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1.
Cancers (Basel) ; 15(1)2023 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-36612319

RESUMEN

The superior diagnostic accuracy of [68Ga]Ga-prostate-specific membrane antigen-11 (PSMA) ([68Ga]Ga-PSMA-11) compared to [18F]F-Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT) in Prostate Cancer (PCa) is established. However, it is currently unclear if the added diagnostic accuracy actually translates into improved clinical outcomes in oligometastatic PCa patients treated with [68Ga]Ga-PSMA-11 PET-guided metastasis-directed therapy (MDT). The present study aimed to assess the impact of these two imaging techniques on Progression-Free Survival (PFS) in a real-world sample of oligometastatic PCa patients submitted to PET-guided MDT. Thirty-seven oligometastatic PCa patients treated with PET-guided MDT were retrospectively enrolled. MDT was guided by [18F]F-Fluorocholine PET/CT in eleven patients and by [68Ga]Ga-PSMA-11 PET/CT in twenty-six. Progression was defined as biochemical recurrence (BR), radiological progression at subsequent PET/CT imaging, clinical progression, androgen deprivation therapy initiation, or death. Clinical and imaging parameters were assessed as predictors of PFS. [18F]F-Fluorocholine PET-guided MDT was associated with significantly lower PFS compared to the [68Ga]Ga-PSMA-11 group (median PFS, mPFS 15.47 months, 95% CI: 4.13−38.00 vs. 40.93 months, 95% CI: 40.93−40.93, respectively; p < 0.05). Coherently, the radiotracer used for PET-guided MDT resulted in predictive PFS at the univariate analysis, as well as the castration-resistant status at the time of MDT and the PSA nadir after MDT. However, in the multivariate analysis, castration resistance and PSA nadir after MDT remained the sole independent predictors of PFS. In conclusion, in the present proof-of-concept study, [68Ga]Ga-PSMA-11 provided higher PFS rates than [18F]F-Fluorocholine imaging in oligometastatic PCa patients receiving PET-guided MDT. Although preliminary, this finding suggests that enlarging the "tip of the iceberg", by detecting a major proportion of the submerged disease thanks to next-generation imaging may favourably impact the oncological outcome of oligometastatic PCa treated with MDT.

2.
Arab J Urol ; 17(3): 243-248, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31489242

RESUMEN

Objectives: To evaluate if the use of a photographic handbook (PH) can be a useful tool to improve the detection of disorders during cystoscopy training, as several hands-on tools have been proposed to improve technical skills but very few aim to improve specificity and sensitivity. Subjects and methods: Eight junior residents (JRs) were divided into two groups: Group A, comprised four JRs with previous limited experience of performing cystoscopies; and Group B, including four inexperienced JRs who were asked to study a specific PH before performing cystoscopies. The findings of the two groups were compared using the chi-squared test. Results: A total of 401 consecutive cystoscopies, of which 214 (53.4%) were performed by Group A and 187 (46.6%) by Group B, were considered. Group B showed superior ability in detecting uncommon findings (i.e., carcinoma in situ, bullous oedema, interstitial cystitis, etc.) with 24/46 (52.2%) detected vs eight of 32 (25%) in Group A (P = 0.016). Conclusions: The PH was a useful tool for improving identification of pathological conditions, which could be used to enhance hands-on simulator and practical tutored training. Abbreviations: CIS: carcinoma in situ; JR: junior resident; PH: photographic handbook; VR: virtual reality Classification: Stones/Endourology.

3.
Low Urin Tract Symptoms ; 11(2): O16-O20, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28990346

RESUMEN

OBJECTIVE: The aims of the present study were to evaluate the outcome of implantation of an artificial urinary sphincter (AUS) in male patients with iatrogenic urinary incontinence and to analyse possible risk factors for resurgery, with particular focus on the effects of posterior urethral strictures (US). METHODS: The outcomes of AUS implantation surgeries performed by 2 surgeons on consecutive patients between January 1999 and 2015 were evaluated retrospectively. Univariate analysis with Cox proportional hazard regression was used to assess correlations between resurgery (explantation or substitution of the urethral cuff) and risk factors. Hazard ratios (HR) associated with AUS survival and 95% confidence intervals (CI) were calculated and Kaplan-Meier were constructed. Patients who underwent resurgery for mechanical failure were excluded from the study. RESULTS: In all, 73 male patients were monitored for a maximum of 190 months (median follow-up duration 36 months). The risk of resurgery was 3.75-fold greater in patients with than without stenosis (HR 3.75; 95% CI 1.47-9.59). In addition, Kaplan-Meier survival curves showed a significantly shorter AUS survival time in patients with than without stenosis treatment. CONCLUSIONS: Prior treatment for US increases the relative risk of AUS failure. Despite not being an absolute contraindication for AUS implantation, we suggest that patients with previous treatment for US are informed of potential risks.


Asunto(s)
Reoperación/estadística & datos numéricos , Estrechez Uretral/complicaciones , Esfínter Urinario Artificial/efectos adversos , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Estrechez Uretral/cirugía , Incontinencia Urinaria/etiología , Incontinencia Urinaria/cirugía
4.
Scand J Urol ; 52(2): 134-138, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29307253

RESUMEN

OBJECTIVE: The treatment of bladder diverticula consists of diverticulectomy, mainly by a laparoscopic approach or transurethral resection of the diverticular neck and fulguration of the mucosa. The endoscopic approach is generally dedicated to small diverticula. The aim of this study was to compare laparoscopic diverticulectomy versus endoscopic fulguration for bladder diverticula larger than 4 cm. MATERIALS AND METHODS: A retrospective review of the medical records of consecutive patients undergoing endoscopic or laparoscopic treatment for bladder diverticula larger than 4 cm at two tertiary hospitals was performed. Therapeutic success was defined as either complete resolution or a decrease of at least 80% in the size of the diverticulum. Complications were recorded and graded according to the Clavien-Dindo classification. RESULTS: All patients were treated with transurethral resection of the prostate in the same operative session. The endoscopic group included a cohort of 20 male patients. The median age, diverticular diameter and operative time were 65 years, 7 cm and 62.5 min, respectively. No early postoperative complications were observed. Therapeutic success was achieved in 15 cases (75%). The laparoscopic group included a cohort of 13 male patients with a median age of 63 years and median diverticular diameter of 7.0 cm. The median operative time was 185 min (p < 0.0001). Two grade III postoperative complications were observed (15.3%). Therapeutic success was achieved in all patients (100%). CONCLUSIONS: Acquired bladder diverticula larger than 4 cm can be effectively managed either by a laparoscopic approach or by endoscopic fulguration.


Asunto(s)
Divertículo/cirugía , Electrocoagulación , Endoscopía , Laparoscopía , Enfermedades de la Vejiga Urinaria/cirugía , Anciano , Electrocoagulación/efectos adversos , Endoscopía/efectos adversos , Humanos , Laparoscopía/efectos adversos , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resección Transuretral de la Próstata , Resultado del Tratamiento
5.
J Allergy Clin Immunol ; 141(6): 2220-2233.e4, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29103633

RESUMEN

BACKGROUND: HIV-associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4+ T cells/µL. CD8+CD28-CD127loCD39+ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients. OBJECTIVES: We sought to analyze the frequency of CD8+CD28-CD127loCD39+ Treg cells in the circulation of HIV-infected patients. METHODS: The frequency of circulating CD8+CD28-CD127loCD39+ Treg cells was analyzed and correlated with viral load and CD4+ T-cell counts/percentages in 93 HIV-1-infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus-infected patients (n = 17), and healthy donors (n = 173). RESULTS: HIV-infected patients had increased circulating levels of functional CD8+CD28-CD127loCD39+ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4+ T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non-AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant. CONCLUSION: HIV infection induces remarkable expansion of CD8+CD28-CD127loCD39+ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Femenino , VIH-1/inmunología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Carga Viral/inmunología
7.
Oncotarget ; 7(6): 6424-35, 2016 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-26824503

RESUMEN

Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFNγ+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently <1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always >1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/patología , Linfocitos T Reguladores/inmunología , Neoplasias de la Vejiga Urinaria/patología , Estudios de Casos y Controles , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Antígenos Específicos del Melanoma/genética , Antígenos Específicos del Melanoma/metabolismo , Clasificación del Tumor , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias , Neoplasia Residual/inmunología , Neoplasia Residual/metabolismo , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/metabolismo
8.
Hum Vaccin Immunother ; 9(12): 2543-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23978951

RESUMEN

Cancer vaccines represent a promising therapeutic approach for which prime time is imminent. However, clinical efficacy must be improved in order for cancer vaccines to become a valid alternative or complement to traditional cancer treatments. Considerable efforts have been undertaken so far to better understand the fundamental requirements for clinically-effective cancer vaccines. Recent data emphasize that important requirements, among others, are (1) the use of multi-epitope immunogens, possibly deriving from different tumor antigens; (2) the selection of effective adjuvants; (3) the association of cancer vaccines with agents able to counteract the regulatory milieu present in the tumor microenvironment; and (4) the need to choose the definitive formulation and regimen of a vaccine after accurate preliminary tests comparing different antigen formulations. The first requirement deals with issues related to HLA restriction of tumor antigen presentation, as well as usefulness of tumor antigen spreading and counteraction of immune escape phenomena, linked to tumor antigen down-modulation, for an effective anti-cancer immune response. The second point underscores the necessity of optimal activation of innate immunity to achieve an efficient adaptive anti-cancer immune response. The third point focuses on the importance to inhibit subsets of regulatory cells. The last requirement stresses the concept that the regimen and formulation of the vaccine impacts profoundly on cancer vaccine efficacy. A new generation of cancer vaccines, provided with both immunological and clinical efficacy, will hopefully soon address these requirements.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/aislamiento & purificación , Inmunoterapia/métodos , Neoplasias/terapia , Humanos , Neoplasias/prevención & control
9.
Cancer Immunol Immunother ; 62(6): 1041-52, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23591981

RESUMEN

BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 µg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.


Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Neoplasias Renales/inmunología , Neoplasias Renales/terapia , Péptidos/administración & dosificación , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Adyuvantes Inmunológicos , Anciano , Anciano de 80 o más Años , Aminoquinolinas/inmunología , Antígenos de Neoplasias/química , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Proliferación Celular , Terapia Combinada , Citotoxicidad Inmunológica , Humanos , Imiquimod , Interferón gamma/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Manitol/análogos & derivados , Manitol/inmunología , Persona de Mediana Edad , Estadificación de Neoplasias , Ácidos Oléicos/inmunología , Péptidos/efectos adversos , Péptidos/inmunología , Fenotipo , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Telomerasa/química , Telomerasa/inmunología , Resultado del Tratamiento
10.
Cancer Immunol Immunother ; 62(5): 851-62, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23359087

RESUMEN

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (Treg). In this study, CD39 expression and function was analyzed in both CD8+ and CD4+CD25(hi) Treg from the peripheral blood of healthy donors as well as from tumor specimens. CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) Treg, and CD39 expression correlated with suppression activity mediated by CD8+ Treg. Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ Treg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function. Collectively, these findings, unveiling a new mechanism of action for CD8+ Treg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.


Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos Infiltrantes de Tumor/citología , Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/citología , Proliferación Celular , Humanos , Tolerancia Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Microscopía Fluorescente , Fenotipo , Linfocitos T Reguladores/citología
11.
Hum Immunol ; 73(3): 207-13, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22285846

RESUMEN

CD8(+) regulatory T cells (Treg) and CD4(+)CD25(+) Treg infiltrate human cancers, thus favoring tumor immune escape. Therefore, in the setting of antitumor therapeutic protocols, it is important to associate antitumor treatment with agents that are able to inhibit Treg function. Cyclophosphamide (CY) has been demonstrated to be effective in counteracting CD4(+)CD25(+) Treg activity. Hence, we tested its inhibitory efficacy on human CD8(+) Treg. Because CY is a prodrug, 4-hydroperoxycyclophosphamide (4-HC), a derivative of CY that in aqueous solution is converted to 4-hydroxycyclophosphamide, an active metabolite of CY, was used. 4-HC significantly inhibited CD8(+) Treg generation and function but only at the higher tested concentration (0.5 µg/mL), that is, in the therapeutic range of the drug. The lower 4-HC concentration tested (0.1 µg/mL) was almost ineffective. 4-HC inhibitory effects were related to apoptosis/necrosis induction. When CD8(+)CD28(+) non-Treg were analyzed for comparative purposes, significantly lower cytotoxic rates among these cells were observed than among CD8(+) Treg, which were differentiated because they did not express the CD28 molecule. These data demonstrate that CD8(+) Treg are inhibited through cytotoxic phenomena by CY, thus supporting the use of this drug at adequate concentrations and schedules of administration as a Treg inhibitor in combinatorial chemo- or immunotherapeutic anticancer protocols.


Asunto(s)
Ciclofosfamida/farmacología , Inmunoterapia Adoptiva , Neoplasias/terapia , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Antígenos CD8/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Ciclofosfamida/análogos & derivados , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Necrosis , Neoplasias/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Escape del Tumor/efectos de los fármacos
12.
Biochem Biophys Res Commun ; 387(3): 531-6, 2009 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-19615976

RESUMEN

The incidence and the rate of progression of chronic kidney diseases (CKD) are for most diseases greater in men than in age-matched women. We have previously shown that testosterone (T) promotes the apoptosis of proximal tubule kidney cells. To better understand the downstream signaling process associated with T-induced apoptosis, we examined the involvement of c-Jun amino terminal kinase (JNK) in a human proximal tubule cell line (HK-2) exposed to T: JNK and its downstream effector c-Jun were rapidly phosphorylated. By blocking androgen receptor, JNK phosphorylation was reduced and 17beta-Estradiol treatment had no effect on it. Similarly, pre-treatment with the JNK inhibitor SP600125 prevented the T-induced apoptosis, the phosphorylation of c-Jun and the upregulation of the Fas/FADD pathway. These data show that the JNK/c-Jun pathway is directly regulated by androgens in vitro and highlight a potential mechanism explaining the reported gender differences in the progression of renal diseases.


Asunto(s)
Andrógenos/fisiología , Apoptosis , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Túbulos Renales/citología , Testosterona/fisiología , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Andrógenos/farmacología , Núcleo Celular/enzimología , Estradiol/farmacología , Proteína Ligando Fas/biosíntesis , Proteína de Dominio de Muerte Asociada a Fas/biosíntesis , Flutamida/farmacología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Túbulos Renales/efectos de los fármacos , Túbulos Renales/enzimología , Masculino , Fosforilación/efectos de los fármacos , Testosterona/farmacología , Receptor fas/biosíntesis
13.
Am J Physiol Renal Physiol ; 295(5): F1563-73, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18768588

RESUMEN

We examined the hypothesis that senescence represents a proximate mechanism by which the kidney is damaged in type 2 diabetic nephropathy (DN). As a first step, we studied whether the senescence-associated beta-galactosidase (SA-beta-Gal) and the cell cycle inhibitor p16INK4A are induced in renal biopsies from patients with type 2 DN. SA-beta-Gal staining was approximately threefold higher (P < 0.05) than in controls in the tubular compartment of diabetic kidneys and correlated directly with body mass index and blood glucose. P16INK4A expression was significantly increased in tubules (P < 0.005) and in podocytes (P = 0.04). Nuclear p16INK4A in glomeruli was associated with proteinuria (P < 0.002), while tubular p16INK4A was directly associated with body mass index, LDL cholesterol, and HbA1c (P < 0.001-0.05). In a parallel set of experiments, proximal tubule cells passaged under high glucose presented a limited life span and an approximately twofold increase in SA-beta-Gal and p16INK4A protein. Mean telomere lengths decreased approximately 20% as an effect of replicative senescence. In addition, mean telomere decreased further by approximately 30% in cells cultivated under high glucose. Our results show that the kidney with type 2 diabetic nephropathy displays an accelerated senescent phenotype in defined renal cell types, mainly tubule cells and, to a lesser extent, podocytes. A similar senescent pattern was observed when proximal tubule cell cultures where incubated under high-glucose media. These changes are associated with shortening tubular telomere length in vitro. These findings indicate that diabetes may boost common pathways involving kidney cell senescence, thus reinforcing the role of the metabolic syndrome on biological aging of tissues.


Asunto(s)
Senescencia Celular/fisiología , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/patología , Riñón/patología , Riñón/fisiopatología , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , LDL-Colesterol/sangre , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Femenino , Fibrosis , Glucosa/farmacología , Hemoglobina Glucada/metabolismo , Humanos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Proteinuria/orina , Proteína de Retinoblastoma/metabolismo , Sulfotransferasas/metabolismo , Telómero/metabolismo , beta-Galactosidasa/metabolismo
14.
J Immunol ; 179(7): 4323-34, 2007 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-17878327

RESUMEN

Tumor growth is allowed by its ability to escape immune system surveillance. An important role in determining tumor evasion from immune control might be played by tumor-infiltrating regulatory lymphocytes. This study was aimed at characterizing phenotype and function of CD8+ CD28- T regulatory cells infiltrating human cancer. Lymphocytes infiltrating primitive tumor lesion and/or satellite lymph node from a series of 42 human cancers were phenotypically studied and functionally analyzed by suppressor assays. The unprecedented observation was made that CD8+ CD28- T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+ CD25+ T regulatory lymphocytes associate with CD8+ CD28- T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant. The infiltration of regulatory T cells seems tumor related, being present in metastatic but not in metastasis-free satellite lymph nodes; it likely depends on both in situ generation (via cytokine production) and recruitment from the periphery (via chemokine secretion). Collectively, these results have pathogenic relevance and implication for immunotherapy of cancer.


Asunto(s)
Antígenos CD28/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica , Neoplasias/inmunología , Neoplasias/patología , Diferenciación Celular , Proliferación Celular , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Humanos , Interleucina-10/biosíntesis , Metástasis Linfática/inmunología , Metástasis Linfática/patología , Estadificación de Neoplasias , Neoplasias/metabolismo , Fenotipo , Receptores CCR2 , Receptores CCR4 , Receptores de Quimiocina/metabolismo , Tasa de Supervivencia
15.
Eur Urol ; 51(5): 1420-7; discussion 1427-8, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17166652

RESUMEN

OBJECTIVES: We report the results of a derma graft corporoplasty in a selected group of patients with congenital penile curvature (CPC) who refused a simple plication technique for the risk of penile shortening, even if minimal. METHODS: Between January 1995 and January 2004, 15 potent patients with CPC underwent corporoplasty with inguinal derma graft, with or without tunica albuginea plication. Mean age was 26.6 years (range 19-36). Six patients had a simple lateral left curvature, three had a simple lateral right curvature, four had a ventro-lateral left curvature, one patient had a ventro-lateral right curvature, and one patient had ventral curvature. In nine patients the preoperative mean IIEF-5 score was 22.55 (range 21-24). All the patients were evaluated after three, six and 12 months. RESULTS: One graft was placed in one patient (6.6%), seven (46.6%) received one graft and underwent a tunica albuginea plication, four (26.6%) received two grafts, three (20%) received two grafts and underwent tunica albuginea plication. A residual curvature after three, six and 12 months was present respectively in all (100%), seven (46.6%) and one (6.6%) patients. No patients had a decrease of penile length. The mean difference in the IIEF-5 score before and after the surgical procedure was not statistically significant. CONCLUSIONS: Surgical correction of CPC with derma grafts in potent patients restores penile straightening with no postoperative shortening and preserves normal erectile capacity. Patient satisfaction indicates that the proposed technique may be used in selected cases.


Asunto(s)
Pene/anomalías , Pene/cirugía , Procedimientos de Cirugía Plástica/métodos , Trasplante de Piel , Adulto , Humanos , Masculino
16.
Blood ; 107(4): 1505-12, 2006 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-16249379

RESUMEN

Telomerase is considered a universal tumor-associated antigen (TAA) due to its high rate of expression by cancers (approximately 90%), and clinical trials are in progress to test the immunotherapeutical efficacy of antitelomerase immunization in patients with cancer. However, the data concerning frequency and functional activity of telomerase-specific cytotoxic T lymphocytes (CTLs) in patients with cancer are few and conflicting, although their knowledge would be mandatory to predict the efficacy of telomerase-specific immunotherapy in selected patients. We performed this study to analyze frequency and cytolytic function of circulating CD8+ T lymphocytes specific for the p540 telomerase peptide in a series of human leukocyte antigen (HLA)-A2+ cancer patients. The results show that most patients with cancer have circulating telomerase-specific CD8+ T lymphocytes, but a high frequency of telomerase-specific CTLs are present only in a fraction of them. Furthermore, CTL lines able to kill telomerase-positive tumor cells, including autologous cancer cells, can be expanded ex vivo from some, but not all, patients with cancer. In conclusion, the results of the study support the development of clinical protocols using telomerase peptides as an immunizing agent. However, they underline the necessity to study single patients immunologically before undergoing vaccination, to select the patients adequately, and to eventually adapt the immunization schedule to the patient's immunologic status.


Asunto(s)
Linfocitos T CD8-positivos/enzimología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/inmunología , Telomerasa/sangre , Línea Celular Tumoral , Antígeno HLA-A2/inmunología , Humanos , Inmunofenotipificación , Depleción Linfocítica , Masculino , Linfocitos T Citotóxicos/enzimología , Linfocitos T Citotóxicos/inmunología
17.
Kidney Int ; 65(4): 1252-61, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15086464

RESUMEN

BACKGROUND: Apoptosis is a mode of cell death that participates in the kidney physiologic remodeling processes and is thought to contribute to cell loss and kidney structural damage in chronic renal diseases. Gender is one factor which contributes to accelerated nephron loss, with progression more rapid in men than in women in diabetic and nondiabetic chronic renal diseases. Mechanisms by which androgens may cause higher rate of progression of chronic renal diseases in men are poorly explored. METHODS: In this study, to investigate the role of androgens on apoptotic damage and its associated mechanisms, we examined the effects of testosterone (T) (0.1 nmol/L to 1 micromol/L) on apoptosis, and apoptosis-related proteins in a proximal human tubule cell line (HK-2 cells). Additional experiments were performed in primary cultures of proximal tubular epithelial cells (PTECs). Cells were grown to subconfluence in normal growth medium, and apoptotic damage was induced by serum deprivation for 24 to 48 hours. Cycloheximide, flutamide (a T-receptor antagonist), 17-beta estradiol, or caspase inhibitors were added to cultures that were successively processed for terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end-labeling (TUNEL) analysis, annexin V/propidium iodide staining, immunofluorescence, or immunoblots to identify effects and apoptotic pathways that could be modulating cell survival. RESULTS: Both morphologic analysis by annexin V/propidium iodide staining and TUNEL showed that physiologic T levels (1 to 10 nmol/L) induced a significant increase in apoptosis both in HK-2 cells and PTECs. In both types of cell lines pretreatment with the androgen receptor antagonist flutamide prevented the T-induced apoptosis. T-induced apoptosis was enhanced by treatment with cycloheximide and prevented by 17beta-estradiol. Fas, Fas ligand (FasL), and Fas-associating death domain containing protein (FADD) were clearly up-regulated within 48 hours of T treatment in HK-2 cells. Also, T significantly increased the expression of Bax protein (P < 0.01 vs. control) (an effect which was blocked by flutamide), and decreased the expression of Bcl-2. Western blot analysis showed that caspase-3 was activated. Moreover, cleavage into an 85-kD poly(ADP-ribose) polymerase-1 (PARP-1) terminal breakdown product was detectable. The changes in cellular morphology induced by T at 48 hours were no longer observed after the addition of caspase-8, caspase-9, and caspase-3 inhibitors to the culture medium. CONCLUSION: These results indicate that T increases the permissiveness of proximal tubule kidney cells to apoptotic effects by triggering an apoptotic pathway involving caspase activation, Fas up-regulation, and FasL expression, thus potentially interacting with mechanisms of cell loss which have been already shown to be activated in chronic renal diseases. This is consistent with a role for T in promoting renal injury in men.


Asunto(s)
Andrógenos/farmacología , Apoptosis/efectos de los fármacos , Túbulos Renales Proximales/fisiología , Testosterona/farmacología , Proteínas de Arabidopsis/metabolismo , Caspasa 3 , Inhibidores de Caspasas , Caspasas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Activación Enzimática , Proteína Ligando Fas , Ácido Graso Desaturasas/metabolismo , Humanos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2 , Receptor fas/metabolismo
18.
Urol Int ; 68(2): 95-8, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11834898

RESUMEN

INTRODUCTION: The aim of our study is to verify the effects of doxazosin on sexual function in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We enrolled 102 patients with BPH, selected by nine Italian Urology Departments. Patients were evaluated with the International Prostatic Symptom Score (I-PSS) and divided into two groups: those with intact sexual activity and those with erectile dysfunction. According to the International Index of Erectile Function (IIEF), the second cohort was divided into three subgroups on the basis of the degree of erectile dysfunction degree (severe, moderate or mild). All patients underwent 3 months of therapy with doxazosin. The effects of doxazosin on sexual activity and on voiding symptoms were monitored at 1, 2 and 3 months with IIEF and I-PSS scales. RESULTS: Eighty-six of the 102 initial patients (84%) were monitored until follow-up was completed. The follow-up at 1 month showed a significant decrease in the I-PSS (p < 0.0001) from 20.2 +/- 2.01 (base visit) to 13.1 +/- 2.21. The mean IIEF was 19.24 +/- 6.59 at baseline and 1 month later the score reached 21.44 +/- 5.40, thus showing a statistically significant increase (p = 0.0177). This is more evident in the group presenting with severe to moderate erectile dysfunction. I-PSS and IIEF do not significantly change at the 2- and 3-month follow-ups. CONCLUSIONS: The use of doxazosin improved sexual function in patients with BPH.


Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Doxazosina/uso terapéutico , Erección Peniana/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Estudios de Casos y Controles , Estudios de Seguimiento , Humanos , Masculino , Hiperplasia Prostática/fisiopatología , Factores de Tiempo
19.
Urol Int ; 68(1): 66-8, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11803272

RESUMEN

Postoperative femoral neuropathy is not a well-recognized complication in urology. We report 2 cases of femoral nerve palsy due to compression ascribed to the use of the self-retaining retractor. In the first case, the left femoral nerve was injured, and in the second case nerve injury was bilateral and synchronous. The clinical symptoms were a weakness of the quadriceps muscle and sensory anesthesia of the surrounding skin.


Asunto(s)
Neuropatía Femoral/etiología , Parálisis/etiología , Pelvis/cirugía , Instrumentos Quirúrgicos/efectos adversos , Procedimientos Quirúrgicos Urológicos/efectos adversos , Procedimientos Quirúrgicos Urológicos/instrumentación , Anciano , Femenino , Neuropatía Femoral/rehabilitación , Humanos , Complicaciones Intraoperatorias/diagnóstico , Masculino , Persona de Mediana Edad , Pelvis/fisiopatología , Periodo Posoperatorio , Pronóstico , Medición de Riesgo , Enfermedades de la Vejiga Urinaria/cirugía
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