Genomic Informatics in the Healthcare System
Salvatore Volpe in Health Informatics, 2022
Another possible explanation for the phenotypic heterogeneity among cases is epigenetic differences. Epigenetic processes such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs can alter the activity of a gene without changing the DNA sequence. To further understand and identify the detail of the heterogeneity, a strategy such as the chromatin immunoprecipitation sequencing (ChIP-Seq) or RNA-Seq can be used. Exploring factors that can account for the phenotypic variability may provide insight into the pathways involved in disease. Furthermore, the comprehensive genetic evaluation and investigation of various individuals with these conditions will likely enlighten the fields of genomic locus heterogeneity and allelic heterogeneity of the genes with a broad spectrum of detected variants.
Ayurveda Renaissance – Quo Vadis?
D. Suresh Kumar in Ayurveda in the New Millennium, 2020
Identifying phenotypic and genetic heterogeneity, gene–gene interactions and allelic spectrum is a major challenge in understanding complex diseases. Of the several factors which contribute to this, phenotypic heterogeneity is a serious limitation encountered in modern medicine (Manchia et al. 2013). Juyal et al. (2012) opine that conditioning association studies on prior risk, predictable in Ayurveda, will uncover much more variation and advance diagnostics and therapeutics. They attempted identification of genetic susceptibility markers in a rheumatoid arthritis (R.A.) cohort by combining the prakṛti-based grouping of individuals with genetic analysis tools. Association of 21 markers from commonly implicated inflammatory and oxidative stress pathways was tested using a case-control approach in a total cohort comprising 325 cases, 356 controls and the three subgroups separately. A few postulates of Ayurveda on the disease characteristics were also tested in the various prakṛti groups using clinico-genetic data (Juyal et al. 2012).
Hematological problems in the neonate
Prem Puri in Newborn Surgery, 2017
vWD is the most frequently inherited bleeding disorder, affecting approximately 1% of the population, and is transmitted in autosomal dominant or recessive patterns. Bleeding tends to be predominantly mucocutaneous. There are three main categories of vWD based on the quantitative level or function of vWF: type 1, 2, or 3. Type 2 is further divided into four separate subtypes: 2A, 2B, 2M, and 2N. There is significant phenotypic heterogeneity even among members of the same family. The majority of individuals have type 1 vWD with type 3 vWD being the rarest form of the disease and having the most severe bleeding phenotype due to complete or almost complete deficiency of vWF. Typically, only patients with type 3 or some type 2 vWD present with bleeding as neonates.29 Bleeding can occur after surgery or trauma. Bleeding into joints is rare and typically only seen in individuals with severe type 3 disease. The diagnosis of vWD is based on three main laboratory assays: (i) quantitative measurement of vWF in plasma, (ii) activity of vWF and its ability to bind platelets, (iii) FVIII activity. High molecular weight multimer analysis can be performed to help differentiate type 2 varieties.25
An evaluation of mepolizumab for the treatment of severe asthma
Published in Expert Opinion on Biological Therapy, 2019
Jaymin B Morjaria, Rosalia Emma, Virginia Fuochi, Riccardo Polosa, Massimo Caruso
Asthma has long been recognized as a heterogeneous condition, both in terms of clinical outcomes and response to therapy. Various phenotypes have been identified based on asthma control and severity, age of onset of disease, obesity, smoking status, and sputum eosinophil counts [7,8,70]. Different molecular pathways underlying asthma inflammation may support this phenotypic heterogeneity. Consequently, intensive research in severe asthma has led to the development of specific biological agents that target specific pathological pathways, such as anti-IgE, anti-IL5, anti-IL4 and anti-IL13, anti-prostaglandin D2 (PGD2) receptor [71,72], and anti-thymic stromal lymphopoietin (TSLP) [73]. Currently, three biologic drugs targeting the IL-5 signaling pathway are approved as an add-on therapy for severe eosinophilic asthma, including mepolizumab (Nucala®, GlaxoSmithKline, UK), reslizumab (CINQAIR®; Teva, Israel) and benralizumab (FASENRATM, AstraZeneca, UK).
New drugs in preclinical and early stage clinical development in the treatment of heart failure
Published in Expert Opinion on Investigational Drugs, 2019
Juan Tamargo, Ricardo Caballero, Eva Delpón
Evaluation of new drugs in the heterogeneous HF population is challenging and the old strategy of treating HF as a single entity (‘one-size-fits-all approach’) is doomed to failure [11,12]. Furthermore, because of the multiple signaling pathways involved in the different HF phenotypes, it is possible that some new drugs were studied in the wrong population or the wrong endpoints were selected based on the underlying pathophysiological mechanisms and/or the MOA of the drug. Improved phenotypic characterization of the HF syndromes based on pathophysiology, clinical/etiologic subtype, type of clinical presentation, and comorbidities would allow to select specific patient phenotypes whose underlying pathophysiological mechanisms can be targeted by the MOA of evaluated drug. This will allow to limit excessive phenotypic heterogeneity and maximize the expected therapeutic benefit by selecting the patients that most likely can benefit. A major limitation is our limited ability to identify the primary mechanism underlying HF and to identify such homogeneous subsets of patients. The development of population-based disease registries collecting clinical, imaging, laboratory, and genetic data, treatment patterns, and causes of death and hospitalizations may facilitate the identification of the right populations and represent the most efficient way for improving the treatment of HF [13].
An update on diagnosis and therapy of metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2018
The most interesting area of research at present in the field of metabolic myopathies is genetics and gene therapy. Whereas, huge progress has been made with regard to genetic diagnosis of metabolic myopathies, gene therapy of metabolic myopathies is still in its early stages and requires extensive scientific effort to reach the clinical level. To stimulate research and achieve progress in the field of gene therapy, it would be important to find out, which genetic or environmental factors determine the phenotypic heterogeneity, gene expression, transcription, and translation. If all open questions can be sufficiently solved, the ultimate goal, the causative treatment of metabolic myopathies by correcting the wrong genetic information, could be reached in the future. Possibly, progress in the genetic diagnosis will enable us to detect the genetic defect already at a preclinical stage to initiate an effective gene therapy not to stop progression of a metabolic myopathy but rather to prevent that a genetically determined defect becomes symptomatic at all.
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