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Budman D.R.,North Shore University Hospital | Tai J.,Feinstein Institute | Calabro A.,North Shore University Hospital | John V.,North Shore University Hospital
Investigational New Drugs | Year: 2011

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Usingmedian effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation. © Springer Science+Business Media, LLC 2010.


Tracey K.J.,Feinstein Institute
Cell | Year: 2016

Simple reflex circuits provide crucial infrastructure for the neurological control of organ systems - even the immune system. Now, Gabanyi et al. reveal a reflex mechanism in gut activated by the presence of pathogens that forces macrophages into a tissue protective phenotype. © 2016 Elsevier Inc.


Fernandes F.,State University of New York at Stony Brook | Chen K.,U.S. National Institutes of Health | Ehrlich L.S.,State University of New York at Stony Brook | Jin J.,Yale University | And 7 more authors.
Traffic | Year: 2011

Phosphatidylinositol 4,5-biphosphate [PI(4,5)P2], the predominant phosphoinositide (PI) on the plasma membrane, binds the matrix (MA) protein of human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus (EIAV) with similar affinities in vitro. Interaction with PI(4,5)P2 is critical for HIV-1 assembly on the plasma membrane. EIAV has been shown to localize in internal compartments; hence, the significance of its interaction with PI(4,5)P2 is unclear. We therefore investigated the binding in vitro of other PIs to EIAV MA and whether intracellular association with compartments bearing these PIs was important for assembly and release of virus-like particles (VLPs) formed by Gag. In vitro, EIAV MA bound phosphatidylinositol 3-phosphate [PI(3)P] with higher affinity than PI(4,5)P2 as revealed by nuclear magnetic resonance (NMR) spectra upon lipid titration. Gag was detected on the plasma membrane and in compartments enriched in phosphatidylinositol 3,5-biphosphate [PI(3,5)P2]. Treatment of cells with YM201636, a kinase inhibitor that blocks production of PI(3,5)P2 from PI(3)P, caused Gag to colocalize with aberrant compartments and inhibited VLP release. In contrast to HIV-1, release of EIAV VLPs was not significantly diminished by coexpression with 5-phosphatase IV, an enzyme that specifically depletes PI(4,5)P2 from the plasma membrane. However, coexpression with synaptojanin 2, a phosphatase with broader specificity, diminished VLP production. PI-binding pocket mutations caused striking budding defects, as revealed by electron microscopy. One of the mutations also modified Gag-Gag interaction, as suggested by altered bimolecular fluorescence complementation. We conclude that PI-mediated targeting to peripheral and internal membranes is a critical factor in EIAV assembly and release. © 2011 John Wiley & Sons A/S.


News Article
Site: www.sciencenews.org

With the help of a neural prosthesis, a quadriplegic man used his paralyzed right hand to grab a bottle, swipe a credit card and play a guitar video game. Bypassing his damaged spinal cord, the system restored his ability to use his thoughts to command his hand to move. Other neural prosthetic systems have allowed paralyzed people to use their brain activity to move computer cursors, robotic limbs and wheelchairs (SN: 11/16/13, p. 22). But the new approach, described online April 13 in Nature, is the first to use brain activity to control a person’s own limb. “We literally are reconnecting the brain to the body,” study coauthor Chad Bouton of the Feinstein Institute for Medical Research in Manhasset, N.Y., said April 12 in a news briefing. Decoding brain signals and correctly stimulating muscles are “really hard things to do individually,” says biomedical engineer Levi Hargrove of the Rehabilitation Institute of Chicago. Putting those together in a human subject is “very impressive,” he says. “There’s more work to be done, of course, but this is very positive and should excite people.” In 2010, college student Ian Burkhart dived into a shallow wave and struck sand. The accident severed his spinal cord, leaving him paralyzed from the shoulders down. Burkhart volunteered to undergo brain surgery in which doctors implanted a patch of electrodes directly into his brain. These electrodes eavesdropped on the activity of nerve cells that control hand movements. Scientists listened to these cells’ behavior as Burkhart watched a range of hand and finger movements on a screen and attempted to copy the motions. A computer system then learned to recognize the neural signals that accompanied each type of movement, and an algorithm translated those signals into movement commands. A flexible sleeve of electrodes strapped to Burkhart’s forearm delivered those instructions directly by stimulating hand muscles. In 2014, Bouton and colleagues announced that Burkhart could open and close his hand using the system. Since then, Burkhart has been able to command more complex hand movements, such as wiggling his thumb in and out and flexing his wrist. The Nature paper describes how this bypass system now allows him to pick up a cup, pour and even pinch his thumb and forefinger together to pluck a skinny stir stick. “The first time when I was able to open and close my hand, it really kind of gave me that sense of hope again for the future,” Burkhart said in the briefing. The technology isn’t ready for life outside of the lab. In its current form, the system must be calibrated each time Burkhart uses it, and the electrodes in the brain may not perform as well with time. And bulky cables connect the brain electrodes to the computer system and forearm sleeve. Scientists are working on making the technology smaller, wireless and easier to use, study coauthor Nick Annetta of Battelle Memorial Institute in Columbus, Ohio, said in the briefing. Neural engineer José Contreras-Vidal of the University of Houston points out that technology that can translate neural activity into electrical impulses may ultimately restore other types of muscle activity, such as walking. “What we need to do is provide solutions and options,” he says.


WASHINGTON (Reuters) - An Ohio man paralyzed in an accident while diving in waves can now pick up a bottle or play the video game Guitar Hero thanks to a small computer chip in his brain that lets his mind guide his hands and fingers, bypassing his damaged spinal cord. Scientists on Wednesday described accomplishments achieved by 24-year-old quadriplegic Ian Burkhart using an implanted chip that relays signals from his brain through 130 electrodes on his forearm to produce muscle movement in his hands and fingers. Burkhart first demonstrated the "neural bypass" technology in 2014 when he was able simply to open and close his hand. But the scientists, in research published in the journal Nature, said he can now perform multiple useful tasks with more sophisticated hand and finger movements. The technology, which for now can only be used in the laboratory, is being perfected with an eye toward a wireless system without the need for a cable running from the head to relay brain signals. "This study marks the first time that a person living with paralysis has regained movement by using signals recorded from within the brain," said bioelectronic medicine researcher Chad Bouton of the New York-based Feinstein Institute for Medical Research, who worked on the study at the Battelle Memorial Institute in Ohio. Burkhart said the technology lets him function like "a normal member of society." The technology potentially could help people not only after spinal cord injuries but after strokes or traumatic brain injuries, Bouton added. Burkhart, a former lacrosse goalie, suffered a broken neck and spinal cord damage at age 19 diving into a wave at North Carolina's Outer Banks in 2010, causing paralysis of his arms and legs. Such injuries disrupt nervous system signal pathways between the brain and muscles. Surgeons implanted the pea-sized chip into his motor cortex, which controls voluntary muscular activity. The chip, connected to a cable running from his head to a sleeve containing the electrodes wrapped around his forearm, sends brain signals that stimulate muscles controlling the hands and fingers. Burkhart, with six wrist and hand motions, could rotate his hand, make a fist, pinch his fingers together, grasp objects like a bottle, spoon and telephone, swipe a credit card and play the video game simulating guitar strumming. Ohio State University Wexner Medical Center neurosurgeon Ali Rezai called the results a "milestone in the evolution of brain-computer interface technology." "Things are kind of moving along better than I imagined," Burkhart said.

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