Significant associations of PAI-1 genetic polymorphisms with osteonecrosis of the femoral head

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption. Previous studies have demonstrated that decreased fibrinolytic activity due to elevated plasminogen activator inhibitor-1 (PAI-1) levels correlates with ONFH pathogenesis. The -675 4G/5G single nucleotide polymorphism (SNP rs1799889) in the PAI-1 gene promoter is associated with PAI-1 plasma level. We investigated whether rs1799889 and two other SNPs of the PAI-1 gene (rs2227631, -844 G/A in the promoter; rs11178, +10700 C/T in the 3'UTR) are associated with increased ONFH risk.</p> <p>Methods</p> <p>Three SNPs in PAI-1 were genotyped in 206 ONFH patients and 251 control subjects, using direct sequencing and a TaqMan^®5' allelic discrimination assay. We performed association analysis for genotyped SNPs and haplotypes with ONFH.</p> <p>Results</p> <p>The 4G allele of rs1799889, A allele of rs2227631, and C allele of rs11178 were significantly associated with increased ONFH risk (p = 0.03, p = 0.003, and p = 0.002, respectively). When we divided the population according to gender, an association between the three SNPs and increased risk of ONFH was found only in men. In another subgroup analysis based on the etiology of ONFH, rs2227631 (A allele) and rs11178 (C allele) in the idiopathic subgroup (p = 0.007 and p = 0.021) and rs1799889 (4G allele) and rs11178 (C allele) in the alcohol-induced subgroup (p = 0.042 and p = 0.015) were associated with increased risk of ONFH. In addition, a certain haplotype (A-4G-C) of PAI-1 was also significantly associated with ONFH (p < 0.001).</p> <p>Conclusion</p> <p>Our findings demonstrated that three SNPs (rs1799889, rs2227631, and rs11178) of the PAI-1 gene were associated with ONFH risk. This study also suggests that PAI-1 SNPs may play an important role in ONFH.</p

Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis

The aim of this study was to investigate the expressions of Toll-like receptor (TLR) 2, TLR4, TLR9, and their correlations with the expression of cytokines that are associated with activation of CD4+ T cells and inflammation including interferon γ (IFNγ), interleukin 4 (IL4), interleukin 17 (IL17), and tumor necrosis factor α (TNFα) in muscle tissues of patients with dermatomyositis (DM) and polymyositis (PM). The expressions of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were measured by real-time reverse transcription–polymerase chain reaction in muscle tissues from 14 patients with DM and PM (nine patients with DM, five patients with PM) and three controls. The expressions of TLR2, TLR4, and TLR9 were also localized with immunohistochemistry. The expression levels of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were significantly high in patients with DM and PM compared with those in the controls, and the expression levels of TLR4 and TLR9 had significant positive correlations with the expressions of IFNγ, IL4, IL17, and TNFα. Immunohistochemistry showed that TLR2, TLR4, and TLR9 were expressed by infiltrating cells of perimysium in DM, whereas they were expressed by infiltrating cells of endomysium in PM. These results suggest that the involvement of TLR4 and TLR9 in immunopathogenesis of DM and PM might be connected with activation of CD4+ T cells

The Function of Heterodimeric AP-1 Comprised of c-Jun and c-Fos in Activin Mediated Spemann Organizer Gene Expression

BACKGROUND:Activator protein-1 (AP-1) is a mediator of BMP or FGF signaling during Xenopus embryogenesis. However, specific role of AP-1 in activin signaling has not been elucidated during vertebrate development. METHODOLOGY/PRINCIPAL FINDINGS:We provide new evidence showing that overexpression of heterodimeric AP-1 comprised of c-jun and c-fos (AP-1(c-Jun/c-Fos)) induces the expression of BMP-antagonizing organizer genes (noggin, chordin and goosecoid) that were normally expressed by high dose of activin. AP-1(c-Jun/c-Fos) enhanced the promoter activities of organizer genes but reduced that of PV.1, a BMP4-response gene. A loss of function study clearly demonstrated that AP-1(c-Jun/c-Fos) is required for the activin-induced organizer and neural gene expression. Moreover, physical interaction of AP-1(c-Jun/c-Fos) and Smad3 cooperatively enhanced the transcriptional activity of goosecoid via direct binding on this promoter. Interestingly, Smad3 mutants at c-Jun binding site failed in regulation of organizer genes, indicating that these physical interactions are specifically necessary for the expression of organizer genes. CONCLUSIONS/SIGNIFICANCE:AP-1(c-Jun/c-Fos) plays a specific role in organizer gene expression in downstream of activin signal during early Xenopus embryogenesis

Newly formed cystic lesions for the development of pneumomediastinum in Pneumocystis jirovecii pneumonia

<p>Abstract</p> <p>Background</p> <p><it>Pneumocystis jirovecii</it>, formerly named <it>Pneumocystis carinii</it>, is one of the most common opportunistic infections in human immunodeficiency virus (HIV)-infected patients.</p> <p>Case presentations</p> <p>We encountered two cases of spontaneous pneumomediastinum with subcutaneous emphysema in HIV-infected patients being treated for <it>Pneumocystis jirovecii </it>pneumonia with trimethoprim/sulfamethoxazole.</p> <p>Conclusion</p> <p>Clinicians should be aware that cystic lesions and bronchiectasis can develop in spite of trimethoprim/sulfamethoxazole treatment for <it>P. jirovecii </it>pneumonia. The newly formed bronchiectasis and cyst formation that were noted in follow up high resolution computed tomography (HRCT) but were not visible on HRCT at admission could be risk factors for the development of pneumothorax or pneumomediastinum with subcutaneous emphysema in HIV-patients.</p

Human Endometrial Side Population Cells Exhibit Genotypic, Phenotypic and Functional Features of Somatic Stem Cells

During reproductive life, the human endometrium undergoes around 480 cycles of growth, breakdown and regeneration should pregnancy not be achieved. This outstanding regenerative capacity is the basis for women's cycling and its dysfunction may be involved in the etiology of pathological disorders. Therefore, the human endometrial tissue must rely on a remarkable endometrial somatic stem cells (SSC) population. Here we explore the hypothesis that human endometrial side population (SP) cells correspond to somatic stem cells. We isolated, identified and characterized the SP corresponding to the stromal and epithelial compartments using endometrial SP genes signature, immunophenotyping and characteristic telomerase pattern. We analyzed the clonogenic activity of SP cells under hypoxic conditions and the differentiation capacity in vitro to adipogenic and osteogenic lineages. Finally, we demonstrated the functional capability of endometrial SP to develop human endometrium after subcutaneous injection in NOD-SCID mice. Briefly, SP cells of human endometrium from epithelial and stromal compartments display genotypic, phenotypic and functional features of SSC

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed