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

The Frustration of Novelty and Basic Psychological Needs as Predictors of Maladaptive Outcomes in Physical Education

Background The need for novelty has been recently proposed as a candidate need within basic psychological needs theory (BPNT). In physical education (PE), research has shown that meeting students’ need for novelty is often positively associated with enhanced (and negatively associated with impaired) pupils’ well-being. Frustrating students’ novelty has also been negatively related to achieving multiple positive outcomes in PE. However, no research has explored whether frustration of novelty is positively associated with maladaptive consequences for pupils in this educational context, which is a necessary criterion to be included within BPNT. Purpose In this correlational study, we aimed to determine whether frustration of novelty was associated with up to 10 maladaptive outcomes in a similar way as the frustration of the three basic psychological needs (autonomy, competence, and relatedness). The maladaptive outcomes analyzed were amotivation, boredom, negative affect, entity beliefs, fear of failure, worry, concentration disruption, somatic and social physique anxiety, and oppositional defiance. Research design Cross-sectional study. Methods A total of 533 students (Mage = 14.47, SD = 1.34; 56.66% female) from eight secondary schools completed online questionnaires assessing their basic psychological needs frustration, novelty frustration and diverse maladaptive outcomes in PE. Pearson's correlations and hierarchical regression analyses controlling by sex, age, and race, were calculated to test the associations among these variables. Findings The correlation coefficients for novelty frustration were like those found for the three basic psychological needs concerning maladaptive outcomes in PE students. Particularly, hierarchical regression analyses showed that frustrating novelty in PE predicted amotivation (β = .11, p = .039), boredom (β = .23, p < .001), entity beliefs (β = .12, p = .039), and concentration disruption (β = .12, p = .049). Conclusions Results showed that novelty frustration was positively related to experiencing some negative consequences in PE, which is an important criterion within BPNT. Future training programs aimed at promoting optimal (and preventing detrimental) motivational styles in PE teachers could use these results to optimize students’ PE experiences

The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis

The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis.BackgroundDuring glomerulogenesis, visceral glomerular epithelial cells (VECs) exit the cell cycle and become terminally differentiated and quiescent. In contrast to other resident glomerular cells, VECs undergo little if any proliferation in response to injury. However, the mechanisms for this remain unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where the cyclin-dependent kinase inhibitor p21Cip1,WAF1 (p21) inhibits cell proliferation and is required for differentiation of many nonrenal cell types.MethodsTo test the hypothesis that p21 is required to maintain a differentiated and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21 knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs were identified by location, morphology, ezrin staining, and electron microscopy. VEC differentiation was measured by staining for Wilms’ tumor-1 gene.ResultsKidneys from unmanipulated p21-/- mice were histologically normal and did not have increased DNA synthesis, suggesting that p21 was not required for the induction of VEC terminal differentiation. Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point, VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs. p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of Wilms’ tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular matrix protein accumulation and apoptosis and decreased renal function (serum urea nitrogen) compared with p21+/+ mice (P < 0.001).ConclusionThese results show that the cyclin kinase inhibitor p21 is not required by VECs to attain a terminally differentiated VEC phenotype. However, the loss of p21, in disease states, is associated with VEC re-entry into the cell cycle and the development of a dedifferentiated proliferative phenotype

DDIT4 (DNA-damage-inducible transcript 4)

Review on DDIT4 (DNA-damage-inducible transcript 4), with data on DNA, on the protein encoded, and where the gene is implicated

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

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

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

Improving consistency in AHP decision-making processes

Decision making in engineering is becoming increasingly complex due to the large number of alternatives and multiple conflicting goals. Powerful decision-support expert systems powered by suitable software are increasingly necessary. In this paper, the multiple attribute decision method known as analytical hierarchy process (AHP), which uses pairwise comparisons with numerical judgments, is considered. Since judgments may lack a minimum level of consistency, mechanisms to improve consistency are necessary. A method to achieve consistency through optimisation is described in this paper. This method has the major advantage of depending on just n decision variables – the number of compared elements – and so is less computationally expensive than other optimisation methods, and can be easily implemented in virtually any existing computer environment. The proposed approach is exemplified by considering a simplified version of one of the most important problems faced by water supply managers, namely, the minimisation of water loss. 2012 Elsevier Inc. All rights reserved.This work has been performed under the support of project IDAWAS, DPI2009-11591 of the Direccionn General de Investigacion del Ministerio de Educacion y Ciencia (Spain) and ACOMP/2011/188 of the Conselleria de Educacion de la Generalitat Valenciana. The first author was supported by Spanish project MTM2010-18539. The third author is also indebted to the Universitat Politecnica de Valencia for the sabbatical leave granted during the first semester of 2011. The use of English in this paper was revised by John Rawlins.Benítez López, J.; Delgado Galván, XV.; Izquierdo Sebastián, J.; Pérez García, R. (2012). Improving consistency in AHP decision-making processes. Applied Mathematics and Computation. 219(5):2432-2441. https://doi.org/10.1016/j.amc.2012.08.079S24322441219