Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatmen

PLANT: A Method for Detecting Changes of Slope in Noisy Trajectories

Time traces obtained from a variety of biophysical experiments contain valuable information on underlying processes occurring at the molecular level. Accurate quantification of these data can help explain the details of the complex dynamics of biological systems. Here, we describe PLANT (Piecewise Linear Approximation of Noisy Trajectories), a segmentation algorithm that allows the reconstruction of time-trace data with constant noise as consecutive straight lines, from which changes of slopes and their respective durations can be extracted. We present a general description of the algorithm and perform extensive simulations to characterize its strengths and limitations, providing a rationale for the performance of the algorithm in the different conditions tested. We further apply the algorithm to experimental data obtained from tracking the centroid position of lymphocytes migrating under the effect of a laminar flow and from single myosin molecules interacting with actin in a dual-trap force-clamp configuration.The authors gratefully acknowledge financial support fromthe European Commission (FP7-ICT-2011-7, grant number 288263), Erasmus Mundus Doctorate Program Europhoton-ics (grant number 159224-1-2009-1-FR-ERA MUNDUS-EMJD), Spanish Ministry of Economy and Competi-tiveness (“Severo Ochoa” Programme for Centres of Excellence in Research & Development SEV-2015-0522,and FIS2014-56107-R grants), Generalitat de Catalunyathrough the CERCA program, Italian Ministry of Uni-versity and Research (FIRB “Futuro in Ricerca” 2013grant n. RBFR13V4M2 and Flagship Project NANOMAX),Fundaci ́o Privada CELLEX (Barcelona), Ente Cassa diRisparmio di Firenze, Human Frontier Science Program (GARGP0027/2012) and LaserLab Europe 4 (GA 654148). C.M.acknowledges funding from the Spanish Ministry of Econ-omy and Competitiveness (MINECO) and the EuropeanSocial Fund (ESF) through the Ram ́on y Cajal program 2015(RYC-2015-17896).Peer ReviewedPostprint (author's final draft

Luminosity- and morphology-dependent clustering of galaxies

How does the clustering of galaxies depend on their inner properties like morphological type and luminosity? We address this question in the mathematical framework of marked point processes and clarify the notion of luminosity and morphological segregation. A number of test quantities such as conditional mark-weighted two-point correlation functions are introduced. These descriptors allow for a scale-dependent analysis of luminosity and morphology segregation. Moreover, they break the degeneracy between an inhomogeneous fractal point set and actual present luminosity segregation. Using the Southern Sky Redshift Survey~2 (da Costa et al. 1998, SSRS2) we find both luminosity and morphological segregation at a high level of significance, confirming claims by previous works using these data (Benoist et al. 1996, Willmer et al. 1998). Specifically, the average luminosity and the fluctuations in the luminosity of pairs of galaxies are enhanced out to separations of 15Mpc/h. On scales smaller than 3Mpc/h the luminosities on galaxy pairs show a tight correlation. A comparison with the random-field model indicates that galaxy luminosities depend on the spatial distribution and galaxy-galaxy interactions. Early-type galaxies are also more strongly correlated, indicating morphological segregation. The galaxies in the PSCz catalog (Saunders et al. 2000) do not show significant luminosity segregation. This again illustrates that mainly early-type galaxies contribute to luminosity segregation. However, based on several independent investigations we show that the observed luminosity segregation can not be explained by the morphology-density relation alone.Comment: aastex, emulateapj5, 20 pages, 13 figures, several clarifying comments added, ApJ accepte

Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance

Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population

Cluster Correlation in Mixed Models

We evaluate the dependence of the cluster correlation length r_c on the mean intercluster separation D_c, for three models with critical matter density, vanishing vacuum energy (Lambda = 0) and COBE normalized: a tilted CDM (tCDM) model (n=0.8) and two blue mixed models with two light massive neutrinos yielding Omega_h = 0.26 and 0.14 (MDM1 and MDM2, respectively). All models approach the observational value of sigma_8 (and, henceforth, the observed cluster abundance) and are consistent with the observed abundance of Damped Lyman_alpha systems. Mixed models have a motivation in recent results of neutrino physics; they also agree with the observed value of the ratio sigma_8/sigma_25, yielding the spectral slope parameter Gamma, and nicely fit LCRS reconstructed spectra. We use parallel AP3M simulations, performed in a wide box (side 360/h Mpc) and with high mass and distance resolution, enabling us to build artificial samples of clusters, whose total number and mass range allow to cover the same D_c interval inspected through APM and Abell cluster clustering data. We find that the tCDM model performs substantially better than n=1 critical density CDM models. Our main finding, however, is that mixed models provide a surprisingly good fit of cluster clustering data.Comment: 22 pages + 10 Postscript figures. Accepted for publication in Ap

Brain Activation Patterns Characterizing Different Phases of Motor Action: Execution, Choice and Ideation.

Motor behaviour is controlled by a large set of interacting neural structures, subserving the different components involved in hierarchical motor processes. Few studies have investigated the neural substrate of higher-order motor ideation, i.e. the mental operation of conceiving a movement. The aim of this functional magnetic resonance imaging study was to segregate the neural structures involved in motor ideation from those involved in movement choice and execution. An index finger movement paradigm was adopted, including three different conditions: performing a pre-specified movement, choosing and executing a movement and ideating a movement of choice. The tasks involved either the right or left hand, in separate runs. Neuroimaging results were obtained by comparing the different experimental conditions and computing conjunction maps of the right and left hands for each contrast. Pre-specified movement execution was supported by bilateral fronto-parietal motor regions, the cerebellum and putamen. Choosing and executing finger movement involved mainly left fronto-temporal areas and the anterior cingulate. Motor ideation activated almost exclusively left hemisphere regions, including the inferior, middle and superior frontal regions, middle temporal and middle occipital gyri. These findings show that motor ideation is controlled by a cortical network mainly involved in abstract thinking, cognitive and motor control, semantic and visual imagery processes

Immunotherapeutic approaches for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patient

Lactate dehydrogenase in hepatocellular carcinoma: something old, something new

Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this diseas