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2.
Ann Surg Oncol ; 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237827

RESUMO

BACKGROUND: This study aimed to assess the impact of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) on the survival outcomes for patients with gastric cancer and peritoneal carcinomatosis (PC). METHODS: A retrospective analysis of the National Cancer Database from 2004 to 2020 identified patients with topography and histology codes consistent with gastric adenocarcinoma who underwent CRS/HIPEC. The exclusion criteria ruled out known other distant metastasis and missing key data. The study compared the CRS/HIPEC group with patients who had stage IV disease (with the same exclusions for distant metastases) and received systemic chemotherapy but no surgery to the primary site. RESULTS: The study included 148 patients who underwent CRS/HIPEC. Their median age was 57 years (interquartile range [IQR], 47-66 years), with 57.4% of the patients identifying as male and 73.6% identifying as white. Most of the CRS/HIPEC patients had locally advanced disease, with 33.8% having pT4 disease and 23% patients having pN3 status. The Charlson-Deyo scores were 0 for 77% and 1 for 16.9% of the patients. The overall survival (OS) among the stage IV patients managed with CRS/HIPEC was significantly longer than for the patients receiving only systemic chemotherapy (median survival, 18.1 vs 9.3 months; p < 0.001), and the 1-year OS was 72.6% versus 38.8% (p < 0.05)). Among the stage IV patients, CRS/HIPEC showed better survival than systemic chemotherapy (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44-0.73; p < .001) when control was used for the Charlson Deyo score, histology, age, and sex. CONCLUSIONS: These results suggest the association of CRS/HIPEC with improved survival for selected patients with gastric adenocarcinoma and peritoneal disease. Some of this difference may have been due to selection bias, but the differences in the survival curves are robust.

4.
Ann Surg Oncol ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39120842

RESUMO

BACKGROUND: Assessment of individual tumor biology and response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. The significance of anthropometric (body composition) changes during chemotherapy as a surrogate for tumor biology in the setting of localized PDAC is unknown. METHODS: A retrospective, single-institution analysis of patients with PDAC who received neoadjuvant therapy (NAT) and pancreatectomy from 2017 to 2021 was performed. Radiologic anthropometric analysis used artificial intelligence-driven software to segment and compute total and sub-compartment muscle area, adipose tissue area, and attenuation values at the level of the L3 vertebra. Kaplan-Meier survival estimates, log-rank tests, and multivariable Cox regression models were used in survival analyses. RESULTS: The inclusion criteria were met by 138 patients. Although decreases in muscle and adipose tissue areas during NAT were predominant, a subset of patients experienced an increase in these compartments. Increases in muscle greater than 5% (hazard ratio [HR], 0.352; 95% confidence interval [CI] 0.135-0.918; p = 0.033) and increases in adipose tissue greater than 15% (HR, 0.375; 95% CI 0.144-0.978; p = 0.045), were significantly associated with improved survival, whereas loss of visceral fat greater than 15% was detrimental (HR 1.853; CI 1.099-3.124; p = 0.021). No significant associations with single time-point anthropometrics were observed. Gains in total muscle and adipose mass were associated with improved pathologic response to systemic therapy and less advanced pathologic tumor stage. CONCLUSIONS: Dynamic anthropometric analysis during NAT for PDAC is a stronger prognostic indicator than measurements taken at a single point in time. Repeated anthropometric analysis during preoperative chemotherapy may serve as a biomarker for individual tumor biology and response to therapy.

5.
Ann Surg Oncol ; 31(10): 6504-6513, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38972927

RESUMO

Resectable cholangiocarcinoma (CCA) arising from the middle of the extrahepatic biliary tree has historically been classified as perihilar or distal CCA, depending on the operation contemplated or performed, namely the associated hepatectomy or pancreaticoduodenectomy, respectively. Segmental bile duct resection is a less invasive alternative for select patients harboring true middle extrahepatic CCA (MCC). A small, yet growing body of literature has emerged detailing institutional experiences with bile duct resection versus pancreaticoduodenectomy or concomitant hepatectomy for MCC. Herein, we provide a brief overview of the epidemiology, preoperative evaluation, and emerging systemic therapies for MCC, and narratively review the existing work comparing segmental resection with pancreaticoduodenectomy or less commonly, hepatectomy, for MCC, with emphasis on the surgical management and oncologic implications of the approach used.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Colangiocarcinoma/cirurgia , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Pancreaticoduodenectomia/métodos , Hepatectomia/métodos
6.
Artigo em Inglês | MEDLINE | ID: mdl-38946145

RESUMO

INTRODUCTION: This is the first systematic review and meta-analysis to investigate the effectiveness of the nasal airflow-inducing maneuver (NAIM) in olfactory rehabilitation for total laryngectomy (TL) patients. METHODS: We conducted a systematic literature search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The inclusion criteria required that patients must have undergone a TL with subsequent NAIM training for at least 2 weeks and olfactory evaluation. The impact of NAIM on olfactory outcomes compared to that at baseline was measured. Olfactory measures included the Sniffin' Sticks Test, Smell Disk Test, Scandinavian Odor Identification Test, and Quick Odor Detection Test. The primary outcome measures were the proportion of patients with normosmia at baseline and after intervention. RESULTS: Seven studies from 2000 to 2023 comprising a total of 290 TL patients met the inclusion criteria. The meta-analysis revealed that prior to intervention, the pooled proportion of patients with normosmia was 0.16 (95% confidence interval [CI]: 0.09‒0.27, p = 0.01). After intervention, the same proportion increased to 0.55 (95% CI: 0.45‒0.68, p = 0.001). Among the included patients, 88.3% were initially anosmic or hyposmic, which was reduced to 48.9% after NAIM practice, with 51.1% achieving normosmia. The percent improvement was not found to be significantly associated with the timing of intervention post-TL (p = 0.18). CONCLUSIONS: NAIM increased the proportion of patients who achieved normosmia in TL patients. NAIM stands out as a safe, easily teachable maneuver with promising results. Further efforts are warranted to provide specific recommendations and guidelines for the use of NAIM in clinical practice.

7.
Ann Surg Oncol ; 31(9): 6127-6137, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38780693

RESUMO

BACKGROUND: Radiologic occult metastatic disease (ROMD) in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo contemporary neoadjuvant chemotherapy (NAC) has not been well studied. This study sought to analyze the incidence, risk factors, and oncologic outcomes for patients who underwent the NAC approach for PDAC. METHODS: A retrospective review analyzed a prospectively maintained database of patients who had potentially resectable PDAC treated with NAC and were offered pancreatectomy at our institution from 2011 to 2022. Multivariable regression analysis was performed to assess risk factors associated with ROMD. Kaplan-Meier curves with log-rank analyses were generated to estimate time-to-event end points. RESULTS: The study enrolled 366 patients. Upfront and borderline resectable anatomic staging comprised 80% of the cohort, whereas 20% had locally advanced disease. The most common NAC regimen was FOLFIRINOX (n = 274, 75%). For 55 patients (15%) who harbored ROMD, the most common site was liver-only metastases (n = 33, 60%). The independent risk factors for ROMD were increasing CA19-9 levels during NAC (odds ratio [OR], 7.01; confidence interval [CI], 1.97-24.96; p = 0.008), indeterminate liver lesions (OR, 2.19; CI, 1.09-4.39; p = 0.028), and enlarged para-aortic lymph nodes (OR, 6.87; CI, 2.07-22.74; p = 0.002) on preoperative cross-sectional imaging. Receipt of palliative chemotherapy (p < 0.001) and eventual formal pancreatectomy (p = 0.04) were associated with survival benefit in the log-rank analysis. The median overall survival (OS) of the patients with ROMD was nearly 15 months from the initial diagnosis, with radiologic evidence of metastases occurring after a median of 2 months. CONCLUSIONS: Radiologic occult metastatic disease remains a clinical challenge associated with poor outcomes for patients who have PDAC treated with multi-agent NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Pancreatectomia , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Terapia Neoadjuvante/mortalidade , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Taxa de Sobrevida , Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Seguimentos , Prognóstico , Fluoruracila/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Oxaliplatina/administração & dosagem , Leucovorina/administração & dosagem , Adulto , Estudos Prospectivos , Irinotecano/administração & dosagem , Metástase Linfática
8.
Cancers (Basel) ; 16(7)2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38611107

RESUMO

Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

9.
J Alzheimers Dis ; 98(4): 1515-1532, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38578893

RESUMO

Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Receptor Muscarínico M4 , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Colinérgicos , Lipídeos
10.
Angiogenesis ; 27(2): 173-192, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38468017

RESUMO

C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each's role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.


Assuntos
Lectinas Tipo C , Neoplasias , Humanos , Angiogênese , Neovascularização Patológica/patologia , Neoplasias/tratamento farmacológico , Transdução de Sinais , Antígenos de Neoplasias , Antígenos CD
11.
J Surg Res ; 296: 742-750, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38368775

RESUMO

INTRODUCTION: Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumor-infiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. METHODS: Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD-L1) expression, and phenotypic characterization of TILs. RESULTS: Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD-L1 expression; two of three (67%) EBVaGC patients exhibited positive PD-L1 expression. Compared to non-EBVaGC, EBV-positive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. CONCLUSIONS: The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD-L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Antígeno B7-H1/metabolismo , Neoplasias Gástricas/patologia , Biomarcadores
12.
Alzheimers Dement ; 19(11): 5159-5172, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37158312

RESUMO

INTRODUCTION: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). METHODS: We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. RESULTS: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DISCUSSION: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.


Assuntos
Doença de Alzheimer , Masculino , Feminino , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Núcleo Accumbens/metabolismo , Neurônios Colinérgicos/metabolismo , Colinérgicos/metabolismo , RNA/metabolismo , RNA de Transferência/metabolismo
13.
J Alzheimers Dis ; 94(1): 227-246, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37212097

RESUMO

BACKGROUND: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. OBJECTIVE: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. METHODS: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). RESULTS: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. CONCLUSION: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Rede de Modo Padrão , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Terminações Pré-Sinápticas/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
14.
Cell Rep ; 42(5): 112528, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37209097

RESUMO

Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded genome editing of synthetic target arrays for lineage tracing (GESTALT) zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expression of protein kinase C delta (PKC-δ, encoded by prkcda) increases the number of HSC clones by up to 80% and expands polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augment HSC competition for residency within the niche and expand defined niche populations. CXCL8 induces association of PKC-δ with the focal adhesion complex, activating extracellular signal-regulated kinase (ERK) signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche that is controlled by CXCL8 and PKC and has significant impact on HSC phylogenetic and phenotypic fate.


Assuntos
Células Endoteliais , Peixe-Zebra , Animais , Humanos , Células Endoteliais/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Filogenia , Proteína Quinase C-delta/metabolismo , Nicho de Células-Tronco , Interleucina-8/metabolismo
15.
Dev Cell ; 58(12): 1037-1051.e4, 2023 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-37119815

RESUMO

The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.


Assuntos
Nicho de Células-Tronco , Fatores de Transcrição , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Endoteliais/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Regulação da Expressão Gênica
16.
Protein Sci ; 32(5): e4635, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36992534

RESUMO

Charged residues on the surface of proteins are critical for both protein stability and interactions. However, many proteins contain binding regions with a high net charge that may destabilize the protein but are useful for binding to oppositely charged targets. We hypothesized that these domains would be marginally stable, as electrostatic repulsion would compete with favorable hydrophobic collapse during folding. Furthermore, by increasing the salt concentration, we predict that these protein folds would be stabilized by mimicking some of the favorable electrostatic interactions that take place during target binding. We varied the salt and urea concentrations to probe the contributions of electrostatic and hydrophobic interactions for the folding of the yeast SH3 domain found in Abp1p. The SH3 domain was significantly stabilized with increased salt concentrations due to Debye-Huckel screening and a nonspecific territorial ion-binding effect. Molecular dynamics and NMR show that sodium ions interact with all 15 acidic residues but do little to change backbone dynamics or overall structure. Folding kinetics experiments show that the addition of urea or salt primarily affects the folding rate, indicating that almost all the hydrophobic collapse and electrostatic repulsion occur in the transition state. After the transition state formation, modest yet favorable short-range salt bridges are formed along with hydrogen bonds, as the native state fully folds. Thus, hydrophobic collapse offsets electrostatic repulsion to ensure this highly charged binding domain can still fold and be ready to bind to its charged peptide targets, a property that is likely evolutionarily conserved over 1 billion years.


Assuntos
Dobramento de Proteína , Domínios de Homologia de src , Termodinâmica , Peptídeos/química , Proteínas/química , Simulação de Dinâmica Molecular , Ureia , Cinética
17.
J Comp Neurol ; 531(18): 2080-2108, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36989381

RESUMO

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8-positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual-hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.


Assuntos
Doença de Alzheimer , Conectoma , Humanos , Doença de Alzheimer/patologia , Spliceossomos/metabolismo , Spliceossomos/patologia , Hipocampo/metabolismo , Proteínas tau/metabolismo , Emaranhados Neurofibrilares/patologia
18.
Domest Anim Endocrinol ; 83: 106785, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36745973

RESUMO

A chemiluminescent immunoassay is commonly employed to measure adrenocorticotrophic hormone (ACTH) concentrations to assist pituitary pars intermedia dysfunction diagnosis. In a previous study, seasonally-dependent assay cross-reactivity to endogenous equine corticotropin-like intermediate lobe peptide (CLIP, ACTH 18-39) was suspected. The present study aimed to demonstrate binding of endogenous equine CLIP to the capture antibody of the ACTH chemiluminescent immunoassay. Liquid chromatography - mass spectrometry (LCMS) methods were optimised to identify selected ions from synthetic human ACTH, α-melanocyte stimulating hormone (α-MSH, ACTH 1-17) and CLIP. Synthetic ACTH and CLIP bound to the capture antibody of the chemiluminescent ACTH assay, but α-MSH did not. Equine endogenous CLIP was detected by LCMS in pony plasma taken in the autumn and could be eluted from the capture antibody of the ACTH chemiluminescent immunoassay. Further research is required to enable quantification of CLIP. Equine CLIP may alter measured ACTH concentrations in vivo.


Assuntos
Hormônio Adrenocorticotrópico , alfa-MSH , Cavalos , Animais , Humanos , Peptídeo da Parte Intermédia da Adeno-Hipófise Semelhante à Corticotropina/metabolismo , alfa-MSH/metabolismo , Anticorpos , Hipófise/metabolismo , Hormônios Estimuladores de Melanócitos/metabolismo
19.
bioRxiv ; 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36798311

RESUMO

Introduction: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). Methods: We analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. Results: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. Discussion: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

20.
Radiography (Lond) ; 29(2): 327-332, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36706601

RESUMO

INTRODUCTION: To establish if the CT dataset acquired during the stress element of myocardial perfusion imaging can be fused to the subsequent rest scan to reduce radiation doses from these procedures. METHODS: 86 rest scans were processed and evaluated using a self-designed project specific tool. Recording processing time, the time between the two data sets selected for fusion and assessing radiographic reports to ensure produced images were of diagnostic quality. RESULTS: 70% of fused scans were acquired 6-7 days apart; the mean (SD) processing time was calculated as 2.03 (0.36) minutes. The Pearson's correlation between these two variables was determined to be 0.22, showing a slight positive correlation although not statistically significant. 100% of the images produced were of diagnostic quality. CONCLUSION: Rest scans can be fused to a previously acquired CT, careful consideration should be given when positioning the patient and to the time interval between acquiring the two data sets, departmental guidelines can assist with this. Staff training may also be beneficial to ensure staff can assess if data sets are fusible prior to completing a scan. IMPLICATIONS FOR PRACTICE: This data provides evidence that retrospective fusion can reduce patient radiation doses in myocardial perfusion imaging without compromising diagnostic outcomes. Dose optimisation is an essential part of the ionising radiation (medical exposure) regulations therefore retrospective fusion should be considered in practice to ensure departmental compliance, although it is noteworthy this study is solely based in a single centred one camera department.


Assuntos
Imagem de Perfusão do Miocárdio , Humanos , Imagem de Perfusão do Miocárdio/métodos , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodos , Doses de Radiação
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