Investigating the role of Hedgehog/GLI1 signaling in glioblastoma cell response to temozolomide.

Resistance to chemotherapy substantially hinders successful glioblastoma (GBM) treatment, contributing to an almost 100% mortality rate. Resistance to the frontline chemotherapy, temozolomide (TMZ), arises from numerous signaling pathways that are deregulated in GBM, including Hedgehog (Hh) signaling. Here, we investigate suppression of Hh signaling as an adjuvant to TMZ using U87-MG and T98G cell lines as in vitro models of GBM. We found that silencing GLI1 with siRNA reduces cell metabolic activity by up to 30% in combination with TMZ and reduces multidrug efflux activity by 2.5-fold. Additionally, pharmacological GLI inhibition modulates nuclear p53 levels and decreases MGMT expression in combination with TMZ. While we surprisingly found that silencing GLI1 does not induce apoptosis in the absence of TMZ co-treatment, we discovered silencing GLI1 without TMZ co-treatment induces senescence as evidenced by a significant 2.3-fold increase in senescence associated β-galactosidase staining, and this occurs in a loss of PTEN-dependent manner. Finally, we show that GLI inhibition increases apoptosis in glioma stem-like cells by up to 6.8-fold in combination with TMZ, and this reduces the size and number of neurospheres grown from glioma stem-like cells. In aggregate, our data warrant the continued investigation of Hh pathway inhibitors as adjuvants to TMZ chemotherapy and highlight the importance of identifying signaling pathways that determine whether co-treatment will be successful

Effects of Dietary Sodium Intake on Blood Flow Regulation During Exercise in Salt Resistant Individuals

PURPOSE: Dietary sodium intake guidelines is ≤2,300 mg/day, yet is exceeded by 90% of Americans. This study examined the impact of a high sodium diet on blood flow regulation during exercise. METHODS: Six males (25 ± 2 years) consumed dietary sodium intake guidelines for two weeks, with one week salt-capsule supplemented (HS: 6,900 mg/day of sodium) and the other week placebo-capsule supplemented (LS: 2,300 mg/day of sodium). At the end of each week, peripheral hemodynamic measurements [blood flow (BF), shear rate (SR), and flow mediated dilation (FMD)/SR)] of the brachial and superficial femoral artery were taken during handgrip (HG) and plantar flexion (PF) exercise, respectively. Each exercise workload was 3 minutes and progressed by 8 kilograms until exhaustion. RESULTS: There were no differences between LS and HS in blood pressure (82 ± 4 v 80 ± 5 mmHg; p = 0.3) or heart rate (56 ± 6 v 59 ± 10 bpm; p = 0.4). HG and PF exercise increased BF, SR, and FMD/SR across workload (p \u3c 0.03 for all), but no difference between diets (p \u3e 0.05 for all). CONCLUSION: Despite previous reports that HS impairs resting vascular function, this study revealed that peripheral vascular function and blood flow regulation during exercise is not impacted by a HS diet.https://scholarscompass.vcu.edu/gradposters/1082/thumbnail.jp

Conservation of Sharp-Tailed Grouse (\u3cem\u3eTympanuchus phasianellus columbianus\u3c/em\u3e) Through Fecal DNA Extraction

Columbian Sharp-tailed Grouse (Tympanuchus phasianellus columbianus) are the rarest of the six extant Sharp-tailed Grouse subspecies. This subspecies experienced a 90% range contraction over the last century and have been extirpated from several states (Figure 1). In Washington alone, populations that once numbered hundreds of thousands of individuals now consist of fewer than 1,000 birds. Conservation efforts—including conservation translocations and habitat management—are underway to help bolster this imperiled subspecies across their range. However, little is known about the ecology of this charismatic species and the factors that may be contributing towards higher rates of decline. The collection of fecal pellets presents an opportunity to better understand Columbian Sharp-tailed Grouse across their range, by providing information on their diet and host ID. As a HERC Fellow in the Conservation Genetics Lab at Boise State University, I have been exploring the potential to use non-invasively collected fecal samples to understand how we can best capture different DNA types, which can be used to better inform the conservation and management of this charismatic grouse

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

APOBEC3G Polymorphism as a Selective Barrier to Cross-Species Transmission and Emergence of Pathogenic SIV and AIDS in a Primate Host

Cellular restriction factors, which render cells intrinsically resistant to viruses, potentially impose genetic barriers to cross-species transmission and emergence of viral pathogens in nature. One such factor is APOBEC3G. To overcome APOBEC3G-mediated restriction, many lentiviruses encode Vif, a protein that targets APOBEC3G for degradation. As with many restriction factor genes, primate APOBEC3G displays strong signatures of positive selection. This is interpreted as evidence that the primate APOBEC3G locus reflects a long-term evolutionary “arms-race” between retroviruses and their primate hosts. Here, we provide direct evidence that APOBEC3G has functioned as a barrier to cross-species transmission, selecting for viral resistance during emergence of the AIDS-causing pathogen SIVmac in captive colonies of Asian macaques in the 1970s. Specifically, we found that rhesus macaques have multiple, functionally distinct APOBEC3G alleles, and that emergence of SIVmac and simian AIDS required adaptation of the virus to evade APOBEC3G-mediated restriction. Our evidence includes the first comparative analysis of APOBEC3G polymorphism and function in both a reservoir and recipient host species (sooty mangabeys and rhesus macaques, respectively), and identification of adaptations unique to Vif proteins of the SIVmac lineage that specifically antagonize rhesus APOBEC3G alleles. By demonstrating that interspecies variation in a known restriction factor selected for viral counter-adaptations in the context of a documented case of cross-species transmission, our results lend strong support to the evolutionary “arms-race” hypothesis. Importantly, our study confirms that APOBEC3G divergence can be a critical determinant of interspecies transmission and emergence of primate lentiviruses, including viruses with the potential to infect and spread in human populations

Trends in Abortion Incidence and Service Availability in North Carolina, 1980-2013

Objectives: Abortion incidence has declined nationally during the last decade. In recent years, many states, including North Carolina, have passed legislation related to the provision of abortion services. Despite the changing political environment, there is no comprehensive analysis on past and current trends related to unintended pregnancy and abortion in North Carolina. Methods: This study is a secondary analysis of vital registration data made publicly available by the North Carolina State Center for Health Statistics. Birth and induced abortion records were obtained for the years 1980 to 2013. We describe abortion incidence and demographic characteristics of women obtaining abortions over time. Results: The number of North Carolina abortions declined 36% between 1980 and 2013. The abortion ratio declined from 26/100 pregnancies (live births and abortions) in 1980 to just 14/100 in 2013. These ratios, however, vary across demographic subgroups. In 2013, the abortion ratio was more than 2 times greater for non-Hispanic black women than non-Hispanic white women (22 and 9, respectively). Among non-Hispanic black and Hispanic women, the abortion ratio is greater among women with a previous pregnancy as compared with women in their first pregnancy. For non-Hispanic white women, the abortion ratios are similar for first and higher-order pregnancies. Conclusions: Trends in North Carolina are similar to national trends; however, detailed analyses by race/ethnicity, age, and parity demonstrate important distinctions among abortion patients over time in the state. We discuss these trends in relation to policy changes and increased access to effective contraceptive

Impacts of ocean warming on the settlement success and post‐settlement survival of Pacific crown‐of‐thorns starfish (Acanthaster cf. solaris)

Ocean warming and population irruptions of crown-of-thorns starfish (CoTS; Acanthaster cf. solaris) are two of the greatest threats to coral reefs. As such, there is significant interest in understanding how CoTS may be directly impacted by rising ocean temperatures. Settlement of planktonic larvae and subsequent metamorphosis is purported to be a major population bottleneck in marine invertebrates, yet it is unknown how ocean warming will impact these processes in CoTS. Herein, the effect of temperature (28 °C ambient, 30 °C, 32 °C, 34 °C) on the settlement success, metamorphic success, and post-settlement survival of this corallivore was explored. While larval settlement was robust to elevated temperature, with at least 94% of larvae settling after 48 h across all temperatures, it was observed that settlement success was lower on substrate that had been pre-treated ≥ 32 °C. Metamorphic success was also significantly constrained at temperatures ≥ 32 °C. At 32 °C and 34 °C metamorphic success was 16% and 63% lower than at ambient temperature, respectively. Significant adverse effects of warming on post-settlement survival were observed at even cooler temperatures, with 10% lower survival at 30 °C compared to at ambient temperature, and at 34 °C, survival was 34% lower. Substantial reductions in metamorphic success and early post-settlement survival at elevated temperatures, as well as negative impacts of warming on the settlement substrate and its capacity to induce settlement, may present a bottleneck for recruitment in a warmer ocean

Effects of elevated temperature on the performance and survival of pacific crown-of-thorns starfish (Acanthaster cf. solaris)

Population irruptions of Pacific crown-of-thorns starfish (Acanthaster cf. solaris) have caused substantial damage to coral reefs, but it is largely unknown how this asteroid will fare in a warmer ocean. We exposed these starfish to one of four thermal treatments, with final temperatures of 26 °C (control, annual average), 28 °C (summer average), 30 °C (summer maximum) and 32 °C (predicted summer maximum by 2100). We measured the righting time, movement rate, standard metabolic rate and probability of survival of the crown-of-thorns starfish at various timepoints over ~ 60 days. We found that while tempera- ture did not affect righting time, it did significantly affect movement rate. The movement rate of starfish increased across the 26 to 30 °C range, with those at 28 °C and 30 °C moving 18 and 27% faster than those at the control temperature. Similarly, the standard metabolic rate of starfish increased from 26 to 30 °C, with metabolism 100% and 260% faster at 28 °C and 30 °C compared to those at the 26 °C control. At 32 °C, individual starfish exhibited a 14% slower movement rate, a 33% slower metabolic rate, and also exhibited a fourfold lower probability of survival than those at 30 °C. These results indicate that 32 °C is above the thermal optimum of crown-of-thorns starfish, suggesting that prolonged exposure to temperatures that are expected to be regularly exceeded under near-future climate change may be detrimental to this species