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1.
Chest ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33621599

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer and have expanded use in small cell lung cancer. Although generally better tolerated than traditional chemotherapy, immune-related adverse events, such as immune checkpoint inhibitor-related pneumonitis (ICI-P), remain poorly understood toxicities that limit ICI treatment and can result in considerable morbidity. In this retrospective case-control study, we assessed a lung cancer cohort to identify ICI-P risk factors. RESEARCH QUESTION: What are the risk factors, clinical presentations, radiographic findings, and outcomes for ICI-P in a real-world lung cancer cohort? Do chronic pulmonary diseases confer increased risk for ICI-P? STUDY DESIGN AND METHODS: Medical records from lung cancer patients receiving nivolumab, pembrolizumab, or combination ipilimumab and nivolumab at six centers in North Carolina were reviewed (January 2004-July 2017). Patients with ICI-P and control participants were characterized, and logistic regression was used to assess for ICI-P risk factors. RESULTS: Three hundred fifteen lung cancer patients who predominantly received nivolumab (76.5%) or pembrolizumab (22%) were included. The incidence of ICI-P was 9.5%, with a median time to diagnosis of 52.5 days. Most patients with ICI-P had cases of high severity, and eight patients (27%) died with ongoing ICI-P treatment. Development of ICI-P was associated independently with the presence of baseline fibrosis on chest CT scan (adjusted OR [aOR], 6.61; 95% CI, 2.48-17.7), a composite measure of obstructive lung disease (aOR, 2.79; 95% CI, 1.07-7.29), and treatment with pembrolizumab (aOR, 2.57; 95% CI, 1.08-6.11). INTERPRETATION: In this cohort, ICI-P was more common and severe than previously reported and carried an unexpectedly high mortality rate. Risk for ICI-P seems to be associated independently with several chronic pulmonary diseases, which may account for the higher incidence of ICI-P in patients with lung cancer.

2.
Radiographics ; 40(1): 200-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917652

RESUMO

Neurodegenerative diseases are a devastating group of disorders that can be difficult to accurately diagnose. Although these disorders are difficult to manage owing to relatively limited treatment options, an early and correct diagnosis can help with managing symptoms and coping with the later stages of these disease processes. Both anatomic structural imaging and physiologic molecular imaging have evolved to a state in which these neurodegenerative processes can be identified relatively early with high accuracy. To determine the underlying disease, the radiologist should understand the different distributions and pathophysiologic processes involved. High-spatial-resolution MRI allows detection of subtle morphologic changes, as well as potential complications and alternate diagnoses, while molecular imaging allows visualization of altered function or abnormal increased or decreased concentration of disease-specific markers. These methodologies are complementary. Appropriate workup and interpretation of diagnostic studies require an integrated, multimodality, multidisciplinary approach. This article reviews the protocols and findings at MRI and nuclear medicine imaging, including with the use of flurodeoxyglucose, amyloid tracers, and dopaminergic transporter imaging (ioflupane). The pathophysiology of some of the major neurodegenerative processes and their clinical presentations are also reviewed; this information is critical to understand how these imaging modalities work, and it aids in the integration of clinical data to help synthesize a final diagnosis. Radiologists and nuclear medicine physicians aiming to include the evaluation of neurodegenerative diseases in their practice should be aware of and familiar with the multiple imaging modalities available and how using these modalities is essential in the multidisciplinary management of patients with neurodegenerative diseases.©RSNA, 2020.

3.
Radiographics ; 40(1): 122-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917664

RESUMO

With phase-contrast imaging, the MRI signal is used to visualize and quantify velocity. This imaging modality relies on phase data, which are intrinsic to all MRI signals. With use of bipolar gradients, degrees of phase shift are encoded and in turn correlated directly with the velocity of protons. The acquisition of diagnostic-quality images requires selection of the correct imaging plane to ensure accurate measurement and selection of the encoding velocity and thus prevent aliasing and achieve the highest signal-to-noise ratio. Multiple applications of phase-contrast imaging are actively used in clinical practice. One of the most common clinical uses is in cardiac valvular flow imaging, at which the data are used to assess the severity of valvular disease and quantify the shunt fraction. In neurologic imaging, phase-contrast imaging can be used to measure the flow of cerebrospinal fluid. This measurement can aid in the diagnosis and direct management of normal pressure hydrocephalus or be used to evaluate the severity of stenosis, such as that in Chiari I malformations. At vascular analysis, phase-contrast imaging can be used to visualize arterial and venous flow, and this application is used most commonly in the brain. Three-dimensional imaging can yield highly detailed flow data in a technique referred to as four-dimensional flow. A more recently identified application is in MR elastography. Shear waves created by using an impulse device can be velocity encoded, and this velocity is directly proportional to the stiffness of the organ, or the shear modulus. This imaging modality is most commonly used in the liver for evaluation of cirrhosis and steatosis, although research on the assessment of other organs is being performed. Phase-contrast imaging is an important tool in the arsenal of MRI examinations and has many applications. Proper use of phase-contrast imaging requires an understanding of the many practical and technical factors and unique physics principles underlying the technique.©RSNA, 2020.

4.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Genética , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
6.
Res Dev Disabil ; 38: 338-44, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25590171

RESUMO

Sensorimotor issues are of increasing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The oculomotor system is a sensorimotor network that can provide insights into functional neurobiology and has well-established methodologies for investigation. In this study, we assessed oculomotor performance among children with high functioning ASD and typically developing children, ages 6-12 years. Children with ASD exhibited greater horizontal saccade latency and greater phase lag during vertical smooth pursuit. Saccades and smooth pursuit are mediated by spatially distant brain regions and the long-fiber tracts connecting them, many of which are implicated in ASD. Training paradigms for oculomotor deficits have shown positive outcomes in other clinical populations, and deficits described here may provide useful targets for interventions.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Acompanhamento Ocular Uniforme/fisiologia , Movimentos Sacádicos/fisiologia , Estudos de Casos e Controles , Criança , Medições dos Movimentos Oculares , Movimentos Oculares/fisiologia , Feminino , Humanos , Masculino
7.
J Glob Infect Dis ; 5(3): 93-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24049362

RESUMO

BACKGROUND: The first case of 2009 pandemic influenza A (H1N1) virus in Gujarat, India, was reported in August 2009. Oseltamivir was used for treatment of pandemic influenza in India. We discuss the clinical characteristics and outcome of the hospitalized patients with H1N1 infection during 2009 pandemic influenza season. MATERIALS AND METHODS: Hospitalized patient with laboratory-confirmed H1N1 flu during August 2009 to February 2010 were included in this retrospective study. Data were collected from hospital ICU charts. Patients discharged from hospital were considered cured from swine flu. Data analysis was performed using CDC software EPI Info v3.5.3. Both univariate and multivariate analyses were conducted. RESULTS: A total of 63 patients were included in the study, of them 41 (65%) males and 22 (35%) females. Median age was 34 (3-69) years and median duration of symptoms before hospitalization was 5 (2-20) days. Common presenting symptoms include fever 58 (92.06%), cough 58 (92.06%), breathlessness 38 (60.31%), common cold 14 (22.22%), vomiting 12 (19.04%), weakness 9 (14.28%), throat pain 7 (11.11%), body ache 5 (7.93%), and chest pain 4 (6.34%). Co-morbidities were seen in 13 (20.63%) patients. Steroids were used in 39 (61.90%) patients, and ventilatory support was required in 17 (26.98%) patients. On presentation chest x-ray was normal in 20 (31.74%) patients, while pulmonary opacities were seen in 43 (68.26%) patients. Forty-seven (74.60%) patients were cured and discharged from hospital, 14 (22.22%) patients died, and 2 (3.17%) patients were shifted to other hospital. Ventilatory requirement, pneumonia, and co-morbidities were the independent predictors of mortality, while age, sex, and steroid use were not associated with increased mortality. CONCLUSION: 2009 pandemic influenza A had the same clinical features as seasonal influenza except vomiting. Mortality rate was high in 2009 H1N1-infected patients with pneumonia, co-morbid conditions, and patients who required ventilatory support.

8.
J Virol ; 83(21): 11064-77, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19710132

RESUMO

Group B coxsackieviruses (CVB) use the CVB and adenovirus receptor (CAR) to enter and infect cells. Some CVB also bind to decay-accelerating factor (DAF), but that interaction alone is insufficient for infection. We previously found that CVB3 entry into polarized human intestinal cells (Caco-2) occurs by a caveolin-dependent but dynamin-independent mechanism that requires DAF-mediated tyrosine kinase signals. In this study, we examined how CVB enter and infect nonpolarized HeLa cells and how DAF binding affects these processes. Using immunofluorescence microscopy and a combination of dominant-negative proteins, small interfering RNAs, and drugs targeting specific endocytic pathways, we found that both DAF-binding and non-DAF-binding virus isolates require dynamin and lipid rafts to enter and infect cells. Unlike what we observed in Caco-2 cells, CVB3 entered HeLa cells with CAR. We found no role for clathrin, endosomal acidification, or caveolin. Inhibition of tyrosine kinases blocked an early event in infection but did not prevent entry of virus into the cell. These results indicate that CVB3 entry into nonpolarized HeLa cells differs significantly from entry into polarized Caco-2 cells and is not influenced by virus binding to DAF.


Assuntos
Antígenos CD55/metabolismo , Dinaminas/metabolismo , Enterovirus Humano B/metabolismo , Microdomínios da Membrana/metabolismo , Internalização do Vírus , Animais , Benzamidas , Antígenos CD55/genética , Células CACO-2 , Caveolinas/metabolismo , Infecções por Coxsackievirus/metabolismo , Filipina/metabolismo , Células HeLa , Humanos , Mesilato de Imatinib , Piperazinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo
10.
Clin Cancer Res ; 15(15): 4944-53, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19602548

RESUMO

PURPOSE: The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8(+) T-cell responses to MHC class I-restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood. EXPERIMENTAL DESIGN: We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8(+) T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library. RESULTS: Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8(+) T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8(+) T cells from patients were predominantly CD28(-) CD57(+) and had relatively short telomeres, consistent with cellular senescence. CONCLUSIONS: Circulating leukemia-specific CD8(+) T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Efeito Enxerto vs Leucemia/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Leucemia Mieloide Aguda/cirurgia , Transplante de Células-Tronco , Adulto , Idoso , Antígenos CD/imunologia , Antígenos CD/metabolismo , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mieloide Aguda/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Telômero/imunologia , Adulto Jovem
11.
Cytotechnology ; 45(1-2): 91-9, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19003246

RESUMO

Telomerase reverse transcriptase hTERT is an attractive target for cancer immunotherapy given its broad expression in human tumors and its demonstrated immunogenicity. Human and murine model systems demonstrate that CD8(+) cytotoxic T-lymphocytes (CTL) and CD4(+) helper T-lymphocytes can recognize dominant epitopes derived from TERT. CTL kill TERT-positive tumor cells of multiple histologies, although there is some disagreement regarding the level of processing and presentation of certain TERT peptides within the context of MHC class I molecules. CTL recognizing modified, low-affinity cryptic TERT epitopes have also been generated that protect against tumor challenge in a murine model. Several phase I clinical trials testing hTERT as a cancer vaccine target have shown the induction of T-cell immune responses but minimal toxicities, including bone marrow toxicity, in patients with multiple types of cancer. Several studies report some patients experiencing clinical benefit, including partial tumor regression, providing further encouragement for hTERT as broadly applicable target for cancer immunotherapy.

12.
Infect Immun ; 71(3): 1470-80, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12595465

RESUMO

The gram-negative bacterium Escherichia coli is the leading cause of urinary tract infection. The interaction between type 1 piliated E. coli and bladder epithelial cells leads to the rapid production of inflammatory mediators, such as interleukin-6 (IL-6) and IL-8. Conflicting reports have been published in the literature regarding the mechanism by which uroepithelial cells are activated by type 1 piliated E. coli. In particular, the role of lipopolysaccharide (LPS) in these responses has been an area of significant debate. Much of the data arguing against LPS-mediated activation of bladder epithelial cells have come from studies using a renal epithelial cell line as an in vitro model of the urinary epithelium. In this report, we analyzed three bladder epithelial cell lines and demonstrated that they all respond to LPS. Furthermore, the LPS responsivity of the cell lines directly correlated with their ability to generate IL-6 after E. coli stimulation. The LPS receptor complex utilized by the bladder epithelial cell lines included CD14 and Toll-like receptors, and signaling involved the activation of NF-kappaB and p38 mitogen-activated protein kinase. Also, reverse transcription-PCR analysis demonstrated that bladder epithelial cells express CD14 mRNA. Thus, the molecular machinery utilized by bladder epithelial cells for the recognition of E. coli is very similar to that described for traditional innate immune cells, such as macrophages. In contrast, the A498 renal epithelial cell line did not express CD14, was hyporesponsive to LPS stimulation, and demonstrated poor IL-6 responses to E. coli.


Assuntos
Proteínas de Drosophila , Escherichia coli/patogenicidade , Fímbrias Bacterianas/fisiologia , Receptores de Lipopolissacarídeos/fisiologia , Lipopolissacarídeos/toxicidade , Glicoproteínas de Membrana/fisiologia , Receptores de Superfície Celular/fisiologia , Bexiga Urinária/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Interleucina-6/biossíntese , Proteínas Quinases Ativadas por Mitógeno/fisiologia , NF-kappa B/fisiologia , Receptores Toll-Like , Células Tumorais Cultivadas , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/microbiologia , Proteínas Quinases p38 Ativadas por Mitógeno
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