Investigating the molecular basic of AMKL and MDS.

Malignant haematopoiesis is usually associated with various genetic lesions such as chromosomal translocations or mutations in individual genes. This thesis investigates the genetic basis of two such syndromes, acute megakaryoblastic leukaemia (AMKL) and myelodysplastic syndrome (MDS). The most common constitutional aneuploidy with predisposition to leukaemia is trisomy 21, also known as Down Syndrome (DS). DS children have a 500-fold increased risk for AMKL. Somatic mutations acquired during foetal haematopoiesis in the GATA1 transcription factor are detected in megakaryoblasts from all the DS patients with AMKL. Here we show that the Gatal mutation co-operates with the chromosome 21 gene, ERGS, to immortalize foetal megakaryocyte progenitors with the phenotype of AMKL megakaryoblasts. We show that ERG-3 promotes megakaryopoiesis and acts as an oncogene and that progenitor cells harbouring a Gatal mutation plus ERG-3 or ERG-3 alone lead to rapid development of leukaemia in vivo. Our data support a model where trisomy 21 overexpressed genes, that promote foetal megakaryopoiesis, co-operate with mutations that arrest development and lead to DS-AMKL. This is also the first direct demonstration of the leukaemogenic activity of full length ERG protein, possibly explaining the poor prognosis of the acute myeloid leukaemias with high expression of ERG. DS patients are also predisposed to TMD (transient myeloproliferative disorder) and MDS (myelodysplastic syndrome) prior to AMKL development. Myelodysplastic syndromes are a group of clonal haematopoietic disorders, characterised by aberrant proliferation and differentiation of cells of the myeloid lineage resulting in severe cytopenia and dysplasia of myeloid, erythroid and megakaryocytes. The most common chromosomal translocation associated with MDS is the t(3 5)(q25q35) translocation. This rearrangement results in a fusion transcript comprised of nucleophosmin (NPM) gene and myeloid leukaemia factor 1 (MLF1) gene. To determine the importance of the NPM-MLF1 fusion protein in the development and progression of MDS to AML, its role in myelopoiesis and megakaryopoiesis was investigated. Our results show that NPM-MLF1 affects the differentiation of myeloid cells. Our preliminary data predicts that NPM may have a role in megakaryopoiesis and its interaction with NPM-MLF1 may affect the function of the fusion protein

Identification of cardiotoxicity related to non-small cell lung cancer (NSCLC) treatments: A systematic review

Introduction In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart’s function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity Methods This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients’ treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760

Development of an Acid Resistant Concrete

Modern infrastructures are designed for long service life and are increasing being built in more aggressive greenfield and brownfield areas. Sulfate, acid-sulfate and acid resistant concrete are engineering solution to these challenges in infrastructures without the need for additional protective membrane associated with conventional concrete. This paper presents an experimental investigation on mechanical properties of concretes made from a new acid-resistant mortar and a conventional concrete, and corresponding reinforced concrete beams, subjected to accelerated acidic environments in UTS laboratory. Concrete properties including compressive strength, modulus of elasticity, mod ulus of rupture, indirect tensile and drying shrinkage were examined. The load carrying capacity of companion reinforced concrete beams were determined. The specimens were tested before and after periods of exposure to sulphuric acid solution with the concentration of 7% and changes of their properties were evaluated. The results enable an understanding of the mechanism of acid attack and the benefit of the use of acid resistant concrete. On the other hand, the effect of acid attack on reinforced concrete beams is highly dependent on the design of the reinforced concrete beams and to a less extent on the acid resistant property of the concrete

Understanding the Complexity of Party Instability in Parliaments

We propose a new typology of parliamentary party switches (switching events) that focuses on three dimensions: (1) the number of MPs and the degree of coordination, (2) the origin of switchers and (3) the destination of switchers – a parliamentary party group (PPG) or independent status. We further distinguish between switches with single and multiple destinations. Our approach sheds new light to party instability in various ways. We elucidate types of party instability to emphasize the complexity of party instability that have eluded the conceptual toolset available thus far. For example, “collective defection” (coordinated movement from one PPG to another), “collective exit” (MPs exiting their parliamentary group to become independent MPs) and “multi-PPG split” (coordinated moves from several PPGs to form a new PPG). Using preliminary data compiled for Instaparty (Party Instability in Parliaments) project from (mostly) Poland and Ireland, we find rich diversity in the forms of parliamentary party instability. While individual defections are much more common than group defections, they are clearly more dominant in Ireland than in Poland; furthermore, switches between PPGs (rather than between PPGs and independent status) have been more common in Poland. Our typology is illustrated by the analysis of the 8th Polish Sejm that provides examples of nearly all single-origin switching events and of most multiorigin ones. The new typology presents the first step of our inquiry into the patterns, causes and consequences of party switching in eight democracies (Estonia, Ireland, Italy, Lithuania, Norway, the Netherlands, Poland and Romania) from 1960s/1990s to early 2020s

Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin

Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homologue neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins. The association between spinophilin and PP1 is increased in the striatum of animal models of Parkinson's disease (PD). However, mechanisms that regulate the association of spinophilin and neurabin with PP1 are unclear. Here, we report that the association between spinophilin and PP1α or PP1γ1 was increased by CDK5 expression and activation in a heterologous cell system. This increased association is at least partially due to phosphorylation of PP1. Conversely, CDK5 expression and activation decreased the association of PP1 with neurabin. As with dopamine depletion, methamphetamine (METH) abuse causes persistent alterations in dopamine signaling which influence striatal medium spiny neuron function and biochemistry. Moreover, both METH toxicity and dopamine depletion are associated with deficits in motor control and motor learning. Pathologically, we observed a decreased association of spinophilin with PP1 in rat striatum evaluated one month following a binge METH paradigm. Behaviorally, we found that loss of spinophilin recapitulates rotarod pathology previously observed in dopamine-depleted and METH-treated animals. Together, these data have implications in multiple disease states associated with altered dopamine signaling such as PD and psychostimulant drug abuse and delineate a novel mechanism by which PP1 interactions with spinophilin and neurabin may be differentially regulated

Does switching pay off? The impact of parliamentary party instability on individual electoral performance

Members of parliament who change their parliamentary party group (PPG) affiliation can be motivated by a variety of factors but the desire to improve their electoral prospects is often argued to be the among the most important. But does switching PPG affiliation improve or damage the electoral performance of those involved? We study the changes in electoral performance of Polish MPs involved in parliamentary party instability since the mid-1990s using an original dataset on all instances of switching compiled by the INSTAPARTY (Party Instability in Parliaments, https://instapartyproject.com) project. In addition to analyzing whether the MPs run for the parliament again in the following election, we zoom in on their electoral performance in terms of personal preference votes. We consider the electoral dividends of different types of switching and find that the effect of switching on personal electoral performance depends on the type of switching MPs were involved in

EEG correlated functional MRI and postoperative outcome in focal epilepsy

Background: The main challenge in assessing patients with epilepsy for resective surgery is localising seizure onset. Frequently, identification of the irritative and seizure onset zones requires invasive EEG. EEG correlated functional MRI (EEG-fMRI) is a novel imaging technique which may provide localising information with regard to these regions. In patients with focal epilepsy, interictal epileptiform discharge (IED) correlated blood oxygen dependent level (BOLD) signal changes were observed in approximately 50% of patients in whom IEDs are recorded. In 70%, these are concordant with expected seizure onset defined by non-invasive electroclinical information. Assessment of clinical validity requires post-surgical outcome studies which have, to date, been limited to case reports of correlation with intracranial EEG. The value of EEG-fMRI was assessed in patients with focal epilepsy who subsequently underwent epilepsy surgery, and IED correlated fMRI signal changes were related to the resection area and clinical outcome. Methods: Simultaneous EEG-fMRI was recorded in 76 patients undergoing presurgical evaluation and the locations of IED correlated preoperative BOLD signal change were compared with the resected area and postoperative outcome. Results: 21 patients had activations with epileptic activity on EEG-fMRI and 10 underwent surgical resection. Seven of 10 patients were seizure free following surgery and the area of maximal BOLD signal change was concordant with resection in six of seven patients. In the remaining three patients, with reduced seizure frequency post-surgically, areas of significant IED correlated BOLD signal change lay outside the resection. 42 of 55 patients who had no IED related activation underwent resection. Conclusion: These results show the potential value of EEG-fMRI in presurgical evaluation

Conceptualisation, development and validation of T-QoL© (Teenagers' Quality of Life): a patient-focused measure to assess quality of life of adolescents with skin diseases

Aim To develop and validate a dermatology-specific quality of life (QoL) instrument for adolescents with skin diseases. Methods Qualitative semi-structured interviews were conducted with adolescents with skin disease to gain in-depth understanding of how skin diseases affect their QoL. A prototype instrument based on the themes identified from content analysis of interviews was tested in several stages, using Classical Test Theory (CTT) and Item Response Theory (IRT) models to develop this new tool and conduct its psychometric evaluation. Results Thirty-three QoL issues were identified from semi-structured interviews with 50 adolescents. A questionnaire based on items derived from content analysis of interviews was subjected to Rasch analysis: factor analysis identified three domains, therefore not supporting the validity of T-QoL as a unidimensional measure. Psychometric evaluation of the final 18-item questionnaire was carried out in a cohort of 203 adolescents. Convergent validity was demonstrated by significant correlation with Skindex-Teen and CDLQI or DLQI. The T-QoL showed excellent internal consistency reliability: Cronbach's α=0.89 for total scale score and 0.85, 0.60, and 0.74 respectively for domains 1, 2 and 3. Test-retest reliability was high in stable subjects. T-QoL showed sensitivity to change in two sub-groups of patients who indicated change in their self-assessed disease severity. Conclusion Built on rich qualitative data from patients, the T-QoL is a simple and valid tool to quantify the impact of skin disease on adolescents’ QoL; it could be used as an outcome measure in both clinical practice and clinical research

Family reported outcomes, an unmet need in the management of a patient's disease: appraisal of the literature

Abstract: Background: A person’s chronic health condition or disability can have a huge impact on the quality of life (QoL) of the whole family, but this important impact is often ignored. This literature review aims to understand the impact of patients' disease on family members across all medical specialities, and appraise existing generic and disease-specific family quality of life (QoL) measures. Methods: The databases Medline, EMBASE, CINHAL, ASSIA, PsycINFO and Scopus were searched for original articles in English measuring the impact of health conditions on patients' family members/partner using a valid instrument. Results: Of 114 articles screened, 86 met the inclusion criteria. They explored the impact of a relative's disease on 14,661 family members, mostly 'parents' or 'mothers', using 50 different instruments across 18 specialities including neurology, oncology and dermatology, in 33 countries including the USA, China and Australia. These studies revealed a huge impact of patients' illness on family members. An appraisal of family QoL instruments identified 48 instruments, 42 disease/speciality specific and six generic measures. Five of the six generics are aimed at carers of children, people with disability or restricted to chronic disease. The only generic instrument that measures the impact of any condition on family members across all specialities is the Family Reported Outcome Measure (FROM-16). Although most instruments demonstrated good reliability and validity, only 11 reported responsiveness and only one reported the minimal clinically important difference. Conclusions: Family members' QoL is greatly impacted by a relative's condition. To support family members, there is a need for a generic tool that offers flexibility and brevity for use in clinical settings across all areas of medicine. FROM-16 could be the tool of choice, provided its robustness is demonstrated with further validation of its psychometric properties.Peer reviewe