Comprehensive characterization of SDH-deficient GIST using NGS data and iPSC models

Gastrointestinal stromal tumors (GIST) are the most common di tumors of the gastrointestinal tract, arising from the interstitial cells of Cajal (ICCs) or their precursors. The vast majority of GISTs (75–85% of GIST) harbor KIT or PDGFRA mutations. A small percentage of GIST (about 10‐15%) do not harbor any of these driver mutations and have historically been called wild-type (WT). Among them, from 20% to 40% show loss of function of the succinate dehydrogenase complex (SDH), also defined as SDH‐deficient GIST. SDH-deficient GISTs display distinctive clinical and pathological features, and can be sporadic or associated with Carney triad or Carney-Stratakis syndrome. These tumors arise most frequently in the stomach with predilection to distal stomach and antrum, have a multi-nodular growth, display a histological epithelioid phenotype, and present frequent lympho-vascular invasion. Occurrence of lymph node metastases and indolent course are representative features of SDH-deficient GISTs. This subset of GIST is known for the immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals the loss of function of the entire SDH-complex. The overall aim of my PhD project consists of the comprehensive characterization of SDH deficient GIST. Throughout the project, clinical, molecular and cellular characterizations were performed using next-generation sequencing technologies (NGS), that has the potential to allow the identification of molecular patterns useful for the diagnosis and development of novel treatments. Moreover, while there are many different cell lines and preclinical models of KIT/PDGFRA mutant GIST, no reliable cell model of SDH-deficient GIST has currently been developed, which could be used for studies on tumor evolution and in vitro assessments of drug response. Therefore, another aim of this project was to develop a pre-clinical model of SDH deficient GIST using the novel technology of induced pluripotent stem cells (iPSC).

A comprehensive experimental and numerical approach for assessing the hydro-mechanical behaviour of river embankments

In this doctoral dissertation, a comprehensive methodological approach for the assessment of river embankments safety conditions, based on the integrated use of laboratory testing, physical modelling and finite element (FE) numerical simulations, is proposed, with the aim of contributing to a better understanding of the effect of time-dependent hydraulic boundary conditions on the hydro-mechanical response of river embankments. The case study and materials selected for the present research project are representative for the riverbank systems of Alpine and Apennine tributaries of the main river Po (Northern Italy), which have recently experienced various sudden overall collapses. The outcomes of a centrifuge test carried out under the enhanced gravity field of 50-g, on a riverbank model, made of a compacted silty sand mixture, overlying a homogeneous clayey silt foundation layer and subjected to a simulated flood event, have been considered for the definition of a robust and realistic experimental benchmark. In order to reproduce the observed experimental behaviour, a first set of numerical simulations has been carried out by assuming, for both the embankments and the foundation unit, rigid soil porous media, under partially saturated conditions. Mechanical and hydraulic soil properties adopted in the numerical analyses have been carefully estimated based on standard saturated triaxial, oedometer and constant head permeability tests. Afterwards, advanced suction-controlled laboratory tests, have been carried out to investigate the effect of suction and confining stresses on the shear strength and compressibility characteristics of the filling material and a second set of numerical simulations has been run, taking into account the soil parameters updated based on the most recent tests. The final aim of the study is the quantitative estimation of the predictive capabilities of the calibrated numerical tools, by systematically comparing the results of the FE simulations to the experimental benchmark.

A comprehensive study of the AGN feedback cycle in galaxy clusters from high resolution X-ray and radio observations

At the center of galaxy clusters, a dramatic interplay known as feedback cycle occurs between the hot intracluster medium (ICM) and the active galactic nucleus (AGN) of the central galaxy. The footprints of this interplay are evident from X-ray observations of the ICM, where X-ray cavities and shock fronts are associated with radio lobe emission tracing energetic AGN outbursts. While such jet activity reduces the efficiency of the hot gas to cool to lower temperatures, residual cooling can generate warm and cold gas clouds around the central galaxy. The condensed gas parcels can ultimately reach the core of the galaxy and be accreted by the AGN. This picture is the result of tremendous advances over the last three decades. Yet, a deeper understanding of the details of how the heating–cooling regulation is achieved and maintained is still missing. In this Thesis, we delve into key aspects of the feedback cycle. To this end, we leverage high-resolution (sub-arcsecond), multifrequency observations (mainly X-ray and radio) of several top-level facilities (e.g., Chandra, JVLA, VLBA, LOFAR). First, we investigate which conditions trigger a feedback response to gas cooling, by studying the properties of clusters where feedback is just about to start. Then, we focus on the details of how the AGN–ICM interaction progresses by examining cavity and shock heating in the cluster RBS797, an exemplary case of the jet feedback paradigm. Furthermore, we explore the importance of shock heating and the coupling of distinct jet power regimes (i.e., FRII, FRI and FR0 radio galaxies) to the environment. Ultimately, as heating models rely on the connection between the direct evidence (the jets) and the smoking gun (the X-ray cavities) of feedback, we examine the cases in which these two are dramatically misaligned.

The road to augmented reality: a comprehensive study of hardware and applications over the last ten years

Augmented reality has been growing extensively over the years in all aspects and multiple fields. My aim in this paper is to present a comprehensive study on augmented reality(AR) hardware and its applications from early developments to the possible future trends. Particularly my research is more focused on last 11 years(2012-2022), where I systematically reviewed 30 research papers per year to get a clear knowledge on trends of AR. A total of 330 publications were reviewed and grouped according to their application. The review's main contribution is to show the entire landscape of AR research and to provide a broad view of how it has evolved. Along with various AR glasses history and specifications are presented in detail. In the penultimate chapter I explained my methodology of research following my analysis from the past to the present along with my thoughts for the future. To conclude my study, In the final chapter I made some statements about possible future with AR, VR and XR(extended reality).

A comprehensive study on robotic manipulation of deformable linear objects

There are many deformable objects such as papers, clothes, ropes in a person’s living space. To have a robot working in automating the daily tasks it is important that the robot works with these deformable objects. Manipulation of deformable objects is a challenging task for robots because these objects have an infinite-dimensional configuration space and are expensive to model, making real-time monitoring, planning and control difficult. It forms a particularly important field of robotics with relevant applications in different sectors such as medicine, food handling, manufacturing, and household chores. In this report, there is a clear review of the approaches used and are currently in use along with future developments to achieve this task. My research is more focused on the last 10 years, where I have systematically reviewed many articles to have a clear understanding of developments in this field. The main contribution is to show the whole landscape of this concept and provide a broad view of how it has evolved. I also explained my research methodology by following my analysis from the past to the present along with my thoughts for the future.

Introducing CHIMeRA: from the development of a comprehensive biomedical database to the analysis of its sub-components.

In this thesis we discuss the expansion of an existing project, called CHIMeRA, which is a comprehensive biomedical network, and the analysis of its sub-components by using graph theory. We describe how it is structured internally, what are the existing databases from which it retrieves information and what machine learning techniques are used in order to produce new knowledge. We also introduce a new technique for graph exploration that is aimed to speed-up the network cover time under the condition that the analyzed graph is stellar; if this condition is satisfied, the improvement in the performance compared to the conventional exploration technique is extremely appealing. We show that the stellar structure is highly recurrent for sub-networks in CHIMeRA generated by queries, which made this technique even more interesting. Finally, we describe the convenience in using the CHIMeRA network for research purposes and what it could become in a very near future.

Desorption/ionization Efficiencies Of Triacylglycerols And Phospholipids Via Easi-ms.

Knowledge of the major effects governing desorption/ionization efficiency is required for the development and application of ambient mass spectrometry. Although all triacylglycerols (TAG) have the same favorable protonation and cationization sites, their desorption/ionization efficiencies can vary dramatically during easy ambient sonic-spray ionization because of structural differences in the carbon chain. To quantify this somewhat surprising and drastic effect, we have performed a systematic investigation of desorption/ionization efficiencies as a function of unsaturation and length for TAG as well as for diacylglycerols, monoacylglycerols and several phospholipids (PL). Affinities for Na(+) as a function of unsaturation level have also been assayed via comprehensive metadynamics calculations to understand the influence of this phenomenon on the ionization efficiency. The results suggest that dipole-dipole interactions within a carbon chain tuned by unsaturation sites govern ionization efficiency of TAG and PL.

Iis--integrated Interactome System: A Web-based Platform For The Annotation, Analysis And Visualization Of Protein-metabolite-gene-drug Interactions By Integrating A Variety Of Data Sources And Tools.

High-throughput screening of physical, genetic and chemical-genetic interactions brings important perspectives in the Systems Biology field, as the analysis of these interactions provides new insights into protein/gene function, cellular metabolic variations and the validation of therapeutic targets and drug design. However, such analysis depends on a pipeline connecting different tools that can automatically integrate data from diverse sources and result in a more comprehensive dataset that can be properly interpreted. We describe here the Integrated Interactome System (IIS), an integrative platform with a web-based interface for the annotation, analysis and visualization of the interaction profiles of proteins/genes, metabolites and drugs of interest. IIS works in four connected modules: (i) Submission module, which receives raw data derived from Sanger sequencing (e.g. two-hybrid system); (ii) Search module, which enables the user to search for the processed reads to be assembled into contigs/singlets, or for lists of proteins/genes, metabolites and drugs of interest, and add them to the project; (iii) Annotation module, which assigns annotations from several databases for the contigs/singlets or lists of proteins/genes, generating tables with automatic annotation that can be manually curated; and (iv) Interactome module, which maps the contigs/singlets or the uploaded lists to entries in our integrated database, building networks that gather novel identified interactions, protein and metabolite expression/concentration levels, subcellular localization and computed topological metrics, GO biological processes and KEGG pathways enrichment. This module generates a XGMML file that can be imported into Cytoscape or be visualized directly on the web. We have developed IIS by the integration of diverse databases following the need of appropriate tools for a systematic analysis of physical, genetic and chemical-genetic interactions. IIS was validated with yeast two-hybrid, proteomics and metabolomics datasets, but it is also extendable to other datasets. IIS is freely available online at: http://www.lge.ibi.unicamp.br/lnbio/IIS/.

[principles Of Universality, Comprehensiveness And Equity In A Hearing Health Care Service].

This article analyzed whether the practices of hearing health care were consistent with the principles of universality, comprehensiveness and equity from the standpoint of professionals. It involved qualitative research conducted at a Medium Complexity Hearing Health Care Center. A social worker, three speech therapists, a physician and a psychologist constituted the study subjects. Interviews were conducted as well as observation registered in a field diary. The thematic analysis technique was used in the analysis of the material. The analysis of interviews resulted in the construction of the following themes: Universality and access to hearing health, Comprehensive Hearing Health Care and Hearing Health and Equity. The study identified issues that interfere with the quality of service and run counter to the principles of Brazilian Unified Health System. The conclusion reached was that a relatively simple investment in training and professional qualification can bring about significant changes in order to promote a more universal, comprehensive and equitable health service.

Construction Of A Manual Of Work Processes And Techniques From Centro De Dispensação De Medicamentos De Alto Custo (cedmac), Hospital De Clínicas, Unicamp.

The Centers for High Cost Medication (Centros de Medicação de Alto Custo, CEDMAC), Health Department, São Paulo were instituted by project in partnership with the Clinical Hospital of the Faculty of Medicine, USP, sponsored by the Foundation for Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP) aimed at the formation of a statewide network for comprehensive care of patients referred for use of immunobiological agents in rheumatological diseases. The CEDMAC of Hospital de Clínicas, Universidade Estadual de Campinas (HC-Unicamp), implemented by the Division of Rheumatology, Faculty of Medical Sciences, identified the need for standardization of the multidisciplinary team conducts, in face of the specificity of care conducts, verifying the importance of describing, in manual format, their operational and technical processes. The aim of this study is to present the methodology applied to the elaboration of the CEDMAC/HC-Unicamp Manual as an institutional tool, with the aim of offering the best assistance and administrative quality. In the methodology for preparing the manuals at HC-Unicamp since 2008, the premise was to obtain a document that is participatory, multidisciplinary, focused on work processes integrated with institutional rules, with objective and didactic descriptions, in a standardized format and with electronic dissemination. The CEDMAC/HC-Unicamp Manual was elaborated in 10 months, with involvement of the entire multidisciplinary team, with 19 chapters on work processes and techniques, in addition to those concerning the organizational structure and its annexes. Published in the electronic portal of HC Manuals in July 2012 as an e-Book (ISBN 978-85-63274-17-5), the manual has been a valuable instrument in guiding professionals in healthcare, teaching and research activities.

Health-related And Socio-demographic Factors Associated With Frailty In The Elderly: A Systematic Literature Review.

Frailty is a syndrome that leads to practical harm in the lives of elders, since it is related to increased risk of dependency, falls, hospitalization, institutionalization, and death. The objective of this systematic review was to identify the socio-demographic, psycho-behavioral, health-related, nutritional, and lifestyle factors associated with frailty in the elderly. A total of 4,183 studies published from 2001 to 2013 were detected in the databases, and 182 complete articles were selected. After a comprehensive reading and application of selection criteria, 35 eligible articles remained for analysis. The main factors associated with frailty were: age, female gender, black race/color, schooling, income, cardiovascular diseases, number of comorbidities/diseases, functional incapacity, poor self-rated health, depressive symptoms, cognitive function, body mass index, smoking, and alcohol use. Knowledge of the complexity of determinants of frailty can assist the formulation of measures for prevention and early intervention, thereby contributing to better quality of life for the elderly.

[diet Quality And Associated Factors Among The Elderly: A Population-based Study In Campinas, São Paulo State, Brazil].

The aim of this study was to assess the quality of diet among the elderly and associations with socio-demographic variables, health-related behaviors, and diseases. A population-based cross-sectional study was conducted in a representative sample of 1,509 elderly participants in a health survey in Campinas, São Paulo State, Brazil. Food quality was assessed using the Revised Diet Quality Index (DQI-R). Mean index scores were estimated and a multiple regression model was employed for the adjusted analyses. The highest diet quality scores were associated with age 80 years or older, Evangelical religion, diabetes mellitus, and physical activity, while the lowest scores were associated with home environments shared with three or more people, smoking, and consumption of soft drinks and alcoholic beverages. The findings emphasize a general need for diet quality improvements in the elderly, specifically in subgroups with unhealthy behaviors, who should be targeted with comprehensive strategies.

[strategies For Integration Of Health Care Practices And Sanitary Surveillance In The Context Of The Implementation Of Rede Cegonha - A Brazilian Mother And Infant Health Care Network].

Mother and infant mortality has been the scope of analysis throughout the history of public health in Brazil and various strategies to tackle the issue have been proposed to date. The Ministry of Health has been working on this and the Rede Cegonha strategy is the most recent policy in this context. Given the principle of comprehensive health care and the structure of the Unified Health System in care networks, it is necessary to ensure the integration of health care practices, among which are the sanitary surveillance actions (SSA). Considering that the integration of health care practices and SSA can contribute to reduce mother and infant mortality rates, this article is a result of qualitative research that analyzed the integration of these actions in four cities in the State of São Paulo/Brazil: Campinas, Indaiatuba, Jaguariúna and Santa Bárbara D'Oeste. The research was conducted through interviews with SSA and maternal health managers, and the data were evaluated using thematic analysis. The results converge with other studies, identifying the isolation of health care practices and SSA. The insertion of SSA in collectively-managed areas appears to be a potential strategy for health planning and implementation of actions in the context under scrutiny.

Musculoskeletal Evaluation In Severe Haemophilia A Patients From Latin America.

There is a paucity of literature on haemophilia treatment in Latin American countries, a region characterized by rapidly improving systems of care, but with substantial disparities in treatment between countries. The aim of this study was to evaluate the musculoskeletal status of haemophilia patients from Latin America and to examine the relationship between musculoskeletal status and treatment practices across countries. The Committee of Latin America on the Therapeutics of Inhibitor Groups conducted a survey of its member country representatives on key aspects of haemophilia treatment in 10 countries. Musculoskeletal status of patients was obtained during routine comprehensive evaluations between March 2009 and March 2011. Eligible patients had severe haemophilia A (factor VIII <1%) without inhibitors (<0.6 BU mL(-1) ) and were ≥5 years of age. Musculoskeletal status was compared between three groups of countries, based primarily on differences in the availability of long-term prophylaxis. Overall, 143 patients (5-66 years of age) were enrolled from nine countries. In countries where long-term prophylaxis had been available for at least 10 years (Group A), patients aged 5-10 years had significantly better mean World Federation of Hemophilia clinical scores, fewer target joints and fewer affected joints than patients from countries where long-term prophylaxis has been available for about 5 years (Group B) or was not available (Group C). In Latin America, the musculoskeletal status of patients with severe haemophilia without inhibitors has improved significantly in association with the provision of long-term prophylaxis. As more countries in Latin America institute this practice, further improvements are anticipated.

Prevalence And Treatment Of Hypertension In Urban And Riverside Areas In Porto Velho, The Brazilian Amazon.

Abstract Introduction: Hypertension (HTN) is a preventable cause of cardiovascular morbidity and mortality. To compare the prevalence, awareness, treatment, and control of HTN among urban and riverside populations in Porto Velho, Amazon region. We conducted a cross-sectional study between July and December 2013 based on a household survey of individuals aged 35-80 years. Interviews by using a standardized questionnaire, and blood pressure (BP), weight, height, and waist circumference measurements were performed. HTN was defined when individuals reported having the disease, received antihypertensive medications, or had a systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg. Awareness was based on self-reports and the use of antihypertensive medications. Control was defined as a BP ≤ 140/90 mm Hg. Among the 1410 participants, 750 (53.19%) had HTN and 473 (63.06%) had diagnosis awareness, of whom 404 (85.41%) received pharmacological treatment but with low control rate. The prevalence and treatment rates were higher in the urban areas (55.48% vs. 48.87% [p = 0.02] and 61.25% vs. 52.30% [p < 0.01], respectively). HTN awareness was higher in the riverside area (61.05% vs. 67.36% ; p < 0.01), but the control rates showed no statistically significant difference (22.11% vs. 23.43% ; p = 0.69). HTN prevalence was higher in the urban population than in the riverside population. Of the hypertensive individuals in both areas, <25% had controlled HTN. Comprehensive public health measures are needed to improve the prevention and treatment of systemic arterial HTN and prevent other cardiovascular diseases.