Recent Research Articles from UNTHSC

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

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Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution.

Wed, 11/29/2017 - 07:38
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Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution.

J Nutr Biochem. 2016 May;31:77-87

Authors: Basha R, Connelly SF, Sankpal UT, Nagaraju GP, Patel H, Vishwanatha JK, Shelake S, Tabor-Simecka L, Shoji M, Simecka JW, El-Rayes B

Abstract
Combination of dietary/herbal spice curcumin (Cur) and COX inhibitors has been tested for improving therapeutic efficacy in pancreatic cancer (PC). The objective of this study was to identify agent with low toxicity and COX-independent mechanism to induce PC cell growth inhibition when used along with Cur. Anticancer NSAID, tolfenamic acid (TA) and Cur combination were evaluated using PC cell lines. L3.6pl and MIA PaCa-2 cells were treated with Cur (5-25μM) or TA (25-100μM) or combination of Cur (7.5μM) and TA (50μM). Cell viability was measured at 24-72h posttreatment using CellTiter-Glo kit. While both agents showed a steady/consistent effect, Cur+TA caused higher growth inhibition. Antiproliferative effect was compared with COX inhibitors, Ibuprofen and Celebrex. Cardiotoxicity was assessed using cordiomyocytes (H9C2). The expression of Sp proteins, survivin and apoptotic markers (western blot), caspase 3/7 (caspase-Glo kit), Annexin-V staining (flow cytometry), reactive oxygen species (ROS) and cell cycle phase distribution (flow cytometry) was measured. Cells were treated with TNF-α, and NF-kB translocation from cytoplasm to nucleus was evaluated (immunofluorescence). When compared to individual agents, combination of Cur+TA caused significant increase in apoptotic markers, ROS levels and inhibited NF-kB translocation to nucleus. TA caused cell cycle arrest in G0/G1, and the combination treatment showed mostly DNA synthesis phase arrest. These results suggest that combination of Cur+TA is less toxic and effectively enhance the therapeutic efficacy in PC cells via COX-independent mechanisms.

PMID: 27133426 [PubMed - indexed for MEDLINE]

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Wed, 11/29/2017 - 07:38
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Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Behav Pharmacol. 2016 Sep;27(6):497-505

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

PMID: 27028902 [PubMed - indexed for MEDLINE]

Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends.

Wed, 11/29/2017 - 07:38
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Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends.

Curr Pharm Des. 2016;22(14):1986-97

Authors: Uteshev VV

Abstract
Expressing functional nicotinic acetylcholine receptors (nAChRs) may be beneficial to central neurons and neuronal networks because activation of nAChRs enhances neuronal resistance to injury, improves attention, cognitive performance, and produces robust anti-inflammatory and analgesic effects in mammals. Although exogenous orthosteric nAChR ligands present valuable tools in treatment of age- and trauma-related neurological deficits, therapeutic approaches that could amplify the brain's innate ability to maintain cholinergic homeostasis and resist injury may serve as intriguing and promising alternatives and have not been fully explored. One of these novel approaches utilizes positive allosteric modulators (PAMs) of nAChRs. Because of the ubiquitous expression of nAChRs in neuronal, glial and immune tissues, highly selective PAMs could amplify multiple endogenous neuroprotective, pro-cognitive, anti-inflammatory and anti-nociceptive cholinergic pathways to offset cholinergic hypofunction and generate therapeutic efficacy by targeting only a single player: i.e., nAChRs activated by endogenous cholinergic tone. In this article, I review the concept of allosteric modulation and current trends in therapeutic applications of nicotinic PAMs.

PMID: 26831463 [PubMed - indexed for MEDLINE]

The Cholinergic Potential, the Vagus Nerve and Challenges in Treatment of Traumatic Brain Injury.

Wed, 11/29/2017 - 07:38
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The Cholinergic Potential, the Vagus Nerve and Challenges in Treatment of Traumatic Brain Injury.

Curr Pharm Des. 2016;22(14):2083-92

Authors: Uteshev VV, Tenovuo O, Gaidhani N

Abstract
Existing treatments of traumatic brain injury (TBI) have failed to reverse tremendous losses in productivity, independence and overall quality of life among TBI victims and therefore, cannot be viewed as sufficient. Although there is no shortage of promising basic concepts that may translate to efficacious therapies after TBI, the accumulated knowledge has yet to deliver treatments that adequately meet clinical and social demands. In this article, we discuss novel concepts, recent advances and accompanying challenges in developing cholinergic and related therapies after TBI.

PMID: 26818869 [PubMed - indexed for MEDLINE]

The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation.

Wed, 11/29/2017 - 07:38
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The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation.

Redox Biol. 2016 Aug;8:98-109

Authors: Liu X, Ward K, Xavier C, Jann J, Clark AF, Pang IH, Wu H

Abstract
Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is an important factor in the pathogenesis of age-related macular degeneration (AMD). Previous studies have shown that RTA 408, a synthetic triterpenoid compound, potently activates Nrf2. This study aimed to investigate the protective effects of RTA 408 in cultured RPE cells during oxidative stress and to determine the effects of RTA 408 on Nrf2 and its downstream target genes. Primary human RPE cells were pretreated with RTA 408 and then incubated in 200μM H2O2 for 6h. Cell viability was measured with the WST-8 assay. Apoptosis was quantitatively measured by annexin V/propidium iodide (PI) double staining and Hoechst 33342 fluorescent staining. Reduced (GSH) and oxidized glutathione (GSSG) were measured using colorimetric assays. Nrf2 activation and its downstream effects on phase II enzymes were examined by Western blot. Treatment of RPE cells with nanomolar ranges (10 and 100nM) of RTA 408 markedly attenuated H2O2-induced viability loss and apoptosis. RTA 408 pretreatment significantly protected cells from oxidative stress-induced GSH loss, GSSG formation and decreased ROS production. RTA 408 activated Nrf2 and increased the expression of its downstream genes, such as HO-1, NQO1, SOD2, catalase, Grx1, and Trx1. Consequently, the enzyme activities of NQO1, Grx1, and Trx1 were fully protected by RTA 408 pretreatment under oxidative stress. Moreover, knockdown of Nrf2 by siRNA significantly reduced the cytoprotective effects of RTA 408. In conclusion, our data suggest that RTA 408 protect primary human RPE cells from oxidative stress-induced damage by activating Nrf2 and its downstream genes.

PMID: 26773873 [PubMed - indexed for MEDLINE]

Aging-related limit of exercise efficacy on motor decline.

Tue, 11/28/2017 - 07:33

Aging-related limit of exercise efficacy on motor decline.

PLoS One. 2017;12(11):e0188538

Authors: Arnold JC, Cantu MA, Kasanga EA, Nejtek VA, Papa EV, Bugnariu N, Salvatore MF

Abstract
Identifying lifestyle strategies and allied neurobiological mechanisms that reduce aging-related motor impairment is imperative, given the accelerating number of retirees and increased life expectancy. A physically active lifestyle prior to old age can reduce risk of debilitating motor decline. However, if exercise is initiated after motor decline has begun in the lifespan, it is unknown if aging itself may impose a limit on exercise efficacy to decelerate further aging-related motor decline. In Brown-Norway/Fischer 344 F1 hybrid (BNF) rats, locomotor activity begins to decrease in middle age (12-18 months). One mechanism of aging-related motor decline may be decreased expression of GDNF family receptor, GFRα-1, which is decreased in substantia nigra (SN) between 12 and 30 months old. Moderate exercise, beginning at 18 months old, increases nigral GFRα-1 and tyrosine hydroxylase (TH) expression within 2 months. In aged rats, replenishing aging-related loss of GFRα-1 in SN increases TH in SN alone and locomotor activity. A moderate exercise regimen was initiated in sedentary male BNF rats in a longitudinal study to evaluate if exercise could attenuate aging-related motor decline when initiated at two different ages in the latter half of the lifespan (18 or 24 months old). Motor decline was reversed in the 18-, but not 24-month-old, cohort. However, exercise efficacy in the 18-month-old group was reduced as the rats reached 27 months old. GFRα-1 expression was not increased in either cohort. These studies suggest exercise can decelerate motor decline when begun in the latter half of the lifespan, but its efficacy may be limited by age of initiation. Decreased plasticity of GFRα-1 expression following exercise may limit its efficacy to reverse motor decline.

PMID: 29176896 [PubMed - in process]

Different Cutpoints for Transient Elastography Lead To Different Associations with Cirrhosis.

Tue, 11/28/2017 - 07:33

Different Cutpoints for Transient Elastography Lead To Different Associations with Cirrhosis.

Clin Gastroenterol Hepatol. 2017 Nov 22;:

Authors: Ojha RP, MacDonald BR, Chu TC, Greenland S

Abstract
Our results illustrate the sensitivity of odds ratios to the transient elastography cutpoint used to define cirrhosis. Given problems with cutpoints, we recommend regression analysis with a continuous or ordinal-outcome model to obtain a summary across the variation.

PMID: 29174788 [PubMed - as supplied by publisher]

Strengthening forensic DNA decision making through a better understanding of the influence of cognitive bias.

Tue, 11/28/2017 - 07:33

Strengthening forensic DNA decision making through a better understanding of the influence of cognitive bias.

Sci Justice. 2017 Nov;57(6):415-420

Authors: Jeanguenat AM, Budowle B, Dror IE

Abstract
Cognitive bias may influence process flows and decision making steps in forensic DNA analyses and interpretation. Currently, seven sources of bias have been identified that may affect forensic decision making with roots in human nature; environment, culture, and experience; and case specific information. Most of the literature and research on cognitive bias in forensic science has focused on patterned evidence; however, forensic DNA testing is not immune to bias, especially when subjective interpretation is involved. DNA testing can be strengthened by recognizing the existence of bias, evaluating where it influences decision making, and, when applicable, implementing practices to reduce or control its effects. Elements that may improve forensic decision making regarding bias include cognitively informed education and training, quality assurance procedures, review processes, analysis and interpretation, and context management of irrelevant information. Although bias exists, reliable results often can be (and have been) produced. However, at times bias can (and has) impacted the interpretation of DNA results negatively. Therefore, being aware of the dangers of bias and implementing measures to control its potential impact should be considered. Measures and procedures that handicap the workings of the crime laboratory or add little value to improving the operation are not advocated, but simple yet effective measures are suggested. This article is meant to raise awareness of cognitive bias contamination in forensic DNA testing and to give laboratories possible pathways to make sound decisions to address its influences.

PMID: 29173454 [PubMed - in process]

Neighborhood Disadvantage and Allostatic Load in African American Women at Risk for Obesity-Related Diseases.

Thu, 11/23/2017 - 07:36

Neighborhood Disadvantage and Allostatic Load in African American Women at Risk for Obesity-Related Diseases.

Prev Chronic Dis. 2017 Nov 22;14:E119

Authors: Tan M, Mamun A, Kitzman H, Mandapati SR, Dodgen L

Abstract
INTRODUCTION: African American women have higher rates of obesity and related chronic disease than other demographic groups. The poorer health of African American women compared with other groups may be explained by allostatic load, or cumulative physiologic stress, due to chronic socioeconomic disadvantage. The objective of this study was to evaluate neighborhood and individual factors contributing to allostatic load in African American women at risk for obesity-related diseases.
METHODS: This study evaluated the relationship of allostatic load with neighborhood disadvantage, individual socioeconomic determinants, and synergism between neighborhood and socioeconomic disadvantage, along with health behaviors and other factors as mediators in African American women. Our sample consisted of 220 African American women at risk of obesity-related diseases enrolled in the Better Me Within program (mean [standard deviation] age, 50.1 [11.2] y; mean [standard deviation] body mass index, 36.7 [8.4] kg/m(2)). Allostatic load score for each participant was calculated by summing the number of biomarkers (of 9 biomarkers) that were determined to be in the high-risk quartile.
RESULTS: Poisson regression of neighborhood disadvantage and individual socioeconomic determinants found that neighborhood disadvantage, but not education level or household income, was significantly associated with allostatic load (β = 0.22, SE, 0.10, P = .04). Tests for mediators showed that household income and alcohol consumption partially mediated the relationship between allostatic load score and neighborhood disadvantage but were not significant.
CONCLUSION: More research is necessary to determine the mechanisms by which neighborhoods can exacerbate and attenuate cumulative disadvantage among African American women. Policies and interventions that focus on neighborhood health may improve the outcomes of individual-level health interventions among women who reside in disadvantaged communities.

PMID: 29166248 [PubMed - in process]

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application.

Tue, 11/21/2017 - 07:34

Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application.

Exp Biol Med (Maywood). 2017 Jan 01;:1535370217743919

Authors: Mallet RT, Olivencia-Yurvati AH, Bünger R

Abstract
Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca(2+) release and re-uptake central to cardiac mechanical performance and to restore β-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca(2+) mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca(2+) homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore β-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes.

PMID: 29154687 [PubMed - as supplied by publisher]

A role for B cells in facilitating defense against an NK cell-sensitive lung metastatic tumor is revealed by stress.

Tue, 11/21/2017 - 07:34

A role for B cells in facilitating defense against an NK cell-sensitive lung metastatic tumor is revealed by stress.

J Neuroimmunol. 2017 Dec 15;313:99-108

Authors: Jones HP, Aldridge B, Boss-Williams K, Weiss JM

Abstract
Stressors impair immune defenses and pose risks among cancer patients. Natural Killer cells are not the sole immune defense against tumor development. Utilizing an NK-sensitive tumor model, this study evaluated immune effects to stress and determined whether lung metastasis resulted from B cells' inability to augment tumorlytic function. Lung metastasis directly correlated with delayed lung B cell accumulation compared to NK, and T cells. Decreased interleukin-12 cytokine and CD80(+) molecule expression by B cells correlated with decreased tumor lysis and increased tumor development. Thus, tumor defenses in the lung given stress exposure can depend on the B cell function.

PMID: 29153616 [PubMed - in process]

Flanking Variation Influences Rates of Stutter in Simple Repeats.

Sat, 11/18/2017 - 07:37
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Flanking Variation Influences Rates of Stutter in Simple Repeats.

Genes (Basel). 2017 Nov 17;8(11):

Authors: Woerner AE, King JL, Budowle B

Abstract
It has been posited that the longest uninterrupted stretch (LUS) of tandem repeats, as defined by the number of exactly matching repeating motif units, is a better predictor of rates of stutter than the parental allele length (PAL). While there are cases where this hypothesis is likely correct, such as the 9.3 allele in the TH01 locus, there can be situations where it may not apply as well. For example, the PAL may capture flanking indel variations while remaining insensitive to polymorphisms in the repeat, and these haplotypic changes may impact the stutter rate. To address this, rates of stutter were contrasted against the LUS as well as the PAL on different flanking haplotypic backgrounds. This study shows that rates of stutter can vary substantially depending on the flanking haplotype, and while there are cases where the LUS is a better predictor of stutter than the PAL, examples to the contrary are apparent in commonly assayed forensic markers. Further, flanking variation that is 7 bp from the repeat region can impact rates of stutter. These findings suggest that non-proximal effects, such as DNA secondary structure, may be impacting the rates of stutter in common forensic short tandem repeat markers.

PMID: 29149052 [PubMed]

HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFβ2 in the Trabecular Meshwork.

Sat, 11/18/2017 - 07:37
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HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFβ2 in the Trabecular Meshwork.

Invest Ophthalmol Vis Sci. 2016 Jul 01;57(8):3698-707

Authors: Bermudez JY, Webber HC, Patel GC, Liu X, Cheng YQ, Clark AF, Mao W

Abstract
PURPOSE: Elevated intraocular pressure (IOP) in primary open-angle glaucoma (POAG) results from glaucomatous damage to the trabecular meshwork (TM). The glaucoma-associated factor TGFβ2 is increased in aqueous humor and TM of POAG patients. We hypothesize that histone acetylation has a role in dysregulated TGFβ2 expression.
METHODS: Protein acetylation was compared between nonglaucomatous TM (NTM) and glaucomatous TM (GTM) cells using Western immunoblotting (WB). Nonglaucomatous TM cells were treated with 10 nM thailandepsin-A (TDP-A), a potent histone deacetylase inhibitor for 4 days. Total and nuclear proteins, RNA, and nuclear protein-DNA complexes were harvested for WB, quantitative PCR (qPCR), and chromatin immunoprecipitation (ChIP) assays, respectively. Paired bovine eyes were perfused with TDP-A versus DMSO, or TDP-A versus TDP-A plus the TGFβ pathway inhibitor LY364947 for 5 to 9 days. Intraocular pressure, TM, and perfusate proteins were compared.
RESULTS: We found increased acetylated histone 3 and total protein acetylation in the GTM cells and TDP-A treated NTM cells. Chromatin immunoprecipitation assays showed that TDP-A induced histone hyperacetylation associated with the TGFβ2 promoter. This change of acetylation significantly increased TGFβ2 mRNA and protein expression in NTM cells. In perfusion-cultured bovine eyes, TDP-A increased TGFβ2 in the perfusate as well as elevated IOP. Histologic and immunofluorescent analyses showed increased extracellular matrix and cytoskeletal proteins in the TM of TDP-A treated bovine eyes. Cotreatment with the TGFβ pathway inhibitor LY364947 blocked TDP-A-induced ocular hypertension.
CONCLUSIONS: Our results suggest that histone acetylation has an important role in increased expression of the glaucoma-associated factor TGFβ2. Histone hyperacetylation may be the initiator of glaucomatous damage to the TM.

PMID: 27403998 [PubMed - indexed for MEDLINE]

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.

Fri, 11/17/2017 - 07:52

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.

J Neurovirol. 2017 Nov 15;:

Authors: Langford D, Oh Kim B, Zou W, Fan Y, Rahimain P, Liu Y, He JJ

Abstract
HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

PMID: 29143286 [PubMed - as supplied by publisher]

Δ(9)-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats.

Thu, 11/16/2017 - 07:38
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Δ(9)-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats.

Psychopharmacology (Berl). 2017 Nov 14;:

Authors: Gatch MB, Forster MJ

Abstract
RATIONALE AND OBJECTIVES: Novel synthetic cannabinoid compounds continue to appear in the market advertised as legal alternatives to marijuana and the older synthetic cannabinoid compounds which are now controlled substances. Most of these newer compounds have been found to act at CB1 receptors, so the purpose of this study was to study the abuse liability of these compounds.
METHODS: Five of these compounds (BB-22, FUB-PB-22, 5F-AMB, NM2201, and MAB-CHMINACA) were tested for their ability to produce discriminative stimulus effects similar to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in rats. The ability of the CB1 receptor inverse agonist rimonabant to antagonize the discriminative stimulus effects of the five test compounds was also tested.
RESULTS: All five of the test compounds fully substituted for the discriminative stimulus effects of Δ(9)-THC at some dose, although MAB-CHMINACA produced an inverted U-shaped dose effect. Rimonabant fully antagonized the Δ(9)-THC-like discriminative stimulus effects of BB-22, 5F-AMB, NM2201, and MAB-CHMINACA but only reduced the effects of FUB-PB-22 to 40-50 % of Δ(9)-THC-appropriate responding.
CONCLUSIONS: These findings suggest that all five of the test compounds produced Δ(9)-THC-like effects and will likely have abuse liability similar to that of the controlled cannabinoid compounds.

PMID: 29138877 [PubMed - as supplied by publisher]

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion.

Mon, 11/13/2017 - 07:36

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion.

Biochem Biophys Res Commun. 2017 Nov 08;:

Authors: Panchoo M, Lacko A

Abstract
Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.

PMID: 29128352 [PubMed - as supplied by publisher]

Direct PCR amplification of DNA from human bloodstains, saliva, and touch samples collected with microFLOQ(®) swabs.

Sat, 11/11/2017 - 07:44

Direct PCR amplification of DNA from human bloodstains, saliva, and touch samples collected with microFLOQ(®) swabs.

Forensic Sci Int Genet. 2017 Oct 26;32:80-87

Authors: Ambers A, Wiley R, Novroski N, Budowle B

Abstract
Previous studies have shown that nylon flocked swabs outperform traditional fiber swabs in DNA recovery due to their innovative design and lack of internal absorbent core to entrap cellular materials. The microFLOQ(®) Direct swab, a miniaturized version of the 4N6 FLOQSwab(®), has a small swab head that is treated with a lysing agent which allows for direct amplification and DNA profiling from sample collection to final result in less than two hours. Additionally, the microFLOQ(®) system subsamples only a minute portion of a stain and preserves the vast majority of the sample for subsequent testing or re-analysis, if desired. The efficacy of direct amplification of DNA from dilute bloodstains, saliva stains, and touch samples was evaluated using microFLOQ(®) Direct swabs and the GlobalFiler™ Express system. Comparisons were made to traditional methods to assess the robustness of this alternate workflow. Controlled studies with 1:19 and 1:99 dilutions of bloodstains and saliva stains consistently yielded higher STR peak heights than standard methods with 1ng input DNA from the same samples. Touch samples from common items yielded single source and mixed profiles that were consistent with primary users of the objects. With this novel methodology/workflow, no sample loss occurs and therefore more template DNA is available during amplification. This approach may have important implications for analysis of low quantity and/or degraded samples that plague forensic casework.

PMID: 29126000 [PubMed - as supplied by publisher]

Comparison of faculty assessment and students' self-assessment of performance during clinical case discussions in a pharmacotherapy capstone course.

Fri, 11/10/2017 - 07:39
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Comparison of faculty assessment and students' self-assessment of performance during clinical case discussions in a pharmacotherapy capstone course.

Med Teach. 2017 Nov 09;:1-6

Authors: Wettergreen SA, Brunner J, Linnebur SA, Borgelt LM, Saseen JJ

Abstract
OBJECTIVES: The primary objective of this study was to compare faculty assessment and third year students' self-assessment of performance in clinical case discussions. The secondary objective was to evaluate if student characteristics influence self-assessments.
METHODS: This retrospective analysis compared faculty and student self-assessment scores for two clinical case discussions using Spearman's correlation and Wilcoxon's signed ranks test. Chi-squared test was used to compare frequency of faculty and student self-assessments indicating the highest possible rating for the pooled score and for each individual component. The pooled score included three individual components: level of engagement, quality of contribution, and professionalism.
RESULTS: Pooled faculty and student self-assessments correlated for both the first (r = 0.41, p < 0.001) and second (r = 0.35; p < 0.001) clinical case discussions. The frequency that faculty and student self-assessment ratings were the highest possible pooled score was similar for both the first (51.3% vs. 44.7%, respectively, p = 0.25) and second (58.6% vs. 47.4%, p = 0.05) clinical case discussions. Student characteristics (age, gender, and grade point average at graduation) did not influence self-assessments.
CONCLUSIONS: Students' self-assessment correlated with faculty assessment of performance during clinical case discussions. Increased use of self-assessments for professional development in pharmacy and other healthcare professional curricula should be considered.

PMID: 29117750 [PubMed - as supplied by publisher]

The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

Fri, 11/10/2017 - 07:39
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The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

J Affect Disord. 2016 Sep 15;202:178-86

Authors: Tsai MT, Erickson SR, Cohen LJ, Wu CH

Abstract
BACKGROUND: Diabetes and anxiety disorders are independent risk factors for stroke. However, it remains unclear whether the risk of stroke is higher among diabetic patients with comorbid anxiety than without comorbid anxiety. Therefore, the purpose of this study was to investigate the association between comorbid anxiety and the risk of stroke among patients with diabetes.
METHODS: This is a retrospective cohort study. We used the National Health Insurance Research Database in Taiwan to identify a diabetes cohort with a new diagnosis of an anxiety disorder but without a history of stroke. The enrollment period was 2001-2006 with up to 11 years of follow-up data. Comorbid anxiety was defined by both a clinical diagnosis of the DSM-IV (ICD-9-CM) and prescriptions for anxiolytic medications. Propensity score matching was performed to balance the selected confounders between the anxiety-exposed group and anxiety non-exposed group. Cox-propositional hazard regression models were used to evaluate the association between comorbid anxiety and the risk of stroke.
RESULTS: Among patients with diabetes (N=40,846), an estimated 5.8% (N=2374) of patients had comorbid anxiety disorders. Diabetic patients with comorbid anxiety were significantly associated with a higher risk of stroke compared to patients without comorbid anxiety (hazard ratio: 1.33, 95% confidence interval: 1.02-1.72).
LIMITATIONS: The severity of anxiety or diabetes could not be measured from the claims data. Residual confounding may still exist.
CONCLUSION: A significantly elevated risk of stroke was observed in association with comorbid anxiety among patients with diabetes. Psychiatrists should consider routine screening for anxiety disorders to prevent a stroke event among patients with diabetes.

PMID: 27262640 [PubMed - indexed for MEDLINE]

Capacity of tTreg generation is not impaired in the atrophied thymus.

Thu, 11/09/2017 - 07:43
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Capacity of tTreg generation is not impaired in the atrophied thymus.

PLoS Biol. 2017 Nov 08;15(11):e2003352

Authors: Oh J, Wang W, Thomas R, Su DM

Abstract
Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.

PMID: 29117183 [PubMed - as supplied by publisher]

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