Increased frequency of hospital admissions with active systemic lupus erythematosus disease activity defined by two different disease activity indices: A cohort study.

The objective of this cohort study was to evaluate the association between the frequency of hospital admissions and disease activity, as defined by two different disease activity measurements: the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), in adult patients with systemic lupus erythematosus (SLEs). Patients with SLE were recruited from the rheumatology outpatient department of a regional hospital in southern Taiwan. SLE-DAS and SLEDAI-2K were used to define SLE disease activity and the cause of hospital admissions was identified by a rheumatologist based on medical records. A generalized linear model (GLM) with gamma distribution and log-linked function was used to analyze variables associated with the frequency of admission. The mean frequency of hospitalization was 0.34 times per year for all-cause and 0.21 times per year for SLE-related admission. Multivariate GLM analysis showed that moderate/severe SLE disease activity defined by SLE-DAS was associated with an increased frequency of all-cause and SLE-related hospital admissions while adjusting for other covariates. Moderate/severe SLE disease activity defined by SLEDAI-2K was only significantly associated with an increased frequency of all-cause hospitalization. When steroid dosage was included in the model, moderate/severe SLE disease activity defined by the SLE-DAS remained significantly associated with SLE-related hospital admissions (p = 0.032). In conclusion, disease activity defined by the SLE-DAS, but not SLEDAI-2K was associated with an increased frequency of SLE-related hospitalization. Steroid dosage, a lower educational level, and smoking were associated with an increased frequency of hospital admissions, whereas underweight and alcohol use were associated with a decreased frequency of hospital admissions. Rheumatologists should promptly control SLE disease activity of their patients, provide them with adequate health education, and maintain steroid doses to as low as possible to reduce the risk of hospital admissions.

Increased risk of hospital admissions in patients with active systemic lupus erythematosus (SLE) classified according to two different SLE disease activity indices: a prospective cohort study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the risk of hospital admissions within one year in patients with active systemic lupus erythematosus (SLE), classified according to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) or the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). METHODS: This study was conducted in adult patients with SLE recruited from the rheumatology outpatient department in a regional hospital in southern Taiwan. SLE disease activity was measured with SLE-DAS and SLEDAI-2K. The computerised patient record database was accessed to identify patients' hospital admissions. Cox regression analyses were used to estimate the hazard ratio (HR) for all-cause and SLE-related hospital admission in SLE patients classified by SLE-DAS and SLEDAI-2K. RESULTS: A total of 326 adult patients with SLE completed this study. All-cause and SLE-related hospital admissions within one year occurred in 17.5% and 12.6% of the patients, respectively. Results of the Cox regression analysis indicated that SLE patients with moderate/severe disease activity classified by the SLE-DAS (HR=2.43, p=0.005) but not moderate/severe disease activity classified by the SLEDAI-2K (HR=1.84, p=0.057) was significantly associated with the risk of SLE-related admissions. However, only moderate/severe disease activity classified by the SLE-DAS was significantly associated with the risk of all-cause admissions (HR=1.94, p=0.016). When steroid dosage was considered, only the steroid dosage was significantly associated all-cause and SLE-related admissions. CONCLUSIONS: In this study, SLE disease activity classified by SLE-DAS was significantly associated with an increased risk for both all-cause and SLE-related hospital admissions. Rheumatologists should be vigilant for increased risk of hospital admissions in patients with moderate/high SLE disease activity as classified by SLE-DAS.

Increased dental visits in patients with rheumatoid arthritis: a secondary cohort analysis of population based claims data.

OBJECTIVE: To study the utilization of dental care in patients with rheumatoid arthritis (RA) and compare the incidence of common dental disorders in patients with and without RA. METHODS: This data used in this study was from the population-based Taiwan's National Health Insurance Research Database. We identified 1337 patients with newly diagnosed RA between January 2000 and December 2012. We also identified 13,370 individual without a diagnosis of RA using frequency matching on 5-year age intervals, sex, and index year. Patients with a diagnosis of primary Sjögren's syndrome were excluded. Dental disorders were identified using respective ICD-9-CM codes confirmed by dentists. The incidence and incidence rate ratio [IRR] of each dental disorders were calculated using Poisson regression. RESULTS: Compared with the comparison cohort, the prevalence of dentist visits in the RA cohort were significantly higher (70.3% vs. 66.7%, p = 0.008) and the frequency of dentist visits in the RA cohort were also significantly higher (median 2.67 vs. 1.78 per year, p < 0.001). In addition, the incidence of visits for dental caries (adjusted IRR 1.16, p < 0.001), pulpitis (adjusted IRR 1.12, p = 0.044), gingivitis (adjusted IRR 1.13, p = 0.027), periodontitis (adjusted IRR 1.13, p = 0.004), and oral ulcer (adjusted IRR 1.24, p = 0.003) were higher in patients with RA. CONCLUSIONS: An elevated prevalence and frequency of dental visits were associated with patients with RA. In addition, elevated incidence of dental disorders, including dental caries, pulpitis, gingivitis, periodontitis, and oral ulceration, were observed. Oral health should be accessed regularly in patients with RA.

Risk of Spine Surgery in Patients with Rheumatoid Arthritis: A Secondary Cohort Analysis of a Nationwide, Population-Based Health Claim Database.

Background and Objectives: To study the risk of spine surgery, including cervical and lumbar spine surgeries in patients with rheumatoid arthritis (RA) compared with those without a diagnosis of RA. Materials and Methods: This is a secondary data analysis using population-based health claim data. We identified newly diagnosed adult patients with RA between January 2000 and December 2012, according to the International Classification of Diseases, Ninth revision, clinical modification code 714.0 from Taiwan's National Health Insurance Research Database. Using data frequency-matched by 10-year age intervals, sex and index year with the RA cohort at a ratio of 5:1, we assembled a comparison cohort. All patients were followed until the study outcomes occurred (overall spine surgery, cervical spine surgery, or lumbar spine surgery) or the end of follow-up. Adjusted incidence rate ratios (aIRR) were calculated using Poisson regression analysis with age group, socioeconomic status, geographical region, and osteoporosis included as potential confounders. Results: We identified 1287 patients with RA and 6435 patients without RA. The incidence of overall spine surgery (aIRR = 2.13, 95% confidence interval (CI) = 1.49-3.04) and lumbar spine surgery (aIRR = 2.14, 95% CI = 1.46-3.15) were all significantly higher in the RA cohort. Moreover, females over 45 years of age were particularly at risk for lumbar spine surgery. In RA patients, older age and the combination with the diagnosis of osteoporosis had an elevated risk for overall and lumbar spine surgery. Conclusion: Patients with RA had an increased risk of receiving spine surgery. Physicians should be vigilant for possible spinal problems in women and older patients with RA.

Increased Risk of Common Orthopedic Surgeries for Patients with Rheumatic Diseases in Taiwan.

Background and Objectives: Rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, and systemic lupus erythematosus (SLE), are characterized by chronic arthritis or spondyloarthritis, which can lead to joint and spine destruction. Our previous studies showed that the risk of common orthopedic surgeries, including total knee replacement (TKR), total hip replacement (THR), or spine surgery, was increased in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. The aim of this review was to summarize the risk of TKR, THR, cervical spine, and lumbar spine surgery on the basis of studies conducted using data from Taiwan's National Health Insurance Research Database (NHIRD). Materials and Methods: The risk of TKR, THR, cervical spine surgery, and lumbar spine surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE was summarized from the results of our previous studies and unpublished findings based on NHIRD data. Results: Patients with rheumatoid arthritis and psoriasis and men with ankylosing spondylitis showed an increased risk of TKR. Patients with rheumatoid arthritis, ankylosing spondylitis, and women with SLE showed an increased risk of receiving THR. Only patients with ankylosing spondylitis had an increased risk of cervical spine surgery, and patients with rheumatoid arthritis or ankylosing spondylitis showed an increased risk of lumbar spine surgery. Although the risk of THR, TKR, or spine surgery in these patients has declined in the era of biologics use, direct evidence for the effects of biologics agents is not yet available. Conclusions: There was an increased risk of common orthopedic surgery in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and SLE. Clinicians should be vigilant to reduce the increased risk of TKR and THR in young and middle-aged patients with rheumatoid arthritis, THR in young patients with ankylosing spondylitis, and young female patients with SLE, as well as cervical spine surgery in young patients with ankylosing spondylitis.

Association of Clinical Manifestations of Systemic Lupus Erythematosus and Complementary Therapy Use in Taiwanese Female Patients: A Cross-Sectional Study.

Background and Objectives: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects predominantly women in the childbearing years. Patients may seek complementary therapies to manage their health and to reduce symptoms. However, to our knowledge, no studies have explored the association between clinical manifestations of SLE and complementary therapies. Therefore, this study aimed to investigate the association of complementary therapies with common clinical manifestations in Taiwanese female patients with SLE. Materials and Methods: A cross-sectional study was conducted at a regional teaching hospital in southern Taiwan. Outpatients from the rheumatology clinic who met the inclusion criteria were consecutively recruited. Demographic data, clinical manifestations of SLE, and types of complementary therapy use were determined using paper-based questionnaire. Multiple logistic regression analyses were conducted to investigate the use of complementary therapies associated with clinical manifestations of SLE. Results: Of the 317 female patients with SLE, 60.9% were 40 years or older. The five SLE clinical manifestations with the highest prevalence were Raynaud's phenomenon (61.2%), photosensitivity (50.2%), Sjögren's syndrome (28.4%), arthralgia and arthritis (22.1%), and renal involvement (14.5%). Multiple logistic regression analyses revealed that Raynaud's phenomenon was significantly associated with fitness walking or strolling (adjusted odds ratio [aOR] 1.77; p = 0.027) and fish oil supplements (aOR 3.55, p < 0.001). Photosensitivity was significantly and inversely associated with the use of probiotics (aOR 0.49; p = 0.019). Renal involvement was significantly associated with the use of probiotics (aOR 2.43; p = 0.026) and visit to the Chinese medicine department in a hospital (aOR 3.14, p = 0.026). Conclusions: We found that different clinical manifestations of SLE were associated with the use of different complementary therapies. Health care providers should have up-to-date knowledge of common complementary therapies and be ready to provide evidence-based advice to patients with SLE.

Increased Serum Levels of Brain-Derived Neurotrophic Factor Contribute to Inflammatory Responses in Patients with Rheumatoid Arthritis.

The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF) in the inflammatory responses in patients with rheumatoid arthritis (RA). Serum levels of BDNF and the precursor form of BDNF (proBDNF) from 625 RA patients and 40 controls were analyzed using enzyme-linked immunosorbent assay. Effects of BDNF on the mitogen-activated protein kinase pathway were analyzed by Western blotting. Microarray analysis was conducted to search BDNF regulated gene expression in Jurkat cells, and the differentially expressed genes were validated using T cells from patients with RA and controls. Serum BDNF levels were significantly elevated in patients with RA compared with the controls. Low serum BDNF levels were found in RA patients with anxiety or receiving biologics treatment. BDNF (20 ng/mL) enhanced the phosphorylation of ERK, JNK, and c-Jun, but suppressed the phosphorylation of p38, whereas BDNF (200 ng/mL) enhanced the phosphorylation of ERK and p38. After validation, the expression of CAMK2A, MASP2, GNG13, and MUC5AC, regulated by BDNF and one of its receptors, NGFR, was increased in RA T cells. BDNF increased the IL-2, IL-17, and IFN-γ expression in Jurkat cells and IL-2 and IFN-γ secretion in activated peripheral blood mononuclear cells.

Risks of ophthalmic disorders in patients with systemic lupus erythematosus - a secondary cohort analysis of population-based claims data.

BACKGROUND: Systemic lupus erythematosus (SLE) can directly affect various part of the ocular system, but there was no comprehensive analysis of ophthalmic disorders of patients with SLE using population-based data. The aim of this study was to investigate the frequency and prevalence of ophthalmic disorders for ophthalmologist visits in adult patients with SLE and to evaluate the risk of dry eye syndrome, cataracts, glaucoma, episcleritis and scleritis, and retinal vascular occlusion in these patients. METHODS: The Taiwan's National Health Insurance Research Database was used to assemble a SLE cohort consisting of newly diagnosed SLE between 2000 and 2012. A comparison cohort was also sampled from the same database and it consisted of 10 patients without SLE for each patient with SLE, based on frequency matching for sex, five-year age interval, and index year. Both cohorts were followed until either the study outcomes have occurred or the end of the follow-up period. RESULTS: Patients with SLE (n = 521) exhibited a significantly higher prevalence (68.1% vs. 60.5%, P = 0.001) and frequency (median 5.51 vs. 1.71 per 10 years, P <  0.001) for outpatient ophthalmologist visits compared with patients without SLE. The risk of dry eye syndrome (adjusted incidence rate ratio [IRR] 4.45, P <  0.001), cataracts (adjusted IRR 3.18, P <  0.001), and glaucoma (adjusted IRR 2.23, P = 0.002) were significantly higher in patients with SLE. In addition, the risk of several SLE related ophthalmic disorders, including episcleritis and scleritis (adjusted IRR 6.11, P <  0.001) and retinal vascular occlusion (adjusted IRR 3.81, P = 0.023) were significantly higher in patients with SLE. CONCLUSIONS: The increased risk of dry eye syndrome, cataracts, glaucoma, episcleritis and scleritis, and retinal vascular occlusion in patients with SLE deserves vigilance.

Predicting the Risk of Ischemic Stroke among Patients with Rheumatoid Arthritis Using a Simplified RA-CHADSV Score Based on the CHA2DS2-VASc Score.

BACKGROUND AND OBJECTIVES: The aim of this retrospective cohort study was to develop a new score (RA-CHADSV) (rheumatoid arthritis - congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack/thromboembolism, and vascular disease), modified from the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, stroke/transient ischemic attack (doubled), vascular disease, age 65-74 years, and female), in predicting the risk of ischemic stroke in rheumatoid arthritis (RA) patients without atrial fibrillation (AF). MATERIALS AND METHODS: Using the Taiwan's National Health Insurance Research Database, 592 patients with RA diagnosed between 2000 and 2002 were identified and followed until first occurrence of ischemic stroke or the last available date in the database. Incidence rate ratios (IRR) of ischemic stroke for the CHA2DS2-VASc score were calculated using Poisson regression models. A new prediction score RA-CHADSV was developed using multiple logistic regression analysis with bootstrap validation. RESULTS: The area under the receiver operating characteristic curve of the newly developed RA-CHADSV score and the CHA2DS2-VASc score were 0.73 (95% confidence interval (CI) 0.64-0.82) and 0.70 (95% CI 0.61-0.79), respectively. The RA-CHADSV score was significantly associated with a higher ischemic stroke incidence in the patients who scored ≥1 (adjusted IRR 7.39, p < 0.001). CONCLUSIONS: A simplified RA-CHADSV score, with comparable efficiency as the CHA2DS2-VASc score, but easier to use clinically was developed for predicting the risk of ischemic stroke among non-AF RA patients.

Modestly Elevated Serum Procalcitonin Levels in Patients with Rheumatoid Arthritis Free of Active Infection.

Background and objectives: To investigate the serum procalcitonin (PCT) levels among patients with rheumatoid arthritis (RA) without active infection compared with healthy controls and to understand the relationship of PCT with RA disease activity, and treatment received by patients. Materials and Methods: Patients aged 20 years and above with clinician-confirmed diagnosis of RA and healthy volunteers were included during regular outpatient visits, and those with active infection symptoms and signs were excluded. RA disease activity was measured using the Disease Activity Score-28 for Rheumatoid Arthritis with erythrocyte sedimentation rate (DAS28-ESR). Medications received by the patients were also recorded. Results: A total of 623 patients with RA and 87 healthy subjects were recruited in this study. The mean PCT were significantly higher in patients with RA (6.90 ± 11.81 × 10-3 ng/mL) compared with healthy controls (1.70 ± 6.12 × 10-3 ng/mL) (p < 0.001) and the difference remained statistically significant after adjusting for age and sex. In addition, multiple linear regression analysis showed that a lower rank-transformed PCT serum level was significantly correlated with the use of biologics (p = 0.017) and a high DAS28-ESR score (p = 0.028) in patients with RA. Conclusion: Patients with RA have a significantly higher serum PCT levels compared with healthy controls. The use of biologics and an active RA disease activity were associated with a lower level of PCT in patients with RA. Further investigation is required to determine the optimal cutoff value of PCT among patients with RA and its association with disease activity and biologic usage.

Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.

Risk of joint replacement surgery in Taiwanese female adults with systemic lupus erythematosus: a population-based cohort study.

BACKGROUND: Female patients with systemic lupus erythematosus (SLE) are prone to have musculoskeletal system involvement, which could lead to joint damage. However, few studies have assessed the incidence of arthroplasty in female patients with SLE. The aim of this study was to investigate the risk of total hip replacement surgery and total knee replacement surgery in patients with SLE. METHODS: We identified 577 female patients with newly diagnosed SLE between 2000 and 2012 using the Taiwan's National Health Insurance Research Database. A comparison cohort was constructed with female patients without SLE in a ratio of 5:1, based on frequency matching for 10-year age interval, and index year, for each patient with SLE. Both cohorts were followed until a diagnosis of the study outcomes or the end of the follow-up period. RESULTS: Female patients with SLE showed a significantly higher incidence of receiving total hip replacement surgery (adjusted incidence rate ratio [aIRR] 6.47; P < 0.001), but not total knee replacement surgery (aIRR 1.81; P = 0.227). Moreover, age-group stratified analyses indicated a high incidence for receiving total hip replacement surgery among young female patients with SLE (aIRR 7.70; P = 0.001). CONCLUSION: Young female patients with SLE had a high risk of receiving total hip replacement surgery, but not total knee replacement surgery.

Construction and application of (Q)SAR models to predict chemical-induced in vitro chromosome aberrations.

In drug development, genetic toxicology studies are conducted using in vitro and in vivo assays to identify potential mutagenic and clastogenic effects, as outlined in the International Council for Harmonisation (ICH) S2 regulatory guideline. (Quantitative) structure-activity relationship ((Q)SAR) models that predict assay outcomes can be used as an early screen to prioritize pharmaceutical candidates, or later during product development to evaluate safety when experimental data are unavailable or inconclusive. In the current study, two commercial QSAR platforms were used to build models for in vitro chromosomal aberrations in Chinese hamster lung (CHL) and Chinese hamster ovary (CHO) cells. Cross-validated CHL model predictive performance showed sensitivity of 80 and 82%, and negative predictivity of 75 and 76% based on 875 training set compounds. For CHO, sensitivity of 61 and 67% and negative predictivity of 68 and 74% was achieved based on 817 training set compounds. The predictive performance of structural alerts in a commercial expert rule-based SAR software was also investigated and showed positive predictivity of 48-100% for selected alerts. Case studies examining incorrectly-predicted compounds, non-DNA-reactive clastogens, and recently-approved pharmaceuticals are presented, exploring how an investigational approach using similarity searching and expert knowledge can improve upon individual (Q)SAR predictions of the clastogenicity of drugs.

In silico toxicology protocols.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

Ratiometric Imaging Using a Single Dye Enables Simultaneous Visualization of Rac1 and Cdc42 Activation.

Biosensors that report endogenous protein activity in vivo can be based on environment-sensing fluorescent dyes. The dyes can be attached to reagents that bind selectively to a specific conformation of the targeted protein, such that binding leads to a fluorescence change. Dyes that are sufficiently bright for use at low, nonperturbing intracellular concentrations typically undergo changes in intensity rather than the shifts in excitation or emission maxima that would enable precise quantitation through ratiometric imaging. We report here mero199, an environment-sensing dye that undergoes a 33 nm solvent-dependent shift in excitation. The dye was used to generate a ratiometric biosensor of Cdc42 (CRIB199) without the need for additional fluorophores. CRIB199 was used in the same cell with a FRET sensor of Rac1 activation to simultaneously observe Cdc42 and Rac1 activity in cellular protrusions, indicating that Rac1 but not Cdc42 activity was reduced during tail retraction, and specific protrusions had reduced Cdc42 activity. A novel program (EdgeProps) used to correlate localized activation with cell edge dynamics indicated that Rac1 was specifically reduced during retraction.

Differential modulation of FXR activity by chlorophacinone and ivermectin analogs.

Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis.

One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Sexual dysfunction in women with primary Sjögren's syndrome: a systematic review and meta-analysis.

INTRODUCTION: Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune condition affecting the exocrine glands, which can adversely affect the sexual activities of women with pSS. OBJECTIVES: The study sought to evaluate the performance of the Female Sexual Function Index (FSFI) score in women with pSS regarding desire, arousal, orgasm, lubrication, satisfaction, and pain compared with those of healthy individuals. METHODS: A systematic review was conducted by examining studies published up to May 2023 using Embase, Web of Science, Scopus, and PubMed with the search terms "sexual" and "Sjögren's syndrome." RESULTS: Out of the 228 articles retrieved, 9 met the criteria for inclusion in this systematic review. Six of these studies were cross-sectional, involving 229 women with pSS and 303 control subjects. Results from the meta-analysis showed that women with pSS had significantly lower scores in all 6 FSFI subdomains and the total FSFI score compared with healthy individuals. Lubrication showed the largest decrease, followed by pain. In addition, women with pSS exhibited significantly higher standardized mean differences in depression and in anxiety, as assessed by the Hospital Anxiety and Depression Scale, when compared with control subjects. CONCLUSION: This updated meta-analysis underscores the importance of assessing genitourinary atrophy, disease-related psychological changes, and dyspareunia in women with pSS. It also emphasizes the need for customized therapeutic approaches to address these sexual dysfunctions effectively.

Live-cell biosensors based on the fluorescence lifetime of environment-sensing dyes.

In this work, we examine the use of environment-sensitive fluorescent dyes in fluorescence lifetime imaging microscopy (FLIM) biosensors. We screened merocyanine dyes to find an optimal combination of environment-induced lifetime changes, photostability, and brightness at wavelengths suitable for live-cell imaging. FLIM was used to monitor a biosensor reporting conformational changes of endogenous Cdc42 in living cells. The ability to quantify activity using phasor analysis of a single fluorophore (e.g., rather than ratio imaging) eliminated potential artifacts. We leveraged these properties to determine specific concentrations of activated Cdc42 across the cell.