Clinical relevance of serum lipids in the carcinogenesis of oral squamous cell carcinoma.

BACKGROUND: Dyslipidaemia is associated with cancers. However, the specific expression of serum lipids in oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) remains unclear, and it remains unknown whether serum lipids are associated with the development of OPMD and OSCC. This study investigated the serum lipid profiles of OPMD and OSCC patients, and the association of serum lipids with the occurrence of OPMD and OSCC. METHODS: A total of 532 patients were recruited from the Affiliated Hospital of Stomatology, Nanjing Medical University. Serum lipid parameters including total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo-A), apolipoprotein B (Apo-B), and lipoprotein (a) (Lpa) were analysed, and clinicopathological data were collected for further analysis. Furthermore, a regression model was used to evaluate the relationship between serum lipids and the occurrence of OSCC and OPMD. RESULTS: After adjusting for age and sex, no significant differences were observed in serum lipid or body mass index (BMI) between OSCC patients and controls (P > 0.05). HDL-C, Apo-A, and Apo-B levels were lower in OSCC patients than in OPMD patients (P < 0.05); HDL-C and Apo-A levels were higher in OPMD patients than in controls (P < 0.05). Furthermore, female OSCC patients had higher Apo-A and BMI values than males. The HDL-C level was lower in patients under 60 years of age than in elders (P < 0.05); and age was related to a higher risk of developing OSCC. Female patients with OPMD had higher TC, HDL-C, and Apo-A levels than males (P < 0.05); OPMD patients over 60 years of age had higher HDL-C than youngers (P < 0.05), whereas the LDL-C level was lower in elders (P < 0.05). The HDL-C and BMI values of the patients with oral leukoplakia (OLK) with dysplasia were more elevated than those of the oral lichen planus group, and the LDL-C, and Apo-A levels in patients with OLK with dysplasia were decreased (P < 0.05). Sex, high HDL-C and Apo-A values were associated with the development of OPMD. CONCLUSION: Serum lipids exhibited certain differences according to the occurrence and development of OSCC; high levels of HDL-C and Apo-A might be markers for predicting OPMD.

Vitamin D receptor genetic polymorphisms are associated with oral lichen planus susceptibility in a Chinese Han population.

BACKGROUND: Vitamin D receptor (VDR) is involved in multiple immune-mediated disorders including oral lichen planus (OLP). This study investigated the association between VDR gene polymorphisms and the risk of OLP. METHODS: In total, 177 OLP patients and 207 healthy participants were recruited from the Affiliated Hospital of Stomatology, Nanjing Medical University. Eight single nucleotide polymorphisms (SNPs: rs731236, rs739837, rs757343, rs2107301, rs2239185, rs7975232, rs11574129 and rs11568820) in the VDR gene were selected and genotyped. RESULTS: The results showed that OLP risk was increased in subjects with the rs2239185 TT genotype (Recessive model: adjusted Odd ratio(OR) = 2.68, 95% Confidence interval(CI) = 1.28-5.62, P = 0.009) and rs7975232 CC genotype (Recessive model: adjusted OR = 2.25, 95% CI = 1.10-4.58, P = 0.026). Moreover, rs2239185 and rs7975232 (P < 0.01) showed significant cumulative effects on OLP risk.Haplotype analysis showed that the CC haplotype (rs2239185-rs7975232) was associated with an increased risk of OLP (OR = 3.11, 95% CI = 1.42-6.83, P = 0.005), compared with the AC haplotype. CONCLUSION: The rs2239185 and rs7975232 variants of VDR may influence OLP susceptibility, and VDR gene polymorphisms may be candidate susceptibility regions for OLP in a Chinese Han population.

Systematic genetic analyses of genome-wide association study data reveal an association between the key nucleosome remodeling and deacetylase complex and bipolar disorder development.

BACKGROUND: Genome-wide association studies (GWASs) are used to identify genetic variants for association with bipolar disorder (BD) risk; however, each GWAS can only reveal a small fraction of this association. This study systematically analyzed multiple GWAS data sets to provide further insights into potential causal BD processes by integrating the results of Psychiatric Genomics Consortium Phase I (PGC-I) for BD with core human pathways and functional networks. METHODS: The i-Gsea4GwasV2 program was used to analyze data from the PGC-I GWAS for BD (the pathways came from Reactome), as well as the nominally significant pathways. We established a gene network of the significant pathways and performed a gene set analysis for each gene cluster of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) GWAS data for the volumes of the intracranial region and seven subcortical regions. RESULTS: A total of 30 of 1816 Reactome pathways were identified and showed associations with BD risk. We further revealed 22 interconnected functional and topologically interacting clusters (Clusters 0-21) that were associated with BD risk. Moreover, we obtained brain transcriptome data from BrainSpan and found significant associations between common variants of the genes in Cluster 1 with the hippocampus (HIP; P = .026; family-wise error [FWE] correction) and amygdala (AMY; P = .016; FEW correction) in Cluster 8 with HIP (P = .022; FWE correction). The genes in Cluster 1 were enriched for the transcriptional co-expression profile in the prenatal AMY, and core genes (CDH4, MTA2, RBBP4, and HDAC2) were identified to be involved in regulating early brain development. CONCLUSION: This study demonstrated that the HIP and AMY play a central role in neurodevelopment and BD risk.

Ubiquitination and regulation of Smad7 in the TGF-ß1/Smad signaling of aristolochic acid nephropathy.

Aristolochic acid I (AAI) affects TGF-ß1/Smad signaling, which causes AA nephropathy (AAN), but the mechanisms are not fully understood. We aimed to clarify whether Arkadia and UCH37 participate in TGF-ß1/Smad signaling via Smad7, and the regulatory mechanisms of Smad7. One side, mice and cultured mouse renal tubular epithelial cells (RTECs) were treated with various AAI doses and concentrations, respectively; on the other side, RTECs were transfected with small interfering RNA (siRNA) expression vectors against Arkadia and UCH37 and then treated with 10 µg/ml AAI. And then detect the mRNA and protein levels of Smad7, UCH37, Arkadia and any other relative factors by RT-PCR and Western blotting. In kidney tissues and RTECs, the mRNA and protein levels of Smad7 decreased with increasing AAI doses concentrations by real-time PCR and Western blotting, whereas those of Arkadia, UCH37, Smad2, Smad3 and TßRI increased. Cells transfected with the Arkadia siRNA expression vector showed reduced mRNA and protein levels of vimentin, α-SMA, Smad2, Smad3 and TßRI after AAI treatment, while those of CK18 and Smad7 increased compared with those of untransfected RTECs. Conversely, cells transfected with the UCH37 siRNA expression vector showed the opposite effect on analyzed signaling molecules after AAI treatment. Arkadia and UCH37 participate in TGF-ß1/Smad signaling-mediated renal fibrosis, and Smad7 blocks TGF-ß1 signaling by inhibiting Smad2/Smad3 phosphorylation and enhancing the degradation of TßRI.

Clinical and pathological studies of eight cases of lipidized fibrous histiocytoma.

Lipidized fibrous histiocytoma (FH) is a rare type of FH. The present study aimed to describe the clinical and pathological features of lipidized FH. A total of eight patients diagnosed with lipidized FH were retrospectively reviewed in the present study. The cohort included three male and five female patients (male to female ratio, 1.7:1) with a mean age of 48 years (range, 38-62 years). In total, four tumors were located on the buttock, three on the lower leg and one on the forearm. Histological, lipidized FH showed a wide spectrum. Some cases included prominent stromal hyalinization and hyalinized vessels with scant lipid-laden histiocytes. Other cases exhibited the prominent lipid-laden histiocytes and scant stromal hyalinization. Overall, lipidized FH must be differentiated from other benign and malignant tumors, taking into account the therapeutic and prognostic differences between these different entities.

DNA methylation profile of Aire-deficient mouse medullary thymic epithelial cells.

BACKGROUND: Medullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model. RESULTS: We identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire(-/-) mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire(-/-) mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire(+/+) mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire(+/+) and Aire(-/-) mTECs but distinct from that of athymic cells and tissues. CONCLUSIONS: These results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is indicated to be involved in the differentiation of the mTEC lineage.

Effects of bone morphogenetic protein 4 on TGF-ß1-induced cell proliferation, apoptosis, activation and differentiation in mouse lung fibroblasts via ERK/p38 MAPK signaling pathway.

Fibroblasts, in particular myofibroblasts, are the critical effector cells in idiopathic pulmonary fibrosis (IPF), a deadly lung disease characterized by abnormal lung remodeling and the formation of "fibroblastic foci". Aberrant activation of TGF-ß1 is frequently encountered and promotes fibroblast proliferation, activation, and differentiation in pulmonary fibrosis. Hence, the inhibition of TGF-ß1-induced lung fibroblast activation holds promise as a therapeutic strategy for IPF. The present study aimed to investigate the potential effect and underlying mechanisms of bone morphogenetic protein 4 (BMP4) on TGF-ß1-induced proliferation, apoptosis, activation and myofibroblast differentiation of adult lung fibroblasts. Here, we demonstrated that BMP4 expression was significantly decreased in TGF-ß1-stimulated mouse primary lung fibroblasts (PLFs). BMP4 inhibited proliferation and apoptosis resistance of TGF-ß1-stimulated mouse PLFs. BMP4 suppressed TGF-ß1-induced fibroblast activation and differentiation in mouse PLFs. We also found that BMP4 inhibited TGF-ß1-induced ERK and p38 MAPK phosphorylation. Our findings indicate that BMP4 exerts its anti-fibrotic effects by regulating fibroblast proliferation, apoptosis, activation and differentiation via the inhibition of the ERK/p38 MAPK signaling pathway, and thus has a potential for the treatment of pulmonary fibrosis.

Gastritis cystica profunda: clinical and pathologic study of seven cases and review of literature.

Gastritis cystica profunda (GCP) is a rare lesion characterized by hyperplasia and cystic dilatation of the gastric glands in the submucosal layer. Here we report seven cases of GCP. The patients are 5 women and 2 men with a mean age of 62 (range, 42-82) years at the time of diagnosis. The patients presented with abdominal distension, sour regurgitation, and heartburn. One case had the previous gastric surgery and the other six cases had no special history. The lesions were located in the fundus (4/7), corpus (1/7), cardia (1/7), and antrum (1/7). Endoscopic analysis revealed pedunculated polyps, or a dome-shaped polyp. Histologically, all cases showed dilated tubular glands, mainly located in the submucosa, among the muscularis mucosa, and occasionally in the lamina propria. The glands were lined by bland single columnar epithelium with infolding features in some areas. Mitotic activity and marked cellular atypia were not present. The stroma in some cases was mildly edematous with infiltrated lymphocytes and plasma cells. There was no epithelial dysplasia in the overlying mucosa. Immunohistochemically, the Ki-67 index was < 1%. P53 immunostaining was generally characterized as wild type in all cases. Based on the morphology of the glands and the cells and the possible mechanism of hyperplasia and cystic dilatation of the gastric glands, it is easy to differentiate GCP from a well-differentiated adenocarcinoma.

Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is a common malignant tumor of the female reproductive system with poor prognosis in advanced, recurrent, and metastatic cases. Identification of reliable molecular markers will help in the development of clinical strategies for early detection, diagnosis, and intervention. Gamma-glutamyl hydrolase (GGH) is a key enzyme in folate metabolism pathway. High expression of GGH is associated with severe clinicopathological features and poor prognosis of several cancers. High GGH expression is also related to cell resistance to antifolate drugs such as methotrexate. In this study we focused on the prognostic value of immunohistochemical GGH expression level in UCEC tissue and RNA-seq data from The Cancer Genome Atlas to establish associations with clinical features and outcomes. Further, we conducted comprehensive bioinformatics analyses to identify and functionally annotate differentially expressed genes (DEGs) associated with UCEC upregulation and assessed the effects of upregulation on immune infiltration. Both GGH mRNA and protein expression levels were elevated in tumor tissues, and higher expression was significantly associated with advanced clinicopathological features and poor prognosis by univariate analysis. Further multivariate analysis identified elevated GGH expression as an independent risk factor for poor outcome. Nomograms including GGH expression yielded a c-index for disease-specific survival prediction of 0.884 (95% confidence interval: 0.861-0.907). A total of 520 DEGs (111 upregulated and 409 downregulated) were identified between high and low GGH expression groups. Analysis using Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Gene set enrichment analysis, and protein‒protein interaction indicated significant associations of altered GGH expression with cell proliferation, immune response, and the occurrence and development of UCEC tumors. Finally, GGH expression level was associated with high Th2 cell and low natural killer CD56bright cell infiltration. Collectively, these findings indicate that GGH drives UCEC progression and could be a useful biomarker for survival prediction as well as a therapeutic target.

Berberine Relieves Metabolic Syndrome in Mice by Inhibiting Liver Inflammation Caused by a High-Fat Diet and Potential Association With Gut Microbiota.

Whether berberine mediates its anti-inflammatory and blood sugar and lipid-lowering effects solely by adjusting the structure of the gut microbiota or by first directly regulating the expression of host pro-inflammatory proteins and activation of macrophages and subsequently acting on gut microbiota, is currently unclear. To clarify the mechanism of berberine-mediated regulation of metabolism, we constructed an obese mouse model using SPF-grade C57BL/6J male mice and conducted a systematic study of liver tissue pathology, inflammatory factor expression, and gut microbiota structure. We screened the gut microbiota targets of berberine and showed that the molecular mechanism of berberine-mediated treatment of metabolic syndrome involves the regulation of gut microbiota structure and the expression of inflammatory factors. Our results revealed that a high-fat diet (HFD) significantly changed mice gut microbiota, thereby probably increasing the level of toxins in the intestine, and triggered the host inflammatory response. The HFD also reduced the proportion of short-chain fatty acid (SCFA)-producing genes, thereby hindering mucosal immunity and cell nutrition, and increased the host inflammatory response and liver fat metabolism disorders. Further, berberine could improve the chronic HFD-induced inflammatory metabolic syndrome to some extent and effectively improved the metabolism of high-fat foods in mice, which correlated with the gut microbiota composition. Taken together, our study may improve our understanding of host-microbe interactions during the treatment of metabolic diseases and provide useful insights into the action mechanism of berberine.

Radiation-induced second primary squamous cell carcinoma of the oral cavity after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The increasing occurrence of radiation-induced second primary squamous cell carcinoma of the oral cavity (RISCCO) after radiotherapy for nasopharyngeal carcinoma (NPC) has become a noteworthy complication that can influence long-term survival. This study aimed to analyze the associations of clinicopathologic characteristics with prognostic factors among patients who developed RISCCO after radiotherapy for NPC. METHODS: A total of 41,446 NPC patients admitted to Sun Yat-sen University Cancer Center (SYSUCC) between August 1989 and January 2019 were reviewed. Among these patients, 88 RISCCO patients who satisfied the inclusion criteria were included in the study. RESULTS: During our study, the incidence of RISCCO after radiotherapy was 0.21% (88/41,446) among NPC patients at SYSUCC. The latency period ranged from 1.0 to 34.0 years (median, 9.0 years), and the latency of RISCCO was notably shorter for patients who received intensity-modulated radiation therapy than that for patients who received conventional radiotherapy using cobalt-60 or 6-MV X-rays (median, 4.0 years vs. 11.0 years, P = 0.013). The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort of 88 patients were 79.0%, 46.6%, and 35.2%, respectively. The 5-year OS rate for the 79 patients who received treatment was 45.7%, and the 5-year OS rate for the 9 patients who refused treatment was 0%. T classification and surgery were identified as independent prognostic factors associated with a high OS rate. CONCLUSIONS: Surgery as the first-choice treatment may improve survival and prognosis. A long-term follow-up is needed for early detection of RISCCO in NPC patients.

Insulinoma-associated protein 2-deficient mice develop severe forms of diabetes induced by multiple low doses of streptozotocin.

Insulinoma-associated protein 2 (IA-2) is the major autoantigen that contributes to the pathogenesis of type 1 diabetes (T1D). IA-2-deficient (IA-2-/-) mice showed impaired insulin secretion after intraperitoneal injection of glucose as well as elevated glucose level in a glucose tolerance test. Despite the fact that 70% of newly diagnosed T1D patients have an antibody against IA-2, the role of IA-2 in the pathogenesis of T1D is largely unknown. In this study, the sensitivity to diabetes induced by streptozotocin (STZ) of IA-2-/- mice was compared with that of wild-type (WT) mice. STZ injection to IA-2-/- mice caused significant elevation of blood glucose and depressed insulin concentration in the pancreas. Furthermore, abnormal ultrastructure in the beta cells of the IA-2-/- mice was revealed by electron microscopy, showing a decreased number of insulin containing vesicles and dilation of the ER-Golgi complex. These results demonstrated that IA-2-/- mice had higher sensitivity to STZ, suggesting a role of IA-2 not only in the secretion but also in the production of insulin.

Octapeptide repeat region of prion protein (PrP) is required at an early stage for production of abnormal prion protein in PrP-deficient neuronal cell line.

An abnormal isoform of prion protein (PrP(Sc)), which is composed of the same amino acids as cellular PrP (PrP(C)) and has proteinase K (PK)-resistance, hypothetically converts PrP(C) into PrP(Sc). To investigate the region important for PrP(Sc) production, we examined the levels of PrP(Sc) in PrP gene-deficient cells (HpL3-4) expressing PrP(C) deleted of various regions including the octapeptide repeat region (OR) or hydrophobic region (HR). After Chandler or Obihiro prion infection, PrP(Sc) was produced in HpL3-4 cells expressing wild-type PrP(C) or PrP(C) deleted of HR at an early stage and further reduced to below the detectable level, whereas cells expressing PrP(C) deleted of OR showed no PrP(Sc) production. The results suggest that OR of PrP(C) is required for the early step of efficient PrP(Sc) production.

A monoclonal antibody (1D12) defines novel distribution patterns of prion protein (PrP) as granules in nucleus.

A monoclonal antibody (mAb) panel to bovine prion protein (PrP) was studied by immunoblotting and immunohistochemistry for scrapie and bovine spongiform encephalopathy. A mAb panel recognized both normal (PrP(C)) and abnormal (PrP(Sc)) isoforms of PrP in murine, ovine and bovine brain tissues. Interestingly, an anti-bovine PrP mAb, 1D12, prepared by immunizing PrP gene-knockout mice with a synthetic polypeptides corresponding to codons 153-166 of the bovine PrP gene showed novel patterns of reactivity for prion-uninfected neuronal cells. An enzyme-linked immunosorbent assay-mapping of the mAb epitopes resulted in a reaction of monoclonal 1D12 to YEDRY and M corresponding to amino acids 156-160 and 165 of bovine PrP. Several patterns of bovine PrP(C) distribution in PrP-deficient neuronal cells (HpL3-4) transfected with bovine PrP were observed after different fixation methods. Stained cell surface was observed after formalin fixation by immunofluorescent assay of 1D12 with confocal microscopy, whereas granules in nucleus were stained after acetone fixation. No reactivity in the nucleus was observed to HpL3-4, or HpL3-4mPrP cells expressing mouse PrP. This is the first paper that has reported the detection of the PrP(C) at both cell surface and nuclei of prion-uninfected cell line.

Species-specific anti-apoptotic activity of cellular prion protein in a mouse PrP-deficient neuronal cell line transfected with mouse, hamster, and bovine Prnp.

The neuroprotective function of prion protein (PrP) was revealed first by the fact that reintroduction of the mouse prion protein gene (Prnp) into a mouse Prnp(-/-) neuronal cell line, HpL3-4, could prevent apoptosis induced by serum deprivation. In the present study, the anti-apoptotic activities of mouse, hamster, and bovine PrP were compared by expressing mouse PrP (MoPrP), hamster PrP (HaPrP), and bovine PrP (BoPrP) in HpL3-4 cells, respectively. Morphological analysis and DNA fragmentation assays demonstrated that HpL3-4 cells expressing HaPrP, BoPrP, and empty vector (EM) showed the typical features of apoptosis with DNA laddering and apoptotic bodies after serum deprivation, whereas HpL3-4 cells expressing MoPrP showed decreased levels of apoptosis in comparison. The levels of histone-associated DNA fragments (mono- and oligonucleosomes) in the cytosol fractions of the cells correlated with the levels of DNA laddering. These results indicate a species-specific anti-apoptotic function of PrP exists, suggesting that the interaction of the mouse PrP with mouse host factors is required for its anti-apoptotic activity.

Detection of proteolytic cleavages of diabetes-associated protein IA-2 beta in the pancreas and the brain using novel anti-IA-2 beta monoclonal antibodies.

Insulinoma-associated protein (IA)-2 beta, an inactive member of the protein-tyrosine phosphatase (PTP) family, is a major autoantigen in type-1 diabetes mellitus. IA-2 beta exists mainly in a 60-kDa form, and is frequently located in the dense-core secretory vesicles of pancreatic beta cells. As IA-2 beta gene-deficient mice exhibit impaired insulin secretions, IA-2 beta is probably involved in insulin secretions. In the present study, we characterized the major forms of IA-2 beta in the brain and pancreas of normal and non-obese diabetic (NOD) mice. Novel monoclonal antibodies (mAbs) against IA-2 beta revealed that this brain protein was of multiple compositions incorporating the 60-, 64-, 67- and 71-kDa forms, which were designated as IA-2 beta 60, IA-2 beta 64, IA-2 beta 67 and IA-2 beta 71, respectively. On the contrary, only the 60-kDa isoform of IA-2 beta was expressed in the mouse pancreas and in the mouse pancreatic beta cell line, MIN6. Sequence analyses revealed that IA-2 beta 60, IA-2 beta 64 and IA-2 beta 71 (brain-derived immunoprecipitated IA-2 beta isoforms) contained alternative NH2- termini starting from Glu489, Ala464, and Ser414, respectively, while IA-2 beta 60 (an MIN6-derived immunoprecipitated IA-2 beta isoform) contained those from Glu489. Consistent with the lack of an NH2-terminal region of IA-2 beta, the isoforms were recognized by their respective mAbs characterized with different epitope regions. Furthermore, Western blotting and immunohistochemistry demonstrated that NOD mice expressed similar isoforms present in the brains and pancreatic islets of C57BL/6J, BALC/CA and ICR mice, accordingly. Taken together, these results suggest that IA-2 beta undergoes at least three distinct proteolytic cleavages.

A systematic analysis of the association studies between CASP8 D302H polymorphisms and breast cancer risk.

Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution D302H in CASP8, is likely to be associated with breast cancer. Several previous studies have reported the association of CASP8 D302H polymorphism with breast cancer; however, the results are inconsistent. To validate the association between CASP8 D302H polymorphism and breast cancer risk, we performed an updated meta-analysis of 18 studies including 27,807 cases and 32,332 controls. We tested the overall association between this SNP and breast cancer susceptibility and stratified subgroups based on countries where cases are from. We confirmed a significant correlation between CASP8 D302H polymorphism and the reduced breast cancer susceptibility in population from UK, Germany and Poland, but no significant association was observed in other countries, such as Finland or USA. Our findings indicate the relationship of SNP CASP8 D302H and breast cancer would not be universal but only be sensitive in some particular European countries. The genetic difference for diverse countries may be useful in individual and precision medicine or health.

A transcriptomic study of myogenic differentiation under the overexpression of PPARγ by RNA-Seq.

To study the cellular and molecular function of peroxisome proliferator-activated receptor γ (PPARγ) in skeletal muscle differentiation, we have generated inducible gain-of-function to overexpress PPARγ in C2C12 myoblasts. In order to identify PPARγ targets, RNA sequencing (RNA-seq) was used to evaluate and quantify the transcriptomes and expression patterns during myogenic differentiation under the overexpression of PPARγ. The formation of myotubes and the expression of muscle-specific myogenic genes such as MyoD and MyoG may be inhibited by PPARγ overexpression. Multiple genes and pathways were significantly involved in this process, including 11 genes such as Fndc9 and Slc14a1 with fundamental change of regulation modes, 9 genes of which were validated by the data of qRT-PCR. Our studies demonstrate that PPARγ would play critical roles on myoblasts differentiation, mediating crosstalk among several pathways and transcription factors. Our data is available in the Gene Expression Omnibus (GEO) database with the accession number as GSE99399.

Comprehensive tissue-specific gene set enrichment analysis and transcription factor analysis of breast cancer by integrating 14 gene expression datasets.

Breast cancer is the most commonly diagnosed malignancy in women. Several key genes and pathways have been proven to correlate with breast cancer pathology. This study sought to explore the differences in key transcription factors (TFs), transcriptional regulation networks and dysregulated pathways in different tissues in breast cancer. We employed 14 breast cancer datasets from NCBI-GEO and performed an integrated analysis in three different tissues including breast, blood and saliva. The results showed that there were eight genes (CEBPD, EGR1, EGR2, EGR3, FOS, FOSB, ID1 and NFIL3) down-regulated in breast tissue but up-regulated in blood tissue. Furthermore, we identified several unreported tissue-specific TFs that may contribute to breast cancer, including ATOH8, DMRT2, TBX15 and ZNF367. The dysregulation of these TFs damaged lipid metabolism, development, cell adhesion, proliferation, differentiation and metastasis processes. Among these pathways, the breast tissue showed the most serious impairment and the blood tissue showed a relatively moderate damage, whereas the saliva tissue was almost unaffected. This study could be helpful for future biomarker discovery, drug design, and therapeutic and predictive applications in breast cancers.

Insertion sequence ISRP10 inactivation of the oprD gene in imipenem-resistant Pseudomonas aeruginosa clinical isolates.

Carbapenem resistance mechanisms were investigated in 32 imipenem-resistant Pseudomonas aeruginosa clinical isolates recovered from hospitalised children. Sequence analysis revealed that 31 of the isolates had an insertion sequence element ISRP10 disrupting the porin gene oprD, demonstrating that ISRP10 inactivation of oprD conferred imipenem resistance in the majority of the isolates. Multilocus sequence typing (MLST) was used to discriminate the isolates. In total, 11 sequence types (STs) were identified including 3 novel STs, and 68.3% (28/41) of the tested strains were characterised as clone ST253. In combination with random amplified polymorphic DNA (RAPD) analysis, the imipenem-resistant isolates displayed a relatively high degree of genetic variability and were unlikely associated with nosocomial infections.