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Journal of Translational Medicine Apr 2017Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use. (Review)
Review
OBJECTIVES
Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use.
METHODS
Extensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics.
KEY FINDINGS
Cystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormality of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy, extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and complication prevention but recently the protein rectifiers are being studied which are claimed to correct underlying structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.
CONCLUSIONS
The treatment has a long way to go as most of the existing therapeutics is for older children. Other limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.
Topics: Cystic Fibrosis; Drug Discovery; Genetic Predisposition to Disease; Humans; Models, Biological
PubMed: 28449677
DOI: 10.1186/s12967-017-1193-9 -
Frontiers in Nutrition 2019An individual's dietary and supplement strategies can influence markedly their physical performance. Personalized nutrition in athletic populations aims to optimize... (Review)
Review
An individual's dietary and supplement strategies can influence markedly their physical performance. Personalized nutrition in athletic populations aims to optimize health, body composition, and exercise performance by targeting dietary recommendations to an individual's genetic profile. Sport dietitians and nutritionists have long been adept at placing additional scrutiny on the one-size-fits-all general population dietary guidelines to accommodate various sporting populations. However, generic "one-size-fits-all" recommendations still remain. Genetic differences are known to impact absorption, metabolism, uptake, utilization and excretion of nutrients and food bioactives, which ultimately affects a number of metabolic pathways. Nutrigenomics and nutrigenetics are experimental approaches that use genomic information and genetic testing technologies to examine the role of individual genetic differences in modifying an athlete's response to nutrients and other food components. Although there have been few randomized, controlled trials examining the effects of genetic variation on performance in response to an ergogenic aid, there is a growing foundation of research linking gene-diet interactions on biomarkers of nutritional status, which impact exercise and sport performance. This foundation forms the basis from which the field of sport nutrigenomics continues to develop. We review the science of genetic modifiers of various dietary factors that impact an athlete's nutritional status, body composition and, ultimately athletic performance.
PubMed: 30838211
DOI: 10.3389/fnut.2019.00008 -
Frontiers in Genetics 2022We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD. We designed a...
We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD. We designed a retrospective study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated. Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559-2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively. USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.
PubMed: 36110214
DOI: 10.3389/fgene.2022.900548 -
The Yale Journal of Biology and Medicine Dec 2022Worldwide, remains a leading nosocomial pathogen that is difficult to treat and constitutes a challenging menace to healthcare systems. shows increased and alarming... (Review)
Review
Worldwide, remains a leading nosocomial pathogen that is difficult to treat and constitutes a challenging menace to healthcare systems. shows increased and alarming resistance to carbapenems, long acknowledged as last-resort antibiotics for treatment of resistant infections. Varied and recalcitrant pathways of resistance to carbapenems can simultaneously occur in , including the production of carbapenemases, broadest spectrum types of β-lactamases that hydrolyze virtually almost all β-lactams, including carbapenems. The organism can produce chromosomal, plasmid-encoded, and integron- or transposon-mediated carbapenemases from different molecular classes. These include Ambler class A (KPC and some types of GES enzymes), class B (different metallo-β-lactamases such as IMP, VIM, and NDM), and class D (oxacillinases with carbapenem-hydrolyzing capacity like OXA-198) enzymes. Additionally, derepression of chromosomal AmpC cephalosporinases in contributes to carbapenem resistance in the presence of other concomitant mechanisms such as impermeability or efflux overexpression. Epidemiologic and molecular evidence of carbapenemases in has been long accumulating, and reports of their existence in different geographical areas of the world currently exist. Such reports are continuously being updated and reveal emerging varieties of carbapenemases and/or new genetic environments. This review summarizes carbapenemases of importance in , highlights their genetic profile, and presents current knowledge about their global epidemiology.
Topics: Humans; Pseudomonas aeruginosa; Genetic Profile; beta-Lactamases; Anti-Bacterial Agents; Carbapenems; Microbial Sensitivity Tests
PubMed: 36568831
DOI: No ID Found -
Cell May 2019Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in...
Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.
Topics: Carcinogens, Environmental; DNA Damage; DNA Mutational Analysis; DNA Repair; DNA Replication; Genetic Profile; Genome, Human; Humans; INDEL Mutation; Mutagenesis; Mutation; Neoplasms; Pluripotent Stem Cells; Whole Genome Sequencing
PubMed: 30982602
DOI: 10.1016/j.cell.2019.03.001 -
JAMA Jul 2023Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal... (Comparative Study)
Comparative Study
IMPORTANCE
Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.
OBJECTIVE
To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.
DESIGN, SETTING, AND PARTICIPANTS
The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021.
EXPOSURE
Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform.
MAIN OUTCOMES AND MEASURES
Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care).
RESULTS
A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.
CONCLUSIONS AND RELEVANCE
The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.
Topics: Clinical Decision-Making; Genetic Profile; Genomics; Prospective Studies; Whole Genome Sequencing; Genetic Testing; Genetic Diseases, Inborn; Humans; Infant, Newborn; Neonatal Screening; Infant; Sequence Analysis, DNA; Mutation
PubMed: 37432431
DOI: 10.1001/jama.2023.9350 -
Cancers Apr 2022Recent advances in our understanding of cancer, driven mainly by the emergence of new technologies have highlighted that heterogeneity shapes not only the genetic...
Recent advances in our understanding of cancer, driven mainly by the emergence of new technologies have highlighted that heterogeneity shapes not only the genetic profile of tumors but also their epigenetic and gene expression profile [...].
PubMed: 35454790
DOI: 10.3390/cancers14081885 -
Maedica Jun 2022Endometriosis is a condition that mainly concerns women of reproductive age, which causes several problems, including subfertility. The phenotypic presentation of...
Endometriosis is a condition that mainly concerns women of reproductive age, which causes several problems, including subfertility. The phenotypic presentation of endometriosis is defined by a complex interplay between genetic profile, immunological and mechanical factors. In this literature review we examine the causality between endometriosis and subfertility, outlining possible mechanisms involved in the pathogenesis. The purpose of this study was to conduct a literature review in order to identify the correlation between endometriosis and subfertility through possible mechanisms involved in the pathogenesis of endometriosis-associated subfertility and treatment. A search in Medline/PubMed was done, using the terms "endometriosis" and "subfertility", to identify the most relevant studies that were published during the last six years. Pathogenesis of endometriosis-associated subfertility is not clear yet, although some data indicate that there are several factors that could affect a patient's fertility. Involved mechanisms include mechanical obstruction such as ovarian tubal dysfunction and the abnormal peritoneal microenvironment, genetic, and epigenetic mechanisms, and immunological traits. It is fundamental to better understand these mechanisms in order to improve the therapeutic approach. The clinical management of endometiosis-related subfertility has to be improved. It is important to consider a change in the classification of endometriosis and, more importantly, an effort to avoid surgical procedures. There is a crucial need for effective protocols and novel targets for specific diagnosis and treatment. Consequently, the importance of understanding pathogenesis and genetic mechanisms is underlined. Future researchers should focus on novel non-invasive treatment methods that target specific pathogenic pathways.
PubMed: 36032627
DOI: 10.26574/maedica.2022.17.2.458 -
Cancers Feb 2021The steady improvement of high-throughput technologies greatly facilitates the implementation of personalized precision medicine. Characterization of tumor heterogeneity... (Review)
Review
The steady improvement of high-throughput technologies greatly facilitates the implementation of personalized precision medicine. Characterization of tumor heterogeneity through image-derived features-radiomics and genetic profile modifications-genomics, is a rapidly evolving field known as radiogenomics. Various radiogenomics studies have been dedicated to colorectal cancer so far, highlighting the potential of these approaches to enhance clinical decision-making. In this review, a general outline of colorectal radiogenomics literature is provided, discussing the current limitations and suggested further developments.
PubMed: 33652647
DOI: 10.3390/cancers13050973 -
ImmunoTargets and Therapy 2018Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic... (Review)
Review
Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient's health, stage, and location of the tumor. The efficiency of these treatments can be decreased due to the development of diverse resistance mechanisms. New therapeutic targets have emerged from studies of the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of the malignant transformation. In this review, we aim to survey therapies approved and under evaluation for melanoma treatment and relevant research on the molecular mechanisms underlying melanomagenesis.
PubMed: 29922629
DOI: 10.2147/ITT.S134842