Targeting G-Quadruplexes within the ADAM-15 Promoter: A Novel Therapeutic Approach for Breast Cancer

ADAM-15 is a protein that is up-regulated in many diseases, particularly breast cancer; its over-expression is correlated with more aggressive and invasive phenotypes. The critical core promoter region of ADAM-15 is capable of forming a secondary DNA structure known as a G-quadruplex. The stabilization of this G-quadruplex has the potential to decrease the transcription of the over-expressed ADAM-15 protein. Six hundred forty compounds were screened for their ability to cause a shift in the melting temperature of an ADAM-15 oligonucleotide using FRET melt. Two compounds, NSC 146771 and NSC 260594, produced a significant shift in the melting temperature; further experimentation, such as circular dichroism, cytotoxicity MTS assays, and RT-qPCR, was performed to confirm the ability of these small molecules to stabilize the G-quadruplexes within the ADAM-15 promoter. Neither compound showed cytotoxicity, and NSC 260594 showed an increased capacity for reducing the transcription of ADAM-15. Further pharmacokinetic and pharmacodynamic experimentation needs to be completed, but NSC 260594 shows potential to significantly decrease ADAM-15 expression and therefore improve the prognosis of breast cancer patients

Drought-Damage Functions for the Estimation of Drought Costs under Future Projections of Climate Change

Drought events and their impacts pose a considerable problem for governments, businesses and individuals. Superimposed on this is the risk of anthropogenic climate change. Climate models are increasingly being used to understand how climate change may affect future drought regimes. However, methodologies to quantify economic costs which could occur under these future scenarios are virtually non-existent. In this study, historic drought events were identified in regional precipitation data using the Standardized Precipitation Index, and their magnitude quantified and linked to reported economic costs. Drought damage functions were created for Australia, Brazil, China, India, Spain/Portugal and the USA. Projections of drought magnitude for 2003–2050 were modeled using the Community Integrated Assessment System, for a range of climate and emission scenarios, and future economic costs estimated. Severe and extreme drought events were projected to cause estimated additional losses ranging between 0.04 and 9 percent of national GDP in Australia, the USA and Spain/Portugal under future scenarios of climate change. The combined effect on global GDP from projected long-term drought events in the countries analyzed resulted in additional annual losses of 0.01 to 0.25 percent. This is considered conservative as the analysis is representative of seven countries only; does not incorporate the possibility of successive drought events, or compounding effects on vulnerability from interactions with other extreme events. Furthermore, it excludes indirect economic effects; social and environmental losses; the possibility of increasing vulnerability due to changing socio-economic conditions; and the possibility of irreversible or systemic collapse of economies as the study highlighted that under future climate change drought magnitude may exceed current experience potentially passing thresholds of social and economic resilience. Stringent mitigation had little effect on the increasing impacts of drought in the first half of the 21st century, so in the short-term adaptation in drought “hot spots” will be crucial

Whither mental health policy-where does it come from and does it go anywhere useful? Comment on “Cross-national diffusion of mental health policy”

Factors influencing cross-national diffusion of mental health policy are important to understand but complex to research. This commentary discusses Shen’s research study on cross-national diffusion of mental health policy; examines the extent to which the three questions researched by Shen (whether countries are more likely to have a mental health policy (a) the earlier a country becomes a member of World Health Organization (WHO), (b) the more international aid a country receives, and (c) the more neighbouring countries already have a mental health policy) are in fact able to assess WHO’s impact on cross-national diffusion of mental health policy. The commentary then suggests a range of more specific questions which may be used to further elucidate the impact of WHO on an individual country, and considers the relative value of published mental health policy compared with the integration of mental health into national health sector strategies and other sector reforms, and concludes with a call for more integration of mental health across all WHO activities at international, regional and country levels

Insights into the use of social comparisons within an advanced cancer setting

Background The PROACT (Patient Reported Outcomes in cancer, impact of Age and Carer role demands associated with Treatment) study had the primary aim of developing two scales measuring the impact of cancer on wellbeing and caregiving responsibilities, for people with cancer and the individuals supporting them. The project consisted of four consecutive studies; the first stage was the collection of qualitative narratives to understand the patient/caregiver experience. This paper reports on an incidental finding from these narratives. Methods The researchers conducted semi-structured interviews exploring participants’ views on the impact cancer had on their quality of life. They interviewed 24 people with stage III/IV cancer from three tumor groups, Lung (n=6), Melanoma (n=9) and Ovarian (n=9), and 23 informal caregivers. Interviews were recorded and transcribed verbatim and a framework was developed through open coding. A framework approach to thematic analysis was employed. Results Twenty themes and 33 sub-themes were identified including topics such as impact for caregiving and employment. There was an unplanned finding of participants recurrently using concepts of ‘luck’ or good fortune when describing their situations. While not a theme itself this narrative was present across the framework, occurring when individuals made comparisons to ‘other’ groups of people perceived as facing more difficulties. Conclusions This analysis provides insight into the use of language by both patients and informal caregivers in the advanced disease setting, laying the foundation for future research exploring any effects this has on dyadic wellbeing. These interpretations form a basis to explore whether this language can be harnessed by healthcare professionals to deliver information in line with an individual’s conceptualization of their situation

Development and validation of the caregiver roles and responsibilities scale in cancer caregivers

Purpose The Caregiver Roles and Responsibilities Scale (CRRS) was developed to facilitate formal assessment of broad life impacts for informal (i.e. unpaid) caregivers to people with cancer. Here we report the development and initial validation. Methods The CRRS was developed from the thematic analysis of two interview studies with cancer patients (stage III-IV breast, gynaecological, lung or melanoma) and caregivers. In the evaluation studies, participants completed the CRRS alongside the Caregiver Quality of Life - Cancer, the main criterion measure for concurrent validity, and the WHOQOL-BREF for additional convergent validity data. Questionnaires were completed at baseline, 7-days and 2-months. Demographic data and patient characteristics were collected at baseline. Results Two-hundred and forty-five caregivers to people with stage I-IV breast, colorectal, gynaecological, head and neck, lung or renal cancer or melanoma completed the CRRS at least once. The final 41 core items selected comprised five subscales: Support and Impact, Lifestyle, Emotional Health and Wellbeing, Self-care and Financial Wellbeing as well as three standalone items. Missing data rate was low (0.6%); there were no ceiling or floor effects for total scores. Cronbach’s alpha was 0.92 for the CRRS-41; 0.75-0.87 for the subscales. CRRS showed good test-retest reliability (ICC=0.91), sensitivity to change and the predicted pattern of correlation with validation measures r=0.75-0.89. The standalone 7-item jobs and careers subscale requires further validation. Conclusions Initial evaluation shows the CRRS has good validity and reliability and is a promising tool for the assessment of the effects of cancer and cancer treatment on the lives and wellbeing of informal caregivers

Development and validation of the patient roles and responsibilities scale in cancer patients

Purpose The Patient Roles and Responsibilities Scale (PRRS) was developed to enable a broader evaluation of the impact of cancer and cancer treatment, measuring ‘real world’ roles and responsibilities such as caring for others and financial and employment responsibilities. Here we report the development and initial validation. Methods The 29-item PRRS was developed from the thematic analysis of two interview studies with cancer patients and caregivers. In the evaluation study, participants completed the PRRS alongside the Social Difficulties Inventory (SDI), the main criterion measure for concurrent validity, and the Functional Assessment of Cancer Therapy – General (FACT-G) and WHO Quality Of Life-BREF (WHOQOL-BREF) for additional convergent validity data. Questionnaires were completed at baseline, 7-days (PRRS only) and 2-months. Demographic data and patient characteristics were collected at baseline. Results One hundred and thirty-five patients with stage III/IV breast, lung or gynaecological cancer or melanoma completed the PRRS at least once. Five items performed poorly and were removed from the scale. The final 16 core items selected comprised 3 dimensions: Family Wellbeing, Responsibilities and Social Life, and Financial Wellbeing, identified in principal component analysis, accounting for 61.5% of total variance. Missing data (0.6%) and floor/ceiling effects were low (0%/1.5%). Cronbach’s alpha was 0.9 for the PRRS-16; 0.79-0.87 for the subscales. PRRS showed good test-retest reliability (ICC-0.86), sensitivity to change and the predicted pattern of correlation with validation measures r=ǀ0.65-0.77ǀ. The standalone 7-item jobs and careers subscale requires further validation. Conclusions Initial evaluation shows the PRRS is psychometrically robust with potential to inform the evaluation of new treatments in clinical trials and real world studies

The pervasive nature of uncertainty – a qualitative study with patients with advanced cancer and their informal caregivers

Purpose: To explore the impact of extended cancer survival on broader aspects of life and wellbeing such as occupational, financial and family life for patients with advanced cancer and their nominated informal caregivers. Methods: In-depth qualitative interviews, transcribed verbatim. A thematic framework was developed from an initial process of open coding and tested iteratively as new data were collected. Results: 24 patient-caregiver dyads with advanced ovarian (9) melanoma (9) or lung cancer (6). Patients were aged 39-84 (median 62 years), caregivers 19-85 (median 54 years). Caregivers were the partners/spouses (15), children (5), siblings (2) and friends (2) of patients. One particular theme, ‘uncertainty’, encompassed many issues such as planning for the future, providing for one’s family, employment and finances. Uncertainties were related to the timescale and trajectory of the disease and lack of control or ability to make plans. There were marked age effects. Accounts from within the same dyad often differed and patients and caregivers rarely discussed concerns with each other. Conclusions: Both patients and their informal caregivers were challenged by the uncertainties around living with advanced cancer and the lack of a defined trajectory. This impacted many diverse areas of life. Although distressing, dyads seldom discussed these concerns with each other. Implications for survivors: Uncertainty is a recurrent issue for cancer survivors and their families impacting broad aspects of their lives and their ability to move forward however patients and caregivers in this study rarely discussed these concerns together. Uncertainty should be discussed periodically, together, and 3 health care professionals could facilitate these discussions. The use of one or more ‘trigger questions’ in clinic appointments may provide an opportunity to start these dialogues

Psychotic Symptoms in Kenya - Prevalence, Risk Factors, and Relationship with Common Mental Disorders

There have been few epidemiological surveys to establish prevalence and associated risk factors of psychosis in Sub-Saharan Africa. This paper reports a population- based epidemiological survey in rural Kenya of the prevalence of psychotic symptoms and their relationship with demographic, socio-economic and other risk factors. A random sample of 2% of all adults living in Maseno, Kisumu District of Nyanza province, Kenya (50,000 population) were studied, aiming for a sample size of 1,000 people. The psychosis screening questionnaire was used to assess the prevalence of psychotic symptoms in the preceding twelve months. The response rate was 87.6%. The prevalence of single psychotic symptoms in rural Kenya was 8% of the adult population, but only 0.6% had two symptoms and none had three or more psychotic symptoms in this sample size. Psychotic symptoms were evenly distributed across this relatively poor rural population and were significantly associated with presence of common mental disorders, and to a lesser extent with poor physical health and housing type. We conclude that single psychotic symptoms are relatively common in rural Kenya and rates are elevated in those with CMD, poor physical health and poor housing

Dark Matter Halo Merger Histories Beyond Cold Dark Matter: I - Methods and Application to Warm Dark Matter

We describe a methodology to accurately compute halo mass functions, progenitor mass functions, merger rates and merger trees in non-cold dark matter universes using a self-consistent treatment of the generalized extended Press-Schechter formalism. Our approach permits rapid exploration of the subhalo population of galactic halos in dark matter models with a variety of different particle properties or universes with rolling, truncated, or more complicated power spectra. We make detailed comparisons of analytically derived mass functions and merger histories with recent warm dark matter cosmological N-body simulations, and find excellent agreement. We show that, once the accretion of smoothly distributed matter is accounted for, coarse-grained statistics such as the mass accretion history of halos can be almost indistinguishable between cold and warm dark matter cases. However, the halo mass function and progenitor mass functions differ significantly, with the warm dark matter cases being strongly suppressed below the free-streaming scale of the dark matter. We demonstrate the importance of using the correct solution for the excursion set barrier first-crossing distribution in warm dark matter - if the solution for a flat barrier is used instead the truncation of the halo mass function is much slower, leading to an overestimate of the number of low mass halos.Comment: 19 pages, 14 figures, MNRAS in press. Comments welcom

Prevalence of Alcohol Consumption and Hazardous Drinking, Tobacco and Drug use in urban Tanzania, and Their associated Risk Factors.

Evidence suggests substance abuse in Tanzania is a growing public health problem. A random sample of 899 adults aged 15-59 in two urban sites of differing levels of poverty surveyed alcohol, tobacco and illicit substance use. Rates of substance use were 17.2%. 8.7% and 0.8% for alcohol, tobacco and cannabis, respectively. Living in the less affluent area was associated with higher lifetime rates of tobacco and alcohol use. Substance use is less prevalent in Tanzania than in richer countries, but lifetime consumption is higher in poorer areas. The association of substance use with a range of socio-economic factors warrants further research