A cerebellar adaptation to uncertain inputs

Noise and variability are inherent and unavoidable features of neural processing. Despite this physiological challenge, brain systems function well, suggesting the existence of adaptations that cope with noise. We report a novel adaptation that the cerebellum implements to maintain correct responses in the face of ambiguous inputs. We found that under these conditions, the cerebellum used a probabilistic binary choice: Although the probability of behavioral response gradually increased or decreased depending on the degree of similarity between current and trained inputs, the size of response remained constant. That way the cerebellum kept responses adaptive to trained input corrupted by noise while minimizing false responses to novel stimuli. Recordings and analysis of Purkinje cells activity showed that the binary choice is made in the cerebellar cortex. Results from large-scale simulation suggest that internal feedback from cerebellar nucleus back to cerebellar cortex plays a critical role in implementation of binary choice

A model study of cellular short-term memory produced by slowly inactivating potassium conductances

Abstract. We analyzed the cellular short-term memory effects induced by a slowly inactivating potassium (Ks) conductance using a biophysical model of a neuron. We first described latency-to-first-spike and temporal changes in firing frequency as a function of parameters of the model, injected current and prior history of the neuron (deinactivation level) under current clamp. This provided a complete set of properties describing the Ks conductance in a neuron. We then showed that the action of the Ks conductance is not generally appropriate for controlling latency-to-first-spike under random synaptic stimulation. However, reliable latencies were found when neuronal population computation was used. Ks inactivation was found to control the rate of convergence to steady-state discharge behavior and to allow frequency to increase at variable rates in sets of synaptically connected neurons. These results suggest that inactivation of the Ks conductance can have a reliable influence on the behavior of neuronal populations under real physiological conditions

A model study of cellular short-term memory produced by slowly inactivating potassium conductances

Abstract. We analyzed the cellular short-term memory effects induced by a slowly inactivating potassium (Ks) conductance using a biophysical model of a neuron. We first described latency-to-first-spike and temporal changes in firing frequency as a function of parameters of the model, injected current and prior history of the neuron (deinactivation level) under current clamp. This provided a complete set of properties describing the Ks conductance in a neuron. We then showed that the action of the Ks conductance is not generally appropriate for controlling latency-to-first-spike under random synaptic stimulation. However, reliable latencies were found when neuronal population computation was used. Ks inactivation was found to control the rate of convergence to steady-state discharge behavior and to allow frequency to increase at variable rates in sets of synaptically connected neurons. These results suggest that inactivation of the Ks conductance can have a reliable influence on the behavior of neuronal populations under real physiological conditions

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution