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1.
J Immunol ; 194(8): 3820-8, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25780034

RESUMEN

Although IL-18 has not previously been shown to promote T lymphopoiesis, results obtained via a novel data mining algorithm (global microarray meta-analysis) led us to explore a predicted role for this cytokine in T cell development. IL-18 is a member of the IL-1 cytokine family that has been extensively characterized as a mediator of inflammatory immune responses. To assess a potential role for IL-18 in T cell development, we sort-purified mouse bone marrow-derived common lymphoid progenitor cells, early thymic progenitors (ETPs), and double-negative 2 thymocytes and cultured these populations on OP9-Delta-like 4 stromal layers in the presence or absence of IL-18 and/or IL-7. After 1 wk of culture, IL-18 promoted proliferation and accelerated differentiation of ETPs to the double-negative 3 stage, similar in efficiency to IL-7. IL-18 showed synergy with IL-7 and enhanced proliferation of both the thymus-derived progenitor cells and the bone marrow-derived common lymphoid progenitor cells. The synergistic effect on the ETP population was further characterized and found to correlate with increased surface expression of c-Kit and IL-7 receptors on the IL-18-treated cells. In summary, we successfully validated the global microarray meta-analysis prediction that IL-18 affects T lymphopoiesis and demonstrated that IL-18 can positively impact bone marrow lymphopoiesis and T cell development, presumably via interaction with the c-Kit and IL-7 signaling axis.


Asunto(s)
Proliferación Celular/fisiología , Interleucina-18/inmunología , Interleucina-7 , Linfopoyesis , Células Precursoras de Linfocitos T/inmunología , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Interleucina-18/agonistas , Interleucina-18/genética , Interleucina-7/agonistas , Interleucina-7/genética , Interleucina-7/inmunología , Linfopoyesis/genética , Linfopoyesis/inmunología , Ratones , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , Células Precursoras de Linfocitos T/citología , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología
2.
Q J Nucl Med Mol Imaging ; 59(4): 462-8, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24695005

RESUMEN

AIM: The aim of this study was to report on the reproducibility of F-18-fluorodeoxyglucose (FDG) PET MTV (metabolic tumor volume) 40% and MTV2.5, as well as on the intratumor reproducibility in patients, predominantly suffering from lung cancer and squamous cell carcinoma of the head and neck (SCCHN). METHODS: Nineteen patients (14 men) who underwent a baseline staging FDG PET-CT examination and a second radiotherapy treatment planning FDG PET-CT examination prior to treatment initiation within 17 days (range: 7-37 days) from each other were included. Bland-Altman analysis was performed on MTV40% and MTVSUV2.5 values obtained of the primary tumor. For voxelwise comparison of the FDG distribution within tumors the transformation matrices, defined on the CT images, were applied to the corresponding FDG images. Accordingly, the MTV40% of the primary tumor volume was defined and copied on the second FDG image. The coordinates and SUV values of each pixel in the corresponding volumes in both FDG images were used for paired comparison. RESULTS: The standard deviation of the percentage spread around the means of both measurements was respectively 32.5% for MTVSUV2.5 versus 18.8% for MTV40%. Using a cut-off value of 1.96 SD, differences exceeding 64% in MTVSUV2.5 and 37% in MTV40% may be considered to be clinically relevant. Correlation coefficients derived from the voxelwise paired comparison of SUV values within MTV40% volumes delineated on scan 1 and scan 2 ranged from 0.67 to 0.96 (mean: 0.83). Bland-Altman plots demonstrated a low reproducibility for low SUV values and a high(er) reproducibility for high SUV values (inverted triangular shape) in all tumor volumes under study. CONCLUSION: The reproducibility of MTV40% proved better than that of MTVSUV2.5 with a cut-off of 37% (increase or decrease) in MTV allowing to define clinically significant changes. Furthermore, intratumoral voxelwise FDG distribution did not change significantly in most of the patients during the time interval studied.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Fluorodesoxiglucosa F18/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Tomografía de Emisión de Positrones , Carga Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello
3.
Nuklearmedizin ; 53(4): 131-8, 2014 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-25100557

RESUMEN

UNLABELLED: In breast cancer CA 15.3 is considered the tumour marker of choice. CA 15.3 is directly related to the disease extent and to hormone status (estrogen receptor ER+/ ER-, progesterone receptor PR+/PR-). This study was designed to assess the impact of disease extent, hormone receptor and HER2-status, and circulating blood volume on the area-under the ROC-curve of CA 15.3 to separate FDG PET positive from negative findings. PATIENTS, METHODS: We retrospectively evaluated 379 FDG PET/CT examinations performed in 80 patients with breast cancer. Blood volumes were derived using the formulas by Nadler and multiplied by their corresponding CA 15.3 measurement. RESULTS: ROC-curve analysis revealed an AUC of 0.695 (p = 0.0001) for CA 15.3 to separate FDG PET positive from negative findings. AUC measurements to separate normal scan findings from loco-regional disease and metastatic disease were 0.527 (p = 0.587) and 0.732 (p = 0.0001), respectively. AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in ER+ and ER- patients, were respectively 0.772 (p = 0.0001) and 0.596 (p = 0.143). AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in PR+ and PR- patients, were respectively 0.675 (p = 0.0001) and 0.694 (p = 0.0001). In HER2-positive and -negative patients, the AUC measurements were respectively 0.594 (p = 0.178) and 0.701 (p = 0.0001) to separate positive from negative FDG PET findings. CONCLUSION: The AUC for CA 15.3 measurements to separate FDG PET positive from negative findings in breast cancer patients with suspected recurrence proved to be directly related to the extent of the recurrent disease and hormone receptor status and inversely related to HER2-status. Correcting CA 15.3 measurements for blood volumes did not impact the AUC.


Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Fluorodesoxiglucosa F18 , Mucina-1/sangre , Recurrencia Local de Neoplasia/diagnóstico , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/terapia , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Humanos , Persona de Mediana Edad , Imagen Multimodal/métodos , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/prevención & control , Curva ROC , Radiofármacos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo/métodos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X/métodos
4.
Acad Med ; 89(12): 1630-5, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25162616

RESUMEN

Oklahoma's health status has been ranked among the worst in the country. In 1972, the University of Oklahoma established the Tulsa branch of its College of Medicine (COM) to expand the physician workforce for northeastern Oklahoma and to provide care for the uninsured patients of the area. In 2008, the Tulsa branch launched a distinct educational track, the University of Oklahoma COM's School of Community Medicine (SCM), to prepare providers equipped and committed to addressing prevalent health disparities.The authors describe the Tulsa branch's Summer Institute (SI), a signature program of the SCM, and how it is part of SCM's process of institutional transformation to align its education, service, and research missions toward improving the health status of the entire region. The SI is a weeklong, prematriculation immersion experience in community medicine. It brings entering medical and physician assistant students together with students and faculty from other disciplines to develop a shared culture of community medicine. The SI uses an unconventional curriculum, based on Scharmer's Theory U, which emphasizes appreciative inquiry, critical thinking, and collaborative problem solving. Also, the curriculum includes Professional Meaning conversations, small-group sessions to facilitate the integration of students' observations into their professional identities and commitments. Development of prototypes of a better health care system enables participants to learn by doing and to bring community medicine to life.The authors describe these and other curricular elements of the SI, present early evaluation data, and discuss the curriculum's incremental evolution. A longitudinal outcomes evaluation is under way.


Asunto(s)
Medicina Comunitaria , Educación de Pregrado en Medicina/métodos , Docentes Médicos , Facultades de Medicina/organización & administración , Estudiantes de Medicina , Actitud del Personal de Salud , Curriculum , Humanos , Oklahoma , Cultura Organizacional , Innovación Organizacional
5.
Q J Nucl Med Mol Imaging ; 58(3): 269-75, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24844256

RESUMEN

Monocytes have been isolated from patient's blood and directly radiolabelled in vitro using a variety of radiopharmaceuticals such as 99mTc-HMPAO, 111In-oxine, 99mTc-colloids and 18F-FDG. Overall, the best labeling results were obtained using 99mTc-HMPAO. The wide availability of 99mTc and of the ligand HMPAO in kit-formulation makes it the most versatile procedure for imaging localized inflammation using in-vitro labeling. Injection of 99mTc-HMPAO labeled monocytes in adult patients has proven safe with an effective dose of 0.011 mSv/Mbq, equivalent to that of 99mTc-HMPAO labeled mixed white blood cells. Furthermore, in a proof of concept studies, in-vitro labeled monocytes were shown to specifically accumulate in the bowels of patients suffering from inflammatory bowel disease as well as in inflamed joints of rheumatoid arthritis patients. Inversely, the decrease in disease activity of inflamed joints of rheumatoid arthritis patients treated by Adalimumab could not be substantiated using 99mTc-HMPAO labelled monocytes suggesting this type of treatment does not reduce monocyte influx. In spite of their wide availability, in-vitro labeling procedures are cumbersome and time-consuming. Furthermore, cell activation may occur during the labeling process and it cannot be excluded that the radiopharmaceuticals used for labelling interfere with ongoing cellular processes. As such, various authors turned towards the development of radiopharmaceuticals for in-vivo labeling of both monocytes and more importantly macrophages, many of which were subsequently validated in animal models. Targets studied in this regard include amongst others the folate receptor, the mannose receptor, the peripheral benzodiazepine receptor as well as more general characteristics of macrophages such as phagocytosis. Various of these novel molecules appear promising and clinical studies using these radiopharmaceuticals are awaited in the near future. Some of these radiopharmaceuticals also reached the clinical stage, respectively the translocating protein targeting radiopharmaceutical 11C-PK11195 and the folate receptor targeting radiopharmaceutical 99mTc-EC20. Uptake of 11C-PK11195 in inflamed joints and sites of atherosclerosis in patients proved to be directly related to the number of peripheral benzodiazepine binding receptors available as well as to the severity of ongoing inflammation. Comparable results were obtained using 99mTc-EC20 in rheumatoid arthritis patients. In spite of these promising results, additional studies are warranted demonstrating that in vivo, quantitative visualization of monocyte trafficking and accumulation of M1 or M2 macrophage subtypes in sites of ongoing inflammation by means of SPECT and PET will contribute to a better understanding of human inflammatory diseases as well as to diagnosis, treatment planning and the development of targeted treatment strategies.


Asunto(s)
Rastreo Celular/métodos , Inflamación/diagnóstico por imagen , Macrófagos/diagnóstico por imagen , Monocitos/diagnóstico por imagen , Radiofármacos , Tomografía Computarizada de Emisión/métodos , Animales , Humanos , Inflamación/inmunología , Inflamación/patología , Marcaje Isotópico/métodos , Macrófagos/inmunología , Monocitos/inmunología , Radiofármacos/inmunología
6.
Nuklearmedizin ; 52(6): 222-7, 2013 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-24108524

RESUMEN

UNLABELLED: 195mPt-cisplatin is regarded as a promising imaging agent for optimizing dosage in patients receiving cisplatin chemotherapy. METHODS: We investigated the whole-body distribution and radiation dosimetry of 195mPt-cisplatin in humans. Whole-body scans were obtained up to 144 h after intravenous injection of 112.4 MBq 195mPt-cisplatin in each of five subjects. Blood samples were taken at various times up to 144 h after injection. Urine was collected up to 114 h after injection for calculation of renal clearance and whole-body clearance. Time/activity curves were generated by fitting the organ-specific geometric mean counts, obtained from regions of interest, on the respective images as a function of the time after injection. OLINDA software package was applied to calculate the absorbed radiation dose for various organs. RESULTS: Most of the activity (32 ± 4%) was excreted in the urine during the first 5 h. The effective clearance half-life derived from extrapolation of the whole-body curve was 40 hours (1.7 days). On average, the highest dose was received by the kidneys (mean dose received 2.68 ± 1.5 mGy/MBq), followed by the spleen (mean dose received 1.6 ± 0.8 mGy/MBq) followed by the liver (mean dose received 1.45 ± 0.38 mGy/MBq). The estimated mean effective dose for the adult subject was 0.185 ± 0.034 mSv/MBq. CONCLUSION: 195mPt-cisplatin proved a safe radiopharmaceutical with a favourable biodistribution for early and delayed imaging of pathology above the diaphragm. The ED obtained was 0.185 ± 0.034 mSv/MBq. The highest organ dose was received by the kidneys (2.68 ± 1.5 mGy/MBq).


Asunto(s)
Cisplatino/farmacocinética , Platino (Metal)/farmacocinética , Radioisótopos/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Imagen de Cuerpo Entero/métodos , Adulto , Cisplatino/administración & dosificación , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Especificidad de Órganos , Platino (Metal)/administración & dosificación , Dosis de Radiación , Radioisótopos/administración & dosificación , Valores de Referencia , Distribución Tisular , Recuento Corporal Total
7.
Eur J Nucl Med Mol Imaging ; 40(8): 1214-22, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23636802

RESUMEN

PURPOSE: Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC). METHODS: (18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (∆SUVmax) and SAM (∆SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS). RESULTS: A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ∆SUVmax of 25.3% and ∆SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ∆SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ∆SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS). CONCLUSION: (18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ∆SAM were found to be significant prognostic factors for PFS and OS.


Asunto(s)
Neoplasias Colorrectales/patología , Fluorodesoxiglucosa F18/farmacocinética , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Fluorouracilo , Humanos , Leucovorina , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Imagen Multimodal , Compuestos Organoplatinos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
8.
Nuklearmedizin ; 52(1): 21-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23358716

RESUMEN

UNLABELLED: Using quantitive VOI analysis, the percentage (99m)Tc-MAA uptake and SUVmax and mean values of liver metastases obtained prior to SIRT were related to treatment response using both a lesion-based and clinical dichotomous approach. Based on the VOI % of (99m)Tc-MAA activity, the estimated (90)Y-microspheres activity/cc (MBq/cc) was calculated from the effective dose injected. Baseline VOI FDG PET SUVmean and max values and estimated MBq/cc values were related to treatment response using a lesion-based approach (% change in SUVmean ≥ 50%) and a clinical dichotomous approach. Fifteen treatment sessions were analyzed (13 patients). Using the lesion-based approach (12 treatment sessions) 40 lesions responded and 37 did not. SUVmax and mean values proved significantly different between non-responding and responding lesions; 18.6 (SD 10.8) versus 13.5 (SD 8.4 ) for SUVmax (p = 0.02) and 11.4 (SD 3.8) versus 6.3 (SD 4.5) for SUVmean (p = 0.002). Using the clinical dichotomous approach (15 treatment sessions / 11 responding), 91 lesions were analyzed; 57 responded. VOI volumes and estimated (90)Y-loaded glass microspheres activity (MBq/cc) did not differ between responders and non responders; 24 cc (SD 27) versus 21 cc (SD 21 cc) (p = 0.4) and 1.95 MBq/cc (SD 1.1 MBq/cc) versus 1.90 MB/cc (SD 2.7 MBq/cc) (p = 0.92). On the contrary, SUVmax and mean values proved significantly different between responders and non-responders; 23.7 (SD 9.8) versus 9.4 (SD 3.8 ) for SUVmax (p = 0.0001) and 13.1 (SD 8.1) versus 4.9 (SD 1.4) for SUVmean. CONCLUSION: These findings suggest that in patients presenting with high baseline SUVmax and mean values, the administration of higher activities or alternatively, other potentially more useful treatment options might be considered.


Asunto(s)
Fluorodesoxiglucosa F18 , Imagenología Tridimensional/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/radioterapia , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Tomografía Computarizada por Rayos X , Radioisótopos de Itrio/uso terapéutico , Anciano , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Radiofármacos/uso terapéutico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del Tratamiento
9.
Br J Cancer ; 106(12): 1926-33, 2012 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-22596235

RESUMEN

BACKGROUND: The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and (18)F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions. METHODS: A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUV(max)) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (K(trans)) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index. RESULTS: Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in K(trans) (P=0.019). In the group of radiological responders, the median baseline SUV(max) was 3.77 (IQR: 2.88-5.60) compared with 7.20 (IQR: 4.67-8.73) in nonresponders (P=0.021). A higher follow-up SUV(max) was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016). CONCLUSION: High relative decrease in K(trans), low follow-up SUV(max) and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundario , Imagen por Resonancia Magnética/métodos , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Compuestos Organoplatinos/uso terapéutico
10.
Med Hypotheses ; 78(6): 814-7, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22513236

RESUMEN

Cancer is a leading cause of death worldwide, with a limited cure rate and late diagnosis for certain types of cancer (e.g. pancreatic cancer). As this disease presents an enormous challenge for scientists, new paradigms in oncology are needed to defeat this serious disease. Currently, several peptide drugs are investigated for their preventive, diagnostic and therapeutic properties in oncology, with already 15 peptide drugs marketed for cancer therapy. However, we suggest that quorum-sensing peptide agonists and antagonists can be used in oncology as well, resulting in a larger potential peptide space. This hypothesis is based on (1) the recent evidence of prokaryote-eukaryote signalling by the use of quorum-sensing signalling molecules, (2) the apoptotic phenomenon seen in bacteria, (3) the clear similarities between the bacterial quorum-sensing mechanisms and the metastatic process tumor cells initiate, (4) the multiple receptor targeting and (5) the possibility of pharmacologic manipulation of peptides, resulting in increased receptor targeting. Up till now, however, the use of quorum-sensing signalling peptides in oncology has not yet been investigated, despite the urgent need for new insights in oncology and the promising perspectives.


Asunto(s)
Modelos Biológicos , Neoplasias/tratamiento farmacológico , Péptidos/fisiología , Péptidos/uso terapéutico , Percepción de Quorum/fisiología , Humanos
11.
BMC Immunol ; 12: 36, 2011 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-21689450

RESUMEN

BACKGROUND: We have developed a 12-parameter/10-color flow cytometric staining method for the simultaneous detection and characterization of 21 mouse thymocyte subpopulations that represent discreet stages of T cell development. To demonstrate the utility of this method, we assessed cytokine receptor expression on mouse thymocyte subsets. These experiments revealed distinct patterns of surface expression of receptors for the cytokines IL-4 and IL-6. RESULTS: The IL-4 receptor α chain (CD124) was highly expressed on the earliest thymocyte subsets, then downregulated prior to T cell receptor ß-selection and finally upregulated in the CD4/CD8 double positive cells prior to positive selection. The IL-6 receptor α chain (CD126) showed a different pattern of expression. It was expressed on the most mature subsets within the CD4 and CD8 single positive (SP) compartments and was absent on all other thymocytes with the exception of a very small cKit-CD4-CD8- population. Intracellular staining of SP thymocytes for phosphorylated STAT-1 demonstrated that IL-6 signaling was confined to the most mature SP subsets. CONCLUSIONS: This 12-parameter staining methodology uses only commercially available fluorochrome-coupled monoclonal antibodies and therefore could be employed by any investigator with access to a 4-laser flow cytometer. This novel staining scheme allowed us to easily phenotype thymocyte subpopulations that span across development, from the early thymic progenitors (ETPs) to the most mature subsets of the CD4 and CD8 single positive populations.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-6/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/metabolismo , Timo/citología , Animales , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Separación Celular , Células Cultivadas , Citometría de Flujo/instrumentación , Citometría de Flujo/métodos , Regulación del Desarrollo de la Expresión Génica/inmunología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Timo/embriología , Timo/crecimiento & desarrollo
12.
Nuklearmedizin ; 50(4): 141-6, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21594304

RESUMEN

PURPOSE: Evaluate the predictive and prognostic value of semi-quantitative FDG-PET variables derived from pretreatment FDG-PET images in patients suffering from locally advanced squamous cell carcinoma of the head and neck (SCCHN), treated by means of concomitant radiochemotherapy. PATIENTS, METHODS: 40 patients with newly diagnosed SCCHN that were treated with concomitant radiochemotherapy underwent FDG-PET/CT for treatment planning; 18 patients had neck dissection prior to their baseline scan and to receiving radiochemotherapy. FDG-PET images were used to calculate metabolic tumour volumes using region growing and a threshold of 50% (MTV50) of primary lesions and involved lymph nodes as well as the mean and maximum standard uptake value (SUVmean and SUVmax) of the primary tumours. RESULTS: Neither SUVmean nor SUVmax values of the primary tumour were significantly different between responders and non-responders whereas MTV50 values of the primary tumour proved significantly higher in non-responders. SUVmean, SUVmax and MTV50 of the primary tumour were not predictive for overall or disease free survival. Contrariwise, dichotomized summed MTV50 values (cut-off≥31 cm3) of the primary tumour and involved lymph nodes in patients that didn't have neck dissection prior to radiochemotherapy were predictive for disease free and overall survival in both univariate and multivariate analysis (p≤0.05). CONCLUSION: Summed MTV50 values of both the primary tumour and involved lymph nodes provided independent prognostic information on disease free and overall survival.


Asunto(s)
Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico , Imagenología Tridimensional/métodos , Tomografía de Emisión de Positrones/métodos , Técnica de Sustracción , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
13.
Res Vet Sci ; 91(3): e125-8, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21316722

RESUMEN

Given its importance in human and canine tumour biology, a profound understanding of tumour hypoxia is of paramount importance. Therefore, the aim of this work was to investigate the relationship between tumour hypoxia and the expression of a number of hypoxia-induced proteins that play a role in tumour metabolism. The hypoxia marker pimonidazole was administered to dogs affected by spontaneous mammary carcinoma and compared with immunohistochemical staining for GLUT1 and 3, HK 2 and CA IX. A statistically significant correlation was found between pimonidazole staining and GLUT1-expression (R=0.607; p=0.001). These results indicate a strong interaction between tumour hypoxia and tumour metabolism by the induction of proteins essential to maintain a stable tumour microenvironment.


Asunto(s)
Enfermedades de los Perros/metabolismo , Neoplasias Mamarias Animales/metabolismo , Animales , Enfermedades de los Perros/cirugía , Perros , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Inmunohistoquímica , Neoplasias Mamarias Animales/cirugía , Nitroimidazoles , Consumo de Oxígeno , Fármacos Sensibilizantes a Radiaciones , Coloración y Etiquetado
14.
Nuklearmedizin ; 50(1): 15-21, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21052609

RESUMEN

AIM: This study aimed at assessing the relationship between over-expression of glucose transporters and hexokinases, tumour proliferation and apoptosis corrected for cellularity and partial volume corrected (pvc) FDG SUV values in primary squamous cell carcinoma of the head and neck (pSCCHN). PATIENTS, METHODS: In 27 consecutive patients suffering from pSCCHN, FDG SUVmax and mean pvc values of the primary tumour were derived from a pre-surgical routine staging FDG PET/CT examination. GLUT-1, GLUT-3, HK-1, HK-3 expression, tumour proliferation (Ki-67 staining) and the number of apoptotic cells (cleaved caspase-3 staining), corrected for tumour cellularity, were subsequently assessed on the corresponding post-surgically obtained biopsies and tumour specimens. FDG SUVmax and mean pvc values of pSCCHN were correlated with the corresponding histological findings. RESULTS: FDG SUV max and mean pvc values correlated significantly: with GLUT-1 scores r = 0.408 (p = 0.04) and r = 0.439 (p = 0.03) as well as with the number of apoptotic cells r = 0.529 (p = 0.008) and r = 0.484 (p = 0.017). The number of apoptotic cells also correlated to GLUT-3 scores: r = 0.62 (p = 0.001) and GLUT-1 scores r = 0.528 (p = 0.008). CONCLUSION: FDG SUV pvc proved significantly related to GLUT-1 expression by tumour cells and to the absolute number of apoptotic cells. The latter finding warrants further exploration and confirmation by additional studies.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Fluorodesoxiglucosa F18/farmacocinética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Hexoquinasa/metabolismo , Adolescente , Adulto , Apoptosis , Carcinoma de Células Escamosas/diagnóstico por imagen , Niño , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Cintigrafía , Regulación hacia Arriba , Adulto Joven
15.
Q J Nucl Med Mol Imaging ; 54(6): 698-703, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21150859

RESUMEN

AIM: The incidence of non-AIDS-related cancers (NADCs) in the AIDS-population has surpassed that of the general population. HIV significantly increases an individual's chances of reactivation of latent tuberculosis (TB) infection and progression to active TB disease. Both HIV, TB and CA present with increased FDG uptake in involved lymph nodes (LNs). The aim of this study was to assess the existence of quantitative differences in FDG uptake by lymph nodes in HIV+/TB-/CA- patients, TB+/HIV-/CA-, TB+/HIV+/CA- patients and HIV-/TB-/CA+ patients. METHODS: Sixteen consecutive referred patients suffering from HIV-1, 21 suffering from HIV-1 and TB and 16 suffering from TB alone were prospectively included. In addition, 30 consecutively referred, previously untreated, HIV and TB negative cancer patients were included. All patients underwent FDG PET imaging. Mean standardized uptake values (SUV mean values) were obtained for involved lymph nodes using region growing and a threshold of 30% in all patients. Results obtained were compared using non-parametric statistics. RESULTS: SUVmean values of involved LNs of HIV+/TB+/CA- patients were significantly higher than SUVmean values of involved LNs of HIV-/TB+/CA- patients and HIV+/TB-/CA patients (P<0.05). Also, SUVmean values of involved LNs of HIV-/TB-/CA+ patients were significantly higher than SUVmean values of involved LNs of HIV+/TB-/CA- patients. HIV+/TB+/CA- patients presented with a significantly higher number of sites of LN involvement when compared to the HIV+/TB-/CA- patient group. CONCLUSION: FDG PET is not useful for assessing malignant lymph node involvement in HIV+, TB+ or HIV+/TB+ patients.


Asunto(s)
Fluorodesoxiglucosa F18/farmacocinética , Infecciones por VIH/metabolismo , Radiofármacos/farmacocinética , Tuberculosis/metabolismo , Adulto , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Neoplasias/patología , Tomografía de Emisión de Positrones/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tuberculosis/complicaciones , Tuberculosis/diagnóstico por imagen
16.
Int Immunol ; 22(5): 387-97, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20203098

RESUMEN

CD27 and CD28 have emerged as indicators demarcating the transition of thymocytes through beta-selection. We found that CD28 exhibits a greater dynamic range of expression during this phase, thus it was employed to further parse the DN/CD44(-) compartment in order to assess IL-7 signaling during the beta-selection process. Plotting CD28 versus CD25 expression revealed six DN/CD44(-) populations. OP9-DL1 stromal cell co-culture was used to demonstrate a developmental linkage from DN3a (CD25(+)CD28(-/lo)) to DN3b (CD25(+)CD28(+)) to DN3c (CD25(int)CD28(+)) to DN4a (CD25(-)CD28(+)) to double positive (DP) and showed the DN4b (CD25(-)CD28(hi)) and DN4c (CD25(-)CD28(-/lo)) populations to be inefficient in producing DP cells. Using CD69 as an additional marker to further parse the DN4a population, we found the pre-DP cells to be the CD44(-)CD25(-)CD28(int)CD69(-)CD4(-/lo)CD8(-/lo) subset. Using this refined developmental scheme, IL-7R alpha expression was found to be transiently up-regulated post-beta-selection in the DN3b and DN3c subsets; however, this increase did not confer enhanced responsiveness over that observed in the DN3a population. CD28 messenger RNA expression was up-regulated in post-beta-selected cells, whereas transcripts for CD27, IL-7R alpha and Bcl-2 were lower than that observed in the DN3a population. This study refines the current thymocyte differentiation scheme to allow for more detailed evaluation of events controlling early T-cell development, specifically surrounding the beta-selection checkpoint.


Asunto(s)
Antígenos CD28/genética , Antígenos CD28/inmunología , Diferenciación Celular , Linfocitos T/citología , Timo/citología , Animales , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Diferenciación Celular/inmunología , Técnicas de Cocultivo , Citometría de Flujo , Regulación del Desarrollo de la Expresión Génica , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Lectinas Tipo C/genética , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Receptores de Interleucina-7/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología , Timo/inmunología
17.
Nuklearmedizin ; 49(1): 35-40, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20162246

RESUMEN

UNLABELLED: The aim of this study is to assess the potential impact of double-phase FDG PET versus routine staging in HIV-negative patients suffering from tuberculosis. PATIENTS, METHODS: 16 consecutive patients suffering from tuberculosis underwent contrast-enhanced CT and double-phase FDG PET imaging (45 min, 120 min). Early (E) and delayed (D) SUVmax values were determined for all identified lesions and % change in SUV calculated (DeltaSUV). RESULTS: Seven patients presented with lung lesions on PET as well as CT (mean SUVmaxE 8.2, mean SUVmaxD 11.1, (p = 0.002), DeltaSUV 35%. In two patients, lesions were judged as non-active on CT. In nine patients, 18 sites of LN involvement were identified on both early and delayed FDG PET images (mean SUVmaxE 6.3, mean SUVmaxD 7.9, (p = 0.0001), DeltaSUV: 25%). 9 out of 18 sites of LN involvement, occurring in five patients, were missed on CT. In four of these five patients, sites of LN involvement were the only sites of extra-pulmonary involvement identified. In 6 out of 16 patients, pleural involvement was identified, respectively in 5 on FDG PET and in 6 on CT imaging (mean SUVmaxE 1.3, mean SUVmaxD 1.7, (p = 0.06), DeltaSUV 21%). In 4 patients, osseous involvement was identified by both FDG PET and CT (mean SUVmaxE 7.2, mean SUVmaxD 10.7, (p = 0,06), DeltaSUV 45%). Finally, in 3 patients, joint involvement was identified on both FDG PET as well as on CT imaging (mean SUVmaxE 4.7, mean SUVmaxD 5.2, DeltaSUV 23%). FDG PET did not identify CT-additional sites of involvement that would have resulted in a prolonged treatment. CONCLUSION: In HIV-negative patients suffering from tuberculosis, FDG PET images suggested a more extensive involvement by Mycobacterium tuberculosis when compared to contrast enhanced CT.


Asunto(s)
Fluorodesoxiglucosa F18 , Pulmón/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Tuberculosis/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Óseas/diagnóstico por imagen , Enfermedades Óseas/etiología , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Lactante , Artropatías/diagnóstico por imagen , Artropatías/etiología , Ganglios Linfáticos/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Proyectos Piloto , Derrame Pleural/diagnóstico por imagen , Estudios Prospectivos , Radiofármacos/farmacocinética , Tuberculosis/complicaciones , Tuberculosis/patología
18.
Hum Immunol ; 71(4): 329-33, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20074604

RESUMEN

Interleukin (IL)-7 is a factor essential for mouse and human thymopoiesis. Mouse thymocytes have altered sensitivities to IL-7 at different developmental stages. CD4/CD8 double positive (DP) mouse thymocytes are shielded from the influence of IL-7 because of loss of CD127 (IL-7Ralpha). In this study, we assessed IL-7 receptor expression and IL-7 signaling in human thymocytes. We found human DP cells to be severely limited in their ability to phosphorylate STAT-5 in response to IL-7. The relative expression levels of the IL-7-inducible proteins Bcl-2 and Mcl-1 were also lower in human DP cells, consistent with a stage-specific decrease in IL-7 responsiveness. IL-7 responses were restored in a subset of cells that matured past the DP stage. Unlike the regulation of IL-7 signaling in mouse thymocytes, loss of IL-7 signaling in human DP cells was not due to absence of CD127, but instead correlated with downregulation of CD132 (common gamma chain).


Asunto(s)
Subunidad gamma Común de Receptores de Interleucina/metabolismo , Interleucina-7/farmacología , Células Precursoras de Linfocitos T/efectos de los fármacos , Receptores de Interleucina-7/metabolismo , Animales , Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Diferenciación Celular , Células Cultivadas , Preescolar , Humanos , Lactante , Recién Nacido , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/inmunología , Interleucina-7/inmunología , Ratones , Células Precursoras de Linfocitos T/citología , Células Precursoras de Linfocitos T/inmunología , Células Precursoras de Linfocitos T/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Timo/citología , Timo/inmunología
19.
J Vet Intern Med ; 24(1): 185-91, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19912519

RESUMEN

BACKGROUND: Systemic arterial thromboembolic events are a serious complication of cardiac disease in cats. OBJECTIVES: To determine if enoxaparin induces an antithrombotic effect in cats at a dosage of 1 mg/kg SC q12h and if this antithrombotic effect is predicted by anti-Xa activity. ANIMALS: Fourteen clinically healthy cats were divided into 3 groups: control (4 cats), treated and assessed at 4 hours (5 cats), and treated and assessed at 12 hours (5 cats). METHODS: A venous stasis model was used and the extent of thrombus formation estimated by measuring thrombus weight and accretion of 125I-fibrinogen. Plasma anti-Xa activity was measured in treated cats. RESULTS: There was a significant reduction in thrombus formation in the 4 h group compared with control (median weight, 0.000 versus 0.565mg/mm, P < .01; median % 125I-fibrinogen accretion, 0.0 versus 42.0%, P < .01). There was a reduction in thrombus formation in the 12 h group (median weight, 0.006 mg/mm, P = .09; median % 125I-fibrinogen accretion, 3.83%, P = .09) but this reduction was not significant. The median percent thrombus inhibition for treated cats was 100.0% at 4 hours and 91.4% at 12 hours. Plasma anti-Xa activity was not significantly correlated with thrombus formation. CONCLUSIONS AND CLINICAL IMPORTANCE: This pilot study demonstrates that enoxaparin, when administered at a dosage of 1 mg/kg SC q12h, produces an antithrombotic effect in a venous statsis model in clinically healthy cats. Furthermore, this study demonstrates that anti-Xa activity is a poor predictor of enoxaparin's antithrombotic effect.


Asunto(s)
Anticoagulantes/uso terapéutico , Enfermedades de los Gatos/prevención & control , Gatos , Enoxaparina/uso terapéutico , Trombosis de la Vena/veterinaria , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Masculino , Proyectos Piloto , Trombosis de la Vena/prevención & control
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