HDAC6 Degradation Inhibits the Growth of High-Grade Serous Ovarian Cancer Cells.

Histone deacetylase 6 (HDAC6) is a unique histone deacetylating enzyme that resides in the cell cytoplasm and is linked to the modulation of several key cancer related responses, including cell proliferation and migration. The promising anti-cancer response of the first-generation HDAC6 catalytic inhibitors continues to be assessed in clinical trials, although its role in high grade serous ovarian cancer is unclear. This study investigated HDAC6 tumor expression by immunohistochemistry in high-grade serous ovarian cancer (HGSOC) tissue samples and a meta-analysis of HDAC6 gene expression in ovarian cancer from publicly available data. The pharmacological activity of HDAC6 inhibition was assessed in a patient-derived model of HGSOC. HDAC6 was found to be highly expressed in HGSOC tissue samples and in the patient-derived HGSOC cell lines where higher HDAC6 protein and gene expression was associated with a decreased risk of death (hazard ratio (HR) 0.38, (95% confidence interval (CI), 0.16-0.88; p = 0.02); HR = 0.88 (95% CI, 0.78-0.99; p = 0.04)). Similarly, the multivariate analysis of HDAC6 protein expression, adjusting for stage, grade, and cytoreduction/cytoreductive surgery was associated with a decreased risk of death (HR = 0.19 (95% CI, 0.06-0.55); p = 0.002). Knock-down of HDAC6 gene expression with siRNA and protein expression with a HDAC6 targeting protein degrader decreased HGSOC cell proliferation, migration, and viability. Conversely, the selective inhibition of HDAC6 with the catalytic domain inhibitor, Ricolinostat (ACY-1215), inhibited HDAC6 deacetylation of α-tubulin, resulting in a sustained accumulation of acetylated α-tubulin up to 24 h in HGSOC cells, did not produce a robust inhibition of HDAC6 protein function. Inhibition of HGSOC cell proliferation by ACY-1215 was only achieved with significantly higher and non-selective doses of ACY-1215. In summary, we demonstrated, for the first time, that HDAC6 over-expression in HGSOC and all ovarian cancers is a favorable prognostic marker. We provide evidence to suggest that inhibition of HDAC6 catalytic activity with first generation HDAC6 inhibitors has limited efficacy as a monotherapy in HGSOC.

Exploring perspectives on chronic obstructive pulmonary disease in people who smoke heroin: a qualitative study.

BACKGROUND: Smoking rather than injecting heroin has become more common over the last 20 years. Although there is an increasing body of evidence describing high levels of chronic obstructive pulmonary disease (COPD) in people who smoke heroin, there is limited evidence documenting the impact of the long-term condition on this population group. AIM: This study aimed to describe the experiences of people who smoke heroin with COPD in Liverpool, UK. DESIGN & SETTING: Participants were purposefully sampled for this qualitative study. They included adults enrolled in an opioid replacement clinic run by Addaction in Liverpool, who had already engaged with spirometry testing for COPD as part of a previous study. METHOD: Semi-structured interviews were performed with participants with spirometrically confirmed COPD in opioid replacement clinics. Data were analysed using a framework analysis approach. RESULTS: Sixteen potential participants were invited to take part in the study, of which 10 agreed and were interviewed. Three themes common to all interviews were identified: functional measures of lung health that impacted on their activities of daily living; inhaler and medication perceptions with erratic use that was not concordant with their prescription; and the impact of difficulties accessing care. CONCLUSION: These findings, along with previous studies highlighting the prevalence of COPD in this population, warrant efforts to integrate community COPD and opioid replacement services to improve outcomes for this vulnerable population.

Screening Heroin Smokers Attending Community Drug Clinics for Change in Lung Function: A Cohort Study.

BACKGROUND: Heroin smokers have high rates of COPD, respiratory morbidity, hospital admission, and mortality. We assessed the natural history of symptoms and lung function in this population over time. METHODS: A cohort of heroin smokers with COPD was followed for 18 to 24 months. At baseline and follow-up, respiratory symptoms were measured by the Medical Research Council Dyspnea Scale (MRC) and the COPD Assessment Tool (CAT), and postbronchodilator spirometry was performed. Frequency of health-care-seeking episodes was extracted from routine health records. Parametric, nonparametric, and linear regression models were used to analyze the change in symptoms and lung function over time. RESULTS: Of 372 participants originally recruited, 161 were assessed at follow-up (mean age, 51.0 ± 5.3 years; 74 women [46%]) and 106 participants completed postbronchodilator spirometry. All participants were current or previous heroin smokers, and 122 (75.8%) had smoked crack. Symptoms increased over time (MRC score increased by 0.48 points per year, P < .001; CAT score increased by 1.60 points per year, P < .001). FEV1 declined annually by 90 ± 190 mL (P < .001). This deterioration was not associated with change in tobacco or heroin smoking status or use of inhaled medications. CONCLUSIONS: Heroin smokers experience a high and increasing burden of chronic respiratory symptoms and a decline in FEV1 that exceeds the normal age-related decline observed among tobacco smokers with COPD and healthy nonsmokers. Targeted COPD diagnostic and treatment services hosted within opiate substitution services could benefit this vulnerable, relatively inaccessible, and underserved group of people.

Screening Heroin Smokers Attending Community Drug Services for COPD.

BACKGROUND: Heroin smoking is associated with deprivation, early onset severe emphysema, premature morbidity and mortality, and high use of health care, but individuals engage poorly with traditional health services. METHODS: In this cross-sectional study, we screened a population of heroin smokers, prescribed opiate substitution therapy by community drug services, for airway disease. We assessed drug exposure, respiratory symptoms, health status, and COPD prevalence. Subjects completed spirometry, completed Medical Research Council (MRC) Dyspnea Scale, COPD Assessment Tool (CAT) questionnaire, recorded drug exposure, and provided feedback. RESULTS: A total of 753 people (73% of those approached) completed screening, with 260 participants (35%) having COPD using FEV1/FVC < 0.7 and 293 (39%) participants having COPD using the lower limit of normal. A further 112 participants (15%) had asthma-COPD overlap (ACO) with features of COPD and asthma. Compared with those with normal spirometry, participants with COPD were more breathless (MRC score 3.1 vs 1.9; P < .001) and had worse health status (CAT score 22.9 vs 13.4; P < .001), respectively. Individuals with COPD had smoked cigarettes (P < .001), heroin (P < .001), and crack (P = .03) for longer and were more likely to still be smoking heroin (P < .01). Feedback was strongly positive, with 92% of respondents happy for other health-care appointments to be colocated with drug key worker appointments. CONCLUSIONS: Most heroin smokers had COPD or ACO, most commonly mild to moderate disease. In high-risk areas, screening this population provides an opportunity to reduce symptoms and risk. Anchoring respiratory health screening to drug center appointments delivers high completion and satisfaction and is an appropriate model for screening other hard-to-reach populations.

BRCA1 and MAD2 Are Coexpressed and Are Prognostic Indicators in Tubo-ovarian High-Grade Serous Carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between BRCA1 and mitotic arrest deficiency protein 2 (MAD2) protein expression, as determined by immunohistochemistry, and clinical outcomes in epithelial ovarian carcinoma (EOC). METHODS: A tissue microarray consisting of 94 formalin-fixed paraffin-embedded EOC with fully matched clinicopathological data were immunohistochemically stained with anti-BRCA1 and anti-MAD2 antibodies. The cores were scored in a semiquantitative manner evaluating nuclear staining intensity and extent. Coexpression of BRCA1 and MAD2 was evaluated, and patient survival analyses were undertaken. RESULTS: Coexpression of BRCA1 and MAD2 was assessed in 94 EOC samples, and survival analysis was performed on 65 high-grade serous carcinomas (HGSCs). There was a significant positive correlation between BRCA1 and MAD2 expression in this patient cohort (P < 0.0001). Both low BRCA1 and low MAD2 are independently associated with overall survival because of HGSC. Low coexpression of BRCA1 and MAD2 was also significantly associated with overall survival and was driven by BRCA1 expression. CONCLUSION: BRCA1 and MAD2 expressions are strongly correlated in EOC, but BRCA1 expression remains the stronger prognostic factor in HGSC.

The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses.

This systematic review and meta-analyses investigates the expression of the cell checkpoint regulator, mitotic arrest deficiency protein 2 (MAD2) in cancerous tissue and examines whether an association exists between MAD2 levels and cancer survival and recurrence. Studies investigating MAD2 expression in cancer tissue utilising immunohistochemistry (IHC) were identified by systematic literature searches of Medline, Embase and Web of Science databases by October 2015. Random effects meta-analyses were performed to generate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of overall and progression-free survival according to MAD2 expression. Forty-three studies were included in the overall review. In 33 studies investigating MAD2 expression by IHC in cancer tissue, a wide range of expression positivity (11-100%) was reported. Higher MAD2 expression was not associated with an increased risk of all-cause mortality in a range of cancers (pooled HR 1.35, 95% CI 0.97-1.87; P = 0.077, n = 15). However, when ovarian cancer studies were removed, a significant pooled HR of 1.59 for risk of all-cause mortality in other cancer patients with higher expressing MAD2 tumours was evident (95% CI, 1.17-2.17; P = 0.003, n = 12). In contrast, higher MAD2 expression was associated with significant decreased risk of all-cause mortality in ovarian cancer patients (pooled HR = 0.50, 95% CI, 0.25-0.97; P = 0.04, n = 3). In conclusion, with the exception of ovarian cancer, increased MAD2 expression is associated with increased risk of all-cause mortality and recurrence in cancer. For ovarian cancer, reduced levels of MAD2 are associated with poorer outcome. Further studies are critical to assess the clinical utility of a MAD2 IHC biomarker.