A mitotic SKAP isoform regulates spindle positioning at astral microtubule plus ends

The Astrin/SKAP complex plays important roles in mitotic chromosome alignment and centrosome integrity, but previous work found conflicting results for SKAP function. Here, we demonstrate that SKAP is expressed as two distinct isoforms in mammals: a longer, testis-specific isoform that was used for the previous studies in mitotic cells and a novel, shorter mitotic isoform. Unlike the long isoform, short SKAP rescues SKAP depletion in mitosis and displays robust microtubule plus-end tracking, including localization to astral microtubules. Eliminating SKAP microtubule binding results in severe chromosome segregation defects. In contrast, SKAP mutants specifically defective for plus-end tracking facilitate proper chromosome segregation but display spindle positioning defects. Cells lacking SKAP plus-end tracking have reduced Clasp1 localization at microtubule plus ends and display increased lateral microtubule contacts with the cell cortex, which we propose results in unbalanced dynein-dependent cortical pulling forces. Our work reveals an unappreciated role for the Astrin/SKAP complex as an astral microtubule mediator of mitotic spindle positioning.Leukemia & Lymphoma Society of America (Scholar Award)National Institute of General Medical Sciences (U.S.) (GM088313)American Cancer Society (121776

Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

BACKGROUND: Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. METHODS: IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) α, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. RESULTS: IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11Rα immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11Rα localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells from cycling and postmenopausal women. SOCS3 staining intensity did not differ between between each tumour and postmenopausal endometrial epithelium but SOCS3 in cycling endometrium was significantly higher compared to postmonopausal and Tumour Grades 2 and 3. IL11 increased pSTAT3/STAT3 in all tumour cell lines, while SOCS3 abundance was increased only in one tumour cell line. CONCLUSIONS: The present study suggests that IL11 in uterine washings may be useful as a diagnostic marker for early stage endometrial cancer. It indicates that IL11, along with its specific receptor, IL11Rα, and downstream signalling molecules, STAT3 and SOCS3, are likely to play a role in the progression of endometrial carcinoma. The precise role of IL11 in endometrial cancer remains to be elucidated

Scaling up screening and treatment for elimination of hepatitis C among men who have sex with men in the era of HIV pre-exposure prophylaxis.

BACKGROUND: Routine HIV pre-exposure prophylaxis (PrEP) and HIV care appointments provide opportunities for screening men who have sex with men (MSM) for hepatitis C virus infection (HCV). However, levels of screening required for achieving the WHO elimination target of reducing HCV incidence by 90% by 2030 among all MSM are unknown. METHODS: An HCV/HIV transmission model was calibrated to UK prevalence of HIV among MSM (4·7%) and chronic HCV infection among HIV-positive MSM (9·9%) and HIV-negative MSM (1.2%). Assuming 12·5% coverage of PrEP among HIV-negative MSM, we evaluated the relative reduction in overall HCV incidence by 2030 (compared to 2018 levels) of HCV screening every 12/6-months (alongside completing direct acting antiviral treatment within 6-months of diagnosis) in PrEP users and/or HIV-diagnosed MSM. We estimated the additional screening required among HIV-negative non-PrEP users to reduce overall incidence by 90% by 2030. The effect of 50% reduction in condom use among PrEP users (risk compensation) was estimated. RESULTS: Screening and treating PrEP users for HCV every 12 or 6-months decreases HCV incidence by 67·3% (uncertainty range 52·7-79·2%) or 70·2% (57·1-80·8%), respectively, increasing to 75·4% (59·0-88·6%) or 78·8% (63·9-90·4%) if HIV-diagnosed MSM are also screened at same frequencies. Risk compensation reduces these latter projections by <10%. To reduce HCV incidence by 90% by 2030 without risk compensation, HIV-negative non-PrEP users require screening every 5·6 (3·8-9·2) years if MSM on PrEP and HIV-diagnosed MSM are screened every 6-months, shortening to 4·4 (3·1-6·6) years with risk compensation. For 25·0% PrEP coverage, the HCV elimination target can be reached without screening HIV-negative MSM not on PrEP, irrespective of risk compensation. INTERPRETATION: At low PrEP coverage, increased screening of all MSM is required to achieve the WHO HCV-elimination targets for MSM in the UK, whereas at higher PrEP coverage this is possible through just screening HIV-diagnosed MSM and PrEP users

Achievement of combined goals of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol with three different statins: Results from VOYAGER

AbstractBackgroundGuidelines suggest that the combination of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) is the most clinically relevant goal for lipid-lowering treatments.MethodsData from VOYAGER, an individual patient data meta-analysis including 32,258 patients from 37 clinical trials, was used to determine the percentage of patients reaching combined goals of LDL-C and non-HDL-C following treatment with simvastatin, atorvastatin, or rosuvastatin. Paired comparisons were made between each dose of rosuvastatin and the same or higher doses of simvastatin and atorvastatin.ResultsEach dose of rosuvastatin brought significantly more patients to the combined goal of LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL than the same or double dose of atorvastatin; atorvastatin 80 mg was significantly superior to rosuvastatin 10 mg (all p < 0.001). Each dose of rosuvastatin helped significantly more patients reach the combined goal than any dose of simvastatin (all p < 0.001), except for rosuvastatin 10 mg versus simvastatin 80 mg (non-significant). Also, each dose of rosuvastatin helped significantly more patients to reach the combined goal of LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL than the same or double dose of atorvastatin (all p < 0.001). Every dose of rosuvastatin was significantly superior to all doses of simvastatin (all p ≤ 0.020), except for rosuvastatin 10 mg versus simvastatin 40 mg and 80 mg (non-significant).ConclusionsPhysicians' choice of statin and dose is important in helping patients achieve the combined LDL-C and non-HDL-C goals recommended in established guidelines

Expression of nodal signalling components in cycling human endometrium and in endometrial cancer

<p>Abstract</p> <p>Background</p> <p>The human endometrium is unique in its capacity to remodel constantly throughout adult reproductive life. Although the processes of tissue damage and breakdown in the endometrium have been well studied, little is known of how endometrial regeneration is achieved after menstruation. Nodal, a member of the transforming growth factor-beta superfamily, regulates the processes of pattern formation and differentiation that occur during early embryo development.</p> <p>Methods</p> <p>In this study, the expression of Nodal, Cripto (co-receptor) and Lefty A (antagonist) was examined by RT-PCR and immunohistochemistry across the menstrual cycle and in endometrial carcinomas.</p> <p>Results</p> <p>Nodal and Cripto were found to be expressed at high levels in both stromal and epithelial cells during the proliferative phase of the menstrual cycle. Although immunoreactivity for both proteins in surface and glandular epithelium was maintained at relatively steady-state levels across the cycle, their expression was significantly decreased within the stromal compartment by the mid-secretory phase. Lefty expression, as has previously been reported, was primarily restricted to glandular epithelium and surrounding stroma during the late secretory and menstrual phases. In line with recent studies that have shown that Nodal pathway activity is upregulated in many human cancers, we found that Nodal and Cripto immunoreactivity increased dramatically in the transition from histologic Grade 1 to histologic Grades 2 and 3 endometrial carcinomas. Strikingly, Lefty expression was low or absent in all cancer tissues.</p> <p>Conclusion</p> <p>The expression of Nodal in normal and malignant endometrial cells that lack Lefty strongly supports an important role for this embryonic morphogen in the tissue remodelling events that occur across the menstrual cycle and in tumourogenesis.</p

The relationship between obstructive sleep apnoea and quality of life in women with polycystic ovary syndrome: a cross-sectional study

Background: Obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS) are associated with significant comorbidities and commonly coexist. The primary aim of this study was to examine the relationship between OSA and quality of life (QoL) in women with PCOS. Methods: We conducted an observational cross-sectional study. PCOS was diagnosed according to the Rotterdam criteria. Women with increased risk of OSA, based on the Berlin questionnaire or the Epworth Sleepiness Scale (ESS), had home-based polysomnography performed (ALICE PDx). Participants were divided into two groups: (a) PCOS only: women with normal ESS and low-risk Berlin questionnaire (no sleep studies performed), or women with normal sleep studies [oxygen desaturation index (ODI) < 5 events/hour]; and (b) PCOS+OSA: women with PCOS and OSA ODI ⩾ 5. QoL was assessed using the World Health Organization QoL questionnaire (WHOQOL-BREF) and the PCOS health-related quality of life questionnaire (PCOSQ). Results: A total of 39 women were included; age (mean ± SD) was 32.2 ± 8.9 years, weight 92.5 ± 23.7 kg and body mass index (BMI) 34.1 ± 7.9 kg/m 2; 38.5% (n = 15) had OSA. Compared with women with PCOS only, women with PCOS+OSA had higher BMI, HbA1c, C-reactive protein and low-density lipoprotein. ODI was independently associated with impaired QoL. Excessive daytime sleepiness (EDS) was independently associated with anxiety, depression and impaired QoL. Conclusions: OSA is highly prevalent and is associated with impaired QoL and worse metabolic profile in women with PCOS. Interventional studies are needed to examine the impact of OSA in women with PCOS. ClinicalTrials.gov Identifier: NCT03065322

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers

The cost-effectiveness of case-finding strategies for achieving hepatitis C elimination among men who have sex with men in the UK.

Modelling suggests hepatitis C virus (HCV) elimination is possible among men who have sex with men (MSM), with key screening groups including HIV-diagnosed MSM and MSM using pre-exposure prophylaxis (PrEP). Mathematical modelling was used to determine the cost-effectiveness of HCV case-finding strategies among MSM from the provider perspective, and to determine which interventions could achieve a 90% reduction in HCV incidence over 2015-2030. At baseline, we assumed symptomatic screening in HIV-negative MSM (including PrEP users) and 12-monthly screening among HIV-diagnosed MSM. Improved case-finding strategies included screening alongside HIV testing in HIV-negative MSM not using PrEP (PrEP non-users); 12/6/3-monthly screening in PrEP users; and 6-monthly screening in HIV-diagnosed MSM, with the cost-effectiveness being compared incrementally. Costs (GBP) and quality-adjusted life years (QALYs) were assessed to estimate the mean incremental cost-effectiveness ratio (ICER) with a time horizon to 2050, compared to a willingness-to-pay threshold of £20,000/QALY. From the baseline, the most incrementally cost-effective strategy is to firstly undertake: (1) 12-monthly HCV screening of PrEP users (gaining 6715 QALYs with ICER £1760/QALY), followed by (2) HCV screening among PrEP non-users alongside HIV testing (gaining 7048 QALYs with ICER £4972/QALY). Compared to the baseline, this combined strategy would cost £46.9 (95%CrI £25.3-£66.9) million and achieve the HCV elimination target in 100% of model runs. Additional screening incurs ICERs >£20,000/QALY compared to this combined strategy. In conclusion, HCV elimination can be achieved cost-effectively among UK MSM. Policymakers should consider scaling-up HCV screening in HIV-negative MSM, especially PrEP users, for achieving this target

Perceived health benefits and willingness to pay for parks by park users: quantitative and qualitative research

Whilst a growing body of evidence demonstrates people derive a range of health and wellbeing benefits from visiting parks, only a limited number of attempts have been made to provide a complementary economic assessment of parks. The aim of this exploratory study was to directly estimate the perceived health and wellbeing benefits attained from parks and the economic value assigned to parks by park users in Victoria, Australia. The research employed a mixed methods approach (survey and interviews) to collect primary data from a selection of 140 park users: 100 from two metropolitan parks in Melbourne and 40 from a park on the urban fringe of Melbourne, Victoria. Our findings suggest that park users derive a range of perceived physical, mental/spiritual, and social health benefits, but park use was predominantly associated with physical health benefits. Overall, our exploratory study findings suggest that park users are willing to pay for parks, as they highly value them as places for exercising, socialising, and relaxing. Importantly, most people would miss parks if they did not exist. The findings aim to provide park managers, public health advocates, and urban policy makers with evidence about the perceived health and wellbeing benefits of park usage and the economic value park visitors place on parks