Pushpa Tandon

Age-dependent changes in receptor-stimulated phosphoinositide turnover in the rat hippocampus.

To study the changes in the hippocampal cholinergic system of chronologically old and behaviorally impaired animals, old (21 months of age) and young (3 months of age) male, Fischer-344 rats were used. The aged animals were tested on a reference memory task (Morris water maze) and found to be functionally impaired as compared to the young controls. Carbachol-stimulated phosphoinositide metabolism was measured in hippocampal slices from young and old rats. Slices were prelabeled with 3H-inositol for 120 min and subjected to muscarinic stimulation in the presence of lithium. Following extraction of the slices with acidified solvent mixture, the inositolphosphates present in the aqueous fraction were isolated by ion exchange chromatography. Receptor-stimulated release of inositolphosphates (IPs) was found to be increased in the hippocampus of older animals. This age-related enhancement of IP release was in contrast to the decrease in choline acetyltransferase (CHAT) activity in the hippocampus. We postulate that alterations in the G-protein coupling with the muscarinic receptor leads to an increase in the phosphoinositide turnover in part as a compensatory mechanism for neuronal cell death and reduced transmitter levels.

Fetal hippocampal cell suspensions ameliorate behavioral effects of intradentate colchicine in the rat

Colchicine, a neurotoxin that preferentially destroys dentate gyrus granule cells and mossy fibers, was injected into the hippocampus of adult rats. Three weeks later, the rats were tested for colchicine-induced hypermotility after which they received fetal hippocampal explants. Locomotor activity was retested three weeks later, after which the rats were trained over a period of four weeks on a food-reinforced, spatial, working memory task in an 8-arm radial maze. Fetal hippocampal explants were found to attenuate significantly the colchicine-induced hypermotility and spatial learning deficits. Histological observations showed the presence of surviving hippocampal explants in both the lesioned and the control rat brains, suggesting that the presence of viable implants facilitates the recovery of behavioral function in rats with spatial memory deficits.

Characterization of Receptor-Coupled Phosphoinositide Hydrolysis in the Rat Hippocampus After Intradentate Colchicine

Abstract: Lesions produced by intradentate hippocampal administration of colchicine have been reported to produce several time‐dependent behavioral and neurochemical changes, including a possible change in the signal transduction process for the cholinergic muscarinic receptor. To characterize further the effects of colchicine on receptor‐coupled hydrolysis of phosphoinositides, colchicine was injected ste‐reotaxically into the dentate gyrus of rats at a dose of 2.5 μg/ site. The animals were killed 1, 3, or 12 weeks after injection and the hippocampi removed and sliced. [3H]Inositol was incorporated into slices, and various receptor agonists known to stimulate inositol phosphate (IP) metabolism were studied. Colchicine administration altered agonist‐stimulated turnover in the hippocampus in a time‐dependent manner. This hy‐perstimulation was receptor‐mediated, because it was blocked by pirenzepine. The hyperstimulation of turnover was observed also with norepinephrine and serotonin. Colchicine had no effect on IP turnover in vitro. The effect of the colchicine lesion was observed only in the hippocampus, because no change in cholinergic muscarinic receptor‐stimulated phosphatidylinositol turnover was observed in the cortex. These studies indicate that intradentate administration of colchicine produces a compensatory change in the signal transduction process in the hippocampus detectable 12 weeks after the lesion.

Colchicine-induced alterations in receptor-stimulated phosphoinositide hydrolysis in the rat hippocampus

Intradentate administration of colchicine has been reported to affect the cholinergic muscarinic system in the hippocampus, causing a reduction in quinclidinylbenzilate binding sites and an increase in choline acetyltransferase activity. Since the cholinergic muscarinic system is coupled to the formation of inositolphosphates in the brain, the effect of intradentate administration of colchicine on the agonist-induced turnover of inositollipid was studied in rats. The animals were sacrificed 12 weeks after injection, and the hippocampi removed and sliced. [3H]Inositol was incorporated into slices in the presence of lithium, and carbachol, a cholinergic muscarinic receptor agonist, was used to study the stimulated turnover of inositollipids. Hippocampal slices taken from colchicine-treated rats showed an increased carbachol-stimulated accumulation of inositolmonophosphate. Thus, intradentate colchicine appears to alter the signal transduction process for the muscarinic cholinergic receptor in the hippocampus, a change that may be associated with compensatory processes following damage to the hippocampus.

The National Institutes of Health Affordable Cancer Technologies Program: Improving Access to Resource-Appropriate Technologies for Cancer Detection, Diagnosis, Monitoring, and Treatment in Low- and Middle-Income Countries

Point-of-care (POC) technologies have proved valuable in cancer detection, diagnosis, monitoring, and treatment in the developed world, and have shown promise in low-and-middle-income countries (LMIC) as well. Despite this promise, the unique design constraints presented in low-resource settings, coupled with the variety of country-specific regulatory and institutional dynamics, have made it difficult for investigators to translate successful POC cancer interventions to the LMIC markets. In response to this need, the National Cancer Institute has partnered with the National Institute of Biomedical Imaging and Bioengineering to create the National Institutes of Health Affordable Cancer Technologies (ACTs) program. This program seeks to simplify the pathway to market by funding multidisciplinary investigative teams to adapt and validate the existing technologies for cancer detection, diagnosis, and treatment in LMIC settings. The various projects under ACTs range from microfluidic cancer diagnostic tools to novel treatment devices, each geared for successful clinical adaptation to LMIC settings. Via progression through this program, each POC innovation will be uniquely leveraged for successful clinical translation to LMICs in a way not before seen in this arena.Point-of-care (POC) technologies have proved valuable in cancer detection, diagnosis, monitoring, and treatment in the developed world, and have shown promise in low-and-middle-income countries (LMIC) as well. Despite this promise, the unique design constraints presented in low-resource settings, coupled with the variety of country-specific regulatory and institutional dynamics, have made it difficult for investigators to translate successful POC cancer interventions to the LMIC markets. In response to this need, the National Cancer Institute has partnered with the National Institute of Biomedical Imaging and Bioengineering to create the National Institutes of Health Affordable Cancer Technologies (ACTs) program. This program seeks to simplify the pathway to market by funding multidisciplinary investigative teams to adapt and validate the existing technologies for cancer detection, diagnosis, and treatment in LMIC settings. The various projects under ACTs range from microfluidic cancer diagnostic tools to novel treatment devices, each geared for successful clinical adaptation to LMIC settings. Via progression through this program, each POC innovation will be uniquely leveraged for successful clinical translation to LMICs in a way not before seen in this arena.

Next-generation imaging development for nanoparticle biodistribution measurements

As nanotechnologies move closer to use in humans, quantitative imaging methods will play a vital role in answering questions of biodistribution. Accurate knowledge of the location and quantity of in vivo nanoconstructs and carriers is a challenging task, and new methods of quantitative imaging at appropriate resolutions are being developed and tested. Sustaining simultaneous advancement in both imaging development and nanotechnology research requires multidisciplinary research teams conducting experiments with interconnected goals. On an even greater scale, networks of multidisciplinary teams focused on similar issues of imaging and probe development offer opportunities for leveraging resources, as well as providing a forum for sharing ideas and creating consensus on solutions to common challenges. The Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms from the National Cancer Institute is just such a network. Four multidisciplinary centers are accepting the challenges of developing and optimizing multimodal imaging hardware and software along with imaging probe development. These efforts are similar to the efforts that will be required for future studies of in vivo nanoparticle biodistribution. In addition to technology development and optimization, the network is organized to confront the challenges of validation of the imaging hardware and associated imaging agents, similar to the methods needed for validating nanomedicine.

The Role of Affordable, Point-of-Care Technologies for Cancer Care in Low- and Middle-Income Countries: A Review and Commentary

As the burden of non-communicable diseases such as cancer continues to rise in low- and middle-income countries (LMICs), it is essential to identify and invest in promising solutions for cancer control and treatment. Point-of-care technologies (POCTs) have played critical roles in curbing infectious disease epidemics in both high- and low-income settings, and their successes can serve as a model for transforming cancer care in LMICs, where access to traditional clinical resources is often limited. The versatility, cost-effectiveness, and simplicity of POCTs warrant attention for their potential to revolutionize cancer detection, diagnosis, and treatment. This paper reviews the landscape of affordable POCTs for cancer care in LMICs with a focus on imaging tools, in vitro diagnostics, and treatment technologies and aspires to encourage innovation and further investment in this space.

Long-term changes in phosphoinositide hydrolysis following colchicine lesions of the nucleus basalis magnocellularis.

The effect of bilateral colchicine lesions of the nucleus basalis magnocellularis (NBM) on agonist-stimulated phosphoinositide (PI) hydrolysis was examined in cortical slices 1, 3, or 14 months after surgery. Colchicine lesions resulted in a loss of acetylcholinesterase staining in the cortex which recovered to control levels by 14 months. Choline acetyltransferase activity in the cortex was decreased by 43% one month after lesioning, but returned to control levels by 3 months. In vitro stimulation with carbachol produced a concentration-dependent increase in PI hydrolysis, which was enhanced 3 and 14 months after NBM lesions. Norepinephrine and quisqualate-stimulated PI hydrolysis was also enhanced 14 months after NBM lesions. These results suggest a slow up-regulation of postsynaptic receptor function following presynaptic loss of transmitter.

The Program for Cancer Detection, Diagnosis, and Treatment Technologies for Global Health: A Pathway for the Translation of Affordable, Minimally-Invasive Point-of-Care (POC) Technologies to Less-Resourced Settings

Abstract 9Cancer kills more people worldwide than HIV/AIDS, tuberculosis, and malaria combined, and low- and middle-income countries (LMICs) bear the majority of this burden. While success in detection, diagnosis, and treatment has been reported in LMICs through the use of low-cost, point-of-care (POC) technologies, this area has been largely overlooked by the medical device industry and venture capital communities, as low-cost solutions offer less financial incentive for investment. The program presented here aims to simplify the pathway to market by funding investigation teams to adapt and validate existing technologies in low-resource settings. This program specifically supports the translation of these technologies, prioritizing patient outcomes in a manner not typically seen.This program, currently in its second year, will soon support 15 technologies for cancer detection, diagnosis, and treatment (e.g., in vitro assays, imaging devices, ablation devices). It is anticipated that by year seven of the ...

Abstract 1428: The program for cancer detection, diagnosis, and treatment technologies for global health: Translating affordable, minimally invasive point-of-care technologies to less-resourced settings

Cancer kills more people worldwide than HIV/AIDS, tuberculosis and malaria combined, and low-and-middle income countries (LMICs) bear the majority of this burden. Success in detection, diagnosis and treatment has been reported in LMICs through the use of low-cost point-of-care (POC) technologies, and the program presented offers a unique pathway to this POC market by funding multidisciplinary investigative teams to adapt and clinically validate existing technologies for cancer detection, diagnosis and treatment in low-resource settings. Each project consists of an adaptation phase (2 years: