Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
1.
Nat Methods ; 19(3): 353-358, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35228725

RESUMO

Recent progress has shown that using wavelengths between 1,000 and 2,000 nm, referred to as the shortwave-infrared or near-infrared (NIR)-II range, can enable high-resolution in vivo imaging at depths not possible with conventional optical wavelengths. However, few bioconjugatable probes of the type that have proven invaluable for multiplexed imaging in the visible and NIR range are available for imaging these wavelengths. Using rational design, we have generated persulfonated indocyanine dyes with absorbance maxima at 872 and 1,072 nm through catechol-ring and aryl-ring fusion, respectively, onto the nonamethine scaffold. Multiplexed two-color and three-color in vivo imaging using monoclonal antibody and dextran conjugates in several tumor models illustrate the benefits of concurrent labeling of the tumor and healthy surrounding tissue and lymphatics. These efforts are enabled by complementary advances in a custom-built NIR/shortwave-infrared imaging setup and software package for multicolor real-time imaging.


Assuntos
Corantes Fluorescentes , Neoplasias , Anticorpos Monoclonais , Humanos , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos
2.
J Transl Med ; 20(1): 375, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982453

RESUMO

BACKGROUND: Several new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model. METHODS: Twenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of [18F]FLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination. RESULTS: [18F]FLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm [18F]FLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy. CONCLUSION: Significant decreases in [18F]FLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of [18F]FLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.


Assuntos
Didesoxinucleosídeos , Neoplasias da Bexiga Urinária , Animais , Biomarcadores , Linhagem Celular Tumoral , Didesoxinucleosídeos/metabolismo , Humanos , Camundongos , Piperazinas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Piridinas , Temozolomida/uso terapêutico , Timidina , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico
3.
Pers Ubiquitous Comput ; 26(2): 365-384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35368316

RESUMO

The work described in this paper builds upon our previous research on adoption modelling and aims to identify the best subset of features that could offer a better understanding of technology adoption. The current work is based on the analysis and fusion of two datasets that provide detailed information on background, psychosocial, and medical history of the subjects. In the process of modelling adoption, feature selection is carried out followed by empirical analysis to identify the best classification models. With a more detailed set of features including psychosocial and medical history information, the developed adoption model, using kNN algorithm, achieved a prediction accuracy of 99.41% when tested on 173 participants. The second-best algorithm built, using NN, achieved 94.08% accuracy. Both these results have improved accuracy in comparison to the best accuracy achieved (92.48%) in our previous work, based on psychosocial and self-reported health data for the same cohort. It has been found that psychosocial data is better than medical data for predicting technology adoption. However, for the best results, we should use a combination of psychosocial and medical data where it is preferable that the latter is provided from reliable medical sources, rather than self-reported.

4.
Clin Infect Dis ; 71(4): 982-988, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31560741

RESUMO

BACKGROUND: Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF. METHODS: This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment. RESULTS: EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84-147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24. CONCLUSIONS: Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch. CLINICAL TRIALS REGISTRATION: NCT02251236.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Quinolonas , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Alanina , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Quinolonas/uso terapêutico , Tenofovir/análogos & derivados
5.
Alzheimer Dis Assoc Disord ; 32(4): 298-304, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30188355

RESUMO

PURPOSE: Studies have reported faster cognitive/functional decline in persons with dementia (PWD) with malnutrition. We investigated whether baseline nutritional status predicted severe dementia and mortality in a population-based sample. PATIENTS: A maximum of 300 PWD were assessed annually for up to 8.6 years. METHODS: Nutritional status was assessed using a modified Mini-Nutritional Assessment (mMNA). Severe dementia was defined as: "severe" rating on the Clinical Dementia Rating or Mini-Mental State Examination score ≤10. Using Cox proportional hazards models, we examined the association between baseline mMNA score (or its subcomponents) with each outcome. Covariates included demographics; dementia onset age, type, and duration; APOE genotype; and residency with caregiver. RESULTS: Compared with "well-nourished," "malnourished" PWD had 3-4 times the hazard of severe dementia [hazard ratio (HR), 4.31; P=0.014] and death (HR, 3.04; P<0.001). Those "at risk for malnutrition" had twice the hazard of severe dementia (HR, 1.98; P=0.064) and 1.5 times the hazard of death (HR, 1.46; P=0.015). mMNA subcomponents of food group intake, weight loss, body mass index, mobility, health status, protein consumption, and mid-arm circumference predicted one or both outcomes. CONCLUSIONS: Nutritional status is an important predictor of clinical outcomes in dementia and may provide an avenue for intervention.


Assuntos
Demência/epidemiologia , Demência/metabolismo , Progressão da Doença , Mortalidade/tendências , Estado Nutricional/fisiologia , Atividades Cotidianas , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Testes de Estado Mental e Demência , Inquéritos e Questionários , Utah/epidemiologia
6.
Int Psychogeriatr ; 30(10): 1499-1507, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29559029

RESUMO

ABSTRACTBackground:The use of FDA approved medications for Alzheimer's disease [AD; FDAAMAD; (cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists)] has been associated with symptomatic benefit with a reduction in formal (paid services) and total costs of care (formal and informal costs). We examined the use of these medications and their association with informal costs in persons with dementia. METHOD: Two hundred eighty participants (53% female, 72% AD) from the longitudinal, population-based Dementia Progression Study in Cache County, Utah (USA) were followed up to ten years. Mean (SD) age at baseline was 85.6 (5.5) years. Informal costs (expressed in 2015 dollars) were calculated using the replacement cost method (hours of care multiplied by the median wage in Utah in the visit year) and adjusted for inflation using the Medical Consumer Price Index. Generalized Estimating Equations with a gamma log-link function were used to examine the longitudinal association between use of FDAAMAD and informal costs. RESULTS: The daily informal cost for each participant at baseline ranged from $0 to $318.12, with the sample median of $9.40. Within the entire sample, use of FDAAMAD was not significantly associated with informal costs (expß = 0.73, p = 0.060). In analyses restricted to participants with mild dementia at baseline (N = 222), use of FDAAMAD was associated with 32% lower costs (expß = 0.68, p = 0.038). CONCLUSIONS: Use of FDAAMAD was associated with lower informal care costs in those with mild dementia only.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/economia , Cuidadores/economia , Inibidores da Colinesterase/uso terapêutico , Demência/tratamento farmacológico , Demência/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Assistência ao Paciente/economia , Receptores de N-Metil-D-Aspartato/uso terapêutico , Idoso , Inibidores da Colinesterase/economia , Efeitos Psicossociais da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Vigilância da População , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Índice de Gravidade de Doença
7.
Pain Med ; 18(3): 428-440, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27497320

RESUMO

Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.


Assuntos
Giro do Cíngulo/patologia , Infecções por HIV/complicações , Neuralgia/patologia , Neuralgia/virologia , Adulto , Idoso , Feminino , Substância Cinzenta , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
J Neurovirol ; 22(2): 170-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26407716

RESUMO

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.


Assuntos
Benzoxazinas/efeitos adversos , Disfunção Cognitiva/fisiopatologia , Função Executiva/efeitos dos fármacos , Infecções por HIV/fisiopatologia , Hepatite C/fisiopatologia , Memória/efeitos dos fármacos , Aprendizagem Verbal/efeitos dos fármacos , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/administração & dosagem , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/imunologia , Coinfecção , Ciclopropanos , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/fisiologia , Hepacivirus/fisiologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Ritonavir/uso terapêutico
9.
J Biomed Inform ; 63: 235-248, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27586863

RESUMO

PURPOSE: Assistive technologies have been identified as a potential solution for the provision of elderly care. Such technologies have in general the capacity to enhance the quality of life and increase the level of independence among their users. Nevertheless, the acceptance of these technologies is crucial to their success. Generally speaking, the elderly are not well-disposed to technologies and have limited experience; these factors contribute towards limiting the widespread acceptance of technology. It is therefore important to evaluate the potential success of technologies prior to their deployment. MATERIALS AND METHODS: The research described in this paper builds upon our previous work on modelling adoption of assistive technology, in the form of cognitive prosthetics such as reminder apps and aims at identifying a refined sub-set of features which offer improved accuracy in predicting technology adoption. Consequently, in this paper, an adoption model is built using a set of features extracted from a user's background to minimise the likelihood of non-adoption. The work is based on analysis of data from the Cache County Study on Memory and Aging (CCSMA) with 31 features covering a range of age, gender, education and details of health condition. In the process of modelling adoption, feature selection and feature reduction is carried out followed by identifying the best classification models. FINDINGS: With the reduced set of labelled features the technology adoption model built achieved an average prediction accuracy of 92.48% when tested on 173 participants. CONCLUSIONS: We conclude that modelling user adoption from a range of parameters such as physical, environmental and social perspectives is beneficial in recommending a technology to a particular user based on their profile.


Assuntos
Simulação por Computador , Demência/reabilitação , Tecnologia Assistiva , Meio Ambiente , Humanos , Qualidade de Vida , Tecnologia
10.
Alzheimers Dement ; 12(8): 917-24, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27103262

RESUMO

INTRODUCTION: Identifying factors associated with lower dementia care costs is essential. We examined whether two caregiver factors were associated with lower costs of informal care. METHODS: A total of 271 care dyads of the Cache County Dementia Study were included. Estimates of informal costs were based on caregiver reports of time spent in care-related activities and inflation-adjusted 2012 Utah median hourly wages. Caregiver coping and emotional closeness with the care-recipient were assessed using the Ways of Coping Checklist-Revised and Relationship Closeness Scale, respectively. RESULTS: Higher closeness was associated with 24% lower costs (expß = 0.763 [95% confidence interval: 0.583-0.999]) in linear mixed models controlling for demographics and baseline dementia severity and duration. Problem-focused coping was not associated with informal costs (P = .354). DISCUSSION: Caregiver closeness, a potentially modifiable factor, predicted lower dementia informal care costs over time. Future studies examining the care environment in closer dyads may identify specific care-related behaviors or strategies that are associated with lower costs.


Assuntos
Cuidadores/psicologia , Efeitos Psicossociais da Doença , Demência , Idoso , Idoso de 80 Anos ou mais , Demência/economia , Demência/enfermagem , Demência/psicologia , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Estados Unidos/epidemiologia
11.
Proc Natl Acad Sci U S A ; 109(44): 18156-61, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-23071333

RESUMO

Chronic intermittent access to alcohol leads to the escalation of alcohol intake, similar to binge drinking in humans. Converging lines of evidence suggest that impairment of medial prefrontal cortex (mPFC) cognitive function and overactivation of the central nucleus of the amygdala (CeA) are key factors that lead to excessive drinking in dependence. However, the role of the mPFC and CeA in the escalation of alcohol intake in rats with a history of binge drinking without dependence is currently unknown. To address this issue, we examined FBJ murine osteosarcoma viral oncogene homolog (Fos) expression in the mPFC, CeA, hippocampus, and nucleus accumbens and evaluated working memory and anxiety-like behavior in rats given continuous (24 h/d for 7 d/wk) or intermittent (3 d/wk) access to alcohol (20% vol/vol) using a two-bottle choice paradigm. The results showed that abstinence from alcohol in rats with a history of escalation of alcohol intake specifically recruited GABA and corticotropin-releasing factor (CRF) neurons in the mPFC and produced working memory impairments associated with excessive alcohol drinking during acute (24-72 h) but not protracted (16 -68 d) abstinence. Moreover, abstinence from alcohol was associated with a functional disconnection of the mPFC and CeA but not mPFC and nucleus accumbens. These results show that recruitment of a subset of GABA and CRF neurons in the mPFC during withdrawal and disconnection of the PFC-CeA pathway may be critical for impaired executive control over motivated behavior, suggesting that dysregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence.


Assuntos
Consumo de Bebidas Alcoólicas , Transtornos Cognitivos/induzido quimicamente , Etanol/efeitos adversos , Córtex Pré-Frontal/patologia , Síndrome de Abstinência a Substâncias , Animais , Ansiedade , Masculino , Ratos , Ratos Wistar
12.
Alzheimers Dement ; 11(8): 946-54, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25614127

RESUMO

BACKGROUND: Dementia costs are critical for influencing healthcare policy, but limited longitudinal information exists. We examined longitudinal informal care costs of dementia in a population-based sample. METHODS: Data from the Cache County Study included dementia onset, duration, and severity assessed by the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Neuropsychiatric Inventory (NPI). Informal costs of daily care (COC) was estimated based on median Utah wages. Mixed models estimated the relationship between severity and longitudinal COC in separate models for MMSE and CDR. RESULTS: Two hundred and eighty-seven subjects (53% female, mean (standard deviation) age was 82.3 (5.9) years) participated. Overall COC increased by 18% per year. COC was 6% lower per MMSE-point increase and compared with very mild dementia, COC increased over twofold for mild, fivefold for moderate, and sixfold for severe dementia on the CDR. CONCLUSIONS: Greater dementia severity predicted higher costs. Disease management strategies addressing dementia progression may curb costs.


Assuntos
Cuidadores/economia , Demência/economia , Demência/terapia , Assistência ao Paciente/economia , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Planejamento em Saúde Comunitária , Demência/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Avaliação de Resultados em Cuidados de Saúde/economia , Avaliação de Resultados em Cuidados de Saúde/métodos , Assistência ao Paciente/métodos , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Fatores de Tempo , Estados Unidos/epidemiologia
13.
Clin Infect Dis ; 58(7): 1015-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24352352

RESUMO

BACKGROUND: Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection. METHODS: This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non-CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16. RESULTS: The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4(+) T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], -31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, -.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T. CONCLUSIONS: This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration NCT00624195.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Barreira Hematoencefálica , Transtornos Cognitivos/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Transtornos Cognitivos/complicações , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
14.
J Neurovirol ; 20(3): 209-18, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24549970

RESUMO

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.


Assuntos
Complexo AIDS Demência/epidemiologia , Complexo AIDS Demência/patologia , Imageamento por Ressonância Magnética , Neuralgia , Complexo AIDS Demência/tratamento farmacológico , Adulto , Antirretrovirais/uso terapêutico , Lesões Encefálicas/epidemiologia , Lesões Encefálicas/patologia , Lesões Encefálicas/virologia , Córtex Cerebral/patologia , Córtex Cerebral/virologia , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/virologia , Fatores de Confusão Epidemiológicos , Estudos Transversais , Feminino , Substância Cinzenta/patologia , Substância Cinzenta/virologia , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/patologia , Transtornos Mentais/virologia , Pessoa de Meia-Idade , Neuralgia/epidemiologia , Neuralgia/patologia , Neuralgia/virologia , Prevalência , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/virologia
15.
Methods Mol Biol ; 2789: 129-135, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38506998

RESUMO

Psoriasis, an auto-inflammatory disorder, has major manifestations in the skin but can affect other organs. Currently, this condition has no cure, and the treatments include anti-inflammatory medications. Nanoparticles are widely used for drug delivery and have found successful applications in therapy for cancer and infectious diseases. Nanoparticles can also be used to deliver anti-inflammatory drugs to sites of inflammation. Moreover, some nanotechnology platforms possess intrinsic anti-inflammatory properties and may benefit the therapy of inflammation-driven disorders. Herein, we present a protocol to study nanotechnology concepts' anti-inflammatory properties in a chemically-induced psoriasis model.


Assuntos
Nanopartículas , Psoríase , Humanos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pele , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia
16.
bioRxiv ; 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39091849

RESUMO

Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac 4 C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNA Leu , increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translation control as well as therapeutic interventions.

17.
bioRxiv ; 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36909507

RESUMO

Wireframe DNA origami can be used to fabricate virus-like particles for a range of biomedical applications, including the delivery of nucleic acid therapeutics. However, the acute toxicity and biodistribution of these wireframe nucleic acid nanoparticles (NANPs) have not previously been characterized in animal models. In the present study, we observed no indications of toxicity in BALB/c mice following therapeutically relevant dosage of unmodified DNA-based NANPs via intravenous administration, based on liver and kidney histology, liver biochemistry, and body weight. Further, the immunotoxicity of these NANPs was minimal, as indicated by blood cell counts and type-I interferon and pro-inflammatory cytokines. In an SJL/J model of autoimmunity, we observed no indications of NANP-mediated DNA-specific antibody response or immune-mediated kidney pathology following the intraperitoneal administration of NANPs. Finally, biodistribution studies revealed that these NANPs accumulate in the liver within one hour, concomitant with substantial renal clearance. Our observations support the continued development of wireframe DNA-based NANPs as next-generation nucleic acid therapeutic delivery platforms.

18.
ACS Appl Bio Mater ; 6(5): 1960-1969, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37040258

RESUMO

Wireframe DNA origami can be used to fabricate virus-like particles for a range of biomedical applications, including the delivery of nucleic acid therapeutics. However, the acute toxicity and biodistribution of these wireframe nucleic acid nanoparticles (NANPs) have not been previously characterized in animal models. In the present study, we observed no indications of toxicity in BALB/c mice following a therapeutically relevant dosage of nonmodified DNA-based NANPs via intravenous administration, based on liver and kidney histology, liver and kidney biochemistry, and body weight. Further, the immunotoxicity of these NANPs was minimal, as indicated by blood cell counts and type-I interferon and pro-inflammatory cytokines. In an SJL/J model of autoimmunity, we observed no indications of NANP-mediated DNA-specific antibody response or immune-mediated kidney pathology following the intraperitoneal administration of NANPs. Finally, biodistribution studies revealed that these NANPs accumulate in the liver within one hour, concomitant with substantial renal clearance. Our observations support the continued development of wireframe DNA-based NANPs as next-generation nucleic acid therapeutic delivery platforms.


Assuntos
Nanopartículas , Ácidos Nucleicos , Camundongos , Animais , Distribuição Tecidual , DNA/química , Ácidos Nucleicos/química , Ácidos Nucleicos/uso terapêutico , Nanopartículas/toxicidade , Nanopartículas/química
19.
Vaccine ; 41(31): 4480-4487, 2023 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-37270364

RESUMO

The species and tissue specificities of HPV (human papillomavirus) for human infection and disease complicates the process of prophylactic vaccine development in animal models. HPV pseudoviruses (PsV) that carry only a reporter plasmid have been utilized in vivo to demonstrate cell internalization in mouse mucosal epithelium. The current study sought to expand the application of this HPV PsV challenge model with both oral and vaginal inoculation and to demonstrate its utility for testing vaccine-mediated dual-site immune protection against several HPV PsV types. We observed that passive transfer of sera from mice vaccinated with the novel experimental HPV prophylactic vaccine RG1-VLPs (virus-like particles) conferred HPV16-neutralizing as well as cross-neutralizing Abs against HPV39 in naïve recipient mice. Moreover, active vaccination with RG1-VLPs also conferred protection to challenge with either HPV16 or HPV39 PsVs at both vaginal and oral sites of mucosal inoculation. These data support the use of the HPV PsV challenge model as suitable for testing against diverse HPV types at two sites of challenge (vaginal vault and oral cavity) associated with the origin of the most common HPV-associated cancers, cervical cancer and oropharyngeal cancer.


Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Vacinas de Partículas Semelhantes a Vírus , Feminino , Camundongos , Animais , Humanos , Anticorpos Antivirais , Mucosa Bucal , Vacinação , Papillomaviridae , Papillomavirus Humano 16
20.
Front Oncol ; 13: 1223915, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37746286

RESUMO

Background: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed. Methods: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization. Results: The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node. Conclusions: The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.

SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa