The nuclear chaperones NPM1 and Bag-1L in the regulation of androgen receptor action in prostate cancer cells

Die Entstehung und Progression von Prostatakarzinomen sind in hohem Maß von Androgenen abhängig. Ihren Effekt entfalten die männlichen Geschlechtshormone durch die Bindung an den Androgen Rezeptor (AR), einen Liganden-gesteuerten Transkriptionsfaktor. In Abwesenheit von Hormonen befindet sich der inaktive AR in einem Komplex mit molekularen Chaperonen im Cytoplasma. Nach Bindung von Androgenen an den AR dissoziieren die Chaperone und der Rezeptor transloziert in den Nukleus, wo er die Expression von AR-regulierten Genen beeinflusst. Es wurde bisher angenommen, dass die Hauptfunktion der Chaperone darin liegt, die geeignete Konformation des AR zur Bindung von Androgenen zu gewährleisten. Es existieren jedoch auch Chaperone, die vorwiegend im Nukleus lokalisiert sind und die transkriptionelle Aktivität des AR beeinflussen. Die Wirkung, die diese Chaperone auf die AR Aktivität und auf die Krebsentwicklung haben, bleibt jedoch unklar. Zwei nukleare Chaperone, deren Beteiligung an der Regulation der transkriptionellen Aktivität des AR bereits gezeigt wurde, sind Bag-1L und NPM1. Der Mechanismus, der der Regulation durch die beiden Chaperone zu Grunde liegt, ist jedoch unbekannt. Das Ziel dieser Arbeit war die Charakterisierung der beiden nuklearen Chaperone (Bag-1L und NPM1) im Bezug auf die Regulation des AR Aktivität und das Wachstum von Prostatakrebszellen. Weiterhin sollte untersucht werden, ob die beiden Proteine ihren Effekt durch einen gemeinsamen oder zwei sich voneinander unterscheidenden Signalwege entfalten. In dieser Arbeit konnte zunächst nachgewiesen werden, dass die beiden Chaperone, neben der jeweiligen Interaktion mit dem AR, auch miteinander interagieren. Eine Herunterregulation von NPM1 führte weiterhin zu einem reduzierten Expressionslevel der Bag-1 Proteine (einschließlich Bag-1L). Darüber hinaus konnte gezeigt werden, dass der Knock-down von NPM1 die Translokationsgeschwindigkeit des AR von Cytoplasma in den Nukleus beeinträchtigt. Dieser Effekt war zum Teil reversibel, wenn in NPM1-Knock-down Zellen Bag-1L überexprimiert wurde. Dies lässt vermuten, dass der beobachtete Effekt teilweise durch reduzierte Bag-1L Level in den NPM1 knock-down Zellen hervorgerufen wurde. Der Knock-down von NPM1 beeinträchtigte ebenfalls die transkriptionelle Aktivität des AR, was bereits für den knock-out von Bag-1L gezeigt werden konnte. Ein Vergleich von genomweiten Transkriptom-Datensätze der NPM1 knock-down Zellen mit denen der bereits veröffentlichten Bag-1L knock-out Zellen zeigte auffallend viele Überlappungen. Durch statistische Auswertung der Gene, die gemeinsam durch die beiden Chaperone reguliert werden, konnte ein Signalweg identifiziert werden, der zu der Bildung von oxidativen Stress in Prostatakrebszellen führt. Oxidativer Stress wurde lange, hauptsächlich mit einer schädlichen Wirkung auf die Zellvitalität in Verbindung gebracht. Neuere Studien zeigen jedoch, dass sich oxidativer Stress auch positiv auf das Überleben von Zellen und deren Proliferation auswirken kann. Da sowohl der knock-down von NPM1, als auch der knock-out von Bag-1L die Expression androgen-abhängiger Gene negativ beeinflusst, die für die Entstehung von oxidativen Stress wichtig sind, liegt die Schlussfolgerung nahe, dass Bag-1L und NPM1 in Prostatakrebszellen interagieren, um AR-vermittelte Signalwege zu aktivieren. Dies führt zur Entstehung von oxidativen Stress, was das Überleben der Tumorzellen begünstigt

The Role of Branding and Packaging in Creating Customer Loyalty in the Toothpaste Market: The Case of Ghana

Branding and packaging are communicable marketing tools that marketers use through their efforts to disseminate information to the general public. It can be inferred that branding and packaging play a vital role in the consumer’s decision to purchase a particular product of their choice, since they are able to identify the products through its branding and packaging. This paper sought to investigate into how branding and packaging influences consumers’ decision and how it influences them to be loyal to a particular brand of product (toothpaste). Data was collected by administering questionnaires to a sample size of 130 out of which 100 were consumers of the various tooth paste and 30 were toothpaste retailers in the Techiman Municipality. Accidental or convenient sampling method, under the non-random sampling technique was used. The study revealed that branding and packaging is an essential tool that influences consumers purchasing behavior in their decision to purchase a particular brand of toothpaste. It was also realized that toothpaste manufacturers use branding and packaging to differentiate their products from that of their competitors. Keywords: Branding, Innovation, Packaging, Loyalt

The Role of Branding and Packaging in Creating Customer Loyalty in the Toothpaste Market: The Case of Ghana

Branding and packaging are communicable marketing tools that marketers use through their efforts to disseminate information to the general public. It can be inferred that branding and packaging play a vital role in the consumer’s decision to purchase a particular product of their choice, since they are able to identify the products through its branding and packaging. This paper sought to investigate into how branding and packaging influences consumers’ decision and how it influences them to be loyal to a particular brand of product (toothpaste). Data was collected by administering questionnaires to a sample size of 130 out of which 100 were consumers of the various tooth paste and 30 were toothpaste retailers in the Techiman Municipality. Accidental or convenient sampling method, under the non-random sampling technique was used. The study revealed that branding and packaging is an essential tool that influences consumers purchasing behavior in their decision to purchase a particular brand of toothpaste. It was also realized that toothpaste manufacturers use branding and packaging to differentiate their products from that of their competitors. Keywords: Branding, Innovation, Packaging, Loyalt

Application of the Consolidated Framework for Implementation Research to examine nurses’ perception of the task shifting strategy for hypertension control trial in Ghana

Background: The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses’ perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. Methods: Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). Results: Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. Conclusion: Assessing stakeholders’ perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention

Weight management merits attention in women with infertility: A cross-sectional study on the association of anthropometric indices with hormonal imbalance in a Ghanaian population

OBJECTIVE: This study determined the association of anthropometric indices with hormonal imbalance among infertile women in a Ghanaian population. RESULTS: Follicle stimulating hormone (FSH) levels (18.47 vs. 8.67, p-value = 0.002), and luteinizing hormone (LH) (12.43 vs. 8.01, p-value = 0.044) were higher in women with primary infertility compared with women presenting with secondary infertility. Waist circumference (WC) and waist-to-height ratio (WHtR) showed significant negative partial correlation with prolactin in both primary and secondary infertile women. Also a significant negative partial correlation was observed between BMI and prolactin in secondary infertile women only. Waist-to-hip ratio (WHR) showed a positive association with LH in both primary and secondary infertility. WHR also showed significant positive correlation to LH/FSH ratio in secondary infertility whereas body adiposity index (BAI) showed a negative correlation to LH/FSH ratio. In a correlation analysis of anthropometric measures with hormonal profile and causes of infertility as a fixed factor, the association between anthropometric indices and fertility hormones was largely dependent on the underlying causes of infertility

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer. Here, we show that BAG1L regulates AR dynamics in the nucleus and its ablation attenuates AR target gene expression especially those involved in oxidative stress and metabolism. We show that a small molecule, A4B17 that targets the BAG domain downregulates AR target genes similar to a complete BAG1L knockout and upregulates the expression of oxidative stress-induced genes involved in cell death. Furthermore, A4B17 outperformed the clinically approved antagonist enzalutamide in inhibiting cell proliferation and prostate tumor development in a mouse xenograft model. BAG1 inhibitors therefore offer unique opportunities for antagonizing AR action and prostate cancer growth

Credit Information Sharing and Loan Default in Developing Countries: The Moderating Effect of Banking Market Concentration and National Governance Quality

Departing from the existing literature, which associates credit information sharing with improved access to credit in advanced economies, we examine whether credit information sharing can also reduce loan default rate for banks domiciled in developing countries. Using a large dataset covering 879 unique banks from 87 developing countries from every continent, over a nine-year period (i.e., over 6,300 observations), we uncover three new findings. First, we find that credit information sharing reduces loan default rate. Second, we show that the relationship between credit information sharing and loan default rate is conditional on banking market concentration. Third, our findings suggest that governance quality at the country level does not have a strong moderating role on the effect of credit information sharing on loan default rate

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation