Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

Purpose: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC).

Methods: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay).

Results: No significant interaction between treatment and PD-L1 status was observed for OS.

p38 activation occurs mainly in microglia in the P301S Tauopathy mouse model.

Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated tau protein in the brain. Many of these pathologies also present an inflammatory component determined by the activation of microglia, the resident immune cells of the brain. p38 MAPK is one of the molecular pathways involved in neuroinflammation.

p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function.

Alzheimer's disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies.

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study.

Background: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified.

Patients And Methods: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs.

Linear Programming and Fuzzy Optimization to Substantiate Investment Decisions in Tangible Assets.

This paper studies the problem of tangible assets acquisition within the company by proposing a new hybrid model that uses linear programming and fuzzy numbers. Regarding linear programming, two methods were implemented in the model, namely: the graphical method and the primal simplex algorithm. This hybrid model is proposed for solving investment decision problems, based on decision variables, objective function coefficients, and a matrix of constraints, all of them presented in the form of triangular fuzzy numbers.

Microglia in Alzheimer's Disease in the Context of Tau Pathology.

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer's disease (AD), the most common form of dementia associated with aging.

Extracellular Monomeric Tau Is Internalized by Astrocytes.

Tau is a microtubule-associated protein that is expressed in neurons. However, in a group of neurodegenerative diseases named tauopathies - characterized by an increase in aggregated and/or hyperphosphorylated Tau - the protein accumulates inside other cells, such as astrocytes and microglia. Given that these glial cells do not produce Tau, its presence can be explained by internalization from the extracellular medium and consequent formation of Tau aggregates.

Maturation Dynamics of the Axon Initial Segment (AIS) of Newborn Dentate Granule Cells in Young Adult C57BL/6J Mice.

Newborn dentate granule cells (DGCs) are generated in the hippocampal dentate gyrus (DG) of rodents through a process called adult hippocampal neurogenesis, which is subjected to tight intrinsic and extrinsic regulation. The use of retroviruses encoding fluorescent proteins has allowed the characterization of the maturation dynamics of newborn DGCs, including their morphological development and the establishment and maturation of their afferent and efferent synaptic connections. However, the study of a crucial cellular compartment of these cells, namely, the axon initial segment (AIS), has remained unexplored to date.

Decreased CX3CL1 Levels in the Cerebrospinal Fluid of Patients With Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the presence of neurofibrillary tangles, constituted by tau protein, and plaques formed by amyloid-beta protein. The disease courses with high neural damage, which leads to memory loss and death. Here we analyzed the presence of CX3CL1, a chemokine expressed by neurons, in cerebrospinal fluid (CSF) samples from control subjects and patients with mild cognitive impairment and AD dementia.

Dephosphorylated rather than hyperphosphorylated Tau triggers a pro-inflammatory profile in microglia through the p38 MAPK pathway.

Tauopathies are a broad set of neurodegenerative dementias characterized by the aggregation of Tau protein. Activated microglia and elevated levels of pro-inflammatory molecules are also pathological hallmarks of tauopathies. In these diseases, intracellular Tau is secreted to the extracellular space, where it interacts with other cells, such as neurons and glia, promoting inflammation.

The Role of Microglia in the Spread of Tau: Relevance for Tauopathies.

Tauopathies are neurodegenerative diseases which course with the accumulation of Tau, mainly in neurons. In addition, Tau accumulates in a hyperphosphorylated and aggregated form. This protein is released into the extracellular space and spreads following a stereotypical pattern, inducing the development of the disease through connected regions of the brain.

Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease.

Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD).

New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy.

Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap.

Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons.

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice.

Cognitive Decline in Neuronal Aging and Alzheimer's Disease: Role of NMDA Receptors and Associated Proteins.

Molecular changes associated with neuronal aging lead to a decrease in cognitive capacity. Here we discuss these alterations at the level of brain regions, brain cells, and brain membrane and cytoskeletal proteins with an special focus in NMDA molecular changes through aging and its effect in cognitive decline and Alzheimer disease. Here, we propose that some neurodegenerative disorders, like Alzheimer's disease (AD), are characterized by an increase and acceleration of some of these changes.

Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons.

Microglia are immune cells that play a crucial role in maintaining brain homeostasis. Among the mechanisms of communication between microglia and neurons, the CX3CL1/CX3CR1 axis exerts a central modulatory role. Animals lacking CX3CR1 microglial receptor (CX3CR1-/- mice) exhibit marked alterations not only in microglia but also in neurons located in various regions of the brain.

Absence of CX3CR1 impairs the internalization of Tau by microglia.

Background: Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism.

Methods: We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1 mice).

Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies.

Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients.

Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice.

Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals.

Implementation and Evaluation of a Technology System to Improve Safety of the Oncohematology Medication Practices.

OBJECTIVE The objective of the study was to describe the process of implementing a technology system to improve safety and quality in all processes involved in the treatment with parenteral antineoplastic agents within an interdisciplinary team and to analyze the errors detected and avoided thanks to this system at the different stages of the process. MATERIALS AND METHODS Observational and retrospective study where the implementation of an expert technology system in all phases of the therapeutic process is described: prescription, validation, preparation and administration of drugs, in which errors found in the different phases are analysed. A descriptive analysis of the errors recorded in the various stages of the process was carried out during 3 months.

Alzheimer's disease as an inflammatory disease.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.

Tau Structures.

Tau is a microtubule-associated protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. In this review, we focus on the primary, secondary, tertiary, and quaternary tau structures. We describe the structure of tau from its specific residues until its conformation in dimers, oligomers, and larger polymers in physiological and pathological situations.

Amyloid β precursor protein regulates neuron survival and maturation in the adult mouse brain.

The amyloid-β precursor protein (APP) is a transmembrane protein that is widely expressed within the central nervous system (CNS). While the pathogenic dysfunction of this protein has been extensively studied in the context of Alzheimer's disease, its normal function is poorly understood, and reports have often appeared contradictory. In this study we have examined the role of APP in regulating neurogenesis in the adult mouse brain by comparing neural stem cell proliferation, as well as new neuron number and morphology between APP knockout mice and C57bl6 controls.

Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus.

Recent experimental data suggest that mood disorders are related to inflammatory phenomena and have led to the "inflammatory hypothesis of depression". Given that the hippocampus is one of the most affected areas in these disorders, we used a model of acute stress (the Porsolt test) to evaluate the consequences of forced swimming on two crucial events related to the pathophysiology of major depression: the functional maturation of newborn granule neurons; and the hippocampal inflammatory milieu. Using PSD95:GFP-expressing retroviruses, we found that forced swimming selectively alters the dendritic morphology of newborn neurons and impairs their connectivity by reducing the number and volume of their postsynaptic densities.