Center for HPV Research at IUPUI

poster abstractHuman Papillomavirus (HPV) infection is highly prevalent among women and men and is associated with a number of diseases including genital warts, cervical cancers, other anogenital cancers in both men and women, and cancers of the head and neck. HPV infections are also associated with millions of dollars in annual health care costs. Two vaccines have been developed to prevent HPV infection. Both are approved for use in females ages 9 through 26, and one vaccine is approved for use in 9 to 26 year old males as well. Both vaccines are efficacious, safe, and cost-effective. Despite the great promise of HPV vaccines, vaccination rates in the U.S. are much lower than desired, with 2011 data indicating that 53% of 13-17 year old females received one or more doses and only 37% completed the 3-dose series. The ongoing medical, psychosocial, and financial costs of HPV infection indicate the need for comprehensive, cross-disciplinary research efforts coordinated with community outreach. We have established the Center for Human Papillomavirus (HPV) Research at IUPUI; which fosters cohesion and collaboration among investigators from multiple disciplines and departments at IUPUI, IU Bloomington, and University of Notre Dame pursuing HPV-related research. This group of accomplished senior faculty and promising junior scholars represents a growing synergy between basic, clinical, and social/behavioral sciences. The Center for HPV Research will provide formal infrastructure and resources for pilot research projects, and a collaborative environment for development of proposals for external funding. By capitalizing on the unique strengths of an internationally recognized faculty and IUPUI’s remarkable culture of collaborative and interdisciplinary research, we will establish a world-class center for HPV research, research training, and research translation. The overall mission of the Center for HPV Research will be to improve understanding of HPV transmission, infection, and prevention of HPV infection and its consequences

The Use of a Visual Motor Test to Identify Lingering Deficits in Concussed Collegiate Athletes

Background: Emerging evidence suggests neurophysiological deficits, such as visual motor coordination (VMC), may persist beyond clinical concussion recovery. Instrumented measurement of upper-limb VMC is critical for neurological evaluation post-concussion and may identify persistent deficits further elucidating persistent neurophysiological impairments not detected by the current clinical assessment battery. Aim: The aim of the study was to determine if a VMC test identifies persistent deficits in concussed collegiate student-athletes who have returned to baseline on clinical concussion assessments. Methods: Thirteen recently concussed intercollegiate student-athletes (male: 7, 18.9±0.7 years, 175.5±12.4 cm, 75.5±23.2 kg), and 13 matched control student-athletes (male: 7, 19.3±1.1 years, 173.5±11.9 cm, 75.8±19.9 kg) completed two testing sessions (T1: \u3c48 h after clinical recovery; T2: 30 days post-concussion) on a visual motor exam. The outcome measures were A* Average score (average number of lights hit on A* exam), simple visual reaction time (SVRT)-RT, and movement time (SVRT-MT) on the Dynavision D2. The dependent variables were compared with a 2 (group) × 2 (time) repeated measures ANOVAs. Results: There was no group interaction in A* average score (F(1,24)=0.036, P=0.849), SVRT-RT (F(1,22)=0.319, P=0.575), and SVRT-MT (F(1,22)=1.179, P=0.188). There was a main effect for time on A* average score (T1: 76.3±10.4 hits; T2: 82.7±11.2 hits; F(1,24)=38.1, P≤0.001) and SVRT-RT (T1: 0.31±0.04; T2: 0.29±0.04 s; F(1,22)=4.9, P=0.039). There was no main effect for SVRT-MT. There were no group differences at either time point. Conclusions: Among recently concussed collegiate student-athletes, no persistent deficits were identified in VMC beyond clinical recovery when assessed by Dynavision D2. This VMC exam may not provide a useful means of tracking recovery following concussion likely due to a substantial practice effect. Relevance for patients: While post-concussion neurophysiological deficits persist beyond clinical recovery, the laboratory based VMC assessment herein did not identify deficits at critical post-concussion time points. Therefore, other clinically translatable VMC assessments should be further investigated

Δ⁹-tetrahydrocannabinol and 2-AG decreases neurite outgrowth and differentially affects ERK1/2 and Akt signaling in hiPSC-derived cortical neurons

Endocannabinoids regulate different aspects of neurodevelopment. In utero exposure to the exogenous psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), has been linked with abnormal cortical development in animal models. However, much less is known about the actions of endocannabinoids in human neurons. Here we investigated the effect of the endocannabinoid 2-arachidonoyl glycerol (2AG) and Δ9-THC on the development of neuronal morphology and activation of signaling kinases, in cortical neurons derived from human induced pluripotent stem cells (hiPSCs). Our data indicate that the cannabinoid type 1 receptor (CB1R), but not the cannabinoid 2 receptor (CB2R), GPR55 or TRPV1 receptors, is expressed in young, immature hiPSC-derived cortical neurons. Consistent with previous reports, 2AG and Δ9-THC negatively regulated neurite outgrowth. Interestingly, acute exposure to both 2AG and Δ9-THC inhibited phosphorylation of serine/threonine kinase extracellular signal-regulated protein kinases (ERK1/2), whereas Δ9-THC also reduced phosphorylation of Akt (aka PKB). Moreover, the CB1R inverse agonist SR 141716A attenuated the decrease in neurite outgrowth and ERK1/2 phosphorylation induced by 2AG and Δ9-THC. Taken together, our data suggest that hiPSC-derived cortical neurons express CB1Rs and are responsive to exogenous cannabinoids. Thus, hiPSC-neurons may represent a good cellular model for investigating the role of the endocannabinoid system in regulating cellular processes in developing human neurons

Rest-Frame Optical Spectra of Three Strongly Lensed Galaxies at z~2

We present Keck II NIRSPEC rest-frame optical spectra for three recently discovered lensed galaxies: the Cosmic Horseshoe (z = 2.38), the Clone (z = 2.00), and SDSS J090122.37+181432.3 (z = 2.26). The boost in signal-to-noise ratio (S/N) from gravitational lensing provides an unusually detailed view of the physical conditions in these objects. A full complement of high S/N rest-frame optical emission lines is measured, spanning from rest-frame 3600 to 6800AA, including robust detections of fainter lines such as H-gamma, [SII]6717,6732, and in one instance [NeII]3869. SDSS J090122.37+181432.3 shows evidence for AGN activity, and therefore we focus our analysis on star-forming regions in the Cosmic Horseshoe and the Clone. For these two objects, we estimate a wide range of physical properties, including star-formation rate (SFR), metallicity, dynamical mass, and dust extinction. In all respects, the lensed objects appear fairly typical of UV-selected star-forming galaxies at z~2. The Clone occupies a position on the emission-line diagnostic diagram of [OIII]/H-beta vs. [NII]/H-alpha that is offset from the locations of z~0 galaxies. Our new NIRSPEC measurements may provide quantitative insights into why high-redshift objects display such properties. From the [SII] line ratio, high electron densities (~1000 cm^(-3)) are inferred compared to local galaxies, and [OIII]/[OII] line ratios indicate higher ionization parameters compared to the local population. Building on previous similar results at z~2, these measurements provide further evidence (at high S/N) that star-forming regions are significantly different in high-redshift galaxies, compared to their local counterparts (abridged).Comment: 16 pages, 8 figures. Accepted for publication in the Astrophysical Journa

Consumer product exposures associated with urinary phthalate levels in pregnant women

Human phthalate exposure is ubiquitous, but little is known regarding predictors of urinary phthalate levels. To explore this, 50 pregnant women aged 18–38 years completed two questionnaires on potential phthalate exposures and provided a first morning void. Urine samples were analyzed for 12 phthalate metabolites. Associations with questionnaire items were evaluated via Wilcoxon tests and t-tests, and r-squared values were calculated in multiple linear regression models. Few measured factors were statistically significantly associated with phthalate levels. Individuals who used nail polish had higher levels of mono-butyl phthalate (p=0.048) than non-users. Mono-benzyl phthalate levels were higher among women who used eye makeup (p=0.034) or used makeup on a regular basis (p=0.004). Women who used cologne or perfume had higher levels of di-(2-ethylhexyl) phthalate metabolites. Household products, home flooring or paneling, and other personal care products were also associated with urinary phthalates. The proportion of variance in metabolite concentrations explained by questionnaire items ranged between 0.31 for mono-ethyl phthalate and 0.42 for mono-n-methyl phthalate. Although personal care product use may be an important predictor of urinary phthalate levels, most of the variability in phthalate exposure was not captured by our relatively comprehensive set of questionnaire items

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Introduction\ud Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity. \ud \ud Methods\ud Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13). \ud \ud Results\ud The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression. \ud \ud Conclusions\ud These findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients. \ud \u

Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma

SummaryWe have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds

Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies

Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcome

Cytokines and Inflammatory Mediators [30-39]: 30. The LPS Stimulated Production of Interleukin-10 is not Associated with -819C/T and -592C/A Promoter Polymorphisms in Healthy Indian Subjects

Background: Interleukin-10 is a pivotal immunoregulatory cytokine with pleiotropic effects on the immune system. IL-10 promoter polymorphisms have been associated with disease susceptibility and the ability to secrete IL-10 in vitro. We suspected that the association of the widely studied -819C/T and -592C/A polymorphisms with the IL-10 production might vary between ethnic groups. Therefore, we examined the association of -819 C/T and -592 C/A promoter polymorphisms with in vitro LPS stimulated secretion of IL-10 in normal healthy Indian volunteers. Methods: Peripheral blood was collected from 103 healthy volunteers and diluted whole blood cultures were set up with 100 ng/ml of LPS as stimulant: supernatant was collected at 24 h and IL-10 levels were assayed by ELISA. Genotyping was done for -819C/T polymorphism in 101 individuals and -592C/A polymorphism in 68 individuals by polymerase chain reaction followed by RFLP. The differences in IL-10 production between the genotypes were analysed by ANOVA. Results: There were 30, 47 and 24 individuals with the CC, CT and TT genotypes with a minor allele (T) frequency of 47% for the -819C/T polymorphism. The CC and TT genotypes at position -819 were strongly associated with CC and AA genotypes at -592 position suggestive of strong linkage disequilibrium. There was no association between the -819 genotype and the in vitro LPS stimulated IL-10 levels. Conclusions: The -819C/T and the -592 C/A polymorphisms of the IL-10 promoter region are not significantly associated with LPS stimulated IL-10 production healthy Indian subjects. Disclosure statement: All authors have declared no conflicts of interes