The role of histone deacetylase 4 (HDAC4) in acquired cisplatin-resistant ovarian cancer

Resistance to platinum is a major problem in the treatment of ovarian cancer. Molecular profiling of isogenic ovarian cancer cell line pairs derived from tumour cells pre- and post- clinical resistance, identified that histone deacetylase 4 (HDAC4) is over-expressed in cisplatin-resistant cells relative to sensitive derivatives. HDAC4 siRNA and HDACi treatment resensitised resistant cells to cisplatin. Furthermore, up-regulation of HDAC4 in cisplatin-resistant ovarian cell lines and tumour sections identified HDAC4 as a potential biomarker of cisplatinresistance. It was observed that HDAC4 interacts with another mediator of platinum resistance, the transcription factor STAT1, and that knockdown of HDAC4 increased acetylation levels of STAT1 protein in platinum resistant cells. Consequent decrease in cisplatin mediated phosphorylation of STAT1 and nuclear translocation of STAT1 were observed. However, STAT1 was found to be acetylated and inactive in platinum sensitive cells, expressing lower levels of HDAC4. Microarray analysis of the platinum resistant cells has identified differentially regulated genes following HDAC4 knockdown. The UCHL1 promoter is methylated in both cisplatin sensitive and resistant paired cells and yet is reexpressed in resistant cells following HDAC4 knockdown. The methylation levels at the UCHL1 promoter were analysed by pyrosequencing method and do not appear to significantly change the methylation level after HDAC4 knockdown. However, ChIP analysis revealed an increase in acetylation at the UCHL1 promoter after HDAC4 knockdown. Conversely, P21 is down-regulated by HDAC4 knockdown in resistant PEO4 cells in contrast to reports of P21 overexpression as a biomarker of HDAC inhibition. Strikingly however, it is upregulated after HDAC4 knockdown in cisplatin-sensitive paired PEO1 cells suggesting that, like STAT1, a fundamental change in its control occurs on acquisition of platinum resistance. This study provides evidence that HDAC4 is required for platinum mediated STAT1 activation; a phenomenon associated with clinical platinum resistance, and identifies frequent HDAC4 over-expression in platinum resistant tumour biopsies. Pharmacological modulation of this pathway is shown to restore sensitivity to cisplatin. Microarray analysis revealed HDAC4 regulated target genes. These studies identify new and clinically relevant insights into platinum resistance which may lead to improved therapeutic options in ovarian cancer

Conditional Sentences in Modern Written Arabic

This study is concerned with the semantic and the functional aspects of Arabic conditional sentences. The motivation behind the study is the existing gaps in previous studies. The framework applied in this study is influenced by some Western linguistic analyses which mainly targeted English conditionals. Additionally, based on the findings, some comparisons between Arabic and English are drawn in order to determine the similarities and the differences between the two languages. This study particularly adopts a certain number of parameters; namely: Modality meanings and their temporal interpretations, the relationship between the two clauses, discourse functional roles and the interaction between conditional particles and other conjunctions and particles. Methodologically, the data included in this study is drawn from a range of Modern Written Arabic sources; hence, the results are proved by empirical evidence based on real texts. This research conducts a qualitative and detailed investigation for the actual use of Modern Written Arabic conditionals with relation to the parameters adopted. As a result, a number of classifications have been identified. These are sometimes supplemented with statistical descriptions. Additionally, this study shows how conditional sentences semantically and functionally act in real Modern Written Arabic texts. i.e. how they denote a variety of meanings and perform functional and textual roles. Finally, the broader contribution of this study is that it provides new insights and a deeper understanding of Arabic conditionals.The Royal Embassy of Saudi Arabia Cultural Bureau Londo

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited. Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive. Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies

Green roof and louvers shading for sustainable mosque buildings in Riyadh, Saudi Arabia

The number of mosque buildings is continuously increasing with the Muslim population, which is in fast growth around the world. In particular, the demand of new mosque buildings is high in the urban areas, due to increasing urban population growth in many parts of Muslims countries, as a result of economic growth and political instabilities in some parts of the Muslims world. Mosques are becoming more overcrowded and as a result a number of researches have been conducted to address the issue of thermal comfort of mosque users. Additionally, mosque building is unique because of its intermittent operation and various users, which require a unique heating or cooling strategies. On the other hand due to environmental pressure to suppress global warming, more energy efficient and sustainable buildings design is one of the current issues in building industries. This research aims to explore the sustainable techniques for mosque buildings in different climate zones. This research assesses a number of mosques buildings in different parts of the world with different climate; and investigates the strategies employed to cool or heat these buildings depending on the climate and season. The effectiveness of the building features in relation to each climate are carefully analysed, and possibility of potential replication of these features elsewhere are examined. This paper examined two techniques, green roof and louver shading in hot arid climate. The eventual objectives are establishing a guideline for architects and mosques building designer at any climate in order to achieve sustainable mosque building. The study concludes that there is a potential saving of up to 10% in cooling loads when green roof and louvers shading are applied on simulated mosque building in Riyadh, thus achieving the environmental feasibility in addition to economic and social benefits

Atrial Dysfunction in Significant Atrial Functional Mitral Regurgitation: Phenotypes and Prognostic Implications

Background: Atrial functional mitral regurgitation (AFMR) is associated with increased morbidity and mortality. Left atrial (LA) size and function in AFMR are poorly characterized. We aimed to assess LA function by reservoir strain (LASr) and estimated reservoir work (LAWr) and their impact on outcome in AFMR. Methods: Consecutive patients at our institution between 2001 and 2019 and with significant (moderate or greater) AFMR were examined. LAWr was estimated as LASr×LA reservoir volume, and patients were grouped by median LASr and LAWr. Outcomes were all-cause death or heart failure hospitalizations. Results: Five hundred fifteen AFMR patients were followed up for 5 (1–17) years. Patients had previously documented atrial fibrillation (AF; 37%), heart failure with preserved ejection fraction (HFpEF) without AF (24%), or both (HFpEF+AF, 39%). LA volume was largest in AF, while LA function parameters were most impaired in the combined HFpEF+AF group. During follow-up, patients with low LASr or LAWr had higher risk of death (P<0.001) and heart failure hospitalization (P<0.05). In Cox regression analyses, low LASr and LAWr, but not LA volume or left ventricular function, were associated with a higher risk of death (LASr: hazard ratio, 2.3 [95% CI, 1.6–3.5]; LAWr: hazard ratio, 3.4 [95% CI, 2.4–4.9]; both P<0.001) after adjustment for clinical and echocardiographic confounders. Low LASr and LAWr were strongest associated with death in HFpEF and HFpEF+AF. Conclusions: LA reservoir function but not LA size is a robust predictor of outcome in significant AFMR. This provides mechanistic insights into the interplay of functional versus geometric LA changes in AFMR.publishedVersio

Adaptability of buildings: a critical review on the concept evolution

Our ever-evolving built environment is continuously facing emerging needs for housing, work, health, and mobility, among others. Yet, buildings are usually designed and set up as finished permanent objects, reflecting the one constant scenario in mind of defined form, function, and performance. Since change is increasingly inevitable in our life, enlarging buildings’ adaptive capacities in response to arising variables and changing conditions over their lifecycle becomes a necessity in seeking global sustainability demands. The concept of building adaptability has been a notable subject in this respect, increasingly stimulating and proposing regenerative alternatives to today’s often obsolete buildings. This paper critically reviews the existing body of knowledge on the concept of adaptability in building research. The main focus is made on the evolution of the concept interpretations and related paradigms, and on the development of its applications and strategies in the light of promoting models and trends. Drawing on the literature as a source of evidence, the paper analyzes and classifies the content of existing studies published in scientific journals and gray literature, focusing on a timeframe from 2015 up-to-date. Moreover, the paper aims to build a constructive discussion to identify potential gaps between the actual state of the art and emerging needs, which should be addressed by further research.This research was funded by the Portuguese Foundation for Science and Technology, grant number PD/BD/150400/201

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer

Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests resistant clones exist within a larger drug sensitive cell-population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically-derived, intra-patient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell-line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 down-regulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of HDAC4, FOLR2, PIK3R1 or STAT1 (p<0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum sensitive but not HDAC4 over-expressing platinum resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum induced STAT1 activation and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors (n=7/16[44%]; p=0.04). Therefore, clinical selection of HDAC4 overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer

Developing building design resilience strategies to climate change risks

A resilient building design assessment tool is developed and presented to assist architects in preparing designs to meet the challenges of climate change. The tool incorporates a set of resilience factors that have been selected as a result of information gathered from an extensive literature review (from 1980 on) and a detailed questionnaire sent out to a sample of architects working in the field, together with a statistical analysis of the collected data. Climate change poses the built environment with an increasing threat of more frequent and severe meteorological events, including heavy precipitation, flooding, powerful storms and winds, lengthy and intense heat waves, and globally rising temperatures. The literature review revealed that there have as yet been few attempts to develop systematically models that integrate climate change risks (CCRs) with corresponding resilience factors in order that CCR resilience can be included in all aspects of a building and its site from the outset. The methodology adopted in this research is based on a critical analysis of the literature and the development of a prototype assessment model. Central to the success of this model is the capture of a set of resilience factors (SFs). As a first step, the researcher clustered climate change risks (CCRs) into four categories: physical, social, economic and management. Next, six aspects of resilience as applied to buildings were identified: site, layout, structure, envelope, system and operation. To ensure that appropriate resilience factors were chosen and incorporated into the model, the author extracted the most relevant factors from the review and divided them among the six key building aspects. In total 85 SFs were incorporated into the model. A questionnaire was prepared and sent out to a large number of practicing and academic architects of differing levels of experience. A statistical analysis of the replies, which included a scoring by the respondents of the effectiveness of each resilience factor, was used to refine and reduce the number of resilience factors, to 28, for inclusion in the assessment tool. The tool was then trialled on three projects to demonstrate its capabilities and effectiveness in assessing the resilience of a building against CCRs. It is hoped that the tool described here will, with further refinements and improvements, become a practical aid to architects faced with designing buildings in a world of increasingly severe hydro-meteorological events