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1.
J Natl Cancer Inst ; 2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34302463

RESUMO

Among racial subgroups, Black men have the highest prostate cancer-specific death rate, yet they also exhibit prolonged overall survival compared to White men when treated with standard therapies, including sipuleucel-T. Differential immune responses may play a role in these observations. We compared circulating immune markers from fifty-four men (18 Black and 36 White men) with metastatic castrate-resistant prostate cancer who received sipuleucel-T and were enrolled on an immune monitoring registry. Markers included longitudinal serum cytokine concentrations, humoral responses, and cellular immunity from baseline until 52 weeks after sipuleucel-T administration. Black men had statistically significantly higher median concentrations of TH2-type (IL-4, IL-10, and IL-13) and inflammatory cytokines (IL-2, IL-12, and IL-6) compared to PSA-matched White men both at baseline and 52 weeks after sipuleucel-T (2-sided P < .05). No differences by race were seen in either the antigen-specific T cell response or in the humoral responses to the immunizing antigen PA2024 and select secondary antigens.

2.
Clin Lymphoma Myeloma Leuk ; 21(8): 545-548, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34024744

RESUMO

BACKGROUND: Cardiac involvement and dysfunction are common in patients presenting with AL and ATTR Amyloidosis. Cardiopulmonary exercise testing (CPET) performance is the gold standard to quantify functional capacity. PATIENTS AND METHODS: In this study, we evaluated CPET measurements in 41 patients with cardiac Amyloidosis and their correlation with current amyloid specific staging criteria. RESULTS: In both AL and ATTR cardiac Amyloidosis, percent predicted peak VO2 is significantly reduced and correlates with biomarker abnormalities. The association of cardiac biomarkers with peak VO2 is stronger for AL Amyloidosis (NT-proBNP (r = -0.57, P=0.006), Troponin (r = -0.70, p < 0.001) than ATTR (NT-proBNP (r = -0.4, P = 0.04) and Troponin (r = -0.57, P = 0.002) despite lower left ventricular mass in the former, suggesting that this may be further evidence for light chain toxicity in AL amyloidosis. CONCLUSION: Our findings suggest further evidence for AL toxicity.

3.
Genes Dev ; 35(7-8): 528-541, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737385

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. P53R175H (homologous to Trp53 R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC remains to be investigated. To investigate p53R175H-mediated molecular mechanisms, we used a carcinogen-induced approach in Trp53R172H/- mice to model ESCC. In the primary Trp53R172H/- tumor cell lines, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We identified the YAP-BIRC5 axis as a potential mediator of Trp53 R172H -mediated metastasis. We demonstrate that expression of Survivin, an antiapoptotic protein encoded by BIRC5, increases in the presence of Trp53R172H Furthermore, depletion of Survivin specifically decreases Trp53R172H-driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.


Assuntos
Neoplasias Pulmonares/fisiopatologia , Survivina/genética , Survivina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Camundongos , Mutação , Metástase Neoplásica , Transcriptoma , Proteína Supressora de Tumor p53/metabolismo
4.
Blood Cancer J ; 11(1): 10, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431806

RESUMO

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04-0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Intervalo Livre de Progressão , Estudos Retrospectivos , Translocação Genética/efeitos dos fármacos , Resultado do Tratamento
5.
Chest ; 159(2): 724-732, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32926871

RESUMO

BACKGROUND: Millions of smartphones contain a photoplethysmography (PPG) biosensor (Maxim Integrated) that accurately measures pulse oximetry. No clinical use of these embedded sensors is currently being made, despite the relevance of remote clinical pulse oximetry to the management of chronic cardiopulmonary disease, and the triage, initial management, and remote monitoring of people affected by respiratory viral pandemics, such as severe acute respiratory syndrome coronavirus 2 or influenza. To be used for clinical pulse oximetry the embedded PPG system must be paired with an application (app) and meet US Food and Drug Administration (FDA) and International Organization for Standardization (ISO) requirements. RESEARCH QUESTION: Does this smartphone sensor with app meet FDA/ISO requirements? Are measurements obtained using this system comparable to those of hospital reference devices, across a wide range of people? STUDY DESIGN AND METHODS: We performed laboratory testing addressing ISO and FDA requirements in 10 participants using the smartphone sensor with app. Subsequently, we performed an open-label clinical study on 320 participants with widely varying characteristics, to compare the accuracy and precision of readings obtained by patients with those of hospital reference devices, using rigorous statistical methodology. RESULTS: "Breathe down" testing in the laboratory showed that the total root-mean-square deviation of oxygen saturation (Spo2) measurement was 2.2%, meeting FDA/ISO standards. Clinical comparison of the smartphone sensor with app vs hospital reference devices determined that Spo2 and heart rate accuracy were 0.48% points (95% CI, 0.38-0.58; P < .001) and 0.73 bpm (95% CI, 0.33-1.14; P < .001), respectively; Spo2 and heart rate precision were 1.25 vs reference 0.95% points (P < .001) and 5.99 vs reference 3.80 bpm (P < .001), respectively. These small differences were similar to the variation found between two FDA-approved reference instruments for Spo2: accuracy, 0.52% points (95% CI, 0.41-0.64; P < .001) and precision, 1.01 vs 0.86% points (P < .001). INTERPRETATION: Our findings support the application for full FDA/ISO approval of the smartphone sensor with app tested for use in clinical pulse oximetry. Given the immense and immediate practical medical importance of remote intermittent clinical pulse oximetry to both chronic disease management and the global ability to respond to respiratory viral pandemics, the smartphone sensor with app should be prioritized and fast-tracked for FDA/ISO approval to allow clinical use. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04233827; URL: www.clinicaltrials.gov.


Assuntos
Aplicativos Móveis , Oximetria/instrumentação , Fotopletismografia/instrumentação , Smartphone , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas Biossensoriais , Aprovação de Equipamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/normas , Fotopletismografia/normas , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
6.
Semin Oncol ; 48(2): 166-170, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33334607

RESUMO

INTRODUCTION: SARS-CoV-2 (S-2) infection duration and its impact on patients with cancer and mild to moderate COVID-19 undergoing cancer-directed therapy (CDT), especially in the underserved population, is not well described. We conducted a retrospective study to analyze S-2 positive (+) patients on CDT to describe the S-2 duration and its impact on CDT. METHODS: Two hundred ninety-nine patients with cancer were tested with nasopharyngeal (NP) S-2 PCR assay at Columbia University Medical Irving Center (CUIMC), a Minority-NCI Community Oncology site, of which 77 (26%) tested positive. We retrospectively analyzed 26 S-2 (+) patients with mild-to-moderate COVID-19 receiving CDT who consented to the study. NP PCR was repeated every 1 to 2 weeks until 2 successive negative (-) PCRs were obtained prior to restarting CDT. Time to 2 (-) PCR and serology results were recorded. Cycling thresholds (Ct) were obtained for S-2 specific targets and represented an indirect measure of viral load. RESULTS: Demographics of N = 26 patients are: Hispanic (N = 17, 65%), Black (N = 1, 4%), White (N = 7, 27%), and undeclared (N = 1, 4%). Among the tumor histologies represented, gastrointestinal (N = 9, 35%), breast (N = 5, 19%), and sarcoma (N = 3, 12%) were most common. Median time to 2 (-) PCR was 32 days. Twenty patients required greater than 14 days to achieve 2 sequential (-) swabs. CDT was delayed in 21 patients (81%) of whom three experienced disease progression, likely attributed to an interruption in CDT, which was delayed by a mean of 53 days. Interestingly, nine (41%) patients had Ct values greater than 34 for the pan SARS target and seven (32%) patients had Ct values greater than 34 for the SARS-COV-2 target. Sixteen of 16 patients on CDT, tested positive for IgG antibodies at the time of consent, despite protracted viral detectability by NP PCR. CONCLUSION: Patients receiving CDT appear to have prolonged detectable S-2 by PCR, which can lead to interruption of CDT and POD in patients. We believe and recommend that patients with asymptomatic to mild COVID-19 and aggressive malignancies are at greatest risk for cancer related morbidity and mortality due to CDT cessation and should be considered for continued CDT without interruption. Ct values and serology testing are tools that can help identify those patients on CDT who may be at greatest risk of worsening COVID-19 or of spreading S-2.


Assuntos
COVID-19/complicações , Neoplasias/virologia , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/terapia , New York/epidemiologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
8.
J Clin Oncol ; 38(13): 1455-1462, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083996

RESUMO

PURPOSE: No established treatments exist for relapsed/refractory systemic light-chain (AL) amyloidosis. Bendamustine has shown potential in the treatment of multiple myeloma. We conducted a phase II, multicenter trial to assess the efficacy and safety of bendamustine with dexamethasone (ben-dex) in patients with persistent or progressive AL amyloidosis after ≥ 1 prior therapy. METHODS: The trial enrolled 31 patients who received bendamustine on days 1 and 2 (100 mg/m2 intravenously) with 40 mg of weekly dexamethasone in 28-day cycles until disease progression or up to 6 cycles after complete hematologic response. The primary objective was the rate of partial hematologic response (PR) or better. RESULTS: Patients received a median of 4 cycles (range, 2-12 cycles) with 57% of patients achieving a PR or better (11% complete response, 18% very good PR). The overall organ response was 29% among the 24 patients who had measurable organ involvement. Treatment was well tolerated with no grade 5 treatment-related adverse events (AEs). Sixty-five percent of patients had a therapy-related grade 3-4 AE. The most common AEs included myelosuppression, fatigue, and nausea/vomiting. The median overall survival was 18.2 months (95% CI, 11.3 to 43.8 months), and hematologic response was associated with prolonged survival (P = .0291). The median progression-free survival was 11.3 months (95% CI, 5.0 to 15.4 months). CONCLUSION: Overall, ben-dex is a viable treatment option with substantial efficacy and limited toxicity for patients with pretreated AL amyloidosis who have limited therapeutic options. This trial was registered at (ClinicalTrials.gov identifier: NCT01222260).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Recidiva Local de Neoplasia , Resultado do Tratamento , Vômito/induzido quimicamente
9.
Prostate ; 80(4): 336-344, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899823

RESUMO

BACKGROUND: Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets. METHODS: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median. Pearson's rank correlation coefficient was used to compare continuous variables. RESULTS: Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042). CONCLUSIONS: Several innate cytokines were associated with biochemically recurrent prostate cancer.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Citocinas/imunologia , Calicreínas/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Idoso , Biomarcadores Tumorais/sangue , Estudos de Coortes , Citocinas/sangue , Progressão da Doença , Método Duplo-Cego , Gosserrelina/administração & dosagem , Humanos , Tolerância Imunológica , Imunidade Inata , Imunossupressores/administração & dosagem , Leuprolida/administração & dosagem , Estudos Longitudinais , Masculino , Recidiva Local de Neoplasia/sangue , Neoplasias da Próstata/sangue , Talidomida/administração & dosagem
10.
JCI Insight ; 5(1)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944090

RESUMO

Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause the fatal neurodegenerative disease giant axonal neuropathy (GAN), in which IF proteins accumulate and aggregate in axons throughout the nervous system, impairing neuronal function and viability. Despite this pathophysiological significance, the upstream regulation and downstream effects of normal and aberrant gigaxonin function remain incompletely understood. Here, we report that gigaxonin is modified by O-linked ß-N-acetylglucosamine (O-GlcNAc), a prevalent form of intracellular glycosylation, in a nutrient- and growth factor­dependent manner. MS analyses of human gigaxonin revealed 9 candidate sites of O-GlcNAcylation, 2 of which ­ serine 272 and threonine 277 ­ are required for its ability to mediate IF turnover in gigaxonin-deficient human cell models that we created. Taken together, the results suggest that nutrient-responsive gigaxonin O-GlcNAcylation forms a regulatory link between metabolism and IF proteostasis. Our work may have significant implications for understanding the nongenetic modifiers of GAN phenotypes and for the optimization of gene therapy for this disease.


Assuntos
Acetilglucosamina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Neuropatia Axonal Gigante/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Antígenos de Neoplasias/metabolismo , Sítios de Ligação , Linhagem Celular , Proteínas do Citoesqueleto/genética , Epigênese Genética , Terapia Genética , Neuropatia Axonal Gigante/etiologia , Neuropatia Axonal Gigante/genética , Neuropatia Axonal Gigante/terapia , Glicosilação , Histona Acetiltransferases/metabolismo , Humanos , Hialuronoglucosaminidase/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Biológicos , Estado Nutricional , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteostase , Serina/metabolismo , Treonina/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
11.
Cell Death Differ ; 27(3): 1008-1022, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31320750

RESUMO

Ferroptosis is a specialized iron-dependent cell death that is associated with lethal lipid peroxidation. Modulation of ferroptosis may have therapeutic potential since it has been implicated in various human diseases as well as potential antitumor activities. However, much remains unknown about the underlying mechanisms and genetic determinants of ferroptosis. Given the critical role of kinases in most biological processes and the availability of various kinase inhibitors, we sought to systemically identify kinases essential for ferroptosis. We performed a forward genetic-based kinome screen against ferroptosis in MDA-MB-231 cells triggered by cystine deprivation. This screen identified 34 essential kinases involved in TNFα and NF-kB signaling. Unexpectedly, the DNA damage response serine/threonine kinase ATM (mutated in Ataxia-Telangiectasia) was found to be essential for ferroptosis. The pharmacological or genetic inhibition of ATM consistently rescued multiple cancer cells from ferroptosis triggered by cystine deprivation or erastin. Instead of the canonical DNA damage pathways, ATM inhibition rescued ferroptosis by increasing the expression of iron regulators involved in iron storage (ferritin heavy and light chain, FTH1 and FTL) and export (ferroportin, FPN1). The coordinated changes of these iron regulators during ATM inhibition resulted in a lowering of labile iron and prevented the iron-dependent ferroptosis. Furthermore, we found that ATM inhibition enhanced the nuclear translocation of metal-regulatory transcription factor 1 (MTF1), responsible for regulating expression of Ferritin/FPN1 and ferroptosis protection. Genetic depletion of MTF-1 abolished the regulation of iron-regulatory elements by ATM and resensitized the cells to ferroptosis. Together, we have identified an unexpected ATM-MTF1-Ferritin/FPN1 regulatory axis as novel determinants of ferroptosis through regulating labile iron levels.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ferroptose , Proteínas Quinases/metabolismo , Proteoma/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Cistina/metabolismo , Ferroptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ferro/metabolismo , Modelos Biológicos , Piperazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
12.
Sci Rep ; 9(1): 7868, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133690

RESUMO

Hookworms are one of the most prevalent and important parasites, infecting ~500 million people worldwide. Hookworm disease is among the leading causes of iron-deficiency anemia in the developing world and is associated with significant growth stunting and malnutrition. In humans, hookworms appear to impair memory and other forms of cognition, although definitive data are hard to come by. Here we study the impact of a human hookworm parasite, Ancylostoma ceylanicum, on cognition in hamsters in a controlled laboratory setting. We developed tests that measure long-term memory in hamsters. We find that hookworm-infected hamsters were fully capable of detecting a novel object. However, hookworm-infected hamsters were impaired in detecting a displaced object. Defects could be discerned at even at low levels of infection, whereas at higher levels of infection, hamsters were statistically unable to distinguish between displaced and non-displaced objects. These spatial memory deficiencies could not be attributed to defects in infected hamster mobility or to lack of interest. We also found that hookworm infection resulted in reproducible reductions in diversity and changes in specific taxanomic groups in the hamster gut microbiome. These data demonstrate that human hookworm infection in a laboratory mammal results in a specific, rapid, acute, and measurable deficit in spatial memory, and we speculate that gut alterations could play some role in these cognitive deficits. Our findings highlight the importance of hookworm elimination and suggest that finer tuned spatial memory studies be carried out in humans.


Assuntos
Ancylostoma/fisiologia , Ancilostomíase/microbiologia , Ancilostomíase/fisiopatologia , Cognição , Microbioma Gastrointestinal , Ancilostomíase/parasitologia , Animais , Cricetinae , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Memória de Longo Prazo
13.
Retina ; 39(8): 1540-1550, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29746403

RESUMO

PURPOSE: To describe spectral domain optical coherence tomography (SD-OCT) findings in an Amish cohort to assess SD-OCT markers for early age-related macular degeneration (AMD). METHODS: The authors performed a family-based prospective cohort study of 1,146 elderly Amish subjects (age range 50-99 years) (2,292 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examinations, SD-OCT using both Cirrus and Spectralis (20 × 20° scan area) instruments, fundus autofluorescence, infrared imaging, and color fundus photography. Spectral domain optical coherence tomography characteristics were analyzed in subjects with AMD (with and without subretinal drusenoid deposits [SDDs]) and normal healthy cohorts. RESULTS: Participants' mean age was 65.2 years (SD ± 11). Color fundus photographic findings in 596 (53%) subjects (1,009 eyes) were consistent with AMD; the remaining 478 (43%) subjects showed no signs of AMD. The choroid was significantly thinner on OCT (242 ± 76 µm, P < 0.001) in those with AMD compared with those without (263 ± 63 µm). Subretinal drusenoid deposits were found in 143 eyes (7%); 11 of the 143 eyes (8%) had no other manifestations of AMD. Drusen volume (P < 0.001) and area of geographic atrophy (P < 0.001) were significantly greater, and choroid was significantly (P < 0.001) thinner in subjects with SDDs versus those without SDDs. CONCLUSION: The authors describe spectral domain optical coherence tomography characteristics in an elderly Amish population with and without AMD, including the frequency of SDD. Although relatively uncommon in this population, the authors confirmed that SDDs can be found in the absence of other features of AMD and that eyes with SDDs have thinner choroids.


Assuntos
Amish/genética , Degeneração Macular/diagnóstico por imagem , Drusas Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Reprodutibilidade dos Testes , Drusas Retinianas/genética
14.
Invest Ophthalmol Vis Sci ; 57(14): 6107-6115, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27832277

RESUMO

Purpose: Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined. Methods: We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes). Results: Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08-2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV. Conclusions: Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.


Assuntos
Fator H do Complemento/genética , DNA/genética , Predisposição Genética para Doença , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Fator H do Complemento/metabolismo , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
15.
Mol Cancer Res ; 14(11): 1045-1053, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27458033

RESUMO

Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature. Therefore, PSMA expression was examined in HUVECs, in vitro and in vivo, and we tested the hypothesis that cancer cell-HUVEC crosstalk could induce the expression of PSMA in HUVECs. Interestingly, conditioned media from several cancer cell lines induced PSMA expression in HUVECs, in vitro, and these lines induced PSMA, in vivo, in a HUVEC coimplantation mouse model. Furthermore, HUVECs in which PSMA expression was induced were able to internalize J591, a mAb that recognizes an extracellular epitope of PSMA as well as nanoparticles bearing a PSMA-binding ligand/inhibitor. These findings offer new avenues to study the molecular mechanism responsible for tumor cell induction of PSMA in neovasculature as well as the biological role of PSMA in neovasculature. Finally, these data suggest that PSMA-targeted therapies could synergize with antiangiogenic and/or other antitumor agents and provide a promising model system to test therapeutic modalities that target PSMA in these settings. IMPLICATIONS: Cancer cells are able to induce PSMA expression in HUVECs, in vitro and in vivo, allowing internalization of PSMA-specific mAbs and nanoparticles bearing a PSMA-binding ligand/inhibitor. Mol Cancer Res; 14(11); 1045-53. ©2016 AACR.


Assuntos
Anticorpos/metabolismo , Antígenos de Superfície/metabolismo , Meios de Cultivo Condicionados/farmacologia , Glutamato Carboxipeptidase II/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Patológica/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/imunologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Neovascularização Patológica/genética
16.
Int J Stroke ; 11(9): 1020-1027, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27435205

RESUMO

BACKGROUND: Silent brain infarcts are common in patients at increased risk of stroke and are associated with a poor prognosis. In patients with asymptomatic carotid stenosis, similar adverse associations were claimed, but the impact of previous infarction or symptoms on the beneficial effects of carotid endarterectomy is not clear. Our aim was to evaluate the impact of prior cerebral infarction in patients enrolled in the Asymptomatic Carotid Surgery Trial, a large trial with 10-year follow-up in which participants whose carotid stenosis had not caused symptoms for at least six months were randomly allocated either immediate or deferred carotid endarterectomy. METHODS: The first Asymptomatic Carotid Surgery Trial included 3120 patients. Of these, 2333 patients with baseline brain imaging were identified and divided into two groups irrespective of treatment assignment, 1331 with evidence of previous cerebral infarction, defined as a history of ischemic stroke or transient ischemic attack > 6 months prior to randomization or radiological evidence of an asymptomatic infarct (group 1) and 1002 with normal imaging and no prior stroke or transient ischemic attack (group 2). Stroke and vascular deaths were compared during follow-up, and the impact of carotid endarterectomy was observed in both groups. RESULTS: Baseline characteristics of patients with and without baseline brain imaging were broadly similar. Of those included in the present report, male gender and hypertension were more common in group 1, while mean ipsilateral stenosis was slightly greater in group 2. At 10 years follow-up, stroke was more common among participants with cerebral infarction before randomization (absolute risk increase 5.8% (1.8-9.8), p = 0.004), and the risk of stroke and vascular death was also higher in this group (absolute risk increase 6.9% (1.9-12.0), p = 0.007). On multivariate analysis, prior cerebral infarction was associated with a greater risk of stroke (hazard ratio = 1.51, 95% confidence interval: 1.17-1.95, p = 0.002) and of stroke or other vascular death (hazard ratio = 1.30, 95% confidence interval: 1.11-1.52, p = 0.001). At 10 years, greater absolute benefits from immediate carotid endarterectomy were seen in those patients with prior cerebral infarction (6.7% strokes immediate carotid endarterectomy vs. 14.7% delayed carotid endarterectomy; hazard ratio 0.47 (0.34-0.65), p = 0.003), compared to those lower risk patients without prior cerebral infarction (6.0% vs. 9.9%, respectively; hazard ratio 0.61 (0.39-0.94), p = 0.005), though it must be emphasized that the first Asymptomatic Carotid Surgery Trial was not designed to test this retrospective and non-randomized comparison. CONCLUSIONS: Asymptomatic carotid stenosis patients with prior cerebral infarction have a higher stroke risk during long-term follow-up than those without prior cerebral infarction. Evidence of prior ischemic events might help identify patients in whom carotid intervention is particularly beneficial.


Assuntos
Estenose das Carótidas/cirurgia , Infarto Cerebral/cirurgia , Endarterectomia das Carótidas , Idoso , Isquemia Encefálica/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/epidemiologia , Infarto Cerebral/complicações , Infarto Cerebral/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/epidemiologia , Modelos de Riscos Proporcionais , Risco , Fatores de Tempo , Resultado do Tratamento
18.
J Acquir Immune Defic Syndr ; 48(1): 1-12, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18300699

RESUMO

Dendritic cells (DCs) from HIV-1-infected individuals display numeric and functional defects, and recent evidence suggests that HIV-1 can directly and indirectly activate DCs in vitro. The in vivo activation state and compartmentalization of DC subsets during HIV-1 infection remain poorly understood, however. We evaluated phenotypic and functional characteristics of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) directly ex vivo in peripheral blood and lymphoid tissue from HIV-1-infected and HIV-seronegative individuals. Analysis of a wide range of chemokine receptors and activation/maturation markers on circulating DCs from viremic HIV-1-infected donors revealed a phenotype indicative of partial activation. Yet, blood DCs from viremic subjects still achieved full maturation when stimulated in vitro. In addition, blood pDCs from viremic individuals had a reduced capacity to migrate to CXCL12 in vitro. Total numbers of both DC subsets were increased in lymph nodes of asymptomatic untreated HIV-1-infected subjects, consistent with DC accumulation in the lymphoid compartment. Lymph node DCs also expressed high levels of CD40 in the absence of increases of other typical activation/maturation markers. Activation and depletion of DCs in blood with accumulation in lymphoid tissue may contribute to HIV-associated chronic immune activation and T-cell dysfunction.


Assuntos
Células Dendríticas/imunologia , Infecções por HIV/patologia , Tecido Linfoide/patologia , Sequência de Bases , Primers do DNA , Citometria de Fluxo , Infecções por HIV/imunologia , HIV-1 , Humanos , Tecido Linfoide/imunologia , Fenótipo
19.
J Clin Immunol ; 26(3): 251-64, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16783464

RESUMO

Defects in number and function of dendritic cells (DCs) have been observed during HIV-1 infection, so therapeutic HIV-1 vaccine approaches that target or activate DCs may improve vaccine immunogenicity. To determine the potential of recombinant Saccharomyces cerevisiae yeast as an HIV-1 vaccine, we investigated interactions between yeast and human DCs. Yeast induced direct phenotypic maturation of monocyte-derived DCs (MDDCs) and enriched blood myeloid DCs (mDCs), but only indirectly matured blood plasmacytoid DCs (pDCs). Yeast-pulsed MDDCs and blood mDCs produced inflammatory cytokines and stimulated strong allo-reactive T cell proliferation. Both blood DC subsets internalized yeast, and when pulsed with yeast recombinant for HIV-1 Gag protein, both stimulated in vitro expansion of Gag-specific CD8+ memory T cells. These results suggest that S. cerevisiae yeast have potent adjuvant effects on human DCs. Furthermore, recombinant yeast-derived antigens are processed by human blood DCs for MHC class-I cross-presentation. These DC-targeting characteristics of yeast suggest that it may be an effective vaccine vector for induction of HIV-1-specific cellular immune responses.


Assuntos
Vacinas contra a AIDS/imunologia , Células Dendríticas/imunologia , HIV-1/imunologia , Saccharomyces cerevisiae/imunologia , Proliferação de Células , Células Cultivadas , Citocinas/biossíntese , Produtos do Gene gag , Humanos , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Recombinação Genética , Saccharomyces cerevisiae/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo
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