Activity Of Specific Populations Research Articles

Mathematical modelling of the influence of ACE I/D polymorphism on blood pressure and antihypertensive therapy

The angiotensin-converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism raises the possibility of personalising ACE inhibitor therapy to optimise its efficiency and reduce side effects in genetically distinct subgroups. However, the extent of its influence among these subgroups is unknown. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of the ACE I/D polymorphism on haemodynamic parameters in humans undergoing antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation and therefore, the lack of association between ACE I/D and blood pressure levels may be due to high ACE activity in specific populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship between ACE I/D and the efficacy of inhibitors of the renin–angiotensin–aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, while different ACE I/D genotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success and its predictive value is limited.

Innovations, Opportunities, and Challenges for Predicting Alteration in Drug-Metabolizing Enzyme and Transporter Activity in Specific Populations.

Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo extrapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of Drug Metabolism and Disposition will summarize the latest progress in in silico, in vitro, and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposition in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps that present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight opportunities for multistakeholder collaboration to advance our collective understanding of this rapidly emerging area. SIGNIFICANCE STATEMENT: This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of drug-metabolizing enzymes and transporters (DMETs) in drug disposition in specific populations. With this commentary for the special issue in Drug Metabolism and Disposition, the authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.

Acute effects of prolactin on hypothalamic prolactin receptor expressing neurones in the mouse.

In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular, widespread expression of prolactin receptor (Prlr) in the brain has highlighted pleiotropic roles for prolactin in regulating neuronal function, including maternal behaviour, reproduction and energy balance. Research into the central actions of prolactin has predominately focused on effects on gene transcription via the canonical JAK2/STAT5; however, it is evident that prolactin can exert rapid actions to stimulate activity in specific populations of neurones. We aimed to investigate how widespread these rapid actions of prolactin are in regions of the brain with large populations of prolactin-sensitive neurones, and whether physiological state alters these responses. Using transgenic mice where the Cre-dependent calcium indicator, GCaMP6f, was conditionally expressed in cells expressing the long form of the Prlr, we monitored changes in levels of intracellular calcium ([Ca2+ ]i ) in ex vivo brain slice preparations as a surrogate marker of cellular activity. Here, we surveyed hypothalamic regions implicated in the diverse physiological functions of prolactin such as the arcuate (ARC) and paraventricular nuclei of the hypothalamus (PVN), as well as the medial preoptic area (MPOA). We observed that, in the ARC of males and in both virgin and lactating females, prolactin can exert rapid actions to stimulate neuronal activity in the majority of Prlr-expressing neurones. In the PVN and MPOA, we found a smaller subset of cells that rapidly respond to prolactin. In these brain regions, the effects we detected ranged from rapid or sustained increases in [Ca2+ ]i to inhibitory effects, indicating a heterogeneous nature of these Prlr-expressing populations. These results enhance our understanding of mechanisms by which prolactin acts on hypothalamic neurones and provide insights into how prolactin might influence neuronal circuits in the mouse brain.

Expanding the Optogenetics Toolkit by Topological Inversion of Rhodopsins

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.

A Biomolecular Network Driven Proteinic Interaction in HCV Clearance.

Hepatitis C virus infection causes chronic liver disease that leads to cancer-related mortality. Presently around 30% of the HCV (infected) affected population get rid of the infection through spontaneous disease clearance. This phenomenon is conducted by a set of reported immune candidate genes. Hence, this study focuses only on these immune-response related genes with aid of network approach, where the idea is to disseminate the network for better understanding of key functional genes and their transcription control activity. Based on the network analysis the IFNG, TNF, IFNB1, STAT1, NFKB1, STAT3, SOCS1, and MYD88 genes are prioritized as hub genes along with their common transcription factors (TFs), IRF9, NFKB1, and STAT1. The dinucleotide frequency of TF binding elements indicated GG-rich motifs in these regulatory elements. On the other hand, gene enrichment report suggests the regulation of response to interferon gamma signaling pathway, which plays central role in the spontaneous HCV clearance. Therefore, our study tends to prioritize the genes, TFs, and their regulatory pathway towards HCV clearance. Even so, the resultant hub genes and their TFs and TF binding elements could be crucial in underscoring the clearance activity in specific populations.

442O - PI3K Kinase Inhibitor GSK2126458 (GSK458): Clinical Activity in Select Patient (PT) Populations Defined by Predictive Markers (STUDY P3K112826)

ABSTRACT Background GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and mTORC2. Cell lines with activation of the PI3K pathway are more likely to be sensitive to GSK458. Methods Pts with advanced solid tumors received GSK458 until disease progression or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID) was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type [WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer, and KRAS-WT metastatic endometrial cancer) were evaluated. Results 170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from 0.1 to 3 mg, the MTD for both QD and BID was 2.5 mg. The median (range) time above the target plasma concentration (20 ng/mL) was longer in BID versus QD dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response relationship between GSK458 plasma concentrations and increases in serum insulin levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none had responses per RECIST. Objective responses were seen in bladder cancer (1/3 PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months, 1PR), but no responses were seen in PIK3CA-mutant breast cancer (1/10: stable for >6 months) or KRAS-WT endometrial cancer (1/12: stable disease for > 6 months). Conclusions Based on its superior pharmacokinetic profile, BID is the recommended schedule for GSK458 monotherapy. Surrogate PD markers (insulin) indicate on target activity. GSK458 showed promising activity in PIK3CA mutant bladder cancer and RCC. Disclosure P. Munster: Phase I Research: GSK J. Specht: Corporate-sponsored research: Pfizer, BMS, Genentech, BiPar Sciences, Boehringer Ingelheim E.C. Dees: Corporate-sponsored research: GSK, Novartis, Genentech/Roche, Millennium A. Tan: Corporate-sponsored research: GSK A. Daud: Membership on an advisory board or board of directors: Oncosec; Corporate-sponsored research: GSK, Pfizer, Merck, Oncosec, Exelixis G. Falchook: Corporate-sponsored research: GSK; GSK Travel reimbursement for ESMO 2010 J. F. Kleha: Stock ownership: GSK; GSK Employee M. Durante: Stock ownership: GSK; GSK Employee D.A. Smith: Stock ownership: GSK; GSK Employee L. Adams: Stock ownership: GSK; GSK Employee J. Greshock: Stock ownership: GSK; GSK Employee S.R. Morris: Stock ownership: GSK; GSK Employee All other authors have declared no conflicts of interest.

Specificity in the functional architecture of primate prefrontal cortex.

Multiple lines of evidence indicate that the performance of complex cognitive processes, such as those involving working memory, depend upon the functional properties of the circuitry of the prefrontal cortex (PFC). In primates, working memory has been proposed to be dependent upon the sustained activity of specific populations of PFC pyramidal cells, with this activity regulated by certain types of GABAergic interneurons. Thus, knowledge of the connectivity between PFC pyramidal cells and interneurons is crucial to the understanding the neural mechanisms that subserve working memory. This paper reviews recent findings that reveal specificity in the spatial organization, synaptic targets and postnatal development of pyramidal cells and interneurons in the primate prefrontal cortex, and considers the relevance of these findings for the neural circuitry that subserves working memory.