Elucidating the role of a positive family history in differentiating between axial and peripheral spondyloarthritis: an ancillary analysis of the ASAS-PerSpA study.

OBJECTIVES: Positive family history (PFH) of spondyloarthritis (SpA) is important in the diagnosis of SpA. However, the contribution of a PFH in differentiating the two SpA subtypes (axial and peripheral spondyloarthritis (pSpA)), in particular the importance of second-degree relative (SDR) has not been well-studied. We aimed to investigate whether PFH of radiographic axial spondyloarthritis (r-axSpA), psoriasis, uveitis, reactive arthritis and inflammatory bowel disease in first-degree relative (FDR) and second-degree relative (SDR) contributes to differentiation between axSpA and pSpA using the data from a multinational cohort study. METHODS: The ASAS-PerSpA study dataset was used to assess the effects of a PFH on differentiating between axSpA and pSpA via generalised structural equation modelling. Model building using backward selection was performed to obtain a final model. Direct, indirect and total effects of the path analysis were calculated. RESULTS: A total of 3803 patients were included: 2458 axSpA and 1345 pSpA patients. FDR (OR: 3.75, 95% CI: 2.86-4.91, p<0.001) and SDR (OR: 4.58, 95% CI: 3.19-6.59, p<0.001) with r-axSpA were positively associated while FDR (OR: 0.262, 95% CI: 0.207-0.331, p<0.001) and SDR (OR: 0.305, 95% CI: 0.221-0.420, p<0.001) with psoriasis were negatively associated with differentiating patients with axSpA from pSpA. CONCLUSIONS: The presence of r-axSpA and psoriasis in FDR or SDR are useful in differentiating axSpA from pSpA. SDR with r-axSpA may contribute greater towards the differentiation than FDR. Clinicians should consider taking an extensive family history of SpA and their subtypes to better differentiate the subtypes within the SpA spectrum.

Measurement Properties of Existing Patient-Reported Outcome Measures on Medication Adherence: Systematic Review.

BACKGROUND: Medication adherence is essential for improving the health outcomes of patients. Various patient-reported outcome measures (PROMs) have been developed to measure medication adherence in patients. However, no study has summarized the psychometric properties of these PROMs to guide selection for use in clinical practice or research. OBJECTIVE: This study aims to evaluate the quality of the PROMs used to measure medication adherence. METHODS: This study was guided by the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Relevant articles were retrieved from the EMBASE, PubMed, Cochrane Library, Web of Science, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases. The PROMs were then evaluated based on the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines. RESULTS: A total of 121 unique medication adherence PROMs from 214 studies were identified. Hypotheses testing for construct validity and internal consistency were the most frequently assessed measurement properties. PROMs with at least a moderate level of evidence for ≥5 measurement properties include the Adherence Starts with Knowledge 20, Compliance Questionnaire-Rheumatology, General Medication Adherence Scale, Hill-Bone Scale, Immunosuppressant Therapy Barrier Scale, Medication Adherence Reasons Scale (MAR-Scale) revised, 5-item Medication Adherence Rating Scale (MARS-5), 9-item MARS (MARS-9), 4-item Morisky Medication Adherence Scale (MMAS-4), 8-item MMAS (MMAS-8), Self-efficacy for Appropriate Medication Adherence Scale, Satisfaction with Iron Chelation Therapy, Test of Adherence to Inhalers, and questionnaire by Voils. The MAR-Scale revised, MMAS-4, and MMAS-8 have been administered electronically. CONCLUSIONS: This study identified 121 PROMs for medication adherence and provided synthesized evidence for the measurement properties of these PROMs. The findings from this study may assist clinicians and researchers in selecting suitable PROMs to assess medication adherence.

Development of an Item Bank to Measure Medication Adherence: Systematic Review.

BACKGROUND: Medication adherence is important in managing the progression of chronic diseases. A promising approach to reduce cognitive burden when measuring medication adherence lies in the use of computer-adaptive tests (CATs) or in the development of shorter patient-reported outcome measures (PROMs). However, the lack of an item bank currently hampers this progress. OBJECTIVE: We aim to develop an item bank to measure general medication adherence. METHODS: Using the preferred reporting items for systematic review and meta-analysis (PRISMA), articles published before October 2019 were retrieved from PubMed, Embase, CINAHL, the Cochrane Library, and Web of Science. Items from existing PROMs were classified and selected ("binned" and "winnowed") according to standards published by the Patient-Reported Outcomes Measurement Information System (PROMIS) Cooperative Group. RESULTS: A total of 126 unique PROMs were identified from 213 studies in 48 countries. Items from the literature review (47 PROMs with 579 items for which permission has been obtained) underwent binning and winnowing. This resulted in 421 candidate items (77 extent of adherence and 344 reasons for adherence). CONCLUSIONS: We developed an item bank for measuring general medication adherence using items from validated PROMs. This will allow researchers to create new PROMs from selected items and provide the foundation to develop CATs.

Validity and reliability of the ten-item Connor-Davidson Resilience Scale (CD-RISC10) instrument in patients with axial spondyloarthritis (axSpA) in Singapore.

We aimed to assess the validity and reliability of the ten-item Connor-Davidson Resilience Scale (CD-RISC10) in patients with axial spondyloarthritis (axSpA) in Singapore. We used cross-sectional data from 108 patients with axSpA recruited from a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2017 to 2018. Analyses were guided by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework. Face validity was assessed through cognitive debriefing interviews (CDIs). Internal consistency was assessed through Cronbach's alpha. Test-retest reliability was assessed through intraclass correlation (ICC). Measurement error was assessed through smallest detectable change (SDC). Construct validity was assessed through six a priori hypotheses through correlation of the CD-RISC10 score with other patient-reported outcome measures. Structural validity was assessed using confirmatory factor analysis (CFA). Fit indices evaluated were root-mean-square error of approximation (RMSEA), comparative fit index (CFI), Tucker-Lewis index (TFI), and standardized root-mean-squared residual (SRMR). Ten patients completed the CDIs and face validity was supported. Among 108 patients (median age: 37(21-77), 81.5% males, 93.5% Chinese), the CD-RISC10 demonstrated good internal consistency (Cronbach's alpha = 0.94), and excellent test-retest reliability [ICC = 0.964 (95% CI 0.937-0.980)]. SDC was calculated as 1.88. Construct validity was established by meeting five out of the six a priori hypotheses. Structural validity was supported as CFA confirmed a one-factor model, with adequate fit statistics after adding three covariances (RMSEA = 0.077; CFI = 0.975; TLI = 0.964; SRMR = 0.036). This study supports the CD-RISC10 as a valid and reliable measure of resilience for use in patients with axSpA.

Factors Associated With Initiation of Biologics in Patients With Axial Spondyloarthritis in an Urban Asian City: A PRESPOND Study.

OBJECTIVE: The aim of this study was to examine if patients' sociodemographic, clinical characteristics, and patient-reported outcomes were associated with biologics initiation in patients with axial spondyloarthritis in Singapore. METHODS: Data from a dedicated registry from a tertiary referral center in Singapore from January 2011 to July 2016 were used. Initiation of first biologics was the main outcome of interest. Logistic regression analyses were used to explore the association of various factors on biologics initiation. RESULTS: Of 189 eligible patients (aged 37.7 ± 13.3 years; 76.2% were males), 30 (15.9 %) were started on biologics during follow-up. In the multivariable analysis model, age (odds ratio [OR]; 0.93; 95% confidence interval [CI], 0.89-0.98; p < 0.01), mental component summary score of Short-Form 36 Health Survey (OR, 0.18; 95% CI, 0.03-0.89; p = 0.04), erythrocyte sedimentation rate (OR, 1.02; 95% CI, 1.00-1.04; p = 0.02), presence of peptic ulcer disease (OR, 10.4; 95% CI, 2.21-48.8; p < 0.01), and lack of good response to nonsteroidal anti-inflammatory drugs (OR, 4.44; 95% CI, 1.63-12.1; p < 0.01) were found to be associated with biologics initiation. CONCLUSIONS: Age, erythrocyte sedimentation rate, mental component summary score, comorbidities of peptic ulcer disease, and responsiveness to nonsteroidal anti-inflammatory drugs were associated with biologics initiation. It is essential that clinicians recognize these factors in order to optimize therapy.

An In-House Developed Probiotics Database E-Reference Information for Healthcare Professionals.

Currently available references provide evidence on efficacy of probiotics strains but exclude product-specific information, making it challenging for healthcare professionals (HCPs) to provide suitable probiotic recommendations to consumers. This study describes the development and evaluation of an online probiotics e-reference database to assist HCPs in delivering evidence-based recommendations on probiotics to consumers. The database currently consists of 556 clinical studies collated through PubMed literature search, 753 probiotic products from multiple retail stores in Singapore and 5708 unique product-study links. Users can search for probiotics based on indication, product or strain. Based on a pilot evaluation by 25 pharmacists practising in hospital and retail settings, 84% agreed that the database helped in assessing the efficacy of probiotic products. All (100%) found the database easy to navigate and most (96%) would continue to use the database as an evidence-based e-reference for probiotic information.

A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways.

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E2 (PGE2) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies.

Ribisins and Certain Analogues Exert Neuroprotective Effects through Activation of the Keap1-Nrf2-ARE Pathway.

Oxidative stress contributes to the pathogenesis of various neurodegenerative diseases and induction of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a validated neuroprotective strategy. Synthetically-derived samples of members of the ribisin class of natural product together with a range of analogues were evaluated for their neuroprotective capacities. Four of the twenty-four compounds tested were found to strongly stimulate antioxidant response element-dependent transcriptional activity in human-derived SH-SY5Y cells. Further, in rat pheochromocytoma PC12 cells and mouse brain cortical cultures these compounds upregulated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene products, namely heme oxygenase (HO-1) and NAD(P)H quinone reductase 1 (NQO1). Functionally speaking, the compounds conferred protection in these cell models challenged with H2 O2 . In silico molecular modeling suggests that certain of the ribisins can dock in the Nrf2-binding Kelch domain in Keap1, while cysteine labeling by biotinylated iodoacetamide suggest that cysteine residues within Keap1 react with the ribisins. It is thus proposed that the most active compounds exert their neuroprotective activities by targeting Keap1, thereby activating Nrf2 and so increasing transactivation of Nrf2-responsive genes that encode for detoxifying and antioxidant enzymes.

Shogaols at proapoptotic concentrations induce G(2)/M arrest and aberrant mitotic cell death associated with tubulin aggregation.

Shogaols have been previously reported to induce cancer cell death via multiple mechanisms, among which one analog 6-shogaol has been reported to cause microtubule damage through specific reaction with sulfhydryl groups in tubulin. In this study, a series of shogaols with different side chain lengths (4-, 6-, 8- and 10-shogaol) was synthesized and evaluated for antiproliferative activity in HCT 116 colon carcinoma and SH-SY5Y neuroblastoma cells. 4- and 6-shogaol were identified as lead compounds possessing the strongest antiproliferative activity. In the soft agar assay, the lead shogaols displayed dose-dependent inhibition on cancer cell colony formation under anchorage-independent conditions. Using HCT 116 as the selected cancer cell line, the molecular events linking shogaols-induced G(2)/M cell cycle arrest to apoptosis characterized by caspase 3 and PARP cleavage were investigated. At sublethal concentrations, the halt at G(2)/M phase was alleviated along time and cells survived. Conversely, proapoptotic concentrations of 4- and 6-shogaol induced irreversible G(2)/M arrest that was at least in part associated with down-regulation of cell cycle checkpoint proteins cdk1, cyclin B and cdc25C, as well as spindle assembly checkpoint proteins mad2, cdc20 and survivin. A dose- and time-dependent accumulation of insoluble tubulin in the insoluble fractions of cell lysates provided evidence that G(2) checkpoint failure led to disruption of microtubule turnover. In summary, our results conclude that shogaols cause apoptosis by inducing aberrant mitosis at least through the attenuation of cell cycle and spindle assembly checkpoint proteins.

Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression.

Pachymic acid (PA), a lanostane-type triterpenoid derived from Poria cocos, possesses demonstrated anti-inflammatory and anti-cancer activities. Nonetheless, the biological properties and mechanism/s of action of PA remain largely undefined. In this study, the activity of PA against breast cancer cell invasion was evaluated. Invasiveness of human-derived MDA-MB-231 and MCF-7 breast carcinoma cells was suppressed by PA at non-lethal concentrations, which was associated with a decrease in matrix metalloproteinase-9 (MMP-9) secretion as a result of PA-mediated down-regulation of MMP-9 mRNA expression. In order to elucidate the underlying anti-invasive mechanism, the effect of PA on transcription factors activator protein-1 (AP-1) and nuclear factor kappaB (NF-κB) was examined using luciferase-based reporter gene assays. PA was found to bring about a reduction in phorbol 12-myristate 13-acetate (PMA)-induced transcriptional activity of NF-κB, but not that of AP-1. In accord with the luciferase activity data, western blot analysis showed that PA inhibited NF-κB signaling pathway, but did not alter the phosphorylation states of mitogen-activated protein kinases including ERK, JNK, and p38 kinase. The inhibition of PA on NF-κB signaling pathway was further attributed to PA-mediated diminution in PMA-induced degradation of inhibitor of kappaBα (IκBα) through preventing phosphorylation of the upstream signal IκB kinase (IKK). A decrease in p65 nuclear translocation was achieved, which led to attenuation of NF-κB transactivation. Taken together, it was concluded that by targeting NF-κB signaling, PA inhibited breast cancer cell invasion through decreasing MMP-9 expression. PA may thus be potentially exploited for use in tumor metastasis intervention.

Development of a Probiotics Practice E-Reference Database for Health Care Professionals.

PURPOSE: Currently available references provide evidence on the efficacy of probiotics strains but exclude product-specific information, making it challenging for health care professionals (HCPs) to provide consumers with suitable recommendations on probiotics. An online probiotics e-reference database was developed to assist HCPs in delivering evidence-based recommendations on probiotics to consumers. The usability and applicability of the database in health care practice were evaluated. METHODS: Information on the efficacy of probiotics and probiotic products was collated using a PubMed literature search, and from local pharmacies and online supplement stores. A web database was compiled using various programming scripts and uploaded onto a web server. The database was beta-tested using an online self-administered questionnaire for community-based pharmacists, and responses were analyzed using descriptive statistics. FINDINGS: The database comprised 584 clinical study excerpts, 449 probiotic products, and 1879 unique product-study links. Users can search for suitable probiotics based on their indication profile or for a specific probiotic product. Information provided includes the probiotic constituents, dosage regimen, and indications of the product, with supporting clinical evidence. Overall, all participants of the beta-test indicated that they were satisfied with the database and were willing to use it again (both, 13 participants [100%]). In addition, all participants indicated that they found the database intuitive to use and smooth functioning, without inconsistencies (both, 13 [100%]). The majority also indicated that they found the information provided to be clear, comprehensive, and useful in health care practice (12 [92.3%] each). IMPLICATIONS: The probiotics e-reference database is an integrated resource that is user-friendly, and provides HCPs with ready access to clear and comprehensive information on probiotic products and clinical studies, so that HCPs can provide consumers with relevant and evidence-based recommendations on probiotics.

Thioredoxin reductase inhibition by antitumor quinols: a quinol pharmacophore effect correlating to antiproliferative activity.

Novel heteroaromatic-substituted 4-hydroxycyclohexa-2,5-dienones (quinols) demonstrate potent in vitro antiproliferative activity and in vivo antitumor activity in tumor xenografts. The mechanism of action of these promising novel anticancer agents, however, remains to be fully elucidated. The thioredoxin (Trx) system comprising Trx, thioredoxin reductase (TrxR), and NADPH participates in a broad range of cellular functions involved in cell survival and proliferation. Accumulating evidence has indicated that the selenocysteine-containing mammalian TrxR is a valid molecular target for development of novel cancer therapeutics. In this study, we demonstrate that structural analogs containing a quinol pharmacophore inhibited TrxR with potencies correlated with their antiproliferative and cytotoxic efficacies. Benzenesulfonyl-6F-indole-substituted quinol (compound 6) irreversibly inhibited TrxR most strongly with a half-maximal inhibitory concentration of 2.7 microM after 1 h of incubation with recombinant rat TrxR. The inhibition was shown to be concentration-, time-, and NADPH-dependent and mediated through a direct quinol attack on the penultimate C-terminal selenocysteine residue. Moreover, TrxR activity in lysates of HCT 116 cells treated with apoptosis-inducing doses of quinols was significantly reduced. From the results obtained, we propose that TrxR inhibition is a critical cellular event that contributes to the proapoptotic effects of quinols.

A systematic review of the association of obesity with the outcomes of inflammatory rheumatic diseases.

This was a systematic review of the literature on the association between obesity and the outcome of inflammatory rheumatic diseases. We conducted a literature search using PubMed®, Embase and PsycINFO®. Articles were classified into three categories based on the effects of obesity on the outcomes of inflammatory rheumatic diseases. The subject population, country, type of studies, number of patients, measurement of obesity and outcomes assessed were presented. Quality was appraised using Kmet et al's criteria. 4,331 articles were screened and 60 were relevant to the objective. Obesity had a negative, positive and neutral association with outcomes of inflammatory rheumatic diseases in 38 (63.3%) studies with 57,612 subjects, 11 (18.3%) studies with 3,866 subjects, and 11 (18.3%) studies with 3,834 subjects, respectively. In most studies, the disease population had been diagnosed with rheumatoid arthritis (RA). Tumour necrosis factor-α inhibitors were mostly associated with negative outcomes. More studies examining subjects outside Europe and North America and diseases other than RA are warranted.

A systematic review of the factors associated with the initiation of biologicals in patients with rheumatological conditions.

OBJECTIVES: Biologicals play a crucial role in managing some of the rheumatological diseases, thus it is important for clinicians, healthcare institutions and policy-makers to understand why biologicals are initiated or refused so as to make better decisions to improve patients' disease outcomes. Although there have been many studies investigating factors associated with the initiation of biologicals for patients with rheumatological conditions, there have been no systematic reviews that provide a comprehensive summary. We aim to provide a summary of factors associated with biologicals' initiation for patients with rheumatological conditions. METHODS: We performed a literature search in PubMed, Embase and PsycINFO. We identified and screened studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Factors were presented according to patient, disease-related, therapy-related, healthcare team-related and system in-place factors. RESULTS: A total 1755 articles were reviewed and 24 articles were found to be relevant to our objective. Forty four factors reviewed were placed into five main categories: patient factors (n=13); disease-related factors (n=11); therapy-related factors (n=7); healthcare team-related factors (n=4) and system in-place-related factors (n=9). The factors studied by the published papers found to be associated with decisions to initiate biologicals varied widely. CONCLUSION: Forty two factors of five different categories were found to be associated with biologicals' initiation for patients with rheumatological conditions. Clinicians need to be mindful of the complex nature of these factors to optimise therapy of patients with rheumatological conditions. Healthcare institutions and policy- makers ought to be aware of any potential barriers to successful biologicals' treatment and address them accordingly.

Validity and reliability of the Assessment of Spondyloarthritis International Society Health Index in English-speaking patients with axial spondyloarthritis in Singapore.

OBJECTIVES: To assess the validity and reliability of the Assessment of Spondyloarthritis International Society Health Index (ASAS HI) among patients with axial spondyloarthritis (axSpA) in Singapore. METHODS: We collected data from English-speaking patients with axSpA seen at a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2017 to 2018. Face validity of the English version of ASAS HI was assessed through cognitive debriefing interviews (CDIs). Structural validity was assessed with confirmatory factor analysis. Convergent construct validity was assessed with 12 a priori hypotheses about the magnitude and direction of correlations between the ASAS HI summary score and other patient-reported outcome measures. Internal consistency was assessed using Cronbach's alpha. Test-retest reliability was assessed by intraclass correlation coefficient (ICC). Measurement error was assessed by analyzing smallest detectable change (SDC). RESULTS: Ten patients (age range 22-46 years, 50% male) participated in CDIs and face validity was supported. Among 108 patients (median age: 37 [21-77], 80.6% males), unidimensionality was confirmed (comparative fit index = 0.960, Tucker-Lewis Index = 0.952, root mean square error of approximation = 0.038, standardized root mean residuals = 0.068, model Chi-square test P = 0.1251) in the 17-item ASAS HI. The ASAS HI showed good internal consistency of 0.83 and excellent test-retest reliability (ICC = 0.95; 95% CI 0.91-0.98) when baseline was compared with week 2. SDC was 1.02. Convergent validity was supported as hypotheses were confirmed in 100% of the results. CONCLUSIONS: This study supports the ASAS HI as a valid and reliable measure of health status for use in patients with axSpA in Singapore.

Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells--evidence for cullin dimerization.

Cullin-based E3 ligases are a large family of ubiquitin ligases with diverse cellular functions. They are composed of one of six mammalian cullin homologues, the Ring finger containing protein Roc1/Rbx1 and cullin homologue-specific adapter and substrate recognition subunits. To be active, cullin-based ligases require the covalent modification of a conserved lysine residue in the cullin protein with the ubiquitin-like protein Nedd8. To characterize this family of E3 ligases in intact cells, we generated a cell line with tetracycline-inducible expression of a dominant-negative mutant of the Nedd8-conjugating enzyme Ubc12, a reported inhibitor of cullin neddylation. Using this cell line, we demonstrate that the substrate recognition subunit Skp2 and the adaptor protein Skp1 are subject to Ubc12-dependent autoubiquitination and degradation. In contrast, cullin protein stability is not regulated by neddylation in mammalian cells. We also provide evidence that Cul1 and Cul3, as well as their associated substrate recognition subunits Skp2 and Keap1, respectively, homooligomerize in intact cells, suggesting that cullin-based ligases are dimeric. Cul3, but not Cul1 homooligomerization is dependent on substrate recognition subunit dimer formation. As shown for other E3 ubiquitin ligases, dimerization may play a role in regulating the activity of cullin-based E3 ligases.

Novel dual-targeting anti-proliferative dihydrotriazine-chalcone derivatives display suppression of cancer cell invasion and inflammation by inhibiting the NF-κB signaling pathway.

Chalcones present in edible plants possess anti-cancer and anti-inflammatory properties, with the Michael acceptor moiety reported to be responsible for their biological activities. In this study, two novel dihydrotriazine-chalcone compounds previously identified to exert anti-proliferative effects through dual-targeting of dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR), were evaluated for their anti-invasive and anti-inflammatory abilities. At non-lethal concentrations, the compounds suppressed in vitro migration of MDA-MB-231 breast carcinoma cells, which was correlated with a dose-dependent downregulation of phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) expression and secretion. At similar concentrations, these chalcone-based compounds suppressed expression of inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated murine macrophage-like RAW 264.7 cells, as well as tumor necrosis factor alpha (TNF-α) in LPS-stimulated human monocytes isolated from healthy donors. Mechanistically, inhibition of cancer cell invasion and inflammation by the compounds were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway, which corroborated with the reported mechanism of action of chalcones. Their abilities to target multiple biological mediators relevant to multi-step carcinogenesis and with bioactivities stronger than those of the parent chalcone scaffold have warranted dihydrotriazine-chalcone compounds as promising candidates for use in pharmacological intervention of aggressive cancers.

Measurement properties of patient reported outcome measures for spondyloarthritis: A systematic review.

OBJECTIVES: This systematic review aimed to identify studies investigating measurement properties of patient reported outcome measures (PROMs) for spondyloarthritis (SpA), and to evaluate their methodological quality and level of evidence relating to the measurement properties of PROMs. METHODS: This systematic review was guided by the preferred reporting items for systematic review and meta-analysis (PRISMA). Articles published before 30 June 2017 were retrieved from PubMed®, Embase®, and PsychINFO® (Ovid). Methodological quality and level of evidence were evaluated according to recommendations from the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). RESULTS: We identified 60 unique PROMs from 125 studies in 39 countries. Twenty-one PROMs were validated for two or more SpA subtypes. The literature examined hypothesis testing (82.4%) most frequently followed by reliability (60.0%). A percentage of 77.7% and 42.7% of studies that assessed PROMs for hypothesis testing and reliability, respectively had "fair" or better methodological quality. Among the PROMs identified, 41.7% were studied in ankylosing spondylitis (AS) only and 23.3% were studied in psoriatic arthritis (PsA) only. The more extensively assessed PROMs included the ankylosing spondylitis quality of life (ASQoL) and bath ankylosing spondylitis functional index (BASFI) for ankylosing spondylitis, and the psoriatic arthritis quality of life questionnaire (VITACORA-19) for psoriatic arthritis. CONCLUSION: This study identified 60 unique PROMs through a systematic review and synthesized evidence of the measurement properties of the PROMs. There is a lack of validation of PROMs for use across SpA subtypes. Future studies may consider validating PROMs for use across different SpA subtypes.

Elucidation of thioredoxin as a molecular target for antitumor quinols.

Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI50 < 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G2-M cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (beta-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 micromol/L) or 2 (500 nmol/L and 1 micromol/L) determined that of > or =10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated >3-fold. Furthermore, quinols 1 and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC50 < 6 micromol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.