Development Of Novel Model Research Articles

Progress in molecular biology and translational science addressing the needs of nano-rare patients.

The healthcare systems in the developed economies were established primarily to address the more prevalent diseases and have been customized to support the provision of therapeutics to rare patients. However, with the ever-broader implementation of genomic sequencing, it is clear that there are significantly more disease-causing mutations in the human genome than realized and that many mutations are much rarer than current definitions of rare disease populations. Given this, I propose parsing patient populations and defining patient populations more precisely. Nano-rare patients are defined as patients having disease-causing mutations that are unique to a single patient or having a known worldwide prevalence of less than 30. These patient populations present unique challenges to healthcare systems that demand the development of novel models for delivery of therapeutics and novel, more efficient drug discovery technologies, such as antisense technology. The challenges presented by nano-rare patients, a novel non-profit model as a means of providing experimental treatments rather than the traditional commercial model, and progress in establishing a non-profit solution are discussed.

Validation study of Bekaert's age estimation model based on DNA methylation rate and development of novel models using Japanese blood samples

Validation study of Bekaert's age estimation model based on DNA methylation rate and development of novel models using Japanese blood samples

A Novel Nonhuman Primate Model of Nonatopic Asthma.

Nonhuman primate models have an essential role in understanding progressive respiratory disease pathogenesis. Immune and physiologic parameters in the nonhuman primate closely reflect the complexity of human systems and provide an exceptional translational impact for the investigation of the mucosal immune changes in response to environmental exposures. This potential warrants the development of novel models that will clarify the interaction of respiratory disease and the inhalable environment and the potential of novel therapies to alleviate the untoward results of these interactions. Nonhuman primate models of asthma can be spontaneous, induced, or experimentally manipulated by various exposures. Here we describe a model of exacerbation of airway hyperreactivity induced by exposure to an air pollutant, ozone, in a cohort of young adult asthmatic rhesus macaques.

Forecasting intra-hour solar photovoltaic energy by assembling wavelet based time-frequency analysis with deep learning neural networks

Due to the expected lack of fossil fuels in near future as well as climate change produced by greenhouse effect as consequence of environmental emissions, renewable energy generation, and specifically solar photovoltaic generation, has become relevant in present energy generation challenge. Photovoltaic generators have strong relationship with solar irradiation and outdoor temperature in energy generation process. These meteorological parameters are volatile and uncertain in nature so, unexpected changes on these parameters produce variations on solar photovoltaic generators’ output power. While many researchers have been focused in recent years on the development of novel models for forecasting involved meteorological parameters in photovoltaic generation, they commonly do not consider an analysis step of the data before using it in the developed models. Hence, the aim of this study consists in assembling a wavelet based time-frequency analysis of the used data with deep learning neural networks to forecast solar irradiation, in next 10 min, to compute solar photovoltaic generation. Results of the validation step showed that the deviation of the proposed forecaster was lower than 4% in 90.60% of studied sample days. Final forecaster’s root mean square error was 35.77 W/m2, which was an accuracy improvement of 37.52% compared against persistence benchmark model.

Implemented models and perspectives of managing lipid metabolism disorders. Concept of rare lipid disease centers

Despite the advances in lipidology over the past decade, the control of dyslipidemia at the population level in Russia, as in a number of European countries, remains unsatisfactory. The need for novel organizational approaches to solving the problem at the regional and federal levels is obvious. This publication provides an overview of the implemented projects and the successful practical experience of lipid centers in Russia, as well as the prospects for the development of novel models that will optimize the care provision for patients with lipid metabolism disorders at the population level.

Modeling the nonlinear behavior of ACC for SCFST columns using experimental-data and a novel evolutionary-algorithm

Axial compression capacity (ACC) is an important parameter for the concrete-filled steel tubular columns to measure the resistance of these fundamental elements, which used in the construction of several structures types. For this purpose, the Gene Expression Programing (GEP) is proposed in this paper as a new framework for the development of novel models with closed-form equations to describe the behavior of the axial compression capacity (ACC) for Square Concrete-Filled Steel Tubular (SCFST) columns. For an accurate ACC modeling, six novel predictive formulas based on the GEP-approach were proposed by incorporating different combinations of the input variables. These latter were obtained from a large dataset that includes 300 experimental tests with different ranges and varieties. Besides, the most known codes and empirical correlations for modeling the behavior of ACC for SCFST columns were reviewed, whereas the performance, accuracy, and efficiency of the proposed models and the excited codes and correlations were investigated and compared using several statistical criteria and graphical illustration. Results show that the best explicit closed-form correlation extracted based on the GEP-approach exhibit an overall coefficient of determination (R2) value of 0.9943. Furthermore, the outcome results indicate that the efficiency of the proposed GEP-based formulations outperform the excited codes and correlations, which proves that the GEP is a powerful technique to derive a new model for modeling the complex behavior of the ACC for SCFST columns.

Abstract IA15: Development of Novel Models and Identification of Therapeutic Vulnerabilities in Highly Aggressive Prostate Cancer In African American Men

Abstract African Americans have the highest mortality rate and shortest survival of any racial/ethnic group in the US for most cancers. An estimated 29,570 cases of prostate cancer are expected to be diagnosed in AA men in 2020. The average annual incidence rate for African American men is 76% higher than the rate in Caucasian Americans. Prostate cancer is the second leading cause of cancer death in African American men, with an estimated 5,350 deaths expected in 2020, which is the highest of all ethnic groups (2.2X higher than Caucasian men). These disparities are appalling and demand immediate action. While the underlying causes are multifactorial, recent studies demonstrate that African American men are at higher risk of being diagnosed with prostate cancer, have higher Gleason grades, and increased risk of progression after radical prostatectomy (RP), even in equal access settings and after accounting for socioeconomic status. These data strongly argue that there is a significant underlying biological/genetic difference between African Americans and Caucasian American men with prostate cancer. Importantly, they highlight an unmet need in order to deliver personalized therapeutic options and ultimately, improve clinical outcomes. Unfortunately, most preclinical studies are performed in prostate cancer cell lines and patient-derived xenografts (PDXs) isolated from patients of Caucasian origin. At Baylor College of Medicine, we are leveraging the high numbers of minority cancer patients in our GU clinics, to generate and utilize innovative prostate cancer PDX and organoid models of diverse racial/ethnic minority origin, which will broaden our understanding of the molecular basis of the disease as well as expedite the drug discovery process. We will discuss preliminary findings from our ongoing studies in genomic and transcriptomic profiling of African American patients, progress in our development of novel prostate cancer models, and lastly, emerging therapeutic opportunities based on precision oncology. Citation Format: Salma Kaochar, Patricia Castro, Sandra Grimm, Darlene Skapura, Matthew Rodriguez, Maurice Dufilho, Cammy Mason, Maria Machado Heredia, Quentxia Wrighting, Jami Daly, Matthew Robertson, Nora Navone, Jacob Berchuck, Matthew Freeman, Zoltan Szallasi, Albert Dobi, Guiherme Godoy, Michael Scheurer, Heidi Dowst, Susan Hilsenbeck, Martha Mims, Anita Sabichi, Edward Yen, Cristian Coarfa, Michael Ittmann, Nicholas Mitsiades. Development of Novel Models and Identification of Therapeutic Vulnerabilities in Highly Aggressive Prostate Cancer In African American Men [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA15.

In-vitro models of human endometriosis.

Endometriosis is one of the most common benign gynecological diseases in women of reproductive age worldwide. In past decades, a number of in-vitro models have been used to investigate the pathology and therapeutic methods for the treatment of endometriosis. The current review summarized the majority of currently available in-vitro models, which utilize a variety of cell or tissues types, including endometriotic cell lines, primary endometrial stromal cells, endometrial stem cells, endometrial explants, peritoneal explants and immune cells. These cells or tissues are cultured individually, co-cultured in 2D or 3D systems with various matrices or cultured in chicken chorioallantotic membranes and amniotic membranes culture systems. These models are able to represent one or more aspects of the process of endometriosis. These models are helpful and can be used to investigate the development of endometriosis and the underlying mechanisms of this disorder in detail, and help investigators select appropriate models for their experiments. Recently, the new concept of endometriosis as a fibrotic condition will lead research to investigate the differentiation of myofibroblasts and the development of fibrosis in endometriotic lesions, which will increase the development of novel models that can be used to investigate endometriotic fibrosis.

Pharmacoepidemiology and Big Data Analytics: Challenges and Opportunities when Moving towards Precision Medicine.

Pharmacoepidemiology is the study of the safety and effectiveness of medications following market approval. The increased availability and size of healthcare utilization databases allows for the study of rare adverse events, sub-group analyses, and long-term follow-up. These datasets are large, including thousands of patient records spanning multiple years of observation, and representative of real-world clinical practice. Thus, one of the main advantages is the possibility to study the real-world safety and effectiveness of medications in uncontrolled environments. Due to the large size (volume), structure (variety), and availability (velocity) of observational healthcare databases there is a large interest in the application of natural language processing and machine learning, including the development of novel models to detect drug-drug interactions, patient phenotypes, and outcome prediction. This report will provide an overview of the current challenges in pharmacoepidemiology and where machine learning applications may be useful for filling the gap.

Deep Learning for Crowd Counting: A Survey

The growth of deep learning for crowd counting is immense in the recent years. This results in numerous deep learning model developed with huge multifariousness. This paper aims to capture a big picture of existing deep learning models for crowd counting. Hence, the development of novel models for future works can be accelerated.

Evidence-Based Review and Discussion Points

Evidence-Based Review and Discussion Points

Tissue-specific genes as an underutilized resource in drug discovery

Tissue-specific genes are believed to be good drug targets due to improved safety. Here we show that this intuitive notion is not reflected in phase 1 and 2 clinical trials, despite the historic success of tissue-specific targets and their 2.3-fold overrepresentation among targets of marketed non-oncology drugs. We compare properties of tissue-specific genes and drug targets. We show that tissue-specificity of the target may also be related to efficacy of the drug. The relationship may be indirect (enrichment in Mendelian disease and PTVesc genes) or direct (elevated betweenness centrality scores for tissue-specifically produced enzymes and secreted proteins). Reduced evolutionary conservation of tissue-specific genes may represent a bottleneck for drug projects, prompting development of novel models with smaller evolutionary gap to humans. We show that the opportunities to identify tissue-specific drug targets are not exhausted and discuss potential use cases for tissue-specific genes in drug research.

Assisted reproductive technologies for endangered species conservation: developing sophisticated protocols with limited access to animals with unique reproductive mechanisms.

Assisted reproductive technologies (ARTs) have been proposed as a means of overcoming the significant challenges of managing small, isolated populations of endangered species in zoos. However, efficient protocols for ARTs do not exist for most endangered species. This review will focus on research efforts to characterize unique reproductive mechanisms and develop species-specific ARTs. Central to these studies are assays to measure steroid metabolites in urine or feces and/or training programs to allow unrestrained blood collections and ultrasound evaluations. The resulting information about estrous cycle dynamics, combined with studies of semen collection and processing, provides the foundation for the development of artificial insemination (AI). In vitro fertilization and embryo transfer are also discussed in relation to the advantages these techniques could provide relative to AI, as well as the significant challenges involved with technologies that require oocytes and embryos. Finally, an argument is made for additional research of nontraditional model species (e.g., domestic cats and dogs) and the development of novel models representing unique taxa. Whether these species are studied by zoo-based researchers with the expressed intent of developing ARTs for conservation or academic scientists interested in basic biology, the resulting information will provide a unique, evolutionary perspective on reproduction that could have wide-reaching benefits. The more information we have available, the better our chances will be of developing effective ARTs and making a difference in conservation efforts for endangered species.

Early Intra-Acinar Events in Pathogenesis of Pancreatitis

Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.

Polypropylene nano-composites at high strain rate impacts: Characterization, failure modes, and modeling

As a major challenge, development of light-weight fibre reinforced polymer (FRP) composite body armour, characterization of candidate matrix polymers at high strain rate impact is the focus in this research. Polypropylene (PP) and the nano-composites with 1-5% by weight of NC (nanoclay) platelets are the candidates considered. In the characterization phase, high strain rate impact and quasi-static loading tests were performed to figure out the limiting (failure) responses. Comparison between the material systems is, subsequently, made to nominate one matrix configuration. Enhancements of mechanical properties with increase in weight percentage of the nanoparticles are observed at both quasi-static and dynamic loadings. Observations of dispersed imposed failure modes, development of novel model for failure modulus and evaluation of peak strength values are also attempted. Keywords : Nano-composite, Impact behaviour, Analytical modelling, Polypropylene, Failure mode.

Models of intrahepatic cholangiocarcinoma: novel tools and therapeutic applications

Models of intrahepatic cholangiocarcinoma: novel tools and therapeutic applications Margaret A Hill,1,2,* William B Alexander,1,2,* Aram F Hezel1,2 1Department of Biomedical Genetics, 2Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA *These authors contributed equally to this work Abstract: Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy, and a number of recent studies have identified an increasing trend in incidence and mortality. As an aggressive disease characterized by early metastasis, surgical resection is not an option for most patients, and chemotherapy has limited benefit. Thus, the prognosis is extremely poor, warranting the development of novel models to improve detection and treatment strategies for this lethal cancer. In this regard, significant technological advancements have provided key tools to model and study iCCA. Furthermore, these technologies are addressing the need for models that can readily be adapted to address different genetic contexts, an important consideration for genetically diverse cancers such as iCCA. In this review, we outline these various available tools, discussing specifically how they have been employed to study iCCA while highlighting important therapeutic implications. Finally, we discuss novel strategies utilizing patient-derived tumor tissue which have promising translational applications. Keywords: cholangiocarcinoma, biliary cancer, models, cell of origin, Cre-Lox, sleeping beauty

Pediatric palliative oncology: the state of the science and art of caring for children with cancer.

Pediatric palliative oncology (PPO) is an emerging field that integrates the principles of palliative care early into the illness trajectory of children with cancer. PPO providers work with interdisciplinary clinicians to provide optimal medical and psychosocial care to children with cancer and their families. Ongoing advances in the field of pediatric oncology, including new treatment options for progressive cancers, necessitate the early integration of palliative care tenets including holistic care, high-quality communication, and assessment and management of refractory symptoms. Research in this emerging field has expanded dramatically over the past several years. This review will focus on advancements within several key areas of the field, specifically regarding investigation of the communication needs and preferences of patients and families, exploration of educational initiatives and interventions to teach PPO principles to clinicians, study of patient-reported and parent-reported tools to better assess and manage refractory symptoms, and development of novel models to integrate palliative care within pediatric oncology. Research findings in the field of PPO, concurrent with advances in the treatment of pediatric cancer, may help improve survival and quality of life for children with cancer.

Next generation tau models in Alzheimer's disease research - virus based gene delivery systems.

Alzheimer's disease (AD) the most common form of dementia is characterized by cognitive decline and progressive loss of neurons in the central nervous system. Despite huge scientific progress, there are only few animal models that recapitulate at least majority of the AD pathology and related symptomatology. Therefore, alternative methods to develop animal models for neurodegenerative diseases are constantly explored. Recently, recombinant adeno-associated viruses (AAVs) are widely used viral vectors in development of novel models for neurodegenerative diseases. AAV vectors expressing full length, mutant or truncated forms of tau demonstrate early and robust pathology characterized by AT8 positivity, NFT formation, motor and cognitive deficits. Furthermore, AAVs have been used in expression of tau in amyloid rodent models thus developing both lesions of amyloid and tau therefore recapitulating AD like features. Major advantage of AAV as a delivery system is the site specific expression of tau, mostly in hippocampus and cortex, and thus elimination of unwanted ectopic transgene expression. These novel models may help in better understanding of AD etiopathogenesis and provide a platform for development and testing of disease modifying drugs in preclinical efficacy studies.

Development of Novel Model for Vaginal Cuff Closure Training in a Box Trainer

Development of Novel Model for Vaginal Cuff Closure Training in a Box Trainer

Novel models to improve access to medicines for chronic diseases in South Africa: an analysis of stakeholder perspectives on community-based distribution models.

BackgroundThe rising demand for chronic disease treatment and the barriers to accessing these medicines have led to the development of novel models for distributing medicines in South Africa’s public sector, including distribution away from health centres, known as community-based distribution (CBD). In this article, we provide a typology of CBD models and outline perceived facilitators and barriers to their implementation using an adapted health systems framework with a view to analysing how future policy decisions on CBD could impact existing models and the health system as a whole.MethodsA qualitative exploratory study comprising in-depth interviews and non-participant observations was conducted between 2012 and 2014 in one province. Study participants consisted of frontline healthcare providers (HCPs) in the public sector and a few policy, supply chain and public health experts. Observations of processes occurred at two CBD sites. We conducted deductive analysis guided by the adapted framework.ResultsModels varied in typology ranging from formal (approved by the Department of Health) to informal (demand-driven) and with or without user-fees. Processes and structures also differed, as did HCPs’ perceptions of what is appropriate. HCPs perceived that CBD models were largely acceptable to patients and accommodating of their needs. Affordability of services linked to charging of user-fees was a contested issue, requiring further exploration. CBD models operated in the absence of formal policy to guide implementation, and this, coupled with the involvement of non-health professionals, issues regarding medicines handling and storage; and limited patient counselling raised concerns about the quality of pharmaceutical services being delivered. Policy decisions on each of the health system elements will likely affect other elements and ultimately influence the structure and operational modalities of models. In anticipation of a future CBD policy, stakeholders cited the need for a context specific lens in order to harmonise with current implementation efforts.ConclusionA formal policy on CBD is required in an effort to standardise services for quality assurance purposes. Frontline HCPs should be involved in the development of such policy to ensure that existing arrangements already working well are not undermined. Further research will seek to contribute towards evidence-based development of policy and service delivery guidelines for CBD activities in South Africa.