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[...]consideration of the value-laden nature of policy interventions and the creation of forums to debate the moral and ethical dimensions of different approaches to urban health and city environments are essential. [...]attention to health inequalities within urban areas should be a key focus of planning the urban environment.

In an attempt to overcome resistance to immune checkpoint inhibitors (ICI), an ever-increasing number of trials are exploring combination treatment approaches. Outcomes of a novel ICI doublet presented by Desai and colleagues are discussed along with emerging novel strategies and a view to future ongoing rational trial design maximising patient benefit.

Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.

Few studies have examined the associations between sleep duration, shiftwork, and exercise to the infrequent menstruation, hyperandrogenism, and ovarian morphological changes observed in women with polycystic ovarian syndrome (PCOS). To examine whether lifestyle factors, including short sleep duration, insufficient exercise, and shiftwork, alone or in combination, are associated with the reproductive and metabolic abnormalities typical of PCOS in a healthy population. Prospective cross-sectional study of 231 women, including healthcare workers recruited for an annual health screen, healthy referral patients from the Women's Clinic and volunteers from the university community at the National University Hospital, Singapore, from 2011 to 2015. The women completed a questionnaire, including their menstrual cycle length, sleep length, frequency of exercise and shift work. Hyperandrogenism (hirsutism score, testosterone, sex hormone binding globulin (SHBG)), ovarian morphology and function (anthral follicle count, ovarian volume, anti-mullerian hormone (AMH)), and metabolic measures (body mass index (BMI), waist hip ratio (WHR), blood pressure, fasting glucose, fasting insulin and fasting lipids) were examined through anthropometric measurements, transvaginal ultrasound scans, and blood tests. No significant associations were observed between shift work, exercise or sleep duration and the androgenic and ovarian measures that define PCOS. However, women reporting fewer than 6 hours of sleep were more likely to report abnormal (short or long) menstrual cycle lengths (OR = 2.1; 95% CI, 1.1 to 4.2). Women who reported fewer than 6 hours of sleep had increased fasting insulin levels (difference in means = 2.13; 95% CI, 0.27 to 3.99 mU/L) and higher odds of insulin resistance (OR = 2.58; CI, 1.16 to 5.76). Lack of regular exercise was associated with higher mean fasting insulin (difference in means = 2.3 mU/L; 95% CI, 0.5 to 4.1) and HOMA-IR (difference in means = 0.49; 95% CI, 0.09 to 0.90) levels. Women with insufficient sleep are at increased risk of menstrual disturbances and insulin resistance, but do not have the hyperandrogenism and polycystic ovarian morphology typical of PCOS. Improved sleep duration may help reduce the risks of diabetes or infertility. Shift work, exercise or sleep duration appear not to impact the androgenic and ovarian measures that define PCOS.

SummaryThe incidence of atypical femoral fractures (AFFs) was 2.95% among 6644 hip and femoral fractures. Independent risk factors included the use of bisphosphonates (BPs), osteopenia or osteoporosis, rheumatoid arthritis, increased femoral curvatures, and thicker femoral cortices. Patients with AFFs and BP treatment were more likely to have problematic healing than those with typical femoral fractures (TFFs) and no BP treatment.IntroductionTo determine the incidence and risk factors of atypical femoral fractures (AFFs), we performed a multicenter case-control study. We also investigated the effects of bisphosphonates (BPs) on AFF healing.MethodsWe retrospectively reviewed the medical records and radiographs of 6644 hip and femoral fractures of patients from eight tertiary referral hospitals. All the radiographs were reviewed to distinguish AFFs from TFFs. Univariate and multivariate logistic regression analyses were performed to identify risk factors, and interaction analyses were used to investigate the effects of BPs on fracture healing.ResultsThe incidence of AFFs among 6644 hip and femoral fractures was 2.95% (90 subtrochanter and 106 femoral shaft fractures). All patients were females with a mean age of 72 years, and 75.5% were exposed to BPs for an average duration of 5.2 years (range, 1–17 years). The use of BPs was significantly associated with AFFs (p < 0.001, odds ratio = 25.65; 95% confidence interval = 10.74–61.28). Other independent risk factors for AFFs included osteopenia or osteoporosis, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex at the shaft level. Interaction analyses showed that patients with AFFs using BPs had a significantly higher risk of problematic fracture healing than those with TFFs and no BP treatment.ConclusionsThe incidence of AFFs among 6644 hip and femoral fractures was 2.95%. Osteopenia or osteoporosis, use of BPs, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex were independent risk factors for the development of AFFs. Patients with AFFs and BP treatment were more likely to have problematic fracture healing than those with TFFs and no BP treatment.

Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35 ) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU. Fenebrutinib, an oral Bruton’s tyrosine kinase inhibitor, reduces disease activity in patients with chronic spontaneous urticaria refractory to antihistamines, suggesting that this treatment type could be an alternative to standard of care anti-IgE therapy.

Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform to achieve direct and multiplexed profiling of circulating RNAs in extracellular vesicles for blood-based GBM characterization. The technology, termed ‘enzyme ZIF-8 complexes for regenerative and catalytic digital detection of RNA’ (EZ-READ), leverages an RNA-responsive transducer to regeneratively convert and catalytically enhance signals from rare RNA targets. Each transducer comprises hybrid complexes – protein enzymes encapsulated within metal organic frameworks – to configure strong catalytic activity and robust protection. Upon target RNA hybridization, the transducer activates directly to liberate catalytic complexes, in a target-recyclable manner; when partitioned within a microfluidic device, these complexes can individually catalyze strong chemifluorescence reactions for digital RNA quantification. The EZ-READ platform thus enables programmable and reliable RNA detection, across different-sized RNA subtypes (miRNA and mRNA), directly in sample lysates. When clinically evaluated, the EZ-READ platform established composite signatures for accurate blood-based GBM diagnosis and subtyping. Current methods to subtype brain tumors rely on invasive biopsies. Here, the authors develop a digital platform to regeneratively convert and catalytically enhance signals from rare circulating RNAs for blood-based characterization of brain tumors.