Gain modulation of synaptic inputs by network state in auditory cortex in vivo

The cortical network recurrent circuitry generates spontaneous activity organized into Up (active) and Down (quiescent) states during slow-wave sleep or anesthesia. These different states of cortical activation gain modulate synaptic transmission. However, the reported modulation that Up states impose on synaptic inputs is disparate in the literature, including both increases and decreases of responsiveness. Here, we tested the hypothesis that such disparate observations may depend on the intensity of the stimulation. By means of intracellular recordings, we studied synaptic transmission during Up and Down states in rat auditory cortex in vivo. Synaptic potentials were evoked either by auditory or electrical (thalamocortical, intracortical) stimulation while randomly varying the intensity of the stimulus. Synaptic potentials evoked by the same stimulus intensity were compared in Up/Down states. Up states had a scaling effect on the stimulus-evoked synaptic responses: the amplitude of weaker responses was potentiated whereas that of larger responses was maintained or decreased with respect to the amplitude during Down states. We used a computational model to explore the potential mechanisms explaining this nontrivial stimulus–response relationship. During Up/Down states, there is different excitability in the network and the neuronal conductance varies. We demonstrate that the competition between presynaptic recruitment and the changing conductance might be the central mechanism explaining the experimentally observed stimulus–response relationships. We conclude that the effect that cortical network activation has on synaptic transmission is not constant but contingent on the strength of the stimulation, with a larger modulation for stimuli involving both thalamic and cortical networks.Fil: Reig, Ramon. Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Zerlaut, Yann. Centre National de la Recherche Scientifique; Francia. Unité de Neurosciences, Information et Complexité; FranciaFil: Vergara, Ramiro Oscar. Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Acústica y Percepción Sonora; ArgentinaFil: Destexhe, Alain. Centre National de la Recherche Scientifique; Francia. Unité de Neurosciences, Information et Complexité; FranciaFil: Sánchez Vives, María V.. Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Institució Catalana de Recerca i Estudis Avancats; Españ

Characterization of fruit products by capillary zone electrophoresis and liquid chromatography using the compositional profiles of polyphenols. Application to authentication of natural extracts

Capillary zone electrophoresis (CZE) and high performance liquid chromatography (HPLC) were applied to the authentication of fruit products based on the compositional profiles of polyphenols. Various sample treatments were used to maximize the overall recovery of polyphenols or specific fractions, such as phenolic acids or anthocyanins. The resulting CZE and HPLC data were treated with Principal Component Analysis (PCA) showing that samples were mainly clustered according to the fruit of origin, with cranberry- and grape-based products clearly separated in groups. A possible adulterated cranberry extract was analyzed more deeply by high resolution mass spectrometry (HRMS) in order to identify the presence of A-type proanthocyanidins, which are characteristic and more abundant in cranberry-based products. In accordance with PCA interpretation, HRMS results indicated that the suspicious sample was not a cranberry-based product, allowing us to validate and demonstrate the suitability of both CZE- and HPLC-proposed methods for the characterization of fruit-based products

Cortical Auditory Adaptation in the Awake Rat and the Role of Potassium Currents

Responses to sound in the auditory cortex are influenced by the preceding history of firing. We studied the time course of auditory adaptation in primary auditory cortex (A1) from awake, freely moving rats. Two identical stimuli were delivered with different intervals ranging from 50 ms to 8 s. Single neuron recordings in the awake animal revealed that the response to a sound is influenced by sounds delivered even several seconds earlier, the second one usually yielding a weaker response. To understand the role of neuronal intrinsic properties in this phenomenon, we obtained intracellular recordings from rat A1 neurons in vitro and mimicked the same protocols of adaptation carried out in awake animals by means of depolarizing pulses of identical duration and intervals. The intensity of the pulses was adjusted such that the first pulse would evoke a similar number of spikes as its equivalent in vivo. A1 neurons in vitro adapted with a similar time course but less than in awake animals. At least two potassium currents participated in the in vitro adaptation: a Na +-dependent K + current and an apamin-sensitive K + current. Our results suggest that potassium currents underlie at least part of cortical auditory adaptation during the awake state.Fil: Abolafia, Juan M.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Vergara, Ramiro Oscar. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS); . Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arnold, M. M.. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Reig, R.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Sanchez Vives, M. V.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS)

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

Metastatic prostate cancer; Chemotherapy; Hormonal therapyCáncer de próstata metastásico; Quimioterapia; Terapia hormonalCàncer de pròstata metastàtic; Quimioteràpia; Teràpia hormonalBackground: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy

Immune checkpoint inhibitors; Metastatic renal carcinoma; Second-line treatmentInhibidors del punt de control immunitari; Carcinoma renal metastàtic; Tractament de segona líniaInhibidores del punto de control inmunitario; Carcinoma renal metastásico; Tratamiento de segunda líneaBackground: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. Patients and methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.This work was supported by Pfizer, S.L.U. (Madrid, Spain). Pfizer, S.L.U. provided an unrestricted research grant with drug funding and drug supply to conduct the study (no grant number)

Determination of polyphenolic profiles by liquid chromatography-electrospray-tandem mass spectrometry for the authentication of fruit extracts

Liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) was applied to the analysis and authentication of fruit-based products and fruit-based pharmaceutical preparations. A Kinetex C18 reversed-phase column under gradient elution with 0.1 % formic acid aqueous solution and methanol mobile phases was used for the simultaneous determination of 26 polyphenols, allowing an acceptable separation in less than 22 min. Instrumental quality parameters such as limits of detection (LOD, values between 12-14 µg/L for 19 of the 26 analyzed polyphenols), linearity (r2 > 0.991), run-to-run and day-to-day precisions (RSD values lower than 9.9 and 13.5 %, respectively), and accuracy (relative errors lower than 8 %) were established. A simple extraction method, consisting of a sample sonication with acetone:water:hydrochloric acid (70:29.9:0.1 v/v/v) and centrifugation, was proposed. Two calibration procedures, external calibration using standards prepared in water and standard addition, were evaluated for polyphenol quantification in several grape and cranberry fruits and processed fruit products. For a 95 % confidence level, no statistical differences were observed between the two calibration methods (p values between 0.06 and 0.95), denoting that external calibration was suitable enough for the quantitative analysis of polyphenols in fruit-based products. The proposed LC-ESI-MS/MS method was then applied to the analysis of polyphenols in 23 grape-based and cranberry-based natural products and pharmaceutical preparations. Polyphenolic concentration data was then analyzed by principal component analysis (PCA) to extract information of the most significant profile data contributing to authentication of natural extracts according to their fruit of origin

Prognostic Gene Expression-Based Signature in Clear-Cell Renal Cell Carcinoma

The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and non-progressive ccRCCs using Illumina Hi-seq 4000. Differentially expressed genes (DEG) were intersected with the RNA-sequencing data from the TCGA. The overlapping genes were used for further analysis. A total of 132 genes were found to be prognosis-related genes. LASSO regression enabled the development of the best prognostic six-gene panel. Cox regression analyses were performed to identify independent clinical prognostic parameters to construct a combined nomogram which includes the expression of CERCAM, MIA2, HS6ST2, ONECUT2, SOX12, TMEM132A, pT stage, tumor size and ISUP grade. A risk score generated using this model effectively stratified patients at higher risk of disease progression (HR 10.79; p < 0.001) and cancer-specific death (HR 19.27; p < 0.001). It correlated with the clinicopathological variables, enabling us to discriminate a subset of patients at higher risk of progression within the Stage, Size, Grade and Necrosis score (SSIGN) risk groups, pT and ISUP grade. In summary, a gene expression-based prognostic signature was successfully developed providing a more precise assessment of the individual risk of progression

Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer.

The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression