Advances in experimental medicine and biology最新文献

This chapter reviews tumor-associated myeloid cells, including macrophages, neutrophils, and other innate immune cells, and their multifaceted roles in supporting breast cancer progression and metastasis. In primary tumors, myeloid cells play key roles in promoting tumor epithelial-mesenchymal transition (EMT) and invasion. They can facilitate intravasation (entry into the bloodstream) and colonization, disrupting the endothelial cell layer and reshaping the extracellular matrix. They can also stimulate angiogenesis, suppress immune cell responses, and enhance cancer cell adaptability. In the bloodstream, circulating myeloid cells enable the survival of disseminated tumor cells via immunosuppressive effects and physical shielding. At the metastatic sites, they prime the premetastatic niche, facilitate tumor cell extravasation, and support successful colonization and outgrowth. Mechanistically, myeloid cells enhance cancer cell survival, dormancy escape, proliferation, and mesenchymal-epithelial transition (MET). Nonetheless, substantial gaps in our understanding persist regarding the functional and spatiotemporal diversity, as well as the evolutionary patterns, of myeloid cells during metastatic progression. Myeloid cell plasticity and differential responses to therapies present key barriers to successful treatments. Identifying specific pro-tumoral myeloid cell subpopulations and disrupting their interactions with cancer cells represent promising therapeutic opportunities. Emerging evidence suggests combining immunomodulators or stromal normalizers with conventional therapies could help overcome therapy-induced immunosuppression and improve patient outcomes. Overall, further elucidating myeloid cell heterogeneity and function throughout the process of breast cancer progression and metastasis will enable more effective therapeutic targeting of these critical stromal cells.

E-cadherin is a transmembrane protein and central component of adherens junctions (AJs). The extracellular domain of E-cadherin forms homotypic interactions with E-cadherin on adjacent cells, facilitating the formation of cell-cell adhesions, known as AJs, between neighbouring cells. The intracellular domain of E-cadherin interacts with α-, β- and p120-catenins, linking the AJs to the actin cytoskeleton. Functional AJs maintain epithelial tissue identity and integrity. Transcriptional downregulation of E-cadherin is the first step in epithelial-to-mesenchymal transition (EMT), a process essential in development and tissue repair, which, in breast cancer, can contribute to tumour progression and metastasis. In addition, loss-of-function mutations in E-cadherin are a defining feature of invasive lobular breast cancer (also known as invasive lobular carcinoma (ILC)), the second most common histological subtype of breast cancer. ILC displays a discohesive, single-file invasive growth pattern due to the loss of functional AJs. Despite being so prevalent, until recently there has been limited ILC-focused research and historically ILC patients have often been excluded from clinical trials. Despite displaying a number of good prognostic indicators, such as low grade and high rates of estrogen receptor positivity, ILC patients tend to have similar or poorer outcomes relative to the most common subtype of breast cancer, invasive ductal carcinoma (IDC). In ILC, E-cadherin loss promotes hyperactivation of growth factor receptors, in particular insulin-like growth factor 1 receptor, anoikis resistance and synthetic lethality with ROS1 inhibition. These features introduce clinical vulnerabilities that could potentially be exploited to improve outcomes for ILC patients, for whom there are currently limited tailored treatments available.

Age-related macular degeneration (AMD) is a progressive disease of the retina, characterised by the degeneration of several cell layers, including the choriocapillaris (CC), retinal pigment epithelium (RPE) and photoreceptors (PR). Because of this, cell replacement therapies have the potential to treat AMD. Previous research has predominantly focussed on the development of a transplantable pluripotent stem cell-derived RPE monolayer, owing to RPE degeneration early in AMD. However, there is now increasing evidence for CC atrophy early in the pathogenesis of AMD. Given the crucial role of the CC in retinal homeostasis, there is significant potential to expand research into CC replacement with the hope of advancing current cell therapies. The RPE and CC have a highly interconnected relationship, and thus, the replacement of one of these cell layers while the other remains dysfunctional may not be optimal for the long-term rescue of vision in AMD. Therefore, one approach would be to replace both the RPE and CC as a combined cell therapy. Here, we outline the importance of CC in health and disease, as well as potential considerations when building a tissue-engineered CC-like vascular network, with a particular focus on pericytes.

The retina is the most metabolically active tissue in the body. It harbors high levels of flavins due to their involvement as enzymatic co-factors in energy production. Flavins are delivered to the body via specific transporters, the ablation of which leads to riboflavin transporter deficiency (RTD) and ariboflavinosis in humans. RTD leads to embryonic lethality in mice, and in humans, it has detrimental effects on the nervous system, causing neurologic abnormalities. However, the reports on the effects of RTD on retinal homeostasis are limited despite the fact that the retina maintains high levels of riboflavin and its derivatives. We have identified retbindin (Rtbdn) as a retina-specific riboflavin-binding protein, ablation of which leads to reduced flavin levels associated with retinal degeneration in mice. To focus attention on the role of flavins in retinal homeostasis, herein, we discuss the specific functions of flavins and Rtbdn and their protective roles in maintaining retinal health.

Rod photoreceptors are light-sensitive neurons of the retina that support vision in dim light. A rod cell consists of an outer segment for phototransduction, an inner segment and soma for energy production and protein synthesis, and a synaptic terminal for vesicle release onto second-order neurons-bipolar and horizontal cells. Mouse rods contain a single ribbon synaptic release site, where vesicles filled with glutamate are released at a rate of up to ~20 vesicles/synapse/second. This high release rate requires a fine balance between synaptic vesicle exocytosis and endocytosis. Here, we review the properties of synaptic transmission and highlight proteins essential for synaptic vesicle recycling at the rod ribbon synapse.

Genetic variants of ABCA4 are associated with a spectrum of inherited retinal degenerations, causing progressive vision loss due to rod and cone photoreceptor death and retinal pigment epithelium atrophy, ultimately leading to blindness. Understanding the functional implications and assessing the pathogenicity of the extensive number of ABCA4 variants, which exceed 3000, remains a formidable challenge. A substantial proportion of these variants remain categorized as variants of uncertain significance (VUS) or exhibit conflicting clinical interpretations (CI). Determining variant pathogenicity is imperative for clinicians to assess long-term outcomes and facilitate precise patient enrollment in ongoing clinical trials. This review aims to provide an overview of the current methodologies used to assess the functional characteristics of ABCA4 variants.

The 13-lined ground squirrel (13-LGS) is an attractive model for vision research due to its cone-dominance, accessibility, and amenability to noninvasive retinal imaging. The ability to interpret results from longitudinal studies in this animal model is limited by a lack of normative data from aged animals. To address this, we used noninvasive imaging to characterize structural changes in the anterior segment and retina in 20 13-LGS aged 5-8 years of age. Our imaging revealed multiple age-related changes in the 13-LGS eye. Phenotypes include lens opacifications, loss of normal cone structure surrounding the optic nerve head, abnormal near-infrared reflectance and short-wavelength fundus autofluorescence signal, altered and disrupted retinal lamination, choroidal thinning, and cone mosaic disruptions and reflectivity alterations. While these qualitative observations were considered abnormal, quantitative measures of retinal thickness and cone density in elderly eyes were comparable to those of young controls. Age-related changes in ocular media and retinal structure in the 13-LGS need to be considered in future longitudinal studies.

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.

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.

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.