Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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Updated: 15 min 48 sec ago

Emerging therapeutics for targeting Akt in cancer.

Fri, 12/30/2016 - 07:33
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Emerging therapeutics for targeting Akt in cancer.

Front Biosci (Landmark Ed). 2016 Jan 01;21:757-68

Authors: Gdowski A, Panchoo M, Treuren TV, Basu A

Abstract
The ultimate goal of cancer therapeutic research is to develop effective, targeted therapeutics that exploit the vulnerabilities of cancer cells. The three isoforms of Akt, also known as protein kinase B (PKB), are important mediators of various pathways that transmit mitogenic signals from the cell's exterior to the effector proteins of the cell's interior. Due to Akt\\\\\\\'s importance in cell functions such as growth, proliferation and cell survival, many cancer cells rely on this pathway to aid in their survival. This dependence can lead to chemoresistance and selection of more adapted populations of cancer cells. Thus, it is important to understand the functional significance of isoform specificity and its relation to chemoresistance. In this review, we have summarized recent studies on Akt isoform specific regulation as well as each isoform's role in chemoresistance, emphasizing their potential as targets for cancer therapy. We have also condensed ongoing clinical studies involving various types of Akt inhibitors while highlighting the type of study, rationale and co-therapies involved in identifying Akt isoforms as promising therapeutic targets.

PMID: 26709804 [PubMed - indexed for MEDLINE]

Tissue loss with subcutaneous immunotherapy--Nicolau syndrome.

Fri, 12/30/2016 - 07:33
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Tissue loss with subcutaneous immunotherapy--Nicolau syndrome.

J Allergy Clin Immunol Pract. 2016 Jan-Feb;4(1):154-5

Authors: Tierce ML, Schultz SM, Lanier BQ

PMID: 26362220 [PubMed - indexed for MEDLINE]

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Wed, 12/28/2016 - 07:42
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Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Invest New Drugs. 2016 Dec 26;:

Authors: Shelake S, Sankpal UT, Paul Bowman W, Wise M, Ray A, Basha R

Abstract
Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth.

PMID: 28025760 [PubMed - as supplied by publisher]

Analogs of microgravity: head-down tilt and water immersion.

Wed, 12/28/2016 - 07:42
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Analogs of microgravity: head-down tilt and water immersion.

J Appl Physiol (1985). 2016 Apr 15;120(8):904-14

Authors: Watenpaugh DE

Abstract
This article briefly reviews the fidelity of ground-based methods used to simulate human existence in weightlessness (spaceflight). These methods include horizontal bed rest (BR), head-down tilt bed rest (HDT), head-out water immersion (WI), and head-out dry immersion (DI; immersion with an impermeable elastic cloth barrier between subject and water). Among these, HDT has become by far the most commonly used method, especially for longer studies. DI is less common but well accepted for long-duration studies. Very few studies exist that attempt to validate a specific simulation mode against actual microgravity. Many fundamental physical, and thus physiological, differences exist between microgravity and our methods to simulate it, and between the different methods. Also, although weightlessness is the salient feature of spaceflight, several ancillary factors of space travel complicate Earth-based simulation. In spite of these discrepancies and complications, the analogs duplicate many responses to 0 G reasonably well. As we learn more about responses to microgravity and spaceflight, investigators will continue to fine-tune simulation methods to optimize accuracy and applicability.

PMID: 26869710 [PubMed - indexed for MEDLINE]

Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging.

Tue, 12/27/2016 - 07:32
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Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging.

Front Pharmacol. 2016;7:466

Authors: Mooberry LK, Sabnis NA, Panchoo M, Nagarajan B, Lacko AG

Abstract
Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins. Additional findings suggest a critical role for SR-BI in cholesterol metabolism, signaling, motility, and proliferation of cancer cells and thus a potential major impact in carcinogenesis and metastasis. Recent findings indicate that the level of SR-BI expression correlate with aggressiveness and poor survival in breast and prostate cancer. Moreover, genomic data show that depending on the type of cancer, high or low SR-BI expression may promote poor survival. This review discusses the importance of SR-BI as a diagnostic as well as prognostic indicator of cancer to help elucidate the contributions of this protein to cancer development, progression, and survival. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed.

PMID: 28018216 [PubMed]

The cross-sectional association between severity of non-cognitive disability and self-reported worsening memory.

Tue, 12/27/2016 - 07:32
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The cross-sectional association between severity of non-cognitive disability and self-reported worsening memory.

Disabil Health J. 2016 Apr;9(2):289-97

Authors: Cannell MB, Bouldin ED, Teigen K, Akhtar WZ, Andresen EM

Abstract
BACKGROUND: Research has demonstrated a clear association between cognitive decline and non-cognitive disability; however, all of these studies focus on disability as a correlate or result of some level of cognitive impairment or dysfunction. The relationship between disability and cognition is likely a complex one, that is currently incompletely described in the literature.
OBJECTIVES: Our objective was to estimate the prevalence of long-term, non-cognitive disability using a population-representative sample of adults aged 18 and older, and then estimate the association between long-term, non-cognitive disability and self-reported worsening memory.
METHODS: Using the 2009 Florida Behavioral Risk Factor Surveillance System (BRFSS), we measured the relationship between non-cognitive disability and worsening memory using multivariable logistic regression analysis weighted to account for the complex sampling design of the BRFSS. We also estimated the adjusted odds of worsening memory by disability severity, classified according to the types of assistance needed.
RESULTS: Approximately 18% (95% confidence interval = (16%, 19%)) of Floridians were living with a long-term, non-cognitive disability in 2009. Among adults with no disability during or prior to the last year, only 5% reported worsening memory. The proportion of Floridians reporting worsening memory increases with increasing severity of disability-related limitations. In a multivariable logistic regression model, odds of worsening memory increased significantly with severity of disability-related limitations.
CONCLUSIONS: These results highlight the association between non-cognitive disability and subsequent increased odds of worsening memory, independent of several other known risk factors, and a dose-response association with disability-related limitations.

PMID: 26493638 [PubMed - indexed for MEDLINE]

Compact NMR relaxometry of human blood and blood components.

Fri, 12/23/2016 - 16:46
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Compact NMR relaxometry of human blood and blood components.

Trends Analyt Chem. 2016 Nov;83(A):53-64

Authors: Cistola DP, Robinson MD

Abstract
Nuclear magnetic resonance relaxometry is a uniquely practical and versatile implementation of NMR technology. Because it does not depend on chemical shift resolution, it can be performed using low-field compact instruments deployed in atypical settings. Early relaxometry studies of human blood were focused on developing a diagnostic test for cancer. Those efforts were misplaced, as the measurements were not specific to cancer. However, important lessons were learned about the factors that drive the water longitudinal (T1) and transverse (T2) relaxation times. One key factor is the overall distribution of proteins and lipoproteins. Plasma water T2 can detect shifts in the blood proteome resulting from inflammation, insulin resistance and dyslipidemia. In whole blood, T2 is sensitive to hemoglobin content and oxygenation, although the latter can be suppressed by manipulating the static and applied magnetic fields. Current applications of compact NMR relaxometry include blood tests for candidiasis, hemostasis, malaria and insulin resistance.

PMID: 28003711 [PubMed]

The Role of Angiotensin Converting Enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia.

Fri, 12/23/2016 - 16:46
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The Role of Angiotensin Converting Enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia.

Am J Physiol Regul Integr Comp Physiol. 2016 Dec 21;:ajpregu.00472.2016

Authors: Faulk K, Shell B, Nedungadi TP, Cunningham JT

Abstract
Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments in order to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was utilized in order to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH in order to affect the downstream PVN region, which may influence SNA and blood pressure.

PMID: 28003214 [PubMed - as supplied by publisher]

Zygomaticomaxillary Morphology and Maxillary Sinus Form and Function: How Spatial Constraints Influence Pneumatization Patterns among Modern Humans.

Thu, 12/22/2016 - 07:38
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Zygomaticomaxillary Morphology and Maxillary Sinus Form and Function: How Spatial Constraints Influence Pneumatization Patterns among Modern Humans.

Anat Rec (Hoboken). 2017 Jan;300(1):209-225

Authors: Maddux SD, Butaric LN

Abstract
Previous research has suggested that the maxillary sinuses may act as "zones of accommodation" for the nasal region, minimizing the impact of climatic-related changes in nasal cavity breadth on surrounding skeletal structures. However, a recent study among modern human crania has identified that, in addition to nasal cavity breadth, sinus morphology also tracks lateral facial form, especially anterior-posterior positioning of the zygomatics. Here, we expand upon this previous study to further investigate these covariation patterns by employing three samples with distinct combinations of nasal and zygomatic morphologies: Northern Asians (n = 28); sub-Saharan Africans (n = 30); and Europeans (n = 29). For each cranium, 30 landmarks were digitized from CT-rendered models and subsequently assigned to either a midfacial or maxillary sinus "block." Two block partial least squares (2B-PLS) analyses indicate that sinus morphology primarily reflects superior-inferior dimensions of the midface, rather than either nasal cavity breadth or zygomatic position. Specifically, individuals with relatively tall midfacial skeletons exhibit more inferiorly and laterally expanded sinuses compared to those with shorter midfaces. Further, separate across-group and within-group 2B-PLS analyses indicate that regional differences between samples primarily build upon a common pattern of midfacial and sinus covariation already present within each regional group. Allometry, while present, only explains a small portion of the midface-sinus covariation pattern. We conclude that previous findings of larger maxillary sinuses among cold-adapted individuals are not predominantly due to possession of relatively narrow nasal cavities, but to greater maxillary and zygomatic heights. Implications for sinus function and midfacial ontogeny are discussed. Anat Rec, 300:209-225, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 28000407 [PubMed - in process]

Impaired sodium-evoked paraventricular nucleus neuronal activation and blood pressure regulation in conscious Sprague-Dawley rats lacking central Gαi2 proteins.

Thu, 12/22/2016 - 07:38
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Impaired sodium-evoked paraventricular nucleus neuronal activation and blood pressure regulation in conscious Sprague-Dawley rats lacking central Gαi2 proteins.

Acta Physiol (Oxf). 2016 Mar;216(3):314-29

Authors: Carmichael CY, Carmichael AC, Kuwabara JT, Cunningham JT, Wainford RD

Abstract
AIM: We determined the role of brain Gαi2 proteins in mediating the neural and humoral responses of conscious male Sprague-Dawley rats to acute peripheral sodium challenge.
METHODS: Rats pre-treated (24-h) intracerebroventricularly with a targeted oligodeoxynucleotide (ODN) (25 μg per 5 μL) to downregulate brain Gαi2 protein expression or a scrambled (SCR) control ODN were challenged with an acute sodium load (intravenous bolus 3 m NaCl; 0.14 mL per 100 g), and cardiovascular parameters were monitored for 120 min. In additional groups, hypothalamic paraventricular nucleus (PVN) Fos immunoreactivity was examined at baseline, 40, and 100 min post-sodium challenge.
RESULTS: In response to intravenous hypertonic saline (HS), no difference was observed in peak change in mean arterial pressure between groups. In SCR ODN pre-treated rats, arterial pressure returned to baseline by 100 min, while it remained elevated in Gαi2 ODN pre-treated rats (P < 0.05). No difference between groups was observed in sodium-evoked increases in Fos-positive magnocellular neurons or vasopressin release. V1a receptor antagonism failed to block the prolonged elevation of arterial pressure in Gαi2 ODN pre-treated rats. A significantly greater number of Fos-positive ventrolateral parvocellular, lateral parvocellular, and medial parvocellular neurons were observed in SCR vs. Gαi2 ODN pre-treated rats at 40 and 100 min post-HS challenge (P < 0.05). In SCR, but not Gαi2 ODN pre-treated rats, HS evoked suppression of plasma norepinephrine (P < 0.05).
CONCLUSION: This highlights Gαi2 protein signal transduction as a novel central mechanism acting to differentially influence PVN parvocellular neuronal activation, sympathetic outflow, and arterial pressure in response to acute HS, independently of actions on magnocellular neurons and vasopressin release.

PMID: 26412230 [PubMed - indexed for MEDLINE]

Selection of highly informative SNP markers for population affiliation of major US populations.

Wed, 12/21/2016 - 07:52
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Selection of highly informative SNP markers for population affiliation of major US populations.

Int J Legal Med. 2016 Mar;130(2):341-52

Authors: Zeng X, Chakraborty R, King JL, LaRue B, Moura-Neto RS, Budowle B

Abstract
Ancestry informative markers (AIMs) can be used to detect and adjust for population stratification and predict the ancestry of the source of an evidence sample. Autosomal single nucleotide polymorphisms (SNPs) are the best candidates for AIMs. It is essential to identify the most informative AIM SNPs across relevant populations. Several informativeness measures for ancestry estimation have been used for AIMs selection: absolute allele frequency differences (δ), F statistics (F ST), and informativeness for assignment measure (In). However, their efficacy has not been compared objectively, particularly for determining affiliations of major US populations. In this study, these three measures were directly compared for AIMs selection among four major US populations, i.e., African American, Caucasian, East Asian, and Hispanic American. The results showed that the F ST panel performed slightly better for population resolution based on principal component analysis (PCA) clustering than did the δ panel and both performed better than the In panel. Therefore, the 23 AIMs selected by the F ST measure were used to characterize the four major American populations. Genotype data of nine sample populations were used to evaluate the efficiency of the 23-AIMs panel. The results indicated that individuals could be correctly assigned to the major population categories. Our AIMs panel could contribute to the candidate pool of AIMs for potential forensic identification purposes.

PMID: 26645290 [PubMed - indexed for MEDLINE]

Two blinking mechanisms in highly confined AgInS2 and AgInS2/ZnS quantum dots evaluated by single particle spectroscopy.

Tue, 12/20/2016 - 07:33
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Two blinking mechanisms in highly confined AgInS2 and AgInS2/ZnS quantum dots evaluated by single particle spectroscopy.

Nanoscale. 2016 Feb 21;8(7):4151-9

Authors: Cichy B, Rich R, Olejniczak A, Gryczynski Z, Strek W

Abstract
Ternary AgInS2 quantum dots (QDs) have been found as promising cadmium-free, red-shifted, and tunable luminescent bio-probes with efficient Stokes and anti-Stokes excitations and luminescence lifetimes (ca. 100 ns) convenient for time resolved techniques like fluorescence life-time imaging. Although the spectral properties of the AgInS2 QDs are encouraging, the complex recombination kinetics in the QDs being still far from understood, limits their full utility. In this paper we report on a model describing the recombination pathways responsible for large deviations from the first-order decay law observed commonly in the ternary chalcogenides. The presented results were evaluated by means of individual AgInS2 QD spectroscopy aided by first principles calculations including the electronic structure and structural reconstruction of the QDs. Special attention was devoted to study the impact of the surface charge state on the excited state relaxation and effect of its passivation by Zn(2+) ion alloying. Two different blinking mechanisms related to defect-assisted charge imbalance in the QD responsible for fast non-radiative relaxation of the excited states as well as surface recharging of the QD were found as the major causes of deviations from the first-order decay law. Careful optimization of the AgInS2 QDs would help to fabricate new red-shifted and tunable fluorescent bio-probes characterized by low-toxicity, high quantum yield, long luminescence lifetime, and time stability, leading to many novel in vitro and in vivo applications based on fluorescence lifetime imaging (FLIM) and time-gated detection.

PMID: 26866468 [PubMed - indexed for MEDLINE]

Effects of Acute Vaporized Nicotine in Non-Tobacco Users at Rest and during Exercise.

Mon, 12/19/2016 - 13:33
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Effects of Acute Vaporized Nicotine in Non-Tobacco Users at Rest and during Exercise.

Int J Exerc Sci. 2016;9(5):607-615

Authors: Fogt DL, Levi MA, Rickards CA, Stelly SP, Cooke WH

Abstract
Smokers, and even non-smokers, may utilize vaporized nicotine delivered by electronic cigarette (EC) due to the perception that EC are "healthier" than traditional tobacco cigarettes. The effects of vaporized nicotine delivered by EC on resting blood pressure (BP) and resting metabolic rate (RMR), or BP and aerobic power during exercise have not been studied. This investigation tested the effects of acute vaporized nicotine inhalation by EC on resting BP and RMR and cycle exercise BP, metabolic responses, and aerobic power in young, normotensive non-smokers. Using a double-blind design, 20 subjects (10 female) participated in two randomized trials: placebo (0 mg nicotine) or nicotine (18 mg nicotine). Participants inhaled from EC once every 30 s for 10 min (20 inhalations total). RMR was assessed 40 min later by indirect calorimetry followed by an incremental cycle test. RMR was not different between trials (p=0.79). Compared to the placebo, resting diastolic pressure (DBP) was 3 mmHg higher with nicotine (p=0.04). VO2peak was not different between the nicotine trial (2.3±0.8 L•min(-1)) and placebo (2.3±0.7 L•min(-1)) trials (p=0.77), and Wmax was also similar between nicotine (201.0±53.8 W) and the placebo (204.8±57.8 W) (p=0.29). During the cycle exercise test, average DBP was higher following nicotine use compared with placebo trial (p=0.05), and exercise DBPpeak after nicotine (79.4±7.6) was significantly higher than placebo (74.9±8.3 mmHg) (p=0.02). Resting systolic blood pressure (SBP) was 3.7 mmHg lower for nicotine trial (p=0.04) but no SBP treatment effect was observed during exercise (p=0.14). Our results show that acute vaporized nicotine inhalation via EC increases resting and exercise DBP but does not affect RMR or cycle aerobic power in young, normotensive non-smokers.

PMID: 27990223 [PubMed - in process]

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

Sat, 12/17/2016 - 07:32

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

J Clin Pharm Ther. 2016 Dec 16;:

Authors: Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, Penzak SR

Abstract
WHAT IS KNOWN AND OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD).
METHODS: This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy.
RESULTS AND DISCUSSION: A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6·5 years (range: 2·8-10·7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10·0 to 49·2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were ≥500, ≥700 and ≥1250 ng/mL in 95%, 60% and 25% of patients, respectively.
WHAT IS NEW AND CONCLUSIONS: Patients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure.

PMID: 27982447 [PubMed - as supplied by publisher]

[Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma].

Sat, 12/17/2016 - 07:32
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[Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma].

Zhonghua Yan Ke Za Zhi. 2016 Jun 11;52(6):471-5

Authors: Mao WM, Liu Y, Wordinger YH, Clark AF, Pang IH

Abstract
Glaucoma is a major cause of blindness in China and the world. Currently, all therapeutic means in treating open-angle glaucoma are limited to control the progression of optic neuropathy by lowering intraocular pressure (IOP). Clinically available medicines lower IOP by either enhancing the uveoscleral pathway or inhibiting aqueous humor production. Since the primary cause of IOP elevation in POAG is elevated outflow resistance in the trabecular outflow pathway, current medicines are not able to correct the underlying pathogenesis and pathophysiology of the disease. In this review article, we discuss a series of new therapeutic targets and therapeutic approaches that are designed to directly modify the pathological changes related to the reduction in trabecular outflow in glaucoma patients. Some of these targets and approaches may produce a significant breakthrough in the treatment of this devastating disease. (Chin J Ophthalmol, 2016, 52: 471-475).

PMID: 27373575 [PubMed - indexed for MEDLINE]

Exercise, but not antioxidants, reversed ApoE4-associated motor impairments in adult GFAP-ApoE mice.

Sat, 12/17/2016 - 07:32
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Exercise, but not antioxidants, reversed ApoE4-associated motor impairments in adult GFAP-ApoE mice.

Behav Brain Res. 2016 May 15;305:37-45

Authors: Chaudhari K, Wong JM, Vann PH, Sumien N

Abstract
Motor dysfunction has been found to be predictive of cognitive dysfunction in Alzheimer's disease and to occur earlier than cognitive impairments. While apolipoprotein (Apo) E4 has been associated with cognitive impairments, it remains unclear whether it also increases risk for motor dysfunction. Exercise and antioxidants are often recommended to reduce cognitive declines, however it is unclear whether they can successfully improve motor impairments. This study was designed to determine the extent of the impact of apolipoprotein genotype on motor function, and whether interventions such as exercise and antioxidant intake can improve motor function. This study is the first to identify the nature of the interaction between antioxidant intake and exercise using a mouse model expressing either the human ApoE3 or ApoE4 isoforms under glial fibrillary acid protein promoter (GFAP-ApoE3 and GFAP-ApoE4 mice). The mice were fed either a control diet or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65mg/g ascorbic acid). Each genotype/diet group was further divided into a sedentary group or a group that followed a 6 days a week exercise regimen. After 8 weeks on their respective treatment, the mice were administered a battery of motor tests to measure reflexes, strength, coordination and balance. GFAP-ApoE4 mice exhibited impaired motor learning and diminished strength compared to the GFAP-ApoE3 mice. Exercise alone was more efficient at improving motor function and reversing ApoE4-associated impairments than antioxidants alone, even though improvements were rather subtle. Contrarily to expected outcomes, combination of antioxidants and exercise did not yield further improvements of motor function. Interestingly, antioxidants antagonized the beneficial effects of exercise on strength. These data suggest that environmental and genetic factors influence the outcome of interventions on motor function and should be investigated more thoroughly and taken into consideration when implementing changes in lifestyles.

PMID: 26892275 [PubMed - indexed for MEDLINE]

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Fri, 12/16/2016 - 07:32
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Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Alzheimers Dement. 2016 Mar;12(3):292-323

Authors: Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR, Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA

Abstract
During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

PMID: 27012484 [PubMed - indexed for MEDLINE]

TCT-204 Optimal duration of dual antiplatelet therapy (DAPT) after second generation drug-eluting stent (DES) implantation in elderly patients: the SECURITY-ELDERLY substudy.

Thu, 12/15/2016 - 07:32
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TCT-204 Optimal duration of dual antiplatelet therapy (DAPT) after second generation drug-eluting stent (DES) implantation in elderly patients: the SECURITY-ELDERLY substudy.

J Am Coll Cardiol. 2016 Nov 01;68(18S):B83

Authors: Ferri LA, Chieffo A, Giustino G, Frasheri A, Garbo R, Masotti-Centol M, Salvatella N, Oteo Dominguez JF, Steffanon L, Tarantini G, Presbitero P, Menozzi A, Pucci E, Mauri J, Sardella G, Colombo A

PMID: 27970378 [PubMed - in process]

Soluble Lectin-like Oxidized Low Density Lipoprotein Receptor-1 as A Novel Biomarker for Large-artery Atherosclerotic Stroke.

Thu, 12/15/2016 - 07:32
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Soluble Lectin-like Oxidized Low Density Lipoprotein Receptor-1 as A Novel Biomarker for Large-artery Atherosclerotic Stroke.

Int J Neurosci. 2016 Dec 14;:1-19

Authors: Huang W, Li Q, Chen X, Lin Y, Xue J, Cai Z, Zhang W, Wang H, Jin K, Shao B

Abstract
Background-Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown associated with the progression of atherosclerosis in endothelial cells. We sought to assess whether the baseline serum sLOX-1 levels are correlated with the presence and short term functional outcome of large-artery atherosclerotic (LAA) stroke. Methods-The study recruited 241 subjects, including 148 consecutive patients with acute ischemic stroke with the subtype of LAA and 93 non-stroke controls. Clinical and laboratory data, including serum concentration of sLOX-1 were collected within 24h of admission, and the severity of LAA stroke patients was evaluated by National Institutes of Health Stroke Scale (NIHSS) score. And functional outcome was assessed by modified Rankin Scale (mRS) 3 months after stroke. The association between sLOX-1 level and the functional outcome at 3 months was analyzed by multiple logistic regression models. Results-Serum levels of sLOX-1 in the LAA stroke patients were significantly higher as compared to normal controls (2.48 ± 0.93 ng/ml vs. 2.22 ± 0.79 ng/ml in the controls, t = 2.301, p = 0.022). The levels of serum sLOX-1 in patients with good outcome were significantly lower than those with poor outcome (2.39 ± 0.94ng/ml vs. 2.77 ± 0.84 ng/ml, p = 0.032). After adjusting for potential confounders, sLOX-1 was still an independent predictor for the function outcome with an adjusted OR of 3.39 (95% CI, 1.61-7.11, p = 0.001). Conclusions-The serum sLOX-1 level was higher in patients with LAA stroke, and it was an independent predictor of functional outcome in patients with LAA ischemic stroke.

PMID: 27967338 [PubMed - as supplied by publisher]

Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.

Thu, 12/15/2016 - 07:32
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Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.

Int J Nanomedicine. 2016;11:1451-60

Authors: Guo S, Pham K, Li D, Penzak SR, Dong X

Abstract
PURPOSE: The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability.
MATERIALS AND METHODS: In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules.
RESULTS: RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution.
CONCLUSION: We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development.

PMID: 27103803 [PubMed - indexed for MEDLINE]

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