A Predictive Network-Based Immune Checkpoint Blockade Immunotherapeutic Signature Optimizing Patient Selection and Treatment Strategies.

Immune checkpoint blockade (ICB) therapy has brought significant advancements to the field of oncology. However, the diverse responses among patients highlight the need for more accurate predictive tools. In this study, insights are drawn from tumor-immunology pathways, and a novel network-based ICB immunotherapeutic signature, termed ICBnetIS, is constructed. The signature is derived from advanced biological network-based computational strategies involving co-expression networks and molecular interactions networks. The efficacy of ICBnetIS is established through its association with enhanced patient survival and a robust immune response characterized by diverse immune cell infiltration and active anti-tumor immune pathways. The validation process positions ICBnetIS as an effective tool in predicting responses to ICB therapy, analyzing ICB data from a broad collection of over 700 samples from multiple cancer types of more than 15 datasets. It achieves an aggregated prediction AUC of 0.784, which outperforms the other nine renowned immunotherapeutic signatures, indicating the superior predictive capability of ICBnetIS. To sum up, the findings suggest ICBnetIS as a potent tool in predicting ICB therapy responses, offering significant implications for patient selection and treatment optimization in oncology. The study highlights the role of ICBnetIS in advancing personalized treatment strategies, potentially transforming the clinical landscape of ICB therapy.

Insight of novel biomarkers for papillary thyroid carcinoma through multiomics.

Introduction: The overdiagnosing of papillary thyroid carcinoma (PTC) in China necessitates the development of an evidence-based diagnosis and prognosis strategy in line with precision medicine. A landscape of PTC in Chinese cohorts is needed to provide comprehensiveness. Methods: 6 paired PTC samples were employed for whole-exome sequencing, RNA sequencing, and data-dependent acquisition mass spectrum analysis. Weighted gene co-expression network analysis and protein-protein interactions networks were used to screen for hub genes. Moreover, we verified the hub genes' diagnostic and prognostic potential using online databases. Logistic regression was employed to construct a diagnostic model, and we evaluated its efficacy and specificity based on TCGA-THCA and GEO datasets. Results: The basic multiomics landscape of PTC among local patients were drawn. The similarities and differences were compared between the Chinese cohort and TCGA-THCA cohorts, including the identification of PNPLA5 as a driver gene in addition to BRAF mutation. Besides, we found 572 differentially expressed genes and 79 differentially expressed proteins. Through integrative analysis, we identified 17 hub genes for prognosis and diagnosis of PTC. Four of these genes, ABR, AHNAK2, GPX1, and TPO, were used to construct a diagnostic model with high accuracy, explicitly targeting PTC (AUC=0.969/0.959 in training/test sets). Discussion: Multiomics analysis of the Chinese cohort demonstrated significant distinctions compared to TCGA-THCA cohorts, highlighting the unique genetic characteristics of Chinese individuals with PTC. The novel biomarkers, holding potential for diagnosis and prognosis of PTC, were identified. Furthermore, these biomarkers provide a valuable tool for precise medicine, especially for immunotherapeutic or nanomedicine based cancer therapy.

The Loss-Function of KNL1 Causes Oligospermia and Asthenospermia in Mice by Affecting the Assembly and Separation of the Spindle through Flow Cytometry and Immunofluorescence.

KNL1 (kinetochore scaffold 1) has attracted much attention as one of the assembly elements of the outer kinetochore, and the functions of its different domains have been gradually revealed, most of which are associated with cancers, but few links have been made between KNL1 and male fertility. Here, we first linked KNL1 to male reproductive health and the loss-function of KNL1 resulted in oligospermia and asthenospermia in mice (an 86.5% decrease in total sperm number and an 82.4% increase in static sperm number, respectively) through CASA (computer-aided sperm analysis). Moreover, we introduced an ingenious method to pinpoint the abnormal stage in the spermatogenic cycle using flow cytometry combined with immunofluorescence. Results showed that 49.5% haploid sperm was reduced and 53.2% diploid sperm was increased after the function of KNL1 was lost. Spermatocytes arrest was identified at the meiotic prophase I of spermatogenesis, which was induced by the abnormal assembly and separation of the spindle. In conclusion, we established an association between KNL1 and male fertility, providing a guide for future genetic counseling regarding oligospermia and asthenospermia, and a powerful method for further exploring spermatogenic dysfunction by utilizing flow cytometry and immunofluorescence.

Three amendments reduced the bioavailability of heavily contaminated soil with arsenic and cadmium and increased the relative feeding value of Lolium perenne L.

Soils heavily contaminated with arsenic (As) and cadmium (Cd) are fully utilized and create economic value by growing forages with high standard limits for heavy metals. In this study, 0.5 %, 1 % and 2 % of applied amounts of lime + ferrous sulfate (LF) and 0.25 %, 0.5 % and 1 % of applied amounts of Fe-modified biochar (MB) and Fe-modified eucalyptus sawdust (MC) were added to As and Cd cocontaminated soil planted with ryegrass (Lolium perenne L.). The results showed that the amendment-induced changes in soil pH and cation exchange capacity (CEC) contributed to the reduction in soil available Cd, which was maximally reduced by up to 76.7 %, 27.6 % and 25.1 % under the LF, MB and MC applications, respectively. In contrast, the available As content was reduced by a maximum of 25.5 % and 23.7 % under the MB and MC treatments, respectively, while LF did not reduce the available As content of the soil. As uptake by ryegrass was not reduced under the LF treatment, but As and Cd contents in the ryegrass shoot were reduced simultaneously under the MB and MC treatments. The relative forage value of ryegrass was enhanced more by MB and MC than by the LF treatment. The lime and ferrous sulfate components of LF could be immobilized against Cd and As, respectively; by characterizing MB and MC, the more available As and Cd fractions of the soil could be converted to less available fractions by electrostatic attraction, surface precipitation or complexation and redox. These results show that the application of amendments to heavily As and Cd cocontaminated soils in combination with ryegrass cultivation can help reduce the toxicity of As and Cd and increase the RFV, a model that may be a novel solution for heavily contaminated As and Cd cocontaminated soils.

Tumor-derived extracellular vesicles induce invalid cytokine release and exhaustion of CD19 CAR-T Cells.

Although CD19 chimeric antigen receptor-T (CAR-T) cells therapy has achieved unparalleled success in B cell malignancies. The dysfunction of CAR-T cells due to exhaustion is considered as a key factor for treatment failure, and the mechanisms of exhaustion remain elusive. Extracellular vesicles (EVs), important media for communication between tumor and immune cells, may contribute to CAR-T cell exhaustion. Here, we demonstrated that CD19+ tumor cells derived EVs (NALM6-EVs) can carry CD19 antigen and activate CD19 CAR-T cells. The transient activation induced a supraphysiologic inflammatory state with increased release of multiple cytokines. Besides, the sustained activation led CD19 CAR-T cells to enter an exhausted state with upregulated inhibitory receptors, decreased expansion ability, exaggerated effector cell differentiation and impaired antitumor activity. Transcriptomic profiling validated these findings and identified dynamic changes in CD8+ effector T, CD8+ exhausted T, CD8+RRM2+ T and T helper cell subpopulations during activation to exhaustion, as well as changes in many cytokines, inflammatory and immune-related pathways. Our findings identify a credible mechanism of CAR-T cell exhaustion that driven by tumor-derived EVs and provide a novel possible trigger for early cytokine release syndrome.

Responses of antioxidant enzymes and key resistant substances in perennial ryegrass (Lolium perenne L.) to cadmium and arsenic stresses.

Cadmium (Cd) and arsenic (As) exist simultaneously in soil environment, which poses a serious threat to the safety of agricultural products and forage production. Four Perennial Ryegrass (Lolium perenne L.) cultivars with different accumulation characteristics ('Nicaragua', 'Venus', 'Excellent' and 'Monro') were selected as the material for pot experiment. The coupled responses of key components and related enzyme activities under combined stresses of Cd and As were investigated. key components contents include Non protein sulfhydryl (NPT), glutathione (GSH) and phytochelatins (PCs). The related enzyme includes (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), γ-glutamylcysteine synthetase (γ-ECS), glutathione synthetase (GSS), phytochelatin synthetases (PCSase) and arsenate reductase (AR). The results showed that Cd contents of perennial ryegrass were higher than those of As contents with TFCd/As < 1. Cd and As contents in roots were in the higher proportion than those in shoots. Compared to control, POD activities increased by 2.72 folds under 120 mg kg-1 As treatment. The contents of PCs increased by 5.68 folds under 120 mg kg-1 As treatment. Under combined Cd and As stress, the MDA contents and antioxidant enzyme activities of 'Venus' were higher than those of 'Nicaragua'. 'Nicaragua', a high accumulation cultivar. Under the combined stresses of Cd and As, the enzyme activities and the key components were significantly correlated (P < 0.05) with the contents of Cd and As. The tolerance to Cd and As was improved with increase in GSH and PCs contents and γ-ECS, GSS, PCSase and AR activities. In conclusion, the antioxidant enzyme system and key resistant substances of perennial ryegrass have important and antagonistic effects on Cd and As stresses.

Reactivation of γ-globin expression using a minicircle DNA system to treat ß-thalassemia.

Reactivation of fetal hemoglobin by editing the B-cell lymphoma/leukemia 11A (BCL11A) erythroid enhancer is an effective gene therapy for ß-thalassemia. Using the CRISPR/Cas9 system, fetal γ-globin expression can be robustly reactivated to mitigate the clinical course of ß-thalassemia. In our study, we found that the transfection efficiencies of CD34+ hematopoietic stem/progenitor cells (HSPCs) were significantly and negatively correlated with the length of plasmids and greatly affected by the linearization of plasmids. Furthermore, the transgene expression of minicircles (MC) without plasmid backbone sequences was better both in vitro and in vivo compared with conventional plasmids. Thus, MC DNA was used to deliver the cassette of Staphylococcus aureus Cas9 (SaCas9) into HSPCs, and a single-guide RNA targeting the erythroid enhancer region of BCL11A was selected. After electroporation with MC DNA, an evident efficiency of gene editing and reactivation of γ-globin expression in erythroblasts derived from unsorted HSPCs was acquired. No significant off-target effects were found by deep sequencing. Furthermore, fragments derived from lentiviral vectors, but not MC DNA, were highly enriched in promoter, exon, intron, distal-intergenic, and cancer-associated genes, indicating that MC DNA provided a relatively safe and efficient vector for delivering transgenes. The developed MC DNA vector provided a potential approach for the delivery of SaCas9 cassette and the reactivation of γ-globin expression for ameliorating syndromes of ß-thalassemia.

Adsorption Characteristics of Modified Eucalyptus Sawdust for Cadmium and Arsenic and Its Potential for Soil Remediation.

In order to explore the utilization of Eucalyptus sawdust (C) and develop its remediation potential in cadmium and arsenic contaminated soil, Eucalyptus sawdust were modified by FeCl3 and NaOH coprecipitation (MC). Characterization technology and pot experiment were used to explore the adsorption mechanism of cadmium and arsenic by MC and the effect of soil remediation. The results showed that iron oxide was loaded on the surface of Eucalyptus sawdust and destroyed the semi fiber structure. The adsorption mechanisms of cadmium and arsenic included electrostatic attraction, precipitation, complexation, redox. The soil pH value reduced by 0.12-0.18 units with 0.25%-1% ratio of application rates of MC to soil weight treatment; The contents of available cadmium and arsenic were reduced by 18%-25% and 12%-18%; MC could promote the transformation of Cd and As from highly active formation to low active formation and had a good application prospect for Cd and As compound pollution remediation.

A de novo pure 21q22.3 deletion in a 9-year-old boy with buried penis: a case report and literature review.

21q deletion has been associated with a wide range of clinical signs, from very mild to severe phenotypes, and with the progress of genetic technology, more patients with this deletion are being diagnosed. This study reports on a 9-year-old boy with a terminal deletion of 4.5 Mb on chromosome 21 in the locus of chr21: 43531239-48119895 (GRCh37/hg19). Dark skin, a buried penis, small testes, dental caries, microcephaly, a low auricle, mental and intellectual retardation, balance disorder and pituitary and callosum dysplasia were observed. The results of a literature review and observation of similar abnormalities, including hypoplasia of corpus callosum, in two patients with non-overlapping deletion regions suggest that there are multiple gene loci regulating brain development on 21q. By comparing the overlapped deletion region in 21q22.3 cases of brain anomalies and/or gonadal dysgenesis, we concluded there were two overlapped microdeletion regions (chr21:43531239-43792093 and chr21:46625055-46884297) that may be related to brain and gonadal development. The same 16.49 Mb deletion of chr21:31578129-48119895 (GRCh37/hg19) was shared in 10 cases, and 24 cases shared the same 5.59 Mb deletion of chr21:42478130-48119895 (GRCh37/hg19) in DECIPHER (Database of Chromasomal Imbalance and Phenotype in Humans using Ensembl Resources), suggesting these were two commonly deleted regions of pure partial 21q. Those patients with the same breakpoints had different phenotypes suggesting the heterogeneity of 21q deletion.

Development of a new genetic reference material system based on Saccharomyces cerevisiae cells.

As an important quality control link of molecular diagnosis, genetic reference materials (RMs) are widely used in various gene detection platforms such as mutation detection, gene quantification, and second generation sequencing. However, contamination, construction, and storage of existing genetic RMs still remain challenges. Here, we established a new genetic RM system based on Saccharomyces cerevisiae. We chose the non-small cell lung cancer (NSCLC) mutation hotspots in Kirsten rat sarcoma viral oncogene (KRAS) and epidermal growth factor receptor (EGFR), using clustered regularly interspaced short palindromic repeats and CRISPR-associated protein (CRISPR-Cas9) system-mediated gene editing technology, combined with the high homologous recombination efficiency of Saccharomyces cerevisiae. A single copy of the target gene was inserted into the yeast genome, and the inserted target gene was stably inherited with the passage of yeast cells. The copy number calculation for the target gene can replays by cell counting. The RM system was evaluated by sequence, copy number, stability, and homogeneity. In summary, the recombinant yeast cell line has ease of construction and screening, stable genetic characteristics, accurate copy number calculation, and convenient culture and preservation. Our findings may provide new ideas and directions for the research and industrialization of genetic RMs.

Research Progress on the Involvement of ANGPTL4 and Loss-of-Function Variants in Lipid Metabolism and Coronary Heart Disease: Is the "Prime Time" of ANGPTL4-Targeted Therapy for Coronary Heart Disease Approaching?

BACKGROUND: Multiple genetic studies have confirmed the definitive link among the loss-of-function variants of angiogenin-like protein 4 (ANGPTL4), significantly decreased plasma triglyceride (TG) levels, and reduced risk of coronary heart disease (CHD). The potential therapeutic effect of ANGPTL4 on dyslipidemia and CHD has been widely studied. OBJECTIVE: This review provides a detailed introduction to the research progress on the involvement of ANGPTL4 in lipid metabolism and atherosclerosis and evaluates the efficacy and safety of ANGPTL4 as a therapeutic target for CHD. RELEVANT FINDINGS: By inhibiting lipoprotein lipase (LPL) activity, ANGPTL4 plays a vital role in the regulation of lipid metabolism and energy balance. However, the role of ANGPTL4 in regulating lipid metabolism is tissue-specific. ANGPTL4 acts as a locally released LPL inhibitor in the heart, skeletal muscle and small intestine, while ANGPTL4 derived from liver and adipose tissue mainly acts as an endocrine factor that regulates systemic lipid metabolism. As a multifunctional protein, ANGPTL4 also inhibits the formation of foam cells in macrophages, exerting an anti-atherogenic role. The function of ANGPTL4 in endothelial cells is still uncertain. The safety of ANGPTL4 monoclonal antibodies requires further evaluation due to their potential adverse effects. CONCLUSION: The biological characteristics of ANGPTL4 are much more complex than those demonstrated by genetic studies. Future studies must elucidate how to effectively reduce the risk of CHD while avoiding potential atherogenic effects and other complications before the "prime time" of ANGPTL4-targeted therapy arrives.

Soluble epoxide hydrolase inhibitors improve angiogenic function of endothelial progenitor cells via ERK/p38-mediated miR-126 upregulation in myocardial infarction mice after exercise.

It is well established that exercise could protect against myocardial infarction (MI). Previously, we found that epoxyeicosatrienoic acids (EETs) could be induced by exercise and has been found to protect against MI via promoting angiogenic function of endothelial progenitor cells (EPCs). However, the underling mechanism of EETs in promoting EPC functions is unclear. C57BL/6 mice were fed with a novel soluble epoxide hydrolase inhibitor (sEHi), TPPU, to increase EET levels, for 1 week before undergoing MI surgery. Mice were then subjected to exercise training for 4 weeks. Bone marrow-derived EPCs were isolated and cultured in vitro. Exercise upregulated miR-126 expression but downregulated the protein levels of its target gene, Spred1, in EPCs from MI mice. TPPU further enhanced the effects of exercise on EPCs. Spred1 overexpression abolished the protective effects of TPPU on EPC functions. Downregulation of miR-126 by antagomiR-126 impaired the inhibitor effects of TPPU on Spred1 mRNA and protein expression. Additionally, TPPU upregulated miR-126 is partially mediated through ERK/p38 MAPK pathway. This study showed that sEHi promoted miR-126 expression, which might be related to the beneficial effect of sEHi on EPC functions in MI mice under exercise conditions, by increasing ERK and p38 MAPK phosphorylation and inhibiting Spred1.

Trans-acting non-synonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection.

Interplay of pioneer transcription factor forkhead box A1 (FOXA1) and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients versus1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a non-synonymous Thr83Ala variant of FOXA1 (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients versus 1030 controls), a tightly linked (CGC)5/6or7 repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10-1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24-1.81, for (CGC)6or7-Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as type 1 iodothyronine deiodinase, UDP glucuronosyltransferase 2 family, polypeptide B17 and sodium/taurocholate cotransporting polypeptide, but correlates with strengthened cellular expression of α-fetoprotein (AFP) and elevated AFP serum concentration in HCC patients (n = 1096). The susceptible FOXA1 cis-variant with (CGC)6or7 repeat strengthens the binding to transcription factor early growth response 1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.

A genetic variant of the NTCP gene is associated with HBV infection status in a Chinese population.

BACKGROUND: To investigate whether genetic variants of the HBV receptor gene NTCP are associated with HBV infection in the Han Chinese population. METHODS: We sequenced the entire 23 kb NTCP gene from 111 HBeAg-positive HBsAg carriers (PSE group), 110 HBeAg-negative HBsAg carriers (PS group), and 110 control subjects. Then, we performed association analyses of suggestively significant SNPs with HBV infection in 1075 controls, 1936 PSs and 639 PSEs. RESULTS: In total, 109 rare variants (74 novel) and 38 single nucleotide polymorphisms (SNPs, one novel) were screened. Of the seven non-synonymous rare variants, six were singletons and one was a double hit. All three damaging rare singletons presented exclusively in the PSE group. Of the five SNPs validated in all 3650 subjects, the T allele of rs4646287 was significantly decreased (p = 0.002) in the PS group (10.1%) and PSE group (8.1%) compared to the controls (10.9%) and was decreased to 7.4% in the PSE hepatocellular carcinoma (HCC) subgroup. Additionally, rs4646287-T was associated with a 0.68-fold (95% CI = 0.51-0.89, p = 0.006) decreased risk of PSE compared with the controls. The NTCP mRNA level was lower in HCC tissues in "CT + TT" carriers than in "CC" carriers. CONCLUSIONS: We found a genetic variant (rs4646287) located in intron 1 of NTCP that may be associated with increased risk of HBV infection in Han Chinese.

Genetic variation in STAT4 predicts response to interferon-α therapy for hepatitis B e antigen-positive chronic hepatitis B.

UNLABELLED: Interferon (IFN)-α is a first-line therapy for chronic hepatitis B (CHB) patients but only initiates a response in a minority of patients. A genetic variant, rs7574865 in STAT4, was recently reported to be associated with risk of developing CHB and hepatitis B virus-related hepatocellular carcinoma. We aimed to determine whether this variant is associated with the response to IFNα treatment for hepatitis B e antigen (HBeAg)-positive CHB patients. We studied 466 HBeAg-positive CHB patients who received either IFNα-2b (n = 224) or pegylated IFNα-2a (n = 242) therapy for 48 weeks and were followed for an additional 24 weeks. The rate of sustained virologic response (SVR), defined as HBeAg seroconversion along with hepatitis B virus DNA level <2000 copies/mL at week 72, was compared among patients with different genotypes of rs7574865. After 48 weeks of treatment and 24 weeks off treatment, the SVR rates in the IFNα-2b and pegylated IFNα-2a therapy groups were 30.4% and 28.9%, respectively. Compared to the rs7574865 GT/TT genotype, the GG genotype (a risk factor of CHB and hepatitis B virus-related hepatocellular carcinoma) was significantly associated with a reduced SVR rate in both patients who received IFNα-2b therapy (21.1% versus 37.2%, P = 0.01) and those who received pegylated IFNα-2a therapy (18.0% versus 41.2%, P = 9.74 × 10(-5) ). In joint analysis of the 466 patients, the GG genotype was associated with an approximately half SVR rate compared to the GT/TT genotype (19.3% versus 39.1%, P = 4.15 × 10(-6) ). A multivariate logistic regression model including rs7574865 and clinical variables showed that rs7574865 was the most significant factor for the prediction of SVR. CONCLUSION: STAT4 rs7574865 is a reliable predictor of response to IFNα therapy for HBeAg-positive CHB patients and may be used for optimizing the treatment of CHB.

c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.

Resistance to temozolomide poses a major clinical challenge in glioblastoma multiforme treatment, and the mechanisms underlying the development of temozolomide resistance remain poorly understood. Enhanced DNA repair and mutagenesis can allow tumour cells to survive, contributing to resistance and tumour recurrence. Here, using recurrent temozolomide-refractory glioblastoma specimens, temozolomide-resistant cells, and resistant-xenograft models, we report that loss of miR-29c via c-Myc drives the acquisition of temozolomide resistance through enhancement of REV3L-mediated DNA repair and mutagenesis in glioblastoma. Importantly, disruption of c-Myc/miR-29c/REV3L signalling may have dual anticancer effects, sensitizing the resistant tumours to therapy as well as preventing the emergence of acquired temozolomide resistance. Our findings suggest a rationale for targeting the c-Myc/miR-29c/REV3L signalling pathway as a promising therapeutic approach for glioblastoma, even in recurrent, treatment-refractory settings.

VAMP8 facilitates cellular proliferation and temozolomide resistance in human glioma cells.

BACKGROUND: Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma. METHODS: The expression of gene and protein were determined by quantitative PCR and Western blot, respectively. Histological analysis of 282 glioma samples and 12 normal controls was performed by Pearson's chi-squared test. Survival analysis was performed using the log-rank test and Cox proportional hazards regression. Cell proliferation and cytotoxicity assay were conducted using Cell Counting Kit-8. Autophagy was detected by confocal microscopy and Western blot. RESULTS: VAMP8 was significantly overexpressed in human glioma specimens and could become a potential novel prognostic and treatment-predictive marker for glioma patients. Overexpression of VAMP8 promoted cell proliferation in vitro and in vivo, whereas knockdown of VAMP8 attenuated glioma growth by arresting cell cycle in the G0/G1 phase. Moreover, VAMP8 contributed to temozolomide (TMZ) resistance by elevating the expression levels of autophagy proteins and the number of autophagosomes. Further inhibition of autophagy via siRNA-mediated knockdown of autophagy-related gene 5 (ATG5) or syntaxin 17 (STX17) reversed TMZ resistance in VAMP8-overexpressing cells, while silencing of VAMP8 impaired the autophagic flux and alleviated TMZ resistance in glioma cells. CONCLUSION: Our findings identified VAMP8 as a novel oncogene by promoting cell proliferation and therapeutic resistance in glioma. Targeting VAMP8 may serve as a potential therapeutic regimen for the treatment of glioma.

Pri-miR-124 rs531564 and pri-miR-34b/c rs4938723 polymorphisms are associated with decreased risk of esophageal squamous cell carcinoma in Chinese populations.

MicroRNAs are a new class of small non-protein-coding RNAs that sometimes function as tumor suppressors or oncogenes. Aberrant expression and structural alteration of microRNAs have been reported to be involved in tumorigenesis and cancer development. Recently, rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, and rs11134527/pri-miR-218 were reported to be associated with risks of various cancers. In order to evaluate the relationship of these SNPs and esophageal squamous cell carcinoma (ESCC) risk, we conducted a case-control study with 1109 ESCC patients and 1275 control subjects to examine the potential association of these pri/pre-miRNA polymorphisms with ESCC susceptibility. As a result, two SNPs were associated with a significant risk of ESCC. We found that the GG genotype of pri-miR-124-1 rs531564 was associated to a significantly decreased risk of ESCC comparing with the CC/CG genotypes (p = 0.005; OR = 0.61, 95% CI = 0.43-0.86). In addition, the CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC (CC VS. TT/TC: p = 0.007, OR = 0.82, 95% CI = 0.71-0.95) in Chinese population. The present study provides the first evidence that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with the risk of ESCC in Chinese population.

MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1.

BACKGROUND: Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. METHODS: MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. RESULTS: MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. CONCLUSION: These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM.