Search

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P

Supplementary Tables 1-2 from MiR-26a Inhibits Cell Growth and Tumorigenesis of Nasopharyngeal Carcinoma through Repression of EZH2

The KEYNOTE-590 trial showed that individuals with advanced esophageal cancer who received Pembrolizumab in combination with chemotherapy as a first-line regimen achieved a significant extension of survival. However, this treatment option increases the financial burden on patients and the economic benefits remain to be further evaluated.A Markov model was used to simulate 10-year survival of patients with esophageal cancer from the perspective of United States (US) Medicare payers. We evaluated the economics of Pembrolizumab plus chemotherapy in the PD-L1 positive score (CPS ≥10) and any PD-L1 expression groups, respectively. We estimated total costs, quality-adjusted life years (QALYs), and calculated incremental cost effectiveness ratios (ICERs). Sensitivity analyses were conducted to explore the impact of uncertainties on the results. Subgroup analysis was also performed.The analysis results showed that the ICER for pembrolizumab plus chemotherapy versus chemotherapy alone was $293,513.17/QALYs in the any PD-L1 expression group. This exceeded the threshold of willingness to pay ($150,000/QALYs). ICERs were most sensitive to the cost of pembrolizumab and the ICERs exceeded $150,000/QALYs in all subgroups.Evidence suggests that first-line pembrolizumab in combination with chemotherapy is not a cost-effective option for advanced esophageal cancer in the US, regardless of PD-L1 expression status.

In nasopharyngeal carcinoma (NPC), the treatment of tumor metastasis and recurrence is challenging and is associated with poor clinical efficacy. Vasculogenic mimicry (VM) is a new blood-supply model of malignant tumor that is closely related to tumors’ distant metastasis. Our previous study demonstrated that miR-124 could target Foxq1 to inhibit NPC metastasis. Whether Foxq1 affects metastasis through vasculogenic mimicry is worth consideration. In this study, we show that VM formation positively correlates with the expression of Foxq1, and EGFR, and the TNM stage in 114 NPC patient samples. Meanwhile, we show that VM-positive NPC patients have a poor prognosis. Furthermore, using in vitro and vivo approaches, we confirm that Foxq1 has a significant effect on NPC metastasis through promoting VM formation, which could be effectively inhibited by EGFR inhibitors (Nimotuzumab or Erlotinib). Also a synergistic efficacy of anti-EGFR and anti-VEGF drugs has been found in NPC inhibition. Mechanistically, the luciferase reporter gene and CHIP assays show that Foxq1 directly binds to the EGFR promoter region and regulates EGFR transcription. In conclusion, our results show that Foxq1 is regulated by miR-124 and that it promotes NPC metastasis by inducing VM via the EGFR signaling pathway. Overall, these results provide a new theoretical support and a novel target selection for anti-VM therapy in the treatment of nasopharyngeal carcinoma.

Jia He,1,2 Zhan Wang,3 Ting Zou,4 Ying Wang,5 Xiang-Ping Li,1,2 Juan Chen1,2 1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, People’s Republic of China; 4National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 5Hunan clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, People’s Republic of ChinaCorrespondence: Juan Chen, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China, Tel +86-731-89753491, Email cj1028@csu.edu.cnObjective: Platinum-based chemotherapy is the first-line treatment of lung cancer. However, different individual and genetic variation effect therapy for lung cancer. The purpose of this study was to evaluate the association between transport genes genetic polymorphisms and the prognosis of platinum-based chemotherapy in lung cancer patients.Methods: A series of 593 patients with treatment of platinum-based chemotherapy were recruited for this study. A total of 21 single-nucleotide polymorphisms in nine transporter genes were selected to investigate their associations with platinum-based chemotherapy prognosis.Results: Patients with ABCG2 rs1448784 CC genotype had a significantly shorter PFS than CT or TT genotypes (Additive model: HR = 1.54, 95% CI = 1.02– 2.35, P = 0.040). In stratification analysis, SLC22A2 rs316003, SLC2A1 rs4658 were related to PFS and AQP9 rs1867380, SLC2A1 rs3820589, SLC22A2 rs316003 indicated were related to OS of platinum-based chemotherapy prognosis.Conclusion: Genetic polymorphisms of rs1448784 in ABCG2 might be potential clinical marker for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.Keywords: lung cancer, platinum-based chemotherapy, prognosis, transporter gene, single nucleotide polymorphisms, SNPs

Coronavirus disease 2019 (COVID-19), an infectious disease caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a persistent global threat. The transmission of SARS-CoV-2 is wide and swift. Rapid detection of the viral RNA and effective therapy are imperative to prevent the worldwide spread of the new infectious disease. Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR)- CRISPR-associated protein (Cas) system is an RNA-directed adaptive immune system, and it has been transformed into a gene editing tool. Applications of CRISPR-Cas system involves in many fields, such as human gene therapy, drug discovery and disease diagnosis. Under the background of COVID-19 pandemic, CRISPR-Cas system shows hidden capacity to fight the emergency in many aspects. This review will focus on the role of gene editing in COVID-19 diagnosis and treatment. We will describe the potential use of CRISPR-Cas-based system in combating COVID-19, from diagnosis to treatment. Furthermore, the limitation and perspectives of this novel technology are also evaluated.

Purpose Tumour-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and provide a barrier against the cytotoxic effector functions of T cells and natural killer (NK) cells. Recently, TAMs have become increasingly recognised as an attractive target in combination therapy with PD-1/PD-L1 immuno-checkpoint blockades (ICBs). However, the relationship between PD-L1 expression and TAMs remains unknown in nasopharyngeal carcinoma (NPC). Patients and Methods A total of 212 NPC patients from Nanfang hospital were collected in this study. We evaluated the expression of PD-L1 in tumor cells, CD68 (pan-macrophages), and CD163 (M2-like macrophage) in NPC tissues using immunohistochemical (IHC) staining. Results The positivity of PD-L1 on tumor cells was 61.3% (130/212). The infiltration densities of CD68+ cells and CD163+ cells in PD-L1-positive NPC tissues were significantly higher than those in PD-L1-negative NPC tissues (P=0.0012 for CD68; P

Background Documented reports proved that Epstein‐Barr virus (EBV) infection increased infiltration of Tregs in malignancy. However, the mechanism of EBV recruitment Tregs into nasopharyngeal carcinoma (NPC) tissues has not been detailed discussion. Methods Expression of EBV nuclear antigen 1 (EBNA1) and Foxp3 in NPC tissue samples was detected by immunohistochemistry. EBNA1+ NPC cell lines were used to coculture with PBMC, naïve T cells, Tregs, and monocytes. Percent of Treg was detected by flow cytometry. Results EBNA1 protein was overexpressed in NPC tissues, and was associated with a number of infiltrated Tregs. EBNA1+ NPC cells converted naïve T cells into Tregs by up‐regulated TGF‐β1. Enhanced CCL20 production in EBNA1‐expressed tumor cells increased Tregs migration. Polarized‐M2 macrophages by EBNA1 expression cells converted naïve T cells into Tregs. Conclusions EBNA1 favors accumulation of Tregs in NPC through: (a) upregulated TGF‐β1 converted naïve T cell into Treg; (b) upregulated CCL20 increased Treg migration; and (c) polarized‐M2 macrophage converted naïve T cell into Treg., It is well known that Tregs accumulated in several EBV‐associated malignancies. Our previous studies also proved Tregs increased in NPC tissues and peripheral blood. However, the mechanism of EBV recruitment Tregs into NPC tissues has not been discussed in detail. EBNA1 protein was highly expressed in NPC tissue specimens, and its expression was associated with number of infiltrated Tregs. EBNA1 expression NPC cells induced naïve T cells into Tregs by upregulated TGF‐β1. Enhanced CCL20 production in EBNA1‐expressed tumor cell increased Tregs migration. Polarized‐M2 macrophages by EBNA1 expression cells converted naïve T cells into Tregs. These findings provided novel insight into the vital role of EBNA1 in recruitment of Tregs in NPC.

Purpose: We aimed to investigate the association of single-nucleotide polymorphisms (SNPs) in HMGB1, REV3L, and NFE2L2 with prognosis in lung cancer patients with platinum-based chemotherapy. Methods: We have recruited 348 lung cancer patients treated with platinum. Log-rank test and Cox regression analysis were used to assess overall survival (OS) and progression-free survival (PFS) among SNP genotypes. Results: The results revealed that patients carrying TC or CC genotype in REV3L rs462779 (HR=0.67, 95% CI=0.51-0.90, P=0.007) and AG or GG genotype in HMGB1 rs1045411 (HR=0.61, 95% CI=0.38-0.99, P=0.046) had a better overall survival. Additionally, carrying TC or TT genotype in rs462779 had a lower risk (OR=0.38, 95% CI=0.17-0.89, P=0.025) of lymph node metastasis, carrying AG or AA genotype in rs1045411 was significantly related to early T stage (OR=0.47, 95% CI=0.29-0.76, P=0.002). In stratified analysis, patients with TC or CC genotype in rs462779 were significantly associated with overall survival in male patients, never-smokers, patients with younger age (≤56), no family history of cancer, adenocarcinoma, advanced stage (stage III or IV), or ECOG PS 0-1. While patients with AG or GG genotype in rs1045411 were significantly associated with overall survival in patients with advanced stage (stage III or IV) or ECOG PS 0-1. Conclusion: Our results indicate that the TC or CC genotype in rs462779 and AG or GG genotype in rs1045411 are contributed to better overall survival. The REV3L rs462779 and HMGB1 rs1045411 may serve as prognosis markers in lung cancer patients with platinum-based chemotherapy.

Background. Lung cancer is one of the major causes of cancer-related mortality worldwide. DNA repair and damage response contribute to genomic instability that accompanies tumor progression. In this study, we focus on evaluating association between DNA repair polymorphisms of EXO1, RPA1, and prognosis in lung cancer patients whom received platinum-based chemotherapy. Methods. 593 lung cancer patients were recruited in this study. We performed genotyping of 19 single nucleotide polymorphisms (SNPs) by Sequenom MassARRAY. Cox regression analysis was used to assess overall survival (OS) and progression-free survival (PFS) among SNP genotypes. Results. Significant differences in PFS and OS were observed in RPA1 rs5030740, EXO1 rs1776148, and rs1047840. Results showed that patients with CC genotype in rs5030740 (recessive model: P = 0.034 ) had a better PFS. Patients with AA or/and AG genotypes in rs1776148 (additive model: P = 0.004 ; dominant model: P = 0.048 ) and AA genotype in rs1047840 (recessive model: P = 0.023 ) had longer OS. We also demonstrated differences in subgroup analysis between rs5030740, rs1776148, rs1047840, and prognosis. Conclusions. Our results indicated that EXO1 rs1776148, rs1047840, and RPA1 rs5030740 were significantly associated with prognosis of lung cancer. Rs1776148, rs1047840, and rs5030740 may act as prognosis markers in lung cancer patients with platinum-based chemotherapy.

Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN.Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only.Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family.Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.

The rare earth materials have attracted intensive attention due to their strong luminescent characteristic. However, the split fine Stark levels are difficult to be determined. Here we report a room-temperature detection for Stark levels of YNbO

With an increasing global burden of coronary artery disease (CAD), early detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus (DM) is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients. Growing evidence suggests that metformin has a protective effect on coronary artery beyond its hypoglycemic effects. Given its global availability, route of administration and cost, metformin provides an alternate/additional therapeutic option for primary and secondary prevention of CAD in DM and non-diabetics alike. Future prospective cohort-based studies and randomized clinical trials are needed to identify ‘at-risk’ population who may potentially benefit from metformin.

Background Panax notoginseng saponins (PNS) as the main effective substances from P. notoginseng with low bioavailability could be bio-converted by human gut microbiota. In our previous study, PNS metabolic variations mediated by gut microbiota have been observed between high fat, high protein (HF-HP) and low fat, plant fiber-rich (LF-PF) dietary subjects. In this study, we aimed to correspondingly characterize the relationship between distinct gut microbial species and PNS metabolites. Methods Gut microbiota were collected from HF-HP and LF-PF dietary healthy adults and profiled by 16S rRNA gene sequencing. PNS were incubated with gut microbiota in vitro. A LC–MS/MS method was developed to quantify the five main metabolites yields including ginsenoside F1 (GF1), ginsenoside Rh2 (GRh2), ginsenoside compound K (GC-K), protopanaxatriol (PPT) and protopanaxadiol (PPD). The selected microbial species, Bifidobacterium adolescentis and Lactobacillus rhamnosus, were employed to metabolize PNS for the corresponding metabolites. Results The five main metabolites were significantly different between the two diet groups. Compared with HF-HP group, the microbial genus Blautia, Bifidobacterium, Clostridium, Corynebacterium, Dorea, Enhydrobacter, Lactobacillus, Roseburia, Ruminococcus, SMB53, Streptococcus, Treponema and Weissella were enriched in LF-PF group, while Phascolarctobacterium and Oscillospira were relatively decreased. Furthermore, Spearman’s correlative analysis revealed gut microbials enriched in LF-PF and HF-HP groups were positively and negatively associated with the five metabolites, respectively. Conclusions Our data showed gut microbiota diversity led to the personalized bioconversion of PNS. Graphic Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00476-5., Highlights Panax notoginseng saponins could be biotransformed to generate five main metabolites, including GF1, GRh2, GC-K, PPT and PPD, by human gut microbiota. Gut microbiota profiles were significantly different in high protein, high fat and low fat, plant fiber-rich diet-pattern groups. Correlation analysis revealed potential relationships between metabolites and gut microbial species. Bifidobacterium adolescentis and Lactobacillus rhamnosus were selected as a representative species to metabolize PNS for the concerned metabolites. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00476-5.

Jia He,1 Zhan Wang,2 Ying Wang,3 Ting Zou,4 Xiang-Ping Li,1 Lei Cao,1 Juan Chen1 1Department of Pharmacy, Xinagya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, People’s Republic of China; 3Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, People’s Republic of China; 4National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of ChinaCorrespondence: Juan ChenDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of ChinaTel/Fax +86-731-89753491Email cj1028@csu.edu.cnPurpose: To investigate the relationships between Wnt1 inducible signaling pathway protein 1 (WISP1) polymorphisms and the prognosis of platinum-based chemotherapy in lung cancer patients.Patients and Methods: A total of 363 lung cancer patients were recruited in this study. All of them received at least two cycles of platinum-based chemotherapy. We used unconditional logistic regression analysis to assess the associations of 39 single nucleotide polymorphisms in WISP1 gene with platinum-based chemotherapy prognosis.Results: The results indicated that patients carried rs2929973 GT or GG genotypes had increased risk of disease progression (HR = 0.712, 95% CI = 0.553– 0.916, P = 0.015). Patients with rs2977551 TT genotype had a significantly decreased risk of progression-free survival than patients carrying CT or CC genotype (HR = 0.723, 95% CI = 0.561– 0.932, P = 0.032) and overall survival (HR = 0.725, 95% CI = 0.552– 0.913, P = 0.045). For rs2977549, patients carrying TT genotype had a significantly longer progression-free survival than patients with CC or CT genotypes (HR = 0.708, 95% CI = 0.550– 0.912, P = 0.017). Among of them, rs16904853, rs10956697, rs2929965, rs2929973, rs7828685, rs2977551 and rs2977549 were related to progression-free survival, and rs10956697 and rs2977551 were related to overall survival in subgroup analyses, respectively.Conclusion: WISP1 rs2929973, rs2977551 and rs2977549 may be contributed to a potential candidate biomarker for prediction of platinum-based chemotherapy prognosis in lung cancer patients.Keywords: lung cancer, platinum-based chemotherapy, prognosis, genetic polymorphism, WISP1

Background: Panax notoginseng saponins (PNS) as the main effective substances from P. notoginseng with low bioavailability could be bio-converted by human gut microbiota. In our previous study, PNS metabolic variations mediated by gut microbiota have been observed between high fat, high protein (HF-HP)-diet and low fat, plant fiber-rich (LF-PF)-diet subjects. In this study, we aimed to correspondingly characterize the relationship between distinct gut microbiota profiles and PNS metabolites. Methods: Gut microbiota were collected from HF-HP and LF-PF healthy adults, respectively and profiled by 16S rRNA gene sequencing. PNS were incubated with gut microbiota in vitro. A LC-MS/MS method was developed to quantify the five main metabolites yields including ginsenoside F1 (GF1), ginsenoside Rh2 (GRh2), ginsenoside compound K (GC-K), protopanaxatriol (PPT) and protopanaxadiol (PPD). The selected microbial species, Bifidobacterium adolescentis and Lactobacillus rhamnosus, were employed to metabolize PNS for the corresponding metabolites.Results: The five main metabolites were significantly different between the two diet groups. Compared with HF-HP group, the microbial genus Blautia, Bifidobacterium, Clostridium, Corynebacterium, Dorea, Enhydrobacter, Lactobacillus, Roseburia, Ruminococcus, SMB53, Streptococcus, Treponema and Weissella were enriched in LF-PF group, while Phascolarctobacterium and Oscillospira were relatively decreased. Furthermore, Spearman’s correlative analysis revealed gut microbiota enriched in LF-PF and HF-HP groups were positively and negatively associated with PNS metabolites yields, respectively. Conclusions: Our data showed gut microbiota diversity led to the personalized bioconversion of PNS.

Lung adenocarcinoma is the most common subtype of non-small cell lung carcinoma. Tanshinone I is an important fat-soluble component in the extract of Salvia miltiorrhiza that has been reported to inhibit lung adenocarcinoma cell proliferation. However, no studies have clearly demonstrated changes in lung adenocarcinoma gene expression and signaling pathway enrichment following Tanshinone I treatment. And it remains unclear whether salvianolate has an effect on lung adenocarcinoma. The present study downloaded the GSE9315 dataset from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) and the underlying signaling pathways involved after Tanshinone I administration in the lung adenocarcinoma cell line CL1-5. The results revealed that there were 28 and 102 DEGs in the low dosage group (0.01 and 0.10 µg/ml Tanshinone I) and medium dosage groups (1 and 10 µg/ml Tanshinone I), respectively. In the low dosage group, DEGs were mainly enriched in 'positive regulation of T-helper cell differentiation' and 'protein complex'. In the medium dosage group, 102 DEGs were enriched in 'MAPK cascade' and 'extracellular exosome'. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated enrichment of both groups in the PI3K-Akt signaling pathway. Furthermore, there were nine overlapping DEGs [ADP ribosylation factor-interacting protein 2, chemokine (C-X-C motif) ligand 6, SH2 domain-containing adaptor protein B, Src homology 2 domain-containing transforming protein1, collagen type VI α1 chain, elastin, integrin subunit α, endoplasmic reticulum mannosyl-oligosaccharide 1,2-α-mannosidase and sterile α motif domain-containing 9 like] between the two groups, which serve to be potential targets for the treatment of lung adenocarcinoma. The present study also investigated the possible effects of salvianolate on lung adenocarcinoma in vivo using nude mouse xenograft models injected with the A549 cell line. The data revealed that salvianolate not only suppressed lung adenocarcinoma tumor growth of in nude mice, but also downregulated the expression levels of ATP7A and ATP7B, which are important proteins in the tumorigenesis and chemotherapy of lung adenocarcinoma. The present study provided evidence for the potential use of Salvia miltiorrhiza extract for treating lung adenocarcinomas in the clinic.

Background Anthracycline are inhibitors of topoisomerase II leading to DNA double strand breaks, and it is widely used for treatment of breast cancer. eIF3a is the largest subunit of eukaryotic translation initiation factor 3 (eIF3) and highly expressed in breast cancer. In this study, we investigated the role of eIF3a in DSB DNA repair and the response of breast cancer patients to anthracycline-based chemotherapy. Methods MTT assay was used to detect anthracycline sensitivity in cell lines. Real-time reverse transcriptase PCR, western blotting and immunofluorescence were performed to assess changes in gene expression levels. Cometassay and end-joining activity assay were conducted to explore the effect of eIF3a in NHEJ repair. Luciferase reporter assay was performed to detect LIG4 5′UTR activity. Immunohistochemistry was used to detect eIF3a, LIG4 and DNA-PKcs expression levels in breast cancer tissues. Results The results showed that eIF3a increased cellular response to anthracyclines by regulating DSB repair activity via influencing the expression of LIG4 and DNA-PKcs at translational level. Breast cancer patients with high level of eIF3a or low level of LIG4 or low level of DNA-PKcs had better anthracycline-based chemotherapy prognosis compared. Moreover, Combined expressions of eIF3a, LIG4 and DNA-PKcs could be better to predict PFS in breast cancer patients with anthracycline-based chemotherapy. Conclusion Our findings suggest that eIF3a effects anthracycline-based chemotherapy response by regulating DSB DNA repair.

Since the outbreak of coronavirus disease 2019 (COVID-19), more than 130,000 people worldwide have been infected. Many studies show that the testis is one of the organs with a high expression of angiotensin-converting enzyme 2 (ACE2), the receptor/binding protein of SARS-CoV-2, which has aroused public concerns about the possible damage to male fertility. This article presents a review and analysis of the existing literature, aiming to achieve an objective understanding of the significance of the ACE2 expression in the testis. Hitherto, clinical and laboratory data available on COVID-19 are not sufficient to provide any direct evidence that the testis is a target organ of the virus. Whether the coronavirus damages fertility in male patients with COVID-19 requires further investigation. In the absence of sufficient research-based evidence, damage of the virus to male fertility should not be over-interpreted.

Purpose Tumour-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and provide a barrier against the cytotoxic effector functions of T cells and natural killer (NK) cells. Recently, TAMs have become increasingly recognised as an attractive target in combination therapy with PD-1/PD-L1 immuno-checkpoint blockades (ICBs). However, the relationship between PD-L1 expression and TAMs remains unknown in nasopharyngeal carcinoma (NPC). Patients and Methods A total of 212 NPC patients from Nanfang hospital were collected in this study. We evaluated the expression of PD-L1 in tumor cells, CD68 (pan-macrophages), and CD163 (M2-like macrophage) in NPC tissues using immunohistochemical (IHC) staining. Results The positivity of PD-L1 on tumor cells was 61.3% (130/212). The infiltration densities of CD68+ cells and CD163+ cells in PD-L1-positive NPC tissues were significantly higher than those in PD-L1-negative NPC tissues (P=0.0012 for CD68; P

BackgroundNasopharyngeal carcinoma (NPC) is primarily caused by the Epstein-Barr virus (EBV) infection in NPC endemic areas. EBNA1 is an EBV-encoded nuclear antigen, which plays a critical role in the maintenance and replication of EBV genome. However, the mechanisms of EBNA1-promoted NPC immune escape are unknown. Regulatory T (Treg) cells are among the key regulators in restraining antitumor responses. However, the mechanisms of accumulation of Treg cells in NPC have not been defined. This study attempted to identify the detailed mechanisms of EBNA1 functions as a tumor accelerator to promote NPC immune escape by enhancing chemoattraction of Treg cells.MethodsmRNA profiles were determined by next-generation sequencing in NPC cells. In vitro and in vivo assays were performed to analyze the role of EBNA1 in regulation of recruitment of Treg cells. Colocation and coimmunoprecipitation analyzes were used to identify the SMAD3/c-JUN complex. Chromatin immunoprecipitation assay and dual luciferase reporter assays were designed to demonstrate c-JUN binding to miR-200a promoter and miR-200a targeting to CXCL12 3’Untranslated Regions. The hepatocellular carcinoma models were designed to demonstrate universality of the CXCL12-CXCR4-Treg axis in promoting immune evasion of various tumors.ResultA novel molecular mechanism was identified that involves EBV-EBNA1-stimulated chemotactic migration of Treg cells toward NPC microenvironment by upregulation of the transforming growth factor-β1 (TGFβ1)-SMAD3-PI3K-AKT-c-JUN-CXCL12-CXCR4 axis and downregulation of miR-200a. EBV-EBNA1 promotes the chemoattraction of Treg cells by governing the protein–protein interactions of the SMAD3/c-JUN complex in a TGFβ1-dependent manner in vitro and in vivo. TGFβ1 suppresses miR-200a by enhancing the SMAD3/c-JUN complex. miR-200a negatively regulates the CXCL12 chemokine by direct targeting of the CXCL12 3’UTR region. However, CXCL12 acts as the target gene of miR-200a and as an inhibitor of miR-200a transcription, and inhibition of miR-200a by CXCL12 is mediated by c-JUN, which directly binds to the miR-200a promoter and forms a c-JUN-miR-200a-CXCL12-c-JUN feedback loop. In addition, enhanced CXCL12 efficiently attracts CXCR4-positive Treg cells to remodel an immunosuppressive microenvironment.ConclusionsEBV-EBNA1 promotes chemotactic migration of Treg cells via the TGFβ1-SMAD3-PI3K-AKT-c-JUN-miR-200a-CXCL12-CXCR4 axis in the NPC microenvironment. These results suggest that EBV-EBNA1 may serve as a potential therapeutic target to reshape the NPC microenvironment.

Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and immunological characteristics of EAP animals are highly consistent with human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which makes EAP an ideal model for this disease. Here, we investigate the influence of EAP on male rat sexual function and the efficacy of anti-inflammatory therapy with celecoxib. EAP rat models were established using male Wistar rats. Rats were randomly assigned to a normal control group, an EAP model group, or an EAP model with celecoxib treatment group (celecoxib group). Behavioral changes, sexual behavioral changes, and erectile function were estimated using an open-field test, a sucrose consumption test, mating experiments, and by intracavernous pressure/mean arterial pressure ratio (ICP/MAP). Histological changes in the prostate were observed by HE staining, and the serum inflammatory factors IL-1β and TNF-α levels were measured by enzyme-linked immunosorbent assay. In addition, serotonin (5-hydroxytryptamine, 5-HT), 5-HT1A receptor, 5-HT2C receptor, and serotonin transporter (SERT) expression levels in the hippocampus and spinal cord (T13-L1, L5-S2) were examined by immunohistochemistry and western blot analysis. Results showed that EAP rats exhibited characteristics of depression, decreased sexual drive, premature ejaculation, and increased threshold of penile erection. Moreover, all these changes were effectively alleviated by celecoxib. Significant increases in prostatic interstitial infiltration by inflammatory cells and in serum IL-1β and TNF-α levels were observed in EAP rats, and these were partially reduced by celecoxib. Additionally, the expression pattern of serotonin system regulators in the hippocampus and spinal cord were altered in EAP model rats, including a decrease in 5-HT levels and an increase in 5-HT1A receptor levels. In conclusion, autoimmune prostatitis impaired rat sexual function, and this was effectively prevented by anti-inflammatory therapy with celecoxib. Moreover, a serotonin system disorder in the central nervous system was likely mediated via inflammation in EAP rats.

STUDY OBJECTIVES: To investigate the fiber-type distribution in palatopharyngeal muscle via adenosine triphosphatase and quantitative real-time polymerase chain reaction in children with severe obstructive sleep apnea (OSA). METHODS: Study participants were 12 children with severe OSA and 15 children with simple snoring as the control group. Both groups were diagnosed by polysomnography and treated with tonsillectomy. The samples of palatopharyngeus muscle were studied under adenosine triphosphatase staining and quantitative real-time polymerase chain reaction to classify the different fiber types. RESULTS: There were no differences in baseline age, body mass index, tonsil size, or sleep stage constitution between the 2 groups. Dominance (>60%) of type I fiber was observed both in children with simple snoring (3/15, 20%) and in those with severe OSA (1/12, 8.3%) via adenosine triphosphatase staining. Predominance of type II fibers was seen in 3/15 (20%) in the control group and 6/12 (50%) in the severe OSA group, respectively. Type grouping was also seen in 8/15 (53.3%) in non-OSA and 6/12 (50%) in severe OSA groups, respectively. There was no difference in distribution of subtype fibers assessed by quantitative real-time polymerase chain reaction between the 2 groups; the mean percentages of type I fibers were 25.8% ± 19.5% and 20.9% ± 16.6%, respectively (P > .05), similar to type IIa fibers (35.2% ± 23.4% and 40.9% ± 28.8%) (P > .05). There was a decrease in the percentage of type I fibers between children younger and older than 12 years (P < 0.05), although this was not due to OSA (P > 0.05). CONCLUSIONS: There were no specific changes via adenosine triphosphatase staining or a difference in distribution of subtype fibers via quantitative real-time polymerase chain reaction between children with severe pediatric OSA and those with simple snoring, whereas the percentage of type I fiber decreased dynamically due to age but not OSA. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trials Registry; Name: A study of the mechanism of the conversion of upper airway expasion muscle’s fiver types of OSA patient which may be mediated by estrogen-related receptor alpha; URL: https://www.chictr.org.cn/showproj.aspx?proj=6144; Identifier: ChiCTR-CCC-13003415. CITATION: Chen H, Huang X, Ye Y, Luo Y, Huang Y, Li X. Muscle type of palatopharyngeal muscle in children with severe obstructive sleep apnea. J Clin Sleep Med. 2020;16(9):1523–1529.

Adenylate cyclase 1 (ADCY1 or AC1) is a member of ADCY superfamily and was primarily found to be expressed in the brain. ADCY1 is responsible for catalyzing ATP to cyclic AMP (cAMP). As a secondary messenger, cAMP can regulate plenty of cellular activities. cAMP can perform its regulation in cellular transport through the binding to cAMP dependent protein kinases (PKAs), cAMP-activated guanine exchange factors (EPACs) and cyclic nucleotide-gated channels functioning in transduction of sensory signals (CNGs). Lung cancer is one of the leading factors of cancer-related death worldwide. Platinum-based chemotherapy is the first-line treatment for advanced lung cancer patients. In addition, surgical treatment, radiation treatment, and molecular targeted therapy are also therapeutic options for lung cancer patients in clinical settings. However, drug resistance and toxicity are the major obstacles that affect chemotherapy outcome and prognosis of lung cancer patients. And the therapeutic efficiency and adverse effects are varying with each individual. In recent years, investigations based on genetic sequencing have revealed the emerging role of ADCY1 mutations in affecting drug efficiency in various cancers such as lung cancer, esophageal cancer and colorectal cancer. The potential function of ADCY1 in chemotherapy resistance is of great importance to be noticed and investigated.

Primary laryngeal epithelial cells are essential to exploring the mechanisms of laryngeal and voice disorders; however, they are difficult to study and apply because of their limited life span. The purpose of this study was to develop a stable and reliable in vitro model for the comprehensive study of the pathogenesis of laryngeal and voice diseases. The pLVTHM-Bmi1 plasmid was constructed and used to immortalize primary laryngeal epithelial cells by lentiviral infection. The expressions of Bmi1, human telomerase reverse transcriptase (hTERT), p53, and pRB pathway proteins were detected by western blotting. Functional characteristics of the immortalized cell lines were verified by cell senescence β-galactosidase staining, 5-ethynyl-2′-deoxyuridine cell proliferation test, and flow cytometry. We successfully introduced Bmi into human subglottic (hSG) cells and human ventricle (hV) cells. Both the human immortalized subglottic Bmi1 (hSG-Bmi1) cell line and the human immortalized ventricle Bmi1 (hV-Bmi1) cell line maintained normal epithelial morphology and divided successfully after more than 20 culture passages. As Bmi1 was overexpressed in these cells, the expression of human telomerase reverse transcriptase (hTERT) and phosphorylated Rb increased while p16 and p21 decreased. Following Bmi1-mediated immortalization, cell senescence decreased significantly, and cell proliferation was accelerated. Tumor formation was not observed for hSG, hV, or hSG-Bmi1, and hV-Bmi1 cells in nude mice. hSG-Bmi1 cells dominated by stratified squamous epithelium and hV-Bmi1 cells dominated by columnar cells were established. The new cell lines lay a foundation for the study of the pathogenic mechanisms of laryngeal and voice diseases.