Molecular Aspects of Medicine最新文献

{"title":"Practical issues related to non-Aspergillus invasive mold infections","authors":"Marcio Nucci ,&nbsp;Simone A. Nouér","doi":"10.1016/j.mam.2023.101230","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101230","url":null,"abstract":"<div><p>Infection by non-<span><em>Aspergillus</em></span><span><span> molds has been increasingly reported. The management of such infections is challenging both for diagnosis and treatment, including the need of well-trained mycologists to properly identify rare fungi, difficulties in distinguishing between contamination, colonization and infection, the lack of randomized studies comparing different drugs or regimens, poor activity of available antifungal agents, lack of correlation between in vitro </span>antifungal susceptibility tests and clinical outcome, and poor prognosis. Mucormycosis and fusariosis are the most frequent non-</span><em>Aspergillus</em><span> mold infections. Mucormycosis occurs more frequently in four major groups of patients: solid organ transplant recipients, patients with hematologic malignancies receiving chemotherapy or hematopoietic cell transplantation, diabetic patients, and immunocompetent individuals who suffer various types of skin and soft tissue trauma. Invasive fusariosis occurs almost exclusively in patients with hematologic malignancies. In this review we discuss practical issues related to the management of these and other non-</span><em>Aspergillus</em> mold infections.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101230"},"PeriodicalIF":10.6,"publicationDate":"2023-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138439145","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":"Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies","authors":"Brintha Selvarajah ,&nbsp;Manuela Platé ,&nbsp;Rachel C. Chambers","doi":"10.1016/j.mam.2023.101227","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101227","url":null,"abstract":"<div><p>Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases. The progressive deposition of a collagen-rich extracellular matrix (ECM) represents the cornerstone of the fibrotic response and culminates in organ failure and premature death. Idiopathic pulmonary fibrosis (IPF) represents the most rapidly progressive and lethal of all fibrotic diseases with a dismal median survival of 3.5 years from diagnosis. Although the approval of the antifibrotic agents, pirfenidone and nintedanib, for the treatment of IPF signalled a watershed moment for the development of anti-fibrotic therapeutics, these agents slow but do not halt disease progression or improve quality of life. There therefore remains a pressing need for the development of effective therapeutic strategies. In this article, we review emerging therapeutic strategies for IPF as well as the pre-clinical and translational approaches that will underpin a greater understanding of the key pathomechanisms involved in order to transform the way we diagnose and treat pulmonary fibrosis.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101227"},"PeriodicalIF":10.6,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138413164","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":"Gene therapies and gene product-based drug candidates for normalizing and preserving tissue functions in animal models of ocular hypertension and glaucoma","authors":"Najam A. Sharif PhD, DSc","doi":"10.1016/j.mam.2023.101218","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101218","url":null,"abstract":"<div><p>More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101218"},"PeriodicalIF":10.6,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134653721","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":"Ubiquitin proteasome system and glaucoma: A survey of genetics and molecular biology studies supporting a link with pathogenic and therapeutic relevance","authors":"Irene Pandino ,&nbsp;Sara Giammaria ,&nbsp;Gabriele Antonio Zingale ,&nbsp;Gloria Roberti ,&nbsp;Manuele Michelessi ,&nbsp;Massimo Coletta ,&nbsp;Gianluca Manni ,&nbsp;Luca Agnifili ,&nbsp;Alice Verticchio Vercellin ,&nbsp;Alon Harris ,&nbsp;Francesco Oddone ,&nbsp;Diego Sbardella","doi":"10.1016/j.mam.2023.101226","DOIUrl":"10.1016/j.mam.2023.101226","url":null,"abstract":"<div><p>Glaucoma represents a group of progressive neurodegenerative diseases characterized by the loss of retinal ganglion cells (RGCs) and their axons with subsequent visual field impairment. The disease develops through largely uncharacterized molecular mechanisms, that are likely to occur in different localized cell types, either in the anterior (e.g., trabecular meshwork cells) or posterior (e.g., Muller glia, retinal ganglion cells) segments of the eye. Genomic and preclinical studies suggest that glaucoma pathogenesis may develop through altered ubiquitin (Ub) signaling. Ubiquitin conjugation, referred to as ubiquitylation, is a major post-synthetic modification catalyzed by E1-E2-E3 enzymes, that profoundly regulates the turnover, trafficking and biological activity of the targeted protein. The development of new technologies, including proteomics workflows, allows the biology of ubiquitin signaling to be described in health and disease. This post-translational modification is emerging as a key role player in neurodegeneration, gaining relevance for novel therapeutic options, such as in the case of Proteolysis Targeting Chimeras technology. Although scientific evidence supports a link between Ub and glaucoma, their relationship is still not well-understood. Therefore, this review provides a detailed research-oriented discussion on current evidence of Ub signaling in glaucoma. A review of genomic and genetic data is provided followed by an in-depth discussion of experimental data on ASB10, parkin and optineurin, which are proteins that play a key role in Ub signaling and have been associated with glaucoma.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101226"},"PeriodicalIF":10.6,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89720265","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":"Computational methods in glaucoma research: Current status and future outlook","authors":"Minjae J. Kim ,&nbsp;Cole A. Martin ,&nbsp;Jinhwa Kim ,&nbsp;Monica M. Jablonski","doi":"10.1016/j.mam.2023.101222","DOIUrl":"10.1016/j.mam.2023.101222","url":null,"abstract":"<div><p>Advancements in computational techniques have transformed glaucoma research, providing a deeper understanding of genetics, disease mechanisms, and potential therapeutic targets. Systems genetics integrates genomic and clinical data, aiding in identifying drug targets, comprehending disease mechanisms, and personalizing treatment strategies for glaucoma. Molecular dynamics simulations offer valuable molecular-level insights into glaucoma-related biomolecule behavior and drug interactions, guiding experimental studies and drug discovery efforts. Artificial intelligence (AI) technologies hold promise in revolutionizing glaucoma research, enhancing disease diagnosis, target identification, and drug candidate selection. The generalized protocols for systems genetics, MD simulations, and AI model development are included as a guide for glaucoma researchers. These computational methods, however, are not separate and work harmoniously together to discover novel ways to combat glaucoma. Ongoing research and progresses in genomics technologies, MD simulations, and AI methodologies project computational methods to become an integral part of glaucoma research in the future.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101222"},"PeriodicalIF":10.6,"publicationDate":"2023-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488122","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":"Advances in understanding glaucoma pathogenesis: A multifaceted molecular approach for clinician scientists","authors":"Eren Ekici ,&nbsp;Sasan Moghimi","doi":"10.1016/j.mam.2023.101223","DOIUrl":"https://doi.org/10.1016/j.mam.2023.101223","url":null,"abstract":"<div><p><span><span>Glaucoma, a leading cause of irreversible blindness worldwide, is a spectrum of neurodegenerative diseases characterized by the gradual deterioration of retinal ganglion cells (RGCs) and optic neuropathy. With complex etiology, glaucoma's major risk factors include elevated intraocular pressure (IOP), advanced age, ethnicity, systemic vascular factors, and </span>genetic predisposition<span>. By 2040, glaucoma is expected to affect over 110 million individuals aged 40 to 80, posing a significant economic burden. Glaucoma can be classified into open-angle, angle-closure, and developmental subtypes, with primary and secondary forms. The disease often progresses silently, gradually impairing the visual field (VF) until it reaches an advanced stage. Understanding the abnormal functional changes associated with glaucoma at the tissue, cellular, molecular, and genetic levels is crucial for comprehending its pathogenesis. This review examines the published data from the past two decades to shed light on the biological mechanisms underlying glaucoma development. The most evident factors in the development of glaucomatous optic neuropathy include elevated IOP, aging, genetic influences, followed by impaired ocular blood flow regulation. These factors are interconnected processes that lead to optic nerve damage, compromised circulation, and structural changes in glial and connective tissues. Contributing factors involve extracellular matrix remodeling, </span></span>excitotoxicity<span><span>, nitric oxide, </span>oxidative stress, and neuroinflammation. Ultimately, all types of glaucoma result in RGC dysfunction and loss, causing irreversible visual impairment. While our understanding of glaucoma pathogenesis is evolving, further research is crucial for a comprehensive understanding of glaucoma pathogenesis and the development of effective treatments.</span></p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101223"},"PeriodicalIF":10.6,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91985488","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":"Signalling pathways and cell death mechanisms in glaucoma: Insights into the molecular pathophysiology","authors":"Devaraj Basavarajappa ,&nbsp;Caridad Galindo-Romero ,&nbsp;Vivek Gupta ,&nbsp;Marta Agudo-Barriuso ,&nbsp;Veer B. Gupta ,&nbsp;Stuart L. Graham ,&nbsp;Nitin Chitranshi","doi":"10.1016/j.mam.2023.101216","DOIUrl":"10.1016/j.mam.2023.101216","url":null,"abstract":"<div><p>Glaucoma is a complex multifactorial eye disease manifesting in retinal ganglion cell (RGC) death and optic nerve degeneration, ultimately causing irreversible vision loss. Research in recent years has significantly enhanced our understanding of RGC degenerative mechanisms in glaucoma. It is evident that high intraocular pressure (IOP) is not the only contributing factor to glaucoma pathogenesis. The equilibrium of pro-survival and pro-death signalling pathways in the retina strongly influences the function and survival of RGCs and optic nerve axons in glaucoma. Molecular evidence from human retinal tissue analysis and a range of experimental models of glaucoma have significantly contributed to unravelling these mechanisms. Accumulating evidence reveals a wide range of molecular signalling pathways that can operate -either alone or via intricate networks - to induce neurodegeneration. The roles of several molecules, including neurotrophins, interplay of intracellular kinases and phosphates, caveolae and adapter proteins, serine proteases and their inhibitors, nuclear receptors, amyloid beta and tau, and how their dysfunction affects retinal neurons are discussed in this review. We further underscore how anatomical alterations in various animal models exhibiting RGC degeneration and susceptibility to glaucoma-related neuronal damage have helped to characterise molecular mechanisms in glaucoma. In addition, we also present different regulated cell death pathways that play a critical role in RGC degeneration in glaucoma.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101216"},"PeriodicalIF":10.6,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49684185","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":"Therapeutic strategies for glaucoma and optic neuropathies","authors":"Jung Lo ,&nbsp;Kamakshi Mehta ,&nbsp;Armaan Dhillon ,&nbsp;Yu-Kai Huang ,&nbsp;Ziming Luo ,&nbsp;Mi-Hyun Nam ,&nbsp;Issam Al Diri ,&nbsp;Kun-Che Chang","doi":"10.1016/j.mam.2023.101219","DOIUrl":"10.1016/j.mam.2023.101219","url":null,"abstract":"<div><p>Glaucoma is a neurodegenerative eye disease that causes permanent vision impairment. The main pathological characteristics of glaucoma are retinal ganglion cell (RGC) loss and optic nerve degeneration. Glaucoma can be caused by elevated intraocular pressure (IOP), although some cases are congenital or occur in patients with normal IOP. Current glaucoma treatments rely on medicine and surgery to lower IOP, which only delays disease progression. First-line glaucoma medicines are supported by pharmacotherapy advancements such as Rho kinase inhibitors and innovative drug delivery systems. Glaucoma surgery has shifted to safer minimally invasive (or microinvasive) glaucoma surgery, but further trials are needed to validate long-term efficacy. Further, growing evidence shows that adeno-associated virus gene transduction and stem cell-based RGC replacement therapy hold potential to treat optic nerve fiber degeneration and glaucoma. However, better understanding of the regulatory mechanisms of RGC development is needed to provide insight into RGC differentiation from stem cells and help choose target genes for viral therapy. In this review, we overview current progress in RGC development research, optic nerve fiber regeneration, and human stem cell-derived RGC differentiation and transplantation. We also provide an outlook on perspectives and challenges in the field.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"94 ","pages":"Article 101219"},"PeriodicalIF":10.6,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240337","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":"Towards modifying the genetic predisposition for glaucoma: An overview of the contribution and interaction of genetic and environmental factors","authors":"Kelsey V. Stuart ,&nbsp;Louis R. Pasquale ,&nbsp;Jae H. Kang ,&nbsp;Paul J. Foster ,&nbsp;Anthony P. Khawaja","doi":"10.1016/j.mam.2023.101203","DOIUrl":"10.1016/j.mam.2023.101203","url":null,"abstract":"<div><p>Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"93 ","pages":"Article 101203"},"PeriodicalIF":10.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9995957","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":"Advances in vaccine development for cancer prevention and treatment in Lynch Syndrome","authors":"Ana M. Bolivar ,&nbsp;Fahriye Duzagac ,&nbsp;Krishna M. Sinha ,&nbsp;Eduardo Vilar","doi":"10.1016/j.mam.2023.101204","DOIUrl":"10.1016/j.mam.2023.101204","url":null,"abstract":"<div><p>Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely <em>MLH1</em>, <em>MSH2</em>, <em>MSH6</em> and <em>PMS2</em>. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal disease to leverage immune-interception strategies. Therefore, the identification of these neoAgs is an ongoing effort for the development of LS cancer preventive vaccines. In this review, we summarize the computational methods used for <em>in silico</em> neoAg prediction, including their challenges, and the experimental techniques used for <em>in vitro</em> validation of their immunogenicity. In addition, we outline results from past and on-going vaccine clinical trials and highlight avenues for improvement and future directions.</p></div>","PeriodicalId":49798,"journal":{"name":"Molecular Aspects of Medicine","volume":"93 ","pages":"Article 101204"},"PeriodicalIF":10.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022517","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}