Zevalin and BEAM (Z-BEAM) versus rituximab and BEAM (R-BEAM) conditioning chemotherapy prior to autologous stem cell transplantation in patients with mantle cell lymphoma.

Early relapse is common in patients with mantle cell lymphoma (MCL) highlighting the unmet need for further improvement of therapeutic options for these patients. CD20 inhibition combined with induction chemotherapy as well as consolidation with high-dose chemotherapy (HDCT) is increasingly considered cornerstones within current therapy algorithms of MCL whereas the role of radioimmunotherapy is unclear. This retrospective single center study compared 46 consecutive MCL patients receiving HDCT in first or second remission. Thirty-five patients had rituximab and BEAM (R-BEAM), and 11 patients received ibritumomab tiuxetan (Zevalin®), an Yttrium-90 labeled CD20 targeting antibody, prior to BEAM (Z-BEAM) followed by autologous stem cell transplantation (ASCT). We observed that the 5-year overall survival (OS) in the R-BEAM and Z-BEAM groups was 55% and 71% (p = 0.288), and the 4-year progression free survival (PFS) was 32% and 41%, respectively (p = 0.300). There were no treatment related deaths in both groups, and we observed no differences in toxicities, infection rates or engraftment. Our data suggest that the Z-BEAM conditioning regimen followed by ASCT is well tolerated, but was not associated with significantly improved survival compared to R-BEAM. Copyright © 2015 John Wiley & Sons, Ltd.

Predicting Psychotherapy Dropouts: A Multilevel Approach

The role of therapeutic processes in predicting premature termination of psychotherapy has been a particular focus of recent research. The purpose of this study was to contrast outpatients who completed therapy and those who dropped out with respect to their self-reported in-session experiences of self-esteem, mastery, clarification and the therapeutic alliance. The 296 patients with mixed disorders were treated with an integrative form of cognitive–behavioural therapy without pre-determined time limit (M = 20.2 sessions). Multilevel analyses indicated that patients who did not completetreatment reported, on average, lower levels of self-esteem, mastery and clarification and lower ratings of their therapeutic alliance in treatment in contrast to patients who completed therapy. Patient-reported change in self-esteem experiences over the course of treatment turned out to be the strongest predictor of dropout from psychotherapy or successful completion. When dropout occurred before the average treatment length was reached, patients reported fewer clarifying experiences as early as the first session and their ratings of the therapeutic alliance were characterized by an absence of positive development. Both of these aspects seem to be involved in patients' decisions to leave treatment early. The findings underscore the importance of the therapeutic process in understanding the mechanisms behind treatment dropout. Copyright © 2014 John Wiley & Sons, Ltd.

Transiente Globale Amnesie versus Transiente Ischämische Attacke – Klinik und Schlaganfallrisiko

Transient global amnesia versus transient ischaemic attack: clinical presentation and cerebral vascular accident risk Transient global amnesia is an acute, benign, isolated and temporarily limited disturbance of memory, that can occur repeatedly but shows no increased risk of cardiovascular events or stroke in particular. Therefore, patients with the typical clinical presentation and a normal brain magnetic resonance-scan require neither further diagnostic nor therapeutic interventions. Since the differential diagnosis of transient global amnesia is wide, and transient ischaemic attacks can present similarly, a careful clinical evaluation and neuroimaging is recommended. In any case of doubt further diagnostic steps according to stroke workup should be initiated. In contrast, a transient ischaemic attack represents a neurological emergency where clinical and diagnostic evaluation must be introduced fast. The rapid establishment of therapeutic and secondary preventive measures decreases the clearly elevated stroke risk and prevents disability.

ENaC activity in collecting ducts modulates NCC in cirrhotic mice.

Cirrhosis is a frequent and severe disease, complicated by renal sodium retention leading to ascites and oedema. A better understanding of the complex mechanisms responsible for renal sodium handling could improve clinical management of sodium retention. Our aim was to determine the importance of the amiloride-sensitive epithelial sodium channel (ENaC) in collecting ducts in compensate and decompensate cirrhosis. Bile duct ligation was performed in control mice (CTL) and collecting duct-specific αENaC knockout (KO) mice, and ascites development, aldosterone plasma concentration, urinary sodium/potassium ratio and sodium transporter expression were compared. Disruption of ENaC in collecting ducts (CDs) did not alter ascites development, urinary sodium/potassium ratio, plasma aldosterone concentrations or Na,K-ATPase abundance in CCDs. Total αENaC abundance in whole kidney increased in cirrhotic mice of both genotypes and cleaved forms of α and γ ENaC increased only in ascitic mice of both genotypes. The sodium chloride cotransporter (NCC) abundance was lower in non-ascitic KO, compared to non-ascitic CTL, and increased when ascites appeared. In ascitic mice, the lack of αENaC in CDs induced an upregulation of total ENaC and NCC and correlated with the cleavage of ENaC subunits. This revealed compensatory mechanisms which could also take place when treating the patients with diuretics. These compensatory mechanisms should be considered for future development of therapeutic strategies.

Bayesian doubly optimal group sequential designs for randomized clinical trials

When conducting a randomized comparative clinical trial, ethical, scientific or economic considerations often motivate the use of interim decision rules after successive groups of patients have been treated. These decisions may pertain to the comparative efficacy or safety of the treatments under study, cost considerations, the desire to accelerate the drug evaluation process, or the likelihood of therapeutic benefit for future patients. At the time of each interim decision, an important question is whether patient enrollment should continue or be terminated; either due to a high probability that one treatment is superior to the other, or a low probability that the experimental treatment will ultimately prove to be superior. The use of frequentist group sequential decision rules has become routine in the conduct of phase III clinical trials. In this dissertation, we will present a new Bayesian decision-theoretic approach to the problem of designing a randomized group sequential clinical trial, focusing on two-arm trials with time-to-failure outcomes. Forward simulation is used to obtain optimal decision boundaries for each of a set of possible models. At each interim analysis, we use Bayesian model selection to adaptively choose the model having the largest posterior probability of being correct, and we then make the interim decision based on the boundaries that are optimal under the chosen model. We provide a simulation study to compare this method, which we call Bayesian Doubly Optimal Group Sequential (BDOGS), to corresponding frequentist designs using either O'Brien-Fleming (OF) or Pocock boundaries, as obtained from EaSt 2000. Our simulation results show that, over a wide variety of different cases, BDOGS either performs at least as well as both OF and Pocock, or on average provides a much smaller trial. ^

Chimpanzee: A predictive model for the human cytochrome P450 3A subfamily

The human cytochrome P450 3A (CYP3A) subfamily is responsible for most of the metabolism of therapeutic drugs; however, an adequate in vivo model has yet to be discovered. This study begins with an investigation of a controversial topic surrounding the human CYP3As--estrogen regulation. A novel approach to this topic was used by defining expression in the estrogen-responsive endometrium. This study shows that estrogen down-regulates CYP3A4 expression in the endometrium. On the other hand, analogous studies showed an increase in CYP3A expression as age increases in liver tissue. Following the discussion of estrogen regulation, is an investigation of the cross-species relationships among all of the CYP3As was completed. The study compares isoforms from piscines, avians, rodents, canines, ovines, bovines, and primates. Using the traditional phylogenetic analyses and employing a novel approach using exon and intron lengths, the results show that only another primate could be the best animal model for analysis of the regulation of the expression of the human CYP3As. This analysis also demonstrated that the chimpanzee seems to be the best available human model. Moreover, the study showed the presence and similarities of one additional isoform in the chimpanzee genome that is absent in humans. Based on these results, initial characterization of the chimpanzee CYP3A subfamily was begun. While the human genome contains four isoforms--CYP3A4, CYP3A5, CYP3A7, and CYP3A43--the chimpanzee genome has five, the four previously mentioned and CYP3A67. Both species express CYP3A4, CYP3A5, and CYP3A43, but humans express CYP3A7 while chimpanzees express CYP3A67. In humans, CYP3A4 is expressed at higher levels than the other isoforms, but some chimpanzee individuals express CYP3A67 at higher levels than CYP3A4. Such a difference is expected to alter significantly the total CYP3A metabolism. On the other hand, any study considering individual isoforms would still constitute a valid method of study for the human CYP3A4, CYP3A5, and CYP3A43 isoforms. ^

Platelets and Anti-Angiogenic Resistance in Ovarian Carcinoma

Background: Resistance to targeted anti-angiogenic therapy is a growing clinical concern given the disappointing clinical impact of anti-angiogenic. Platelets represent a component of the tumor microenvironment that are implicated in metastasis and represent a significant reservoir of angiogenic regulators. Thrombocytosis has been shown to be caused by malignancy and associated with adverse clinical outcomes, however the causal connections between these associations remain to be identified. Materials and Methods: Following IRB approval, patient data were collected on patients from four U.S. centers and platelet levels through and after therapy were considered as indicators of recurrence of disease. In vitro effects of platelets on cancer cell proliferation, apoptosis, and migration were examined. RNA interference was used to query signaling pathways mediating these effects. The necessity of platelet activation for in vitro effect was analyzed. In vivo orthotopic models were used to query the impact of thrombocytosis and thrombocytopenia on the efficacy of cytotoxic chemotherapy, the effect of aspirin on thrombocytosis and cancer, and platelet effect on anti-angiogenic therapy. Results: Platelets were found to increase at the time of diagnosis of ovarian cancer recurrence in a pattern comparable to CA-125. Platelet co-culture increased proliferation, increased migration, and decreased apoptosis in all cell lines tested. RNA interference implicated platelet derived growth factor alpha (PDGFRA) and transforming growth factor beta-receptor 1 (TGFBR1) signaling. Biodistribution studies suggested minimal platelet sequestration of taxanes. Blockade of platelet activation blocked in vitro effects. In vivo, thrombocytosis blocked chemotherapeutic efficacy, thrombocytopenia increased chemotherapeutic efficacy, and aspirin therapy partially blocked the effects of thrombocytosis. In vivo, withdrawal of anti-angiogenic therapy caused loss of therapeutic benefit with evidence of accelerated disease growth. This effect was blocked by use of a small-molecule inhibitor of Focal Adhesion Kinase. Anti-angiogenic therapy was also associated with increased platelet infiltration into tumor that was not seen to the same degree in the control or FAK-inhibitor-treated mice. Conclusions: Platelets are active participants in the growth and metastasis of tumor, both directly and via facilitation of angiogenesis. Blocking platelets, blocking platelet activation, and blocking platelet trafficking into tumor are novel therapeutic avenues supported by this data. Copyright © 2012 Justin Neal Bottsford-Miller, all rights reserved.

Efficiency from pharmacy inventory technology: A means to improving quality in non-profit hospitals

Hospitals, like all organizations, have both a mission and a finite supply of resources with which to accomplish that mission. Because the inventory of therapeutic drugs is among the more expensive resources needed by a hospital to achieve its mission, a conceptual model of structure plus process equals outcome posits that adequate emphasis should be placed on optimization of the organization's investment in this important structural resource to provide highest quality outcomes. Therefore emphasis should be placed on the optimization of pharmacy inventory because lowering the financial investment in drug inventory and associated costs increases productive efficiency, a key element of quality. ^ In this study, a post-intervention analysis of a hospital pharmacy inventory management technology implementation at The University of Texas M.D. Anderson Cancer Center was conducted to determine if an intervention which reduced a hospital's financial investment in pharmaceutical inventory provided an opportunity to incrementally optimize the organization's mix of structural resources thereby improving quality of care. The results suggest that hospital pharmacies currently lacking technology to support automated purchasing logistics and perpetual, real-time inventory management for drugs may achieve measurable benefits from the careful implementation of such technology, enabling the hospital to lower its investment in on-hand inventory and, potentially, to reduce overall purchasing expenditures. ^ The importance of these savings to the hospital and potentially to the patient should not be underestimated for their ability to generate funding for previously unfunded public health programs or in their ability to provide financial relief to patients in the form of lower drug costs given the current climate of escalating healthcare costs and tightening reimbursements.^

The Kramer sampling theorem revisited

The classical Kramer sampling theorem provides a method for obtaining orthogonal sampling formulas. Besides, it has been the cornerstone for a significant mathematical literature on the topic of sampling theorems associated with differential and difference problems. In this work we provide, in an unified way, new and old generalizations of this result corresponding to various different settings; all these generalizations are illustrated with examples. All the different situations along the paper share a basic approach: the functions to be sampled are obtaining by duality in a separable Hilbert space H through an H -valued kernel K defined on an appropriate domain.

La implementación arquitectónica de los acristalamientos activos con agua circulante, y su contribución en edificios de consumo de energía casi nulo

La presente Tesis Doctoral evalúa la contribución de una fachada activa, constituida por acristalamientos con circulación de agua, en el rendimiento energético del edificio. Con especial énfasis en la baja afección sobre su imagen, su integración ha de favorecer la calificación del edificio con el futuro estándar de Edificio de consumo de Energía Casi Nulo (EECN). El propósito consiste en cuantificar su aportación a limitar la demanda de climatización, como solución de fachada transparente acorde a las normas de la energía del 2020. En el primer capítulo se introduce el planteamiento del problema. En el segundo capítulo se desarrollan la hipótesis y el objetivo fundamental de la investigación. Para tal fin, en el tercer capítulo, se revisa el estado del arte de la tecnología y de la investigación científica, mediante el análisis de la literatura de referencia. Se comparan patentes, prototipos, sistemas comerciales asimilables, investigaciones en curso en Universidades, y proyectos de investigación y desarrollo, sobre envolventes que incorporan acristalamientos con circulación de agua. El método experimental, expuesto en el cuarto capítulo, acomete el diseño, la fabricación y la monitorización de un prototipo expuesto, durante ciclos de ensayos, a las condiciones climáticas de Madrid. Esta fase ha permitido adquirir información precisa sobre el rendimiento del acristalamiento en cada orientación de incidencia solar, en las distintas estaciones del año. En paralelo, se aborda el desarrollo de modelos teóricos que, mediante su asimilación a soluciones multicapa caracterizadas en las herramientas de simulación EnergyPlus y IDA-ICE (IDA Indoor Climate and Energy), reproducen el efecto experimental. En el quinto capítulo se discuten los resultados experimentales y teóricos, y se analiza la respuesta del acristalamiento asociado a un determinado volumen y temperatura del agua. Se calcula la eficiencia en la captación de la radiación y, mediante la comparativa con un acristalamiento convencional, se determina la reducción de las ganancias solares y las pérdidas de energía. Se comparan el rendimiento del acristalamiento, obtenido experimentalmente, con el ofrecido por paneles solares fototérmicos disponibles en el mercado. Mediante la traslación de los resultados experimentales a casos de células de tamaño habitable, se cuantifica la afección del acristalamiento sobre el consumo en refrigeración y calefacción. Diferenciando cada caso por su composición constructiva y orientación, se extraen conclusiones sobre la reducción del gasto en climatización, en condiciones de bienestar. Posteriormente, se evalúa el ahorro de su incorporación en un recinto existente, de construcción ligera, localizado en la Escuela de Arquitectura de la Universidad Politécnica de Madrid (UPM). Mediante el planteamiento de escenarios de rehabilitación energética, se estima su compatibilidad con un sistema de climatización mediante bomba de calor y extracción geotérmica. Se describe el funcionamiento del sistema, desde la perspectiva de la operación conjunta de los acristalamientos activos e intercambio geotérmico, en nuestro clima. Mediante la parametrización de sus funciones, se estima el beneficio adicional de su integración, a partir de la mejora del rendimiento de la bomba de calor COP (Coefficient of Performance) en calefacción, y de la eficiencia EER (Energy Efficiency Ratio) en refrigeración. En el recinto de la ETSAM, se ha analizado la contribución de la fachada activa en su calificación como Edificio de Energía Casi Nula, y estudiado la rentabilidad económica del sistema. En el sexto capítulo se exponen las conclusiones de la investigación. A la fecha, el sistema supone alta inversión inicial, no obstante, genera elevada eficiencia con bajo impacto arquitectónico, reduciéndose los costes operativos, y el dimensionado de los sistemas de producción, de mayor afección sobre el edificio. Mediante la envolvente activa con suministro geotérmico no se condena la superficie de cubierta, no se ocupa volumen útil por la presencia de equipos emisores, y no se reduce la superficie o altura útil a base de reforzar los aislamientos. Tras su discusión, se considera una alternativa de valor en procesos de diseño y construcción de Edificios de Energía Casi Nulo. Se proponen líneas de futuras investigación cuyo propósito sea el conocimiento de la tecnología de los acristalamientos activos. En el último capítulo se presentan las actividades de difusión de la investigación. Adicionalmente se ha proporcionado una mejora tecnológica a las fachadas activas existentes, que ha derivado en la solicitud de una patente, actualmente en tramitación. ABSTRACT This Thesis evaluates the contribution of an active water flow glazing façade on the energy performance of buildings. Special emphasis is made on the low visual impact on its image, and the active glazing implementation has to encourage the qualification of the building with the future standard of Nearly Zero Energy Building (nZEB). The purpose is to quantify the façade system contribution to limit air conditioning demand, resulting in a transparent façade solution according to the 2020 energy legislation. An initial approach to the problem is presented in first chapter. The second chapter develops the hypothesis and the main objective of the research. To achieve this purpose, the third chapter reviews the state of the art of the technology and scientific research, through the analysis of reference literature. Patents, prototypes, assimilable commercial systems, ongoing research in other universities, and finally research and development projects incorporating active fluid flow glazing are compared. The experimental method, presented in fourth chapter, undertakes the design, manufacture and monitoring of a water flow glazing prototype exposed during test cycles to weather conditions in Madrid. This phase allowed the acquisition of accurate information on the performance of water flow glazing on each orientation of solar incidence, during different seasons. In parallel, the development of theoretical models is addressed which, through the assimilation to multilayer solutions characterized in the simulation tools EnergyPlus and IDA-Indoor Climate and Energy, reproduce the experimental effect. Fifth chapter discusses experimental and theoretical results focused to the analysis of the active glazing behavior, associated with a specific volume and water flow temperature. The efficiency on harvesting incident solar radiation is calculated, and, by comparison with a conventional glazing, the reduction of solar gains and energy losses are determined. The experimental performance of fluid flow glazing against the one offered by photothermal solar panels available on the market are compared. By translating the experimental and theoretical results to cases of full-size cells, the reduction in cooling and heating consumption achieved by active fluid glazing is quantified. The reduction of energy costs to achieve comfort conditions is calculated, differentiating each case by its whole construction composition and orientation. Subsequently, the saving of the implementation of the system on an existing lightweight construction enclosure, located in the School of Architecture at the Polytechnic University of Madrid (UPM), is then calculated. The compatibility between the active fluid flow glazing and a heat pump with geothermal heat supply system is estimated through the approach of different energy renovation scenarios. The overall system operation is described, from the perspective of active glazing and geothermal heat exchange combined operation, in our climate. By parameterization of its functions, the added benefit of its integration it is discussed, particularly from the improvement of the heat pump performance COP (Coefficient of Performance) in heating and efficiency EER (Energy Efficiency Ratio) in cooling. In the case study of the enclosure in the School of Architecture, the contribution of the active glazing façade in qualifying the enclosure as nearly Zero Energy Building has been analyzed, and the feasibility and profitability of the system are studied. The sixth chapter sets the conclusions of the investigation. To date, the system may require high initial investment; however, high efficiency with low architectural impact is generated. Operational costs are highly reduced as well as the size and complexity of the energy production systems, which normally have huge visual impact on buildings. By the active façade with geothermal supply, the deck area it is not condemned. Useful volume is not consumed by the presence of air-conditioning equipment. Useful surface and room height are not reduced by insulation reinforcement. After discussion, water flow glazing is considered a potential value alternative in nZEB design and construction processes. Finally, this chapter proposes future research lines aiming to increase the knowledge of active water flow glazing technology. The last chapter presents research dissemination activities. Additionally, a technological improvement to existing active facades has been developed, which has resulted in a patent application, currently in handling process.

Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator

cAMP-dependent phosphorylation activates the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelia. However, the protein phosphatase (PP) that dephosphorylates and inactivates CFTR in airway and intestinal epithelia, two major sites of disease, is not certain. We found that in airway and colonic epithelia, neither okadaic acid nor FK506 prevented inactivation of CFTR when cAMP was removed. These results suggested that a phosphatase distinct from PP1, PP2A, and PP2B was responsible. Because PP2C is insensitive to these inhibitors, we tested the hypothesis that it regulates CFTR. We found that PP2Cα is expressed in airway and T84 intestinal epithelia. To test its activity on CFTR, we generated recombinant human PP2Cα and found that it dephosphorylated CFTR and an R domain peptide in vitro. Moreover, in cell-free patches of membrane, addition of PP2Cα inactivated CFTR Cl− channels; reactivation required readdition of kinase. Finally, coexpression of PP2Cα with CFTR in epithelia reduced the Cl− current and increased the rate of channel inactivation. These results suggest that PP2C may be the okadaic acid-insensitive phosphatase that regulates CFTR in human airway and T84 colonic epithelia. It has been suggested that phosphatase inhibitors could be of therapeutic value in cystic fibrosis; our data suggest that PP2C may be an important phosphatase to target.

NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint

The transcription factor NF-κB is a pivotal regulator of inflammatory responses. While the activation of NF-κB in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-κB in animal models of RA. We demonstrate that in vitro, NF-κB controlled expression of numerous inflammatory molecules in synoviocytes and protected cells against tumor necrosis factor α (TNFα) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-κB was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-κB by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IκBα profoundly enhanced apoptosis in the synovium of rats with SCW- and pristane-induced arthritis. This indicated that the activation of NF-κB protected the cells in the synovium against apoptosis and thus provided the potential link between inflammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-κB. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-κB.

Quantifying single gene copy number by measuring fluorescent probe lengths on combed genomic DNA

An approach was developed for the quantification of subtle gains and losses of genomic DNA. The approach relies on a process called molecular combing. Molecular combing consists of the extension and alignment of purified molecules of genomic DNA on a glass coverslip. It has the advantage that a large number of genomes can be combed per coverslip, which allows for a statistically adequate number of measurements to be made on the combed DNA. Consequently, a high-resolution approach to mapping and quantifying genomic alterations is possible. The approach consists of applying fluorescence hybridization to the combed DNA by using probes to identify the amplified region. Measurements then are made on the linear hybridization signals to ascertain the region's exact size. The reliability of the approach first was tested for low copy number amplifications by determining the copy number of chromosome 21 in a normal and trisomy 21 cell line. It then was tested for high copy number amplifications by quantifying the copy number of an oncogene amplified in the tumor cell line GTL-16. These results demonstrate that a wide range of amplifications can be accurately and reliably quantified. The sensitivity and resolution of the approach likewise was assessed by determining the copy number of a single allele (160 kb) alteration.

Imaging the functioning human brain

One of the most exciting methodological advances for brain research field arises in functional brain imaging, which enables us to localize and characterize neural activity and biochemical events in the living human brain. Recently developed event-related functional MRI makes it possible to visualize the brain activity associated with cognitive processes with the temporal resolution of the hemodynamic response. In addition, the high sensitivity and selectivity of positron-emission tomography allow us to probe the neurochemical processes at the molecular level. Positron-emission tomography also has been applied to investigate the effects of therapeutic drugs as well as the effects of drugs of abuse.

Congruences between modular forms: Raising the level and dropping Euler factors

We discuss the relationship among certain generalizations of results of Hida, Ribet, and Wiles on congruences between modular forms. Hida’s result accounts for congruences in terms of the value of an L-function, and Ribet’s result is related to the behavior of the period that appears there. Wiles’ theory leads to a class number formula relating the value of the L-function to the size of a Galois cohomology group. The behavior of the period is used to deduce that a formula at “nonminimal level” is obtained from one at “minimal level” by dropping Euler factors from the L-function.