Citations

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

ABSTRACT Angiogenesis and inflammation are regarded as important factors in the pathogenesis of chronic inflammation, cancer, and wound healing. Recent studies have supported prior evidence that common signaling pathways are involved in angiogenesis and inflammatory responses; however, key factors controlling both processes remain unclear. Although tripartite motif‐containing (TRIM)‐28 is known to have an immunosuppressive role in immune cells, its expression level and role in endothelial cells (ECs) are still unclear. In this study, we investigated the role of TRIM28 in inflammatory responses and angiogenic activity of ECs for the first time. We showed that TRIM28 is the most abundant TRIM family member and is localized in nuclei of ECs. Small interfering RNA‐mediated knockdown of TRIM28 strikingly suppressed expression of TNF receptor (TNFR)‐1 and −2, decreased TNFα‐induced phosphorylation of IKKα/β and IκBα and degradation of IκBα and nuclear translocation of p65, and suppressed basal level and TNF‐α‐induced expression of chemokines and adhesion molecules, including VCAM‐1, IL‐6, ICAM‐1, E‐selectin, and monocyte chemoattractant protein (MCP)‐1. Unexpectedly, IL‐8 was potentiated by TRIM28 knockdown in ECs in an NF‐κB‐inducing kinase–dependent manner. Meanwhile, knockdown of TRIM28 inhibited expression of VEGF receptor 2 and suppressed VEGF‐induced proliferation and tube formation by ECs. Finally, knockdown of TRIM28 suppressed recruitment of ECs in vivo in a murine synthetic basement membrane model. In summary, we found that TRIM28 acts as a central factor in controlling endothelial inflammatory responses and angiogenic activities by retaining expression of TNFR‐1 and −2 and VEGF receptor 2 in ECs.—Wang, Y., Li, J., Huang Y., Dai, X., Liu, Y., Liu, Z., Wang, Y., Wang, N., Zhang, P. Tripartite motif–containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR1 and −2 and VEGFR2 in endothelial cells. FASEB J. 31, 2026–2036 (2017). www.fasebj.org

Heart transplantation is a surgical procedure performed on patients with end-stage heart failure or other irreversible heart disease, Heart transplant prolongs the life of severe heart disease patients. Most of the receipts could survive more than 2-3 years, five-year survival rate could reach 70-80% with immunosuppressive therapy, rejection still an important problem after transplantation. Currently, traditional calcineurin inhibitors, antimetabolite agents, and steroids, wildly used after transplantation, the new generation of immunosuppressive medicines have been developed, and cell-based immunotherapy, as mesenchymal stem cell, myeloid-derived suppressor cells, dendritic cells, pluripotent cells and Treg cells are promising to be used in cellular immunotherapy in organ transplantation.

The cardiology diagnostic are the methods of identifying current or past heart conditions, which can advise caregivers on patient diagnosis and provide a proper therapy plan, nowadays couple new diagnostic methods have been developed and some of them like radionuclide myocardial perfusion imaging, coronary computed tomography angiogram, cardiac magnetic resonance imaging, intravascular ultrasonography, optical coherence tomography, intravascular thermography, intravascular elastography, and near-infrared spectroscopy have been approved for clinical use. Not only the advanced technologies, the new biomarkers, and genetic markers may provide new potential targets for the diagnosis, therapy, and prevention of heart diseases.

Significance Antigen recognition by the immune system triggers rapid, specific, and protective responses, which are counterbalanced by inhibitory checkpoints to minimize potentially harmful immunity. The programmed death-1/ programmed death ligand-1 (PD-1/PD-L1) checkpoint is overreactive in cancer patients, curbing antitumor immunity. Whether a failing PD-1/PD-L1 checkpoint contributes to spontaneous autoimmune disease in humans is unknown. Here, we found that in patients with the autoimmune vasculitis giant cell arteritis, antigen-presenting cells provide insufficient negative signaling; unleashing highly activated T cells to infiltrate and damage the walls of large arteries. Thus, immunoinhibitory signals protect large arteries against inflammatory attack and checkpoint activation may be a suitable strategy to treat autoimmune vasculitis.

Introduction: The increasing use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology to examine pancreatic neoplasms has led to an increase in the diagnosis of metastases to the pancreas. Renal cell carcinoma (RCC) is the most common metastasis to the pancreas. Our study examines 33 cases of metastatic RCC to the pancreas sampled by EUS-FNA from four large tertiary care hospitals. Materials and Methods: We searched the cytopathology database for RCC metastatic to the pancreas diagnosed by EUS-FNA from January 2005 to January 2015. Patient age, history of RCC, nephrectomy history, follow-up postnephrectomy, radiological impression, and EUS-FNA cytologic diagnosis were reviewed. Results: Thirty-three patients were identified. The average age was 67.5 years (range, 49–84 years). Thirty-two patients had a previous documented history of RCC. One patient had the diagnosis of pancreatic metastasis at the same time of the kidney biopsy. Thirty-one patients had been treated with nephrectomy. Twenty-seven patients were being monitored annually by computed tomography or magnetic resonance imaging. Twenty-five patients had multiple masses by imaging, but 8 patients had a single mass in the pancreas at the time of EUS-FNA. EUS-FNA of 20 cases showed classic morphology of RCC. Thirteen cases had either “atypical” clinical-radiologic features or morphologic overlaps with primary pancreatic neoplasms or other neoplasms. Cell blocks were made on all 13 cases and immunochemical stains confirmed the diagnosis. Conclusions: EUS-FNA cytology is useful for the diagnosis of metastatic RCC to the pancreas. Cytomorphology can be aided with patient history, imaging analyses, cell blocks, and immunochemical stains.

Background: Plantar fasciotomy, a common operative procedure to relieve chronic heel pain, has been suggested to decrease foot arch stability. A systematic evaluation of the biomechanical consequences of partial or total plantar fascia release is essential to the understanding of the biomechanical rationale behind these operative procedures. Methods: A geometrical detailed three-dimensional (3-D) finite element (FE) model of the human foot and ankle, incorporating geometrical and contact nonlinearities, was constructed by 3-D reconstruction of MR images. Partial and complete plantar fascia releases were simulated to evaluate the corresponding biomechanical effects on load distribution of the bony, ligamentous, and encapsulated soft-tissue structures. Results: Partial and total plantar fascia release may decrease arch height but did not necessarily cause total collapse of the foot arch even with additional dissection of the long plantar ligament. Operative release of the plantar fascia was compromised by increased strains of the plantar ligaments and intensified stress in the midfoot and metatarsal bones. Load redistribution among the centralized metatarsal bones and focal stress relief at the calcaneal insertion were predicted with different types of fasciotomy. Conclusions: The FE model suggested that plantar fascia release may provide relief of focal stress and therefore could relieve associated heel pain. However, these operative procedures may pose a risk to arch stability and clinically may produce dorsolateral midfoot pain. The initial strategy for treating plantar fasciitis should be nonoperative. If surgery is necessary, partial release of less than 40% of the fascia is recommended to minimize the effect on arch instability and maintain normal foot biomechanics.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3 , in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.