Dissecting BMI1 Protein-Protein Interactions Through Chemical Biology.

BMI1 has emerged as a key oncogenic factor in many cancers, associated with unregulated cellular proliferation, tumor metastasis and cancer-initiating cell self-renewal. BMI1 is best characterized as a component of the canonical vertebrate polycomb repression complex 1 (PRC1) which negatively regulate transcription of hundreds of genes through ubiquitination of histone H2A. Previous work suggested that BMI1 has multiple protein binding partners within the PRC1 complex and we were motivated by the prospects to target these protein-protein interactions (PPIs) with small molecule inhibitors. This dissertation describes a multi-pronged campaign to: 1) characterize BMI1 PPIs at the molecular level and 2) develop novel chemical tools to explore BMI1 function in both normal and cancer biology. Using X-ray crystallography and solution NMR approaches we solved the 3D structure of BMI1 in complex with its PRC1 binding partner protein PHC2. Supporting biochemical and biophysical characterization of the BMI1 PPI domain demonstrated a novel mode of self-association of this domain. Mutagenic disruption of both BMI1-PHC2 and BMI1-BMI1 interactions blocks cellular proliferation demonstrating that multiple PPIs are critical for BMI1 function. To identify small molecule inhibitors of BMI1 we designed two biochemical assays to quantify the BMI1-PHC2 interaction and these assays were used as a platform for high-throughput screening. Through this screen we identified three classes of small molecule inhibitors that bind directly to BMI1 to disrupt the BMI1-PHC2 interaction, representing three different strategies for BMI1 inhibitor development. As a complementary approach to inhibit BMI1 we developed a specific inhibitor of Ring1B/BMI1- mediated H2A ubiquitination with potent inhibitory activity both in vitro and in cells. Mechanistic characterization demonstrates that Ring1B/BMI1 inhibitors induce significant protein conformational change and the inhibitor-bound conformation is incompatible with nucleosome binding by Ring1B. These molecules represent the first direct-binding inhibitors of Ring1B/BMI1 and have a novel mechanism of action to block direct protein-nucleosome interaction. Overall, this work contributes to the understanding of BMI1 function through characterization of its multiple PPIs and demonstrates that these interactions can be inhibited by small molecules representing novel strategies to target this protein for development of new chemical tools or potential therapeutics for cancer.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113363/1/flvgray_1.pd

The Grizzly, March 27, 2003

America at War: President Bush says Victory is Certain in Iraq • A Day in the Life of a UN Weapons Inspector • Celebrate Women\u27s History Month • A Fine Ursinus Fellow • Project Vote Smart Approves Five Scholarships for Ursinus College Students • Psyched up for Psycho Beach Party • Calling All Talents • Silence Broken: Korean Comfort Women • Men\u27s Basketball Falls to Scranton • Howard Earns All-American Honors • Dougherty 11th at NCAA Track Championshipshttps://digitalcommons.ursinus.edu/grizzlynews/1532/thumbnail.jp

Hepatitis C Virus Screening Strategies to Improve Early Identification and Treatment: ​ A Scoping Review​

Purpose/Background Hepatitis C virus (HCV) is the most common bloodborne infection in the United States (Ludden et al., 2022). Sadly, over half of the individuals living with chronic HCV are unaware of their condition (Halket et al., 2022). Due to rising numbers, HCV screening guidelines have been updated to recommend that every adult be screened at least once (Patel et al, 2021). Despite these guidelines, screening rates remain low. This scoping review aims to examine current research on HCV screening and strategies to improve early diagnosis and treatment. Methods This review began with a literature search using CINAHL and PubMed and the key phrases hepatitis C, screening, birth cohort, CDC, electronic medical record (EMR), and lifestyle risk. Inclusion criteria were publication within the last five years, English language, and full-text availability. Seven of the 28 articles meeting this criteria were selected based on their applicability, high-quality, and rigor. Specific data points were abstracted from these articles and compiled in an Excel spreadsheet. Results Three studies that evaluated the effectiveness of universal screening versus risk and/or birth cohort screening found that universal screening resulted in higher screening rates. EMR interventions based on risk and/or birth cohort were evaluated in six of the studies, with all six reporting increased screening rates. Additionally, one study found that screening rates increased when EMR-based interventions were paired with provider education. Implications for Nursing Practice The results of this review suggest that application of universal screening and the incorporation of EMR-based interventions lead to an appreciable increase in HCV screening and diagnosis, but studies that implement these interventions based on universal screening guidelines are needed. Most importantly, this review revealed that healthcare providers and patients need education on current screening guidelines, testing, and treatment so HCV can be diagnosed and treated early

Problem formulation in the environmental risk assessment for genetically modified plants

Problem formulation is the first step in environmental risk assessment (ERA) where policy goals, scope, assessment endpoints, and methodology are distilled to an explicitly stated problem and approach for analysis. The consistency and utility of ERAs for genetically modified (GM) plants can be improved through rigorous problem formulation (PF), producing an analysis plan that describes relevant exposure scenarios and the potential consequences of these scenarios. A properly executed PF assures the relevance of ERA outcomes for decision-making. Adopting a harmonized approach to problem formulation should bring about greater uniformity in the ERA process for GM plants among regulatory regimes globally. This paper is the product of an international expert group convened by the International Life Sciences Institute (ILSI) Research Foundation

Extreme Conservation Leads to Recovery of the Virunga Mountain Gorillas

As wildlife populations are declining, conservationists are under increasing pressure to measure the effectiveness of different management strategies. Conventional conservation measures such as law enforcement and community development projects are typically designed to minimize negative human influences upon a species and its ecosystem. In contrast, we define “extreme” conservation as efforts targeted to deliberately increase positive human influences, including veterinary care and close monitoring of individual animals. Here we compare the impact of both conservation approaches upon the population growth rate of the critically endangered Virunga mountain gorillas (Gorilla beringei beringei), which increased by 50% since their nadir in 1981, from approximately 250 to nearly 400 gorillas. Using demographic data from 1967–2008, we show an annual decline of 0.7%±0.059% for unhabituated gorillas that received intensive levels of conventional conservation approaches, versus an increase 4.1%±0.088% for habituated gorillas that also received extreme conservation measures. Each group of habituated gorillas is now continuously guarded by a separate team of field staff during daylight hours and receives veterinary treatment for snares, respiratory disease, and other life-threatening conditions. These results suggest that conventional conservation efforts prevented a severe decline of the overall population, but additional extreme measures were needed to achieve positive growth. Demographic stochasticity and socioecological factors had minimal impact on variability in the growth rates. Veterinary interventions could account for up to 40% of the difference in growth rates between habituated versus unhabituated gorillas, with the remaining difference likely arising from greater protection against poachers. Thus, by increasing protection and facilitating veterinary treatment, the daily monitoring of each habituated group contributed to most of the difference in growth rates. Our results argue for wider consideration of extreme measures and offer a startling view of the enormous resources that may be needed to conserve some endangered species

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Urban partnerships for educational equity and successful educational transitions.

School counseling graduate students provide assistance to inner city middle and high school students to prepare them for post-secondary educational options