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ID PMID Title PublicationDate abstract
31392427 Detection of tiopronin in body fluids and pharmaceutical products using red-emissive DNA-s 2019 Aug 8 Tiopronin is a widely used drug for treatment of cystinuria, rheumatoid arthritis and hepatic disorders. It is also an antidote to heavy metal poisoning and a radioprotective agent. A method is described for rapid and sensitive determination of tiopronin using DNA-stabilized silver nanoclusters (DNA-AgNCs) as a fluorescent probe. Tiopronin can selectively bind to DNA-AgNCs to form a stable Ag-S bond upon which the red photoluminescence (best measured at excitation/emission wavelengths of 590/640 nm) is quenched. The finding is used to design an assay that has a linear response in the 1-150 nM tiopronin concentration range and a 270 pM limit of detection. Compared with previously reported methods, the present approach is more rapid, highly sensitive and selective. It has been successfully applied in the detection of tiopronin in spiked urine and serum, and in pharmaceutical products (tablets and injections). Graphical abstract An ultrasensitive and reliable method for tiopronin assay is developed using red-emissive silver nanoclusters as a fluorescent probe. It has been successfully applied in the determination of tiopronin in biological fluids and pharmaceutical products.
35111494 Efficacy and risks of fondaparinux 7.5 mg for deep vein thrombosis after total knee arthr 2019 OBJECTIVES: High-dose fondaparinux therapy at 7.5 mg/day (FPX 7.5 mg) for deep vein thrombosis (DVT) may increase the risk of hemorrhage. We investigated the efficacy and safety of FPX 7.5 mg to treat DVT after total knee arthroplasty. METHODS: This study included 101 patients (91 with osteoarthritis, 10 with rheumatoid arthritis; mean age at total knee arthroplasty: 72.9 years) with asymptomatic postoperative DVT. Medical prophylaxis for DVT was started on postoperative day 1. Vascular ultrasound was conducted within 2 days postoperatively; patients were switched to FPX 7.5 mg after DVT diagnosis. Ultrasound was repeated to monitor DVT resolution. Adverse reactions were assessed. RESULTS: DVT resolved in 72 patients (71.3%) receiving FPX 7.5 mg. There were no significant differences between patients with versus without DVT resolution in the timing of FPX 7.5 mg therapy, treatment period, age, body mass index, or D-dimer or hemoglobin levels. There was no significant difference in DVT outcome between patients starting FPX 7.5 mg within 4 days postoperatively versus on day 5 or later, or between patients treated for ≤7 versus ≥8 days. Hemoglobin decreased to ≤7 g/dL in three patients (2.9%). CONCLUSIONS: FPX 7.5 mg can be expected to resolve DVT in 71.3% of patients; however, the risk of associated hemorrhagic complications may be higher than the risk of pulmonary embolism. To treat DVT with FPX 7.5 mg without compromising safety, patients should be selected carefully and the timing of treatment should be adjusted appropriately.
31852274 Prevalence of autoimmune disease in women with premature ovarian failure. 2020 Feb Objective: The aim of the study was to investigate the relationship between premature ovarian failure and autoimmune disease.Methods: This interdisciplinary prospective study included 52 consecutively recruited women with premature ovarian failure, aged 18-40 years. Diagnosis of premature ovarian failure was defined as amenorrhoea lasting more than 4 months and anti-Müllerian hormone levels below the age-appropriate range. Women with an abnormal karyotype or Fragile X syndrome were excluded from the study. All participants were screened by a rheumatologist for the presence of underlying autoimmune disease.Results: The average age at first diagnosis of premature ovarian failure was 29.5 years; 92.3% of participants (n = 48) presented with a secondary amenorrhoea, while only 7.7% (n = 4) had primary amenorrhoea. Of all 52 participants, 40.4% (n = 21) had at least one confirmed autoimmune disease, including Hashimoto's disease, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Crohn's disease, polyglandular autoimmune syndrome and coeliac disease. Response rates for hormonal stimulation therapy were low and the presence of autoimmune disease was associated with poor infertility treatment outcome.Conclusions: We found a high prevalence of autoimmune disease in women with premature ovarian failure. Screening for autoimmune diseases should be offered to all women with premature ovarian failure.
31673418 Cartilage-gut-microbiome axis: a new paradigm for novel therapeutic opportunities in osteo 2019 DNA of gut microbiota can be found in synovium of osteoarthritis and rheumatoid arthritis. This finding could result from the translocation of still alive bacteria from gut to joints through blood, since the diversified dormant microbiota of healthy human blood can be transiently resuscitated in vitro. The recent finding of gut microbiome in human cartilage, which differed between osteoarthritis and controls, suggests that a similar trafficking of dead or alive bacteria from gut microbiota physiologically occurs between gut and epiphysial bone marrow. Subchondral microbiota could enhance cartilage healing and transform components of deep cartilage matrix in metabolites with immunosuppressive properties. The differences of microbiome observed between hip and knee cartilage, either in osteoarthritis or controls, might be the counterpart of subtle differences in chondrocyte metabolism, themselves in line with differences in DNA methylation according to joints. Although bacteria theoretically cannot reach chondrocytes from the surface of intact cartilage, some bacteria enter the vascular channels of the epiphysial growth cartilage in young animals, whereas others can infect chondrocytes in vitro. In osteoarthritis, the early osteochondral plate angiogenesis may further enhance the ability of microbiota to locate close to the deeper layers of cartilage, and this might lead to focal dysbiosis, low-grade inflammation, cartilage degradation, epigenetic changes in chondrocytes and worsening of osteoarthritis. More studies on cartilage across different ethnic groups, weights, and according to age, are needed, to confirm the silent presence of gut microbiota close to human cartilage and better understand its physiologic and pathogenic significance.
31572052 Dentists' awareness about the link between oral and systemic health. 2019 Sep BACKGROUND: Oral health is integral to systemic health. There is a growing body of evidence of an association between periodontal and systemic diseases. The aim of the study was to evaluate the awareness of dentists regarding link between oral and systemic health. MATERIALS AND METHODS: Data was collected using a self-administered pilot-tested questionnaire. Dentists awareness about link between oral and systemic link was assessed on five point likert scale. Data was entered and analysed using SPSS. RESULTS: Of the 588 dentists, 500 completed the questionnaire (response rate 85.03%). About 93% of the participants (mean age 25.82 ± 4.21 years) agreed that oral health was associated with systemic health. Most dentists were aware of a connection between periodontal disease and diabetes (84.4%) and heart disease (70.2%). Similarly, 85.6% believed in the negative impact of oral disease on the quality of life of patients. More female than male dentists were aware of the relationship between periodontal disease and adverse pregnancy outcomes, diabetes, and rheumatoid arthritis (P < 0.001). Most dentists (97%) believed that more patients would seek oral care if they were aware of the oral-systemic link. After adjustments, private dentists were 4.65 times more likely than public dentists to believe in improving access to oral care with increased patient awareness of the oral-systemic connection (P = 0.011). CONCLUSIONS: Most dentists were aware of the oral-systemic link. They believed that patients' access to oral care would improve if they were aware of a connection between oral and systemic health. Therefore, patients should be informed of the oral-systemic link to improve their oral health.
31414593 Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4. 2019 Sep 16 Tofacitinib (TFT) is an oral JAK inhibitor which has been approved for the treatment of moderately and severely active rheumatoid arthritis. TFT was found to show concentration-, time-, and NADPH-dependent inhibition of CYP3A4, and irreversibility of the inactivation was also observed. Incubation (40 min, 37 °C) of recombinant CYP3A4 with TFT at 200 μM resulted in >70% loss of CYP3A4 activity. Estimated k(inact) and K(I) were 0.037 min(-1) and 93.2 μM, respectively. GSH and superoxide dismutase/catalase revealed minor or little protection against the CYP3A4 inactivation. Furthermore, ketoconazole attenuated TFT-mediated CYP3A4 inactivation. Epoxide and α-keto-aldehyde intermediates of TFT were trapped and characterized in microsomal incubations, respectively. The aldehyde intermediate is believed to be the key for the enzyme inactivation. Multiple P450 enzymes, including CYPs2C19, 3A4, 2D6, and 1A2, participated in the metabolism of TFT to the epoxide, while the formation of the aldehyde was mainly catalyzed by CYP3A4. In conclusion, TFT was proven to be a mechanism-based inactivator of CYP3A4.
31308818 Impact of NR1I2, adenosine triphosphate-binding cassette transporters genetic polymorphism 2019 Jul BACKGROUND: Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in NR1I2, adenosine triphosphate-binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals. METHODS: Forty-two targeted variants in seven genes were genotyped in 54 participants using Sequenom MassARRAY system to investigate their association with major pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD). Subsequently, molecular docking was simulated using the AutoDock Vina program. RESULTS: ABCC4 rs1751034 TT and rs1189437 TT were associated with increased exposure of CK and decreased exposure of 20(S)-PPD, whereas CFTR rs4148688 heterozygous carriers had the lowest maximum concentration (C(max)) of CK. The area under the curve from zero to the time of the last quantifiable concentration (AUC(last)) of CK was decreased in NR1I2 rs1464602 and rs2472682 homozygous carriers, while C(max) was significantly reduced only in rs2472682. ABCC4 rs1151471 and CFTR rs2283054 influenced the pharmacokinetics of 20(S)-PPD. In addition, several variations in ABCC2, ABCC4, CFTR, and NR1I2 had minor effects on the pharmacokinetics of CK. Quality of the best homology model of multidrug resistance protein 4 (MRP4) was assessed, and the ligand interaction plot showed the mode of interaction of CK with different MRP4 residues. CONLUSION: ABCC4 rs1751034 and rs1189437 affected the pharmacokinetics of both CK and 20(S)-PPD. NR1I2 rs1464602 and rs2472682 were only associated with the pharmacokinetics of CK. Thus, these hereditary variances could partly explain the interindividual differences in the pharmacokinetics of CK.
31258530 Extracellular Chromatin Triggers Release of Soluble CEACAM8 Upon Activation of Neutrophils 2019 Increased concentrations of extracellular chromatin are observed in cancer, sepsis, and inflammatory autoimmune diseases like systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). In SLE and RA, extracellular chromatin may behave as a danger-associated molecular pattern (DAMP). Polymorphonuclear neutrophils (PMN) are described as typical pro-inflammatory cells but possess also immunoregulatory properties. They are activated in SLE and RA but surprisingly remain moderately studied in these diseases, and especially the disease-associated stimuli triggering PMN activation are still not completely characterized. PMN express plasma membrane carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 (CD66b) and secrete a soluble form of CEACAM8 after activation. Soluble CEACAM8 has in turn immunoregulatory functions. However, few natural stimuli inducing soluble CEACAM8 secretion by PMN have been identified. Here we demonstrate for the first time that extracellular chromatin triggers secretion of soluble CEACAM8 by primary human PMN. Priming of PMN was not required. Secretion was associated with activation of PMN. Similar induction of soluble CEACAM8 release was observed with purified mono-nucleosomes as well as long chromatin fragments and occurred in a time-dependent and concentration-dependent manner. Results indicate that chromatin induces both neo-synthesis of soluble CEACAM8 and release of soluble CEACAM8 through degranulation. In addition, we report the presence of soluble CEACAM8 at high concentration in the synovial fluid of RA patients. Thus, we describe here a novel mechanism by which a natural DAMP, with inflammatory properties in SLE and RA, induces soluble CEACAM8 secretion by activated PMN with potential immunoregulatory consequences on other immune cells, including PMN.
31252215 The IL-23/IL-17 pathway in human chronic inflammatory diseases - new insight from genetics 2019 Jun Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function and diminished quality of life, as well as for society, because of the associated high health-care costs, and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.
31211186 The Role of Gene Therapy in Cartilage Repair. 2019 Mar The key principle of gene delivery to articulations by direct intra-articular injection is to release complementary DNA (cDNA)-encoding medical products that will lead to maintained, endogenous production of the gene products within the articulation. In fact, this has been accomplished for both in vivo and ex vivo gene delivery, using several vectors, genes, and cells in some animal models. Some clinical trials for rheumatoid arthritis and osteoarthritis (OA) using retrovirus vectors for ex vivo gene delivery and adeno-associated virus (AAV) for in vivo delivery have been reported. AAV is of special attention because, contrary to other viral vectors, it can enter deep within joint cartilage and transduce chondrocytes in situ. This quality is of special significance in OA, in which modifications in chondrocyte metabolism are believed to be crucial to the pathophysiology of the disease. The clinical effectiveness of TissueGene-C (TG-C), a cell and gene therapy for OA consisting of nontransformed and transduced chondrocytes (3:1) retrovirally transduced to overexpress TGF-β1 has been reported in patients with knee OA. The most common complications of TG-C were peripheral edema (9%), arthralgia (8%), articular swelling (6%), and injection site pain (5%). TG-C was associated with relevant ameliorations in function and pain. Gene therapy appears to be a viable method for the management of articular cartilage defects and OA.
31157574 An introduction of the role of probiotics in human infections and autoimmune diseases. 2019 Aug During the last decades, studies exploring the role of microorganisms inhabiting human body in different scenarios have demonstrated the great potential of modulating them to treat and prevent diseases. Among the most outstanding applications, probiotics have been used for over a century to treat infections and inflammation. Despite the beneficial role of other probiotics, Lactobacillus and Bifidobacterium species are the most frequently used, and have been effective as a therapeutic option in the treatment/prevention of dental caries, periodontal diseases, urogenital infections, and gastrointestinal infections. Additionally, as gastrointestinal tract harbors a great diversity of microbial species that directly or indirectly modulate host metabolism and immune response, the influence of intestinal microbiota, one of the targets of therapies using probiotics, on the biology of immune cells can be explored to treat inflammatory disorders or immune-mediated diseases. Thus, it is not surprising that probiotics have presented promising results in modulating human inflammatory diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease, among others. Hence, the purpose of this review is to discuss the potential of therapeutic approaches using probiotics to constrain infection and development of inflammation on human subjects.
31066364 [Facts and figures of clinical pathways in Italy: results from the PDTA Net project.]. 2019 Apr The approval of clinical pathways (CPWs) represents a key step to focus the care management on the patient. The PDTA Net project, by ReS Foundation and CINECA, aims to create a reference tool to study how the local organizational models influence healthcare and clinical outcomes. The article shows the analysis of all CPWs approved by Italian Regions and Autonomous Provinces until 31/12/2018. The search for documents was performed on the institutional websites through specific keywords. CPWs were filled into a database, according to the Region, publication year, disease of interest (distinguishing between chronic diseases with high epidemiological impact and rare diseases) and relevant clinical area. All documents were analyzed by geographical and temporal distribution, the latter also according to ministerial measures. From 2005 to 2018, 536 Regional CPWs were approved (316 for chronic diseases with a high epidemiological impact and 220 for rare diseases). The Regions with the highest number of CPWs of chronic diseases were Umbria (34 CPWs) and Piemonte (33). The most addressed clinical areas were: oncology (72), neurology (60), cardiology (34) and metabolic disorders (22). The most issued diseases were: diabetes (17), trauma/polytrauma (15), chronic obstructive pulmonary disease and multiple sclerosis (12 each), stroke (11), rheumatoid arthritis, breast cancer and colorectal neoplasms (10 each). The publication of the documents was affected by ministerial measures (Balduzzi Law, National Chronicity Plan, Diabetic Disease Plan and National Dementia Plan). The majority of CPWs on rare diseases was retrieved in Regions with activated Rare Disease Networks: Lombardia (110 CPWs), Lazio (64) and Toscana (17). This study showed that, to date, in Italy there are several CPWs published at Regional level, nevertheless their structure and application are heterogeneous and strongly influenced by the National Plans. All analyzed documents are available through the web platform of the project https://fondazioneres.it/pdta/. This project could be useful for health system stakeholders, in order to encourage the transition to new health governance and making CPWs effective governance tools.
31049064 Epstein-Barr Virus- (EBV-) Immortalized Lymphoblastoid Cell Lines (LCLs) Express High Leve 2019 Epstein-Barr virus (EBV) is one of the common human herpesvirus types in the world. EBV is known to infect more than 95% of adults in the world. The virus mainly infects B lymphocytes and could immortalize and transform the cells into EBV-bearing lymphoblastoid cell lines (LCLs). Limited studies have been focused on characterizing the surface marker expression of the immortalized LCLs. This study demonstrates the generation of 15 LCLs from sixteen rheumatoid arthritis (RA) patients and a healthy volunteer using B95-8 marmoset-derived EBV. The success rate of LCL generation was 88.23%. All CD19+ LCLs expressed CD23 (16.94-58.9%) and CD27 (15.74-80.89%) on cell surface. Our data demonstrated two distinct categories of LCLs (fast- and slow-growing) (p<0.05) based on their doubling time. The slow-growing LCLs showed lower CD23 level (35.28%) compared to fast-growing LCLs (42.39%). In contrast, the slow-growing LCLs showed higher percentage in both CD27 alone and CD23+CD27+ in combination. Overall, these findings may suggest the correlations of cellular CD23 and CD27 expression with the proliferation rate of the generated LCLs. Increase expression of CD23 may play a role in EBV immortalization of B-cells and the growth and maintenance of the EBV-transformed LCLs while CD27 expression might have inhibitory effects on LCL proliferation. Further investigations are warranted to these speculations.
30865072 Lacrimal Gland Orbital Lobe Cysts Associated With Lymphoid Hyperplasia or Mucosa-Associate 2019 May/Jun Large cysts in the orbital lobe of the lacrimal gland are rare and are associated with Sjögren syndrome and B-cell mucosa-associated lymphoid tissue lymphoma. The authors describe 4 new cases of large orbital lobe lacrimal gland cysts. The first 2 patients, both with Sjögren syndrome, had unilateral cysts associated with chronic inflammation. Mucosa-associated lymphoid tissue lymphoma was also identified in the cyst wall of the second case and could not be completely excluded in the first case. The third patient, with a history of rheumatoid arthritis, had bilateral cysts, again associated with mucosa-associated lymphoid tissue lymphoma. The fourth patient, with no history of systemic disease, had a unilateral cyst associated with reactive lymphoid hyperplasia. Finally, the authors report the long-term outcomes of 3 previously reported cases.
30608391 Hand tendinopathy risk factors in Taiwan: A population-based cohort study. 2019 Jan De Quervain's disease, carpal tunnel syndrome (CTS), and trigger finger (digit) are three common pathological conditions of the hand. They are considered overuse syndromes and occur predominantly in females. The prevalence rate and cause-specific risks of these three tendinopathies have not yet been clarified. Data from 41,871 cases listed in the Taiwan National Health Insurance Research Database (NHIRD) from 2010 to 2014 were analyzed. The prevalence rate of these 3 conditions by age, sex, and the risk factors of female-dominant diseases (e.g., osteoporosis, rheumatoid arthritis [RA], and tendinopathy), diabetes mellitus, and hormone antagonist treatment was evaluated. We found that 1.59% of the population developed CTS, 0.49% developed de Quervain's, and 1.07% developed trigger finger. Cases were more likely to develop the three hand tendinopathies if they were female, between 50 and 59 years old, and, according to a multivariate analysis, comorbid with RA, diabetes, using hormone antagonists. Our findings should provide an understanding of the risk factors associated with hand tendinopathy.
30540228 Activin A in Mammalian Physiology. 2019 Jan 1 Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
30408584 The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 2019 Jan Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.
30362576 Dielectrophoretic characterization and separation of monocytes and macrophages using 3D ca 2019 Jan Monocyte heterogeneity and its prevalence are revealed as indicator of several human diseases ranking from cardiovascular diseases to rheumatoid arthritis, chronic kidney diseases, autoimmune multiple sclerosis, and stroke injuries. When monocytes and macrophages are characterized and isolated with preserved genetic, phenotypic and functional properties, they can be used as label-free biomarkers for precise diagnostics and treatment of various diseases. Here, the dielectrophoretic responses of the monocytes and macrophages were examined. We present 3D carbon-electrode dielectrophoresis (carbon-DEP) as a separation tool for U937 monocytes and U937 monocyte-differentiated macrophages. The carbon-electrodes advanced the usability and throughput of DEP separation, presented wider electrochemical stability. Using the 3D carbon-DEP chip, we first identified the selective positive and negative DEP responses and specific crossover frequencies of monocytes and macrophages as their signatures for separation. The crossover frequency of monocytes and macrophages was 17 and 30 kHz, respectively. Next, we separated monocyte and macrophage subpopulations using their specific dielectrophoretic responses. Afterward, we used a fluorescence-activated cell sorter to confirm our results. Finally, we enriched 70% of monocyte cells from the mixed cell population, in other words, concentration of monocyte cells to macrophage cells was five times increased, using the 30-kHz, 10-Vpp electric field and 1 μL/min flow rate.
30350281 LC-MS/MS Method for the Quantification of the Leflunomide Metabolite, Teriflunomide, in Hu 2019 Leflunomide is a prodrug that is metabolized to the active metabolite, teriflunomide (A77 1726), to inhibit the enzyme dihydroorotate dehydrogenase and decrease the synthesis of pyrimidine nucleotides for DNA and RNA synthesis. Teriflunomide is primarily used for the treatment of rheumatoid arthritis and multiple sclerosis.A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify the drug teriflunomide over a concentration range of 5 ng/mL-200 μg/mL in serum or plasma. The calibration curve was divided into two separate overlapping regions of the analytical measurement range, with a high curve and a low curve range. Samples are first analyzed using the high-range calibration curve after a 100-fold dilution of the sample extract. Samples falling below the upper curve region are evaluated again without dilution and quantified, if possible, against the low curve calibration standards. This method can be used to support therapeutic drug monitoring of patients that are administered with leflunomide therapy.
30306455 Upregulation of HRD1 promotes cell migration and invasion in colon cancer. 2019 Apr 3-Hydroxy-3-methylglutaryl reductase degradation (HRD1) is an E3 ubiquitin ligase that functions by promoting degradation of misfolded proteins in processes such as embryogenesis and rheumatoid arthritis. However, little is known about the role of HRD1 in cancer. The aim of the present study was to investigate the expression pattern and functions of HRD1 in human colon cancer (CC). We found that HRD1 expression was increased significantly in human CC tissues, and its overexpression was associated with TNM stage, tumor differentiation, tumor invasive depth, and distant metastasis. Knockdown of HRD1 using small hairpin (sh) RNA plasmid significantly inhibited CC cell migration and invasion. Furthermore, the silencing of HRD1 decreased the expression of MMP-2 and MMP-9, which is critical for CC cell migration and invasion. Taken together, these results revealed that HRD1 is overexpressed in CC and promotes migration and invasion of CC cells. Inhibition of HRD1 may be considered as an effective anti-CC strategy.