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: 29 min 6 sec ago

Prevention of Dopamine Dysregulation Syndrome in Parkinson's Disease: A Case Report.

Fri, 12/14/2018 - 13:30
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Prevention of Dopamine Dysregulation Syndrome in Parkinson's Disease: A Case Report.

Prim Care Companion CNS Disord. 2018 Apr 26;20(2):

Authors: Luchsinger WT, Gambhir N, DeMoss D

PMID: 29701928 [PubMed - indexed for MEDLINE]

Basics on the use of acid-sensing ion channels' inhibitors as therapeutics.

Thu, 12/13/2018 - 07:28
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Basics on the use of acid-sensing ion channels' inhibitors as therapeutics.

Neural Regen Res. 2019 Mar;14(3):395-398

Authors: Dibas J, Al-Saad H, Dibas A

Abstract
Since the discovery of acid-sensing ion channels in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. Acid-sensing ion channels play important roles in mediating pain sensation during diseases such as stroke, inflammation, arthritis, cancer, and recently migraine. More interestingly, acid-sensing ion channels may explain the sex differences in pain between males and females. Also, the ability of acid-sensing ion channel blockers to exert neuroprotective effects in a number of neurodegenerative diseases has added a new dimension to their therapeutic value. The current failure rate of ~45% of new drugs (due to toxicity issues) and saving of up to 7 years in the life span of drug approval makes drug repurposing a high priority. If acid-sensing ion channels' blockers undergo what is known as "drug repurposing", there is a great potential to bring them as medications with known safety profiles to new patient populations. However, the route of administration remains a big challenge due to their poor penetration of the blood brain and retinal barriers. In this review, the promise of using acid-sensing ion channel blockers as neuroprotective drugs is discussed.

PMID: 30539804 [PubMed]

Early detection of metabolic dysregulation using water T2 analysis of biobanked samples.

Thu, 12/13/2018 - 07:28
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Early detection of metabolic dysregulation using water T2 analysis of biobanked samples.

Diabetes Metab Syndr Obes. 2018;11:807-818

Authors: Mishra I, Jones C, Patel V, Deodhar S, Cistola DP

Abstract
Background: The ability to use frozen biobanked samples from cohort studies and clinical trials is critically important for biomarker discovery and validation. Here we investigated whether plasma and serum water transverse relaxation times (T2) from frozen biobanked samples could be used as biomarkers for metabolic syndrome (MetS) and its underlying conditions, specifically insulin resistance, dyslipidemia, and subclinical inflammation.
Methods: Plasma and serum aliquots from 44 asymptomatic, non-diabetic human subjects were biobanked at -80°C for 7-9 months. Water T2 measurements were recorded at 37°C on 50 µL of unmodified plasma or serum using benchtop nuclear magnetic resonance relaxometry. The T2 values for freshly drawn and once-frozen-thawed ("frozen") samples were compared using Huber M-values (M), Lin concordance correlation coefficients (ρc), and Bland-Altman plots. Water T2 values from frozen plasma and serum samples were compared with >130 metabolic biomarkers and analyzed using multi-variable linear/logistic regression and ROC curves.
Results: Frozen plasma water T2 values were highly correlated with fresh (M=0.94, 95% CI 0.89, 0.97) but showed a lower level of agreement (ρc=0.74, 95% CI 0.62, 0.82) because of an average offset of -5.6% (-7.1% for serum). Despite the offset, frozen plasma water T2 was strongly correlated with markers of hyperinsulinemia, dyslipidemia, and inflammation and detected these conditions with 89% sensitivity and 91% specificity (100%/63% for serum). Using optimized cut points, frozen plasma and serum water T2 detected hyperinsulinemia, dyslipidemia, and inflammation in 23 of 44 subjects, including nine with an early stage of metabolic dysregulation that did not meet the clinical thresholds for prediabetes or MetS.
Conclusion: Plasma and serum water T2 values from once-frozen-thawed biobanked samples detect metabolic dysregulation with high sensitivity and specificity. However, the cut points for frozen biobanked samples must be calibrated independent of those for freshly drawn plasma and serum.

PMID: 30538517 [PubMed]

Glia-immune interactions post-ischemic stroke and potential therapies.

Thu, 12/13/2018 - 07:28
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Glia-immune interactions post-ischemic stroke and potential therapies.

Exp Biol Med (Maywood). 2018 Dec 11;:1535370218818172

Authors: Hersh J, Yang SH

Abstract
IMPACT STATEMENT: This article reviews glial cell interactions with the immune system post-ischemic stroke. Research has shown that glial cells in the brain play a role in altering phenotypes of other glial cells and have downstream immune cell targets ultimately regulating a neuroinflammatory response. These interactions may play a deleterious as well as beneficial role in stroke recovery. Furthermore, they may provide a novel way to approach potential therapies, since current stroke drug therapy is limited to only one Food and Drug Administration-approved drug complicated by a narrow therapeutic window. Until this point, most research has emphasized neuroimmune interactions, but little focus has been on bidirectional communication of glial-immune interactions in the ischemic brain. By expanding our understanding of these interactions through a compilation of glial cell effects, we may be able to pinpoint major modulating factors in brain homeostasis to maintain or discover ways to suppress irreversible ischemic damage and improve brain repair.

PMID: 30537868 [PubMed - as supplied by publisher]

Risk Factors Associated with Poor Physical Fitness in Three- to Six-Year-Old Children in Tujia-Nationality Settlement of China.

Wed, 12/12/2018 - 10:30
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Risk Factors Associated with Poor Physical Fitness in Three- to Six-Year-Old Children in Tujia-Nationality Settlement of China.

Evid Based Complement Alternat Med. 2018;2018:5702190

Authors: Liu X, Xiang Z, Liu C, Shi X, Yi X, Cheng M, Schenck H, Bates J

Abstract
Background: Physical fitness has been recognized not only as an integrated predictor of the body's functional status, but also as an important marker of health outcomes. The aim of this study was to examine the factors associated with physical fitness among 3-6-year-old children within the Tujia-Nationality settlement in the years 2005, 2010, and 2014.
Methods: Demographics questionnaires and fitness assessment were performed to identify the risk factors for poor physical fitness (PPF) among 3- to 6-year-old children in the years 2005, 2010, and 2014 in the area of southwest Hubei of China.
Results: Of the 2128 children, 495 were classified as PPF (23.3%). In 2005, the percentage of PPF children was 21.7%, and the percentage of PPF children decreased from 29.1% in 2010 to 18.8% in 2014. Furthermore, Urban area children had a significant risk of PPF than rural area children (OR=1.299, P=0.031). Three-year-old children had 2.150-fold risk of PPF as compared to 6-year-old children. The children with less than 0.5 hours of activity time per day had 1.95-fold risk of PPF as compared to those with 1-2-hour activity time per day, respectively. Underweight and overweight/obese children had 2.74-fold and 1.67-fold risk of PPF as compared to normal weight children. Children had 1.97-fold risk of PPF when their father's schooling ceased after middle school and 1.51-fold risk of PPF when their father's schooling ceased after high school, respectively.
Conclusions: These results demonstrated that the incidence of PPF children went up from 2005 to 2010 and then down from 2010 to 2014 within the Tujia settlement. For the children in this area, the risk factors associated with PPF included urban location, younger age, less than 1-hour activity time per day in kindergarten, underweight/overweight, low father's education level, and mother's childbearing age being less than 20 years.

PMID: 30532796 [PubMed]

Response to Pazopanib in Patients With Relapsed Osteosarcoma.

Wed, 12/12/2018 - 10:30
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Response to Pazopanib in Patients With Relapsed Osteosarcoma.

J Pediatr Hematol Oncol. 2018 Dec 07;:

Authors: Elete KR, Albritton KH, Akers LJ, Basha R, Ray A

Abstract
Axial skeleton primary tumor, metastatic disease at presentation, incomplete surgical resection, and <90% tumor necrosis have all been known to influence prognosis adversely in osteosarcoma. Relapse of osteosarcoma, typically occurring within the first 18 months of therapy, with an incidence rate of 50% is treated with surgery, chemotherapy, and targeted therapy. Here, we discuss 2 patients treated with pazopanib, a multi-tyrosine kinase inhibitor presently approved to treat renal cell carcinoma and soft tissue sarcomas. Case 1 achieved positive response and remains on pazopanib. Case 2 sustained gastrointestinal toxicity requiring suspension of drug, despite achieving stable disease.

PMID: 30531600 [PubMed - as supplied by publisher]

Potential Overestimation of Racial Disparities in Response to the 8-Week Ledipasvir/Sofosbuvir Regimen for Hepatitis C Virus Genotype 1 Infection.

Wed, 12/12/2018 - 10:30
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Potential Overestimation of Racial Disparities in Response to the 8-Week Ledipasvir/Sofosbuvir Regimen for Hepatitis C Virus Genotype 1 Infection.

Gastroenterology. 2018 11;155(5):1646-1647.e2

Authors: Ojha RP, MacDonald BR, Chu TC, Marcus JL

PMID: 30118741 [PubMed - indexed for MEDLINE]

Evaluation of the precision ID mtDNA whole genome panel on two massively parallel sequencing systems.

Wed, 12/12/2018 - 10:30
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Evaluation of the precision ID mtDNA whole genome panel on two massively parallel sequencing systems.

Forensic Sci Int Genet. 2018 09;36:213-224

Authors: Woerner AE, Ambers A, Wendt FR, King JL, Moura-Neto RS, Silva R, Budowle B

Abstract
Sequencing whole mitochondrial genomes by capillary electrophoresis is a costly and time/labor-intensive endeavor. Many of the previous Sanger sequencing-based approaches generated amplicons that were several kilobases in length; lengths that are likely not amenable for most forensic applications. However, with the advent of massively parallel sequencing (MPS) short-amplicon multiplexes covering the entire mitochondrial genome can be sequenced relatively easily and rapidly. Recently, the Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific by Applied Biosystems™) has been introduced. This panel is composed of 162 amplicons (in two multiplexes) that are considerably smaller in length (∼163bp) and thus are more amenable to analyzing challenged samples. This panel was evaluated on both the Ion S5™ System (Thermo Fisher Scientific) and the MiSeq™ FGx Desktop Sequencer (Illumina). A script was developed to extract phased haplotypes associated with these amplicons. Levels of read-depth were compared across sequencing pools and between sequencing technologies and haplotype concordances were assessed. Given modest thresholds on read depth, the haplotypes identified by either technology were consistent. Nuclear mitochondrial sequences (Numts) were also inferred, and the effect of different mapping strategies commonly used to filter out Numts were contrasted. Some Numts are co-amplified with this amplification kit, and while the choice of reference sequence can mitigate some of these effects, some data from the mitochondrial genome were lost in the process in this study. This study demonstrates that the Ion and MiSeq platforms provide consistent haplotype estimation of the whole mitochondrial genome, thus providing further support for the reliability and validity of the Precision ID mtDNA Whole Genome Panel.

PMID: 30059903 [PubMed - indexed for MEDLINE]

Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs.

Wed, 12/12/2018 - 10:30
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Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs.

Pharmacol Rev. 2018 07;70(3):684-711

Authors: Dalwadi DA, Ozuna L, Harvey BH, Viljoen M, Schetz JA

Abstract
Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others. Efavirenz-based treatment is generally well-tolerated in children, although some experience persistent concentration problems, as well as sleep disturbances, psychotic reactions, and seizures. In an effort to link basic with clinical research, parameters associated with efavirenz brain exposure are discussed, and factors that increase efavirenz levels are explored in depth as they are expected to contribute to NPAE risk. These include the role of modifiable and nonmodifiable risk factors such as diet, weight, and drug-drug interactions and sex, age, and ethnicity/pharmacogenetics. In addition to NPAEs, this review explores what is known about antiretroviral (ARV) drugs being used for recreational purposes. Although multiple ARV drugs are covered, special attention is devoted to efavirenz given that the majority of reports of NPAEs and illicit use of ARV drugs concern efavirenz. The evolving molecular mechanistic basis of NPAEs and abuse of efavirenz point to a complex and polymodal receptor pharmacology. Animal studies to date primarily point to a serotonergic mechanism of action. Recently emerging associations between HIV-associated neurocognitive disorder and efavirenz use, and possible contributions of the mitochondrial-immune-inflammatory-redox cascade are explored in the context of the signaling mechanisms that appear to be involved.

PMID: 29945900 [PubMed - indexed for MEDLINE]

Increasing the discrimination power of ancestry- and identity-informative SNP loci within the ForenSeq™ DNA Signature Prep Kit.

Wed, 12/12/2018 - 10:30
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Increasing the discrimination power of ancestry- and identity-informative SNP loci within the ForenSeq™ DNA Signature Prep Kit.

Forensic Sci Int Genet. 2018 09;36:60-76

Authors: King JL, Churchill JD, Novroski NMM, Zeng X, Warshauer DH, Seah LH, Budowle B

Abstract
The use of single nucleotide polymorphisms (SNPs) in forensic genetics has been limited to challenged samples with low template and/or degraded DNA. The recent introduction of massively parallel sequencing (MPS) technologies has expanded the potential applications of these markers and increased the discrimination power of well-established loci by considering variation in the flanking regions of target loci. The ForenSeq Signature Preparation Kit contains 165 SNP amplicons for ancestry- (aiSNPs), identity- (iiSNPs), and phenotype-inference (piSNPs). In this study, 714 individuals from four major populations (African American, AFA; East Asian, ASN; US Caucasian, CAU; and Southwest US Hispanic, HIS) previously reported by Churchill et al. [Forensic Sci Int Genet. 30 (2017) 81-92; DOI: https://doi.org/10.1016/j.fsigen.2017.06.004] were assessed using STRait Razor v2s to determine the level of diversity in the flanking regions of these amplicons. The results show that nearly 70% of loci showed some level of flanking region variation with 22 iiSNPs and 8 aiSNPs categorized as microhaplotypes in this study. The heterozygosities of these microhaplotypes approached, and in one instance surpassed, those of some core STR loci. Also, the impact of the flanking region on other forensic parameters (e.g., power of exclusion and power of discrimination) was examined. Sixteen of the 94 iiSNPs had an effective allele number greater than 2.00 across the four populations. To assess what effect the flanking region information had on the ancestry inference, genotype probabilities and likelihood ratios were determined. Additionally, concordance with the ForenSeq UAS and Nextera Rapid Capture was evaluated, and patterns of heterozygote imbalance were identified. Pairwise comparison of the iiSNP diplotypes determined the probability of detecting a mixture (i.e., observing ≥ 3 haplotypes) using these loci alone was 0.9952. The improvement in random match probabilities for the full regions over the target iiSNPs was found to be significant. When combining the iiSNPs with the autosomal STRs, the combined match probabilities ranged from 6.40 × 10-73 (ASN) to 1.02 × 10-79 (AFA).

PMID: 29935396 [PubMed - indexed for MEDLINE]

Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3.

Wed, 12/12/2018 - 10:30
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Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3.

Nat Commun. 2018 05 25;9(1):2082

Authors: Zuo Z, Smith RN, Chen Z, Agharkar AS, Snell HD, Huang R, Liu J, Gonzales EB

Abstract
Acid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca2+) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca2+ results in channel opening, with the site's location remaining unresolved. Here we show that a ring of rat ASIC3 (rASIC3) glutamates (Glu435), located above the channel gate, modulates proton sensitivity and contributes to the formation of the elusive Ca2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-affinity Ca2+ site atop the channel pore. Furthermore, the reported observations provide clarity for past controversies regarding ASIC channel gating. Our findings enhance understanding of ASIC gating mechanisms and provide structural and energetic insights into this unique calcium-binding site.

PMID: 29802295 [PubMed - indexed for MEDLINE]

Insertion within the flanking region of the D10S1237 locus.

Wed, 12/12/2018 - 10:30
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Insertion within the flanking region of the D10S1237 locus.

Forensic Sci Int Genet. 2018 07;35:e4-e6

Authors: Novroski NMM, Woerner AE, Budowle B

PMID: 29729851 [PubMed - indexed for MEDLINE]

Planktonic microbial profiling in water samples from a Brazilian Amazonian reservoir.

Wed, 12/12/2018 - 10:30
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Planktonic microbial profiling in water samples from a Brazilian Amazonian reservoir.

Microbiologyopen. 2018 04;7(2):e00523

Authors: Cabral BCA, Hoffmann L, Budowle B, Ürményi TP, Moura-Neto RS, Azevedo SMFO, Silva R

Abstract
Our comprehension of the dynamics and diversity of freshwater planktonic bacterial communities is far from complete concerning the Brazilian Amazonian region. Therefore, reference studies are urgently needed. We mapped bacterial communities present in the planktonic communities of a freshwater artificial reservoir located in the western Amazonian basin. Two samples were obtained from rainy and dry seasons, the periods during which water quality and plankton diversity undergo the most significant changes. Hypervariable 16S rRNA and shotgun sequencing were performed to describe the first reference of a microbial community in an Amazonian lentic system. Microbial composition consisted mainly of Betaproteobacteria, Cyanobacteria, Alphaproteobacteria, and Actinobacteria in the dry period. The bacteria distribution in the rainy period was notably absent of Cyanobacteria. Microcystis was observed in the dry period in which the gene cluster for cyanotoxins was found. Iron acquisition gene group was higher in the sample from the rainy season. This work mapped the first inventory of the planktonic microbial community of a large water reservoir in the Amazon, providing a reference for future functional studies and determining other communities and how they interact.

PMID: 29380948 [PubMed - indexed for MEDLINE]

No association between global DNA methylation in peripheral blood and lung cancer risk in nonsmoking women: results from a multicenter study in Eastern and Central Europe.

Wed, 12/12/2018 - 10:30
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No association between global DNA methylation in peripheral blood and lung cancer risk in nonsmoking women: results from a multicenter study in Eastern and Central Europe.

Eur J Cancer Prev. 2018 01;27(1):1-5

Authors: Davis A, Tao MH, Chen J, Scelo G, Bencko V, Fabianova E, Foretova L, Janout V, Lissowska J, Mates D, Mates IN, Rudnai P, Zaridze D, Boffetta P

Abstract
Alterations in global DNA methylation have been suggested to play an important role in cancer development. We evaluated the association of global DNA methylation in peripheral blood with the risk of lung cancer in nonsmoking women from six countries in Central and Eastern Europe. This multicenter case-control study included primary, incident lung cancer cases diagnosed from 1998 to 2001 and controls frequency-matched for geographic area, sex, and age. Global methylation was assessed in peripheral blood DNA from 83 nonsmoking female cases and 181 nonsmoking female controls using the luminometric methylation assay (LUMA). Unconditional logistic regression models were used to estimate associations between DNA methylation in the blood and the risk of lung cancer. LUMA methylation level was not associated with the risk of lung cancer in nonsmoking women. Associations were not significantly different according to different strata of age, BMI, alcohol drinking, or second-hand tobacco smoke exposure status. In our study of nonsmoking women, the LUMA methylation level in peripheral blood was not associated with the risk of lung cancer. Our findings do not support an association of global blood DNA methylation with the risk of lung cancer in nonsmoking women.

PMID: 27045934 [PubMed - indexed for MEDLINE]

An ensemble-based likelihood ratio approach for family-based genomic risk prediction.

Fri, 12/07/2018 - 09:58
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An ensemble-based likelihood ratio approach for family-based genomic risk prediction.

J Zhejiang Univ Sci B. 2018 Dec.;19(12):935-947

Authors: An H, Wei CS, Wang O, Wang DH, Xu LW, Lu Q, Ye CY

Abstract
OBJECTIVE: As one of the most popular designs used in genetic research, family-based design has been well recognized for its advantages, such as robustness against population stratification and admixture. With vast amounts of genetic data collected from family-based studies, there is a great interest in studying the role of genetic markers from the aspect of risk prediction. This study aims to develop a new statistical approach for family-based risk prediction analysis with an improved prediction accuracy compared with existing methods based on family history.
METHODS: In this study, we propose an ensemble-based likelihood ratio (ELR) approach, Fam-ELR, for family-based genomic risk prediction. Fam-ELR incorporates a clustered receiver operating characteristic (ROC) curve method to consider correlations among family samples, and uses a computationally efficient tree-assembling procedure for variable selection and model building.
RESULTS: Through simulations, Fam-ELR shows its robustness in various underlying disease models and pedigree structures, and attains better performance than two existing family-based risk prediction methods. In a real-data application to a family-based genome-wide dataset of conduct disorder, Fam-ELR demonstrates its ability to integrate potential risk predictors and interactions into the model for improved accuracy, especially on a genome-wide level.
CONCLUSIONS: By comparing existing approaches, such as genetic risk-score approach, Fam-ELR has the capacity of incorporating genetic variants with small or moderate marginal effects and their interactions into an improved risk prediction model. Therefore, it is a robust and useful approach for high-dimensional family-based risk prediction, especially on complex disease with unknown or less known disease etiology.

PMID: 30507077 [PubMed - in process]

Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transcription Factors.

Fri, 12/07/2018 - 09:58
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Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transcription Factors.

Cell Physiol Biochem. 2018 Nov 30;51(4):1894-1907

Authors: Hurtado M, Sankpal UT, Kaba A, Mahammad S, Chhabra J, Brown DT, Gurung RK, Holder AA, Vishwanatha JK, Basha R

Abstract
BACKGROUND/AIMS: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated.
METHODS: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks.
RESULTS: The IC50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G2/M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring.
CONCLUSION: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

PMID: 30504717 [PubMed - as supplied by publisher]

Impact of Environmental Stressors on Tolerance to Hemorrhage in Humans.

Thu, 12/06/2018 - 09:54

Impact of Environmental Stressors on Tolerance to Hemorrhage in Humans.

Am J Physiol Regul Integr Comp Physiol. 2018 Dec 05;:

Authors: Crandall CG, Rickards CA, Johnson BD

Abstract
Hemorrhage is a leading cause of death in the military and civilian settings and approximately 85% of potentially survivable battlefield deaths are hemorrhage related. Both Soldiers and civilians are exposed to a number of environmental and physiological conditions that have the potential to alter tolerance to a hemorrhagic insult. The objective of this review article is to summarize the known impact of commonly encountered environmental and physiological conditions on hemorrhagic tolerance, primarily in humans. The majority of the presented studies use lower-body negative pressure (LBNP) to simulate a hemorrhagic insult, although some studies employed incremental blood withdrawal. This review first addresses the use of LBNP as a model of hemorrhage-induced central hypovolemia, and then addresses the effects of the following conditions on tolerance to LBNP: passive and exercise-induced heat stress with and without accompanying hypohydration/dehydration, hypothermic exposure, and altitude/hypoxia exposure. By understanding the effects of these environmental and physiological conditions on responses to a hemorrhagic challenge, including tolerance, targeted strategies and interventions can be developed and applied to reduce the impact of such conditions on tolerance to a hemorrhagic insult, and ultimately improve survival from blood loss injuries.

PMID: 30517019 [PubMed - as supplied by publisher]

Nanopore sequencing: An enrichment-free alternative to mitochondrial DNA sequencing.

Wed, 12/05/2018 - 09:50

Nanopore sequencing: An enrichment-free alternative to mitochondrial DNA sequencing.

Electrophoresis. 2018 Dec 04;:

Authors: Zascavage RR, Thorson K, Planz JV

Abstract
Mitochondrial DNA sequence data is often utilized in disease studies, conservation genetics and forensic identification. The current approaches for sequencing the full mtGenome typically require several rounds of PCR enrichment during Sanger or MPS protocols followed by fairly tedious assembly and analysis. Here we describe an efficient approach to sequencing directly from genomic DNA samples without prior enrichment or extensive library preparation steps. A comparison is made between libraries sequenced directly from native DNA and the same samples sequenced from libraries generated with nine overlapping mtDNA amplicons on the Oxford Nanopore MinION device. The native and amplicon library preparation methods and alternative base calling strategies were assessed to establish error rates and identify trends of discordance between the two library preparation approaches. For the complete mtGenome, 16,569 nucleotides, an overall error rate of approximately 1.00% was observed. As expected with mtDNA, the majority of error was detected in homopolymeric regions. The use of a modified basecaller that corrects for ambiguous signal in homopolymeric stretches reduced the error rate for both library preparation methods to approximately 0.30%. Our study indicates that direct mtDNA sequencing from native DNA on the minION device provides comparable results to those obtained from common mtDNA sequencing methods and is a reliable alternative to approaches using PCR-enriched libraries. This article is protected by copyright. All rights reserved.

PMID: 30511783 [PubMed - as supplied by publisher]

Use of the Muddiest Point Technique as an exam review in an integrated pharmacotherapy course.

Sat, 12/01/2018 - 09:32
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Use of the Muddiest Point Technique as an exam review in an integrated pharmacotherapy course.

Curr Pharm Teach Learn. 2018 Sep;10(9):1295-1302

Authors: Bullock KC, Gibson C, Howard M, Liu J, Tatachar A, Yuet WC

Abstract
BACKGROUND AND PURPOSE: The objective of this study was to evaluate the impact in student pharmacists' exam performance learning outcomes and satisfaction after integrating the Muddiest Point assessment technique into exam reviews.
EDUCATIONAL ACTIVITY AND SETTING: In 2016, the Muddiest Point, a formative assessment tool, was used to develop exam review sessions for second-year student pharmacists in an integrated pharmacotherapy course focused on the cardiovascular system. Performance scores on all four exams were compared between students in the 2015 and 2016 courses. Students' complexity of learning was categorized using a taxonomy of learning structure. A survey was used to evaluate student perceptions of exam reviews and the Muddiest Point technique (MPT).
FINDINGS: Scores were higher on the second exam for the 83 students in the 2016 course (78.0% vs. 86.0%, p<0.001). There was no difference on other exam scores or overall course failures. Muddiest points submitted by students demonstrated a variety of taxonomy of learning levels. Student pharmacists surveyed at the conclusion of the course agreed that exam reviews were helpful for their preparation for exams and that the MPT was a valuable use of class time.
SUMMARY: Incorporating the MPT into exam reviews maintained exam scores and supported evaluation of student learning. In addition, student pharmacists were satisfied with this exam review method.

PMID: 30497634 [PubMed - in process]

Current state of Alzheimer's fluid biomarkers.

Fri, 11/30/2018 - 09:29
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Current state of Alzheimer's fluid biomarkers.

Acta Neuropathol. 2018 Nov 28;:

Authors: Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, Fagan AM, Hampel H, Mielke MM, Mikulskis A, O'Bryant S, Scheltens P, Sevigny J, Shaw LM, Soares HD, Tong G, Trojanowski JQ, Zetterberg H, Blennow K

Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

PMID: 30488277 [PubMed - as supplied by publisher]

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