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Ancestry inference and admixture component estimations of Chinese Kazak group based on 165 AIM-SNPs via NGS platform.

Recent Research Articles from UNTHSC - Fri, 12/18/2020 - 05:54
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Ancestry inference and admixture component estimations of Chinese Kazak group based on 165 AIM-SNPs via NGS platform.

J Hum Genet. 2020 May;65(5):461-468

Authors: Xie T, Shen C, Liu C, Fang Y, Guo Y, Lan Q, Wang L, Ge J, Zhou Y, Wen S, Yang Q, Zhu B

Abstract
Predicting the biogeographical ancestries of populations and unknown individuals based on ancestry-informative markers (AIMs) has been widely applied in providing DNA clues to criminal investigations, correcting the factor of population stratification in genome-wide association studies (GWAS), and working as the basis of predicting the externally visible characteristics (EVCs) of individuals. The present study chose Chinese Xinjiang Kazak (XJK) group as research object using a 165 AIM-SNPs panel via next generation sequencing (NGS) technology to reveal its ancestral information and genetic background by referencing the populations' data from 1000 Genomes Phase 3. After the Bonferroni correction, there were no significant deviations at the 165 AIM-SNP loci except two loci with homozygote in the studied XJK group. Ancestry information inference and populations genetic analyses were conducted basing on multiplex statistical methods such as forensic statistical parameter analyses, estimation of the success ratios with cross-validation, population tree, principal component analysis (PCA), and genetic structure analysis. The present results revealed that XJK group had the admixed ancestral components of East Asian and European populations with the ratio of about 62:37.

PMID: 32081902 [PubMed - indexed for MEDLINE]

Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders.

Recent Research Articles from UNTHSC - Thu, 12/17/2020 - 07:31
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Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders.

Front Neurol. 2020;11:593146

Authors: Cisneros IE, Ghorpade A, Borgmann K

Abstract
Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND.

PMID: 33324330 [PubMed]

Breastfeeding practices among childhood cancer survivors.

Recent Research Articles from UNTHSC - Wed, 12/16/2020 - 06:20
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Breastfeeding practices among childhood cancer survivors.

J Cancer Surviv. 2020 08;14(4):586-599

Authors: Ogg S, Klosky JL, Chemaitilly W, Srivastava DK, Wang M, Carney G, Ojha R, Robison LL, Cox CL, Hudson MM

Abstract
PURPOSE: This cross-sectional study compared breastfeeding outcomes among childhood cancer survivors to those of women in the general population and evaluated whether breastfeeding is adversely affected by cancer treatment or endocrine-related late effects.
METHODS: A self-reported survey ascertained breastfeeding practices and incorporated items from the questionnaires used in the Infant Feeding Practices Study II (IFPS II) to allow comparison with the general population. Among 710 eligible survivors, 472 (66%) responded. The participants were predominantly non-Hispanic White (84%), married (73%), and had some college or less (60%). The mean maternal age at the time of birth of the first child after cancer treatment was 24 years (SD 24.3 ± 4.8).
RESULTS: Fewer survivors planned to breastfeed than did IFPS II controls (67% vs. 82%, P < .0001), and fewer survivors initiated breastfeeding (66% vs. 85%, P < .0001). The median breastfeeding duration was shorter among survivors, with early undesired weaning occurring sooner in the survivor group (1.4 months, interquartile range (IQR) 0.5-3.5 months) than in the IFPS II group (2.7 months, IQR 0.9-5.4 months). A higher proportion of survivors reported an unfavorable breastfeeding experience (19% vs. 7.5%, P < .0001) and early, undesired weaning (57.5%, 95% CI 51-64) than did IFPS II participants (45.2%, 95% CI 44-47, P = .0164). Among survivors who expressed intention and chose to breastfeed, 46% endorsed disrupted lactation related to physiologic problems with high risk in those overweight/obese.
CONCLUSIONS: Survivors are at risk of negative breastfeeding experiences; however, lactation outcomes were not significantly associated with cancer diagnosis, treatments, or endocrine complications.
IMPLICATIONS FOR CANCER SURVIVORS: Prior research has not examined the association of cancer treatments and clinically validated late effects with lactation outcomes in a clinically diverse childhood cancer survivor cohort. Findings from this study suggest that childhood cancer survivors, especially those who are overweight/obese, are at risk of having negative breastfeeding experiences. Early undesired weaning, physiologic problems related to lactation and misconceptions about breastfeeding, especially fears of passing on cancer through breastmilk, highlight the need for counseling and specialized support to optimize lactation outcomes in this vulnerable population.

PMID: 32291564 [PubMed - indexed for MEDLINE]

Functional connectome biotypes of chemotherapy-related cognitive impairment.

Recent Research Articles from UNTHSC - Wed, 12/16/2020 - 06:20
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Functional connectome biotypes of chemotherapy-related cognitive impairment.

J Cancer Surviv. 2020 08;14(4):483-493

Authors: Kesler SR, Petersen ML, Rao V, Harrison RA, Palesh O

Abstract
PURPOSE: Cancer-related cognitive impairment (CRCI) is a common neurotoxicity among patients with breast and other cancers. Neuroimaging studies have demonstrated measurable biomarkers of CRCI but have largely neglected the potential heterogeneity of the syndrome.
METHODS: We used retrospective functional MRI data from 80 chemotherapy-treated breast cancer survivors to examine neurophysiologic subtypes or "biotypes" of CRCI. The breast cancer group consisted of training (N = 57) and validation (N = 23) samples.
RESULTS: An unsupervised clustering approach using connectomes from the training sample identified three distinct biotypes. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.001, corrected) differed significantly between the biotypes and also from 103 healthy female controls. We then built a random forest classifier using connectome features to distinguish between the biotypes (accuracy = 91%) and applied this to the validation sample to predict biotype assignment. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.005, corrected) differed significantly between the predicted biotypes and healthy controls. Biotypes were also characterized by divergent clinical and demographic factors as well as patient reported outcomes.
CONCLUSIONS: Neurophysiologic biotypes may help characterize the heterogeneity associated with CRCI in a data-driven manner based on neuroimaging biomarkers.
IMPLICATIONS FOR CANCER SURVIVORS: Our novel findings provide a foundation for detecting potential risk and resilience factors that warrant further study. With further investigation, biotypes might be used to personalize assessments of and interventions for CRCI.

PMID: 32157609 [PubMed - indexed for MEDLINE]

Canaloplasty and Trabeculotomy ab interno with the OMNI System Combined with Cataract Surgery in Open-Angle Glaucoma: 12-month Outcomes from the ROMEO Study.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Canaloplasty and Trabeculotomy ab interno with the OMNI System Combined with Cataract Surgery in Open-Angle Glaucoma: 12-month Outcomes from the ROMEO Study.

J Cataract Refract Surg. 2020 Dec 09;:

Authors: Hirsch L, Cotliar J, Vold S, Selvadurai D, Campbell AG, Ferreira G, Aminlari A, Cho A, Heersink S, Hochman M, Gallardo M, Williamson B, Phan R, Nelson C, Dickerson JE

Abstract
PURPOSE: Provide safety and effectiveness outcomes 12 months post-surgically for sequential canaloplasty and trabeculotomy with the OMNI system combined with cataract surgery in mild-to-moderate open-angle glaucoma (OAG).
SETTING: Eleven ophthalmology practices and surgery centers located in eight states (AL, AR, CA, KS, LA, MO, NY, TX).
DESIGN: Retrospective, multicenter, single arm METHODS:: IRB approved. Twelve surgeons contributed 81 patients meeting eligibility criteria: OAG, 12-month follow-up, medicated intraocular pressure (IOP) ≤36 mmHg on ≤ 4 medications preoperatively. Analysis stratified by baseline (BL) IOP; >18 mmHg (group 1), ≤ 18 mmHg (Group 2). Success defined as proportion with ≥ 20% reduction in IOP OR IOP between 6 and 18 mmHg (inclusive) AND on the same or fewer medications without secondary surgical intervention (SSI). Other endpoints included mean IOP and medications at 12 months. Safety included best corrected visual acuity (BCVA) and adverse events (AE).
RESULTS: Primary success was met by 79% (Group 1) and 81% (Group 2). Mean IOP was reduced in Group 1 (21.9 to 15.1 mmHg, p < 0.0001), and remained controlled in Group 2 (14.1 to 13.4 mmHg, p = 0.3177). Medications went from 2.0 ± 1.3 to 1.1 ± 1.1 (Group 1) and from 1.6 ± 1.3 to 0.9 ± 1.2 (Group 2). AE were typical for cataract or angle surgery. Mild inflammation (11%), IOP spikes (5%), hyphema (4%). 4 patients (5%) required an SSI.
CONCLUSIONS: The OMNI system provides effective IOP reduction, sustained IOP control, and meaningful medication reduction for up to 12 months postoperative.

PMID: 33315733 [PubMed - as supplied by publisher]

Dental visits in Medicaid-enrolled youth with mental illness: an analysis of administrative claims data.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Dental visits in Medicaid-enrolled youth with mental illness: an analysis of administrative claims data.

BMC Health Serv Res. 2020 Dec 11;20(1):1138

Authors: Stockbridge EL, Dhakal E, Griner SB, Loethen AD, West JF, Vera JW, Nandy K

Abstract
BACKGROUND: State Medicaid plans across the United States provide dental insurance coverage to millions of young persons with mental illness (MI), including those with attention deficit hyperactivity disorder (ADHD), depression, anxiety, bipolar disorder, and schizophrenia. There are significant oral health challenges associated with MI, and providing dental care to persons with MI while they are young provides a foundation for future oral health. However, little is known about the factors associated with the receipt of dental care in young Medicaid enrollees with MI. We aimed to identify mental and physical health and sociodemographic characteristics associated with dental visits among this population.
METHODS: We retrospectively analyzed administrative claims data from a Medicaid specialty health plan (September 2014 to December 2015). All enrollees in the plan had MI and were ≥ 7 years of age; data for enrollees aged 7 to 20 years were analyzed. We used two-level, mixed effects regression models to explore the relationships between enrollee characteristics and dental visits during 2015.
RESULTS: Of 6564 Medicaid-enrolled youth with MI, 29.0% (95% CI, 27.9, 30.1%) had one or more visits with a dentist or dental hygienist. Within youth with MI, neither anxiety (Adjusted odds ratio [AOR] = 1.15, p = 0.111), post-traumatic stress disorder (AOR = 1.31, p = 0.075), depression (AOR = 1.02, p = 0.831), bipolar disorder (AOR = 0.97, p = 0.759), nor schizophrenia (AOR = 0.83, p = 0.199) was associated with dental visits in adjusted analyses, although having ADHD was significantly associated with higher odds of dental visits relative to not having this condition (AOR = 1.34, p < 0.001). Age, sex, race/ethnicity, language, and education were also significantly associated with visits (p < 0.05 for all).
CONCLUSIONS: Dental utilization as measured by annual dental visits was lower in Medicaid-enrolled youth with MI relative to the general population of Medicaid-enrolled youth. However, utilization varied within the population of Medicaid-enrolled youth with MI, and we identified a number of characteristics significantly associated with the receipt of dental services. By identifying these variations in dental service use this study facilitates the development of targeted strategies to increase the use of dental care in - and consequently improve the current and long-term wellbeing of - the vulnerable population of Medicaid-enrolled youth with MI.

PMID: 33308226 [PubMed - in process]

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling.

Sci Rep. 2020 06 17;10(1):9815

Authors: Roberts AL, Mavlyutov TA, Perlmutter TE, Curry SM, Harris SL, Chauhan AK, McDowell CM

Abstract
Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage, which leads to impaired aqueous humor outflow. Here, we explore a novel molecular mechanism involved in glaucomatous TM damage. We investigated the role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA (FN-EDA), in TGFβ2-induced ocular hypertension in mice. We utilized transgenic mouse strains that either constitutively express only FN containing the EDA isoform or contain an EDA-null allele and express only FN lacking EDA, with or without a mutation in Tlr4, in our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2. IOP was measured over time and eyes accessed by immunohistochemistry for total FN and FN-EDA expression. Constitutively active EDA caused elevated IOP starting at 14 weeks of age. Ad5.TGFβ2 induced ocular hypertension in wildtype C57BL/6J mice and further amplified the IOP in constitutively active EDA mice. TLR4 null and EDA null mice blocked Ad5.TGFβ-induced ocular hypertension. Total FN and FN-EDA isoform expression increased in response to Ad5.TGFβ2. These data suggest that both TLR4 and FN-EDA contribute to TGFβ2 induced ocular hypertension.

PMID: 32555351 [PubMed - indexed for MEDLINE]

Differentiation of Hispanic biogeographic ancestry with 80 ancestry informative markers.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Differentiation of Hispanic biogeographic ancestry with 80 ancestry informative markers.

Sci Rep. 2020 05 08;10(1):7745

Authors: Setser CH, Planz JV, Barber RC, Phillips NR, Chakraborty R, Cross DS

Abstract
Ancestry informative single nucleotide polymorphisms (SNPs) can identify biogeographic ancestry (BGA); however, population substructure and relatively recent admixture can make differentiation difficult in heterogeneous Hispanic populations. Utilizing unrelated individuals from the Genomic Origins and Admixture in Latinos dataset (GOAL, n = 160), we designed an 80 SNP panel (Setser80) that accurately depicts BGA through STRUCTURE and PCA. We compared our Setser80 to the Seldin and Kidd panels via resampling simulations, which models data based on allele frequencies. We incorporated Admixed American 1000 Genomes populations (1000 G, n = 347), into a combined populations dataset to determine robustness. Using multinomial logistic regression (MLR), we compared the 3 panels on the combined dataset and found overall MLR classification accuracies: 93.2% Setser80, 87.9% Seldin panel, 71.4% Kidd panel. Naïve Bayesian classification had similar results on the combined dataset: 91.5% Setser80, 84.7% Seldin panel, 71.1% Kidd panel. Although Peru and Mexico were absent from panel design, we achieved high classification accuracy on the combined populations for Peru (MLR = 100%, naïve Bayes = 98%), and Mexico (MLR = 90%, naïve Bayes = 83.4%) as evidence of the portability of the Setser80. Our results indicate the Setser80 SNP panel can reliably classify BGA for individuals of presumed Hispanic origin.

PMID: 32385290 [PubMed - indexed for MEDLINE]

Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging.

Int J Mol Sci. 2020 Mar 11;21(6):

Authors: Zhang H, Jin K

Abstract
People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, PTEN, p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were EIF4EBP1, insulin receptor, PDK1, PTEN, paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.

PMID: 32168775 [PubMed - indexed for MEDLINE]

Endothelin-1 Mediated Decrease in Mitochondrial Gene Expression and Bioenergetics Contribute to Neurodegeneration of Retinal Ganglion Cells.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Endothelin-1 Mediated Decrease in Mitochondrial Gene Expression and Bioenergetics Contribute to Neurodegeneration of Retinal Ganglion Cells.

Sci Rep. 2020 02 27;10(1):3571

Authors: Chaphalkar RM, Stankowska DL, He S, Kodati B, Phillips N, Prah J, Yang S, Krishnamoorthy RR

Abstract
Endothelin-1 (ET-1) is a vasoactive peptide that is elevated in aqueous humor as well as circulation of primary open angle glaucoma (POAG) patients. ET-1 has been shown to promote degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs), however, the precise mechanisms are still largely unknown. In this study, RNA-seq analysis was used to assess changes in ET-1 mediated gene expression in primary RGCs, which revealed that 23 out of 156 differentially expressed genes (DEGs) had known or predicted mitochondrial function, of which oxidative phosphorylation emerged as the top-most enriched pathway. ET-1 treatment significantly decreased protein expression of key mitochondrial genes including cytochrome C oxidase copper chaperone (COX17) and ATP Synthase, H+ transporting, Mitochondrial Fo Complex (ATP5H) in primary RGCs and in vivo following intravitreal ET-1 injection in rats. A Seahorse ATP rate assay revealed a significant decrease in the rate of mitochondrial ATP production following ET-1 treatment. IOP elevation in Brown Norway rats showed a trend towards decreased expression of ATP5H. Our results demonstrate that ET-1 produced a decrease in expression of vital components of mitochondrial electron transport chain, which compromise bioenergetics and suggest a mechanism by which ET-1 promotes neurodegeneration of RGCs in glaucoma.

PMID: 32107448 [PubMed - indexed for MEDLINE]

Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Recent Research Articles from UNTHSC - Tue, 12/15/2020 - 05:35
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Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Am J Alzheimers Dis Other Demen. 2020 Jan-Dec;35:1533317519896725

Authors: Wang H, Shi X, Schenck H, Hall JR, Ross SE, Kline GP, Chen S, Mallet RT, Chen P

Abstract
Although intermittent hypoxia training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This pilot study examined IHT's safety and therapeutic efficacy in elderly patients with amnestic MCI (aMCI). Seven patients with aMCI (age 69 ± 3 years) alternately breathed 10% O2 and room-air, each 5 minutes, for 8 cycles/session, 3 sessions/wk for 8 weeks. The patients' resting arterial pressures fell by 5 to 7 mm Hg (P < .05) and cerebral tissue oxygenation increased (P < .05) following IHT. Intermittent hypoxia training enhanced hypoxemia-induced cerebral vasodilation (P < .05) and improved mini-mental state examination and digit span scores from 25.7 ± 0.4 to 27.7 ± 0.6 (P = .038) and from 24.7 ± 1.2 to 26.1 ± 1.3 (P = .047), respectively. California verbal learning test score tended to increase (P = .102), but trail making test-B and controlled oral word association test scores were unchanged. Adaptation to moderate IHT may enhance cerebral oxygenation and hypoxia-induced cerebrovasodilation while improving short-term memory and attention in elderly patients with aMCI.

PMID: 31902230 [PubMed - indexed for MEDLINE]

Dengue Seroprevalence and Seroconversion in Urban and Rural Populations in Northeastern Thailand and Southern Laos.

Recent Research Articles from UNTHSC - Fri, 12/11/2020 - 14:02

Dengue Seroprevalence and Seroconversion in Urban and Rural Populations in Northeastern Thailand and Southern Laos.

Int J Environ Res Public Health. 2020 Dec 07;17(23):

Authors: Doum D, Overgaard HJ, Mayxay M, Suttiprapa S, Saichua P, Ekalaksananan T, Tongchai P, Rahman MS, Haque U, Phommachanh S, Pongvongsa T, Rocklöv J, Paul R, Pientong C

Abstract
Dengue is the most rapidly spreading mosquito-borne viral disease in the world. The detection of clinical cases enables us to measure the incidence of dengue infection, whereas serological surveys give insights into the prevalence of infection. This study aimed to determine dengue seroprevalence and seroconversion rates in northeastern Thailand and southern Laos and to assess any association of mosquito control methods and socioeconomic factors with dengue virus (DENV) infection. Cross-sectional seroprevalence surveys were performed in May and November 2019 on the same individuals. Blood samples were collected from one adult and one child, when possible, in each of 720 randomly selected households from two urban and two rural sites in both northeastern Thailand and southern Laos. IgG antibodies against DENV were detected in serum using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Overall, 1071 individuals participated in the study. The seroprevalence rate was high (91.5%) across all 8 study sites. Only age and province were associated with seroprevalence rates. There were 33 seroconversions during the period from May to November, of which seven reported fever. More than half of the seroconversions occurred in the rural areas and in Laos. Dengue seroconversion was significantly associated with young age (<15 years old), female gender, province, and duration of living in the current residence. No socioeconomic factors or mosquito control methods were found to be associated with seroprevalence or seroconversion. Notably, however, the province with most seroconversions had lower diurnal temperature ranges than elsewhere. In conclusion, our study has highlighted the homogeneity of dengue exposure across a wide range of settings and most notably those from rural and urban areas. Dengue can no longer be considered to be solely an urban disease nor necessarily one linked to poverty.

PMID: 33297445 [PubMed - in process]

Role of LLT1 and PCNA as Natural Killer Cell Immune Evasion Strategies of HCT 116 Cells.

Recent Research Articles from UNTHSC - Wed, 12/09/2020 - 07:03

Role of LLT1 and PCNA as Natural Killer Cell Immune Evasion Strategies of HCT 116 Cells.

Anticancer Res. 2020 Dec;40(12):6613-6621

Authors: Malaer JD, Mathew PA

Abstract
BACKGROUND/AIM: Cancer stem cells (CSCs) are a subpopulation of cells that retain self-renewal and pluripotency capabilities, are resistant to chemotherapy, and are thought to facilitate metastasis. Target cell expression of proliferating cell nuclear antigen (PCNA) or lectin-like transcript 1 (LLT1) inhibits natural killer (NK) cell functions. The purpose of this study was to characterize the expression of LLT1 or PCNA as NK cell evasion strategies of HCT 116, a colorectal cancer cell line.
MATERIALS AND METHODS: Protein expression was determined by flow cytometry and/or confocal microscopy. Stem-like cells were sorted and characterized, and NK cell effector functions measured by interferon-γ secretion and cytotoxicity assay.
RESULTS: PCNA expressing cells are potential CSCs, blocking PCNA alters interferon-γ secretion, and blocking PCNA or LLT1 increases cytotoxicity.
CONCLUSION: PCNA is a potential biomarker of stem-like colon cancer cells. Based on the results of this study, PCNA and LLT1 should be further explored as in vivo immunotherapeutic targets for NK cell-mediated killing.

PMID: 33288556 [PubMed - in process]

A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors.

Recent Research Articles from UNTHSC - Tue, 12/08/2020 - 05:42
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A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors.

ChemMedChem. 2020 Dec 07;:

Authors: Liu W, Yang K, Ma X, Ma Y, Alugubelli Y, Scott D, Vatansever E, Drelich A, Sankaran B, Geng Z, Blankenship L, Ward H, Sheng Y, Hsu J, Kratch K, Zhao B, Hayatshahi H, Liu J, Li P, Fierke C, Tseng CT, Xu S

Abstract
The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2M Pro ) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1M Pro ), we have designed and synthesized a series of SC2M Pro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2M Pro active site cysteine C145. All inhibitors display high potency with IC 50 values at or below 100 nM. The most potent compound MPI3 has as an IC 50 value as 8.5 nM. Crystallographic analyses of SC2M Pro bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and ACE2 + A549 cells. Two inhibitors MP5 and MPI8 completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 µM and ACE2 + A549 cells at 0.16-0.31 µM.

PMID: 33283984 [PubMed - as supplied by publisher]

Quantitative measurements of IR780 in formulations and tissues.

Recent Research Articles from UNTHSC - Tue, 12/08/2020 - 05:42
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Quantitative measurements of IR780 in formulations and tissues.

J Pharm Biomed Anal. 2020 Nov 20;:113780

Authors: Wang J, Zhang J, Nguyen NTD, Chen YA, Hsieh JT, Dong X

Abstract
PURPOSE: IR780 iodide, a promising near-infrared dye, is widely used to prepare nanoparticles as a theranostic agent for tumor imaging and therapy. However, there are no validated (bio)analytical methods to measure IR780 in nanoparticles and tissues in literature. The aim of this study is to develop and validate a new HPLC method to measure IR780 concentration in IR780 formulations as well as a new LC-MS/MS method to measure IR780 concentration in tissue samples, particularly in liver and lung.
MATERIALS AND METHODS: IR780 granules that produced IR780 in situ self-assembled nanoparticles upon contact with water were prepared at two drug loadings (0.2 % and 0.37 %). An HPLC method was developed and validated to measure IR780 concentrations in IR780 granules and nanoparticles. Furthermore, a validated LC-MS/MS method was developed to measure IR780 in mouse liver and lung. Both HPLC method and LC-MS/MS method were validated in terms of specificity, stability, linearity, limit of detection, limit of quantification, accuracy and precision.
RESULTS: Both HPLC method and LC-MS/MS method achieved the criteria for method validation. The HPLC method was accurate in the concentration range of 0.5-25 μg/mL. The measured drug loadings were 95 % of the theoretical drug loadings. The validated LC-MS/MS method can quantitatively measure the concentrations of IR780 in liver and lung. The linear range of the LC-MS/MS method was 1-1000 ng/mL for both liver and lung samples. IR780 granules showed the lung selectivity compared to IR780 solution at 2 h after oral administration.
CONCLUSION: A validated HPLC method was developed to measure IR780 concentration in pharmaceutical formulations and a validated LC-MS/MS method was developed to measure IR780 concentration in tissues. These quantitative methods provide reliable measurements of IR780 in pharmaceutic formulations and biological samples, which will significantly facilitate the research of IR780 as a theranostic agent for cancer therapy and imaging.

PMID: 33280993 [PubMed - as supplied by publisher]

Cystatin C is a Potential Predictor of Unfavorable Outcomes for Cerebral Ischemia with IV-tPA Treatment: A Multicenter Prospective Nested Case-Control Study.

Recent Research Articles from UNTHSC - Sun, 12/06/2020 - 06:55
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Cystatin C is a Potential Predictor of Unfavorable Outcomes for Cerebral Ischemia with IV-tPA Treatment: A Multicenter Prospective Nested Case-Control Study.

Eur J Neurol. 2020 Dec 04;:

Authors: Chang Z, Zou H, Xie Z, Deng B, Que R, Huang Z, Weng G, Wu Z, Pan Y, Wang Y, Li M, Xie H, Zhu S, Xiong L, Mok VC, Jin K, Yenari MA, Wei X, Wang Q

Abstract
BACKGROUND: This study is to explore whether Cystatin C could be used as a potential predictor of the clinical outcomes in acute ischemic stroke patients treated by intravenous tissue plasminogen activator.
METHODS: We performed an observational study with a retrospective analysis of data from 125 acute ischemic stroke patients with intravenous thrombolysis. General linear models were applied to assess Cystatin C levels between groups with different outcomes; logistic regression analysis and receiver operating characteristic curves were adopted to identify the association between Cystatin C and the therapeutic effects.
RESULTS: Compared with the Good&Sustained Benefit group (≥4 reduction in National Institutes of Health Stroke Scale or a score of 0-1 at 24 hours and 7 days) and the Good Functional Outcome group (modified Rankin Scale 0-2 at 90 days), serum Cystatin C baseline levels were increased in the non-Good&Sustained Benefit and non-Good Functional Outcome groups. Logistic regression analysis found that Cystatin C was an independent negative prognostic factor for Good&Sustained Benefit (odds ratio = 0.010, p = 0.005) and Good Functional Outcome (odds ratio = 0.011, p = 0.021) after adjustment for potential influencing factors. Receiver operating characteristic curves showed the Cystatin C-involved combined models provided credible efficacy for predicting post-90-day favorable clinical outcomes (area under the curve = 0.86, p < 0.001).
CONCLUSIONS: Elevated serum Cystatin C is independently associated with unfavorable clinical outcomes after intravenous tissue plasminogen activator therapy in acute ischemic stroke. Our findings provide new insights into discovering potential mediators for neuropathological process or treatment in stroke.

PMID: 33277774 [PubMed - as supplied by publisher]

Use of a Health Advocacy Model for Survivors of Interpersonal Violence.

Recent Research Articles from UNTHSC - Sun, 12/06/2020 - 06:55
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Use of a Health Advocacy Model for Survivors of Interpersonal Violence.

Int J Environ Res Public Health. 2020 Dec 02;17(23):

Authors: Grace J, Walters ST, Gallegos I, Thompson EL, Spence EE

Abstract
This article examines the implementation of a health advocacy model designed for survivors of interpersonal violence (IPV) in a metropolitan area of North Texas. Using a framework influenced by motivational interviewing, solution-focused therapy, and trauma-informed care, this program engaged IPV survivors in creating health and safety goals. Goal attainment scaling was used to track progress after each health advocacy encounter. Clients could set their own goals for healthcare, self-care, and safety. The program served 419 clients and 648 goals were set by clients at the first visit. Among all goals, 89% selected goals focused on healthcare, with 47% of those selecting obtaining health insurance or coverage as a need. These results demonstrate the need for an enhanced healthcare response for this population. The remaining goals selected were self-care (7%) and safety (3%). The design of the health advocacy intervention shows promise towards filling the gaps between IPV and healthcare service delivery systems.

PMID: 33276649 [PubMed - as supplied by publisher]

Shorter length of hospital stay for hip fracture in those with dementia and without a known diagnosis of osteoporosis in the USA.

Recent Research Articles from UNTHSC - Sat, 12/05/2020 - 07:42
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Shorter length of hospital stay for hip fracture in those with dementia and without a known diagnosis of osteoporosis in the USA.

BMC Geriatr. 2020 Dec 03;20(1):523

Authors: Rasu RS, Zalmai R, Karpes Matusevich AR, Hunt SL, Phadnis MA, Rianon N

Abstract
BACKGROUND: About 50% of all hospitalized fragility fracture cases in older Americans are hip fractures. Approximately 3/4 of fracture-related costs in the USA are attributable to hip fractures, and these are mostly covered by Medicare. Hip fracture patients with dementia, including Alzheimer's disease, have worse health outcomes including longer hospital length of stay (LOS) and charges. LOS and hospital charges for dementia patients are usually higher than for those without dementia. Research describing LOS and acute care charges for hip fractures has mostly focused on these outcomes in trauma patients without a known pre-admission diagnosis of osteoporosis (OP). Lack of documented diagnosis put patients at risk of not having an appropriate treatment plan for OP. Whether having a diagnosis of OP would have an effect on hospital outcomes in dementia patients has not been explored. We aim to investigate whether having a diagnosis of OP, dementia, or both has an effect on LOS and hospital charges. In addition, we also report prevalence of common comorbidities in the study population and their effects on hospital outcomes.
METHODS: We conducted a cross-sectional analysis of claims data (2012-2013) for 2175 Medicare beneficiaries (≥65 years) in the USA.
RESULTS: Compared to those without OP or dementia, patients with demenia only had a shorter LOS (by 5%; P = .04). Median LOS was 6 days (interquartile range [IQR]: 5-7), and the median hospital charges were $45,100 (IQR: 31,500 - 65,600). In general, White patients had a shorter LOS (by 7%), and those with CHF and ischemic heart disease (IHD) had longer LOS (by 7 and 4%, respectively). Hospital charges were 6% lower for women, and 16% lower for White patients.
CONCLUSION: This is the first study evaluating LOS in dementia in the context of hip fracture which also disagrees with previous reporting about longer LOS in dementia patients. Patients with CHF and IHD remains at high risk for longer LOS regardless of their diagnosis of dementia or OP.

PMID: 33272213 [PubMed - in process]

Identification of novel alternative splicing biomarkers for breast cancer with LC/MS/MS and RNA-Seq.

Recent Research Articles from UNTHSC - Sat, 12/05/2020 - 07:42
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Identification of novel alternative splicing biomarkers for breast cancer with LC/MS/MS and RNA-Seq.

BMC Bioinformatics. 2020 Dec 03;21(Suppl 9):541

Authors: Zhang F, Deng CK, Wang M, Deng B, Barber R, Huang G

Abstract
BACKGROUND: Alternative splicing isoforms have been reported as a new and robust class of diagnostic biomarkers. Over 95% of human genes are estimated to be alternatively spliced as a powerful means of producing functionally diverse proteins from a single gene. The emergence of next-generation sequencing technologies, especially RNA-seq, provides novel insights into large-scale detection and analysis of alternative splicing at the transcriptional level. Advances in Proteomic Technologies such as liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), have shown tremendous power for the parallel characterization of large amount of proteins in biological samples. Although poor correspondence has been generally found from previous qualitative comparative analysis between proteomics and microarray data, significantly higher degrees of correlation have been observed at the level of exon. Combining protein and RNA data by searching LC-MS/MS data against a customized protein database from RNA-Seq may produce a subset of alternatively spliced protein isoform candidates that have higher confidence.
RESULTS: We developed a bioinformatics workflow to discover alternative splicing biomarkers from LC-MS/MS using RNA-Seq. First, we retrieved high confident, novel alternative splicing biomarkers from the breast cancer RNA-Seq database. Then, we translated these sequences into in silico Isoform Junction Peptides, and created a customized alternative splicing database for MS searching. Lastly, we ran the Open Mass spectrometry Search Algorithm against the customized alternative splicing database with breast cancer plasma proteome. Twenty six alternative splicing biomarker peptides with one single intron event and one exon skipping event were identified. Further interpretation of biological pathways with our Integrated Pathway Analysis Database showed that these 26 peptides are associated with Cancer, Signaling, Metabolism, Regulation, Immune System and Hemostasis pathways, which are consistent with the 256 alternative splicing biomarkers from the RNA-Seq.
CONCLUSIONS: This paper presents a bioinformatics workflow for using RNA-seq data to discover novel alternative splicing biomarkers from the breast cancer proteome. As a complement to synthetic alternative splicing database technique for alternative splicing identification, this method combines the advantages of two platforms: mass spectrometry and next generation sequencing and can help identify potentially highly sample-specific alternative splicing isoform biomarkers at early-stage of cancer.

PMID: 33272210 [PubMed - in process]

Interferon gamma release assay tests are associated with persistence and completion of latent tuberculosis infection treatment in the United States: Evidence from commercial insurance data.

Recent Research Articles from UNTHSC - Fri, 12/04/2020 - 06:08
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Interferon gamma release assay tests are associated with persistence and completion of latent tuberculosis infection treatment in the United States: Evidence from commercial insurance data.

PLoS One. 2020;15(12):e0243102

Authors: Stockbridge EL, Loethen AD, Annan E, Miller TL

Abstract
BACKGROUND: Risk-targeted testing and treatment of latent tuberculosis infection (LTBI) is a critical component of the United States' (US) tuberculosis (TB) elimination strategy, but relatively low treatment completion rates remain a challenge. Both treatment persistence and completion may be facilitated by diagnosing LTBI using interferon gamma release assays (IGRA) rather than tuberculin skin tests (TST).
METHODS: We used a national sample of administrative claims data to explore associations diagnostic test choice (TST, IGRA, TST with subsequent IGRA) and treatment persistence and completion in persons initiating a daily dose isoniazid LTBI treatment regimen in the US private healthcare sector between July 2011 and March 2014. Associations were analyzed with a generalized ordered logit model (completion) and a negative binomial regression model (persistence).
RESULTS: Of 662 persons initiating treatment, 327 (49.4%) completed at least the 6-month regimen and 173 (26.1%) completed the 9-month regimen; 129 (19.5%) persisted in treatment one month or less. Six-month completion was least likely in persons receiving a TST (42.2%) relative to persons receiving an IGRA (55.0%) or TST then IGRA (67.2%; p = 0.001). Those receiving an IGRA or a TST followed by an IGRA had higher odds of completion compared to those receiving a TST (aOR = 1.59 and 2.50; p = 0.017 and 0.001, respectively). Receiving an IGRA or a TST and subsequent IGRA was associated with increased treatment persistence relative to TST (aIRR = 1.14 and 1.25; p = 0.027 and 0.009, respectively).
CONCLUSIONS: IGRA use is significantly associated with both higher levels of LTBI treatment completion and treatment persistence. These differences are apparent both when IGRAs alone were administered and when IGRAs were administered subsequent to a TST. Our results suggest that IGRAs contribute to more effective LTBI treatment and consequently individual and population protections against TB.

PMID: 33270737 [PubMed - as supplied by publisher]

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