P = 0.025). Expression quantitative trait loci (eQTL) analysis indicated that rs752107 C allele corresponded to a significant reduction of WNT3A expression. We described a genetic variant of WNT3A rs752107 in Wnt/β-catenin signaling strongly associated with the risk of EH, HF and IS for the first time.

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.

Abstract Eukaryotic initiation factor 3 (EIF3) is one of the largest and most complex translation initiation factors, which consists of 13 subunits named eukaryotic translation initiation factor 3 subunit A (EIF3a) to EIF3m. EIF3a is the largest subunit of EIF3. Previous studies suggested that EIF3a is a housekeeping gene, recent results have found that EIF3a is closely related to the tumorigenesis and drug resistance. Circular RNAs (circRNAs) derived from biologically important gene can play an important role in gene regulation. However, the mechanism underlying circRNAs’ biological functions is not well understood yet. In this work, we screened 31 EIF3a‐derived circRNAs, in which two circEIF3as were identified to be correlated with cisplatin drug sensitivity in lung cancer. Two circEIF3as were found involved in RNA‐binding proteins‐mediated biological processes and may be related to translational regulation according to bioinformatics analyses. CircEIF3as, the transcriptional initiation factor EIF3a transcribed circRNAs, are associated with both drug sensitivity and translation regulation. These findings mean that they may have a functional synergy effect with EIF3a or be valuable therapeutic targets for treatment like EIF3a. This is the first study that exploits circRNAs screening from EIF3a in lung cancer, our findings provide a novel perspective on the function of EIF3a and circEIF3as in lung cancer.

Gap junctions (GJs) are multiple cellular intercellular connections that allow ions to pass directly into the cytoplasm of neighboring cells. Electrical coupling mediated by GJs plays a role in the generation of highly synchronous electrical activity. Accumulative investigations show that GJs in the brain are involved in the generation, synchronization and maintenance of seizure events. At the same time, GJ blockers exert potent curative potential on epilepsy in vivo or in vitro. This review aims to shed light on the role of GJs in epileptogenesis. Targeting GJs is likely to be served as a novel therapeutic approach on epileptic patients.

Background: DCBLD2 is highly expressed in various cancers, including colorectal cancer. DCBLD2 overexpression promotes tumor occurrence, development, and metastasis. However, DCBLD2 sensitivity to chemotherapy drugs and its mechanism on tumor development are unknown.Methods: DCBLD2 expression differences in cancer and normal tissues were obtained from GEO and TCGA databases. DCBLD2 influence on prognosis was also compared, and the database analysis results were verified via the analysis of clinical samples. GDSC database was used to analyze the effect of DCBLD2 expression difference on 5-FU drug sensitivity on tumor cells. CCK-8, clone formation, scratch, Transwell invasion and migration assays were used to assess DCBLD2 effects on the proliferation, metastasis, and 5-FU drug sensitivity on HCT116 and Caco-2 colorectal cancer cells. Angiogenesis and Matrigel plug assays were used to study the effect of DCBLD2 on angiogenesis. Q-RCR and Western Blot were used to analyze DCBLD2 impact on the EMT signaling pathway, and TAP-MS assay with Co-IP verification was used to identify the downstream target proteins binding to DCBLD2.Results: Both database and clinical sample validation results showed that the expression of DCBLD2 in colorectal cancer tissues was significantly higher than that in normal tissues, leading to poor prognosis of patients. GDSC database analysis showed that DCBLD2 overexpression caused tumor cell resistance to 5-FU. The results of in vitro and in vivo experiments showed that the inhibition of DCBLD2 reduced the proliferation, migration and invasion of colorectal cancer cells, inhibited the angiogenesis of endothelial cells, and enhanced the drug sensitivity to 5-FU. The results of q-RCR and Western Blot experiments showed that the inhibition of DCBLD2 can suppress the EMT signal. The results of TAP-MS assay showed that the proteins bound to DCBLD2 were enriched to the Focal adhesion pathway. The results of Co-IP assay show that DCBLD2 can combine with ITGB1, the key factor of Focal adhesion pathway.Conclusion: DCBLD2 may affect the development of colorectal cancer by regulating cell proliferation and motility, and modulate 5-FU resistance. Down-regulation of DCBLD2 can inhibit EMT signal and angiogenesis. DCBLD2 can combine with ITGB1, the key signal factor of the Focal adhesion pathway.

PurposePancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with high heterogeneity and dismal survival rates. Tumor immune microenvironment plays a critical role in sensitive to chemotherapy and prognosis. Herein, we determined the relevance of the composition of tumor-infiltrating immune cells to clinical outcomes in PDACs, and we evaluated these effects by molecular subtype.Experimental DesignData of 1,274 samples from publically available datasets were collected. Molecular subtypes were predicted with support vector machine. Twenty-two subsets of immune cells were estimated with CIBERSORTx. The associations between each cell subset and overall survival (OS), relapse free survival (RFS), and complete response (CR) to chemotherapy were evaluated, modelling cellular proportions as quartiles.ResultsAn immune-related cluster was identified with unsupervised hierarchical clustering of hallmark pathways. Of the immune cells investigated, M0 macrophages emerged as closely associated with worse OS (HR =1.23, 95% CI = 1.15–1.31, p=1.57×10-9) and RFS (HR = 1.14, 95% CI =1.04–1.25, p=2.93×10-3), regardless of molecular subtypes. The CD8+ T cells conferred favorable survival. The neutrophils conferred poor OS overall (HR=1.17, 95% CI=1.10–1.23, p=1.74×10-7) and within the classical subtype. In the basal-like subtype, activated mast cells were associated with worse OS. Consensus clustering revealed six immune subgroups with distinct survival patterns and CR rates. The higher expression of PD1 was associated with better OS.ConclusionsThe immune cellular composition infiltrate in PDAC are likely to have effects on prognosis. Further exploration of the cellular immune response has the potential to identify candidates for immunotherapy.

Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a contributing factor of neuronal death activation and there is compelling evidence supporting antioxidants hold promise in abrogating seizure-related cell modality. Lapatinib, a well-known anti-cancer drug, has been traditionally reported to exert anti-tumor effect via modulating oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. However, whether lapatinib is beneficial for inhibiting neuronal death and epileptic seizure remains unknown. Here, we found that lapatinib remarkably prevented kainic acid (KA)-epileptic seizures in mice and ferroptosis, a newly defined cell death which is associated with oxidative stress, was involved in the neuroprotection of lapatinib. In the ferroptotic cell death model, lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. In a mouse model of KA-triggered seizure, it was also validated that lapatinib blocked GPX4-dependent ferroptosis. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis.

Therapeutic targeting of extracellular proteins has attracted huge attention in treating human diseases. The lysyl oxidases (LOXs) are a family of secreted copper-dependent enzymes which initiate the covalent crosslinking of collagen and elastin fibers in the extracellular microenvironment, thereby facilitating extracellular matrix (ECM) remodeling and ECM homeostasis. Apart from ECM-dependent roles, LOXs are also involved in other biological processes such as epithelial-to-mesenchymal transition (EMT) and transcriptional regulation, especially following hypoxic stress. Dysregulation of LOXs is found to underlie the onset and progression of multiple pathologies, such as carcinogenesis and cancer metastasis, fibrotic diseases, neurodegeneration and cardiovascular diseases. In this review, we make a comprehensive summarization of clinical and experimental evidences that support roles of for LOXs in disease pathology and points out LOXs as promising therapeutic targets for improving prognosis. Additionally, we also propose that LOXs reshape cell-ECM interaction or cell-cell interaction due to ECM-dependent and ECM-independent roles for LOXs. Therapeutic intervention of LOXs may have advantages in the maintenance of communication between ECM and cell or intercellular signaling, finally recovering organ function.

The worldwide incidence of skin cutaneous melanoma (SKCM) is increasing at a more rapid rate than other tumors. Aberrant alternative splicing (AS) is found to be common in cancer; however, how this process contributes to cancer prognosis still remains largely unknown. Mutations in RNA-binding proteins (RBPs) may trigger great changes in the splicing process. In this study, we comprehensively analyzed DNA and RNA sequencing data and clinical information of SKCM patients, together with widespread changes in splicing patterns induced by RBP mutations. We screened mRNA expression-related and prognosis-related mutations in RBPs and investigated the potential affections of RBP mutations on splicing patterns. Mutations in 853 RBPs were demonstrated to be correlated with splicing aberrations (p < 0.01). Functional enrichment analysis revealed that these alternative splicing events (ASEs) may participate in tumor progress by regulating the modification process, cell-cycle checkpoint, metabolic pathways, MAPK signaling, PI3K-Akt signaling, and other important pathways in cancer. We also constructed a prediction model based on overall survival-related AS events (OS-ASEs) affected by RBP mutations, which exhibited a good predict efficiency with the area under the curve of 0.989. Our work highlights the importance of RBP mutations in splicing alterations and provides effective biomarkers for prediction of prognosis of SKCM.

ObjectiveLung cancer is one of the most prevalent cancers and the leading cause of cancer-related death in the world. Platinum-based chemotherapy plays an important role in lung cancer treatment, but the therapeutic effect varies from person to person. Heat shock proteins (HSPs) have been reported to be associated with the survival time of lung cancer patients, which may be a potential biomarker in lung cancer treatment. The aim of this study was to investigate the association between genetic polymorphisms and the prognosis in lung cancer patients treated with platinum-based chemotherapy.MethodsWe performed genotyping in 19 single nucleotide polymorphisms (SNPs) of HSP genes and Rho family genes of 346 lung cancer patients by SequenomMassARRAY. We used Cox proportional hazard models, state and plink to analyze the associations between SNPs and the prognosis of lung cancer patients.ResultsWe found that the polymorphisms of HSPB1 rs2070804 and HSPA4 rs3088225 were significantly associated with lung cancer survival (p=0.015, p=0.049*, respectively). We also discovered the statistically significant differences between rs2070804 with age, gender, histology and stage, rs3088225 with gender and stage, which can affect lung cancer prognosis.ConclusionThe results of our study suggest that HSPB1 rs2070804 (G>T) and HSPA4 rs3088225 (A>G) may be useful biomarkers for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.

Platinum-based chemotherapy remains the cornerstone of treatment for many malignancies. However, although therapeutic efficiency varies greatly among individuals, there is a lack of pharmacogenomic biomarkers that can be used in clinical settings to identify chemosensitive patients and allow stratification. With the development of high-throughput screening techniques and systems biology approaches, a growing body of evidence has shown that platinum resistance is a multifactorial, multi-dimensional, dynamic process incorporating genetic background, tumor evolution and gut microbes. This review critically summarizes potential pharmacogenomic biomarkers for predicting the efficacy of platinum drugs and provides a comprehensive, time-varying perspective that integrates multiple markers.

Efficient DNA repair is critical for cell survival following exposure to DNA topoisomerase I (Top1) inhibitors camptothecin, a nature product from which the common chemotherapeutic drugs irinotecan and topotecan are derived. The camptothecin-derived agents exert their antitumor activities by specifically stabilizing the Top1–DNA covalent complexes (Top1cc) and blocking the DNA religation step. When exposed to these DNA damage agents, tumor cells quickly activate DNA damage response. This allows sufficient time to remove the Top1ccs and prevent tumor cells from apoptosis. Several repair pathways have been implicated in this process. One of the most relevant repair modes is DNA single strand break repair (SSBR) pathway. The expression level or mutagenesis of specific repair factors involved in SSBR pathway may play an indispensable role in individual’s capacity of repairing camptothecin induced DNA damage. Therefore, understanding of the tolerance pathways counteracted to camptothecin cytotoxicity is crucial in alleviating chemotherapy resistance. This review focus on the SSBR pathway in repair camptothecin induced DNA damage, aiming to provide insights into the potential molecular determinants of camptothecin chemosensitivity.

Single-nucleotide variants (SNVs) are the most common genetic variants and universally present in the human genome. Genome-wide association studies (GWASs) have identified a great number of disease or trait-associated variants, many of which are located in non-coding regions. Long intergenic non-protein coding RNAs (lincRNAs) are the major subtype of long non-coding RNAs; lincRNAs play crucial roles in various disorders and cellular models via multiple mechanisms. With rapid growth in the number of the identified lincRNAs and genetic variants, there is great demand for an investigation of SNVs in lincRNAs. Hence, in this article, we mainly summarize the significant role of SNVs within human lincRNA regions. Some pivotal variants may serve as risk factors for the development of various disorders, especially cancer. They may also act as important regulatory signatures involved in the modulation of lincRNAs in a tissue- or disorder-specific manner. An increasing number of researches indicate that lincRNA variants would potentially provide additional options for genetic testing and disease risk assessment in the personalized medicine era.

Background: Increasing evidence supports that the immune infiltration of tumours is associated with prognosis. Here, we sought to assess the relevance of the cellular composition of the immune infiltrate to survival after platinum-based chemotherapy amongst patients with high-grade serous ovarian cancer and evaluate these effects by molecular subtype. Methods: We searched publicly available databases and identified 13 studies with more than 2000 patients. We estimated the proportions of 22 immune cell subsets by using a computational approach (CIBERSORT). Then, we investigated the associations between each immune cell subset and progression-free survival (PFS) and overall survival (OS), with cellular proportions modelled as quartiles. Findings: A high fraction of M1 [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.86–0.99] and M0 (HR = 0.93, 95% CI = 0.87–0.99) macrophages emerged as the most closely associated with favourable OS. Neutrophils were associated with poor OS (HR = 1.06, 95% CI = 1.00–1.13) and PFS (HR = 1.10, 95% CI = 1.02–1.13). Amongst the immunoreactive tumours, the M0 macrophages and the CD8+ T cells were associated with improved OS, whereas the M2 macrophages conferred worse OS. Interestingly, PD-1 was associated with good OS (HR=0.89, 95% CI = 0.80–1.00) and PFS (HR=0.89, 95% CI = 0.79–1.01) in this subtype. Four subgroups of tumours with distinct survival patterns were identified using immune cell proportions with unsupervised clustering. Interpretation: Further investigations of the quantitative cellular immune infiltrations in tumours may contribute to therapeutic advances. Keywords: Tumour-immune infiltration, Platinum, High grade serous ovarian cancer, Overall survival, Progression-free survival

Abstract Background Human telomerase reverse transcriptase (hTERT) is highly expressed in over 80% of tumors, including human epithelial ovarian cancer (EOC). However, the mechanisms through which hTERT is up-regulated in EOC and promotes tumor progression remain unclear. The aim of this study is to identify RIF1 as a novel molecular target that modulate hTERT signaling and EOC growth. Methods RIF1 expression in ovarian cancer, benign and normal ovarian tissues was examined by immunohistochemistry. The biological role of RIF1 was revealed by MTS, colony formation and sphere formation assays. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify RIF1 as a novel hTERT promoter-binding protein in EOC cells. The role of RIF1 on tumorigenesis in vivo was detected by the xenograft model. Results RIF1 expression is upregulated in EOC tissues and is closely correlated with FIGO stage and prognosis of EOC patients. Functionally, RIF1 knockdown suppressed the expression and promoter activity of hTERT and consequently inhibited the growth and CSC-like traits of EOC cells. RIF1 knockdown also inhibited tumorigenesis in xenograft model. RIF1 overexpression had the opposite effect. Luciferase reporter assay and ChIP assay verified RIF1 directly bound to hTERT promoter to upregulate its expression. The rescue experiments suggested hTERT overexpression rescued the inhibition of EOC cell growth and CSC-like traits mediated by RIF1 knockdown. Consistently, hTERT knockdown abrogated the RIF1-induced promotion of EOC cell growth and CSC-like traits. Conclusions RIF1 promotes EOC progression by activating hTERT and the RIF1/hTERT pathway may be a potential therapeutic target for EOC patients.

Abstract Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

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Abstract Background Epigenetic alterations are strongly associated with the development of cancer. The aim of this study was to identify epigenetic pattern in squamous cell lung cancer (LUSC) on a genome-wide scale. Results Here we performed DNA methylation profiling on 24 LUSC and paired non-tumor lung (NTL) tissues by Illumina Human Methylation 450 K BeadArrays, and identified 5214 differentially methylated probes. By integrating DNA methylation and mRNA expression data, 449 aberrantly methylated genes accompanied with altered expression were identified. Ingenuity Pathway analysis highlighted these genes which were closely related to the carcinogenesis of LUSC, such as ERK family, NFKB signaling pathway, Hedgehog signaling pathway, providing new clues for understanding the molecular mechanisms of LUSC pathogenesis. To verify the results of high-throughput screening, we used 56 paired independent tissues for clinical validation by pyrosequencing. Subsequently, another 343 tumor tissues from the Cancer Genome Atlas (TCGA) database were utilized for further validation. Then, we identified a panel of DNA methylation biomarkers (CLDN1, TP63, TBX5, TCF21, ADHFE1 and HNF1B) in LUSC. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the performance of biomarkers individually, suggesting that they could be suitable as potential diagnostic biomarkers for LUSC. Moreover, hierarchical clustering analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation. Conclusions Collectively, these results suggest that DNA methylation plays critical roles in lung tumorigenesis and may potentially be proposed as a diagnostic biomarker. Trial registration ChiCTR-RCC-12002830 Date of registration: 2012–12-17.

Abstract This study aims to identify promising biomarkers for the early detection of lung cancer and evaluate the prognosis of lung cancer patients. Genome-wide mRNA expression data obtained from the Gene Expression Omnibus (GSE19188, GSE18842 and GSE40791), including 231 primary tumor samples and 210 normal samples, were used to discover differentially expressed genes (DEGs). NEK2, DLGAP5 and ECT2 were found to be highly expressed in tumor samples. These results were experimentally confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The elevated expression of the three candidate genes was also validated using the Cancer Genome Atlas (TCGA) datasets, which consist of 349 tumor and 58 normal tissues. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the diagnostic value of these lung cancer biomarkers, and the results suggested that NEK2, DLGAP5 and ECT2 expression levels could robustly distinguish lung cancer patients from normal subjects. Finally, Kaplan-Meier analysis revealed that elevated NEK2, DLGAP5 and ECT2 expression was negatively correlated with both overall survival (OS) and relapse-free survival (RFS). Taken together, these findings indicate that these three genes might be used as promising biomarkers for the early detection of lung cancer, as well as predicting the prognosis of lung cancer patients.

Abstract Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p

Abstract Background MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has been reported for its role in the genesis and progression of tumors. Forkhead box M1 (FoxM1), another transcriptional factor, is considered to be an independent predictor of poor survival in many solid cancers. The aim of the present study was to investigate the clinical significance of the correlation between MYBL2 and FoxM1 in glioma and the possible mechanism of FoxM1and MYBL2 expression. Methods MYBL2 and FoxM1expression in cancerous tissues and cell lines were determined by reverse transcription-PCR (RT-PCR), Western blotting and immunostaining. The co-expression of MYBL2 and FoxM1 was analyzed in low-grade glioma (LGG) and glioblastoma (HGG) cohorts of TCGA using cBioportal and UCSC Xena. And, the role of MYBL2 and FoxM1 in glioma cell progression and the underlying mechanisms were studied by using small interfering RNA (si-RNA) and pcDNA3.1 + HAvectors. Furthermore, the effects of MYBL2 and FoxM1 in cell proliferation, cell cycle progression, apoptosis, migration, invasion, and adhesion were determined by cell proliferation assays, flow cytometry analysis, transwell migration and cell adhesion assay. Results MYBL2 and FoxM1 expression are significantly associated with clinical stages and overall survival of glioma patients. In cohorts of TCGA, patients with high MYBL2 but without radio-chemotherapy had the highest hazard ratio (adjusted HR = 5.29, 95% CI = 1.475–18.969, P

Abstract Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10−5). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.

Abstract Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens.

Abstract Salvia miltiorrhiza (SM) is widely used to treat microcirculatory disturbance-related diseases; its lipophilic components play important roles in this application. Cryptotanshinone (CTS), tanshinone I (TSI) and tanshinone IIA (TSA) are the most widely-studied lipophilic ingredients, but low oral bioavailability limits their clinical application. It has been proven that micronization could improve the bioavailability of some drugs, so we’ve conducted this randomized study to investigate whether micronized granular powder (GP) of SM could improve the bioavailability of tanshinones compared with traditional decoction (TD). An oral dose of TD or GP of SM was administrated to subjects and blood samples were collected at predetermined time points. The plasma concentrations of tanshinones were detected by a validated method and pharmacokinetic parameters were calculated using a non-compartmental model. GP of SM resulted in a significant increase in mean maximum plasma concentration (C max ), elimination half-life and area under concentration-time curve (AUC) of tanshinones, with the plasma AUC of CTS, TSI and TSA in GP 5–184, 4–619 and 5–130 times higher than TD. In addition, the individual variances of C max and AUC were much lower after GP administration. Summarily, tanshinones in micronized GP of SM had higher oral bioavailability and lower individual variances, thus we speculate that it may indicate a better clinical efficacy and be a better choice than current treatments.

Abstract Background Colon cancer (CC) is a heterogeneous disease influenced by complex gene networks. As such, the relationship between networks and CC should be elucidated to obtain further insights into tumour biology. Results Weighted gene co-expression network analysis, a powerful technique used to extract co-expressed gene networks from mRNA expressions, was conducted to identify 11 co-regulated modules in a discovery dataset with 461 patients. A transcriptional module enriched in cell cycle processes was correlated with the recurrence-free survival of the CC patients in the discovery (HR = 0.59; 95% CI = 0.42–0.81) and validation (HR = 0.51; 95% CI = 0.25–1.05) datasets. The prognostic potential of the hub gene Centromere Protein-A (CENPA) was also identified and the upregulation of this gene was associated with good survival. Another cell cycle phase-related gene module was correlated with the survival of the patients with a KRAS mutation CC subtype. The downregulation of several genes, including those found in this co-expression module, such as cyclin-dependent kinase 1 (CDK1), was associated with poor survival. Conclusion Network-based approaches may facilitate the discovery of biomarkers for the prognosis of a subset of patients with stage II or III CC, these approaches may also help direct personalised therapies.

Abstract Dysregulated long noncoding RNAs (lncRNAs) are potential markers of several tumor prognoses. This study aimed to develop a lncRNA expression signature that can predict chemotherapeutic sensitivity for patients with advanced stage and high-grade serous ovarian cancer (HGS-OvCa) treated with platinum-based chemotherapy. The lncRNA expression profiles of 258 HGS-OvCa patients from The Cancer Genome Atlas were analyzed. Results revealed that an eight-lncRNA signature was significantly associated with chemosensitivity in the multivariate logistic regression model, which can accurately predict the chemosensitivity of patients [Area under curve (AUC) = 0.83]. The association of a chemosensitivity predictor with molecular subtypes indicated the excellent prognosis performance of this marker in differentiated, mesenchymal, and immunoreactive subtypes (AUC > 0.8). The significant correlation between ZFAS1 expression and chemosensitivity was confirmed in 233 HGS-OvCa patients from the Gene Expression Omnibus datasets (GSE9891, GSE63885, and GSE51373). In vitro experiments demonstrated that the ZFAS1 expression was upregulated by cisplatin in A2008, HeyA8, and HeyC2 cell lines. This finding suggested that ZFAS1 may participate in platinum resistance. Therefore, the evaluation of the eight-lncRNA signature may be clinically implicated in the selection of platinum-resistant HGS-OvCa patients. The role of ZFAS1 in platinum resistance should be further investigated.

NBIA (Neurodegeneration with brain iron accumulation) is a group of inherited neurologic disorders characterized by marked genetic heterogeneity, in which iron atypical accumulates in basal ganglia resulting in brain magnetic resonance imaging changes, histopathological abnormalities, and neuropsychiatric clinical symptoms.With the rapid development of high-throughput sequencing technologies, ten candidate genes have been identified, including PANK2, PLA2G6, C19orf12, WDR45, FA2H, ATP13A2, FTL, CP, C2orf37, and COASY. They are involved in seemingly unrelated cellular pathways, such as iron homeostasis (FTL, CP), lipid metabolism (PLA2G6, C19orf12, FA2H), Coenzyme A synthesis (PANK2, COASY), and autophagy (WDR45, ATP13A2).In particular, PANK2, COASY, PLA2G6, and C19orf12 are located on mitochondria, which associate with certain subtypes of NBIA showing mitochondria dysregulation. However, the relationships among those four genes are still unclear. Therefore, this review is specifically focused on dysregulation of mitochondria in NBIA and afore-mentioned four genes, with summaries of both pathological and clinical findings.

Epilepsy is a serious neurological disorder and is characterized by recurrent and unprovoked seizures. A critical pathological factor in the seizure genesis is neuronal loss. Until now, apart from the known regulatory cell death pathways, ferroptosis is a newly discovered type of cell death with the features of iron accumulation and the excessive production of lipid reactive oxygen species (ROS). In our present work, it was illustrated that ferroptosis occurs in murine models of pentylenetetrazole (PTZ) kindling and pilocarpine (Pilo)-induced seizures. In both of these seizure models, treatment with ferroptosis inhibitor ferrostatin-1 (Fer-1) efficiently alleviates seizures. This was achieved through elevated levels of glutathione peroxidase 4 (GPX4) and glutathione (GSH) as well as inhibitions of lipid degradation products including 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), iron accumulation, and PTGS2 mRNA in the hippocampus. It was concluded that ferroptosis is involved in seizure genesis in PTZ- and Pilo-treated mice, while the suppression of ferroptosis mitigates PTZ kindling, and Pilo-induced seizures in mice.