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1.
Childs Nerv Syst ; 40(3): 863-868, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38135826

RESUMEN

AIM: Single-level selective dorsal rhizotomy (SDR) surgery requires an intra-operative level check to identify the L1 vertebral level or the conus medullaris. Typically, this requires a pre-operative or intra-operative x-ray. We present our experience using initial transcutaneous ultrasound as an alternative to x-ray level check. METHODS: A prospective SDR database was used to identify patients. The operation notes were reviewed to identify the level check method and any complications or wrong-level surgery. RESULTS: Data are reported for the first 160 SDR surgeries performed within our centre, mean age 6.47 years (range 2.5-19 years). The first 11 patients had combined x-ray and transcutaneous ultrasound for pre-incision level check. This allowed the neurosurgeon to assess the accuracy and feasibility of using transcutaneous ultrasound instead of x-ray. The subsequent 149 patients had ultrasound alone for transcutaneous pre-incision level check. An intra-operative ultrasound level check was performed for all patients following skin incision and dissection down to the spinal lamina. In this way, the conus level was confirmed before dural opening. For all patients at all ages, the combination of initial transcutaneous ultrasound followed by intra-operative ultrasound allowed accurate identification of the conus. There were no instances of wrong-level surgery. Learning points are presented within this paper. CONCLUSION: Combined use of transcutaneous ultrasound followed by intra-operative ultrasound can allow accurate identification of the conus, saving radiation exposure and potentially improving theatre efficiency. Appropriate training and experience are required for any neurosurgeon using these techniques.


Asunto(s)
Parálisis Cerebral , Rizotomía , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Rizotomía/métodos , Estudios Prospectivos , Parálisis Cerebral/cirugía , Ultrasonografía , Columna Vertebral , Resultado del Tratamiento , Espasticidad Muscular/cirugía
2.
J Med Imaging Radiat Oncol ; 64(4): 546-555, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32386110

RESUMEN

INTRODUCTION: There is some evidence to suggest that patients with underlying pulmonary fibrosis (PF) have increased risk of adverse respiratory and survival outcomes, when treated with conventional, long-course radiotherapy (RT) for non-small-cell lung cancer (NSCLC). We performed a retrospective analysis to determine the size of these risks. METHODS: Data from 21 patients with PF (cases) were retrospectively analysed for respiratory toxicity and mortality outcomes, and compared with 84 patients without PF (non-cases). Age and mean lung dose were included as covariates in regression analyses. The additional predictive value of other patient, disease and treatment characteristics on radiation pneumonitis (RP) risk and severity was explored. RESULTS: There was a numerical (though not statistically significant) increase in grade ≥ 2 RP among PF cases (OR 2.74, P = 0.074). Cases were significantly more likely to discontinue radical treatment early (OR 6.10, P = 0.015). There was a significant association between increased RP severity and underlying PF (P = 0.039), with RP strongly implicated in the death in 3 of 21 cases (14.3%) compared to 1 non-case (1.2%). Cases experienced increased grade ≥ 2 respiratory toxicity otherwise (OR 4.35, P = 0.020) and poorer median overall survival (0.6 versus 1.7 years, P < 0.001). Two cases, and no non-cases, died during the proposed RT period. None of the analysed patient, disease or treatment factors, was a significant additional predictor of RP risk/severity. CONCLUSION: Patients with PF are at increased risk of treatment discontinuation, respiratory morbidity and mortality, and poor survival following conventional RT for NSCLC. Caution should be exercised when offering high-dose RT to these patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/radioterapia , Fibrosis Pulmonar/epidemiología , Neumonitis por Radiación/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Causalidad , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tiempo
4.
Br J Surg ; 106(3): 263-266, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30277259

RESUMEN

BACKGROUND: The non-operative management of splenic injury in children is recommended widely, and is possible in over 95 per cent of episodes. Practice appears to vary between centres. METHODS: The Trauma Audit and Research Network (TARN) database was interrogated to determine the management of isolated paediatric splenic injuries in hospitals in England and Wales. Rates of non-operative management, duration of hospital stay, readmission and mortality were recorded. Management in paediatric surgical hospitals was compared with that in adult hospitals. RESULTS: Between January 2000 and December 2015 there were 574 episodes. Children treated in a paediatric surgical hospital had a 95·7 per cent rate of non-operative management, compared with 75·5 per cent in an adult hospital (P < 0·001). Splenectomy was done in 2·3 per cent of children in hospitals with a paediatric surgeon and in 17·2 per cent of those treated in an adult hospital (P < 0·001). There was a significant difference in the rate of non-operative management in children of all ages. There was some improvement in non-operative management in adult hospitals in the later part of the study, but significant ongoing differences remained. CONCLUSION: The management of children with isolated splenic injury is different depending on where they are treated. The rate of non-operative management is lower in hospitals without a paediatric surgeon present.


Asunto(s)
Bazo/lesiones , Heridas no Penetrantes/terapia , Adolescente , Niño , Preescolar , Inglaterra , Femenino , Disparidades en Atención de Salud , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Tiempo de Internación/estadística & datos numéricos , Masculino , Esplenectomía/estadística & datos numéricos , Centros Quirúrgicos/estadística & datos numéricos , Gales
5.
Trials ; 19(1): 467, 2018 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-30157910

RESUMEN

BACKGROUND: Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). METHODS: Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. DISCUSSION: The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN45536692 . Registered on 9 August 2016. EudraCT no. 2015-004433-26.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Zoledrónico/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Método Doble Ciego , Inglaterra , Estudios de Factibilidad , Humanos , Mesotelioma/patología , Estudios Multicéntricos como Asunto , Pemetrexed/administración & dosificación , Neoplasias Pleurales/patología , Factores de Tiempo , Resultado del Tratamiento , Ácido Zoledrónico/efectos adversos
6.
J Anim Sci ; 95(7): 3057-3067, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28727094

RESUMEN

Diets containing more than 20% distiller's dried grains with solubles (DDGS) reduce fat firmness in pork, but supplementation of cottonseed oil or crude glycerol may improve fat firmness. The objective of this study was to assess the effect of feeding minimally refined cottonseed oil or crude glycerol on growth performance, carcass composition, and fat quality of growing-finishing pigs. Mixed sex pigs ( = 216; 24 ± 4 kg initial BW) were blocked by BW and allotted to 1 of 3 dietary treatments: 1) a basal corn-soybean meal diet with 40% DDGS (CON), 2) CON diet plus 5% minimally refined cottonseed oil added throughout the experiment (COT), or 3) CON fed during the first 8 wk and CON + 8% crude glycerol fed during the last 6 wk of the experiment (GLY). Although diets were not isocaloric, total AA-to-ME ratios were calculated to be equal among diets. Carcass composition was estimated using real-time ultrasound 2 d before harvest. Gilts (16/treatment) closest to the mean BW of each pen were harvested (115 ± 8 kg BW), and bellies were retrieved for in-depth analysis of fat quality. Belly fat was sampled and analyzed for fatty acid composition. Overall, ADFI of pigs fed COT (2.30 kg/d) was less ( < 0.01) than that of pigs fed CON or GLY (2.47 and 2.49 kg/d, respectively). Pigs fed COT (0.93 kg/d) had greater ( < 0.01) ADG compared with pigs fed CON or GLY (0.88 and 0.87 kg/d, respectively). Greater ( < 0.01) G:F was observed for pigs fed COT (0.41) than for pigs fed CON or GLY diets (0.36 and 0.35, respectively). Final BW of pigs fed COT (124.3 kg) was greater ( < 0.01) than that of pigs fed CON or GLY (118.9 and 118.6 kg, respectively). Pigs fed COT had greater ( < 0.01) HCW (94.9 kg) compared with pigs fed CON or GLY (89.9 and 89.2 kg, respectively). No differences were observed for dressing percentage (75.7, 76.3, and 75.3%), fat-free carcass lean percentage (50.5, 49.7, and 50.0%), and belly flop angle (6.21, 8.57, and 6.06°) for CON, COT, and GLY, respectively. Pigs assigned to COT had higher ( < 0.01) melting point of belly fat compared with pigs assigned to CON or GLY (30.4 vs. 26.3 and 25.3°C, respectively). Pigs fed COT had increased ( < 0.05) SFA, PUFA, and iodine value (IV) compared with CON-fed pigs. Glycerol supplementation had no influence on SFA, MUFA, and PUFA concentrations or IV of belly, jowl, and back fat compared with CON. In conclusion, COT diets improved growth performance due to greater energy density, but carcass composition was not affected by treatments. In this experiment, feeding neither COT nor GLY improved fat firmness of pigs fed diets containing 40% DDGS.


Asunto(s)
Aceite de Semillas de Algodón/farmacología , Suplementos Dietéticos , Glicerol/farmacología , Carne Roja/normas , Porcinos/fisiología , Tejido Adiposo/efectos de los fármacos , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Metabolismo Energético , Ácidos Grasos/farmacología , Femenino , Yodo/farmacología , Masculino , Glycine max , Porcinos/crecimiento & desarrollo , Zea mays
9.
Pak J Pharm Sci ; 29(4): 1223-30, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27393435

RESUMEN

The present study investigates the effect of different growth media and chemical enhancer on silent genes in Aspergillus carbonarius (NRL-369) for secondary metabolites production and its in vitro biological activities. Results revealed that Aspergillus carbonarius (NRL-369) grown in Czapeak yeast extract broth medium produced more metabolites compared with other media. Chemical epigenetic modifiers (suberoyl-anilide hydroxamic acid (SAHA) and 5-azacytidine (5-AZA) at concentration of 15mM were effective for the expression of silent genes resulting in increased secondary metabolites production. Secondary metabolites extracted in ethyl acetate and fractionized in n-Hexane showed variable degree of growth inhibitions of the tested microorganisms. Similarly, these samples were also active against brine shrimps and Lemna.


Asunto(s)
Aspergillus/metabolismo , Animales , Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Artemia , Aspergillus/efectos de los fármacos , Azacitidina/farmacología , Medios de Cultivo
10.
Respir Med ; 115: 53-9, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27215504

RESUMEN

BACKGROUND: COPD patients are advised vaccination against seasonal influenza, yet few studies have evaluated the protective antibody titers obtained in this patient group. AIMS: 1) To describe protective titers in COPD patients who self-reported influenza vaccination compared with vaccinated subjects without COPD and unvaccinated COPD patients, 2) analyze whether clinical parameters predicted influenza-specific antibody titers, and 3) whether antibody titers to influenza A at baseline could predict exacerbation risk or 5 years all-cause mortality. METHODS: Influenza A (H1N1 and H3N2) titers were measured by haemagglutination inhibition assay in serum from 432 COPD patients and 77 controls in the Bergen COPD Cohort Study, at yearly visits between 2006/09. Titers of 40 or above were considered protective. We examined the variables sex, age, body composition, smoking, GOLD stage, yearly exacerbations, inhaled steroids, and Charlson score as predictive of titers, both univariately and in a multivariable model estimated by generalized estimating equations. The exacerbation incidence rate ratios and mortality hazard ratios were assessed by negative binominal and cox regression models respectively. RESULTS: At baseline, 59% of COPD patients reported influenza vaccination during the last season. Levels of predictive titers varied considerably each season, but trended lower in COPD patients compared with controls. Neither sex, age, body composition, smoking, comorbidities, GOLD stage nor use of inhaled steroids consistently predicted titers. Having high titers at baseline did not impact later risk for exacerbations, but seemed to be associated with higher all-cause mortality, even after adjustment for COPD disease characteristics. CONCLUSION: Vaccination coverage for influenza is imperfect for COPD patients in Norway, and there is a concern that immunization is suboptimal.


Asunto(s)
Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Autoinforme , Vacunación/métodos , Adulto , Anciano , Anticuerpos Antivirales/sangre , Estudios de Cohortes , Comorbilidad , Femenino , Pruebas de Inhibición de Hemaglutinación/métodos , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/epidemiología , Gripe Humana/terapia , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Mortalidad , Noruega/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estaciones del Año , Fumar/inmunología , Vacunación/efectos adversos
11.
Diabet Med ; 33(10): 1347-51, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26757409

RESUMEN

AIMS: Childhood cancer survivors treated with haematopoietic stem cell transplantation (HSCT) and total body irradiation are at an increased risk of developing diabetes early in life due to insulin resistance and ß-cell dysfunction, but the optimal screening method is unknown. The National Institute for Health and Care Excellence guidelines for community diabetes screening recommend using fasting glucose ≥ 7 mmol/l and/or HbA1c ≥ 48 mmol/mol (6.5%) for diagnosis and, fasting glucose 5.5-6.9 mmol/l or HbA1c 42-47 mmol/mol (6-6.5%) to indicate high risk. This study aimed to evaluate the sensitivities of fasting glucose and HbA1c in the diagnosis of diabetes and impaired glucose tolerance in childhood HSCT survivors. METHOD: The patients were 35 (male = 19) HSCT survivors from a single UK centre under follow-up from 2006 to 2013. Patients had a median age (range) of 19.2 (13.1-26.2) years and had been treated for acute lymphoblastic (n = 31) or myeloid (n = 4) leukaemia when aged 7.8 (2.4-16.7) years. The outcome measures were oral glucose tolerance test (OGTT), fasting glucose and HbA1c . RESULTS: OGTT identified 6 patients with diabetes (120-min glucose ≥ 11.1 mmol/l), 12 with impaired glucose tolerance (120-min glucose 7.8-11.0 mmol/l) and 2 with impaired fasting glucose (≥ 7 mmol/l). Fasting glucose ≥ 7 mmol/l or HbA1c ≥ 48 mmol/mol identified two of the six patients with diabetes diagnosed on OGTT. Fasting glucose ≥ 5.5 mmol/l and HbA1c ≥ 42 mmol/mol identified three and two patients, respectively, with diabetes. Only 1 of 12 patients with impaired glucose tolerance had a fasting glucose ≥ 5.5 mmol/l and none had HbA1c ≥ 42 mmol/mol (≥ 6%). CONCLUSIONS: The fasting glucose and HbA1c cut-offs used in UK population screening only identified one-third of HSCT survivors with diabetes and do not identify those at risk. Diabetes screening in HSCT survivors requires standard OGTTs.


Asunto(s)
Supervivientes de Cáncer , Diabetes Mellitus/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Leucemia/terapia , Tamizaje Masivo/métodos , Irradiación Corporal Total , Niño , Preescolar , Diabetes Mellitus/sangre , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Leucemia/rehabilitación , Masculino , Factores de Riesgo , Irradiación Corporal Total/efectos adversos
12.
Gene Ther ; 22(11): 908-16, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26133785

RESUMEN

Cystic fibrosis (CF) is due to mutations in the CFTR gene, which prevents correct folding, trafficking and function of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. The dysfunctional effect of CFTR mutations, principally the F508del-CFTR mutant, is further manifested by hypersecretion of the pro-inflammatory chemokine interleukin-8 into the airway lumen, which further contributes to morbidity and mortality. We have hypothesized that microRNA (miR)-based therapeutics could rescue the dysfunctional consequences of mutant CFTR. Here we report that a miR-16 mimic can effectively rescue F508del-CFTR protein function in airway cell lines and primary cultures, of differentiated human bronchial epithelia from F508del homozygotes, which express mutant CFTR endogenously. We also identify two other miRs, miR-1 and miR-302a, which are also active. Although miR-16 is expressed at basal comparable levels in CF and control cells, miR-1 and miR-302a are undetectable. When miR mimics are expressed in CF lung or pancreatic cells, the expression of the F508del-CFTR protein is significantly increased. Importantly, miR-16 promotes functional rescue of the cyclic AMP-activated apical F508del-CFTR chloride channel in primary lung epithelial cells from CF patients. We interpret these findings to suggest that these miRs may constitute novel targets for CF therapy.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Fibrosis Quística/terapia , MicroARNs/genética , Línea Celular , Células Cultivadas , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Células Epiteliales/patología , Terapia Genética/métodos , Humanos , MicroARNs/administración & dosificación , MicroARNs/biosíntesis , Mutación , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Mucosa Respiratoria/patología
13.
Int J Surg Case Rep ; 5(6): 335-8, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24811427

RESUMEN

INTRODUCTION: Chilaiditi's syndrome (symptomatic hepatodiaphragmatic interposition of the colon) is an exceptionally rare cause of bowel obstruction and may present difficulty in diagnosis and management. This is the first reported case of colonic volvulus occurring in Chilaiditi's syndrome in association with intestinal malrotation and this case study describes its successful management. PRESENTATION OF CASE: An 18 year old male presented as an emergency with vague abdominal pain and a past history of gastroschisis repair with intestinal malrotation. CT scanning showed a closed loop obstruction due to a volvulus of the colon herniating under the falciform ligament. The patient was successfully treated by surgical reduction of the hernia, anatomical correction of the malrotation and caecopexy with a tube caecostomy. At six month follow up the patient was well and asymptomatic. DISCUSSION: In nine of the previously reported cases of Chilaiditi's syndrome with colonic volvulus, treatment was by partial colonic resection of which a third underwent stoma formation. One patient died as a consequence of anastomotic leak following primary anastomosis. We therefore suggest an alternative approach to management. CONCLUSION: Chilaiditi's syndrome with colonic volvulus in association with intestinal malrotation has not previously been described. As there is no consensus in the literature as to how to manage such a case we suggest that reduction of the volvulus, anatomical correction of the malrotation and fixation of the caecum by tube caecostomy results in a successful outcome. This approach avoids the need for colonic resection and possible stoma formation.

14.
Diagn Cytopathol ; 42(4): 285-91, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24167030

RESUMEN

Brushing cytology is frequently utilized for the investigation of pancreatic and biliary strictures but is associated with low diagnostic sensitivity. The Papanicolaou Society of Cytopathology has presented a system for diagnostic classification which includes the categories benign, atypical, suspicious for malignancy and malignant. We studied a series of 216 pancreatic and biliary brushings with either histologic follow-up or a minimum of 6 months clinical follow-up to determine outcomes for the diagnostic categories ("benign," "atypical, favor reactive," "atypical, not otherwise specified," "atypical, suspicious" and "malignant"). Eighty-six of the 216 (39.8%) were designated "atypical" with 10 of these designated as "atypical favor reactive." Forty-five were called "atypical not otherwise specified" and 31 were interpreted as "atypical suspicious for malignancy." On follow-up, 2 of 10 (20%) "atypical favor reactive" were eventually associated with a malignant diagnosis and 23 of 31 (74.2%) "atypical, suspicious for malignancy" demonstrated a malignant outcome. The remaining 45 brushings in the "atypical" category were "atypical not otherwise specified," and 62% of these were associated with malignancy on follow-up. Stratification of the "atypical" category into "atypical favor reactive," "atypical, not otherwise specified" and "atypical, suspicious for malignancy" improves diagnostic accuracy. The "atypical suspicious for malignancy" category has a follow-up similar to the "malignant" category while the "atypical favor reactive" category is associated with a clinical outcome similar to that of the "benign" category.


Asunto(s)
Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/patología , Conductos Biliares/patología , Citodiagnóstico/métodos , Páncreas/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/patología , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Factores de Riesgo , Adulto Joven
15.
Int J Radiat Oncol Biol Phys ; 88(2): 395-403, 2014 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-24315565

RESUMEN

PURPOSE: To determine whether radiation therapy (RT) could mobilize viable tumor cells into the circulation of non-small cell lung cancer (NSCLC) patients. METHODS AND MATERIALS: We enumerated circulating tumor cells (CTCs) by fluorescence microscopy of blood samples immunostained with conventional CTC markers. We measured their DNA damage levels using γ-H2AX, a biomarker for radiation-induced DNA double-strand breaks, either by fluorescence-activated cell sorting or by immunofluorescence microscopy. RESULTS: Twenty-seven RT-treated NSCLC patients had blood samples analyzed by 1 or more methods. We identified increased CTC numbers after commencement of RT in 7 of 9 patients treated with palliative RT, and in 4 of 8 patients treated with curative-intent RT. Circulating tumor cells were also identified, singly and in clumps in large numbers, during RT by cytopathologic examination (in all 5 cases studied). Elevated γ-H2AX signal in post-RT blood samples signified the presence of CTCs derived from irradiated tumors. Blood taken after the commencement of RT contained tumor cells that proliferated extensively in vitro (in all 6 cases studied). Circulating tumor cells formed γ-H2AX foci in response to ex vivo irradiation, providing further evidence of their viability. CONCLUSIONS: Our findings provide a rationale for the development of strategies to reduce the concentration of viable CTCs by modulating RT fractionation or by coadministering systemic therapies.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Histonas/análisis , Neoplasias Pulmonares/radioterapia , Células Neoplásicas Circulantes/efectos de la radiación , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de la radiación , Supervivencia Celular , Roturas del ADN de Doble Cadena , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Microscopía Fluorescente , Persona de Mediana Edad , Células Neoplásicas Circulantes/patología
16.
Oncogene ; 32(45): 5283-91, 2013 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-23178486

RESUMEN

The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.


Asunto(s)
Linfocitos B/metabolismo , Linfoma de Células B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Apoptosis , Carcinogénesis , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Xenoinjertos , Humanos , Ratones , Ratones SCID , Trasplante de Neoplasias , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Antígenos de Linfocitos B/metabolismo
17.
Br J Cancer ; 106(3): 525-37, 2012 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-22233923

RESUMEN

BACKGROUND: Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood. METHODS: We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice. RESULTS: Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice. CONCLUSION: This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development.


Asunto(s)
Adenocarcinoma/patología , Neoplasias de la Mama/patología , Calcinosis/patología , Neoplasias Mamarias Experimentales/patología , Fosfatasa Alcalina/metabolismo , Animales , Carbonato de Calcio/metabolismo , Oxalato de Calcio/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Durapatita/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Fosfatos/metabolismo
18.
Scand J Immunol ; 74(2): 210-8, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21438900

RESUMEN

In these case reports, we investigated pandemic influenza 2009 vaccination of primary hypogammaglobulinaemic patients. Three combined variable immunodeficiency (CVID) patients and one X-linked agammaglobulinaemia (XLA) patient were vaccinated with the pandemic vaccine A/California/7/2009 (H1N1)-like split virus (X179a) adjuvanted with the oil-in-water emulsion AS03. Subsequently, serum and peripheral blood mononuclear cells were sampled and used to measure the haemagglutination inhibition (HI) and antibody-secreting cell (ASC) responses. In addition, the IFN-γ, IL-2 and TNF-α producing CD4(+) Th1-cell response was determined as these cytokines are important indicators of cell-mediated immunity. Two of the CVID patients responded to vaccination as determined by a >4-fold rise in HI antibodies. These subjects also had influenza-specific ASC numbers, which, albeit low, were higher than prevaccination levels. In addition, vaccination induced CD4(+) Th1-cell responses in both the XLA patient and the CVID patients, although the frequency of influenza-responsive cells varied amongst the patients. These results suggest that hypogammaglobulinaemia patients can mount a CD4(+) Th1 cell-mediated response to influenza vaccination and, additionally, that influenza vaccination of some hypogammaglobulinaemia patients can produce an influenza-specific humoral immune response. The findings should be confirmed in larger clinical studies.


Asunto(s)
Agammaglobulinemia/inmunología , Vacunas contra la Influenza/inmunología , Células TH1/inmunología , Vacunación/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Células Productoras de Anticuerpos/inmunología , Linfocitos B/inmunología , Ensayos Clínicos como Asunto , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/efectos adversos , Gripe Humana/inmunología , Gripe Humana/prevención & control , Interferón gamma/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/inmunología
19.
Hum Pathol ; 42(4): 602-4, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21208642

RESUMEN

Malakoplakia is a rare granulomatous disorder of unknown etiology and usually affects patients with underlying immunosuppression. This disorder usually involves the genitourinary tract but has been reported in a wide array of anatomical sites. We present a case of extragenitourinary malakoplakia, developing in a patient with a history of plasma cell myeloma, which clinically mimicked recurrent extramedullary myelomatous involvement. Radiologically, this lesion was a 10-cm soft-tissue mass located in the left flank and iliacus muscle. Excisional biopsy revealed a histiocytic infiltrate with histologic features diagnostic of malakoplakia. This case demonstrates the clinical and pathologic diagnostic challenges of malakoplakia arising outside the genitourinary tract. Given that it can closely mimic malignancy in such settings, malakoplakia should be considered in the differential diagnosis of soft-tissue masses developing in patients with hematologic malignancy and iatrogenic immunosuppression. This case highlights the importance for awareness on the part of clinicians, radiologists, and pathologists that malakoplakia can present as a soft-tissue mass.


Asunto(s)
Malacoplasia/complicaciones , Malacoplasia/patología , Mieloma Múltiple/complicaciones , Anciano , Antibacterianos/uso terapéutico , Cefepima , Cefalosporinas/uso terapéutico , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Malacoplasia/microbiología , Masculino , Metronidazol/uso terapéutico , Mieloma Múltiple/terapia , Metástasis de la Neoplasia/patología , Neoplasias de los Tejidos Blandos/patología , Trasplante de Células Madre
20.
J Phys Chem A ; 114(23): 6527-33, 2010 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-20481568

RESUMEN

To better define the mechanisms by which condensed-phase halides may be oxidized to form gas-phase halogens under polar conditions, experiments have been conducted whereby frozen solutions containing chloride (1 M), bromide (1.6 x 10(-3) to 5 x 10(-2) M), iodide (<1 x 10(-5) M), and nitrate (0.01 to 1 M) have been illuminated by ultraviolet light in a continually flushed cell. Gas-phase products are quantified using chemical ionization mass spectrometry, and experiments were conducted at both 248 and 263 K. Br(2) was the dominant product, along with smaller yields of IBr and trace BrCl and I(2). The Br(2) yields were largely independent of the Br(-)/Cl(-) ratio of the frozen solution, down to seawater composition. However, the yields of halogens were strongly dependent on the levels of NO(3)(-) and acidity in solution, consistent with a mechanism whereby NO(3)(-) photolysis yields OH that oxidizes the condensed-phase halides. In support, we observed the formation of gas-phase NO(2), formed simultaneously with OH. Gas-phase HONO was also observed, suggesting that halide oxidation by HONO in the condensed phase may also occur to some degree. By measuring the production rate of condensed-phase OH, using benzoic acid as a radical trap, we determine that the molar yield of Br(2) formation relative to OH generation is 0.6, consistent with each OH being involved in halide oxidation. These studies suggest that gas-phase halogen formation should occur simultaneously with NO(x) release from frozen sea ice and snow surfaces that contain sufficient halides and deposited nitrate.


Asunto(s)
Congelación , Gases/química , Halógenos/química , Halógenos/síntesis química , Radical Hidroxilo/química , Nitratos/química , Fotólisis , Atmósfera , Bromo/química , Soluciones
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