Interocular yoking in human saccades examined by mutual information analysis

International audienceABSTRACT : BACKGROUND : Saccadic eye movements align the two eyes precisely to foveate a target. Trial-by-trial variance of eye movement is always observed within an identical experimental condition. This has often been treated as experimental error without addressing its significance. The present study examined statistical linkages between the two eyes' movements, namely interocular yoking, for the variance of eye position and velocity. METHODS : Horizontal saccadic movements were recorded from twelve right-eye-dominant subjects while they decided on saccade direction in Go-Only sessions and on both saccade execution and direction in Go/NoGo sessions. We used infrared corneal reflection to record simultaneously and independently the movement of each eye. Quantitative measures of yoking were provided by mutual information analysis of eye position or velocity, which is sensitive to both linear and non-linear relationships between the eyes' movements. Our mutual information analysis relied on the variance of the eyes movements in each experimental condition. The range of movements for each eye varies for different conditions so yoking was further studied by comparing GO-Only vs. Go/NoGo sessions, leftward vs. rightward saccades. RESULTS : Mutual information analysis showed that velocity yoking preceded positional yoking. Cognitive load increased trial variances of velocity with no increase in velocity yoking, suggesting that cognitive load may alter neural processes in areas to which oculomotor control is not tightly linked. The comparison between experimental conditions showed that interocular linkage in velocity variance of the right eye lagged that of the left eye during saccades. CONCLUSIONS : We conclude quantitative measure of interocular yoking based on trial-to-trial variance within a condition, as well as variance between conditions, provides a powerful tool for studying the binocular movement mechanism

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

GUCY2C as a Target for CAR-T Cells to Treat Pancreatic Cancer

Background: Pancreatic cancer is an extremely deadly cancer with a survival rate of only 10.8%. Currently, surgical resection is the only potentially curative treatment, with modestly improved survival after resection. This low survival rate, and the minority of patients who present eligible for surgery, indicates the clear need for additional therapies. Guanylyl cyclase C (GUCY2C), a transmembrane protein selectively expressed by normal intestinal epithelial cells, but not normal pancreatic cells, is expressed in select pancreatic adenocarcinomas and is available as a potential target for directed therapy. Chimeric antigen receptor (CAR) T cell therapy genetically reprograms a patient’s own T cells to express a receptor that targets tumor antigens. We have previously shown GUCY2C CAR-T cells efficacy in mouse models of intraperitoneal colorectal cancer, as well as subcutaneous gastric and esophageal cancers. GUCY2C CAR-T cell therapy could serve as an adjunct in pancreatic cancer treatment at multiple points along the clinical management pathway including as adjuvant therapy in resected patients, neoadjuvant therapy in borderline resectable patients, and as primary treatment in metastatic patients. Here, we created an orthotopic mouse model of metastasizing human pancreatic cancer that can be used to test the efficacy of GUCY2C-directed CAR T cells at each stage along the patient management continuum. Methods: A GUCY2C-expressing pancreatic adenocarcinoma cell line (AsPC-1) as well as two patient derived xenografts (PDXs) from the National Cancer Institute were acquired. GUCY2C expression was confirmed with RNA, protein and shRNA knockdown. Orthotopic mouse models were created by surgically implanting AsPC-1 cells or PDXs into the pancreatic tail. Luciferase was added to AsPC-1 cells using lentiviral transduction to track tumor growth. Biomarker status of PDXs was established to monitor tumor growth and treatment efficacy. GUCY2C CAR-T cells were used in vitro to demonstrate therapeutic efficacy against AsPC-1 cells. Results: AsPC-1 cells implanted in the pancreatic tail metastasized to liver and lungs, revealed by gross morphology, histology, and quantitative RT-PCR analysis. In that context, luciferase fluorescence permitted monitoring of disease progression by IVIS imaging in vivo, without the need to sacrifice mice. An in vitro killing assay demonstrated that AsPC-1 cells were specifically killed by GUCY2C-directed CAR-T cells, compared to non-directed CAR-T cells. Orthotopic implantation of PDXs produced pancreatic tumors in 100% of recipient mice, which could be monitored using circulating CEA. Conclusions: GUCY2C is expressed in a proportion of pancreatic adenocarcinomas, but not normal pancreatic tissue. We have established the efficacy of our GUCY2C-targeted CAR-T cells in in vivo models of disseminated intraperitoneal colorectal cancer, as well as subcutaneous gastric and esophageal cancers models, in mice. Moving forward, we will use this newly created orthotopic model of pancreatic cancer to explore the efficacy of GUCY2C-directd CAR T cells to treat primary and metastatic tumors, to improve the management of patients along the entire disease continuum