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The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/terapia , Androstenos/uso terapéutico , Benzamidas/uso terapéutico , Terapia Combinada/métodos , Docetaxel/uso terapéutico , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas/métodos , Humanos , Masculino , Oncología Médica , Nitrilos/uso terapéutico , Orquiectomía , Feniltiohidantoína/uso terapéutico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/terapia , Radioterapia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Sociedades Médicas , España , Tiohidantoínas/uso terapéuticoRESUMEN
PURPOSE: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. METHODS: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. RESULTS: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. CONCLUSION: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.
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Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias Testiculares , Espera Vigilante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Quimioterapia Adyuvante , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Cisplatino/uso terapéutico , Supervivencia sin Enfermedad , Etopósido/uso terapéutico , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Orquiectomía , Red Testicular/patología , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Seminoma/tratamiento farmacológico , Seminoma/patología , Seminoma/cirugía , España , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Resultado del TratamientoRESUMEN
SuperCam is a highly integrated remote-sensing instrumental suite for NASA's Mars 2020 mission. It consists of a co-aligned combination of Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), Visible and Infrared Spectroscopy (VISIR), together with sound recording (MIC) and high-magnification imaging techniques (RMI). They provide information on the mineralogy, geochemistry and mineral context around the Perseverance Rover. The calibration of this complex suite is a major challenge. Not only does each technique require its own standards or references, their combination also introduces new requirements to obtain optimal scientific output. Elemental composition, molecular vibrational features, fluorescence, morphology and texture provide a full picture of the sample with spectral information that needs to be co-aligned, correlated, and individually calibrated. The resulting hardware includes different kinds of targets, each one covering different needs of the instrument. Standards for imaging calibration, geological samples for mineral identification and chemometric calculations or spectral references to calibrate and evaluate the health of the instrument, are all included in the SuperCam Calibration Target (SCCT). The system also includes a specifically designed assembly in which the samples are mounted. This hardware allows the targets to survive the harsh environmental conditions of the launch, cruise, landing and operation on Mars during the whole mission. Here we summarize the design, development, integration, verification and functional testing of the SCCT. This work includes some key results obtained to verify the scientific outcome of the SuperCam system.
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The management of genitourinary cancer, including bladder, prostate, renal and testicular cancer, has evolved dramatically in recent years due to a better understanding of tumour genetic mutations, alterations in molecular pathways, and to the development of new kinds of drugs such as targeted therapies and immunotherapies. In the field of immunotherapy, new drugs focused on stimulating, enhancing and modulating the immune system to detect and destroy cancer, have been recently discovered. Research in oncology moves quickly and new data of great relevance for clinical practice are communicated every year. For this reason, a group of experts, focused exclusively on the treatment of genitourinary tumours and who get together every year in the BestGU conference to assess the latest progress in this field have summarized the most important advances in a single review, along with a critical assessment of whether these results should alter daily clinical practice.
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Neoplasias Urogenitales/genética , Neoplasias Urogenitales/terapia , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Cistectomía , Drogas en Investigación/uso terapéutico , Femenino , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Neoplasias Renales/genética , Neoplasias Renales/terapia , Masculino , Terapia Molecular Dirigida/métodos , Mutación , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/terapia , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/terapia , Nefrectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
Short-chain enoyl-CoA hydratase (ECHS1) is a mitochondrial beta-oxidation enzyme involved in the metabolism of acyl-CoA fatty acid esters, as well as in valine metabolism. ECHS1 deficiency has multiple manifestations, including Leigh syndrome early at birth or in childhood with poor prognosis, to cutis laxa, exercise-induced dystonia and congenital lactic acidosis. Here we describe the case of a newborn with mutations in ECHS1 that caught our attention after the incidental finding of 3-hydroxy-butyryl\3-hydroxy-isobutyryl\malonylcarnitine (C4OH\C3DC) and tiglylcarnitine (C5:1) on blood spot in the newborn screening (NBS) program. Diagnosis was suspected based on the analysis of organic acids on dried urine spot. A moderate increase of 2-methyl-2,3-dihydroxybutyric acid, was detected, which is a known marker of this disease. Exome analysis showed c.404A>G (p.Asn135Ser) mutation in homozygosis in the ECHS1 gene. The child was therefore admitted to the hospital. Initial examination showed little response to auditory stimuli and mild hypertonia of the extremities. Clinical deterioration was evident at 4 months of age, including neurological and cardiac involvement, and the patient died at 5 months of age. This case illustrates how an incidental detection in the NBS Program can lead to the diagnosis ECHS1 deficiency. Although it is a severe disease, with no treatment available, early detection would allow adequate genetic counseling avoiding the odyssey that suffered most of these families.
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In this article, we review de state of the art on the management of renal cell carcinoma (RCC) and provide recommendations on diagnosis and treatment. Recent advances in molecular biology have allowed the subclassification of renal tumours into different histologic variants and may help to identify future prognostic and predictive factors. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. No adjuvant therapy has demonstrated a clear benefit in overall survival. Considering the whole population of patients with advanced disease, the combination of axitinib with either pembrolizumab or avelumab increase response rate and progression-free survival, compared to sunitinib, but a longer overall survival has only been demonstrated so far with the pembrolizumab combo. For patients with IMDC intermediate and poor prognosis, nephrectomy should not be considered mandatory. In this subpopulation, the combination of ipilimumab and nivolumab has also demonstrated a superior response rate and overall survival vs. sunitinib. In patients progressing to one or two antiangiogenic tyrosine-kinase inhibitors, both nivolumab and cabozantinib in monotherapy have shown benefit in overall survival compared to everolimus. Although no clear sequence can be recommended, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in patients with metastatic RCC.
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Ensayos Clínicos como Asunto/normas , Neoplasias Renales/terapia , Guías de Práctica Clínica como Asunto/normas , Humanos , Oncología Médica , Sociedades MédicasRESUMEN
PURPOSE: There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years. METHODS/PATIENTS: The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated. RESULTS: In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p = 0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope = 0.218, p = 0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs. CONCLUSIONS: The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Masculino , Neoplasias/mortalidad , Estudios RetrospectivosRESUMEN
The original article shows two mistakes, which are listed here.
RESUMEN
Androgen deprivation treatment was the only treatment available for metastatic prostate cancer until recently, with docetaxel as the only treatment with a proven survival benefit in castration-resistant prostate cancer (CRPC). Several drugs have been approved in the castration-resistant disease (sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223). More recently, docetaxel and abiraterone have been moved to the hormone-sensitive disease setting, achieving better patient survival. The purpose of this article is to define the state of the art in the treatment of prostate carcinoma.
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Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Humanos , MasculinoRESUMEN
BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.
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Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Seminoma/tratamiento farmacológico , Seminoma/radioterapia , Adolescente , Adulto , Terapia Combinada , Supervivencia sin Enfermedad , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Nomogramas , Orquiectomía , Factores de Riesgo , Seminoma/patología , Seminoma/cirugíaRESUMEN
BACKGROUND: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. RESULTS: High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). CONCLUSIONS: We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.
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Carcinoma de Células Renales/tratamiento farmacológico , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Hipoxia de la Célula/efectos de los fármacos , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Indoles/efectos adversos , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , Pirroles/efectos adversos , ARN Mensajero/biosíntesis , Sunitinib , Sobrevida , Resultado del Tratamiento , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: Immunotherapy (IL-2 and INF-α) was the treatment of choice for advanced renal cell carcinoma (RCC) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s. This clinical trial explored the efficacy and toxicity of sequential treatment of IL-2 plus INF-α followed by sorafenib. METHODS: Eligibility criteria included measurable, non-resectable, histologically confirmed predominantly clear cell RCC, no prior systemic treatment, and ECOG PS 0-2. The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 × 10(6) IU on days 1-6 of weeks 1, 2, 4 and 5 plus s.c. INF-α at 6 × 10(6) IU on days 1, 3 and 5 of weeks 1-6. Responders received 6 additional weeks of this regimen. All patients received oral sorafenib (400 mg bid) after immunotherapy until disease progression. The primary endpoint was progression-free survival. RESULTS: Forty-one patients were enrolled, median age 57 years. ECOG was 0/1 in 17/20 patients, 35 patients had prior nephrectomy and 18 patients pure clear cell cancer. Median PFS was 7.4 months (95 % CI 6.5-13.1) and OS was 16.6 months (95 % CI not reached). In 36 patients evaluable for response, ORR was 44.4 % and control rate was 94.4 %. Most adverse events (AEs) were Grade 1 or 2 toxicities (84.7 %). During immunotherapy the most common AEs were pyrexia (82.9 %), asthenia (56.1 %) and anorexia (46.3 %), whereas during sorafenib were diarrhoea (48.8 %) and hand-foot syndrome (46.3 %). CONCLUSIONS: A sequential regimen of IL-2 and INF-α followed by sorafenib showed effectiveness and manageable toxicity in patients with advanced RCC.
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Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Interleucina-2/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/terapia , Terapia Combinada/métodos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia/métodos , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/administración & dosificación , Probabilidad , Sorafenib , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Complejos de ATP Sintetasa/genética , Acidosis/genética , Cardiomegalia/genética , Retardo del Crecimiento Fetal/genética , Glutaratos/metabolismo , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Complejos de ATP Sintetasa/deficiencia , Acidosis/metabolismo , Acidosis/patología , Cardiomegalia/metabolismo , Cardiomegalia/patología , Niño , Consanguinidad , Análisis Mutacional de ADN , Femenino , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/deficiencia , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Heterocigoto , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Proteínas de la Membrana/deficiencia , Proteínas Mitocondriales/deficiencia , Proteínas/genética , Proteínas/metabolismo , Eliminación de Secuencia , Proteína Inhibidora ATPasaRESUMEN
The mechanisms involved in antiparasitic activity of the natural nonflavonoid polyphenol resveratrol (RESV) on the turbot (Psetta maxima) scuticoliate parasite Philasterides dicentarchi were investigated. At concentrations higher than 50microM, RESV caused significant inhibition of the in vitro growth of the ciliates, which was apparent on the third day of culture and, at the same concentration, RESV caused significant inhibition of O(2) consumption. RESV, at a concentration of 100microM, produced a significant increase in the production of intracellular reactive oxygen species (ROS), which were inhibited by the addition of 1mM of L (+) ascorbic acid. RESV (100microM) also caused significant inhibition of peroxidase, catalase and superoxide dismutase activities, but stimulated the activity of the redox regulating enzyme glutathione S-transferase. Confocal microscopy with the mitochondria-sensitive dye MitoTracker Orange CMTMRos revealed that RESV at concentrations higher than 50microM significantly increased the levels of fluorescence inside mitochondria and, at the same concentration, also caused an increase in the vacuolization of the trophozoites. The results obtained in the present study suggest that the inhibitory activity of RESV on the ciliate P. dicentrarchi is related to the induction of oxidative stress and to the inability of the parasite to eliminate ROS as a result of modified activity of antioxidant enzymes.
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Antiprotozoarios/farmacología , Cilióforos/efectos de los fármacos , Peces Planos/parasitología , Estilbenos/farmacología , Animales , Antioxidantes/metabolismo , Apoptosis , Relación Dosis-Respuesta a Droga , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Especies Reactivas de Oxígeno , Resveratrol , Factores de TiempoRESUMEN
BACKGROUND: Aproximately 5-10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. RESULTS: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). CONCLUSION: This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.
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Cromosomas Humanos X , Variación Genética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Análisis por Micromatrices/métodos , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Niño , Preescolar , Aberraciones Cromosómicas , Mapeo Cromosómico , Cromosomas Artificiales Bacterianos/genética , Eliminación de Gen , Dosificación de Gen , Duplicación de Gen , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/patología , Fenotipo , Sensibilidad y EspecificidadRESUMEN
The effects exerted by cysteine proteinases isolated from the histiophagous ciliate Philasterides dicentrarchi on the phagocytic functions of turbot pronephric leucocytes (PL) were investigated. The enzymes were tested at concentrations of 125, 250 and 500 microg ml(-1), and it was found that the viability of the leucocytes was not affected after treatment for 24h. Leucocyte migration was inhibited by the cysteine proteinases in a dose-dependent manner, whereas the ascitic fluid obtained from turbot experimentally infected with P. dicentrarchi induced high chemotactic activity in the turbot PL. The proteinases did not affect yeast cell phagocytosis but increased intracellular production of the superoxide anion (O2(-)). Stimulation with the proteinases did not alter the PGE2 levels in supernatants from 24-h cultures of PL, however, beta-glucans (100 microg ml(-1)) provoked a large increase in PGE2 levels, which were inhibited after addition of 10 microg ml(-1) of indomethacin, a non-selective inhibitor of COX2 enzymatic activity. The mean PGE2 level in ascitic fluid from turbot, experimentally infected with P. dicentrarchi, was 500 pg ml(-1), and the addition of low levels of PGE2 (62.5 pg ml(-1)) to PL cultures stimulated O2(-) production, although addition of PGE2 at concentrations higher than 250 pg ml(-1) blocked the increase in stimulation. Addition of cysteine proteinases to 24-h cultures of PL also increased mRNA levels in the pro-inflammatory cytokine interleukin-1beta. The results revealed the capacity of cysteine proteinases isolated from P. dicentrarchi to modulate the innate immune response of turbot, which together with the inflammation mediators produced during infection, may play an important role in pathogenesis of the disease and in the survival of the parasite.
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Enfermedades de los Peces/inmunología , Peces Planos/inmunología , Factores Inmunológicos/farmacología , Leucocitos/efectos de los fármacos , Oligohimenóforos/enzimología , Péptido Hidrolasas/farmacología , Animales , Líquido Ascítico/inmunología , Quimiotaxis/efectos de los fármacos , Infecciones por Cilióforos/inmunología , Infecciones por Cilióforos/veterinaria , Proteínas del Sistema Complemento/inmunología , Dinoprostona/inmunología , Dinoprostona/farmacología , Enfermedades de los Peces/parasitología , Peces Planos/parasitología , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1beta/genética , Riñón/efectos de los fármacos , Leucocitos/inmunología , Fagocitosis/efectos de los fármacos , Estallido Respiratorio/efectos de los fármacos , Estallido Respiratorio/inmunología , Superóxidos/inmunologíaRESUMEN
Ovarian and cervical cancers are significant health problems. This article provides an update in selected management topics. Paclitaxel and platinum derivatives are the first-line treatment for patients with advanced disease. In selected patients, intraperitoneal chemotherapy has been associated with improved survival but the broad applicability of this strategy is limited by issues of toxicity and feasibility. Management of patients with recurrent disease is based on a number of factors and includes surgery in selected cases, platinum-based chemotherapy for patients with platinum-sensitive disease and other agents such as topotecan and pegylated liposomal formulation of doxorubicin for patients with platinum-resistant disease. In cervical cancer, the most significant issue/event is the demonstration of superior survival with topotecan and cisplatin compared to cisplatin alone. Finally, new agents such as epidermal growth factor receptor inhibitors and antiangiogenic agents are being currently tested in these settings.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Cisplatino/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Humanos , Inyecciones IntraperitonealesRESUMEN
Ornithine transcarbamylase deficiency is an X-linked semidominant trait that is the most frequent inborn error of the urea cycle. Three hundred and fifty different mutations, including mostly point mutations and a small proportion of large rearrangements have been reported. Conventional molecular diagnosis is highly reliable for point mutations but can miss gross rearrangements. We describe a contiguous gene syndrome involving the RPGR, OTC and TM4SF2 genes in a male patient with severe neonatal OTC deficiency identified by the conventional molecular approach. Molecular characterization was ascertained by X chromosome CGH array and confirmed by MLPA. Complete deletion of the OTC gene led to absent OTC enzymatic activity in liver and to a severe clinical phenotype. The maternal phenotype, characterized by less severe hyperammonaemic crises associated with neurological impairment would result from a deficient but not null OTC activity due to random X chromosome inactivation in the liver. Our cases are similar toothers described presenting with OTC deficient phenotype in which OTC and contiguous genes are affected. Clinical expression would be conditioned by complete OTC deficiency in males and by X chromosome inactivation in females, leading to compensation by the normal allele in tissues such as blood or muscle but not sufficiently in liver. The application of high-resolution genetic techniques allows the characterization of causative mutations such as large deletions in order to guide genetic counselling and prenatal diagnosis.
Asunto(s)
Cromosomas Humanos X , Eliminación de Gen , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Ornitina Carbamoiltransferasa/genética , Análisis Mutacional de ADN , Proteínas del Ojo/genética , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana , Proteínas del Tejido Nervioso/genética , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/enzimología , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Síndrome , TetraspaninasRESUMEN
Ornithine transcarbamylase deficiency (OTCD), the X-linked, most frequent urea cycle error, results from mutations in the OTC gene, encoding a 354-residue polypeptide. To date 341 OTCD clinical mutations, including 222 missense single nucleotide changes (mSNCs), have been compiled (Hum Mutat 2006;27:626). OTCD mutation detection might be simplified if the entire repertoire of OTCD-causing mutations were known. We estimate the size of this repertoire from 23 new OTCD patients exhibiting 22 different mutations, of which 9, including 4 mSNCs, are novel. The complete repertoire of OTCD-causing mutations is estimated as 560 mutations (95% confidence interval, 422-833 mutations), including 290 mSNCs (95% confidence interval, 230-394 mSNCs). Thus, OTCD diagnosis based on the screening for known mutations might attain 90% sensitivity in <5 years. Since disease-causing mSNCs represent <20% of the 2064 possible OTC mSNCs, simple approaches are essential for discrimination between causative and trivial mSNCs. Observation of the OTC structure appears a simple approach for such discrimination, comparing favourably in our sample with three formalized structure-based and/or sequence-based in silico assessment methods, and supporting the causation of complete deficiency by the mutations p.Pro305Arg and p.Ser96Phe, and of partial deficiency by p.Asp41Gly, p.Glu122Gly, p.Leu179Phe, p.Pro220Thr and p.Glu273del. Five non-mSNC novel mutations (p.Gly71X, a 7-nucleotide and a 10-nucleotide duplication and deletion in exon 5, G>A transitions at bases +1 and +5 of introns 4 and 9, respectively) are obviously pathogenic. The previously reported mSNCs p.Arg26Gln, p.Arg40His, p.Glu52Lys, pLys88Asn, p.Arg129His, p.Asn161Ser, p.Thr178Met, p.His202Tyr, p.Ala208Thr and p.His302Arg, found in our cohort, are also discussed.