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ID PMID Title PublicationDate abstract
31562126 Emergent high fatality lung disease in systemic juvenile arthritis. 2019 Dec OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
30967689 Fixation of the Various Coronal Plane Fracture Fragments, Including the Entire Coronoid Pr 2019 Mar BACKGROUND: We introduce several methods for fixation of unique Mayo type II olecranon fractures with the coronal plane fragment (CPF) including the entire coronoid process and report the radiological and clinical results through a case series. MATERIALS AND METHODS: 12 patients were operated using this method with a mean age of 44 years. CPFs were fixed with concurrent fixation by a locking plate screw for the olecranon in three patients (method 1), cerclage wiring in six patients (method 2), a mini plate in two patients (method 3), and a double-locking plate (method 4) in one patient. We accessed the fragment through an additional medial coronoid approach after identifying the olecranon fragment through a dorsal approach (methods 1-3). In method 4, the CPF was fixed through a dorsal approach between the comminuted metaphyseal fragments. RESULTS: With the exception of one patient with delayed union, all patients had achieved union at 3-month followup. The mean flexion extension arc was 125°. The mean pronation/supination was 72.5°/71.7° (range, 60-80°/60-80°). The mean visual analog scale score for elbow pain was 0.92 (range, 0-2), and the mean Mayo Elbow Performance Score was 86.7 (range, 80-90). The mean Disabilities of the Arm, Shoulder, and Hand score was 10.2 (range, 4-14). There were no major complications. CONCLUSION: A thorough preoperative understanding of the fragment patterns and preparation of tools for adequate reduction and fixation are necessary for satisfactory clinical and radiological outcomes. However, further comparative trials of conservative management versus surgery for CPF fixation, and any differences in outcomes according to the CPF fixation options, are required.
30388075 Paraneoplastic polyarthritis as the first manifestation of lingual carcinoma. 2019 Jan Paraneoplastic polyarthritis is an inflammatory arthritis, is usually seronegative, and has a temporal and pathophysiological relationship with an underlying malignancy. Although head and neck tumors may be a cause of paraneoplastic polyarthritis, its association with tongue carcinoma has not been previously reported. We present the case of a 69-year-old man who was a former smoker and presented with polyarthritis since 2 months in the wrists, proximal interphalangeal joints, knees, and elbows, with increased levels of acute-phase reactants; negativity for rheumatoid factor, anticitrullinated cyclic peptide antibody, and antinuclear antibody; and negative results for crystals and microorganisms in the synovial fluid. Cervical computed tomography and posterior rhinoscopy were performed, which detected an asymptomatic lesion on the base of the tongue, whose biopsy was compatible with nonkeratinizing squamous cell carcinoma. Polyarthritis did not respond to glucocorticoids at medium doses (oral prednisone 20 mg/day) but progressively resolved after the initiation of antineoplastic therapy.
31129640 Henoch-Schonlein purpura associated with HLA-B27 positive axial spondyloarthritis in a you 2019 May 24 Axial spondyloarthropathies are characterised by bilateral sacroiliitis, asymmetric oligoarthritis, association with the human leucocyte antigen (HLA)-B27, enthesitis and dactylitis. Although IgA nephropathy has a well-documented association with seronegative spondyloarthropathies, the association with Henoch-Schonlein purpura (HSP) has been documented only in few case reports. The present case is that of a 26-year-old man who presented with fever, lower limb arthritis, abdominal pain, palpable purpura over the buttocks and lower limbs, and clinical features of sacroiliitis. His blood tests showed elevated inflammatory markers and rheumatoid factor was negative. CT scan of the sacroiliac joints confirmed sacroiliitis. Skin biopsy revealed neutrophilic small vessel vasculitis. HLA-B27 was positive in blood. A diagnosis of HSP with HLA-B27 positive axial spondyloarthritis was made. HSP can be associated with HLA-B27 positive axial spondyloarthritis and has to be considered while evaluating for causes of cutaneous small vessel vasculitis in such patients.
30975190 A simplified lung ultrasound for the diagnosis of interstitial lung disease in connective 2019 Apr 11 BACKGROUND: Interstitial lung disease (ILD) is a common complication of connective tissue disease (CTD) and a leading cause of morbidity and mortality. There are various lung ultrasound (LUS) scoring systems with different lung intercostal spaces (LIS). The purpose of this meta-analysis was to find a simplified LUS method for the assessment of CTD-ILD. METHODS: We systematically retrieved lung ultrasound diagnostic studies on CTD-ILD in PubMed, Embase, and Web of Science databases. Summary diagnostic accuracy, including sensitivity, specificity, and area under the curve (AUC), was analyzed. Subgroup analysis was conducted according to different LIS and diseases. RESULTS: The 11 studies included in this meta-analysis comprised a total of 487 patients with CTD. The pooled sensitivity and specificity of the LUS were 0.859 (95% confidence interval (CI) 0.812-0.898) and 0.839 (95% CI 0.782-0.886), respectively, illustrating its great value for CTD-ILD diagnosis. In addition, there were six methods to evaluate LIS, including 72, 65, 50, 14, 10, and all LIS. The pooled sensitivity and specificity of 14 LIS were 0.982 (95% CI 0.904-1.000) and 0.875 (95% CI 0.710-0.965), respectively. The pooled positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odd ratio (DOR) of 14 LIS were 7.297 (95% CI 6.050-17.45), 0.029 (95% CI 0.006-0.147), and 292.30 (95% CI 35.53-2403.8), respectively. Moreover, the AUC for systemic sclerosis (SSc) and rheumatoid arthritis (RA) was 0.929 and 0.981, respectively; the DOR for SSc and RA was 42.93 (95% CI 17.75-103.79) and 80.24 (95% CI 8.107-796.09), respectively. CONCLUSIONS: We found a modified and simplified method of LUS, by scanning 14 LIS in a short time, which had a very high sensitivity and specificity.
30894058 KLF2 (kruppel-like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy. 2019 Dec Macroautophagy/autophagy is involved in myeloid cellular repair, destruction, and osteoclast differentiation; conversely, KLF2 (kruppel-like factor 2 [lung]) regulates myeloid cell activation and differentiation. To investigate the specific role of KLF2 in autophagy, osteoclastic differentiation was induced in monocytes in presence or absence of the autophagy inhibitor 3-methyladenine (3-MA), KLF2 inducer geranylgeranyl transferase inhibitor (GGTI298), and adenoviral overexpression of KLF2. We found that the number of autophagic cells and multinucleated osteoclasts were significantly decreased in presence of 3-MA, GGTI298, and KLF2 overexpressed cells indicating involvement of KLF2 in these processes. In addition, autophagy-related protein molecules were significantly decreased after induction of KLF2 during the course of osteoclastic differentiation. Furthermore, induction of arthritis in mice reduced the level of Klf2 in monocytes, and enhanced autophagy during osteoclastic differentiation. Mechanistically, knocking down of KLF2 increased the level of Beclin1 (BECN1) expression, and conversely, KLF2 over-expression reduced the level of BECN1 in monocytes. Moreover, 3-MA and GGTI298 both reduced myeloid cell proliferation concomitantly upregulating senescence-related molecules (CDKN1A/p21 and CDKN1B/p27(kip1)). We further confirmed epigenetic regulation of Becn1 by modulating Klf2; knocking down of Klf2 increased the levels of histone activation marks H3K9 and H4K8 acetylation in the promoter region of Becn1; and overexpression of Klf2 decreased the levels of H4K8 and H3K9 acetylation. In addition, osteoclastic differentiation also increased levels of H3K9 and H4K8 acetylation in the promoter region of Becn1. Together these findings for the first time revealed that Klf2 critically regulates Becn1-mediated autophagy process during osteoclastogenesis.Abbreviations: ACP5/TRAP: acid phosphatase 5, tartrate resistant; Ad-KLF2: adenoviral construct of KLF2; ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1, autophagy related; C57BL/6: inbred mouse strain C57 black 6; ChIP: chromatin immunoprecipitation; CSF1/MCSF: colony stimulating factor 1 (macrophage); CTSK: cathepsin K; EV: empty vector; GGTI298: geranylgeranyl transferase inhibitor; H3K9Ac: histone H3 lysine 9 acetylation; H4K8Ac: histone H4 lysine 8 acetylation; K/BxN mice: T cell receptor (TCR) transgene KRN and the MHC class II molecule A(g7) generates K/BxN mice; KLF2: kruppel-like factor 2 (lung); 3MA: 3-methyladenine; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MDC: monodansylcadaverine; NFATc1: nuclear factor of activated T cells 1; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; p21/CDKN1A: cyclin dependent kinase inhibitor 1A; p27(kip1)/CDKN1B: cyclin-dependent kinase inhibitor 1B; PCR: polymerase chain reaction; PtdIns3K: phosphoinositide 3-kinase; RA: rheumatoid arthritis; siKlf2: small interfering KLF2 ribonucleic acid; NS: non-specific; RAW 264.7: abelson murine leukemia virus transformed macrophage cell line; TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11; TSS: transcriptional start site; UCSC: University of California, Santa Cruz.
31379105 Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexistin 2019 Dec OBJECTIVE: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. METHODS: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. RESULTS: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. CONCLUSION: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.
31872588 [Transcriptome analysis of venom gland and identification of functional genes for snake ve 2019 Nov Agkistrodon acutus is a traditional Chinese herb medicine which has immunological regulation,anti-tumor,anti-inflammatory and analgesic effects,which is mainly used for the treatment of rheumatoid arthritis,ankylosing spondylitis,sjogren's syndrome and tumors. In order to excavate more important functional genes from A. acutus,the transcriptome of the venom gland was sequenced by the Illumina Hi Seq 4000,and 32 862 unigenes were assembled. Among them,26 589 unigenes were mapped to least one public database. 2 695 unigenes were annotated and assigned to 62 TF families,and 5 920 SSR loci were identified. The majority of mapped unigenes was from Protobothrops mucrosquamatus in the NR database,which revealed their closest homology. Three secretory phospholipase A_2 with different amino acid sequences showed similar spatial structures and all had well-conserved active sites. The 3 D structural models of C-type lectin showed conserved glycosylation binding sites( Asn45). This study will lay the foundation for the further study of the function of snake venom protein,and promoting the development and utilization of genome resources from A. acutus.
31866272 Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors fo 2020 Jan 15 Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3-5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC(50) = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC(50) > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.
31816725 Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by 2020 Feb 1 Therapeutic drug monitoring (TDM) help to improve treatment efficacy and safety. Therefore, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous monitoring of 11 tyrosine kinase inhibitors (TKIs) in human plasma. TKIs included in the assay are used in the treatment of chronic myeloid leukemia (CML: imatinib, dasatinib, nilotinib, bosutinib, ponatinib), polycythemia vera (ruxolitinib), chronic lymphocytic leukemia (ibrutinib) and rheumatoid arthritis (filgotinib, tofacitinib, baricitinib, peficitinib). Caffeine was also included in the method. Caffeine increases the acidity of the stomach and decreases its pH as well as is a competitive inhibitor of cytochrome P450 isoenzymes. Thus, it may influence absorption and metabolism of some TKIs, by modifying their plasma levels. The analytes of interest and their stable isotope-labeled internal standards were extracted from 200 μL of human plasma. Microelution-solid phase extraction (μ-SPE) was optimized for method validation and compared to simple protein precipitation (PPT). A gradient elution on a Poroshell 120 EC-C18 column at 60 °C and a flow rate of 0.5 mL/min was applied for analyte separation. The analytical run lasted 8 min and it was followed by a re-equilibration time of 4 min. Dynamic multiple reaction monitoring scan in the positive ionization mode was applied to improve method sensitivity. Endogenous plasma phospholipids can strongly affect MS analysis. Hence, the monitoring of endogenous phospholipids was included in the assay. Full validation of the method was achieved, including tests of precision, accuracy, trueness, linearity, extraction recovery, matrix effect, process efficiency, stability, sensitivity (with excellent LLOQs), selectivity, identity confirmation and carry-over effect. Regarding sample cleanup, more than 91% of early eluting and more than 96% of late eluting endogenous phospholipids were eliminated by μ-SPE when compared to PPT. This method enables the simultaneous plasma monitoring of 11 TKIs and caffeine and ensures high effectiveness in phospholipids elimination. The present approach is currently used in our clinical practice, being applied to TDM of dasatinib, imatinib, nilotinib and ponatinib. TKIs plasma monitoring helps to individualize dose adjustment and manage adverse effects in CML patients.
31715194 Coronary artery calcium scoring for individualized cardiovascular risk estimation in impor 2019 Sep The 2018 and 2019 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of so-called "risk-enhancing factors" in borderline to intermediate risk individuals. These include high-risk race/ethnicity (e.g. South Asian origin), chronic kidney disease, a family history of premature ASCVD, the metabolic syndrome, chronic inflammatory disorders (e.g. rheumatoid arthritis [RA], psoriasis, or chronic human immunodeficiency virus [HIV]), and conditions specific to women, among others. Studies suggest, however, that risk may be highly heterogeneous within these subgroups. The AHA/ACC guidelines also recommend consideration of coronary artery calcium (CAC) scoring for further risk assessment in borderline to intermediate risk individuals in whom management is uncertain. Although the combination of risk enhancing factors and CAC burden (together with Pooled Cohort estimates) may lead to more accurate ASCVD risk assessment, few publications have closely examined the interplay between risk enhancing factors and CAC scoring for personalized risk estimation. Our aim is to review the relevant literature in this area. Although further research is clearly needed, CAC assessment seems a highly valuable option to inform individualized ASCVD risk management in these important, often highly heterogeneous patient subgroups.
31578516 Transcriptional and epigenetic regulation of macrophages in atherosclerosis. 2020 Apr Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.
31538203 HIF-transcribed p53 chaperones HIF-1α. 2019 Nov 4 Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.
31408840 Protective effects of Clematichinenoside AR against inflammation and cytotoxicity induced 2019 Oct Clematichinenoside AR (AR), a major active ingredient extracted from traditional Chinese herb Clematis chinensis Osbeck, has been demonstrated to possess anti-inflammatory and immune-modulatory activities in the treatment of experimental rheumatoid arthritis (RA). The therapeutic potential of AR was supposed to be closely correlated to its ability against tumor necrosis factor-α (TNF-α). Therefore, we aimed to explore the protective effects of Clematichinenoside AR against inflammation and cytotoxicity induced by human TNF-α. AR treatment significantly decreased IL-6 and IL-8 secretion, and attenuated MMP-1 production in human RA-derived fibroblast-like synoviocyte MH7A cells stimulated by recombinant human TNF-α (rhTNF-α). AR might antagonize rhTNF-α-induced responses in MH7A cells through inhibiting p38 and ERK MAPKs signal activation. In TNF-α-sensitive murine fibroblast L929 cells, AR treatment attenuated the proliferation inhibition ratio induced by rhTNF-α/ActD and antagonized rhTNF-α-induced cytotoxicity. The cellular and nuclear morphological alterations in apoptotic characteristics induced by rhTNF-α/ActD in L929 cells were observed to be attenuated by the pretreatment with AR under a phase-contrast and fluorescence microscopy, respectively. The Annexin V-FITC/PI double-staining assay was performed to confirm that AR pretreatment obviously decreased the cell death. The antagonistic effects of AR against rhTNF-α-induced cytotoxicity might be potentially attributed to the degeneration of reactive oxygen species and the increasing of mitochondrial membrane potential, along with the suppression of durative phosphorylation of c-Jun N-terminal kinase (JNK). Collectively, our results indicated that AR antagonizes the inflammatory and cytotoxic activities induced by human TNF-α effectively in vitro, which provided further evidence for a novel mechanism underlying AR for treating RA correlating with excessive TNF-α production.
31275058 Abnormal Expression of DICER1 Leads to Dysregulation of Inflammatory Effectors in Human Sy 2019 Dysregulation of multiple microRNAs widely takes place during rheumatoid arthritis (RA) and experimental arthritides. This study is performed to explore the possible mechanism underlying DICER1 deficiency-mediated inflammation in human synoviocytes SW982. Firstly, RNAi of DICER1 led to increased COX2, MMP3, and MMP13 protein production, while DICER1 overexpression could reduce MMP13 expression. Secondly, the increase of IL-8 and decrease of TGF-β1 and TIMP1 were determined in the supernatant derived from DICER1 siRNA-treated cells, while DICER1 overexpression was found capable to reverse this effect. Ingenuity pathway analysis (IPA) software predicted that the Dicer1 deficiency-induced dysregulated cytokines in synoviocytes could possibly lead to the inflammatory disorders in the synovial tissue. Moreover, DICER1 deficiency could also reduce apoptosis, while DICER1 overexpression was found to decrease the proliferation and enhance apoptosis. In addition, DICER1 deficiency could lower the expression of multiple RA-related miRNAs such as miR-155. Meanwhile, DICER1 overexpression could rescue their low expression levels. And then, gain or loss of miR-155 function could regulate the protein levels of MMP3 and MMP13. These results indicated that DICER1 might play its role through regulating its downstream RA-related miRNAs. Our data demonstrated that DICER1 deficiency could cause multiple proinflammatory events in human synoviocytes SW982. This mechanism study might provide the possible target molecule to modify the inflammatory destruction and overproliferation in synoviocytes.
31259173 Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Pr 2019 Rhenium-188 ((188)Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify (188)Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of (188)Re from the (188)W/(188)Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) (188)Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of (188)Re agents for therapy is similar to imaging agents prepared with (99m)Tc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on (188)Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these (188)Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of (188)Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that (188)Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.
31111393 Androgen deprivation therapy and the risk of tenosynovitis in prostate cancer patients. 2019 Jul OBJECTIVES: Androgen deprivation therapy (ADT) use in prostate cancer (PCa) patients has been reported to have an association with rheumatoid arthritis. We aimed to assess the impact of ADT on the subsequent risk of tenosynovitis. METHODS: Using data from the National Health Insurance Research Database of Taiwan between 2001 and 2013, 3309 patients with PCa were identified. Among them, 729 ADT patients comprised the study group with 729 matched non-ADT controls. We used a 1:1 propensity score matched analysis. The demographic characteristics and comorbidities of the patients were analyzed; Cox proportional hazards regression was used to calculate the hazard ratios (HR) for the risk of tenosynovitis. RESULTS: There were 224 (15.3%) patients with newly diagnosed tenosynovitis. Compared with non-ADT patients, ADT patients had a lower risk of subsequent tenosynovitis with an adjusted HR of 0.38 [95% confidence interval (CI) 0.28-0.51; P < 0.001]. CONCLUSIONS: ADT use apparently did not increase the risk of tenosynovitis in patients with PCa. Further studies are warranted to assess the clinical significance.
31039360 Intervention of Inflammatory Monocyte Activity Limits Dermal Fibrosis. 2019 Oct Monocytes and monocyte-derived cells are important players in the initiation, progression, and resolution of inflammatory skin reactions. As inflammation is a prerequisite for fibrosis development, we focused on the role of monocytes in cutaneous fibrosis, the clinical hallmark of patients suffering from systemic sclerosis. Investigating the function of monocytes in reactive oxygen species-induced dermal fibrosis, we observed that early monocyte depletion partially reduced disease severity. Low numbers of inflammatory Ly6C(high) monocytes, as well as inhibition of CCR2 and CCL2 in wild type animals by a specific L-RNA aptamer, mitigated disease parameters, indicating a pivotal role for CCR2(+) inflammatory monocytes and the CCR2/CCL2 axis in fibrosis development. Of note, mice lacking splenic reservoirs failed to recruit monocytes to the skin and developed less fibrosis. Furthermore, enforced monocyte conversion into noninflammatory, patrolling Ly6C(low) monocytes by a nuclear receptor Nur77-agonist also resulted in significantly impaired cutaneous inflammation and dermal fibrosis. Most evident, pronounced monocyte conversion in interferon stimulated gene 12-deficient mice with pronounced nuclear Nur77 signaling completely protected from dermal fibrosis. Our study shows that inflammatory monocytes that are recruited from splenic reservoirs play a key role in the development of skin fibrosis and can be therapeutically challenged by forced conversion via the Nur77/interferon stimulated gene 12 axis.
31038654 Latent tuberculosis infection in patients with rheumatic diseases. 2019 Apr 25 Most people infected by Mycobacterium tuberculosis (Mtb) do not have any signs or disease symptoms, a condition known as latent tuberculosis infection (LTBI). The introduction of biological agents, mainly tumor necrosis factor (TNF) inhibitors, for the treatment of immune-mediated diseases such as Rheumatoid Arthritis (RA) and other rheumatic diseases, increased the risk of reactivation of LTBI, leading to development of active TB. Thus, this review will approach the aspects related to LTBI in patients with rheumatologic diseases, especially those using iTNF drugs. For this purpose it will be considered the definition and prevalence of LTBI, mechanisms associated with diseases and medications in use, criteria for screening, diagnosis and treatment. Considering that reactivation of LTBI accounts for a large proportion of the incidence of active TB, adequate diagnosis and treatment are crucial, especially in high-risk groups such as patients with rheumatologic diseases.
30887238 Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Vario 2019 Mar 18 A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL). Moderate interactions [mean AUC fold change, ≤ 2.08 (midazolam) or 2.36 (simvastatin)] was predicted for CYP3A4 probe substrates and weak interactions (mean AUC fold change, ≤ 1.29-1.97) were predicted for CYP2C19, CYP2C9, and CYP2D6 substrates. No notable interaction was predicted with CYP1A2. Although ethnic differences led to differences in simulated exposure for some of the probe substrates, there were no marked differences in the predicted magnitude of the change in exposure following IL-6-mediated suppression of CYPs. Decreased levels of serum albumin (as reported in NMO patients) had little impact on the magnitude of the simulated IL-6-mediated drug interactions. This PBPK modeling approach allowed us to leverage knowledge from different disease and ethnic populations to make predictions of cytokine-related DDIs in a rare disease population where actual clinical studies would otherwise be difficult to conduct.