Site for WUH TrialNet: NATURAL HISTORY STUDY OF THE DEVELOPMENT OF TYPE 1 DIABETES
Site for The TrialNet Natural History Study of the Development of T1D is divided into Screening and Monitoring stages. Each stage will require separate informed consent for entry. Screening involves testing relatives of individuals with diabetes for the presence of islet autoantibodies. Individuals who have autoantibodies will be enrolled into the Monitoring stage (see Appendix Schedule of Assessments). The study will use a prospective cohort design.The algorithm below shows the flow of participants in the Screening and Monitoring stages. The Screening stage involves measurement of GAD65A, IA-2A, and mIAA, (with a positive result for any of these leading to measurement of ICA and ZnT8A) to determine whether the participant is eligible for the Monitoring stage. As additional diabetes-related autoantibodies are discovered and validated, they may also be included in Screening. Participants will be eligible for Monitoring if they have at least two positive autoantibodies on a Screening sample or at least one positive autoantibody on two separate Screening samples. Participants younger than 18 years old who are negative for all autoantibodies will be offered annual autoantibody rescreening until their 18th birthday. Participants 18 or older with a single positive autoantibody on the first Screening sample but no positive autoantibodies on a confirmatory test will be offered annual rescreening for two years.
Site for WUH: AGCT1532: Phase 3 Accelerated BEP Trial: A randomised phase 3 trial of accelerated versus standard BEP chemotherapy for patients with intermediate and poor-risk metastatic germ cell tumours
Site for To determine if accelerated BEP (Bleomycin, Etoposide, cisPlatin) is superior to standard BEP as first-line chemotherapy for intermediate and poor-risk metastatic GCTs.
Site for WUH: Circulating Exosome Effects on Cholesterol Handling: Impact on Cardiovascular Risk in Obesity
Site for Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Obesity increases risk for coronary heart disease and stroke. Prevention or regression of atherosclerosis would be informed by better understanding of the mechanisms that underlie development of atherosclerosis. Addressing this, we have identified a potential link between obese fat and atherosclerosis via exosomes. These exosomes, are capable of communicating between cells at a distance. The experiments proposed will define a mechanism by which obesity can lay the foundation for atherosclerosis and cardiovascular disease. Further, this will be useful in identifying obese patients at highest risk of developing cardiovascular disease, and thus may benefit the most from pharmaceutical or surgical intervention.One of the hallmarks of atherosclerosis is macrophage cholesterol efflux impairment which leads to intracellular accumulation of modified low-density lipoprotein (LDL) and subsequent formation of plaque forming lipid-rich foam cells. Macrophage cholesterol homeostasis is a delicate balance among influx, endogenous synthesis, esterification/hydrolysis and efflux. Even with this knowledge, it is unclear how obesity impairs cholesterol homeostasis. While the link between obesity and atherosclerosis is strong epidemiologically, large variations exist in individual responses to obesity. For example, some patients with high adiposity have normal cardiovascular health, while others with low adiposity have frank atherosclerosis. Exosomes are actively shed endocytic vesicles that transport lipids, sugars, nucleic acids, and proteins between cells at a distance. Exosomal function is largely determined by their microRNA content. MicroRNAs (miRNAs) are non-coding RNA (19–22 nucleotides) that post-transcriptionally regulate gene expression by base-pairing with the 3' untranslated region of complementary messenger RNA targets. The biological contexts that determine the exosomal microRNA-ome and their relationship to atherosclerosis remain to be clarified.
Site for WUH: COG# AGCT1531: A Phase 3 Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients with Germ Cell Tumors
Site for ?Despite recent improvements in outcome for children with newly diagnosed high-risk neuroblastoma, cure rates remain unsatisfactory. Further, these gains have been the result of interventions during the Consolidation (tandem autologous stem cell transplant) and Post-Consolidation (dinutuximab immunotherapy) phases of treatment, while rates of disease control during Induction have not improved in recent COG trials. The current phase 3 trial seeks to improve the event-free survival (EFS) for children with high-risk neuroblastoma through early integration of promising novel targeted therapies: targeted radiopharmaceutical therapy with 131I-MIBG or the ALK inhibitor, crizotinib. After enrollment, patients will receive one cycle of Induction chemotherapy. Subsequent therapy will be based upon MIBG avidity and ALK status. Patients with MIBG-avid, ALK wild type (or ALK unknown) disease will be randomized to one of three arms: A) current COG recommended high-risk therapy including four more cycles of Induction chemotherapy and surgical resection of the primary tumor, Consolidation with tandem transplant and focal external beam radiation, and dinutuximab immunotherapy with isotretinoin; B) current COG recommended high-risk therapy with the addition of a block of 131I-MIBG after the third Induction cycle; or C) current COG recommended high-risk therapy with the addition of a block of 131I-MIBG after the third Induction cycle and substitution of busulfan / melphalan (BuMel) single autologous stem cell transplant in place of tandem transplant. Patients with MIBG non-avid, ALK wild type (or ALK unknown) disease will be non-randomly assigned to receive current COG recommended high-risk therapy without the addition of 131I-MIBG. Patients with ALK aberrant tumors (ALK tyrosine kinase mutation or ALK amplification) will be non-randomly assigned to receive crizotinib added to current COG recommended high-risk therapy. The primary endpoint is EFS and 774 eligible and evaluable patients are anticipated to enroll over approximately 5 years. Key secondary endpoints are toxicity, end-Induction response, and overall survival. Late effects of therapy including targeted therapies will be compared with late effects of current COG recommended treatment. Embedded correlative studies seek to understand predictors of benefit and resistance to 131I-MIBG and crizotinib.
Site for WUH: Effect of storage on breast milk cytokines in premature infants in the first 4 weeks after birth
Site for The Objective of this study is to evaluate the effect of storage of freshly expressed breast milk at different temperatures (Room air, 4°C, -20°C) on cytokine levels at different stages of breast milk maturation from week 1 to 4 at different gestational ages. Our central hypothesis is that freezing(-20°C) of breast milk will decrease the anti-inflammatory cytokine levels in breast milk and hence decrease the protective effectson the infant’s GI track to prevent NEC. Also, we hypothesize that anti-inflammatory cytokine levels will decrease as the breast milk matures from week 1 to 4. The significance of this project is that we could change the way we routinely store premature breast milk in the Neonatal Intensive Care Unit, to preserve its protective cytokines.
Site for WUH: Impact of medical and surgical weight loss on lipocalin prostaglandin D2 synthase (LPGDS) and bile acid levels.
Site for Eligible participants for this study will include adult patients undergoing (1) weight loss surgery or (2) participating in Winthrop’s Weight Management Program. Serum samples will be drawn on subjects pre-operatively and before starting the weight program. Then they will be drawn 4, 8, and 12 weeks post-operatively. We will measure L-PGDS levels in bariatric surgery, and participants in the Winthrop Weight Management Program. Forty five subjects will be in each study group.
Site for WUH: Methotrexate and Cholesterol Transport Regulation: Impact of Treatment Regimen in Diabetes and Metabolic Syndrome
Site for Will reducing inflammation prevent a second heart attack? This application proposes a mechanism-based study designed to assess the impact of low-dose methotrexate (LD MTX, dose 15-20 mg weekly) on markers of disrupted cholesterol transport and metabolism in post-MI patients enrolled in the Cardiovascular Inflammation Reduction Trial (CIRT, HL101422).Access to CIRT study subjects represents a unique opportunity to deepen our understanding of the inflammatory hypothesis of atherothrombosis.CIRT, funded by NHLBI,is a randomized, double blind, placebo-controlled clinical trialdesigned to determinewhether LD MTX will reduce recurrent cardiovascular (CV) events in 7,000 stable post-myocardial infarction (MI) patientswith type 2 diabetes (DM) or metabolic syndrome(1). We and others have shown that alterationsin cholesterol transport gene and protein expression provide a reliable signature of MTX responsiveness and related anti-atherogenic effect (2, 3). Despite the potential significance of studies demonstrating that MTX can restore cholesterol transport protein expression in vitro, the effect and mechanism of MTX therapy in humans at risk for CV events in vivois not known. Thepresent study will explore whether extent of change in these transport proteins with LD MTX providesanindicatorof efficacy. Improvement in cholesterol handling may indicate that theindividual is a responder andshould be continued on MTX.The pathogenesis of atherosclerosis involves interplay among cholesterol transport, cholesterol metabolism and inflammatory pathways.Current research is focused on this interplayand how it might be regulated (4). Our laboratory has shown thatMTX has potent atheroprotective properties that exert influence at multiple points in cholesteroltransport and metabolism and that inflammationplays a significant role not only in autoimmune disorders, but in atherosclerosis and DM(1).Anti-inflammatory effects of MTX are largely mediated through release of adenosine, an endogenous purine nucleoside that suppresses inflammatory cytokinesshown to be elevated in DM and metabolic syndrome(5, 6).Physiological effects of adenosine are triggered by engagement of 4 classes of G protein-coupled receptors: A1, A2A, A2Band A3. We have shown that the A2AR potentiates cholesterol removal by modifying expression of cholesterol transport proteins (7). Adenosine, via interaction with the A2AR, may be responsible for the capacity of MTX to reduce death rates from atherosclerotic CVdisease (ASCVD) in the autoimmune disorder rheumatoid arthritis (RA) (8).MTX spurs adenosine release, leading to A2AR ligation, anti-inflammatory effects and improved cholesterol balance. HYPOTHESIS 1:MTX will correct impairment of cholesterol balance induced by the inflammatory state in DM and metabolic syndrome. HYPOTHESIS 2:Adenosine release byMTX will shift cholesterol metabolism toward a less atherogenic state via a mechanism involving activation of the adenosine A2Areceptor. To test our hypotheses, the following 2aims are proposed:SPECIFICAIM 1:Examine the impact of LD MTX on cholesterol transportgenes in peripheral blood mononuclear cells (PBMC) from post-MI patients with DM or metabolic syndrome. In PBMCretrieved from the same subject before and after LD MTX, we will measure changes in cholesterol flux genes (immunoblot, quantitative real-time reversetranscription-polymerase chain reaction [QRT-PCR]). To gain a better understanding of the link among MTX, adenosine and regulation of cholesterol transport, we will compare adenosine receptor subtypeexpression (QRT-PCR) and distribution pattern (immunocytochemistry)in PBMC obtained from DM and metabolic syndrome patients before and after MTX treatment.SPECIFIC AIM 2:Investigate the effect of LD MTX on the atherogenic properties of plasma from CIRT subjects with DM and metabolic syndrome. To evaluate the impact of plasma milieu on cholesterol metabolism, we will assess differences in cholesterol transport proteinexpression in naïve monocytes/macrophages cultured in plasma obtained pre-/post-MTX or placebo. We will document the effect of plasma on foamcell transformation (oil red O), neutral and polar lipid content (Nile red, enzymatic assay) and cholesterol efflux (CholeFlux assay).
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