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We examined the relative associations of aortic and carotid artery stiffness with cerebrovascular disease (CeVD), cognition, and dementia subtypes in a memory clinic cohort of 272 participants (mean age = 75.4, SD = 6.8). We hypothesized that carotid artery stiffness would have greater effects on outcomes, given its proximate relationship to the brain. Aortic and carotid artery stiffness were assessed with applanation tonometry and carotid ultrasonography, respectively. CeVD markers included white matter hyperintensities (WMH), lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Cognition was assessed by the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a neuropsychological battery. Multivariable linear regression was conducted to determine associations of arterial stiffness with WMH and cognition, while logistic regression analysed associations with CeVD markers and dementia subtypes. Carotid artery stiffness z-score was associated with WMH, cortical infarcts, vascular cognitive impairment, and MMSE, independent of age, sex, education, vascular risk factors, and aortic stiffness z-score. Although aortic stiffness z-score was independently associated with cortical infarcts, this became non-significant after further adjusting for carotid artery stiffness z-score. We found that carotid artery stiffness had greater effects on CeVD, cognitive function and impairment in memory clinic patients compared to aortic stiffness.
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Tissue engineering has long sought to rapidly generate perfusable vascularized tissues with vessel sizes spanning those seen in humans. Current techniques such as biological 3D printing (top-down) and cellular self-assembly (bottom-up) are resource intensive and have not overcome the inherent tradeoff between vessel resolution and assembly time, limiting their utility and scalability for engineering tissues. We present a flexible and scalable technique termed SPAN - Sacrificial Percolation of Anisotropic Networks, where a network of perfusable channels is created throughout a tissue in minutes, irrespective of its size. Conduits with length scales spanning arterioles to capillaries are generated using pipettable alginate fibers that interconnect above a percolation density threshold and are then degraded within constructs of arbitrary size and shape. SPAN is readily used within common tissue engineering processes, can be used to generate endothelial cell-lined vasculature in a multi-cell type construct, and paves the way for rapid assembly of perfusable tissues.
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Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval. Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans. Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.
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The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/normas , Detección Precoz del Cáncer/métodos , Tamizaje Masivo/métodos , Tamizaje Masivo/normasRESUMEN
Optical coherence tomography angiography (OCTA) has transformed ocular vascular imaging, revealing microvascular changes linked to various systemic diseases. This review explores its applications in diabetes, hypertension, cardiovascular diseases, and neurodegenerative diseases. While OCTA provides a valuable window into the body's microvasculature, interpreting the findings can be complex. Additionally, challenges exist due to the relative non-specificity of its findings where changes observed in OCTA might not be unique to a specific disease, variations between OCTA machines, the lack of a standardized normative database for comparison, and potential image artifacts. Despite these limitations, OCTA holds immense potential for the future. The review highlights promising advancements like quantitative analysis of OCTA images, integration of artificial intelligence for faster and more accurate interpretation, and multi-modal imaging combining OCTA with other techniques for a more comprehensive characterization of the ocular vasculature. Furthermore, OCTA's potential future role in personalized medicine, enabling tailored treatment plans based on individual OCTA findings, community screening programs for early disease detection, and longitudinal studies tracking disease progression over time is also discussed. In conclusion, OCTA presents a significant opportunity to improve our understanding and management of systemic diseases. Addressing current limitations and pursuing these exciting future directions can solidify OCTA as an indispensable tool for diagnosis, monitoring disease progression, and potentially guiding treatment decisions across various systemic health conditions.
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Movies of human induced pluripotent stem cell (hiPSC)-derived engineered cardiac tissue (microbundles) contain abundant information about structural and functional maturity. However, extracting these data in a reproducible and high-throughput manner remains a major challenge. Furthermore, it is not straightforward to make direct quantitative comparisons across the multiple in vitro experimental platforms employed to fabricate these tissues. Here, we present "MicroBundlePillarTrack," an open-source optical flow-based package developed in Python to track the deflection of pillars in cardiac microbundles grown on experimental platforms with two different pillar designs ("Type 1" and "Type 2" design). Our software is able to automatically segment the pillars, track their displacements, and output time-dependent metrics for contractility analysis, including beating amplitude and rate, contractile force, and tissue stress. Because this software is fully automated, it will allow for both faster and more reproducible analyses of larger datasets and it will enable more reliable cross-platform comparisons as compared to existing approaches that require manual steps and are tailored to a specific experimental platform. To complement this open-source software, we share a dataset of 1,540 brightfield example movies on which we have tested our software. Through sharing this data and software, our goal is to directly enable quantitative comparisons across labs, and facilitate future collective progress via the biomedical engineering open-source data and software ecosystem.
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Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ+ PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.
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Administración Intranasal , Anticuerpos Antiprotozoarios , Entamoeba histolytica , Entamebiasis , Interferón gamma , Leucocitos Mononucleares , Liposomas , Macaca mulatta , Vacunas Antiprotozoos , Animales , Entamoeba histolytica/inmunología , Liposomas/inmunología , Liposomas/administración & dosificación , Vacunas Antiprotozoos/inmunología , Vacunas Antiprotozoos/administración & dosificación , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Leucocitos Mononucleares/inmunología , Entamebiasis/prevención & control , Entamebiasis/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Inyecciones Intramusculares , Inmunogenicidad Vacunal , Adyuvantes de Vacunas/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Linfocitos B/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Antígenos de Protozoos/inmunología , Inmunidad Humoral , Memoria Inmunológica , Proteínas Protozoarias/inmunologíaRESUMEN
PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial. PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel. RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4-11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8-2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1. CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play. SIGNIFICANCE: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation.
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Paclitaxel , Receptores de Glucocorticoides , Humanos , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Albúminas/farmacología , Animales , Adulto , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular TumoralRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Current diagnostic modalities of AD generally focus on detecting the presence of amyloid ß and tau protein in the brain (for example, positron emission tomography [PET] and cerebrospinal fluid testing), but these are limited by their high cost, invasiveness, and lack of expertise. Retinal imaging exhibits potential in AD screening and risk stratification, as the retina provides a platform for the optical visualization of the central nervous system in vivo, with vascular and neuronal changes that mirror brain pathology. Given the paradigm shift brought by advances in artificial intelligence and the emergence of disease-modifying therapies, this article aims to summarize and review the current literature to highlight 8 trends in an evolving landscape regarding the role and potential value of retinal imaging in AD screening.
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BACKGROUND: Housing has been associated with dementia risk and disability, but associations of housing with differential patterns of neuropsychiatric symptoms (NPS) among dementia-free older adults remain to be explored. The present study sought to explore the contribution of housing status on NPS and subsyndromes associated with cognitive dysfunction in community-dwelling dementia-free elderly in Singapore. METHODS: A total of 839 dementia-free elderly from the Epidemiology of Dementia in Singapore (EDIS) study aged ≥ 60 were enrolled in the current study. All participants underwent clinical, cognitive, and neuropsychiatric inventory (NPI) assessments. The housing status was divided into three categories according to housing type. Cognitive function was measured by a comprehensive neuropsychological battery. The NPS were assessed using 12-term NPI and were grouped into four clinical subsyndromes: psychosis, hyperactivity, affective, and apathy. Associations of housing with composite and domain-specific Z-scores, as well as NPI scores, were assessed using generalized linear models (GLM). Binary logistic regression models analysed the association of housing with the presence of NPS and significant NPS (NPI total scores ≥ 4). RESULTS: Better housing status (5-room executive apartments, condominium, or private housing) was associated with better NPS (OR = 0.49, 95%CI = 0.24 to 0.98, P < 0.05) and significant NPS profile (OR = 0.20, 95%CI = 0.08 to 0.46, P < 0.01), after controlling for demographics, risk factors, and cognitive performance. Compared with those living in 1-2 room apartments, older adults in better housing had lower total NPI scores (ß=-0.50, 95%CI=-0.95 to -0.04, P = 0.032) and lower psychosis scores (ß=-0.36, 95%CI=-0.66 to -0.05, P = 0.025), after controlling for socioeconomic status (SES) indexes. Subgroup analysis indicated a significant correlation between housing type and NPS in females, those of Malay ethnicity, the more educated, those with lower income, and those diagnosed with cognitive impairment, no dementia (CIND). CONCLUSIONS: Our study showed a protective effect of better housing arrangements on NPS, especially psychosis in a multi-ethnic Asian geriatric population without dementia. The protective effect of housing on NPS was independent of SES and might have other pathogenic mechanisms. Improving housing could be an effective way to prevent neuropsychiatric disturbance among the elderly.
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Demencia , Humanos , Masculino , Femenino , Anciano , Singapur/epidemiología , Demencia/epidemiología , Demencia/etnología , Demencia/psicología , Demencia/prevención & control , Anciano de 80 o más Años , Vida Independiente , Vivienda , Pruebas Neuropsicológicas , Persona de Mediana Edad , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etnología , Disfunción Cognitiva/psicologíaRESUMEN
Movies of human induced pluripotent stem cell (hiPSC)-derived engineered cardiac tissue (microbundles) contain abundant information about structural and functional maturity. However, extracting these data in a reproducible and high-throughput manner remains a major challenge. Furthermore, it is not straightforward to make direct quantitative comparisons across the multiple in vitro experimental platforms employed to fabricate these tissues. Here, we present "MicroBundlePillarTrack," an open-source optical flow-based package developed in Python to track the deflection of pillars in cardiac microbundles grown on experimental platforms with two different pillar designs ("Type 1" and "Type 2" design). Our software is able to automatically segment the pillars, track their displacements, and output time-dependent metrics for contractility analysis, including beating amplitude and rate, contractile force, and tissue stress. Because this software is fully automated, it will allow for both faster and more reproducible analyses of larger datasets and it will enable more reliable cross-platform comparisons as compared to existing approaches that require manual steps and are tailored to a specific experimental platform. To complement this open-source software, we share a dataset of 1,540 brightfield example movies on which we have tested our software. Through sharing this data and software, our goal is to directly enable quantitative comparisons across labs, and facilitate future collective progress via the biomedical engineering open-source data and software ecosystem.
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Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico , Asia/epidemiología , Anticuerpos Monoclonales/uso terapéutico , Diagnóstico Precoz , Péptidos beta-AmiloidesRESUMEN
Generating stable and customizable topography on hydrogel surfaces with contact guidance potential is critical as it can direct/influence cell growth. This necessitates the development of new techniques for surface patterning of the hydrogels. We report on the design of a square grid template for surface patterning hydrogels. The template was 3-D printed and has the diameter of a well in a 24-well plate. Hyaluronic acid methacrylate (HA) hydrogel precursor solutions were cast on the 3D printed template's surface, which generated 3D square shape topographies on the HA hydrogel surface upon demolding. The 3D Laser Microscopy has shown the formation of a periodic array of 3D topographies on hydrogel surfaces. 3D Laser and Electron Microscopy Imaging have revealed that this new method has increased the surface area and exposed the underlying pore structure of the HA hydrogels. To demonstrate the method's versatility, we have successfully applied this technique to generate 3D topography on two more acrylate hydrogel formulations, gelatin Methacrylate and polyethylene glycol dimethacrylate. Human neonatal dermal fibroblast cells were used as a model cell line to evaluate the cell guidance potential of patterned HA hydrogel. Confocal fluorescence microscopy imaging has revealed that the 3D surface topographies on HA hydrogels can guide and align the actin filaments of the fibroblasts presumably due to the contact guidance mechanism. The newly developed methodology of 3D topography generation in acrylate hydrogels may influence the cell responses on hydrogel surfaces which can impact biomedical applications such as tissue engineering, wound healing, and disease modeling.
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Fibroblastos , Ácido Hialurónico , Hidrogeles , Impresión Tridimensional , Propiedades de Superficie , Hidrogeles/química , Hidrogeles/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Ácido Hialurónico/química , Metacrilatos/química , Acrilatos/química , Células Cultivadas , Polietilenglicoles/químicaRESUMEN
Background: Blood biomarkers are proposed as a diagnostic alternative to amyloid PET or cerebrospinal fluid (CSF) analyses for the diagnosis of Alzheimer's disease (AD). Relatively little is known of the natural history of patients identified by different blood biomarkers. Objective: To identify patients with elevated plasma phosphorylated tau (pTau)181 from a prior Phase 2a trial, and explore the natural histories of their clinical progression, and potential efficacy of Xanamem, a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in these patients. Methods: A prespecified, double-blind analysis was conducted in 72 participants with clinically diagnosed AD and available plasma samples from baseline and Week 12 of the "XanADu" Phase 2a trial of Xanamem versus placebo. The analysis prespecified plasma pTau181â>âmedian to identify patients more likely to have AD ("H", >â6.74 pg/mL, nâ=â34). Cohen's d (d) of≥0.2 defined potential clinical significance. Results: In the placebo group, H patients showed greater clinical progression compared to L patients (pTau181≤median) on ADCOMS (dâ=â0.55, pâ<â0.001), CDR-SB (dâ=â0.63, pâ<â0.001), MMSE (dâ=â0.52, pâ=â0.12), and ADAS-Cog14 (dâ=â0.53, pâ=â0.19). In H patients, a potentially clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS mean difference 0.6 units, dâ=â0.41, pâ=â0.09) and Neuropsychological Test Battery (NTB; LS mean difference 1.8 units, dâ=â0.26, pâ=â0.48) but not ADCOMS or ADAS-Cog14. Conclusions: This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits.
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Enfermedad de Alzheimer , Biomarcadores , Progresión de la Enfermedad , Proteínas tau , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/sangre , Proteínas tau/sangre , Masculino , Femenino , Método Doble Ciego , Anciano , Biomarcadores/sangre , Fosforilación , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Persona de Mediana Edad , Anciano de 80 o más Años , Carbolinas/uso terapéuticoRESUMEN
Previous lung-on-chip devices have facilitated significant advances in our understanding of lung biology and pathology. Here, we describe a novel lung-on-a-chip model in which human induced pluripotent stem cell-derived alveolar epithelial type II cells (iAT2s) form polarized duct-like lumens alongside engineered perfused vessels lined with human umbilical vein endothelium, all within a 3D, physiologically relevant microenvironment. Using this model, we investigated the morphologic and signaling consequences of the KRASG12D mutation, a commonly identified oncogene in human lung adenocarcinoma (LUAD). We show that expression of the mutant KRASG12D isoform in iAT2s leads to a hyperproliferative response and morphologic dysregulation in the epithelial monolayer. Interestingly, the mutant epithelia also drive an angiogenic response in the adjacent vasculature that is mediated by enhanced secretion of the pro-angiogenic factor soluble uPAR. These results demonstrate the functionality of a multi-cellular in vitro platform capable of modeling mutation-specific behavioral and signaling changes associated with lung adenocarcinoma.
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Acute ischemic stroke (AIS) and traumatic brain injury (TBI) are two severe neurological events, both being major causes of death and prolonged impairment. Their incidence continues to rise due to the global increase in the number of people at risk, representing a significant burden on those remaining impaired, their families, and society. These molecular and cellular mechanisms of both stroke and TBI present similarities that can be targeted by treatments with a multimodal mode of action, such as traditional Chinese medicine. Therefore, we performed a detailed review of the preclinical and clinical development of MLC901 (NeuroAiDTMII), a natural multi-herbal formulation targeting several biological pathways at the origin of the clinical deficits. The endogenous neurobiological processes of self-repair initiated by the brain in response to the onset of brain injury are often insufficient to achieve complete recovery of impaired functions. This review of MLC901 and its parent formulation MLC601 confirms that it amplifies the natural self-repair process of brain tissue after AIS or TBI. Following AIS and TBI where "time is brain", many patients enter the post-acute phase with their functions still impaired, a period when "the brain needs time to repair itself". The treatment goal must be to accelerate recovery as much as possible. MLC901/601 demonstrated a significant reduction by 18 months of recovery time compared to a placebo, indicating strong potential for facilitating the improvement of health outcomes and the more efficient use of healthcare resources.
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Lesiones Traumáticas del Encéfalo , Medicamentos Herbarios Chinos , Accidente Cerebrovascular Isquémico , Investigación Biomédica Traslacional , Humanos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Animales , Medicina Basada en la Evidencia , Medicina Tradicional China/métodos , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Ensayos Clínicos como AsuntoRESUMEN
We introduce an adaptor-based strategy for regulating fluorescein-binding synthetic Notch (SynNotch) receptors using ligands based on conjugates of fluorescein isomers and analogs. To develop a versatile system, we evaluated the surface expression and activities of multiple constructs containing distinct extracellular fluorescein-binding domains. Using an optimized receptor, we devised ways to regulate signaling via fluorescein-based chemical transformations, including an approach based on a bio-orthogonal chemical ligation and a spatially controllable strategy via the photo-patterned uncaging of an o -nitrobenzyl-caged fluorescein conjugate. We further demonstrate that fluorescein-conjugated extracellular matrix (ECM)-binding peptides can regulate SynNotch activity depending on the folding state of collagen-based ECM networks. Treatment with these conjugates enabled cells to distinguish between folded versus denatured collagen proteins and enact dose-dependent gene expression responses depending on the nature of the signaling adaptors presented. To demonstrate the utility of these tools, we applied them to control the myogenic conversion of fibroblasts into myocytes with spatial and temporal precision and in response to denatured collagen-I, a biomarker of multiple pathological states. Overall, we introduce an optimized fluorescein-binding SynNotch as a versatile tool for regulating transcriptional responses to extracellular ligands based on the widely used and clinically-approved fluorescein dye.
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Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline. Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function. Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (ß = -0.50, 95%CI: -0.91, -0.09) and executive function (ß = -0.77, 95%CI: -1.25, -0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition. Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.
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Although tissue culture plastic has been widely employed for cell culture, the rigidity of plastic is not physiologic. Softer hydrogels used to culture cells have not been widely adopted in part because coupling chemistries are required to covalently capture extracellular matrix (ECM) proteins and support cell adhesion. To create an in vitro system with tunable stiffnesses that readily adsorbs ECM proteins for cell culture, we present a novel hydrophobic hydrogel system via chemically converting hydroxyl residues on the dextran backbone to methacrylate groups, thereby transforming non-protein adhesive, hydrophilic dextran to highly protein adsorbent substrates. Increasing methacrylate functionality increases the hydrophobicity in the resulting hydrogels and enhances ECM protein adsorption without additional chemical reactions. These hydrophobic hydrogels permit facile and tunable modulation of substrate stiffness independent of hydrophobicity or ECM coatings. Using this approach, we show that substrate stiffness and ECM adsorption work together to affect cell morphology and proliferation, but the strengths of these effects vary in different cell types. Furthermore, we reveal that stiffness mediated differentiation of dermal fibroblasts into myofibroblasts is modulated by the substrate ECM. Our material system demonstrates remarkable simplicity and flexibility to tune ECM coatings and substrate stiffness and study their effects on cell function.
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Predicting the course of neurodegenerative disorders early has potential to greatly improve clinical management and patient outcomes. A key challenge for early prediction in real-world clinical settings is the lack of labeled data (i.e., clinical diagnosis). In contrast to supervised classification approaches that require labeled data, we propose an unsupervised multimodal trajectory modeling (MTM) approach based on a mixture of state space models that captures changes in longitudinal data (i.e., trajectories) and stratifies individuals without using clinical diagnosis for model training. MTM learns the relationship between states comprising expensive, invasive biomarkers (ß-amyloid, grey matter density) and readily obtainable cognitive observations. MTM training on trajectories stratifies individuals into clinically meaningful clusters more reliably than MTM training on baseline data alone and is robust to missing data (i.e., cognitive data alone or single assessments). Extracting an individualized cognitive health index (i.e., MTM-derived cluster membership index) allows us to predict progression to AD more precisely than standard clinical assessments (i.e., cognitive tests or MRI scans alone). Importantly, MTM generalizes successfully from research cohort to real-world clinical data from memory clinic patients with missing data, enhancing the clinical utility of our approach. Thus, our multimodal trajectory modeling approach provides a cost-effective and non-invasive tool for early dementia prediction without labeled data (i.e., clinical diagnosis) with strong potential for translation to clinical practice.