Analysis of mRNA-miRNA interaction network reveals the role of CAFs-derived exosomes in the immune regulation of oral squamous cell carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) have significant tumor regulatory functions, and CAFs-derived exosomes (CAFs-Exo) released from CAFs play an important role in the progression of oral squamous cell carcinoma (OSCC). However, a lack of comprehensive molecular biological analysis leaves the regulatory mechanisms of CAFs-Exo in OSCC unclear. METHODS: We used platelet derived growth factor-BB (PDGF-BB) to induce the transformation of human oral mucosa fibroblast (hOMF) into CAFs, and extracted exosomes from the supernatant of CAFs and hOMF. We validated the effect of CAFs-Exo on tumor progression by exosomes co-culture with Cal-27 and tumor-forming in nude mice. The cellular and exosomal transcriptomes were sequenced, and immune regulatory genes were screened and validated using mRNA-miRNA interaction network analysis in combination with publicly available databases. RESULTS: The results showed that CAFs-Exo had a stronger ability to promote OSCC proliferation and was associated with immunosuppression. We discovered that the presence of immune-related genes in CAFs-Exo may regulate the expression of PIGR, CD81, UACA, and PTTG1IP in Cal-27 by analyzing CAFs-Exo sequencing data and publicly available TCGA data. This may account for the ability of CAFs-Exo to exert immunomodulation and promote OSCC proliferation. CONCLUSIONS: CAFs-Exo was found to be involved in tumor immune regulation through hsa-miR-139-5p, ACTR2 and EIF6, while PIGR, CD81, UACA and PTTG1IP may be potentially effective targets for the treatment of OSCC in the future.

The genes for sensory perception of sound should be considered in gene diagnosis of congenital sensorineural hearing loss and microtia.

Congenital sensorineural hearing loss (CSHL) and microtia are development-related diseases, sharing some factors and affecting children's hearing. However, genetic tests only focus on CSHL. We try to identify the common molecular mechanism of CSHL and microtia as candidates combining gene diagnosis biomarkers. Whole-exon sequencing (WES), Sanger sequencing, qPCR, and bioinformatics analyses were performed in microtia family (F1), family two, whose proband suffered from microtia and CSHL (F2), five microtia, and four CSHL individuals, respectively. We found that 40% microtia and 40% CSHL relevant genes were detected in F1 and a sharing pathway: the sensory perception of sound was identified. Moreover, the copy number variation in proband F2 was identified in one gene of the sharing pathway: EYA1. Meanwhile, two variants of BUB3 were identified in F1 data. BUB3 is related to development, dog ear type, direct and indirect interaction with microtia, and CSHL relevant genes. Notably, although the allele frequency of two variants of BUB3 showed significant differences between microtia and CSHL, the special microtia-relevant genotype also could be detected in one CSHL sample. These results suggest that the sensory perception of sound and the development of relevant pathways may be the common pathways of microtia and CSHL. Genes of these pathways can be used as candidates combining gene diagnosis biomarkers.

Identification of cancer hallmark-associated gene and lncRNA cooperative regulation pairs and dictate lncRNA roles in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumour in the oral and maxillofacial region. Numerous cancers share ten common traits ("hallmarks") that govern the transformation of normal cells into cancer cells. Long non-coding RNAs (lncRNAs) are important factors that contribute to tumorigenesis. However, very little is known about the cooperative relationships between lncRNAs and cancer hallmark-associated genes in OSCC. Through integrative analysis of cancer hallmarks, somatic mutations, copy number variants (CNVs) and expression, some OSCC-specific cancer hallmark-associated genes and lncRNAs are identified. A computational framework to identify gene and lncRNA cooperative regulation pairs (GLCRPs) associated with different cancer hallmarks is developed based on the co-expression and co-occurrence of mutations. The distinct and common features of ten cancer hallmarks based on GLCRPs are characterized in OSCC. Cancer hallmark insensitivity to antigrowth signals and self-sufficiency in growth signals are shared by most GLCRPs in OSCC. Some key GLCRPs participate in many cancer hallmarks in OSCC. Cancer hallmark-associated GLCRP networks have complex patterns and specific functions in OSCC. Specially, some key GLCRPs are associated with the prognosis of OSCC patients. In summary, we generate a comprehensive landscape of cancer hallmark-associated GLCRPs that can act as a starting point for future functional explorations, the identification of biomarkers and lncRNA-based targeted therapy in OSCC.

Spherical silica nanoparticles promote malignant transformation of BEAS-2B cells by stromal cell-derived factor-1α (SDF-1α).

OBJECTIVE: This study aimed to examine the role of spherical silica nanoparticles (SiNPs) on human bronchial epithelial (BEAS-2B) cells through inflammation. METHODS: Human mononuclear (THP-1) cells and BEAS-2B cells were co-cultured in transwell chambers and treated with 800 mmol/L benzo[ a]pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE) and 12.5 µg/mL SiNPs for 24 hours. For controls, cells were treated with BPDE alone. Subcutaneous tumorigenicity and epithelial-mesenchymal transition (EMT) of BEAS-2B cells were measured. The cells were blocked with a stromal cell-derived factor-1α (SDF-1α)-specific antibody. EMT was analyzed in cells treated with 800 mmol/L BPDE and 12.5 µg/mL SiNPs relative to matched control cells and xenografts in vivo. Serum SDF-1α levels were measured in 23 patients with lung adenocarcinoma in Xuanwei, in 25 with lung adenocarcinoma outside Xuanwei, and in 22 with benign pulmonary lesions in Xuanwei. RESULTS: SiNPs significantly promoted tumorigenesis and EMT, induced the release of SDF-1α, and activated AKT (ser473) in BEAS-2B cells. EMT and phosphorylated AKT (ser473) and glycogen synthase kinase-3ß levels were decreased when blocked by SDF-1α antibody in BEAS-2B cells. SDF-1α was mainly secreted by THP-1 cells. CONCLUSION: SiNPs combined with BPDE promote EMT of BEAS-2B cells via the AKT pathway by inducing release of SDF-1α from THP-1 cells.

The interactive effects of ketamine and ethanol on dopamine expression in the ventral tegmental area of rats.

BACKGROUND: A number of studies have demonstrated the significant and rapid antidepressant effects of ketamine, which is also known as a neurotoxic and illicit drug. Ketamine and alcohol are increasingly used together in clubs by teenagers and young adults. Previous studies have proven that chronic ketamine consumption induces a delayed and persistent activation of the dopamine (DA) system. However, the rewarding properties of recreational ketamine abuse remain unclear, and the underlying mechanisms of the effects on the DA system after administration of ketamine with ethanol are yet to be explored. METHODS: Here, we evaluated the effects of two different doses of ketamine (30 mg/kg and 60 mg/kg) with and without ethanol (0.3156 g/kg) on DA concentration in the rat's ventral tegmental area (VTA), a vital region in the reward and motivation system. We explored the effects of the combined drug treatment on the expression profiling of the DA metabolism genes, tyrosine hydroxylase, dopa decarboxylase, vesicular monoamine transporter 2, and synaptosomal-associated protein 25, as well as protein expression level of brain-derived neurotrophic factor in the rat's VTA. RESULTS: We found that administration of ketamine with ethanol led to a significant increase of DA in the VTA associated with differential regulation of mRNA levels of the four DA metabolism genes and protein levels of brain-derived neurotrophic factor. Moreover, the rewarding properties of coadministration of ketamine and ethanol were related to dopaminergic neuron activation in the VTA. CONCLUSION: These results indicated the possibility that combined drug treatment might positively affect the mesencephalic DA reward system.

Role of CT scan in differentiating the type of colorectal cancer.

OBJECTIVES: Most colorectal cancers are classical adenocarcinomas (AC), and less frequent subtypes include mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC). The purpose of this study was to evaluate the computed tomography (CT) findings that can help to differentiate MAC and SC from AC. METHODS: CT scans of 168 patients with pathologically proven MAC and 67 patients with pathologically proven SC were analyzed, and 220 patients with classical AC were also included as a control group. CT findings of the three groups were compared and contrasted in terms of the bowel involvement patterns, contrast enhancement patterns, and presence or absence of bowel obstruction, intratumoral calcification, pericolic fat infiltration, and local tumor extension to adjacent organs. Statistical analyses were made by using the one-way analysis of variance, least significant difference test, and Pearson's chi-square test. RESULTS: Compared with classical AC, the MAC showed more severe (6.29±2.69 cm vs 4.57±1.74 cm, P<0.001) and higher percentage of occurrence of eccentric bowel-wall thickening (37.2% vs 11.5%, P<0.001). Heterogeneous contrast enhancement was most common in MAC (P<0.01), and MAC showed more areas with hypoattenuation (P<0.001). The presence of intratumoral calcification was most frequent in MAC (17.9% vs 2% vs 6.8%) (P<0.001); the SC also were more severe (5.75±2.28 cm vs 4.57±1.74 cm. P=0.001) than AC, but SC tend to show more cases of concentric even bowel-wall thickening (67.2%); homogeneous contrast enhancement was most common in SC (P<0.01), and it showed a target appearance. The presence of peritoneal seeding was most frequent in SC (35.8% vs 8% vs 2.7%, P<0.001), while the presence of regional lymph node metastasis (P=0.190) and direct invasion of adjacent organs or metastasis (P=0.323) were not significantly different among them. CONCLUSION: Some radiological features by CT can be used to classify different colon tumor types.

Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry.

AIM: Ketamine and ethanol are increasingly being used together as recreational drugs in rave parties. Their effects on the dopamine (DA) system remain largely unknown. This study aimed to investigate the effects of consuming two different concentrations of ketamine with and without alcohol on the DA system. MATERIALS AND METHODS: We employed the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of the combined administration of two different doses of ketamine (30mg/kg and 60mg/kg) with ethanol (0.3156g/kg). We evaluated the effects of the combined drug treatment on the transcriptional output of tyrosine hydroxylase (TH), dopa decarboxylase (DDC), synaptosomal-associated protein 25 (SNAP25), and vesicular monoamine transporter 2 (VMAT2) as well as protein expression level of brain-derived neurotrophic factor (BDNF) in rat prefrontal cortex (PFC) and striatum. KEY FINDINGS: We found that rats exhibited a dose-dependent, drug-paired, place preference to ketamine and ethanol associated with an elevated DA level in the striatum but not in the PFC. Moreover, treatment involving low- or high-dose ketamine with or without ethanol caused a differential regulatory response in the mRNA levels of the four DA metabolism genes and the cellular protein abundance of BDNF via the cortex-striatum circuitry. SIGNIFICANCE: This study investigated the molecular mechanisms that occur following the combined administration of ketamine and ethanol in the DA system, which could potentially lead to alterations in the mental status and behavior of ketamine/ethanol users. Our findings may aid the development of therapeutic strategies for substance abuse patients.

Association between fifteen risk factors and progressing ischemic stroke in the Han population of northeast China.

BACKGROUND: The mortality and disability associated with progressing ischemic stroke are much higher than general ischemic stroke. This study was conducted to determine the risk factors for progressing ischemic stroke in the Han population of northeast China. METHODS: A total of 2511 patients with ischemic stroke within 24 hours admitted to Department of Neurology, First Affiliated Hospital of Harbin Medical University were studied, from November 2007 to May 2009. All of the patients were classified into the progressing or non-progressing group according to the scores of the Scandinavian Neurological Stroke Scale. Fifteen putative risk factors were evaluated. The influence of risk factors for progressing ischemic stroke was analyzed with the simple Logistic analysis, the multiple Logistic analysis, and the stepwise Logistic regression model. All the statistical analysis was performed by SAS 9.1. RESULTS: Totally 359 (14.3%) patients met the criteria for progressing ischemic stroke. The Logistic analysis showed that age, family stroke history, smoking history, hypertension on admission, a drop in blood pressure after admission to the hospital, high serum glucose on admission, and fever were related to progressing ischemic stroke in the Han population of northeast China. CONCLUSION: People of the ischemic stroke with these factors are more likely to develop progressing ischemic stroke.

Meta-analysis of different test indicators: Helicobacter pylori infection and the risk of colorectal cancer.

BACKGROUND AND AIMS: Recent studies have demonstrated the relationship between Helicobacter pylori infection and the risk of colorectal carcinoma. However, the results of these studies remain controversial as the studies were relatively small in size and partially differed in designs, and so we reviewed the published studies and carried out a meta-analysis to further explore this relationship. MATERIALS AND METHODS: We performed an extensive systematic review to find all the published case-control studies up to Jan. 2007 using electronic searching, hand searching, and reference lists of retrieved articles. Odds ratio (OR) was employed to evaluate the relationship of H. pylori infection and risk of colorectal cancer. Summary estimates were obtained using random effect models according to the result of a statistical test for heterogeneity across the studies. The presence of possible publication bias was assessed using different statistical approaches. RESULTS: Thirteen studies were included, and summary OR 1.49 (95% confidence interval [CI] 1.17-1.91) was estimated for the association between H. pylori infection and colorectal cancer. Summary OR 1.56 (95% CI 1.14-2.14) was estimated for the association between immunoglobulin G antibody and colorectal cancer risk. By trimming and filling, the number of inputted studies was zero, and summary OR was still 1.49 (95% CI 1.17-1.91). The graphical funnel plot appeared asymmetrical, but there was no statistical evidence of publication bias. The method of fail-safe suggested that the effect of publication bias was small. CONCLUSION: Current evidence, though limited, suggests that there is a possible increase in risk of colorectal cancer because of H. pylori infection.