Advances in experimental medicine and biology最新文献

{"title":"A Knockin Model with the Mouse Equivalent to the c.2299delG Mutation in Usherin Exhibits Early-Onset Hearing Loss and Progressive Retinal Degeneration.","authors":"Lars Tebbe, Muayyad R Al-Ubaidi, Muna I Naash","doi":"10.1007/978-3-031-76550-6_42","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_42","url":null,"abstract":"<p><p>Usher syndrome (USH) is the predominant cause of inherited deaf-blindness, largely attributed to type 2A (USH2A) mutations, and particularly the prevalent c.2299delG mutation. While knockout models successfully replicated the cochlear phenotype of USH, recapitulating the retinal phenotype proved challenging. Given that patient mutations often lead to mutant protein expression rather than its absence, we developed a knockin model expressing the mouse equivalent of the c.2299delG mutation in USH2A. This model exhibited a functional decline in the retina, characterized by retinal degeneration, structural anomalies in the connecting cilium and outer segment, and mislocalization of mutant USH2A and its interacting partners ADGRV1 and whirlin. Remarkably, retinal symptoms manifested earlier than in the Ush2a^-/- mice. In the cochlea, the expression of truncated USH2A resulted in congenital hearing loss and disorganized stereocilia bundles. Thus, this knockin model underscores the necessity of expressing the mutant protein to faithfully reproduce the USH phenotype, providing valuable insights into the pathology of USH.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"253-257"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABCA4 c.5461-6T>C Causes Stargardt Disease Through Exon Skipping.","authors":"Mathieu Quinodoz, Ana Belén Iglesias-Romero, Francesca Cancellieri, Karolina Kaminska, Hendrik P N Scholl, Maximilian Pfau, Carlo Rivolta","doi":"10.1007/978-3-031-76550-6_10","DOIUrl":"https://doi.org/10.1007/978-3-031-76550-6_10","url":null,"abstract":"<p><p>Stargardt disease (STGD1) is an inherited retinal dystrophy that follows an autosomal recessive inheritance in which photoreceptors degenerate, leading to progressive vision loss that starts from the central retina. The severity of symptoms can vary considerably depending on the mutations: they range from severe childhood-onset to late-onset milder forms, the latter being caused by specific hypomorphic variants. In this study, we describe a novel non-canonical splicing variant: NM_000350.3:c.5461-6T>C. This variant was found in compound heterozygosity with a frequent pathogenic hypomorphic variant, p.Gly1961Glu, in a patient with Stargardt disease and her affected brother. In silico tools predicted a low effect on splicing, but experimental validation, in contrast, showed this DNA change to be causing severe splicing alterations.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1468 ","pages":"57-62"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Diseases Are Associated with Cognitive Decline and Dementia.","authors":"Chenyi Gao, Jing Kang","doi":"10.1007/978-3-031-79146-8_11","DOIUrl":"https://doi.org/10.1007/978-3-031-79146-8_11","url":null,"abstract":"<p><p>Common oral diseases, including periodontitis and dental caries, and their endpoint as tooth loss are controllable yet highly prevalent among adults worldwide. Cognitive decline also poses significant global public health challenges during the aging process, especially the pathological form of cognitive decline such as dementia. Dementia is irreversible and is one of the leading causes of death, disability, and dependency in the aging population. Emerging research suggests a bidirectional association between oral diseases and cognitive decline or dementia. This potential link has implications for designing better oral care plans for patients with dementia and recognizing oral diseases as modifiable risk factors for dementia prevention.This chapter provides an overview of the association between oral diseases and cognitive decline, followed by a discussion of current evidence on such associations in two directions: (1) the impact of cognitive decline or dementia on oral health and (2) the role of oral diseases as modifiable risk factors for dementia. We critically evaluate several hypotheses regarding the underlying mechanisms of this association, including (1) life-course hypothesis, (2) shared inflammation and bacterial infection mechanisms, (3) malnourishment mechanism, (4) pain pathway, and (5) sensory feedback pathway.However, the association between oral diseases and cognitive decline or dementia remains controversial due to limited high-quality evidence, particularly from biomedical research. Much of the existing evidence is from observational studies prone to confounding bias, with inconclusive questions about causation and the direction of causality.This chapter concludes by emphasizing the need for future studies with robust methodological designs, including randomized controlled trials, biomedical studies, and innovative research techniques such as Mendelian randomization. Such studies are crucial for disease prevention and enhancing patient care and quality of life. By providing a comprehensive overview, this chapter contributes to an advanced understanding of this field, addresses current study gaps, and suggests future research directions.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1472 ","pages":"171-183"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Diet and Nutrition on the Oral Microbiome.","authors":"Simona Santonocito, Alessandro Polizzi, Gaetano Isola","doi":"10.1007/978-3-031-79146-8_4","DOIUrl":"https://doi.org/10.1007/978-3-031-79146-8_4","url":null,"abstract":"<p><p>At present, it is well known that oral health is essential for the well-being of the body as a whole, thanks to the increasing awareness of how various oral diseases, including periodontal disease, oral carcinomas, and other conditions, have a close connection with various systemic disorders. In recent decades, studies on the oral microbiome have increasingly emphasized how the balance between the host and the microbial species that coexist there is essential for oral health at all stages of life. However, there are many factors capable of interfering with that balance, and diet is precisely one of them. The real influence of diet on the oral microbiota, and consequently on oral health, has been much debated. In this context, the observation of two key periods in human history, the Neolithic and the Industrial Revolution, has proved to be diriment. The foods and processing techniques that emerged in these two historical periods, in association with changes in customs and habits, significantly altered the central constituents of the human diet, including macronutrient proportions, glycemic load, fatty acid composition, sodium and potassium levels, micronutrient levels, dietary pH, and fiber content taken in by human beings. The introduction of these foods into the daily human routine has been linked to a decline in oral health and an increase of several other diseases, including cardiovascular diseases, inflammatory bowel disease, rheumatic diseases, many cancers, and obesity. The aim of this chapter is to update the current knowledge and further discuss the role of diet and nutrition on oral health.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1472 ","pages":"53-69"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in the Role of Non-coding RNAs in Fetal Alcohol Spectrum Disorders.","authors":"Ariana N Pritha, Andrea A Pasmay, Shahani Noor","doi":"10.1007/978-3-031-81908-7_7","DOIUrl":"https://doi.org/10.1007/978-3-031-81908-7_7","url":null,"abstract":"<p><p>Despite numerous preclinical studies modeling fetal alcohol spectrum disorder (FASD)-associated neurodevelopmental deficits to date, a comprehensive molecular landscape dictating these deficits remains poorly understood. Non-coding RNAs constitute a substantial layer of epigenetic regulation of gene expression at the transcriptional, post-transcriptional, translational, and post-translational levels. Yet, little is known about the differential expression of non-coding RNAs in the context of prenatal alcohol exposure (PAE) that are mechanistically linked with FASD-related neurobehavior deficits. This chapter reviews our current knowledge from preclinical studies in non-coding RNA-mediated molecular mechanisms that may underlie FASD pathophysiology. This chapter also summarizes relevant clinical evidence and current efforts in utilizing these non-coding RNA molecules as biomarkers of PAE-associated deficits impacting central nervous system (CNS) function. Unraveling the diverse roles of various species of non-coding RNAs is critical to enhancing our comprehension of these intricate molecular pathways. Understanding these pathways would likely contribute to identifying critical molecular target(s) for developing efficient treatment strategies and prognostic and diagnostic markers fostering advancements in treating and managing FASD-related CNS dysfunction.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1473 ","pages":"129-155"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defects of Cortical Microcircuits Following Early Exposure to Alcohol.","authors":"Alberto Granato","doi":"10.1007/978-3-031-81908-7_1","DOIUrl":"https://doi.org/10.1007/978-3-031-81908-7_1","url":null,"abstract":"<p><p>The interplay between excitatory pyramidal neurons and GABAergic interneurons is the basic building block of neocortical microcircuits and plays a critical role in carrying out higher cognitive functions. Cortical circuits are deeply and permanently disrupted by exposure to alcohol during brain development, the main non-genetic cause of intellectual disability. Here, I review experimental studies of fetal alcohol spectrum disorders, dealing with permanent cellular and molecular alterations of neocortical neurons and their connections.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1473 ","pages":"3-13"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Developmental Alcohol Exposure on Sleep Physiology.","authors":"Valentina Licheri, Jonathan L Brigman","doi":"10.1007/978-3-031-81908-7_6","DOIUrl":"https://doi.org/10.1007/978-3-031-81908-7_6","url":null,"abstract":"<p><p>The present chapter summarizes the clinical and preclinical findings collected to date, showing the impact of developmental alcohol exposure on sleep physiology. Sleep is a complex physiological process that plays a pivotal role in maintaining overall health and well-being via its involvement in regulating physiological, cognitive, and emotional functions. Clinical studies consistently report a high prevalence of sleep disturbances in children and adolescents diagnosed with fetal alcohol spectrum disorders (FASDs), including short sleep duration, sleep anxiety, bedtime resistance, increased sleep fragmentation, and parasomnias. It is established that alcohol consumption during gestation impairs brain development, leading to structural and functional alterations that may affect sleep architecture. In addition, clinical investigations have found a significant correlation between sleep-wake cycle disruptions and cognitive impairments after developmental alcohol exposure, and sleep disturbances are increasingly recognized as a substantial problem among FASD patients. However, the molecular mechanisms underlying these disturbances are poorly understood. Surprisingly, few studies with animal models of FASDs have characterized the effect of developmental ethanol exposure on sleep physiology, and these have focused on high doses. This chapter provides an overview of the current knowledge, reports the sleep disturbances in FASD patients, and then summarizes the gap in understanding the molecular and physiological mechanisms.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1473 ","pages":"111-127"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melanoma Cell Adhesion Molecule (CD 146) in Endometrial Physiology and Disorder.","authors":"Priyanka Hilage, Mrunal N Damle, Rakesh Kumar Sharma, Meghnad G Joshi","doi":"10.1007/5584_2024_826","DOIUrl":"10.1007/5584_2024_826","url":null,"abstract":"<p><p>The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":" ","pages":"131-148"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Implications of Breast Cancer Intrinsic Subtypes.","authors":"Alejandro Rios-Hoyo, Naing-Lin Shan, Philipp L Karn, Lajos Pusztai","doi":"10.1007/978-3-031-70875-6_21","DOIUrl":"https://doi.org/10.1007/978-3-031-70875-6_21","url":null,"abstract":"<p><p>Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5 years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5 years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5 years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1464 ","pages":"435-448"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microenvironmental Regulation of Dormancy in Breast Cancer Metastasis: \"An Ally that Changes Allegiances\".","authors":"Evrim Ceren Kabak, Sok Lin Foo, Maria Rafaeva, Ivan Martin, Mohamed Bentires-Alj","doi":"10.1007/978-3-031-70875-6_18","DOIUrl":"https://doi.org/10.1007/978-3-031-70875-6_18","url":null,"abstract":"<p><p>Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1464 ","pages":"373-395"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}