El trabajo en equipo

Este es el último punto del manuscrito, que inesperadamente ha cobrado vida y se ha trasladado a la introducción, y es que el trabajo en equipo se ha convertido en un trabajo que busca equipo. Por este motivo, tras denunciar al autor, solicita encontrar un equipo que lo corrija, incremente, modifique e ilumine. Inmediatamente he pensado en posibles candidatos, que propondré al primero que acepte formar equipo, para dar cumplida satisfacción a un texto que ha salido reivindicativo y fiel a sí mism

Cyclosporin A and doxorubicin-ifosfamide in resistant solid tumours: a phase I and an immunological study.

In order to test whether circumvention of clinical resistance can be obtained in common solid tumours by targeting different drug resistance mechanisms, a phase I clinical and immunological study was designed. The purpose of the study was to determine the dose of cyclosporin A (CsA), in combination with doxorubicin (DOX) and ifosfamide (IFX), needed to achieve steady-state whole-blood levels of 2000 ng ml-1 and the associated toxicity of this combination. Treatment consisted of CsA 5 mg kg-1 as a 2 h loading infusion, followed by a CsA 3 day continuous infusion (c.i.) (days 1-3) at doses that were escalated from 10 to 18 mg kg-1 day-1. Chemotherapy consisted of DOX 55 mg m-2 by i.v. 24 h c.i. (day 2) and IFX 2 g m-2 i.v. over 1 h on days 1 and 3. Treatments were repeated every 4 weeks. Eighteen patients with previously treated resistant solid tumours received 39 cycles. Mean steady-state CsA levels > or = 2000 ng ml-1 were reached at 5 mg kg-1 loading dose followed by a 3 day c.i. of 16 mg kg-1 day-1 or greater. Haematological toxicity was greater than expected for the same chemotherapy alone. One patient died of intracranial haemorrhage due to severe thrombopenia. Other observed toxicities were: asymptomatic hyperbilirubinaemia (46% cycles), mild nephrotoxicity (20% cycles), hypomagnesaemia (72% cycles), mild increase in body weight (100% cycles), hypertension (15% cycles) and headache (15% cycles). Overall the toxicity was acceptable and manageable. No alterations in absolute lymphocyte number, the lymphocyte subsets studied (CD3, CD4, CD8, CD19) or CD4/CD8 ratio were observed in patients receiving more than one treatment cycle, although there were significant and non-uniform variations in the values of the different lymphocyte subsets studied when pre- and post-treatment values were compared. There was also a significant increase in the CD4/CD8 ratio. Tumour regressions were observed in two patients (epidermoid carcinoma of the cervix and Ewing's sarcoma). The CsA dose recommended for phase II trials is a 5 mg kg-1 loading dose followed by a 3-day c.i. of 16 mg kg-1 day-1 simultaneously with DOX and IFX at the doses administered in this study

Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies

Therapeutic monoclonal antibodies (mAbs), including immune checkpoint inhibitors (ICIs), are an important breakthrough for the treatment of cancer and have dramatically changed clinical outcomes in a wide variety of tumours. However, clinical response varies among patients receiving mAb-based treatment, so it is necessary to search for predictive biomarkers of response to identify the patients who will derive the greatest therapeutic benefit. The interaction of mAbs with Fc gamma receptors (Fc gamma R) expressed by innate immune cells is essential for antibody-dependent cellular cytotoxicity (ADCC) and this binding is often critical for their in vivo efficacy. Fc gamma RIIa (H131R) and Fc gamma RIIIa (V158F) polymorphisms have been reported to correlate with response to therapeutic mAbs. These polymorphisms play a major role in the affinity of mAb receptors and, therefore, can exert a profound impact on antitumor response in these therapies. Furthermore, recent reports have revealed potential mechanisms of ICIs to modulate myeloid subset composition within the tumour microenvironment through Fc gamma R-binding, optimizing their anti-tumour activity. The purpose of this review is to highlight the clinical contribution of Fc gamma R polymorphisms to predict response to mAbs in cancer patients

Post-surgical complications in patients undergoing radical cystectomy according to the patient’s nutritional status

Introducción: La cistectomía radical es el tratamiento de elección para los tumores vesicales musculo-invasivos presentando una gran morbilidad y una considerable tasa de mortalidad. Un factor importante a tener en cuenta es el estado nutricional del paciente ya que puede impactar de forma negativa en la evolución clínica de los pacientes. Material y métodos: Realizamos un estudio retrospectivo de las cistectomías realizadas entre 2012 y 2015 en el servicio de Urología de HU Son Espases y se evalúa la aparición de complicaciones postoperatorias según el estado nutricional calórico calculado a través del IMC, el estado nutricional proteico calculado a través de la albúmina postoperatoria inmediata y el estado nutricional inmunológico a través de los linfocitos totales. Resultados: Presentaron alguna complicación el 42% de los pacientes. Un 21% presentaron únicamente una complicación Clavien II y un 21% presentaron una complicación mayor a Clavien III o más de una complicación. Se encontraron diferencias estadísticamente significativas según el estado nutricional proteico (Normal-leve vs moderado-grave) en la fuga de la anastomosis uretero-ileal. No se encontraron diferencias en el resto de variables. Conclusiones: La mayoría de pacientes sometidos a cistectomía radical con derivación urinaria tipo intestinal presentan algún estado de malnutrición proteica postoperatoria. En nuestra serie, el estado nutricional proteico del paciente presenta una relación con la aparición de fuga de la anastomosis uretero-ileal.Radical cystectomy is the election treatment for muscle-invasive bladder tumors presenting a high morbidity and significant mortality rate. An important factor to consider is the nutritional status of the patient because it can negatively impact the clinical course of patients. Methods: We perfomed a retrospective study of radical cystectomies with intestinal conduct between 2012 and 2015 in the department of Urology in HU Espases and we evaluated the postoperative complications according to the caloric nutritional status calculated by BMI, protein nutritional status calculated by the immediate postoperative albumin and the inmunological nutritional status by total account of lymphocites. Results: Developed complications the 42% of patients. 21% had only one complication Clavien II and 21% had one complication Clavien III or more than one complication. We found statistically significant differences with the protein nutritional status (mild Normal-vs moderate to severe) in the escape of the ureter-ileal anastomosis. No differences in the other variables were found. Conclusions: Most patients undergoing radical cystectomy with intestinal conduct type have a postoperative state of protein malnutrition. In our series, the protein nutritional status of the patient has a relationship with the occurrence of leakage from the ureter-ileal anastomosis

Impact of a nudging intervention and factors associated with vegetable dish choice among European adolescents.

PURPOSE: To test the impact of a nudge strategy (dish of the day strategy) and the factors associated with vegetable dish choice, upon food selection by European adolescents in a real foodservice setting. METHODS: A cross-sectional quasi-experimental study was implemented in restaurants in four European countries: Denmark, France, Italy and United Kingdom. In total, 360 individuals aged 12-19 years were allocated into control or intervention groups, and asked to select from meat-based, fish-based, or vegetable-based meals. All three dishes were identically presented in appearance (balls with similar size and weight) and with the same sauce (tomato sauce) and side dishes (pasta and salad). In the intervention condition, the vegetable-based option was presented as the "dish of the day" and numbers of dishes chosen by each group were compared using the Pearson chi-square test. Multivariate logistic regression analysis was run to assess associations between choice of vegetable-based dish and its potential associated factors (adherence to Mediterranean diet, food neophobia, attitudes towards nudging for vegetables, food choice questionnaire, human values scale, social norms and self-estimated health, country, gender and belonging to control or intervention groups). All analyses were run in SPSS 22.0. RESULTS: The nudging strategy (dish of the day) did not show a difference on the choice of the vegetable-based option among adolescents tested (p = 0.80 for Denmark and France and p = 0.69 and p = 0.53 for Italy and UK, respectively). However, natural dimension of food choice questionnaire, social norms and attitudes towards vegetable nudging were all positively associated with the choice of the vegetable-based dish. Being male was negatively associated with choosing the vegetable-based dish. CONCLUSIONS: The "dish of the day" strategy did not work under the study conditions. Choice of the vegetable-based dish was predicted by natural dimension, social norms, gender and attitudes towards vegetable nudging. An understanding of factors related to choosing vegetable based dishes is necessary for the development and implementation of public policy interventions aiming to increase the consumption of vegetables among adolescents

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Multiple cycles of dose-intensive chemotherapy with repeated stem cell support as induction treatment in metastatic breast cancer: a feasibility study

The purpose of this trial was to study feasibility and tolerance of a dose-intensive multicyclic alternating induction chemotherapy with repeated stem cell support in a series of 43 metastatic breast cancer patients. Anthracycline-naive patients (n = 21) received cyclophosphamide 2.5 g/m2 plus doxorubicin 80 mg/m2 alternating every 14 days with paclitaxel 200-350 mg/m2 plus cisplatin 120 mg/m2. Patients who had previously received anthracyclines (n = 22) received cisplatin 120 mg/m2 plus etoposide 600 mg/m2 alternating with paclitaxel 200-350 mg/m2 plus ifosfamide 8 g/m2. Peripheral blood stem cells were infused after every course except the first, with a median CD34+ dose of 2.1 ´ 106/kg per cycle. Positive selection of CD34+ cells was performed in good mobilizers. The median number of cycles administered was six (4-8), and the time interval between them was 17 days. Median summation dose intensities (SDI) actually administered for the CA-TP and PE-TI protocol were 4.95 and 4.69, respectively (87% of scheduled SDI). There were 15 complete (35%) and 21 partial responses (49%), for an overall response rate of 84% (95% CI, 73%-95%). Infection or neutropenic fever occurred in 50% of the cycles. There was one treatment-related death. After a median follow-up of 26 months, the median event-free-survival was 12 months (95% CI: 10-14) and overall survival was 31 months. These high dose-intensity induction treatments seem to be feasible with sequential stem cell support

Factores influyentes en el tiempo hasta la progresión bioquímica después de prostatectomía radical

INTRODUCTION: We assessed the time-influencing clinical-pathological factors for biochemical progression of an equal series of patients from a single institution. MATERIALS AND METHODS: Retrospective analysis of 278 patients with biochemical progression following prostatectomy. We considered biochemical progression to be PSA>0.4 ng/ml. We performed the trial using the Cox model (univariate and multivariate) and using the Student's t-test to compare averages. RESULTS: With a mean follow-up of 4 (±3 DE) years, the univariate study showed a mean until progression for the Gleason score 2-6 in the biopsy of 824 days and 543 for the Gleason score 7-10 (p=0.003). For negative surgical margins, the mean was 920 days and 545 for positive margins (p=0.0001). In the case of a Gleason score 2-7 in the specimen, the mean was 806 days and 501 for a Gleason score 8-10 (p=0.001). Lastly, the mean for the cases with Ki-67 negative in the specimen ( 10%) (p=0.003). In the multivariate study, Ki-67 (OR 1.028; IC 95% 1-1.01; p=0.0001) and Gleason score 8-10 (OR 1.62; IC 95% 1.5-2.45; p=0.026) in the specimen, and initial PSA >10 ng/ml (OR 1.02; IC 95% 1.01-1.04; p=0.0001) were independent variables. Using these variables, we designed a predictive model with three groups. The time until the progression of each group was 1,081, 551 and 218 days respectively. CONCLUSION: The Gleason score 7-10 in the prostate biopsy, the presence of Ki-67, the positive margins and the Gleason score 8-10 in the specimen, and the initial PSA > 10 ng/ml are time-influencing factors until biochemical progression. Pathological Gleason score 8-10, PSA > 10 ng/ml and Ki-67 are independent factors