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1.
JAMA Oncol ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529012

RESUMO

Importance: Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated. Objective: To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. Design, Setting, and Participants: This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021. Main Outcomes and Measures: Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. Results: The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers. Conclusions and Relevance: This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.

2.
Traffic Inj Prev ; : 1-7, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34582303

RESUMO

OBJECTIVE: Computational modeling has been shown to be a useful tool for simulating representative motorsport impacts and analyzing data for relative injury risk assessment. Previous studies have used computational modeling to analyze the probability of injury in specific regions of a 50th percentile male driver. However, NASCAR drivers can represent a large range in terms of size and female drivers are becoming increasingly more common in the sport. Additionally, motorsport helmets can be outfitted with external attachments, or enhanced helmet systems (EHS), whose effect is unknown relative to head and neck kinematics. The current study expands on this previous work by incorporating the F05-OS and M95-OS into the motorsport environment in order to determine correlations between metrics and factors such as PDOF, resultant ΔV occupant size, and EHS. METHODS: A multi-step computational process was used to integrate the Global Human Body Models Consortium family of simplified occupant models into a motorsport environment. This family included the 5th percentile female (F05-OS), 50th percentile male (M50-OS), and 95th percentile male (M95-OS), which provide a representative range for the size and sex of drivers seen in NASCAR's racing series'. A series of 45 representative impacts, developed from real-world crash data, and set of observed on-track severe impacts were conducted with these models. These impacts were run in triplicate for three helmet configurations: bare helmet, helmet with visor, helmet with visor and camera. This resulted in 450 total simulations. A paired t-test was initially performed as an exploratory analysis to study the effect of helmet configuration on 10 head and neck injury metrics. A mixed-effects model with unstructured covariance matrix was then utilized to correlate the effect between five independent variables (resultant ΔV, body size, helmet configuration, impact quadrant, and steering wheel position) and a selection of 25 metrics. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Risk estimates from the M50-OS with bare helmet were used as reference values to determine the effect of body size and helmet configuration. The paired t-test found significance for helmet configuration in select head-neck metrics, but the relative increase in these metrics was low and not likely to increase injury risk. The mixed-effects model analyzed statistical relationships across multiple types of variables. Within the mixed-effects model, no significance was found between helmet configuration and metrics. The greatest effect was found from resultant ΔV, body size, and impact quadrant. CONCLUSIONS: Overall, smaller drivers showed statistically significant reductions in injury metrics, while larger drivers showed statistically significant increases. Lateral impacts showed the greatest effect on neck metrics and, on average, showed decreases for head metrics related to linear acceleration and increases for head metrics related to angular velocity. HBM parametric studies such as this may provide an avenue to assist injury detection for motorsport incidents, improve triage effectiveness, and assist in the development of safety standards.

3.
Mol Metab ; 54: 101342, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34563731

RESUMO

OBJECTIVE: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. METHODS: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. RESULTS: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (PMA <2.02 × 10-27). Trait associations were replicated in IRASFS African Americans (PAA < 1.12 × 10-07). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (SI), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h2 > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA = 9.00 × 10-41, PAA = 2.31 × 10-10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR = 6.64 × 10-07). CONCLUSIONS: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.

4.
Cells ; 10(9)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34572134

RESUMO

Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.

5.
Nutrients ; 13(7)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34371931

RESUMO

The purpose of this study was to examine the independent and joint associations of acid-producing diets and depressive symptoms with physical health among breast cancer survivors. We studied a cohort of 2944 early stage breast cancer survivors who provided dietary, physical health, demographic, and lifestyle information at baseline, year 1, and year 4. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). Physical health was measured using the Rand 36-Item Short Form Health Survey (SF-36), consisting of physical functioning, role limitation due to physical function, bodily pain, general health, and overall physical health subscales. Increased dietary acid load and depression were each independently and significantly associated with reduced physical health subscales and overall physical health. Further, dietary acid load and depression were jointly associated with worse physical health. For instance, depressed women with dietary acid load higher than median reported 2.75 times the risk (odds ratio = 2.75; 95% confidence interval: 2.18-3.47) of reduced physical function and 3.10 times the risk of poor physical health (odds ratio = 3.10; 95% confidence interval: 2.53-3.80) compared to non-depressed women with dietary acid load lower than median. Our results highlight the need of controlling acid-producing diets and the access of mental care for breast cancer survivors.


Assuntos
Ácidos/efeitos adversos , Afeto , Neoplasias da Mama/terapia , Sobreviventes de Câncer/psicologia , Depressão/complicações , Dieta/efeitos adversos , Saúde Mental , Ácidos/metabolismo , Adulto , Depressão/diagnóstico , Depressão/psicologia , Feminino , Nível de Saúde , Humanos , Concentração de Íons de Hidrogênio , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo
6.
Anesthesiology ; 135(3): 482-493, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237134

RESUMO

BACKGROUND: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and µ receptors produces analgesia with reduced side effects in nonhuman primates. METHODS: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with µ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. RESULTS: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] µg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] µg/kg). Pretreatment with antagonists selective for nociceptin and µ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 µg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 µg; 3,009 ± 1,474 scratches). CONCLUSIONS: In nonhuman primates, the µ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/µ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.


Assuntos
Indóis/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptores Opioides/agonistas , Compostos de Espiro/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Fentanila/administração & dosagem , Injeções Espinhais , Macaca mulatta , Masculino , Peptídeos Opioides/administração & dosagem , Receptores Opioides/fisiologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/fisiologia
7.
Neurology ; 97(9): e953-e963, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34233941

RESUMO

OBJECTIVE: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (ß-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02286167.


Assuntos
Neoplasias Encefálicas/dietoterapia , Encéfalo/metabolismo , Dieta Rica em Proteínas e Pobre em Carboidratos/métodos , Dieta Cetogênica/métodos , Glioma/dietoterapia , Adulto , Idoso , Jejum/metabolismo , Estudos de Viabilidade , Feminino , Humanos , Cetose/metabolismo , Masculino , Pessoa de Meia-Idade
8.
Alzheimers Dement ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34310039

RESUMO

INTRODUCTION: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings. RESULTS: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment. CONCLUSIONS: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.

9.
PLoS One ; 16(7): e0254562, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34252155

RESUMO

Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d'Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d'Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations.

10.
Oncol Nurs Forum ; 48(4): 412-422, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34143000

RESUMO

OBJECTIVES: To examine the prevalence of depressive symptoms and associated risk factors in older adult breast cancer survivors (BCS) and age-matched non-cancer controls. SAMPLE & SETTING: Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcome Survey linked dataset from 1998 to 2012, BCS and non-cancer controls aged 65 years or older were identified. METHODS & VARIABLES: Depressive symptoms, comorbidities, functional limitations, socio-demographics, and health-related information were examined. Univariate and multivariable logistic regression and marginal models were performed. RESULTS: 5,421 BCS and 21,684 controls were identified. BCS and non-cancer controls had similar prevalence of depressive symptoms. Having two or more comorbidities and functional limitations were strongly associated with elevated risk of depressive symptoms in BCS and non-cancer controls. IMPLICATIONS FOR NURSING: Having multiple comorbidities and multiple functional status are key factors associated with depressive symptoms in older adult BCS and non-cancer controls. Nurses are in an ideal position to screen older adult BCS and non-cancer controls at risk for depressive symptoms.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Idoso , Depressão/epidemiologia , Feminino , Humanos , Medicare , Sobreviventes , Estados Unidos/epidemiologia
11.
Vet Surg ; 50(5): 933-943, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33969898

RESUMO

OBJECTIVE: Design 3D printed skull contoured brain biopsy guides (3D-SCGs) from computed tomography (CT) or T1-weighted magnetic resonance imaging (T1W MRI). STUDY DESIGN: Feasibility study. SAMPLE POPULATION: Five beagle dog cadavers and two client-owned dogs with brain tumors. METHODS: Helical CT and T1W MRI were performed on cadavers. Planned target point was the head of the caudate nucleus. Three-dimensional-SCGs were created from CT and MRI using commercially available open-source software. Using 3D-SCGs, biopsy needles were placed into the caudate nucleus in cadavers, and CT was performed to assess needle placement accuracy, followed by histopathology. Three-dimensional-SCGs were then created and used to perform in vivo brain tumor biopsies. RESULTS: No statistical difference was found between the planned target point and needle placement. Median needle placement error for all planned target points was 2.7 mm (range: 0.86-4.5 mm). No difference in accuracy was detected between MRI and CT-designed 3D-SCGs. Median needle placement error for the CT was 2.8 mm (range: 0.86-4.5 mm), and 2.2 mm (range: 1.7-2.7 mm) for MRI. Biopsy needles were successfully placed into the target in the two dogs with brain tumors and biopsy was successfully acquired in one dog. CONCLUSION: Three-dimensional-SCGs designed from CT or T1W MRI allowed needle placement within 4.5 mm of the intended target in all procedures, resulting in successful biopsy in one of two live dogs. CLINICAL SIGNIFICANCE: This feasibility study justifies further evaluation of 3D-SCGs as alternatives in facilities that do not have access to stereotactic brain biopsy.


Assuntos
Neoplasias Encefálicas/veterinária , Doenças do Cão/patologia , Imageamento por Ressonância Magnética/veterinária , Modelos Anatômicos , Impressão Tridimensional , Crânio , Animais , Biópsia/veterinária , Biópsia por Agulha/métodos , Biópsia por Agulha/veterinária , Encéfalo , Neoplasias Encefálicas/patologia , Cadáver , Doenças do Cão/diagnóstico , Cães , Estudos de Viabilidade , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/veterinária
12.
BMC Musculoskelet Disord ; 22(1): 388, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902505

RESUMO

BACKGROUND: Knee osteoarthritis (KOA) is increasingly more prevalent and significant number of patients require knee arthroplasty. Although knee arthroplasty is generally successful, it takes months to recover physical function. Preoperative physical function is known to predict postoperative outcomes and exercise can improve preoperative physical function. However, patients with KOA have difficulty exercise on land due to pain and stiffness, while water exercise can be better tolerated. We hypothesized that preoperative water exercise to improve preoperative physical function will improve postoperative outcomes after total knee arthroplasty (TKA). METHODS: We enrolled 43 participants who were scheduled for elective TKA in 4-8 weeks and scored at or below 50th percentile in mobility assessment tool-sf (MAT-sf). All enrolled participants were assessed on 1) clinical osteoarthritis symptom severity using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 2) physical function using Short Physical Performance Battery (SPPB), 3) self-reported mobility using Mobility Assessment Tool-short form (MAT-sf), 4) depression using Geriatric Depression Scale-short form (GDS-sf), 5) cognitive function using Montreal Cognitive Assessment (MoCA). Blood samples for high-sensitivity-C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were stored at - 80 °C then all samples were analyzed together. All the enrolled participants were randomly assigned to the aquatic exercise intervention (AEI) or usual care group. Sixty minute sessions of AEI was conducted three times a week for 4-8 weeks. Participants in both groups were evaluated within 1 week before their scheduled surgery, as well as 4 weeks after the surgery. RESULTS: The mean age was 67.1 (±6.2), 44% were female, 74% were White. There is no statistically significant difference in combined outcome of any complication, unscheduled ER visit, and disposition to nursing home or rehab facility by AEI. However, AEI was associated with more favorable outcomes: WOMAC scores (p < 0.01), chair-stand (p = 0.019), MAT-sf as well as improved depression (p = 0.043) and cognition (p = 0.008). CONCLUSION: 4-8 weeks of aquatic exercise intervention resulted in improved functional outcomes as well as improved depression and cognition in elderly patients undergoing TKA. A larger study is warranted to explore the role of water exercise in clinical and functional outcomes of TKA.


Assuntos
Artroplastia do Joelho , Osteoartrite do Joelho , Adulto , Idoso , Artroplastia do Joelho/efeitos adversos , Terapia por Exercício , Feminino , Humanos , Masculino , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/cirurgia , Projetos Piloto , Exercício Pré-Operatório , Resultado do Tratamento
13.
Biochem Pharmacol ; 188: 114520, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741328

RESUMO

Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free conditions. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons.


Assuntos
Dor do Câncer/fisiopatologia , Crescimento Neuronal/fisiologia , Células Receptoras Sensoriais/fisiologia , Células A549 , Adulto , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/fisiopatologia , Células Cultivadas , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Crescimento Neuronal/efeitos dos fármacos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Células Receptoras Sensoriais/efeitos dos fármacos
14.
Adv Sci (Weinh) ; 8(5): 2002718, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33717841

RESUMO

Crystallinity and crystal orientation have a predominant impact on a materials' semiconducting properties, thus it is essential to manipulate the microstructure arrangements for desired semiconducting device performance. Here, ultra-uniform hole-transporting material (HTM) by self-assembling COOH-functionalized P3HT (P3HT-COOH) is fabricated, on which near single crystal quality perovskite thin film can be grown. In particular, the self-assembly approach facilitates the P3HT-COOH molecules to form an ordered and homogeneous monolayer on top of the indium tin oxide (ITO) electrode facilitate the perovskite crystalline film growth with high quality and preferred orientations. After detailed spectroscopy and device characterizations, it is found that the carboxylic acid anchoring groups can down-shift the work function and passivate the ITO surface, retarding the interface carrier recombination. As a result, the device made with the self-assembled HTM show high open-circuit voltage over 1.10 V and extend the lifetime over 4,300 h when storing at 30% relative humidity. Moreover, the cell works efficiently under much reduced light power, making it useful as power source under dim-light conditions. The demonstration suggests a new facile way of fabricating monolayer HTM for high efficiency perovskite devices, as well as the interconnecting layer needed for tandem cell.

15.
PLoS One ; 16(3): e0247257, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661917

RESUMO

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2-3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.


Assuntos
Afro-Americanos/genética , Metilação de DNA/efeitos dos fármacos , Loci Gênicos , Variação Genética , Metabolômica , Acidente Vascular Cerebral , Vitaminas/administração & dosagem , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/prevenção & controle
16.
J Bone Oncol ; 26: 100346, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33425674

RESUMO

Prostate cancer (PCa) metastasizes to bone, where the bone marrow microenvironment controls disease progression. However, the cellular interactions that result in active bone marrow metastases are poorly understood. A better understanding of these interactions is critical to success in the pursuit of effective treatments for this life ending disease. Anecdotally, we observe that after intracardiac injection of PCa cells, one of the greatest tools to investigate the mechanisms of bone-metastatic disease, animals frequently present with mandible metastasis before hind limb metastasis. Therefore, in this study, we investigated whether the bone cells derived from the mouse mandible influence PCa progression differently than those from the hind limb. Interestingly, we found that osteoblasts harvested from mouse mandibles grew faster, expressed more vascular endothelial growth factor (VEGF), increased vascularity and formed more bone, and stimulated faster growth of PCa cells when cultured together than osteoblasts harvested from mouse hind limbs. Additionally, these findings were confirmed in vivo when mouse mandible osteoblasts were co-implanted into mice with PCa cells. Importantly, the enhancement of PCa growth mediated by mandible osteoblasts was not shown to be due to their differentiation or proliferation activities, but may be partly due to increased vascularization and expression of VEGF.

17.
EBioMedicine ; 63: 103192, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418508

RESUMO

BACKGROUND: The United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA). METHODS: MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively. FINDINGS: We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells. INTERPRETATION: These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA. FUNDING: NIH.


Assuntos
Biomarcadores , Encéfalo/metabolismo , Exossomos/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Oxicodona/efeitos adversos , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Expressão Gênica , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Microglia/metabolismo , Doenças Neurodegenerativas/diagnóstico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxicodona/administração & dosagem , Transporte Proteico , Proteoma , Proteômica/métodos
18.
J Immigr Minor Health ; 23(5): 1026-1034, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33469784

RESUMO

It is important to understand genetics within the context of health. This paper assesses (a) genetic knowledge among Mexican-born farmworker and non-farmworker adults; (b) their interpersonal and device sources of genetic knowledge; and (c) the association between their genetic knowledge and the sources of this genetic knowledge.Interviews were conducted with Mexican-born farmworkers (100) and non-farmworkers (100) in North Carolina. Participants answered 15 questions to assess genetic knowledge, and sources from which they had seen or heard about genes and genetics.Results show limited knowledge of genetics, with farmworkers and non-farmworkers providing a similar level of correct responses (6.6 versus 7.3), but with farmworkers providing more incorrect responses (4.0 versus 2.7). Important sources of genetic information for farmworkers were promotoras (47%), compared to teachers (49%) for non-farmworkers.This study demonstrates a need for increased dissemination of genetic information to Mexican-origin farmworkers and non-farmworkers.


Assuntos
Fazendeiros , Migrantes , Adulto , Agricultura , Comunicação , Hispano-Americanos , Humanos , Conhecimento , México , North Carolina
19.
J Gerontol A Biol Sci Med Sci ; 76(2): 277-285, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-32504466

RESUMO

BACKGROUND: Muscle metrics derived from computed tomography (CT) are associated with adverse health events in older persons, but obtaining these metrics using current methods is not practical for large datasets. We developed a fully automated method for muscle measurement on CT images. This study aimed to determine the relationship between muscle measurements on CT with survival in a large multicenter trial of older adults. METHOD: The relationship between baseline paraspinous skeletal muscle area (SMA) and skeletal muscle density (SMD) and survival over 6 years was determined in 6,803 men and 4,558 women (baseline age: 60-69 years) in the National Lung Screening Trial (NLST). The automated machine learning pipeline selected appropriate CT series, chose a single image at T12, and segmented left paraspinous muscle, recording cross-sectional area and density. Associations between SMA and SMD with all-cause mortality were determined using sex-stratified Cox proportional hazards models, adjusted for age, race, height, weight, pack-years of smoking, and presence of diabetes, chronic lung disease, cardiovascular disease, and cancer at enrollment. RESULTS: After a mean 6.44 ± 1.06 years of follow-up, 635 (9.33%) men and 265 (5.81%) women died. In men, higher SMA and SMD were associated with a lower risk of all-cause mortality, in fully adjusted models. A one-unit standard deviation increase was associated with a hazard ratio (HR) = 0.85 (95% confidence interval [CI] = 0.79, 0.91; p < .001) for SMA and HR = 0.91 (95% CI = 0.84, 0.98; p = .012) for SMD. In women, the associations did not reach significance. CONCLUSION: Higher paraspinous SMA and SMD, automatically derived from CT exams, were associated with better survival in a large multicenter cohort of community-dwelling older men.

20.
Drug Deliv ; 27(1): 1686-1694, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33263448

RESUMO

Multimodality 3D Optical Imaging (OI)/CT has the potential to play a major role in drug development for glioblastomas (GBM), as it is an accessible preclinical method. To demonstrate the potential of 3D OI/CT to visualize orthotopic GBM implantation, we labeled GBM cells with Cy7 and imaged their location using 3D OI/CT. To confirm the accuracy of the spatial localization and demonstrate the ability to image locoregionally delivered therapies, we labeled mouse albumin with Cy7 (Cy7ALB) and delivered it via locoregional infusion 1 mm or 3 mm into the brain and demonstrated correlation of signal between the 3D OI/CT and post necropsy brain slices. In addition, we demonstrated the potential of systemically delivered Cy7ALB contrast to detect blood-brain barrier (BBB) permeability caused by orthotopic GBMs using 3D OI/CT. We also tested the potential of 3D OI/CT to assess focal BBB permeability induced by high intensity focused ultrasound (HIFU), a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. We demonstrated the ability of systemic Cy7ALB contrast together with 3D OI/CT to accurately assess real-time HIFU-induced BBB permeability, which correlated to post necropsy imaging of brains. Furthermore, we demonstrated that 3D OI/CT can also image the therapeutic distribution of a Cy7-labeled anti-PD-1 antibody, a prototype translational antibody therapy. We successfully imaged real-time antibody distribution after HIFU-induced BBB permeability, which correlated with post necropsy Cy7 signal and translational PET imaging after injection of [89Zr] anti-PD-1 antibody. Thus, we demonstrated the broad potential of using 3D OI/CT as an accessible preclinical tool to develop anti-GBM therapies.

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