Molecular Aspects of Medicine最新文献

{"title":"Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics","authors":"Yash Gupta ,&nbsp;Oleksandr V. Savytskyi ,&nbsp;Matt Coban ,&nbsp;Amoghavarsha Venugopal ,&nbsp;Vasili Pleqi ,&nbsp;Caleb A. Weber ,&nbsp;Rohit Chitale ,&nbsp;Ravi Durvasula ,&nbsp;Christopher Hopkins ,&nbsp;Prakasha Kempaiah ,&nbsp;Thomas R. Caulfield","doi":"10.1016/j.mam.2022.101151","DOIUrl":"10.1016/j.mam.2022.101151","url":null,"abstract":"<div><p>With more than 5 million fatalities and close to 300 million reported cases, COVID-19 is the first documented pandemic due to a coronavirus that continues to be a major health challenge. Despite being rapid, uncontrollable, and highly infectious in its spread, it also created incentives for technology development and redefined public health needs and research agendas to fast-track innovations to be translated. Breakthroughs in computational biology peaked during the pandemic with renewed attention to making all cutting-edge technology deliver agents to combat the disease. The demand to develop effective treatments yielded surprising collaborations from previously segregated fields of science and technology. The long-standing pharmaceutical industry's aversion to repurposing existing drugs due to a lack of exponential financial gain was overrun by the health crisis and pressures created by front-line researchers and providers. Effective vaccine development even at an unprecedented pace took more than a year to develop and commence trials. Now the emergence of variants and waning protections during the booster shots is resulting in breakthrough infections that continue to strain health care systems. As of now, every protein of SARS-CoV-2 has been structurally characterized and related host pathways have been extensively mapped out. The research community has addressed the druggability of a multitude of possible targets. This has been made possible due to existing technology for virtual computer-assisted drug development as well as new tools and technologies such as artificial intelligence to deliver new leads. Here in this article, we are discussing advances in the drug discovery field related to target-based drug discovery and exploring the implications of known target-specific agents on COVID-19 therapeutic management. The current scenario calls for more personalized medicine efforts and stratifying patient populations early on for their need for different combinations of prognosis-specific therapeutics. We intend to highlight target hotspots and their potential agents, with the ultimate goal of using rational design of new therapeutics to not only end this pandemic but also uncover a generalizable platform for use in future pandemics.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101151"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10198404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro high-content tissue models to address precision medicine challenges","authors":"Samson Afewerki ,&nbsp;Thiago Domingues Stocco ,&nbsp;André Diniz Rosa da Silva ,&nbsp;André Sales Aguiar Furtado ,&nbsp;Gustavo Fernandes de Sousa ,&nbsp;Guillermo U. Ruiz-Esparza ,&nbsp;Thomas J. Webster ,&nbsp;Fernanda R. Marciano ,&nbsp;Maria Strømme ,&nbsp;Yu Shrike Zhang ,&nbsp;Anderson Oliveira Lobo","doi":"10.1016/j.mam.2022.101108","DOIUrl":"10.1016/j.mam.2022.101108","url":null,"abstract":"<div><p>The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content <em>in vitro</em> tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative <em>in vitro</em> models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101108"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9283979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data structuring may prevent ambiguity and improve personalized medical prognosis","authors":"Claudia R. Libertin ,&nbsp;Prakasha Kempaiah ,&nbsp;Yash Gupta ,&nbsp;Jeanne M. Fair ,&nbsp;Marc H.V. van Regenmortel ,&nbsp;Athos Antoniades ,&nbsp;Ariel L. Rivas ,&nbsp;Almira L. Hoogesteijn","doi":"10.1016/j.mam.2022.101142","DOIUrl":"10.1016/j.mam.2022.101142","url":null,"abstract":"<div><p>Topics expected to influence personalized medicine (PM), where medical decisions, practices, and treatments are tailored to the individual patient, are reviewed. Lack of discrimination due to different biological conditions that express similar values of numerical variables (ambiguity) is regarded to be a major potential barrier for PM. This material explores possible causes and sources of ambiguity and offers suggestions for mitigating the impacts of uncertainties.</p><p>Three causes of ambiguity are identified: (1) delayed adoption of innovations, (2) inadequate emphases, and (3) inadequate processes used when new medical practices are developed and validated. One example of the first problem is the relative lack of medical research on “compositional data” –the type that characterizes leukocyte data. This omission results in erroneous use of data abundantly utilized in medicine, such as the blood cell differential. Emphasis on data output ‒not biomedical interpretation that facilitates the use of clinical data‒ exemplifies the second type of problems. Reliance on tools generated in other fields (but not validated within biomedical contexts) describes the last limitation.</p><p>Because reductionism is associated with these problems, non-reductionist alternatives are reviewed as potential remedies. <em>Data structuring</em> (converting <em>data</em> into <em>information</em>) is considered a key element that may promote PM. To illustrate a process that includes data-information-knowledge and decision-making, previously published data on COVID-19 are utilized.</p><p>It is suggested that ambiguity may be prevented or ameliorated. Provided that validations are grounded on biomedical knowledge, approaches that describe certain criteria – such as non-overlapping data intervals of patients that experience different outcomes, immunologically interpretable data, and distinct graphic patterns – can inform, at personalized bases, earlier and/or with fewer observations.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101142"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9291134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging technologies in personalized medicine","authors":"Christopher E. Hopkins","doi":"10.1016/j.mam.2023.101182","DOIUrl":"10.1016/j.mam.2023.101182","url":null,"abstract":"<div><p>A variety of technologies are emerging to help clinicians provide patient-specific diagnosis and therapies. This special edition of the Molecular Aspects of Medicine is a collection of mini reviews covering a broad range of topics, from systems to model patient variants and discover therapies (Microphysiological systems with patient derived tissue and CRISPR-humanized animal models), to new modalities in diagnostics and therapeutics (Extracellular Vesicles, RNA therapeutics, microbiome and molecular dynamics).</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101182"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9285067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles as personalized medicine","authors":"Danielle J. Beetler ,&nbsp;Damian N. Di Florio ,&nbsp;Katelyn A. Bruno ,&nbsp;Tsuneya Ikezu ,&nbsp;Keith L. March ,&nbsp;Leslie T. Cooper Jr. ,&nbsp;Joy Wolfram ,&nbsp;DeLisa Fairweather","doi":"10.1016/j.mam.2022.101155","DOIUrl":"10.1016/j.mam.2022.101155","url":null,"abstract":"<div><p>Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs are cell source-specific, inducing distinct signaling responses in recipient cells. The specificity of EVs and their accumulation in fluid spaces that are accessible for liquid biopsies make them highly attractive as potential biomarkers and therapies for disease. The duality of EVs as favorable (therapeutic) or unfavorable (pathological) messengers is context dependent and remains to be fully determined in homeostasis and various disease states. This review describes the use of EVs as biomarkers, drug delivery vehicles, and regenerative therapeutics, highlighting examples involving viral infections, cancer, and neurological diseases. There is growing interest to provide personalized therapy based on individual patient and disease characteristics. Increasing evidence suggests that EV biomarkers and therapeutic approaches are ideal for personalized medicine due to the diversity and multifunctionality of EVs.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101155"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0f/57/nihms-1853804.PMC10073244.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9549875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives for the application of neurogenetic research in programming Neurorehabilitation","authors":"Bartosz Bagrowski","doi":"10.1016/j.mam.2022.101149","DOIUrl":"10.1016/j.mam.2022.101149","url":null,"abstract":"<div><p>Certain genetic variants underlie the proper functioning of the nervous system. They affect the nervous system in all aspects - molecular, systemic, cognitive, computational and sensorimotor. The greatest changes in the nervous system take place in the process of its maturation in the period of psychomotor development, as well as during neurorehabilitation, the task of which is to rebuild damaged neuronal pathways, e.g. by facilitating movement or training cognitive functions. Certain genetic polymorphisms affect the effectiveness of the processes of reconstruction or restoration of neural structures, which is clearly reflected in the effects of neurorehabilitation. This review presents the perspectives for the application of neurogenetic research in programming neurorehabilitation by determining the relationship of as many as 16 different genetic polymorphisms with specific functions of importance in rehabilitation. Thanks to this broad view, it may be possible to predict the effectiveness of rehabilitation on the basis of genetic testing, which would significantly contribute to the development of personalized medicine and to the optimal management of medical services in healthcare systems.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101149"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9283996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases","authors":"Noelle D. Germain ,&nbsp;Wendy K. Chung ,&nbsp;Patrick D. Sarmiere","doi":"10.1016/j.mam.2022.101148","DOIUrl":"10.1016/j.mam.2022.101148","url":null,"abstract":"<div><p>Advances in genome sequencing have greatly facilitated the identification of genomic variants underlying rare neurodevelopmental and neurodegenerative disorders. Understanding the fundamental causes of rare monogenic disorders has made gene therapy a possible treatment approach for these conditions. RNA interference (RNAi) technologies such as small interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA (shRNA), and other oligonucleotide-based modalities such as antisense oligonucleotides (ASOs) are being developed as potential therapeutic approaches for manipulating expression of the genes that cause a variety of neurological diseases. Here, we offer a brief review of the mechanism of action of these RNAi approaches; provide deeper discussion of the advantages, challenges, and specific considerations related to the development of RNAi therapeutics for neurological disease; and highlight examples of rare neurological diseases for which RNAi therapeutics hold great promise.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101148"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9283997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems to model the personalized aspects of microbiome health and gut dysbiosis","authors":"Cristina Matthewman ,&nbsp;Alexandra Narin ,&nbsp;Hannah Huston ,&nbsp;Christopher Edward Hopkins","doi":"10.1016/j.mam.2022.101115","DOIUrl":"10.1016/j.mam.2022.101115","url":null,"abstract":"<div><p>The human gut microbiome is a complex and dynamic microbial entity that interacts with the environment and other parts of the body including the brain, heart, liver, and immune system. These multisystem interactions are highly conserved from invertebrates to humans, however the complexity and diversity of human microbiota compositions often yield a context that is unique to each individual. Yet commonalities remain across species, where a healthy gut microbiome will be rich in symbiotic commensal biota while an unhealthy gut microbiota will be experiencing abnormal blooms of pathobiont bacteria. In this review we discuss how omics technologies can be applied in a personalized approach to understand the microbial crosstalk and microbial-host interactions that affect the delicate balance between eubiosis and dysbiosis in an individual gut microbiome. We further highlight the strengths of model organisms in identifying and characterizing these conserved synergistic and/or pathogenic host-microbe interactions. And finally, we touch upon the growing area of personalized therapeutic interventions targeting gut microbiome.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101115"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9296026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving regulatory landscape in regenerative medicine","authors":"Danielle J. Beetler ,&nbsp;Damian N. Di Florio ,&nbsp;Ethan W. Law ,&nbsp;Chris M. Groen ,&nbsp;Anthony J. Windebank ,&nbsp;Quinn P. Peterson ,&nbsp;DeLisa Fairweather","doi":"10.1016/j.mam.2022.101138","DOIUrl":"10.1016/j.mam.2022.101138","url":null,"abstract":"<div><p>Regenerative medicine as a field has emerged as a new component of modern medicine and medical research that encompasses a wide range of products including cellular and acellular therapies. As this new field emerged, regulatory agencies like the Food and Drug Administration (FDA) rapidly adapted existing regulatory frameworks to address the transplantation, gene therapy, cell-based therapeutics, and acellular biologics that fall under the broader regenerative medicine umbrella. Where it has not been possible to modify existing regulation and processes, entirely new frameworks have been generated with the intention of providing flexible, forward-facing systems to regulate this rapidly growing field. This review discusses the current state of FDA regulatory affairs in the context of stem cells and extracellular vesicles by highlighting gaps in the current regulatory system and then discussing where regulatory science in regenerative medicine may be headed based on these gaps and the FDA's historical ability to deal with emerging fields. Lastly, we utilize case studies in stem cell and acellular based treatments to demonstrate how regulatory science has evolved in regenerative medicine and highlight the ongoing clinical efforts and challenges of these therapies.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101138"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10162454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics","authors":"Christopher E. Hopkins ,&nbsp;Trisha Brock ,&nbsp;Thomas R. Caulfield ,&nbsp;Matthew Bainbridge","doi":"10.1016/j.mam.2022.101153","DOIUrl":"10.1016/j.mam.2022.101153","url":null,"abstract":"<div><p>Precision medicine strives for highly individualized treatments for disease under the notion that each individual's unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient's genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, <em>ergo</em>, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on <em>C. elegans</em>, as a contrast to tissue culture and <em>in silico</em> approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"91 ","pages":"Article 101153"},"PeriodicalIF":10.6,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073243/pdf/nihms-1855177.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9913306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}