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32551397 Safety and efficacy of abatacept in patients with treatment-resistant SARCoidosis (ABASARC 2020 Sep INTRODUCTION: Sarcoidosis is a granulomatous systemic disease that becomes chronic in approximately one third of affected patients resulting in quality of life and functional impairment. Immunosuppressive drugs other than steroids represent alternative therapeutic options, but side effects like liver and bone marrow toxicity or increased susceptibility to infections limit their use. Pathophysiological studies in sarcoidosis patients demonstrate altered regulatory T-cell functions with a reduced expression of CTLA-4 (CD152) and prolonged inflammation. Therefore, interfering with CTLA-4 using abatacept might be a therapeutic option in sarcoidosis similar to rheumatoid arthritis therapy. METHODS/DESIGN: This is a multicenter prospective open-labeled single arm phase II study addressing the safety of abatacept in sarcoidosis patients. 30 patients with chronic sarcoidosis requiring immunosuppressive therapy beyond 5 mg prednisolone equivalent will be treated with abatacept in combination with corticosteroids for one year in two centers.The primary endpoint is the number and characterization of severe infectious complications under treatment with abatacept.Secondary endpoints are the rate of all infections, patient-related outcomes (assessed by questionnaires), lung function and immunological parameters including alveolar inflammation assessed by bronchoaveolar lavage. DISCUSSION: This is the first trial of abatacept in patients with sarcoidosis. It is hypothesized that administration of abatacept is safe in patients with chronic sarcoidosis and can limit ongoing inflammation. Patients' wellbeing is assessed by established questionnaires. Immunological work-up will highlight the effect of abatacept on inflammatory pathways in sarcoidosis. TRIAL REGISTRATION: The trial has been registered at the German Clinical Trial Registry (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00011660.
32155675 Antioxidant and protective effect of Stachys pilifera Benth against nephrotoxicity induced 2020 May The aim of current study was to assess the antioxidant and renoprotective effects of Stachys pilifera Benth (S.P.B.) hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). Adult rats with bodyweight of 180-220 g were divided into five groups (n = 7) treated as follows: group 1, control; group 2, CP; group 3, pretreatment with S.P.B. before CP; group 4, posttreatment with S.P.B. after CP; and, group 5, S.P.B. extract. A single dose of CP (7 mg/kg) was intraperitoneally injected on the fifth day and hydroalcoholic extract of S.P.B. (500 mg kg(-1)  day(-1) ) was orally administered. The levels of oxidative stress markers, biochemical tests, and histopathological staining were assayed in serum and renal tissue. Also, the chemical composition of S.P.B. extract was determined by GC-MS analysis. The main compositions of S.P.B. extract identified by GC-MS analysis, were hexadeca-2,6,10,14-tetraen-1-ol, 3,7,11,16-tetramethyl (24.77%), thymol (14.1%), and linolenic acid (13.4%). In groups treated and pretreated with S.P.B., blood urea nitrogen, creatinine, malondialdehyde, and nitric oxide metabolite in serum as well as malondialdehyde and protein carbonyl content of kidney tissues were significantly decreased in comparison to CP group; in contrast, total thiol group showed a significant increase in treated group as compared to CP group. Furthermore, histological investigation indicated that treatment with S.P.B. improved renal damages induced by CP. The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more investigations to define the mechanism of S.P.B. action. PRACTICAL APPLICATIONS: In different regions of Iran, Stachys is demonstrated by 34 species, out of which 13 are endemic, one of these endemic species is Stachys pilifera Benth (S.P.B.). The oil of S.P.B. is mainly consisted of cis-chrysanthenyl acetate, cis-chrysanthenol, spathulenol, β-caryophyllene, linalool, and terpinen-4-ol. Moreover, phytochemical studies have shown the presence of compounds such as diterpenes, phenylethanoid glycosides, saponins, terpenoides, and flavonoids in Stachys species. The aerial parts of S.P.B. are consumed as herbal tea to treat several disorders, for example, infections, asthma, and rheumatoid arthritis in Iranian folk medicine. The aim of current study was to evaluate the antioxidant and protective effects of S.P.B. hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more researches to define the mechanism of S.P.B. action.
32146745 [The clinical significance of serum autoantibodies and HLA-B(27) molecule testing in Uygur 2020 Mar 1 Objective: To explore the clinical value of serum autoantibodies and human leukocyte antigen (HLA-B(27)) molecular testing in Uygur patients with human immunodeficiency virus (HIV) infection. Method: A total of 727 HIV-infected Uygur patients who visited Kuche infectious diseases hospital during May 2016 to March 2017 were include in this study. The other 390 healthy people were enrolled as controls. Serum antinuclear antibodies (ANA), anti-cyclic citrullinated peptide (CCP) antibody, anti-extractable nuclear antigen (ENAs) antibody and HLA-B(27) molecule were tested. Result: Among 727 HIV-infected Uygur patients, 317 were males and 410 were females with mean age (35.52±13.44) years old. The mean duration of disease was (6.34±3.05) years. There were 697 (95.87%) patients receiving highly active antiretroviral therapy (HAART) with mean duration of treatment (5.52±3.47) years. The mean CD4(+)T cell count was (520±271) cells/μl in 202 HIV-infected patients, and mean virus load was (108 139±20 498) copies/ml in 20 HIV-infected patients. Rheumatic manifestations were recorded in 238 (32.74%) HIV-infected Uygur patients, mainly with dry mouth and dry eye (15.41%) , alopecia (9.90%) , arthralgia (8.94%) , ect. Compared with the health controls, positive ANA was more common in HIV infected Uygur patients (33.43% vs. 17.43%, P<0.001) with low titers (ANA titer:1∶100) . HIV-infected Uygur patients had higher positive anti-u1-RNP antibodies positive rate (1.10%), but lower anti-SSA antibodies positive rate (0.14%) and anti-CCP antibodies positive rate (0.28%). Patients with positive ANA in HAART group were significantly less than that in non-treatment group (32.71% vs. 50.00%, P=0.049). There were no correlations between ANA and duration of HAART, CD4(+)T cell counts and virus load (r values 0.061, 0.047, 0.121, respectively. P>0.05). Only one female patient was HLA-B(27) positive (0.14%), which was significantly lower than that in healthy controls (3.08%) (P<0.001). Also, only one patient was diagnosed with rheumatoid arthritis (RA). Conclusion: Autoimmune manifestations are common in HIV-infected Uygur patients. Several autoantibodies are positive, but the coincidence of rheumatic diseases is rare. It's noted that patients with autoimmune manifestations should be considered as a differential diagnosis of HIV infection.
32113051 Prevent action of magnoflorine with hyaluronic acid gel from cartilage degeneration in ant 2020 Jun According to the Chinese medicine, magnoflorine exerted significant anti-inflammatory effects and potentially promoted synthesis of proteoglycans in chondrocytes to reverse the progression of rheumatoid arthritis. However, the latent beneficial effect of magnoflorine for the treatment of traumatic osteoarthritis (OA) is still unknown. Therefore, we aim to demonstrate the efficacy of magnoflorine combined with HA-gel in attenuating cartilage degeneration in anterior cruciate ligament transection (ACLT) induced OA rat model. We found that the histological results showed the elevated cartilage matrix, chondrogenic signals and chondroprogenitor cells in HA-gel + magnoflorine treatment. HA-gel + magnoflorine treatment resulted in a decreased modified Mankin's score, and a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (whole cartilage), compared to ACLT and HA-gel groups. Furthermore, both the volume ratios of HC/Sum and HC/CC were negatively correlated with modified Mankin's scores. Finally, HA-gel + magnoflorine could significantly increase the BV/TV, Tb.Th, and decrease the Tb.Pf, Po(tot), Conn.Dn and Tb.Sp. In vitro, 50 μg/ml magnoflorine treatment could significantly increase the viability, S-phase, migration rate and chondrogenesis of chondroprogenitor cells. There were significant downregulations of MAPK/NF-κB signaling, and upregulations of chondrogenic signals in 50 μg/ml magnoflorine treatment. There were significant downregulations of proinflammatory cytokines and upregulation of IL-10 in HA-gel + magnoflorine treated group. Therefore, our study elucidated a protective effect of HA-gel + magnoflorine on attenuating cartilage degradation and maintaining SCB stabilization in ACLT induced OA.
32016664 Retinal vascular inflammatory and occlusive changes in infectious and non-infectious uveit 2020 Mar PURPOSE: Retinal vasculitis and occlusive changes are important signs of posterior uveitis and are possible diagnostic markers for uveitis. However, the frequency of arteritis and phlebitis in various uveitis entities, including infectious uveitis (IU) and non-infectious uveitis (NIU), have not been systematically investigated. STUDY DESIGN: Retrospective. METHODS: We investigated the frequency of retinal vascular inflammatory and occlusive changes in patients with IU and NIU. The study included 283 patients with intermediate, posterior, or pan-uveitis who were diagnosed with IU (presumed tuberculous uveitis, acute retinal necrosis, cytomegalovirus retinitis, human T-cell lymphotropic virus type 1-associated uveitis, toxoplasmic retinitis, syphilitic uveitis, rubella virus-associated uveitis, fungal endophthalmitis, and bacterial endophthalmitis) or NIU (sarcoidosis, Behçet's disease, Vogt-Koyanagi-Harada disease, human leukocyte antigen-B27-associated uveitis, systemic lupus erythematosus retinopathy, psoriatic uveitis, rheumatoid arthritis/collagen disease-associated uveitis, multiple sclerosis-associated uveitis, and sympathetic ophthalmia). All patients underwent fluorescein angiography (FA) and color photography examinations of the fundus. Presence of inflammatory and occlusive changes was determined by FA images. RESULTS: Significantly higher positive ratios of phlebitis, vein sheathing, vein occlusion, arteritis, artery sheathing, artery occlusion, and avascular areas were observed in the IU group than in the NIU group (p < 0.05). Notably, the discrepancy between IU and NIU was prominent with regard to retinal arterial changes (arteritis [57.9% vs 11.2%], inflammatory artery sheathing [33.7% vs 0%], and artery occlusion [22.1% vs 3.7%], respectively; p < 0.0001). CONCLUSION: Findings of vasculitis and occlusion, especially in retinal arteries, in FA strongly suggest an infectious origin of active uveitis.
31914413 A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) d 2020 Feb 7 Interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, as well as transforming growth factor β-activated kinase 1 (TAK1), are protein kinases essential for transducing inflammatory signals from interleukin receptors. IRAK family proteins and TAK1 have high sequence identity within the ATP-binding pocket, limiting the development of highly selective IRAK-1/4 or TAK1 inhibitors. Beyond kinase activity, IRAKs and TAK1 act as molecular scaffolds along with other signaling proteins, complicating the interpretation of experiments involving knockin or knockout approaches. In contrast, pharmacological manipulation offers the promise of targeting catalysis-mediated signaling without grossly disrupting the cellular architecture. Recently, we reported the discovery of takinib, a potent and highly selective TAK1 inhibitor that has only marginal activity against IRAK-4. On the basis of the TAK1-takinib complex structure and the structure of IRAK-1/4, here we defined critical contact sites of the takinib scaffold within the nucleotide-binding sites of each respective kinase. Kinase activity testing of takinib analogs against IRAK-4 identified a highly potent IRAK-4 inhibitor (HS-243). In a kinome-wide screen of 468 protein kinases, HS-243 had exquisite selectivity toward both IRAK-1 (IC(50) = 24 nm) and IRAK-4 (IC(50) = 20 nm), with only minimal TAK1-inhibiting activity (IC(50) = 0.5 μm). Using HS-243 and takinib, we evaluated the consequences of cytokine/chemokine responses after selective inhibition of IRAK-1/4 or TAK1 in response to lipopolysaccharide challenge in human rheumatoid arthritis fibroblast-like synoviocytes. Our results indicate that HS-243 specifically inhibits intracellular IRAKs without TAK1 inhibition and that these kinases have distinct, nonredundant signaling roles.
31678520 Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to in 2020 Jan 5 Transferosomes, also known as transfersomes, are ultradeformable vesicles for transdermal applications consisting of a lipid bilayer with phospholipids and an edge activator and an ethanol/aqueous core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or amongst the lipid bilayer. Compared to liposomes, transferosomes are able to reach intact deeper regions of the skin after topical administration delivering higher concentrations of active substances making them a successful drug delivery carrier for transdermal applications. Most transferosomes contain phosphatidylcholine (C18) as it is the most abundant lipid component of the cell membrane, and hence, it is highly tolerated for the skin, decreasing the risk of undesirable effects, such as hypersensitive reactions. The most common edge activators are surfactants such as sodium deoxycholate, Tween® 80 and Span® 80. Their chain length is optimal for intercalation within the C18 phospholipid bilayer. A wide variety of drugs has been successfully encapsulated within transferosomes such as phytocompounds like sinomenine or apigenin for rheumatoid arthritis and leukaemia respectively, small hydrophobic drugs but also macromolecules like insulin. The main factors to develop optimal transferosomal formulations (with high drug loading and nanometric size) are the optimal ratio between the main components as well as the critical process parameters for their manufacture. Application of quality by design (QbD), specifically design of experiments (DoE), is crucial to understand the interplay among all these factors not only during the preparation at lab scale but also in the scale-up process. Clinical trials of a licensed topical ketoprofen transferosomal gel have shown promising results in the alleviation of symptons in orthreothritis with non-severe skin and subcutaneous tissue disorders. However, the product was withdrawn from the market which probably was related to the higher cost of the medicine linked to the expensive manufacturing process required in the production of transferosomes compared to other conventional gel formulations. This example brings out the need for a careful formulation design to exploit the best properties of this drug delivery system as well as the development of manufacturing processes easily scalable at industrial level.
31669506 Sentinel biomarkers in HCV positive patients with mixed cryoglobulinemia. 2020 Jan BACKGROUND: Infections, autoimmunity and cancer play a role as determinants of etiology in Hepatitis C virus (HCV) related mixed cryoglobulinemia (MC). Several factors of risk have been suggested as markers of pathogenesis and progression of HCV-related MC into B cell Non-Hodgkin's Lymphoma (B-NHL). Here, we evaluated IgG subclass distribution, free light chains (FLCs) and vascular endothelial growth factor (VEGF) as a new combination of biomarkers. METHODS: We measured IgG1-4 subclasses, FLCs and VEGF levels in sera 53 from HCV-related MC, in comparison with 40 sera from HCV negative patients with rheumatoid arthritis (RA) and 30 from healthy blood donors (HBD). RESULTS: IgG3 levels were significantly higher in HCV-MC patients with a decrement of IgG2 and IgG4; FLC levels significantly increased in both MC and RA patients' groups; serological VEGF was higher in HCV-MC patients than in HBD in correlation with k and λ levels. CONCLUSION: Our results suggest that a specific IgG subclasses pattern together with raised levels of FLCs and VEGF could represent the biomarker "signature" of an inflammation multistage of acquired immune system.
31203509 Management of bone health in patients with cancer: a survey of specialist nurses. 2020 Mar BACKGROUND: Patients with cancer can experience bone metastases and/or cancer treatment-induced bone loss (CTIBL), and the resulting bone complications place burdens on patients and healthcare provision. Management of bone complications is becoming increasingly important as cancer survival rates improve. Advances in specialist oncology nursing practice benefit patients through better management of their bone health, which may improve quality of life and survival. METHODS: An anonymised online quantitative survey asked specialist oncology nurses about factors affecting their provision of support in the management of bone metastases and CTIBL. RESULTS: Of 283 participants, most stated that they worked in Europe, and 69.3% had at least 8 years of experience in oncology. The most common areas of specialisation were medical oncology, breast cancer and/or palliative care (20.8-50.9%). Awareness of bone loss prevention measures varied (from 34.3% for alcohol intake to 77.4% for adequate calcium intake), and awareness of hip fracture risk factors varied (from 28.6% for rheumatoid arthritis to 74.6% for age > 65 years). Approximately one-third reported a high level of confidence in managing bone metastases (39.9%) and CTIBL (33.2%). International or institution guidelines were used by approximately 50% of participants. Common barriers to better specialist care and treatment were reported to be lack of training, funding, knowledge or professional development. CONCLUSION: This work is the first quantitative analysis of reports from specialist oncology nurses about the management of bone metastases and CTIBL. It indicates the need for new nursing education initiatives with a focus on bone health management.
30033738 Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttrauma 2020 Jul OBJECTIVE: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury. DESIGN: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of 1129 proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired t test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini post hoc analysis. RESULTS: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 (P = 0.08, standardized response mean [SRM] = 1.00), MMP-3 (P = 0.05, SRM = 0.90), ADAM12 (P = 0.03, SRM = 1.31), aggrecan (P = 0.08, SRM = 1.13), and CTX-II (P = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways. CONCLUSIONS: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury.
31587329 Targeting MDM2 for novel molecular therapy: Beyond oncology. 2020 May The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
33615102 Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg-Ca 2021 Feb Legg-Calvé-Perthes disease (LCPD) is a childhood ischemic osteonecrosis (ON) of the femoral head associated with the elevation of proinflammatory cytokine interleukin-6 (IL-6) in the synovial fluid. Currently, there is no effective medical therapy for patients with LCPD. In animal models of ischemic ON, articular chondrocytes produce IL-6 in response to ischemic ON induction and IL-6 receptor blockade improves bone healing. High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released from dying cells. In addition, extracellular HMGB1 protein is a well-known proinflammatory cytokine elevated in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. The purpose of this study was to investigate IL-6-related proinflammatory cytokines, including HMGB1, in the synovial fluid of patients with LCPD. Our working hypothesis was that HMGB1, produced by articular chondrocytes following ischemic ON, plays an important role in IL-6 upregulation. Here, HMGB1 protein levels were significantly higher in the synovial fluid of patients with LCPD by threefold compared with controls (p < 0.05), and were highly correlated with IL-6 levels (Pearson correlation coefficient 0.94, p < 0.001, R (2) = 0.87). In the mouse model of ischemic ON, both HMGB1 gene expression and protein levels were elevated in the articular cartilage. In vitro studies revealed a significant elevation of HMGB1 and IL-6 proteins in the supernatants of human chondrocytes exposed to hypoxic and oxidative stresses. Overexpressed HMGB1 protein in the supernatants of chondrocytes synergistically increased IL-6 protein. Silencing HMGB1 RNA in human chondrocytes significantly repressed inteleukin-1β (IL-1β) gene expression, but not IL-6. Further, both IL-1β and tumor necrosis factor-α (TNF-α) protein levels in the synovial fluid of patients with LCPD were significantly correlated with IL-6 protein levels. Taken together, these results suggest that proinflammatory cytokines, HMGB1, tumor necrosis factor-α (TNF-α), and IL-1β, are significantly involved with IL-6 in the pathogenesis of LCPD. This study is clinically relevant because the availability of multiple therapeutic targets may improve the development of therapeutic strategy for LCPD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
33037966 Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases. 2021 Apr There are more than 80 kinds of autoimmune diseases known at present, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), as well as other disorders. Autoimmune diseases have a characteristic of immune responses directly attacking own tissues, leading to systematic inflammation and subsequent tissue damage. B cells play a vital role in the development of autoimmune diseases and differentiate into plasma cells or memory B cells to secrete high-affinity antibody or provide long-lasting function. Drugs targeting B cells show good therapeutic effects for the treatment of autoimmune diseases, such as rituximab (anti-CD20 antibody). Src family protein kinases (SFKs) are believed to play important roles in a variety of cellular functions such as growth, proliferation, and differentiation of B cell via B cell antigen receptor (BCR). Lck/Yes-related novel protein tyrosine kinase (LYN), BLK (B lymphocyte kinase), and Fyn are three different kinds of SFKs mainly expressed in B cells. LYN has a dual role in the BCR signal. On the one hand, positive signals are beneficial to the development and maturation of B cells. On the other hand, LYN can also inhibit excessively activated B cells. BLK is involved in the proliferation, differentiation, and immune tolerance of B lymphocytes, and further affects the function of B cells, which may lead to autoreactive or regulatory cellular responses, increasing the risk of autoimmune diseases. Fyn may affect the development of autoimmune disorders via the differentiation of B cells in the early stage of B cell development. This article reviews the recent advances of SFKs in B lymphocytes in autoimmune diseases.
33036598 Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a c 2020 Oct 9 BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.
32810618 De novo transcriptomic and proteomic analysis and potential toxin screening of Mesobuthus 2021 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: As well-known medicinal materials in traditional Chinese medicine, scorpions, commonly called as Quanxie () in Chinese, have been widely used to treat several diseases such as rheumatoid arthritis, apoplexy, epilepsy and chronic pain for more than a thousand years. Not only in the ancient times, the scorpions have also been recorded nowadays in the Pharmacopoeia of the People's Republic of China since 1963. AIM OF STUDY: This study aims to explore the differences in composition of the venom of scorpions from different regions by using the method of transcriptomics and proteomics. MATERIALS AND METHODS: Whole de novo transcriptomes, proteomics and their bioinformatic analyses were performed on samples of the scorpion Mesobuthus martensii and their venoms from four different provinces with clear geographical boundaries, including Hebei, Henan, Shandong and Shanxi. RESULTS: The four captured samples had the same morphology, and the conserved CO-1 sequence matched that of M. martensii. A total of 141,003 of 174,653 transcripts were identified as unigenes, of which we successfully annotated 51,627 (36.61%), 21,970 (15.58%), 7,168 (5.08%), and 45,263 (32.10%) unigenes with the NR, GO, KEGG and SWISSPROT databases, respectively, while a total of 427 proteins were collected from the protein extracted from venoms. Both GO and KEGG annotations exhibited only slight differences among the four samples while the expression level of gene and protein was quite different. A total of 249 toxin-related unigenes were successfully screened, including 41 serine proteases and serine protease inhibitors, 39 potassium channel toxins, 38 phospholipases, 16 host defense peptides, 9 metalloproteases, and 50 other toxins. Although the toxin species were similar among the four samples, the gene expression of each toxin varied considerably, for example, the scorpion from HB province has the most abundant expression quality in sequences c48391_g1, c55239_g1 and c47749_g1 while the lowest expressions of c51178_g1, c62033_g3 and c63754_g2. CONCLUSION: The regional differences in the transcriptomes and proteomes of M. martensii are mainly from expression levels e.g. toxins rather than expression species, of which the method can be further extended to evaluate the qualities of traditional Chinese medicines obtained from different regions.
32730846 Mitoxantrone, pixantrone and mitoxantrone (2-hydroxyethyl)piperazine are toll-like recepto 2020 Nov 1 Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα production was not mediated through cytotoxity at ≤ 1 µM concentration for pixantrone and mitoxantrone (2-hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.
32569872 Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts. 2020 Sep Extended osteoclast longevity is deeply involved in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis, though the mechanisms that determine osteoclast lifespan are not fully understood. Here we present findings indicating that the newly characterized gene Merlot, which encodes a highly conserved yet uncharacterized protein in vertebrates, is an important regulator for termination of osteoclastogenesis via induction of apoptosis. Mice lacking Merlot exhibited low bone mass due to increased osteoclast and bone resorption. Furthermore, osteoclast precursors overexpressing Merlot failed to differentiate into mature osteoclasts, while Merlot deficiency led to hyper-nucleation and prolonged survival of osteoclasts, accompanied by sustained nuclear localization of nuclear factor of activated T cell c1 (NFATc1) and derepression of glycogen synthase kinase-3β (GSK3β) activity, known to regulate NFATc1 activity and induce apoptosis. Merlot-deficient osteoclasts were found to represent suppression of caspase-3-mediated apoptosis and Merlot deficiency caused transcriptional downregulation of a proapoptotic cascade, including Bax, Bak, Noxa, and Bim, as well as the executor caspase members Casp-3, -6, and -7, and upregulation of anti-apoptotic Bcl2, resulting in a low apoptotic threshold. Thus, Merlot regulates osteoclast lifespan by inhibition of differentiation and simultaneous induction of apoptosis via regulation of the NFATc1-GSK3β axis.
32494704 Prevention and treatment of autoimmune diseases with plant virus nanoparticles. 2020 May Plant viruses are natural, self-assembling nanostructures with versatile and genetically programmable shells, making them useful in diverse applications ranging from the development of new materials to diagnostics and therapeutics. Here, we describe the design and synthesis of plant virus nanoparticles displaying peptides associated with two different autoimmune diseases. Using animal models, we show that the recombinant nanoparticles can prevent autoimmune diabetes and ameliorate rheumatoid arthritis. In both cases, this effect is based on a strictly peptide-related mechanism in which the virus nanoparticle acts both as a peptide scaffold and as an adjuvant, showing an overlapping mechanism of action. This successful preclinical testing could pave the way for the development of plant viruses for the clinical treatment of human autoimmune diseases.
32320330 Sex Differences in Autoimmune Multimorbidity in Type 1 Diabetes Mellitus and the Risk of C 2020 Apr Background: Autoimmune diseases are usually more prevalent in women. The risks of cardiovascular and renal disease in those with multiple autoimmune diseases have not been fully described. Materials and Methods: Using a national database from a large health insurer in the United States (years 2001-2017) containing ∼75 million members, we calculated age- and sex-specific co-prevalence of 12 autoimmune disorders for individuals with type 1 diabetes. We then evaluated whether concomitant autoimmune diseases were associated with renal failure, ischemic stroke, and myocardial infarction. Results: Of the 179,248 people diagnosed with type 1 diabetes, 1 in 4 had a concomitant autoimmune disease (27.03%; 95% confidence interval [CI] = 26.83%-27.24%), with hypothyroidism, rheumatoid arthritis, and celiac disease being the most common. The prevalence of autoimmune disease was 1.9 times greater in female than male patients (p < 0.001). In female patients with type 1 diabetes, one in three had another autoimmune disease (35.62%; 95% CI = 35.30%-35.94%) compared with one in five male patients (19.17%; 95% CI = 18.92%-19.42%). The risk of renal failure, ischemic stroke, and myocardial infarction increased with a greater number of concomitant autoimmune diseases (p < 0.001, test for trend for both female and male patients). Patients with type 1 diabetes who had multiple sclerosis or myasthenia gravis experienced an approximate threefold increase in risk of ischemic stroke (odds ratio [OR] = 3.57, OR = 3.22, respectively). Patients with type 1 diabetes and Addison's disease had a threefold increased risk of renal failure. Conclusions: Patients with type 1 diabetes, particularly women, frequently have coexisting autoimmune diseases that are associated with higher rates of renal failure, ischemic stroke, and myocardial infarction. Additional study is warranted, as are preventive efforts in this high-risk population.
32130895 Germline Features Associated with Immune Infiltration in Solid Tumors. 2020 Mar 3 The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8(+) T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.