Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer.

Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

Education and employment for young people with diabetes.

Educational achievements and employment experiences were examined using a postal questionnaire in a random sample of diabetic clinic attenders and non-diabetic control subjects aged 16-21 years, selected from 13 different centres in Great Britain. A response rate of 63% and 42% for diabetic and control subjects, respectively, was obtained. The diabetic group experienced a significantly greater number of health difficulties and problems at school (compared with their control group (21% vs 11%, p = 0.01) and there was a significant difference in perceived useful careers advice obtained at school for the two groups (5% vs 59%, p < 0.0001, diabetic and control groups, respectively). There was no difference in the number of General Certificates of Secondary Education (GCSEs) and Advanced (A) level qualifications obtained between the two groups. Of the young people who had left school, diabetic adolescents were significantly more likely to report having lost their jobs than their non-diabetic counterparts (19% vs 6%, p = 0.002). The diabetic group were also more likely to report that they were unable to do the job they wanted compared with the non-diabetic group (28% vs 16%, p = 0.005) and were more likely to report shift work problems (41% vs 12%, p = 0.04). With the increasing rate of unemployment it is important that youngsters with diabetes obtain specific diabetes-orientated vocational guidance in order to plan their careers and provision should be made for this in educational establishments.

Employers' attitudes to diabetes.

In order to examine the knowledge and attitude of employers to diabetes and diabetic employees, a questionnaire was sent to a random sample of approximately 2500 businesses and industries in eight different areas of the United Kingdom. Information was collected on the employment of people with diabetes, such as sickness absence, suitability of types of job for the diabetic person, the proportion of people with diabetes registered as disabled, and the provision of pension schemes. Only 1% of firms claimed that they would not consider a person with diabetes for employment within the firm. Nearly a third of employers did not know whether they employed anyone with diabetes. Over a quarter of the manufacturing industries reported some jobs that were unsuitable and 8% reported certain unfavourable job conditions for a diabetic employee such as shift work, working at heights, strenuous work, etc. A total of 7% of those firms with a diabetic employee reported that diabetic workers were more often absent from work due to sickness and 16% of firms employing a diabetic person did not allow paid time off for clinic visits. The attitude of the majority of employers seemed to indicate that diabetes in itself does not limit employment prospects since most people with diabetes have few problems arising from their condition and can make good employees in a range of occupations.

Unemployment and diabetes.

Unemployment was examined in a random sample of diabetic clinic attenders and a group of non-diabetic control subjects aged 17-65 years, selected from eight different centres in Great Britain. Data on employment were obtained using a postal questionnaire and medical details were collected from diabetic clinic notes. Out of a 61% response rate, 22% of males and 12% of females with diabetes were unemployed compared with 8 and 5% of the control group (both p less than 0.001). A greater percentage of people with diabetes were economically inactive, that is retired, unable to work, ill or housewives compared with the control group (29 vs 14%, p less than 0.001). Young people with diabetes (16-25 years) had the highest rates of unemployment. A matched pairs analysis confirmed that diabetic men had higher unemployment rates than their controls (14 vs 7%, p less than 0.001). Comparisons were made between unemployment rates for the eight geographical areas and published unemployment statistics; unemployment rates were significantly higher for men with diabetes except at one centre. A stepwise multiple logistic regression analysis indicated that variables which were predictive of unemployment were similar to those expected for people without diabetes. Unemployment is apparently a problem for the person with diabetes, especially for the young.

Employment problems and diabetes.

A survey of employment problems in a random sample of diabetic patients and a group of control subjects aged 17-65 years was carried out in eight centres in the UK. Data were linked to information collected from patients' diabetic clinic notes relating to the presence and treatment of any diabetic complications and quality of diabetic control. Difficulties in obtaining employment because of diabetes were reported by 13% of diabetic patients, and because of illness by 2% of control subjects (p less than 0.001). Nine percent of diabetic patients and 2% of control subjects reported having to change their job because of their illness (p less than 0.001), and 7% of people with diabetes and 2% of people without diabetes reported losing a job because of their illness (p less than 0.001). Diabetic shift workers were twice as likely as control subjects working shifts to experience problems with their job (18 vs 8%, p = 0.045). Reports of any sickness absence in the last 12 months were not significantly different for people with and without diabetes (49 vs 45%). Sickness absence in excess of 20 days in the last 12 months was more common among diabetic patients than control subjects (29 vs 16%, p less than 0.001). People with diabetes are more likely to experience problems in obtaining employment and staying employed than people without diabetes.

Deposition of SiO2 films with high laser damage thresholds by ion-assisted electron-beam evaporation.

SiO(2) thin films (approximately 100 nm thick) with transmittivity and a laser damage threshold nearly equal to those of bulk material are deposited on silica substrates by the technique of ion-assisted electron-beam evaporation. The influence of film packing density on the laser damage threshold is investigated by the technique of photoacoustic probe beam deflection. It is shown that films with lower packing density may have a higher laser damage threshold and as a consequence better heat dissipation.