Connexins and Diabetes

Cell-to-cell interactions via gap junctional communication and connexon hemichannels are involved in the pathogenesis of diabetes. Gap junctions are highly specialized transmembrane structures that are formed by connexon hemichannels, which are further assembled from proteins called “connexins.” In this paper, we discuss current knowledge about connexins in diabetes. We also discuss mechanisms of connexin influence and the role of individual connexins in various tissues and how these are affected in diabetes. Connexins may be a future target by both genetic and pharmacological approaches to develop treatments for the treatment of diabetes and its complications

Population based time trends and socioeconomic variation in use of radiotherapy and radical surgery for prostate cancer in a UK region: continuous survey

Objective To examine variation in the management of prostate cancer in patients with different socioeconomic status

Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

Economic Abuse and Care-seeking Practices for HIV and Financial Support Services in Women Employed by Sex Work: A Cross-Sectional Baseline Assessment of a Clinical Trial Cohort in Uganda

Economic hardship is a driver of entry into sex work, which is associated with high HIV risk. Yet, little is known about economic abuse in women employed by sex work (WESW) and its relationship to uptake of HIV prevention and financial support services. This study used cross-sectional baseline data from a multisite, longitudinal clinical trial that tests the efficacy of adding economic empowerment to traditional HIV risk reduction education on HIV incidence in 542 WESW. Mixed effects logistic and linear regressions were used to examine associations in reported economic abuse by demographic characteristics, sexual behaviors, HIV care-seeking, and financial care-seeking. Mean age was 31.4 years. Most WESW were unmarried (74%) and had less than primary school education (64%). 48% had savings, and 72% had debt. 93% reported at least one economic abuse incident. Common incidents included being forced to ask for money (80%), having financial information kept from them (61%), and being forced to disclose how money was spent (56%). WESW also reported partners/relatives spending money needed for bills (45%), not paying bills (38%), threatening them to quit their job(s) (38%), and using physical violence when earning income (24%). Married/partnered WESW (OR = 2.68, 95% CI:1.60–4.48), those with debt (OR = 1.70, 95% CI:1.04–2.77), and those with sex-work bosses (OR = 1.90, 95% CI:1.07–3.38) had higher economic abuse. Condomless sex (β = +4.43, p < .05) was higher among WESW experiencing economic abuse, who also had lower odds of initiating PrEP (OR = .39, 95% CI:.17–.89). WESW experiencing economic abuse were also more likely to ask for cash among relatives (OR = 2.36, 95% CI:1.13–4.94) or banks (OR = 2.12, 95% CI:1.11–4.03). The high prevalence of HIV and economic abuse in WESW underscores the importance of integrating financial empowerment in HIV risk reduction interventions for WESW, including education about economic abuse and strategies to address it. Programs focusing on violence against women should also consider economic barriers to accessing HIV prevention services

Inbreeding depression across the lifespan in a wild mammal population

Inbreeding depression is of major concern for the conservation of threatened species, and inbreeding avoidance is thought to be a key driver in the evolution of mating systems. However, the estimation of individual inbreeding coefficients in natural populations has been challenging, and, consequently, the full effect of inbreeding on fitness remains unclear. Genomic inbreeding coefficients may resolve the long-standing paucity of data on inbreeding depression in adult traits and total fitness. Here we investigate inbreeding depression in a range of life history traits and fitness in a wild population of red deer (Cervus elaphus) in Scotland using individual inbreeding coefficients derived from dense Single-Nucleotide Polymorphism (SNP) data ([Formula: see text]). We find associations between [Formula: see text] and annual breeding success in both sexes, and between maternal inbreeding coefficient and offspring survival. We also confirm previous findings of inbreeding depression in birth weight and juvenile survival. In contrast, inbreeding coefficients calculated from a deep and comparatively complete pedigree detected inbreeding depression in juvenile survival, but not in any adult fitness component. The total effect of inbreeding on lifetime breeding success (LBS) was substantial in both sexes: for [Formula: see text] [Formula: see text] , a value resulting from a half-sib mating, LBS declined by 72% for females and 95% for males. Our results demonstrate that SNP-based estimates of inbreeding provide a powerful tool for evaluating inbreeding depression in natural populations, and suggest that, to date, the prevalence of inbreeding depression in adult traits may have been underestimated

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Trends and variation in the management of oesophagogastric cancer patients: a population-based survey

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates potential variation in the quality of care of cancer patients. We aimed to examine whether recent changes in the treatment of oesophagogastric cancers have been distributed equally among different patient subgroups.</p> <p>Methods</p> <p>We analysed population-based cancer registry data about the treatment patterning of oesophagogastric cancer (other than oesophageal squamous cell carcinoma) during 1995-2006.</p> <p>Results</p> <p>There were 14,077 patients aged ≥40 years (69% men). There was only limited information on stage, and no information on co-morbidity status. During successive triennia, curative surgery use decreased from 28% to 20% (p < 0.001) whilst chemotherapy use increased from 9% to 30% (p < 0.001). Use of palliative surgery and of radiotherapy increased significantly but modestly (7% to 10%, and 9% to 11%, respectively). In multivariable logistic regression adjusting for age group, gender, diagnosis period and tumour type, curative surgery and chemotherapy were used less frequently in more deprived patients [per increasing deprivation group Odds Ratio (OR) = 0.96, 95% Confidence Interval (CI) 0.93-0.99, and OR = 0.90, 95%CI 0.87-0.93, respectively, p < 0.001 for both)]. Chemotherapy was also used less frequently in women (OR = 0.76, p < 0.001).</p> <p>Conclusions</p> <p>During the study period, curative surgery decreased by a third and chemotherapy use increased by more than three-fold, reflecting improvements in the appropriateness and quality of management, but chemotherapy use, in particular, was unequal, both by socioeconomic status and gender.</p