IntroductionObesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity.MethodsA total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65) and non-obese (NOB). Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135), corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped.ResultsCompared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values.ConclusionsChildhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.
PS children do not exhibit global perturbations in their PBL transcriptional response, suggesting that current normative PSG criteria are overall valid. However, subtle differences in functionally coherent pathways involved in glycemic homeostasis were detected and confirmed in a larger independent pediatric cohort indicating that PS may carry increased risk for end-organ morbidity in susceptible children.
For recipients of allogeneic hematopoietic stem cell transplant (HSCT), mycophenolate mofetil (MMF) plus tacrolimus combination is mostly used in reduced-intensity (RIC), and nonmyeloablative conditioning (NMAC) whereas methotrexate and tacrolimus combination is preferred in myeloablative conditioning (MAC). We present single institution outcomes in patients undergoing allogeneic HSCT with both MAC and NMAC/RIC regimen using MMF and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. Data from all adult patients who underwent allogeneic HSCT from 2007 to 2017 was collected from Data Back to Centers webbased application of Center for International Blood and Marrow Transplant Research (CIBMTR). A total of 150 patients were included with the mean age of 46.9 years. For the patients who received MAC (n=109), the cumulative incidence of grade II-IV acute GVHD at day 100 was 37%, grade II-IV acute GVHD at one year was 51%, and chronic GVHD at one year was 38%. For the patients who received NMAC/RIC (n=41), the cumulative incidence of grade II-IV acute GVHD at day 100 was 31%, grade II-IV acute GVHD at one year was 28%, and chronic GVHD at one year was 36%. This institutional analysis shows that the combination of MMF and tacrolimus yields acceptable outcomes for the prevention of acute and chronic GVHD.
Background: Overexpression of anti-apoptotic proteins such as MCL-1 has been implicated in resistance to the BCL2 inhibitor venetoclax in relapsed/refractory AML (R/R-AML). Therapeutic agents that reduce resistance to venetoclax as well as exhibiting intrinsic anti-tumor activity may synergize with venetoclax to increase response rates in this difficult to treat patient population. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies have shown that radiation-induced DNA damage reduces the level of MCL1 in tumor cells. The monoclonal antibody radioconjugate lintuzumab-225Ac is a highly cytotoxic alpha-radiation emitter that selectively targets CD33, a cell surface antigen expressed on the majority of AML cells but not on non-hematopoietic tissues. Prior clinical studies with lintuzumab-225Ac have demonstrated potent single agent anti-leukemic activity (ASH 2017, 2018). The short range, high-energy alpha-particle emissions from lintuzumab-225Ac elicit single and double-strand DNA breaks in targeted tumor cells. In venetoclax-resistant cell lines in vitro, lintuzumab-225Ac promotes MCL1 degradation resulting in increased cell sensitivity to venetoclax. In vivo mouse xenograft models with venetoclax-resistant AML tumor lines demonstrated enhanced tumor regression and increased survival in mice receiving both venetoclax and lintuzumab-225Ac. This study is the first study to combine radioimmunotherapy with venetoclax in patients with R/R-AML. Study Design: The Phase I portion of the study will use a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-225Ac when given in combination with venetoclax. The planned dose levels for lintuzumab-225Ac are 0.5, 1.0, and 1.5 µCi/kg. As an exploratory endpoint, BH3 profiling will be performed on patient marrow samples to assess for MCL1 activity. Eligible patients include R/R-AML patients aged 18 years and older with adequate organ function, ECOG Performance Status 0-2, and more than 25% of leukemic blasts CD33 positive by flow cytometry. Patients with antecedent MDS, MPNs, or therapy-related AML are eligible. Other than the cycle 1 dose ramp up to reduce the risk of tumor lysis syndrome, patients receive venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle with dose modification for the use of CYP3A inhibitors. The Lintuzumab-225Ac is administered as a single dose on Day 1 of each cycle (see Study Schema). Results: Three R/R AML patients with a median age of 54 years (range 49-75) have been enrolled to date (see Table 1). The enrolled patients had a median of 2 therapies (2-3) and a median bone marrow blast percentage of 30% (range 20 - >60). All 3 patients had poor risk with adverse cytogenetics, and each patient has an additional high-risk marker (FLT3-ITD+, antecedent JAK2+ myelofibrosis, or TP53 mutation). There have been no lintuzumab-225Ac related dose limiting toxicities (DLT) or non-hematologic Grade 3 or greater related AEs. Patient 1 obtained a partial response with a decrease in BM leukemic blasts from >60% to 30-40% after cycle 1. Efficacy in the other 2 patients at this dose level is too early to evaluate. Conclusion: Combining lintuzumab Ac225 with venetoclax in patients with R/R-AML has an acceptable initial clinical safety profile at the level of 0.5 µCi/kg of lintuzumab-225Ac. Results in the first lintuzumab-225Ac dose cohort are encouraging, and the trial will continue to enroll to evaluate the hypothesis that there will be clinical synergy consistent with pre-clinical studies. Disclosures Hegazi: Tempus: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy. Harpel:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Miao:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ludwig:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Schiller:Abbvie: Research Funding; Kaiser Permanente: Consultancy; Geron: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Kite Pharma: Research Funding; Karyopharm: Research Funding; DeltaFly: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Jazz Pharmaceuticals: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Mateon: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Ariad: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Astellas Pharma: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Deciphera: Research Funding; Genentech-Roche: Research Funding. OffLabel Disclosure: Venetoclax use in relapsed-refractory AML.
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