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ID PMID Title PublicationDate abstract
29203226 Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases. 2018 Feb IL-17-producing γδ (γδ17) T cells form a versatile subset of cells that respond rapidly to innate stimuli and support the pro-inflammatory functions of different myeloid and lymphoid lineages, being particularly critical in the early stages of inflammatory and autoimmune responses. In mice, under homeostatic conditions, these innate-like lymphocytes are pre-programmed in the fetal thymus, through an intricate process involving both T cell receptor-dependent and -independent signals, which allows them to readily produce IL-17 upon stimulation. However, given their transcriptional and epigenetic wiring, γδ17 T cells are permissive to different environmental instructions, and can readily acquire the ability to co-produce multiple cytokines, such as IFN-γ, IL-22 and GM-CSF, that further propagate inflammation. Moreover, strong IL-23 signals, which are abundantly found in autoinflammatory conditions, are able to induce de novo differentiation of γδ17 T cells from uncommitted precursors, both in mice and humans. This notwithstanding, the exact mechanisms responsible for γδ17 T cell pathogenicity and multifunctionality are still poorly understood, especially in humans. The pathogenic roles attributed to γδ17 T cells in autoimmune diseases stem mainly from their ability to recruit different inflammatory myeloid populations to the target tissue, and to modulate αβ T cell function, either by enhancing inflammatory T(H)17 responses, or by restraining regulatory T(reg) cell activity. Given their capacity to link key inflammatory axes of innate and adaptive immunity, a better understanding of the molecular basis underpinning γδ17 T cell plasticity, and how much this feature accounts for their pathophysiological roles, may be critical for developing novel therapeutic approaches. In this review, we discuss the importance of γδ17 T cells in breaking tolerance and enhancing inflammation in various autoimmune diseases, such as multiple sclerosis, psoriasis and rheumatoid arthritis under the light of their basic biological traits, e.g. development, activation, effector functions and plasticity.
28284771 Prevalence of musculoskeletal manifestations and related disabilities in a Peruvian urban 2018 Sep OBJECTIVE: Estimate the prevalence of musculoskeletal manifestations and related disabilities of an urban population living at high altitude in Juliaca, Puno, Peru, using the Community Oriented Program for Control of Rheumatic Diseases (COPCORD) questionnaire and Health Assessment Questionnaire (HAQ) disability index. METHODS: A cross-sectional study was performed in a sample of 1095 people. In each interview, the COPCORD methodology and the HAQ were applied. The city was divided into 8 sectors. RESULTS: In all, 614 (56.1%) women were evaluated; 44% were from the Quechua community and 5.1% were Aymara. Before the final 7 days of the study, 132 people (12.05%; 95% CI 9.99-14.11) reported musculoskeletal pain. During the final 7 days of the study, 347 people (31.69%; 95% CI 28.36-35.02) who were predominately women (218; 35.5%; 95% CI 30.8-40.2) reported musculoskeletal pain. The most frequent rheumatic diseases were rheumatoid arthritis (1.27%), gout (0.64%), hand osteoarthritis (OA) (2.83%), knee OA (1.55%), hip OA (0.37%), fibromyalgia (1.09%), and soft tissue rheumatism (8.86%). The HAQ showed an incremental increase proportional to age. The HAQ average for the population was 0.18 (±0.36). Ten people (5.71%) of 175 with rheumatic disease received the services of a shaman. CONCLUSION: It is the first COPCORD study in an urban native population living at high altitude in Peru. The population affected by chronic rheumatic disease preferred professional rather than traditional care; this population had access to limited medical services. Impaired functional capacity measured by HAQ was associated with advanced age.
33343711 Short-term rates of radiolucency after primary total shoulder arthroplasty using a cementl 2020 Dec BACKGROUND: Total shoulder arthroplasty has shown good clinical efficacy in treating primary and secondary degenerative conditions of the glenohumeral joint. Glenoid loosening, however, remains the commonest cause of failure. The purpose of this study was to investigate the rate of radiographic periprosthetic lucency associated with the use of an uncemented, pegged, metal-backed polyethylene glenoid component. MATERIALS AND METHODS: A retrospective, single-centre study using the Epoca (Synthes, Paoli, Pennsylvania) metal-backed glenoid component. Operations were performed by two experienced consultant upper limb surgeons. Radiographs were analysed for immediate post-operative component seating and periprosthetic radiolucent lines at predefined regular post-operative intervals. Intra- and inter-observer reliability was assessed to improve validity of results. RESULTS: Mean age and follow-up was 72 (48-91) years and 2.5 years (2-5), respectively. Main indications for total shoulder arthroplasty were primary osteoarthritis, rheumatoid arthritis, revision for failed hemi-arthroplasty and acute fracture. Ninety-six per cent of components were completely seated post-operatively. Fifty-four (95%) of the 57 shoulders had no periprosthetic radiolucent lines at most recent follow-up. Complete post-operative glenoid seating was significantly associated with the absence of later periprosthetic radiolucency (p < 0.01). CONCLUSION: This study reports low early radiolucency rates with the pegged, uncemented, metal-backed polyethylene glenoid prosthesis used. Excellent post-operative glenoid seating is associated with a significantly lower rate of radiolucency. Longer follow-up data are required to confirm these early promising results.Level of evidence: Therapeutic, level IV.
31497760 The Prevalence of Systemic Rheumatic Diseases Among Breast Cancer Patients and Its Relatio 2019 Jun OBJECTIVES: This study aims to investigate the prevalence of systemic rheumatic diseases (SRDs) among patients with breast cancer (BC) and to identify the clinicopathological characteristics of these patients. PATIENTS AND METHODS: A total of 3,744 female patients with BC (mean age 49±11.7 years; range, 18 to 92 years) followed in Hacettepe University Faculty of Medicine, Medical Oncology Department between January 2006 and December 2015 were retrospectively assessed. Patients with or without SRD were compared in terms of clinicopathological features including age, menopausal state, smoking status, Body Mass Index (BMI), age of menarche, age at first labor, and number of children. The groups were also evaluated regarding tumor grade, stage, estrogen receptor and progesterone receptor expression, human epidermal growth factor receptor 2 overexpression, and survival. RESULTS: Of the patients analyzed, 68 (1.81%) had concomitant SRD. Among these patients, 33 (48.6%) had rheumatoid arthritis, eight (11.8%) had familial Mediterranean fever, eight (11.8%) had Behçet's disease, four (5.8%) had Sjögren's syndrome, four (5.8%) had systemic lupus erythematosus, six (8.8%) had ankylosing spondylitis, three (4.4%) had systemic sclerosis, one (1.4%) had polymyositis, and one (1.4%) had temporal arteritis. The groups with or without SRDs were similar in terms of age, smoking status, BMI, menopausal state, breast feeding duration, age at menarche and first birth. Stage 1 and 2 BC was more prevalent in SRD patients (74.6% vs. 64.5%, p=0.018). The rate to receive chemotherapy was significantly lower in patients with SRD. However, there was no significant difference in five-year overall survival rates between patients with or without SRD. CONCLUSION: Among patients with BC, 1.81% had concomitant SRD. These patients were diagnosed at early stages and given chemotherapy less frequently. However, they had similar survival rates compared to those without SRDs.
30590021 17-β-estradiol enhances neutrophil extracellular trap formation by interaction with estro 2019 Mar 15 Cell death-associated neutrophil extracellular trap formation (NETosis) occurs during various autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, as well as during gestation. Although increasing estrogen concentrations associated with pregnancy might induce NETosis via nuclear estrogen receptor (ERα/ERβ), little is known about the mechanisms associated with estrogen-induced NETosis. Here, we investigated the effects of estrogen (17-β-estradiol; E2) on NETosis, focusing on mechanisms associated with estrogen membrane receptor (GPR30) in neutrophil-like HL-60 cells. Our results show that E2 and the GPR30 agonist G-1 increases level of NETosis and NET formation. Moreover, NETosis-associated intracellular and extracellular histone citrullination and peptidyl arginine deiminase 4 (PAD4) expression were also increased by E2 or G-1 treatment. Furthermore, GPR30 antagonist pre-treatment inhibited increases in NETosis and PAD4 expression mediated by G-1 and partially inhibited these effects mediated by E2. These results demonstrate that E2 treatment induces NETosis via not only ERα/ERβ but also GPR30 in neutrophil-like HL-60 cells.
30572710 Impact of Yoga on Inflammatory Biomarkers: A Systematic Review. 2019 Mar BACKGROUND: Many chronic conditions, including heart disease, cancer, and rheumatoid arthritis, are associated with underlying chronic inflammatory processes. Literature reviews have analyzed a variety of integrative therapies and their relationships with chronic inflammation. This systematic review is unique in reporting solely on yoga's relationship with inflammation. Its purpose was to synthesize current literature examining the impact of yoga interventions on inflammatory biomarkers in adults with chronic inflammatory-related disorders. METHOD: Searches of several electronic databases were conducted. Inclusion criteria were (a) English language, (b) sample age >18 years old, (c) yoga interventions involving postures with or without yoga breathing and/or meditation, and (d) measured inflammatory biomarkers. RESULTS: The final review included 15 primary studies. Of these, seven were rated as excellent and eight as average or fair. There was considerable variability in yoga types, components, frequency, session length, intervention duration, and intensity. The most common biomarkers measured were interleukin-6 ( n = 11), C-reactive protein ( n = 10), and tumor necrosis factor ( n = 8). Most studies reported positive effects on inflammatory biomarkers ( n = 11) from baseline to post yoga intervention. Analysis of the dose showed higher total dose (>1,000 min) resulted in greater improvements in inflammation. CONCLUSION: This review suggests that yoga can be a viable intervention to reduce inflammation across a multitude of chronic conditions. Future studies with detailed descriptions of yoga interventions, measurement of new and well-established inflammatory biomarkers, and larger sample sizes are warranted to advance the science and corroborate results.
30502718 A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorder 2019 Jan The T helper 17 (Th17) cells contain a dynamic subset of CD4+ T-cells that are able to develop into other different lineage subsets, including the Th1-like Th17 cells. These cells co-express retinoic acid-related orphan receptor gamma t (RORγt) and transcription factor T-box-expressed-in-T-cells (T-bet) and produce both interleukin (IL)-17 and interferon (IFN)-γ. Recent reports have shown that Th1-like Th17 cells play crucial roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, as well as, some primary immunodeficiency with autoimmune features. Here, the actual mechanisms for Th17 cells plasticity to Th1-like Th17 cells are discussed and reviewed in association to the role that Th1-like Th17 cells have on inflammatory and autoimmune disorders.
30444912 Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulatio 2018 Adenosine deaminase (ADA) catalyzes the deamination of adenosine, which is important in purine metabolism. ADA is ubiquitous to almost all human tissues, and ADA abnormalities have been reported in various diseases, including rheumatoid arthritis. ADA can be divided into two conformations based on the inhibitor that it binds to: open and closed forms. Here, we chose three ligands, namely, FR117016 (FR0), FR221647 (FR2) (open form), and HDPR (PRH, closed form), to investigate the inhibition mechanism of ADA and its effect on ADA through molecular dynamics simulations. In open forms, Egap and electrostatic potential (ESP) indicated that electron transfer might occur more easily in FR0 than in FR2. Binding free energy and hydrogen bond occupation revealed that the ADA-FR0 complex had a more stable structure than ADA-FR2. The probability of residues Pro159 to Lys171 of ADA-FR0 and ADA-FR2 to form a helix moderately increased compared with that in nonligated ADA. In comparison with FR0 and FR2 PRH could maintain ADA in a closed form to inhibit the function of ADA. The α7 helix (residues Thr57 to Ala73) of ADA in the closed form was mostly unfastened because of the effect of PRH. The number of H bonds and the relative superiority of the binding free energy indicated that the binding strength of PRH to ADA was significantly lower than that of an open inhibitor, thereby supporting the comparison of the inhibitory activities of the three ligands. Alanine scanning results showed that His17, Gly184, Asp295, and Asp296 exerted the greatest effects on protein energy, suggesting that they played crucial roles in binding to inhibitors. This study served as a theoretical basis for the development of new ADA inhibitors.
30190373 Endoglycosidase S Enables a Highly Simplified Clinical Chemistry Procedure for Direct Asse 2018 Dec Over the past 30 years, it has been firmly established that a wide spectrum of (autoimmune) diseases such as rheumatoid arthritis, Crohn's and lupus, but also other pathologies like alcoholic and non-alcoholic steatohepatitis (ASH and NASH) are driven by chronic inflammation and are hallmarked by a reduced level of serum IgG galactosylation. IgG (under)galactosylation is a promising biomarker to assess disease severity, and monitor and adjust therapy. However, this biomarker has not been implemented in routine clinical chemistry because of a complex analytical procedure that necessitates IgG purification, which is difficult to perform and validate at high throughput. We addressed this issue by using endo-β-N-acetylglucosaminidase from Streptococcus pyogenes (endoS) to specifically release Fc N-glycans in whole serum. The entire assay can be completed in a few hours and only entails adding endoS and labeling the glycans with APTS. Glycans are then readily analyzed through capillary electrophoresis. We demonstrate in two independent patient cohorts that IgG undergalactosylation levels obtained with this assay correlate very well with scores calculated from PNGaseF-released glycans of purified antibodies. Our new assay allows to directly and specifically measure the degree of IgG galactosylation in serum through a fast and completely liquid phase protocol, without the requirement for antibody purification. This should help advancing this biomarker toward clinical implementation.
30168415 Randomized, double-blind, placebo-controlled, phase I study of the safety and pharmacokine 2018 Nov OBJECTIVE: Namilumab is an investigational human monoclonal antibody to human granulocyte-macrophage colony-stimulating factor (GM-CSF). A phase I study of repeated namilumab dosing (150 or 300 mg subcutaneously) in non-Japanese patients with rheumatoid arthritis reported no safety concerns. The objective of this study was to report the safety (primary endpoint) and pharmacokinetic/pharmacodynamic effects of namilumab in healthy Japanese and Caucasian men aged 20 - 45 years (NCT02354599). MATERIALS AND METHODS: 24 Japanese subjects were randomized to a single dose of namilumab (80, 150, or 300 mg; n = 6/group) or placebo (n = 6; 2 subjects randomized/matched dose); 8 Caucasian subjects received namilumab 150 mg (n = 6) or placebo (n = 2). RESULTS: Overall, 29 subjects completed the study (2 withdrew voluntarily; 1 due to a serious adverse event (AE) unrelated to treatment). Baseline demographics were similar across treatment groups; mean age and weight were higher in Caucasians. Namilumab was well tolerated, with no notable safety concerns or pharmacokinetic/pharmacodynamic differences between Japanese and Caucasian subjects. AEs were mild to moderate, with no dose-proportional increase in Japanese subjects. Area under the serum concentration-time curve from zero to infinity (AUC(0-∞)) and maximum serum concentration (C(max)) increased in a dose-proportional manner in Japanese subjects. AUC(0-∞) was similar in Japanese (575.2 µg×day/mL) and Caucasian (559.7 µg×day/mL) 150-mg groups. C(max) was ~ 40% higher in Japanese subjects. Mean plasma total GM-CSF concentration-time profiles were similar in the Japanese and Caucasian 150-mg groups. Namilumab induced no clinically-relevant antibody response. CONCLUSION: Namilumab was well tolerated in Japanese and Caucasian subjects; namilumab 150 mg had similar pharmacokinetics in both populations, supporting further clinical development of this dose.
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30135635 Antigenic and immunogenic properties of chondrocytes. Implications for chondrocyte therape 2018 In physiological conditions chondrocytes are protected from contact with immunocompetent cells by the extracellular matrix, and transplanted fragments of allogeneic cartilage are not rejected. Cartilage produced by allogeneic chondrocytes, however, evokes the immune response of the recipient and is gradually destroyed. Immunisation by allogeneic chondrocytes is induced by the contact of their surface molecules with cells of the immune system. Chondrocytes constitutively express class I and, in some species, class II major histocompatibility complex (MHC) molecules. Expression of MHC class II molecules is induced in vitro by pro-inflammatory cytokines and in vivo in the course of the rejection of transplanted allogeneic cartilage. Low level of MHC class II molecules is found on the surface of human articular chondrocytes in patients with rheumatoid arthritis and osteoarthritis. Cartilage produced by transplanted allogeneic chondrocytes is destroyed by monocytes/macrophages and cytotoxic T and natural killer (NK) cells. NK cells show spontaneous cytotoxic reactivity against isolated chondrocytes and participate in the rejection of transplanted isolated chondrocytes. Chondrocytes express molecules that can serve as potential antigens in inflammatory joint diseases. Chondrocytes express cartilage-specific membrane antigen (CH65), human cartilage glycoprotein-39 (HC gp-39), hyaluronan binding adhesion molecule CD44, thymocyte antigen-1 (Thy-1) - CD90, signal transducer - CD24, lymphocyte function-associated antigen-3 (LFA-3) - CD58, and type I transmembrane protein Tmp21. On the other hand, although chondrocytes express major histocompatibility complex (MHC) class I and class II molecules, they can also exert immunosuppressive and immunomodulatory effects on immunocompetent cells. Isolated chondrocytes do not trigger an efficient allogeneic immune response in vitro and suppress, in a contact-dependent manner, proliferation of activated T cells. This suppression is associated with the expression by chondrocytes of multiple negative regulators of immune response. Chondrocytes express programmed death-ligand (PD-L), chondromodulin-I and indoleamine 2,3-dioxygenase (IDO), molecules that promote self-tolerance and suppress the immune system.
30096787 mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. 2018 Aug 8 Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.
30045682 Case series of unique adverse events related to the use of ibrutinib in patients with B-ce 2019 Jul BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor has reformed the treatment of various B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although generally well tolerated, here we describe our institutional experience of unique adverse effects encountered with the use of ibrutinib in patients with B-cell lymphomas. METHODS: This is a retrospective observational study done at a tertiary care facility, to evaluate adverse events in patients with B-cell malignancies on treatment with ibrutinib between 2014 and 2018. Further details including type of malignancy, cytogenetics, interventions for treatment of the side effect, and outcomes were obtained through electronic health record. CASE SERIES: We found 10 patients with unique adverse events related to ibrutinib. Among those, six had chronic lymphocytic leukemia, two had Waldenstrom's macroglobulinemia, and two had mantle cell lymphoma. The events included palindromic rheumatoid arthritis, diffuse spongiotic dermatitis, bullous pemphigoid, recurrent hemorrhagic stroke, peripheral neuropathy, recurrent paronychia, intramedullary fibrosis, recurrent joint pains, pulmonary aspergillosis, dyspnea with exacerbation of atrial fibrillation, and resolution of autoimmune hemolytic anemia. CONCLUSION: Our case series illustrates the wide variety of unique events recognized in patients treated with ibrutinib, some of which required cessation and most had dose reduction of the treatment. Thus, stressing the importance of early identification and intervention for the events to avoid worsening of toxicity and inability to continue treatment in such patients.
29733418 Genome-wide association study and functional analysis of feet and leg conformation traits 2018 May 4 Feet and leg conformation is evaluated as a subset of conformational structure traits in dairy and beef cattle and is related to the feet and leg quality that can compromise the animals' productive performance and longevity. The aim of this study was to perform a genome-wide association study (GWAS) of two traits related to feet and leg conformation in Nellore cattle to identify chromosomal regions related to the expression of these traits. Phenotypic and pedigree data from 104,725 animals and genotypes from 1,435 animals and 407,730 SNPs were used. Feet and leg structure was evaluated as a binary trait (FL1) to identify yearling animals with feet and leg problems or as categorical score (FL2) to assess the overall quality of their feet and leg. The top ten 1-Mb windows that explained the largest proportion of the total genetic variance were identified and functional enrichment analyses were performed. The 10 windows with large effects obtained for FL1 are located on chromosomes 1, 2, 6, 7, 8, 10, and 14, and together explained 8.96% of the additive genetic variance. For FL2, these windows are located on chromosomes 1, 7, 10, 11, 18, 20, 22, 28, and 29, explaining 8.98% of the additive genetic variance. Several candidate genes were identified, including DLX2 which is associated with osteogenic differentiation, IL-1β and IL-1A associated with some properties of articular cartilage, PiT1 which plays an important role in bone physiology, and CTSL associated with rheumatoid arthritis. The results presented here should contribute to a better understanding of the genetic and physiologic mechanisms regulating both traits, and identifies candidate genes for future investigation of causal mutations.
29706647 The microbiome and autoimmunity: a paradigm from the gut-liver axis. 2018 Jun Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
29599617 Resolvin E1 Inhibits Osteoclastogenesis and Bone Resorption by Suppressing IL-17-induced R 2018 Mar BACKGROUND: Resolvin E1 (RvE1) derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid is known to be a potent pro-resolving lipid mediator that prevents chronic inflammation and osteoclastogenesis. We investigated the inhibitory effects of RvE1 on osteoclastogenesis and bone resorption to clarify its therapeutic potential for rheumatoid arthritis (RA). METHODS: Receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation was assessed with tartrate-resistant acid phosphatase staining. RANKL-induced bone resorption was assessed by the measurement of pit formation using calcium phosphate-labeled fluorescent polyanionic molecules in RAW264.7 cells as osteoclast precursors. The effects of RvE1 on the RANKL-induced mRNA expression of osteoclast-specific genes and transcriptional factors such as c-fos and nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells were measured by quantitative real-time PCR. The distribution of NFATc1 induced by RANKL was evaluated by immunofluorescence staining in RAW264.7 cells. To analyze the mechanism of the inhibitory effect of RvE1 on osteoclastogenesis, we measured IL-17-induced RANKL mRNA expression in MC3T3-E1 osteoblast cells treated with RvE1 using quantitative real-time PCR and determined the level of prostaglandin E(2) (PGE(2)) production by enzyme-linked immunosorbent assay. RESULTS: RvE1 significantly suppressed RANKL-induced osteoclast differentiation and bone resorption. RvE1 inhibited the RANKL-induced mRNA expression of osteoclast-specific genes along with the transcription factors NFATc1 and c-fos. Moreover, NFATc1 translocation from the cytoplasm to the nucleus of RAW264.7 cells was suppressed following RvE1 treatment. RvE1 also inhibited IL-17-induced RANKL mRNA expression and PGE(2) production in MC3T3-E1 cells. CONCLUSION: RvE1 inhibited osteoclastogenesis and bone resorption by suppressing RANKL-induced NFATc1 and c-fos expression in osteoclasts and IL-17-induced RANKL expression through the autocrine action of PGE(2) in osteoblasts. Our data suggest RvE1 as a new therapeutic target of RA.
29563728 Aggressive Angioimmunoblastic T Cell Lymphomas (AITL) with Soft Tissue Extranodal Mass Var 2018 Mar Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell non-Hodgkin lymphoma with an aggressive fatal course and it has varied clinical presentation with an uncommon presentation when they present as soft tissue masses or when there is spill in the peripheral blood or there are composite lymphomas that are rare presentations. Common presentations include lymphadenopathy, fever and systemic symptoms, hemolytic anemias, skin rashes, and rheumatoid arthritis. The classical histopathology is absence of follicles in lymph nodes with presence of high endothelial venules and the tumor cells of small to medium-sized lymphocytes with pale cytoplasm mixed with reactive T cells. On immunohistochemistry, the cells are positive for CD3, CD4, CD10, BCL2, and CXCL13. In this observational study, the clinicopathologic presentation and the immunohistochemical profile of five cases who initially presented with a soft tissue mass which is an extremely rare presentation of this rare type of non-Hodgkin lymphoma that was diagnosed at our center with peripheral blood and bone marrow involvement and the clinicopathologic presentation, immunohistochemical profile, and response to treatment on follow-up are correlated with the literature review. One case had a fulminant and aggressive course and was fatal within 2 months of diagnosis. The rest of the four cases are on regular chemotherapy and follow-up. Our five cases had presented with soft tissue masses, two in the axillary regio,n two in the hand, and one in the scapular region with an extranodal presentation, and there was associated lymphadenopathy which developed subsequently with classic histomorphology and immunohistochemical findings. The age range was 46-54 years and all five cases were males. Three cases were with anemia (hemoglobin range 6.5-8.0 mg/dl) and all five cases were having peripheral blood plasmacytosis. Histopathology was classic with paracortical involvement with polymorphous population of cells with neoplastic lymphocytes of small and large sizes with numerous arborizing blood vessels which correspond to high endothelial venules. Microscopically, three architectural patterns; pattern I was seen in three cases (60%) and then pattern II and III in one case each (20% each). Immunohistochemistry revealed CD4+, CD8-, CXCL13+, CD10+, BCL6+, CD19, CD20, CD1a, Tdt, CD21, and CD23+ in follicular dendritic cells. AITL is a rare and aggressive non-Hodgkin lymphoma with varied clinical presentation with classic histomorphology with various patterns which may cause diagnostic dilemma and immunophenotypic findings, and prompt and early diagnosis is mandatory for institution of therapy.
29468982 Novel Patents Targeting Interleukin-17A; Implications in Cancer and Inflammation. 2018 BACKGROUND: IL-17A is a founding member of the IL-17 family that has been implicated in the pathogenesis of inflammatory-associated diseases such as cancer and autoimmune disease. In cancer, IL-17A participates in many key events for tumor development, in part by affecting innate and adaptive immune system and also by direct modulation of many pro-tumor events. Moreover, IL-17A dysregulation at the site of inflammation is associated with rheumatoid arthritis, multiple sclerosis, psoriasis, among others. IL-17A has emerged as a topic of interest and is under profound investigation for its involvement in several types of inflammatory-associated diseases. OBJECTIVE: This review aims to present an overview of the state of the art of IL-17A role in cancer and inflammation, as well as to describe recent patents targeting IL-17A with relevant clinical and biological properties for the prevention and treatment of cancer and inflammatory diseases. METHODS: Relevant information was obtained by searching in PubMed using IL-17A or IL-17, cancer and inflammation as keywords, while relevant patents were obtained mainly from Google Patents. RESULTS: Literature data indicated IL-17A as important biomolecule in the physiopathology of cancer and inflammatory diseases. Whereas, novel patents (2010 to 2017) targeting IL-17A are focused mainly on describing strategies to modulate IL-17A per se, co-modulation by bispecific antibodies to blocking IL-17A and important cytokines for IL-17A functions, upstream mechanisms and compounds to regulate IL-17A expression. CONCLUSION: The promising effects of patented agents against IL-17A may open new opportunities to therapeutic intervention targeting at different levels of involvement in the pathogenesis of cancer and inflammatory diseases.
29458876 Bone densitometry status and its associated factors in peri and post menopausal females: A 2018 Feb OBJECTIVE: Osteoporosis is a skeletal disorder characterized by diminished bone strength that increases the risk of fracture at instances of trivial trauma. Asians have a lower bone mass than the west. The present study was designed to add data from India on women above the age of 40 years with respect to low bone mineral density (BMD) and its associated high risk factors. MATERIALS AND METHODS: After a written informed consent, a detailed history was taken. Basal metabolic index was recorded, and biochemical and endocrine tests were done, followed by dual X ray absorptiometry scan. RESULTS: Average age of the study population was 46.54 years and BMI 26.58. The prevalence of osteopenia in the study was 36%, and that of osteoporosis, 4%; the overall prevalence of low BMD being 40%. Proportion of women with low BMD increased with advancing age and menopausal status. On endocrine evaluation, 53.44% cases with insufficient vitamin D, 62.5% with hyperparathyroidism, 100% with hypothyroidism, 75% with hyperthyroidism suffered from low BMD. Among chronic diseases, 75% women with diabetes, 33.3% with hypertension, 25% with deranged liver function and 50% with rheumatoid arthritis were found to have low BMD. 46.75% women with sun exposure less than one hour daily had poor bone mineralization. The proportion of women with normal BMD decreased from 84.09% to 43.33% with decrease in daily physical work. On logistic regression analysis, insufficient serum vitamin D concentrations, less physical work and inadequate sun exposure were found to be significantly associated with low BMD. CONCLUSION: Low BMD is not a disorder confined to postmenopausal women alone. It is widely prevalent in women above 40 years of age. Screening women above 40 in the absence of any high risk factors has the potential of nipping this silent killer in the bud.
29309829 Targeting cytokines in reduction of depressive symptoms: A comprehensive review. 2018 Apr 20 Heterogeneity in response to conventional antidepressants is a well-recognized limitation of evidence-based pharmacological treatments of major depressive disorder (MDD). Abnormal activation of inflammatory pathways is postulated as one likely mechanism contributing to treatment resistance in MDD. In a subset of depressed patients, the balance between pro- and anti-inflammatory cytokines is thought to be altered, causing mood symptoms due to inflammation, as seen in co-morbid depression associated with inflammatory conditions (e.g. psoriasis, hepatitis C, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis). The objectives of the current narrative review are to critically evaluate the literature about the effects of cytokine blockers on clinical outcomes in MDD and in the reduction of depressive symptom severity in individuals using these medications primarily to treat inflammatory conditions. A small number of clinical trials assessing the effects of cytokine blockers for depression and depressive symptoms have been completed. These trials suggest that in individuals with immune dysfunction (e.g. elevated pro-inflammatory cytokine levels), cytokine blockers may allow for improved clinical outcomes in MDD that would not be achievable with current conventional antidepressants alone. Additional well-designed clinical trials to assess the clinical utility of anti-inflammatory medications for the treatment of depression and depressive symptoms are merited. Further, the use of anti-inflammatories show promise for disease modifying effects that may alter illness trajectory, rather than solely ameliorating current mood symptoms.