Subconductance states in a semimicroscopic model for a tetrameric pore.

A physical model for a structured tetrameric pore is studied. The pore is modeled as a device composed of four subunits, each one exhibiting two possible states (open and closed). The pore is located within a membrane that separates two reservoirs with ionic solutions. All variables of the model follow physical dynamical equations accounting for the internal structure of the pore, derived from a single energy functional and supplemented with thermal noises. An extensive study of the resulting ionic intensity is performed for different values of the control parameters, mainly membrane potential and reservoir ion concentrations. Two possible physical devices are studied: voltage-gated (including a voltage sensor in each subunit) and non-voltage-gated pores. The ionic flux through the pore exhibits several distinct dynamical configurations, in particular subconductance states, which indicate very different dynamical internal states of the subunits. Such subconductance states become much easier to observe in sensorless pores. These results are compared with available experimental data on tetrameric K channels and analytical predictions.

Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: A phase 2 study from GELTAMO.

Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and efficacy of adding lenalidomide to R-ESHAP (LR-ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1-14 of every 21-day cycle, in combination with R-ESHAP at standard doses. Responding patients underwent autologous stem-cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell-of-origin (COO) classification was performed. Forty-six patients were included. The ORR after LR-ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non-refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty-eight patients (61%) underwent ASCT. At a median follow-up of 41 months, the estimated 3-year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment-related deaths during LR-ESHAP cycles. In conclusion, LR-ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL.

Landau theory for cellular patterns driven by lateral inhibition interaction.

The phenomenology of Landau theory with spatial coupling through diffusion has been widely used in the study of phase transitions and patterning. Here we follow this theory and apply it to study theoretically and numerically continuous and discontinuous transitions to periodic spatial cellular patterns driven by lateral inhibition coupling. As opposed to diffusion, lateral inhibition coupling drives differences between adjacent cells. We analyze the appearance of errors in these patterns (disordered metastable states) and propose mechanisms to prevent them. These mechanisms are based on a temporal-dependent lateral inhibition coupling strength, which can be mediated, among others, by gradients of diffusing molecules. The simplicity and generality of the framework used herein is expected to facilitate future analyses of additional phenomena taking place through lateral inhibition interactions in more complex scenarios.

Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study.

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.

Results of R-ESHAP as salvage therapy in refractory/relapsed follicular lymphoma: a real-world experience on behalf of GELCAB group.

There is no standard treatment for relapsed follicular lymphoma (FL). Although platinum-based combinations are one of the most used treatments, few data have been reported in this setting. Our aim was to analyse R-ESHAP efficacy in relapsed FL patients. We retrospectively analysed 80 FL patients treated with R-ESHAP in the first or successive relapses. Responding patients received a stem cell transplantation following R-ESHAP. Seventeen histologically transformed patients were included. Median age was 50 years. At R-ESHAP initiation, 85% of the patients were in an advanced stage, 28% had a bulky disease and 40% had increased LDH. There were no statistically significant differences between POD24 and non-POD24 patients in terms of response to R-ESHAP (ORR 72% vs. 93%, p = 0.109). When analyzing R-ESHAP efficacy according to the response to the immediately previous line, patients achieving CR or PR had better CR rates to R-ESHAP than those who did not respond (CR of 57% vs. 15%, respectively, p = 0.009), as well as differences in OS (7.2 vs. 1.4 years, p < 0.0001) and in PFS (2.1 vs. 0.3 years, p < 0.0001). R-ESHAP is an effective treatment in relapsed FL patients who respond to the previous line and has to be considered as an adequate alternative for some patients.

Posttransplant monomorphic Burkitt's lymphoma: clinical characteristics and outcome of a multicenter series.

Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.

Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets.

Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.

Autologous stem cell transplantation (ASCT) in patients with mantle cell lymphoma: a retrospective study of the Spanish lymphoma group (GELTAMO).

Guidelines recommend autologous stem cell transplantation (ASCT) consolidation in first complete or partial response after regimens including rituximab (R) and high-dose AraC (HDAC), but its use beyond that response is questioned. We present a retrospective analysis of 268 patients with MCL who received ASCT. With a median follow-up for survival patients of 54 months, progression-free survival and overall survival for the whole series were 38 and 74 months, respectively, and for patients transplanted in first CR 49 and 97 months, respectively. Patients without CR before transplant were analyzed separately, those who achieved CR after transplantation had better PFS (48 vs 0.03 months, p < 0.001) and OS (92 vs 16 months, p < 0.001) than the remaining. In univariate analysis, first CR at transplant (p = 0.01) and prior rituximab (p = 0.02) were the variables associated with PFS. For OS, the same variables resulted significant (p = 0.03 and p < 0.001, respectively). In multivariate analysis, only the status at transplant (first CR) remained significant. This retrospective study concludes that ASCT consolidation in first CR induces high survival rates. In other stages of disease, the need of ASCT as consolidation may be questioned.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in a subset of high-risk patients with diffuse large B-cell lymphoma receiving first line systemic therapy in a prospective trial.

The dissemination in the central nervous system (CNS) is an uncommon but fatal complication occurring in patients with diffuse large B-cell lymphoma (DLBCL). Standard prophylaxis has been demonstrated to reduce CNS relapse and improve survival rates. Intrathecal (IT) liposomal cytarabine allows maintaining elevated drug levels in the cerebrospinal fluid for an extended period of time. Data on the efficacy and safety of liposomal cytarabine as CNS prophylaxis in patients with DLBCL are still insufficient. The objective of the present study was to evaluate the effectiveness and safety of the prophylaxis with IT liposomal cytarabine in prevention of CNS relapse in high-risk patients with DLBCL who were included in a trial of first line systemic therapy with 6 cycles of dose-dense R-CHOP every 14 days. Twenty-four (18.6 %) out of 129 patients were identified to have risk factors for CNS involvement, defined as follows: >30 % bone marrow infiltration, testes infiltration, retroperitoneal mass ≥10 cm, Waldeyer ring, or bulky cervical nodes involvement. Liposomal cytarabine (50 mg) was administered by lumbar puncture the first day of the 1st, 2nd, and 6th cycle of R-CHOP14 scheme. Among 70 IT infusions, grade 3-4 adverse events reported were headache (one patient) and nausea/vomiting (one patient). With a median follow-up of 40.1 months, no CNS involvement by DLBCL was observed in any patient. In conclusion, IT liposomal cytarabine is safe, feasible, and effective for CNS prophylaxis, causing few associated risks and little discomfort to patients with DLBCL.

SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150.

SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Studies on the action of SPRY2 in major cancers are conflicting and its role remains unclear. Here we have dissected SPRY2 action in human colon cancer. Global transcriptomic analyses show that SPRY2 downregulates genes encoding tight junction proteins such as claudin-7 and occludin and other cell-to-cell and cell-to-matrix adhesion molecules in human SW480-ADH colon carcinoma cells. Moreover, SPRY2 represses LLGL2/HUGL2, PATJ1/INADL and ST14, main regulators of the polarized epithelial phenotype, and ESRP1, an epithelial-to-mesenchymal transition (EMT) inhibitor. A key action of SPRY2 is the upregulation of the major EMT inducer ZEB1, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEB1 in human colon tumors. Mechanistically, ZEB1 upregulation by SPRY2 results from the combined induction of ETS1 transcription factor and the repression of microRNAs (miR-200 family, miR-150) that target ZEB1 RNA. Moreover, SPRY2 increased AKT activation by epidermal growth factor, whereas AKT and also Src inhibition reduced the induction of ZEB1. Altogether, these data suggest that AKT and Src are implicated in SPRY2 action. Collectively, these results show a tumorigenic role of SPRY2 in colon cancer that is based on the dysregulation of tight junction and epithelial polarity master genes via upregulation of ZEB1. The dissection of the mechanism of action of SPRY2 in colon cancer cells is important to understand the upregulation of this gene in a subset of patients with this neoplasia that have poor prognosis.

Plerixafor in patients with lymphoma and multiple myeloma: effectiveness in cases with very low circulating CD34+ cell levels and preemptive intervention vs remobilization.

This retrospective study presents data from 105 consecutive multiple myeloma and lymphoma patients who had PB CD34+ cell counts <10/µL on day 4 of steady-state G-CSF mobilization for autologous hematopoietic cell transplantation. Our results confirm the capacity of plerixafor to improve mobilization outcomes in this clinical setting. In addition, they show that the effectiveness of plerixafor, compared with G-CSF only, translates to patients with very low (<3.5/µL) circulating CD34+ cell counts: overnight CD34+ cell count expansion (5.3- vs 1.7-fold), overall CD34+ cell yield (2.29 vs 0.15 × 10(6) CD34+ cells per kg) and patients yielding ⩾2 × 10(6) CD34+ cells per kg (63% vs 3%). Furthermore, our data also show that preemptive plerixafor is significantly more effective and more efficient than in remobilization: CD34+ cell yield in the first apheresis (3.28 vs 2.0 × 10(6) CD34+ cells per kg) and overall (3.73 vs 2.44 × 10(6) CD34+ cells per kg), patients yielding ⩾2 × 10(6) CD34+ cells per kg in the first apheresis (85% vs 44%) and overall (92% vs 64%), all this requiring less days and doses of plerixafor treatment (1.08 vs 1.48). These data would advocate using plerixafor as an early preemptive intervention based on day 4 circulating CD34+ counts, including very high-risk patients with very low circulating levels.

Brownian colloids in underdamped and overdamped regimes with nonhomogeneous temperature.

The motion of Brownian particles when temperature is spatially dependent is studied by stochastic simulations and theoretical analysis. Nonequilibrium steady probability distributions P(st)(z,v) for both underdamped and overdamped regimes are analyzed. The existence of local kinetic energy equipartition theorem is also discussed. The transition between both regimes is characterized by a dimensionless friction parameter. This study is applied to three physical systems of colloidal particles.

Theoretical study of a molecular turbine.

We present an analytic and stochastic simulation study of a molecular engine working with a flux of particles as a turbine. We focus on the physical observables of velocity, flux, power, and efficiency. The control parameters are the external conservative force and the particle densities. We revise a simpler previous study by using a more realistic model containing multiple equidistant vanes complemented by stochastic simulations of the particles and the turbine. Here we show that the effect of the thermal fluctuations into the flux and the efficiency of these nanometric devices are relevant to the working scale of the system. The stochastic simulations of the Brownian motion of the particles and turbine support the simplified analytical calculations performed.

Unconventional dynamic hysteresis in a periodic assembly of paramagnetic colloids.

Dynamic hysteresis phenomena are widespread in physical sciences and describe the complex behavior of systems driven out of equilibrium by a periodic forcing. We use here paramagnetic colloids above a stripe-patterned garnet film as the model system to study dynamic hysteresis, the latter induced when the particles are periodically translated by an oscillating magnetic field. In contrast to the expected behavior for a bistable system, we observe that the area of the hysteresis loop decreases by increasing the driving frequency and reduces to zero for frequencies higher than 5-7s(-1). To explain the experimental results, we develop a simple model based on an overdamped Brownian particle driven by a periodic potential with an oscillating amplitude.

Emergent bimodal firing patterns implement different encoding strategies during gamma-band oscillations.

Upon sensory stimulation, primary cortical areas readily engage in narrow-band rhythmic activity between 30 and 90 Hz, the so-called gamma oscillations. Here we show that, when embedded in a balanced network, type-I excitable neurons entrained to the collective rhythm show a discontinuity in their firing-rates between a slow and a fast spiking mode. This jump in the spiking frequencies is characteristic to type II neurons, but is not present in the frequency-current curve (f-I curve) of isolated type I neurons. Therefore, this rate bimodality arises as an emerging network property in type I population models. We have studied the mechanisms underlying the generation of these two firing modes, in order to reproduce the spiking activity of in vivo cortical recordings, which is known to be highly irregular and sparse. We have also analyzed the relation between afferent inputs and the single unit activity, and between the latter and the local field potential (LFP) phase, in order to establish how the collective dynamics modulates the spiking activity of the individual neurons. Our results reveal that the inhibitory-excitatory balance allows two encoding mechanisms, for input rate variations and LFP phase, to coexist within the network.

Adherence and factors associated with influenza vaccination among subjects with asthma in Spain.

PURPOSE: Influenza has a high morbidity and mortality rate and an increased risk of complications in vulnerable individuals. Children and adults with asthma have a high risk of complications, hospitalisation and even death. The objectives of this study were as follows: to compare influenza vaccination coverage in Spain in a population of asthmatics aged ≥ 16 years with an equivalent population of non-asthmatics; to identify the factors that influence vaccination coverage among patients with asthma; and to compare coverage during the period 2006/2007 with that of 2009/2010. METHODS: We used data from the 2009 European Health Survey (EHS), which included a population of 22,188 individuals (≥ 16 years of age), of whom 1,669 [7.5 %; 95 % confidence interval (CI), 7.13-7.98] had asthma. The dependent variable was the answer (yes/no) to a question asking whether or not the interviewed person had been vaccinated against seasonal (not pandemic) influenza in the previous season. As independent variables, we analysed socio-demographic characteristics, health-related variables and the use of health care services. RESULTS: Vaccination coverage was 35.2 % (95 % CI, 32.5-37.9) among asthmatics and 22.1 % (95 % CI, 21.4-22.7) among non-asthmatics (p < 0.001). The probability of being vaccinated is almost twice as high for asthmatics as it is for non-asthmatics [odds ratio (OR), 1.92; 95 % CI, 1.69-2.17]. Among asthmatics, vaccination coverage increased with age, worse self-rated health status and not smoking. No significant change in coverage was observed between the study periods. CONCLUSIONS: Seasonal influenza vaccination coverage among Spanish asthmatics is lower than desired and has not improved in recent years. Urgent strategies are necessary in order to increase vaccination coverage among asthmatics.

Transport and diffusion of overdamped Brownian particles in random potentials.

We present a numerical study of the anomalies in transport and diffusion of overdamped Brownian particles in totally disordered potential landscapes in one and in two dimensions. We characterize and analyze the effects of three different disordered potentials. The anomalous regimes are characterized by the time exponents that exhibit the statistical moments of the ensemble of particle trajectories. The anomaly in the transport is always of the subtransport type, but diffusion presents a greater variety of anomalies: Both subdiffusion and superdiffusion are possible. In two dimensions we present a mixed anomaly: subdiffusion in the direction perpendicular to the force and superdiffusion in the parallel direction.

Speeding chemical reactions by focusing.

We present numerical results for a chemical reaction of colloidal particles which are transported by a laminar fluid and are focused by periodic obstacles in such a way that the two components are well mixed and consequently the chemical reaction is speeded up. The roles of the various system parameters (diffusion coefficients, reaction rate, and obstacles sizes) are studied. We show that focusing speeds up the reaction from the diffusion limited rate ∼t(-1/2) to very close to the perfect mixing rate, ∼t(-1).

Molecular motors in conservative and dissipative regimes.

We present a theoretical study of a rotatory molecular motor under a conservative torque regime. We show that conservative and dissipative regimes present a different observable phenomenology. Our approach starts with a preliminary deterministic calculation of the motor cycle, which is complemented with stochastic simulations of a Langevin equation under a flashing ratchet potential. Finally, by using parameter values obtained from independent experimental information, our theoretical predictions are compared with experimental data of the F(1)-ATPase motor of the Bacillus PS3.