215 results on '"D, Mittelman"'
Search Results
2. Impact of Telemedicine Versus In-Person Pediatric Outpatient Type 1 Diabetes Visits on Immediate Glycemic Control: Retrospective Chart Review
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Christopher Ferber, Steven D Mittelman, Tannaz Moin, Holly Wilhalme, and Rebecca Hicks
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
BackgroundChildren and adolescents with type 1 diabetes require frequent outpatient evaluation to assess glucose trends, modify insulin doses, and screen for comorbidities. Continuous glucose monitoring (CGM) provides a detailed glycemic control assessment. Telemedicine has been increasingly used since the COVID-19 pandemic. ObjectiveTo investigate CGM profile parameter improvement immediately following pediatric outpatient diabetes visits and determine if visit modality impacted these metrics, completion of screening laboratory tests, or diabetic emergency occurrence. MethodsA dual-center retrospective review of medical records assessed the CGM metrics time in range and glucose management indicator for pediatric outpatient diabetes visits during 2021. Baseline values were compared with those at 2 and 4 weeks post visit. Rates of completion of screening laboratory tests and diabetic emergencies following visits were determined. ResultsA total of 269 outpatient visits (41.2% telemedicine) were included. Mean time in range increased by 1.63% and 1.35% at 2 and 4 weeks post visit (P=.003 and .01, respectively). Mean glucose management indicator decreased by 0.07% and 0.06% at 2 and 4 weeks post visit (P=.003 and .02, respectively). These improvements in time in range and glucose management indicator were seen across both telemedicine visits and in-person visits without a significant difference. However, patients seen in person were 2.69 times more likely to complete screening laboratory tests (P=.03). Diabetic emergencies occurred too infrequently to analyze. ConclusionsOur findings demonstrate an immediate improvement in CGM metrics following outpatient visits, regardless of modality. While statistically significant, the magnitude of these changes was small; hence, multiple visits over time would be required to achieve clinically relevant improvement. However, completion of screening laboratory tests was found to be more likely after visits occurring in person. Therefore, we suggest a hybrid approach that allows patient convenience with telemedicine but also incorporates periodic in-person assessment.
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- 2024
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3. Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity
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Evan R. Abt, Khalid Rashid, Thuc M. Le, Suwen Li, Hailey R. Lee, Vincent Lok, Luyi Li, Amanda L. Creech, Amanda N. Labora, Hanna K. Mandl, Alex K. Lam, Arthur Cho, Valerie Rezek, Nanping Wu, Gabriel Abril-Rodriguez, Ethan W. Rosser, Steven D. Mittelman, Willy Hugo, Thomas Mehrling, Shanta Bantia, Antoni Ribas, Timothy R. Donahue, Gay M. Crooks, Ting-Ting Wu, and Caius G. Radu
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Immunology ,Metabolism ,Medicine - Abstract
Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.
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- 2022
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4. Targeting Adiposity and Inflammation With Movement to Improve Prognosis in Breast Cancer Survivors (The AIM Trial): Rationale, Design, and Methods
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Dong-Woo Kang, Rebekah L. Wilson, Paola Gonzalo-Encabo, Mary K. Norris, Marybeth Hans, Meghan Tahbaz, Jackie Dawson, Danny Nguyen, Amber J. Normann, Alexandra G. Yunker, Nathalie Sami, Hajime Uno, Jennifer A. Ligibel, Steven D. Mittelman, and Christina M. Dieli-Conwright
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exercise ,circuit training ,randomized controlled trial ,obesity ,chronic inflammation ,adipose tissue ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundObesity is a significant contributor to breast cancer recurrence and mortality. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise interventions to target chronic inflammation has a potential to improve obesity- and breast cancer-related outcomes; however, no studies have investigated the roles of exercise in modulating adipose tissue inflammation in breast cancer survivors. Also, it is unclear which exercise prescription would be optimal to maximize the outcomes. Therefore, we designed a randomized controlled trial (Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors [AIM] Trial) to examine the mechanisms by which different modalities of exercise impact chronic inflammation as a biomarker of breast cancer prognosis.MethodsThe AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program versus a traditional aerobic and resistance exercise (TARE) program and attention control (AC) on adipose tissue inflammation in breast cancer survivors. 276 patients who are diagnosed with stage 0-III breast cancer, post-treatment, sedentary, and centrally obese are randomized to one of the three groups. The CARE and TARE groups participate in thrice-weekly supervised exercise sessions for 16 weeks. The AC group are offered the CARE program after the intervention period. The primary endpoint is adipose tissue inflammation assessed by core biopsy and blood draw. The secondary and tertiary endpoints are sarcopenic obesity, physical fitness and function, and patient reported outcomes. The exploratory outcomes are long-term breast cancer outcomes.DiscussionThis is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Our findings are anticipated to contribute to a better understanding of exercise modalities and mechanisms on adipose tissue inflammation that can potentially improve breast cancer prognosis.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT03091842 identifier [NCT#03091842].
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- 2022
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5. Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells
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Jonathan Tucci, Ting Chen, Katherine Margulis, Etan Orgel, Rebecca L. Paszkiewicz, Michael D. Cohen, Matthew J. Oberley, Rachel Wahhab, Anthony E. Jones, Ajit S. Divakaruni, Cheng-Chih Hsu, Sarah E. Noll, Xia Sheng, Richard N. Zare, and Steven D. Mittelman
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adipocytes ,FFA ,microenvironment ,leukemia ,lipid droplets ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundThere is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.MethodsWe cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.ResultsAdipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.ConclusionThese findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.
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- 2021
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6. Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice
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Jonathan Tucci, Waseem Alhushki, Ting Chen, Xia Sheng, Yong-Mi Kim, and Steven D. Mittelman
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Obesity ,Adipose tissue ,Dietary intervention ,Chemotherapy ,Caloric restriction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background It is becoming increasingly recognized that weight and nutritional status can impact cancer survival. We have previously shown that obese mice with syngeneic acute lymphoblastic leukemia (ALL) have poorer response to chemotherapy treatment than control mice. We therefore investigated whether dietary intervention could improve outcome from the most common pediatric cancer, ALL. Methods Diet-induced obese (DIO) mice raised on a 60% calories from fat diet and control mice were implanted with syngeneic ALL cells. Some DIO mice were switched to the low-fat control diet. Survival from ALL was assessed without or with chemotherapy treatment starting at the time of the diet switch. Cells from DIO mice before and after diet switch were assessed by FACS for BrdU incorporation and phosphorylation status of AKT, S6K, and EIF2a. Similar experiments were done with human ALL xenografts. Mouse and human ALL cells were cultured in media with 10% or 5% fetal bovine serum, and sensitivity to chemotherapies assessed. Results DIO mice had poorer survival (17%) after vincristine monotherapy than control mice on a 10% low fat diet (42%; n = 12/group; p = 0.09, log rank). However, switching obese mice to the low-fat diet prior to initiation of vincristine led to dramatically improved survival (92%, p
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- 2018
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7. Wearable Devices Beyond Activity Trackers in Youth with Obesity: Summary of Options
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Sri Nikhita Chimatapu, Steven D. Mittelman, Manal Habib, Antonia Osuna-Garcia, and Alaina P. Vidmar
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Pediatrics, Perinatology and Child Health - Published
- 2023
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8. Supplementary Table S1 from Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin
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Steven D. Mittelman, Stan G. Louie, Etan Orgel, Michael Neely, Matthew J. Oberley, Christina M. Dieli-Conwright, Omar Cortez-Toledo, Hua Pei, Jonathan Tucci, Jean-Hugues Parmentier, and Xia Sheng
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Primer sequences used for rtPCR.
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- 2023
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9. Supplementary Figure 2 from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Figure 2 from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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10. Supplementary Figure Legends 1-4 from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Figure Legends 1-4 from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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11. Supplementary Methods and Materials from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Methods and Materials from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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12. Supplementary Figure 3 from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Figure 3 from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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13. Supplementary Figure 1 from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Figure 1 from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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14. Supplementary Figure 4 from Adipocytes Impair Leukemia Treatment in Mice
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Steven D. Mittelman, Nora Heisterkamp, Anna Butturini, Stan G. Louie, Vassilios I. Avramis, Ara S. Moses, Anna Arutyunyan, Ehsan A. Ehsanipour, Marina P. Proektor, Jason P. Yun, and James W. Behan
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Supplementary Figure 4 from Adipocytes Impair Leukemia Treatment in Mice
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- 2023
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15. An <scp>addiction‐based</scp> digital weight loss intervention: A <scp>multi‐centre</scp> randomized controlled trial
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Alaina P. Vidmar, Sarah J. Salvy, Choo Phei Wee, Robert Pretlow, D. Steven Fox, Jennifer K. Yee, Cambria Garell, Suzette Glasner, and Steven D. Mittelman
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Nutrition and Dietetics ,Health Policy ,Pediatrics, Perinatology and Child Health ,Public Health, Environmental and Occupational Health ,Article - Abstract
OBJECTIVE: This randomized clinical trial tested the effectiveness of an addiction-based digital weight-loss intervention, focusing on withdrawal/abstinence from self-identified problem foods, snacking and excessive amounts at meals, and discomfort displacement, with and without coaching, compared to an in-person, multi-disciplinary, care model among adolescents with obesity. We hypothesized that the digital intervention with coaching would yield greater weight loss and lower delivery burden than the standard clinical arm, and greater participant engagement than the digital arm without coaching. METHODS: Adolescents were randomized to app intervention, with or without coaching, or in-person multidisciplinary obesity intervention for 6 months. The primary outcome was change in %BMI(p95) at weeks 12 and 24. A mixed-effects linear regression model was used to assess the association between change in %BMI(p95) and intervention arm. We were also interested in assessing delivery burden, participant engagement and evaluating the relationships between weight change and demographic characteristics, mood, executive function and eating behaviours. RESULTS: All adolescents (n = 161; BMI ≥95th%, age 16 ± 2.5 year; 47% Hispanic, 65% female, 59% publicly insured) lost weight over 24-weeks (−1.29%, [−1.82, −0.76], p < 0.0001), with no significant weight loss difference between groups (p = 0.3). Girls lost more weight than boys, whereas binge eating behaviour at baseline was associated with increase in %BMI(p95) when controlling for other covariates. There was no association between ethnicity, mood, timing of intervention in relation to the pandemic, or executive function and change in %BMI(p95). CONCLUSIONS: Contrary with our hypothesis, our results showed no difference in the change in BMI status between treatment arms. Since efficacy of this digital intervention was not inferior to in-person, multi-disciplinary care, this could offer a reasonable weight management option for clinicians, based on youth and family specific characteristics, such as accessibility, resources, and communication styles.
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- 2022
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16. From soup to nuts: Obesity impairs chemotherapy during early and late phases of acute lymphoblastic leukemia treatment
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Etan Orgel and Steve D. Mittelman
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Cancer Research ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Obesity ,Precursor Cell Lymphoblastic Leukemia-Lymphoma - Published
- 2022
17. Increased prevalence of CRLF2 rearrangements in obesity-associated acute lymphoblastic leukemia
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Etan Orgel, Jiyoon Kim, Matthew J. Oberley, Gang Li, Steven D. Mittelman, and Gordana Raca
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Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Lymphoblastic Leukemia ,Immunology ,Adipose tissue ,Biochemistry ,Cohort Studies ,Internal medicine ,medicine ,Humans ,Obesity ,Receptors, Cytokine ,Child ,Receptor ,Gene Rearrangement ,Extramural ,business.industry ,Hispanic or Latino ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Adipose Tissue ,Female ,business ,Cohort study - Published
- 2021
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18. Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial
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Celia Framson, Jonathan Tucci, Steven D. Mittelman, Etan Orgel, Matthew J. Oberley, Gang Li, Weili Sun, Christina M. Dieli-Conwright, Rubi Buxton, David R. Freyer, and Jiyoon Kim
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0301 basic medicine ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Childhood Leukemia ,Pediatric Cancer ,Overweight ,law.invention ,Young Adult ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Randomized controlled trial ,Clinical Research ,Interquartile range ,law ,Internal medicine ,Glycemic load ,medicine ,Humans ,Obesity ,Prospective Studies ,Child ,Prospective cohort study ,Nutrition ,Cancer ,Pediatric ,Lymphoid Neoplasia ,Surrogate endpoint ,business.industry ,Prevention ,Nutrients ,Hematology ,Odds ratio ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,030104 developmental biology ,Residual ,030220 oncology & carcinogenesis ,Neoplasm ,medicine.symptom ,business - Abstract
Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL’s end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).
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- 2021
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19. Effect of Body Fat on Population Pharmacokinetics of High‐Dose Methotrexate in Pediatric Patients With Acute Lymphoblastic Leukemia
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Etan Orgel, Christopher Douglas, Teresa Nabais, Michael Neely, and Steven D. Mittelman
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Male ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Adolescent ,Population ,Models, Biological ,030226 pharmacology & pharmacy ,Gastroenterology ,Body fat percentage ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Obesity ,Prospective Studies ,Dosing ,Child ,Prospective cohort study ,education ,Pharmacology ,Body surface area ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Area under the curve ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Methotrexate ,Adipose Tissue ,Area Under Curve ,Creatinine ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Nearly all international regimens for pediatric acute lymphoblastic leukemia (ALL) incorporate intravenous "high dose" methotrexate (HDMTX, ≥1 gram/m2 ) to penetrate the central nervous system. Dosing is routinely adjusted for body surface area (BSA) but limited data describe the pharmacokinetics of HDMTX, particularly in obese and/or large patients. To understand the impact of body size (BSA) and body fat percentage (BFP) on HDMTX pharmacokinetics, we performed a secondary analysis of 36 children and adolescents 10-21 years old treated for newly diagnosed ALL and who were enrolled in a prospective study examining body composition. All patients received 5 grams/m2 of HDMTX infused over 24 hours. Plasma methotrexate concentrations were measured at +24, +42, and +48 hours. At 48 hours, ≥0.4 μmol/L was defined as "delayed elimination" necessitating prolonged supportive care. BFP was measured using dual-energy x-ray absorptiometry. A nonparametric population pharmacokinetic model was constructed with subsequent simulations to explore effects of BSA and BFP extremes. Despite standard BSA-adjusted dosing, we found significant intra-patient variability in mean MTX concentration (38%, range 1.2-86%). BSA and BFP were not linearly associated with increased area under the curve (AUC, p = 0.74 and p = 0.12), but both larger size (BSA) and greater obesity (BFP) were associated with an approximately twofold higher risk for delayed elimination at 48 hours. HDMTX AUC was not associated with toxicity. MTX pharmacokinetics vary among and even within patients despite BSA-adjusted dosing. Obesity and large size are identified as new risk factors for delayed elimination requiring further investigation. This article is protected by copyright. All rights reserved.
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- 2021
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20. Obese Skeletal Muscle-Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome
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Ting Yao, Hongmei Yan, Xiaopeng Zhu, Qiongyue Zhang, Xingyu Kong, Shanshan Guo, Yonghao Feng, Hui Wang, Yinghui Hua, Jing Zhang, Steven D. Mittelman, Peter Tontonoz, Zhenqi Zhou, Tiemin Liu, and Xingxing Kong
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Mice ,Endocrinology, Diabetes and Metabolism ,Fatty Acids ,Interferon Regulatory Factors ,Internal Medicine ,Metabolome ,Animals ,Humans ,Obesity ,Erratum ,Muscle, Skeletal ,Amino Acids, Branched-Chain - Abstract
In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle were not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species (human and mouse), and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated that IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of the high-fat diet (HFD), increased branched-chain amino acids (BCAAs) level of serum and muscle, and re-programmed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAAs and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity (DIO).
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- 2022
21. A Burkholderia pseudomallei Colony Variant Necessary for Gastric Colonization
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C. R. Austin, A. W. Goodyear, I. L. Bartek, A. Stewart, M. D. Sutherland, E. B. Silva, A. Zweifel, N. P. Vitko, A. Tuanyok, G. Highnam, D. Mittelman, P. Keim, H. P. Schweizer, A. Vázquez-Torres, S. W. C. Dow, and M. I. Voskuil
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Microbiology ,QR1-502 - Abstract
ABSTRACT Diverse colony morphologies are a hallmark of Burkholderia pseudomallei recovered from infected patients. We observed that stresses that inhibit aerobic respiration shifted populations of B. pseudomallei from the canonical white colony morphotype toward two distinct, reversible, yet relatively stable yellow colony variants (YA and YB). As accumulating evidence supports the importance of B. pseudomallei enteric infection and gastric colonization, we tested the response of yellow variants to hypoxia, acidity, and stomach colonization. Yellow variants exhibited a competitive advantage under hypoxic and acidic conditions and alkalized culture media. The YB variant, although highly attenuated in acute virulence, was the only form capable of colonization and persistence in the murine stomach. The accumulation of extracellular DNA (eDNA) was a characteristic of YB as observed by 4′,6-diamidino-2-phenylindole (DAPI) staining of gastric tissues, as well as in an in vitro stomach model where large amounts of eDNA were produced without cell lysis. Transposon mutagenesis identified a transcriptional regulator (BPSL1887, designated YelR) that when overexpressed produced the yellow phenotype. Deletion of yelR blocked a shift from white to the yellow forms. These data demonstrate that YB is a unique B. pseudomallei pathovariant controlled by YelR that is specifically adapted to the harsh gastric environment and necessary for persistent stomach colonization. IMPORTANCE Seemingly uniform populations of bacteria often contain subpopulations that are genetically identical but display unique characteristics which offer advantages when the population is faced with infrequent but predictable stresses. The pathogen Burkholderia pseudomallei is capable of forming several reversible colony types, and it interconverted between one white type and two yellow types under certain environmental stresses. The two yellow forms exhibited distinct advantages in low-oxygen and acidic environments. One yellow colony variant was the only form capable of chronic stomach colonization. Areas of gastric infection were marked by bacteria encased in a DNA matrix, and the yellow forms were able to produce large amounts of extracellular DNA in vitro. We also identified the regulator in control of yellow colony variant formation. These findings demonstrate a role in infection for colony variation and provide a mechanism for chronic stomach colonization—a frequently overlooked niche in melioidosis.
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- 2015
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22. Erratum. Obese Skeletal Muscle–Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome. Diabetes 2022;71:2256–2271
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Ting Yao, Hongmei Yan, Xiaopeng Zhu, Qiongyue Zhang, Xingyu Kong, Shanshan Guo, Yonghao Feng, Hui Wang, Yinghui Hua, Jing Zhang, Steven D. Mittelman, Peter Tontonoz, Zhenqi Zhou, Tiemin Liu, and Xingxing Kong
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Endocrinology, Diabetes and Metabolism ,Internal Medicine - Published
- 2022
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23. Nutrition and Chemotherapy in the Epidemic of Obesity
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Rebecca L. Paszkiewicz and Steven D. Mittelman
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medicine.medical_specialty ,business.industry ,Psychological intervention ,Cancer ,Tumor initiation ,medicine.disease ,Affect (psychology) ,Systemic inflammation ,Obesity ,Metastasis ,Intervention (counseling) ,medicine ,medicine.symptom ,Intensive care medicine ,business - Abstract
Cancer and obesity affect millions of people across the world. The role of obesity in cancer has come to the forefront over the past few decades. Epidemiologic studies have shown that obesity increases cancer incidence and worsens outcomes. There are many possibly underlying mechanisms that may explain why the obese state is favorable to cancer initiation and progression that include increases in local and systemic inflammation, alterations in available fuels, and underlying behaviors or genetics that put patients at risk of both diseases. In fact, some obesity-related conditions are causal for certain cancers. There is data that various diet interventions are helpful in preventing tumor initiation, growth, and metastasis. This chapter will focus on the data of dietary intervention impacts on the efficacy of treatment. Overall, diet interventions show increased efficacy or decreased side effects of chemotherapy. However, with a number of preclinical studies but only a handful of data in humans, more work needs to be done to determine which intervention is best and in which cases.
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- 2021
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24. Iodine Nutrition in Weaning Infants in the United States
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Miriam Segura-Harrison, Lewis E. Braverman, Angela M. Leung, Steven D. Mittelman, Xuemei He, Michael W. Yeh, Harvey K. Chiu, Elizabeth N. Pearce, Lin Du, and Roja Fallah
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Male ,and promotion of well-being ,Endocrinology, Diabetes and Metabolism ,Iodine nutrition ,Physiology ,brain development ,Cardiovascular ,Recommended Dietary Allowances ,Oral and gastrointestinal ,Child Development ,0302 clinical medicine ,Endocrinology ,Iodine and Endemic Goiter ,2.2 Factors relating to the physical environment ,Medicine ,Aetiology ,Infant Nutritional Physiological Phenomena ,Cancer ,Pediatric ,infants ,iodine ,digestive, oral, and skin physiology ,Age Factors ,Brain ,Micronutrient ,Los Angeles ,Infant Formula ,Stroke ,030220 oncology & carcinogenesis ,Zero Hunger ,Female ,Infant Food ,Nutritive Value ,Iodine ,Adult ,Brain development ,Clinical Sciences ,Nutritional Status ,chemistry.chemical_element ,030209 endocrinology & metabolism ,Weaning ,Endocrinology & Metabolism ,03 medical and health sciences ,Humans ,3.3 Nutrition and chemoprevention ,Metabolic and endocrine ,Nutrition ,business.industry ,Prevention ,Infant ,Prevention of disease and conditions ,medicine.disease ,Iodine deficiency ,Bottle Feeding ,chemistry ,iodine nutrition ,business ,Boston - Abstract
BACKGROUND:As iodine is a requisite micronutrient for infant brain development, infants are at risk for iodine deficiency during the weaning period when their diet transitions from milk (breast-milk, infant formula, or follow-on formula) to solid food. Dietary iodine intake during this weaning period is likely minimal, as the iodine content of commercial baby food is not regulated, and the addition of salt to baby food is not recommended. This study reports the current status of iodine nutrition among weaning infants in the United States. METHODS:Subjects (n = 60; 50% Caucasian, 30% black) were infants
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- 2019
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25. The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia
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Xia eSheng and Steven D Mittelman
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Adipocytes, White ,Apoptosis ,Drug Resistance ,Leukemia ,Lipolysis ,Obesity ,Pediatrics ,RJ1-570 - Abstract
Obesity is responsible for ~90,000 cancer deaths per year, increasing cancer incidence and impairing its treatment. Obesity has also been shown to impact hematological malignancies, through as yet unknown mechanisms. Adipocytes are present in bone marrow and the microenvironments of many types of cancer, and have been found to promote cancer cell survival. In this review, we explore several ways in which obesity might cause leukemia treatment resistance. Obese patients may be at a treatment disadvantage due to altered pharmacokinetics of chemotherapy and dosage capping based on ideal body weight. The adipose tissue provides fuel to cancer cells in the form of amino acids and free fatty acids. Adipocytes have been shown to cause cancer cells to resist chemotherapy-induced apoptosis. In addition, obese adipose tissue is phenotypically altered, producing a milieu of pro-inflammatory adipokines and cytokines, some of which have been linked to cancer progression. Given the prevalence of obesity, understanding its role and adipose tissue in ALL treatment is necessary for evaluating current treatment regimen and revealing new therapeutic targets.
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- 2014
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26. Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells
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Katherine Margulis, Rachel Wahhab, Jonathan Tucci, Cheng-Chih Hsu, Steven D. Mittelman, Etan Orgel, Michael D Cohen, Matthew J. Oberley, Ajit S. Divakaruni, Rebecca L. Paszkiewicz, Sarah E Noll, Xia Sheng, Richard N. Zare, Anthony E. Jones, and Ting Chen
- Subjects
0301 basic medicine ,Cancer Research ,adipocytes ,lipid droplets ,Cell ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adipocyte ,Lipid droplet ,Lipidomics ,medicine ,RC254-282 ,Unsaturated fatty acid ,Original Research ,leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Lipid metabolism ,Metabolism ,microenvironment ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Lipogenesis ,lipids (amino acids, peptides, and proteins) ,FFA - Abstract
BackgroundThere is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.MethodsWe cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.ResultsAdipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.ConclusionThese findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.
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- 2021
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27. Energy Management for Personalized Weight Reduction (EMPOWER) Program: Three-Year Outcome Data
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A P, Vidmar, C, Fink, B, Torres, B, Manzanarez, S D, Mittelman, C P, Wee, and C, Borzutzky
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Multi-Disciplinary Clinic ,Weight Loss ,Obesity ,Pediatrics ,Article - Abstract
Background The current consensus guidelines for management of pediatric obesity recommend clinic-based, family-centered, multi-disciplinary interventions. It is well reported that these programs often only lead to modest improvements in BMI status. The individual factors that differentiate which patient’s BMI status will improve vs. worsen remains understudied. A retrospective cohort study was conducted to evaluate the outcomes of EMPOWER clinic and identify the participant specific characteristics that predicted BMI status improvement in this population. Methods Youth who completed at least 6 visits in EMPOWER were included. Paired t-test was utilized to evaluate the mean change in zBMI, modified BMIz and %BMIp95 from baseline to 6th visit, and multivariate mixed effect models were utilized to analyze effect of baseline characteristics on change in BMI status. Results 92 participants were included in the analysis, 87% with severe obesity and 66% Hispanic. At the 6th visit, there was a significant reduction in zBMI (−0.09 SD, p
- Published
- 2020
28. Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
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Yong-Mi Kim, William L. Carroll, Hye Na Kim, Halvard Bonig, Lars Klemm, Eugene Park, Heather Ogana, Cheryl L. Willman, Adèle De Arcangelis, Elisabeth Georges-Labouesse, Yongsheng Ruan, Alan S. Wayne, Thomas G. Graeber, Steven D. Mittelman, Solomon Lee, Hisham Abdel-Azim, Chintan Parekh, Elizabeth Wayner, Johanna ten Hoeve, Nora Heisterkamp, Etan Orgel, Huimin Geng, Matthew J. Oberley, Eun Ji Gang, Deepa Bhojwani, Aspram Minasyan, Jennifer Pham, Markus Müschen, Yao-Te Hsieh, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
- Subjects
Male ,Antibodies, Neoplasm ,medicine.drug_class ,Immunology ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Integrin alpha6 ,Biochemistry ,Tyrosine-kinase inhibitor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,FYN ,LYN ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Animals ,Humans ,Cell adhesion ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Lymphoid Neoplasia ,Chemistry ,Cell adhesion molecule ,Cell Biology ,Hematology ,medicine.disease ,Antibodies, Neutralizing ,Neoplasm Proteins ,3. Good health ,Pyrimidines ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,B-cell leukemia ,Cancer research ,Female ,Tyrosine kinase ,Gene Deletion ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.
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- 2020
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29. Flattening the Learning Curve: A Case-Based Video Orientation for a Subspeciality Residency Rotation
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Shahram Yazdani, Christina M Southern Reh, Ranjit V. Shenoy, Steven D. Mittelman, and Anju Relan
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medicine.medical_specialty ,Pediatric endocrinology ,business.industry ,Internship and Residency ,Intervention group ,Patient care ,Clinical knowledge ,03 medical and health sciences ,0302 clinical medicine ,Learning curve ,Orientation (mental) ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Physical therapy ,medicine ,Humans ,030212 general & internal medicine ,Clinical Competence ,Curriculum ,business ,Child ,Rotation (mathematics) ,Learning Curve - Abstract
OBJECTIVE To determine whether a clinically focused rotation orientation delivered through e-learning videos would be an effective method to improve residents' clinical knowledge and confidence. METHODS A pre-post study design evaluated for change in knowledge and confidence between a control and intervention group of residents assigned to outpatient pediatric endocrinology rotations at 2 residency programs from July 2017 to March 2019. The intervention group utilized the first morning of the rotation to complete the video curriculum designed to rapidly orient residents to common clinical management tasks in outpatient pediatric endocrinology. RESULTS A total of 35 of 41 residents (85%) completed the study (control group: 18/19 [95%]; intervention group: 17/22 [77%]). Score increase from pretest to post-test was significantly higher for intervention group compared to control group (+24.7% ± 12.1 vs +5.8% ± 7.9, P < .0001). Confidence increases were significantly higher in the intervention group compared to control group in 3 of 5 topics. Two themes illustrated residents' perspectives of this e-learning curriculum: 1) increase in foundational clinical knowledge and 2) improvement in efficiency of learning and patient care. CONCLUSIONS This clinically focused rotation orientation delivered through e-learning videos was an effective method to improve residents' clinical knowledge, without reliance on faculty to deliver this orientation throughout the academic year. Further studies should be pursued in various settings.
- Published
- 2020
30. Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth
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Steven D. Mittelman, Ernst W. Schmid, Milica Momcilovic, Peter J. Mullen, Christopher J. Halbrook, Apisadaporn Thambundit, Costas A. Lyssiotis, Simon R.V. Knott, Felicia Surjono, Heather R. Christofk, David B. Shackelford, and Abigail S. Krall
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0303 health sciences ,Asparaginase ,Anabolism ,Cell growth ,Context (language use) ,mTORC1 ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Respiration ,Asparagine ,Intracellular ,030304 developmental biology - Abstract
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived asparagine and impairs mTORC1 activity. Providing exogenous asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumour asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo, our findings suggest that asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism.
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- 2020
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31. ABNORMALITIES IN AUTONOMIC FUNCTION IN OBESE BOYS AT RISK FOR INSULIN RESISTANCE AND OBSTRUCTIVE SLEEP APNEA
- Author
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Steven D. Mittelman, Sally L. Davidson Ward, Michael C. K. Khoo, Rajeev Bhatia, Winston H Tran, Thomas G. Keens, Daniel J. Lesser, and Flavia M. G. S. Oliveira
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Blood Glucose ,Male ,medicine.medical_specialty ,Sleep Apnea ,Adolescent ,Blood Pressure ,Polysomnography ,Baroreflex ,Autonomic Nervous System ,Pediatrics ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Risk Factors ,Heart Rate ,Models ,030225 pediatrics ,Internal medicine ,Humans ,Medicine ,Heart rate variability ,Obesity ,Child ,medicine.diagnostic_test ,Obstructive ,business.industry ,Sleep apnea ,Vagus Nerve ,Cardiorespiratory fitness ,medicine.disease ,Obstructive sleep apnea ,Neurological ,Pediatrics, Perinatology and Child Health ,Public Health and Health Services ,Cardiology ,Insulin Resistance ,business ,030217 neurology & neurosurgery - Abstract
Study Objectives: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism and daytime autonomic function in obese pediatric subjects. Methods: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures. Results: Baseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose. Conclusions: These findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present.
- Published
- 2018
32. Obesity and risk for venous thromboembolism from contemporary therapy for pediatric acute lymphoblastic leukemia
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Roxana Carmona, Saskia Prasca, Yasmin Rawlins, Steven D. Mittelman, Lingyun Ji, Richard H. Ko, Etan Orgel, Guy Young, and Deepa Bhojwani
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Population ,030204 cardiovascular system & hematology ,Overweight ,Asymptomatic ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Obesity ,cardiovascular diseases ,Child ,education ,Retrospective Studies ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Infant ,Retrospective cohort study ,Venous Thromboembolism ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,equipment and supplies ,medicine.disease ,Thrombosis ,Thromboelastography ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,Female ,medicine.symptom ,business ,Body mass index - Abstract
Introduction Acute lymphoblastic leukemia (ALL) therapy confers risk for venous thromboembolism (VTE) and associated acute and long-term morbidity. Obesity increases VTE risk in the general population but its impact on ALL therapy-associated VTE is unknown. Methods In a retrospective cohort of children treated for ALL between 2008 and 2016 (n = 294), we analyzed obesity at diagnosis (body mass index [BMI] ≥95%) and subsequent development of VTE. A subset participated in two concurrent prospective ALL trials studying body composition via dual-energy X-ray absorptiometry (DXA) (n = 35) and hypercoagulability via thromboelastography (TEG) (n = 46). Secondary analyses explored whether precise measurement of body fat and/or global hemostasis ex vivo by TEG could further delineate VTE risk in the obese. Results Overall, we found 27/294 (9.2%) patients developed symptomatic VTE during therapy, 19/27 (70%) occurred during Induction. Study-defined “serious” VTE developed in 4/294 (1.4%) of patients. Obesity but not overweight was strongly predictive of symptomatic VTE (obesity odds ratio = 3.8, 95% confidence interval 1.5–9.6, p = 0.008). In the DXA subset, only 2/35 patients developed symptomatic VTE. However, within those prospectively screened during Induction, 30% (14/46) developed VTE; eight (17%) of these were asymptomatic and found only via screening. Conclusions In this pediatric ALL cohort, obesity conferred more than a three-fold increased risk for symptomatic VTE. In a subgroup of patients who underwent active screening, up to a third were noted to have VTE (symptomatic and asymptomatic). TEG did not predict VTE. Additional studies are necessary to validate these findings and to further refine a risk-stratified approach to thrombo-prevention during ALL therapy.
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- 2018
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33. A randomized controlled trial testing an adherence-optimized Vitamin D regimen to mitigate bone change in adolescents being treated for acute lymphoblastic leukemia
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Nicole M. Mueske, Steven D. Mittelman, Richard Sposto, Tishya A. L. Wren, Vicente Gilsanz, Anna Butturini, Etan Orgel, and David R. Freyer
- Subjects
0301 basic medicine ,Vitamin ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Bone density ,Gastroenterology ,Article ,vitamin D deficiency ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,Bone Density ,law ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Directly Observed Therapy ,Cholecalciferol ,Bone Density Conservation Agents ,business.industry ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Vitamin D Deficiency ,medicine.disease ,Surgery ,Osteopenia ,Regimen ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,business - Abstract
Adolescents with acute lymphoblastic leukemia (ALL) develop osteopenia early in therapy, potentially exacerbated by high rates of concurrent Vitamin D deficiency. We conducted a randomized clinical trial testing a Vitamin D-based intervention to improve Vitamin D status and reduce bone density decline. Poor adherence to home supplementation necessitated a change to directly observed therapy (DOT) with intermittent, high-dose Vitamin D3 randomized versus standard of care (SOC). Compared to SOC, DOT Vitamin D3 successfully increased trough Vitamin 25(OH)D levels (p = .026) with no residual Vitamin D deficiency, 100% adherence to DOT Vitamin D3, and without associated toxicity. However, neither Vitamin D status nor supplementation impacted bone density. Thus, this adherence-optimized intervention is feasible and effective to correct Vitamin D deficiency in adolescents during ALL therapy. Repletion of Vitamin D and calcium alone did not mitigate osteopenia, however, and new, comprehensive approaches are needed to address treatment-associated osteopenia during ALL therapy.
- Published
- 2017
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34. Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia
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Rebecca L. Paszkiewicz, Ting Chen, Jessica L. Sea, Etan Orgel, Abigail S. Krall, Matthew J. Oberley, Linsey Stiles, and Steven D. Mittelman
- Subjects
levocarnitine ,hepatotoxicity ,Cancer Research ,Pediatric Cancer ,Childhood Leukemia ,medicine.medical_treatment ,Lymphoblastic Leukemia ,Clinical Sciences ,Immunology ,macromolecular substances ,Acute lymphoblastic leukemia ,PEG-asparaginase ,Article ,Levocarnitine ,03 medical and health sciences ,Mice ,Rare Diseases ,0302 clinical medicine ,Carnitine ,PEG ratio ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Animals ,Asparaginase ,Humans ,Cytotoxicity ,Cancer ,Pediatric ,Chemotherapy ,business.industry ,Prevention ,Induction chemotherapy ,Hematology ,Induction Chemotherapy ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Oncology ,030220 oncology & carcinogenesis ,Acute Disease ,Cancer research ,business ,030215 immunology - Abstract
Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.
- Published
- 2019
35. Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia
- Author
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Steven D. Mittelman, Etan Orgel, and Jessica L. Sea
- Subjects
Oncology ,Cancer Research ,Cardiovascular ,Oral and gastrointestinal ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,2.1 Biological and endogenous factors ,Hormone metabolism ,Public Health Surveillance ,Aetiology ,Cancer ,Pediatric ,0303 health sciences ,Articles ,General Medicine ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Stroke ,Leukemia ,030220 oncology & carcinogenesis ,medicine.medical_specialty ,Pediatric Research Initiative ,Childhood Leukemia ,Pediatric Cancer ,Oncology and Carcinogenesis ,Malignancy ,03 medical and health sciences ,Rare Diseases ,Internal medicine ,Acute lymphocytic leukemia ,Endocrine system ,Humans ,Obesity ,Oncology & Carcinogenesis ,Mortality ,Metabolic and endocrine ,030304 developmental biology ,Nutrition ,Inflammation ,business.industry ,medicine.disease ,Hormones ,Pancreatitis ,business ,Energy Metabolism - Abstract
The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy.
- Published
- 2019
36. Central diabetes insipidus associated with refeeding in anorexia nervosa: A case report
- Author
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Steven D. Mittelman, Philip S. Mehler, Apisadaporn Thambundit, and Elaine L. Rosen
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Weakness ,Pediatrics ,medicine.medical_specialty ,business.industry ,Clinical course ,medicine.disease ,Additional research ,Disease causation ,Psychiatry and Mental health ,Lethargy ,Polyuria ,Anorexia nervosa (differential diagnoses) ,Diabetes insipidus ,Medicine ,medicine.symptom ,business - Abstract
Anorexia nervosa (AN) has been associated with a multitude of hypothalamic pituitary abnormalities, although it is unknown which aberrations reflect disease causation and which are the consequences of severe malnutrition. Among these endocrinopathies, hypothalamic-posterior pituitary aberrations have been described, including disorders of osmoregulation. We report the case of an adolescent female with a history of severe AN, restricting subtype, treated aggressively with multiple hospitalizations. During hospitalization for severe weakness and lethargy, her course of medical stabilization was complicated by significant polyuria, ultimately diagnosed as central diabetes insipidus (DI). This is the first reported case, to our knowledge, of a severely malnourished adolescent with AN-restricting subtype developing central DI during the refeeding process for medical stabilization, thus adding to the small body of existing literature on disordered osmoregulation in this patient population. This case report raises the question as to whether the frequency of central DI during refeeding is greater than that previously recognized. Additional research should focus on how neuroendocrine dysregulation of water balance might impact the clinical course of AN and its treatment.
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- 2019
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37. Proposed endocrine funding priorities for the NICHD strategic plan: expert opinion from the Pediatric Endocrine Society
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Steven D. Mittelman, Michelle Katz, and Kanakadurga Singer
- Subjects
Adult ,Male ,Pediatric Obesity ,Disorders of Sex Development ,030209 endocrinology & metabolism ,Pediatrics ,Transgender Persons ,Article ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Research Support as Topic ,Surveys and Questionnaires ,Endocrine system ,Medicine ,Humans ,030212 general & internal medicine ,Pediatricians ,Child ,Expert Testimony ,Societies, Medical ,Aged ,Strategic planning ,business.industry ,Puberty ,Genetic Diseases, Inborn ,National Institute of Child Health and Human Development (U.S.) ,Public relations ,Middle Aged ,Training Support ,United States ,Leadership ,Diabetes Mellitus, Type 1 ,Endocrinologists ,Diabetes Mellitus, Type 2 ,Expert opinion ,Pediatrics, Perinatology and Child Health ,Female ,business - Published
- 2019
38. An addiction-based mobile health weight loss intervention: protocol of a randomized controlled trial
- Author
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Jennifer K. Raymond, Choo Phei Wee, Alaina P. Vidmar, Sarah J. Salvy, Steven D. Mittelman, Cassandra Fink, D. Steven Fox, and Robert Pretlow
- Subjects
Male ,Pediatric Obesity ,Weight loss ,Comparative Effectiveness Research ,and promotion of well-being ,Psychological intervention ,Cardiovascular ,Pediatrics ,Medical and Health Sciences ,California ,Oral and gastrointestinal ,law.invention ,Executive Function ,Substance Misuse ,0302 clinical medicine ,Randomized controlled trial ,law ,Eating addiction ,Weight management ,Pharmacology (medical) ,Single-Blind Method ,030212 general & internal medicine ,Mobile health ,mHealth ,Health Education ,General Clinical Medicine ,media_common ,Cancer ,Pediatric ,General Medicine ,Health Services ,Coaching ,Mobile Applications ,Weight Reduction Programs ,Stroke ,Research Design ,Patient Satisfaction ,Female ,Public Health ,medicine.symptom ,0305 other medical science ,medicine.medical_specialty ,Adolescent ,media_common.quotation_subject ,Clinical Trials and Supportive Activities ,Article ,Self-Control ,03 medical and health sciences ,Clinical Research ,Intervention (counseling) ,mental disorders ,Behavioral and Social Science ,medicine ,Humans ,Obesity ,Psychiatry ,Metabolic and endocrine ,Nutrition ,030505 public health ,business.industry ,Addiction ,Prevention ,Body Weight ,Mentors ,Feeding Behavior ,Prevention of disease and conditions ,Brain Disorders ,Addiction medicine ,Good Health and Well Being ,Patient Compliance ,3.1 Primary prevention interventions to modify behaviours or promote wellbeing ,Food Addiction ,business - Abstract
Background The notion of obesity as an addictive process is controversial. However, studies show that between 5.9 and 30.7% of adolescents with obesity report food or eating addiction. Few weight management interventions have tested techniques based on addiction medicine principles. Methods This multi-center randomized control trial (RCT) is designed to test the effectiveness of a mobile health (mHealth) weight-loss intervention based on addiction principles, such as withdrawal and tolerance, in a sample of 180 adolescents (ages 14–18) recruited from four pediatric weight management clinics in Southern California. Akin to a Multiphase Optimization Strategy (MOST) design evaluating multicomponent behavioral interventions, we will compare the combination of an app + phone coaching (App+Coach) to app alone (App) and in-clinic multi-disciplinary (Clinic) intervention arms. The primary outcome is mean change in zBMI and %BMIp95 over 18 months. We hypothesize that youth who receive App+Coach will have a greater reduction in body weight over the 18-month study period at a lower cost than standard of care models. Secondary outcomes include adherence to treatment regimen, intervention satisfaction, effect of the intervention on metabolic factors and activity level. We will also explore potential moderators of intervention effectiveness such as addictive eating habits, self-regulation and executive functioning. Conclusions New and creative approaches are needed to address pediatric obesity. If successful, this RCT may provide an innovative and cost-effective mHealth approach, based on addiction methods, for weight loss among adolescents with overweight and obesity.
- Published
- 2019
39. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth
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David B. Shackelford, Steven D. Mittelman, Ernst W. Schmid, Peter J. Mullen, Milica Momcilovic, Simon R.V. Knott, Abigail S. Krall, Apisadaporn Thambundit, Heather R. Christofk, Felicia Surjono, Costas A. Lyssiotis, and Christopher J. Halbrook
- Subjects
0301 basic medicine ,Physiology ,cancer metabolism ,mTORC1 ,Medical Biochemistry and Metabolomics ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Mice, Inbred NOD ,Neoplasms ,Asparagine ,Cancer ,Tumor ,Nucleotides ,Chemistry ,asparagine ,Metformin ,Mitochondria ,Survival Rate ,Biochemistry ,Intracellular ,Asparaginase ,Context (language use) ,Mechanistic Target of Rapamycin Complex 1 ,cancer treatment ,Cell Line ,Endocrinology & Metabolism ,03 medical and health sciences ,Cell Line, Tumor ,Respiration ,Animals ,Humans ,Molecular Biology ,Cell Proliferation ,Aspartic Acid ,Cell growth ,ATF4 ,dietary restriction ,Cell Biology ,asparaginase ,Activating Transcription Factor 4 ,Diet ,030104 developmental biology ,Electron Transport Chain Complex Proteins ,Inbred NOD ,Biochemistry and Cell Biology ,respiration ,030217 neurology & neurosurgery - Abstract
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.
- Published
- 2021
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40. Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response
- Author
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Steven D. Mittelman, James W. Behan, Jean-Hugues Parmentier, Jonathan Tucci, Xia Sheng, Nora Heisterkamp, and Lingyun Ji
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0301 basic medicine ,Oncology ,Drug Resistance ,Drug resistance ,medicine.disease_cause ,Antioxidants ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Antibiotics ,Adipocyte ,Adipocytes ,oxidative stress ,glutathione ,Antibiotics, Antineoplastic ,Tumor ,Leukemia ,Hematology ,Cell Death ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Glutathione ,Antineoplastic ,030220 oncology & carcinogenesis ,Research Paper ,medicine.drug ,medicine.medical_specialty ,Daunorubicin ,Oncology and Carcinogenesis ,adipocyte ,Cell resistance ,Cell Line ,03 medical and health sciences ,Cell Line, Tumor ,3T3-L1 Cells ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Humans ,drug resistance ,business.industry ,Gene Expression Profiling ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Immunology ,Neoplasm ,Reactive Oxygen Species ,ALL ,business ,Oxidative stress - Abstract
// Xia Sheng 1 , Jonathan Tucci 1 , Jean-Hugues Parmentier 1 , Lingyun Ji 2 , James W. Behan 1 , Nora Heisterkamp 3, 4, 5 , Steven D. Mittelman 1, 4, 6 1 Diabetes and Obesity Program, Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, USA 2 Department of Biostatistics, Children’s Hospital Los Angeles, Los Angeles, CA, USA 3 Division of Hematology/Oncology and Bone Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA, USA 4 Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 5 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 6 Departments of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence to: Steven D. Mittelman, email: smittelman@chla.usc.edu Keywords: ALL, adipocyte, oxidative stress, glutathione, drug resistance Received: February 11, 2016 Accepted: September 19, 2016 Published: September 26, 2016 ABSTRACT Adipocytes promote cancer progression and impair treatment, and have been shown to protect acute lymphoblastic leukemia (ALL) cells from chemotherapies. Here we investigate whether this protection is mediated by changes in oxidative stress. Co-culture experiments showed that adipocytes protect ALL cells from oxidative stress induced by drugs or irradiation. We demonstrated that ALL cells induce intracellular ROS and an oxidative stress response in adipocytes. This adipocyte oxidative stress response leads to the secretion of soluble factors which protect ALL cells from daunorubicin (DNR). Collectively, our investigation shows that ALL cells elicit an oxidative stress response in adipocytes, leading to adipocyte protection of ALL cells against DNR.
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- 2016
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41. Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome
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Steven D. Mittelman, D. Jeandron, Mitchell E. Geffner, Colleen Azen, I. Hsu, and Parisa Salehi
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0301 basic medicine ,medicine.medical_specialty ,media_common.quotation_subject ,030209 endocrinology & metabolism ,Overweight ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Internal medicine ,Diabetes mellitus ,medicine ,media_common ,Nutrition and Dietetics ,business.industry ,Health Policy ,Public Health, Environmental and Occupational Health ,nutritional and metabolic diseases ,Appetite ,medicine.disease ,Obesity ,030104 developmental biology ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Ghrelin ,medicine.symptom ,business ,Exenatide ,Body mass index ,medicine.drug - Abstract
SummaryBackground Prader–Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. Objective The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS. Methods Ten overweight and obese subjects with PWS (13–25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months. Results Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin. Conclusions This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.
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- 2016
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42. Abstract 6059: Targeting the anthracycline metabolizing enzyme AKR1C3 in adipocytes to improve cytotoxicity
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Etan Orgel, Michael Neely, Steven D. Mittelman, Stan G. Louie, and Vladislava Paharkova
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chemistry.chemical_classification ,Cancer Research ,Enzyme ,Oncology ,chemistry ,Anthracycline ,Cancer research ,Cytotoxicity - Abstract
Introduction: We have reported that mouse and human adipocytes take up and metabolize the anthracycline, daunorubicin (DNR), reducing its concentration in the adipocyte microenvironments. This may contribute to anthracycline resistance for cancers, which reside in adipocyte rich environments such as omentum and bone marrow. Adipocytes express several carbonyl- and aldo-keto reductases (CBRs and AKRs) which metabolize and inactivate anthracyclines, and it is unclear which of these might be important targets to improve treatment outcome. Experimental Procedures: We knocked out AKR1C3 in the human preadipocyte cell line Chub S7 using CRISPR/Cas9 gene editing technology. We chose AKR1C3 first as it is one of the overexpressed enzymes in adipocytes with the highest anthracycline-metabolizing activity. We delivered ribonucleoprotein complexes of CRISPR-Cas9 enzyme plus guide RNAs by nucleofection. Then we established single-cell derived clones and tested for successful KO by Western blot. Finally, we quantified adipocyte lysate AKR activity using a colorimetric assay based on NADPH-dependent reduction of phenanthrenequinone. Data Summary: We chose three Chub S7 preadipocyte clones that demonstrated successful AKR1C3 knockout based on almost undetectable protein expression by western blot. AKR activity was significantly reduced in all three clones; control preadipocytes had 44±4.7, while clones had activity of 28±7.3, 33±3.4, and 35±5.7 pmol/min/µg (p Conclusions: These findings demonstrate that AKR1C3 knockout can be successfully done in human preadipocytes using a CRISPR-Cas9 system. Knockout of AKR1C3 significantly reduces overall aldoketoreductase activity in preadipocyte cells. This implies that a substantial portion of preadipocyte AKR activity is dependent on the isoenzyme, AKR1C3. Future testing is needed to determine whether AKR1C3 KO will reduce the clearance of anthracyclines from the cancer microenvironment, and may represent a treatment target to enhance anthracycline cytotoxicity. Citation Format: Vladislava Paharkova, Etan Orgel, Michael Neely, Stan. Louie, Steven Mittelman. Targeting the anthracycline metabolizing enzyme AKR1C3 in adipocytes to improve cytotoxicity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6059.
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- 2020
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43. Fasting Mimicking Diet promotes immunotherapy-associated changes and inhibits autophagy to promote cancer free survival in Acute Lymphoblastic Leukemia models
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Roberta Buono, Jonathan Tucci, Raffaello Cutri, Novella Guidi, Serghei Mangul, Matteo Pellegrini, David A Fruman, Steven D. Mittelman, and Valter Longo
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Immunology ,Immunology and Allergy - Abstract
One of the new therapeutic strategy to promote cancer free survival is to combine dietary intervention like fasting or fasting mimicking diets (FMDs) with cancer treatments. FMDs enhance the efficacy of a wide variety of therapies ranging from chemotherapy to kinase inhibitors to immunotherapy, weakening cancer cells while protecting normal cells and tissues. In this work we show that FMD in combination with vincristine (VC), enhance the death of acute lymphoblastic leukemia (ALL) by inhibition of autophagy and induction of apoptosis by p53 modulation and activation of caspase-3. Our data indicates that a periodic FMD increases the efficacy of VC and extends the cancer free survival of an in-vivo mouse syngeneic pre-B ALL model. We identify in human and mice leukemic cells that the autophagy inhibition is the mechanism used by FMD to potentiate the cytotoxic effect of VC. Finally, in vivo treatment of FMD+VC with an autophagy inhibitor shows a synergistic effect on increasing survival in ALL mice. Furthermore, FMD induces activation of anticancer immunity. The gene expression profile consistent with anti-cancer immune responses resulting from VC plus FMD together with accelerated cancer progression when these treatments were combined with anti-CD8 antibodies indicate a central role of the immune system in these effects. Thus, the inhibition of autophagy and enhancement of immune responses are responsible for the ability of FMD to promote cancer free survival in ALL mice.
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- 2020
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44. An addiction model‐based mobile health weight loss intervention in adolescents with obesity
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D. S. Fox, Cassandra Fink, Alaina P. Vidmar, Claudia Borzutzky, Steven D. Mittelman, R. Pretlow, and Choo Phei Wee
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0301 basic medicine ,Pediatric Obesity ,medicine.medical_specialty ,Adolescent ,Food addiction ,media_common.quotation_subject ,Pilot Projects ,030209 endocrinology & metabolism ,Article ,Childhood obesity ,Body Mass Index ,03 medical and health sciences ,0302 clinical medicine ,Intervention (counseling) ,Weight Loss ,mental disorders ,Weight management ,medicine ,Humans ,Overeating ,Child ,Psychiatry ,Retrospective Studies ,media_common ,Yale Food Addiction Scale ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Health Policy ,Addiction ,Public Health, Environmental and Occupational Health ,medicine.disease ,Mobile Applications ,Telemedicine ,Treatment Adherence and Compliance ,Weight Reduction Programs ,Addiction medicine ,Food ,Pediatrics, Perinatology and Child Health ,Costs and Cost Analysis ,Feasibility Studies ,Female ,Food Addiction ,business - Abstract
Author(s): Vidmar, AP; Pretlow, R; Borzutzky, C; Wee, CP; Fox, DS; Fink, C; Mittelman, SD | Abstract: Background: Clinical approaches to treating childhood obesity can be expensive and poorly reimbursed, and often produce suboptimal results. It has been theorized that overeating may have addictive qualities, and a sizable number of adolescents with obesity endorse addictive habits. Interestingly, few weight management interventions have tested techniques founded in addiction medicine principles. We therefore performed a pilot study of an addiction model based mHealth weight loss intervention in adolescents.Methods: Adolescents with obesity were recruited from an multidisciplinary weight management clinic (EMPOWER). Adolescents without significant obesity comorbidities, who exhibited signs of addictive eating, based on the Yale Food Addiction Scale, were enrolled in a pilot study of an interactive, addiction-based, weight loss smartphone app with coaching (http://clinicaltrials.gov: NCT02689154). The app was designed to help subjects omit problem foods, avoid snacking and reduce meal size. A contemporary cohort of adolescents who completed the EMPOWER program were evaluated. Feasibility of recruitment, adherence, retention rates, BMI change and cost of intervention were examined.Results: Eighteen participants were recruited to app intervention. App participants had higher retention (100% vs. 37%) and lower total cost per patient ($855.15 vs. $1428.00) than the EMPOWER clinic participants. App participants exhibited a significant decrease in zBMI and %BMIp95 over the 6 months (p l 0.001 and p = 0.001), which was comparable to the age-matched EMPOWER program completers (p = 0.31 and p = 0.06).Conclusions: An addiction medicine-based mHealth intervention targeted for adolescents was feasible to implement, resulted in high retention and adherence rates, and reduced zBMI and %BMIp95 in a more cost-effective manner than an in-clinic intervention.
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- 2018
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45. Fasting serum blood measures of bone and lipid metabolism in children with myelomeningocele for early detection of cardiovascular and bone fragility risk factors
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Steven D. Mittelman, Tishya A. L. Wren, Richard K. Kremer, Nicole M. Mueske, Alexander Van Speybroeck, and Deirdre D. Ryan
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Male ,medicine.medical_specialty ,Meningomyelocele ,medicine.medical_treatment ,Physiology ,Parathyroid hormone ,Bone and Bones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Child ,Research Articles ,Creatinine ,biology ,Spina bifida ,business.industry ,Cholesterol ,Insulin ,Leptin ,Fasting ,Lipid Metabolism ,medicine.disease ,Bone Diseases, Metabolic ,Endocrinology ,chemistry ,Alanine transaminase ,Cardiovascular Diseases ,Case-Control Studies ,biology.protein ,Female ,Neurology (clinical) ,Insulin Resistance ,Metabolic syndrome ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
This study examined serum levels in children with myelomeningocele to identify the prevalence of pre-clinical signs of disease.A prospective, cross-sectional study.Patients were actively recruited from multidisciplinary care clinics at tertiary children's hospitals from 2010-2012. The control comparison group was recruited by word-of-mouth.Twenty-eight children with myelomeningocele (93% Hispanic; 17 males; 10.0 ± 2.1 years) and 58 controls (84% Hispanic; 30 males; 10.4 ± 2.4 years) provided ≥ 8-hour fasting blood samples with concomitant dual-energy x-ray absorptiometry measurements of body fat.Not applicable.The serum analysis included a lipid panel (cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein), insulin, glucose, leptin, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, albumin, creatinine, calcium, phosphatase, parathyroid hormone, and vitamin D.Children with myelomeningocele had higher body fat (35.2% versus 29.9%, p=0.01) and altered lipid profiles (lower high-density lipoprotein levels, 43.9 mg/dL versus 51.6 mg/dL, P = 0.03) suggesting elevated risk of metabolic syndrome. They also had a higher prevalence of vitamin D deficiency (43% versus 17%, p=0.02) and significantly lower levels of calcium (9.4 mg/dL versus 9.7 mg/dL, P = 0.003) and alkaline phosphatase (187.0 U/L versus 237.0 U/L, P = 0.003). Unexpectedly children with myelomeningocele had lower parathyroid hormone levels (14.5 pg/mL versus 18.4 pg/mL, P = 0.02) than controls despite lower calcium, vitamin D and alkaline phosphatase levels. This suggests an alteration in the sensing mechanism or response of the parathyroid gland to normal physiological stimuli in patients with myelomeningocele.Children with myelomeningocele have abnormal biochemical markers for cardiovascular disease, insulin resistance and bone and mineral metabolism. Early recognition and monitoring of these risk factors in patients with myelomeningocele may help prevent later complications.
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- 2015
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46. Abstract CN10-03: Childhood obesity and leukemia: Opportunities for intervention
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Steven D. Mittelman
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Oncology ,Cancer Research ,Vincristine ,medicine.medical_specialty ,Cancer prevention ,business.industry ,Cancer ,Adipose tissue ,Overweight ,medicine.disease ,Obesity ,Childhood obesity ,Surgery ,Leukemia ,Internal medicine ,medicine ,medicine.symptom ,business ,medicine.drug - Abstract
Obesity is a major contributor to cancer mortality, and is responsible for ~90,000 cancer deaths per year in the U.S. Part of this association can be attributed to the effect of obesity to increase cancer incidence, while obesity has been shown to worsen the outcome from a number of types of cancer. Retrospective studies have shown that obese children diagnosed with the high-risk form of the most common childhood cancer, acute lymphoblastic leukemia (HR-ALL) have a substantially higher risk of relapse than lean children. We have investigated these associations, generating laboratory models to investigate how obesity might impact ALL progression and treatment. Using two mouse models, we found that obesity accelerates the appearance of spontaneous leukemia. We have further discovered that obese mice implanted with leukemia had poorer survival after treatment with either vincristine or L-asparaginase. We have identified several effects of adipocytes which appear to contribute to this worse outcome. Adipocytes attract ALL cells to migrate into adipose tissue via secretion of the chemokine CXCL12, protect ALL cells from a number of chemotherapies, absorb chemotherapy leading to unfavorable pharmacokinetics, and secrete glutamine and possibly other fuels to support leukemia cell proliferation. In all, adipocytes have a number of effects which likely contribute to the worse prognosis in obese patients with ALL. These effects are particularly concerning given the high prevalence of overweight and obesity in leukemia patients. Two-thirds of adults and one-third of children in the U.S. are either overweight or obese. Almost half of new patients with HR-ALL in our institution are overweight and obese. Furthermore, we have observed that the body fat of these patients increases by ~20% during the first month of treatment, and even further by several months into therapy. HR-ALL patients therefore have a large and increasing burden of adipose tissue which may directly impair leukemia treatment and worsen prognosis. We now have evidence that the effect of obesity might be reversible. A retrospective analysis of HR-ALL patients showed that those who were obese at diagnosis, but lost weight and became non-obese for more than half of their treatment, had an improved outcome, similar to patients who were never overweight or obese. Experiments in our laboratory demonstrated that switching obese mice to a low-fat diet at start of ALL treatment substantially improves outcome from vincristine treatment, compared to those continued on the high fat-diet (92% vs. 17% survival, p These bench and clinical findings set the stage for an obesity-targeted intervention in children with ALL. We hypothesize that targeting obesity during leukemia treatment will reduce body fat gain, improve quality of life, and potentially improve outcome. Citation Format: Steven D. Mittelman. Childhood obesity and leukemia: Opportunities for intervention. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN10-03.
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- 2015
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47. Increased Abdominal Adiposity in Adolescents and Young Adults With Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
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Steven D. Mittelman, Sheree M. Schrager, Mitchell E. Geffner, Mimi S. Kim, Vicente Gilsanz, Anh Dao-Tran, and Anna Ryabets-Lienhard
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Adult ,Male ,Pediatric Obesity ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Abdominal Fat ,Subcutaneous Fat ,Adipose tissue ,Context (language use) ,Intra-Abdominal Fat ,Biochemistry ,Childhood obesity ,Young Adult ,Endocrinology ,Congenital adrenal hyperplasia due to 21-hydroxylase deficiency ,Internal medicine ,medicine ,Humans ,Congenital adrenal hyperplasia ,Child ,Adiposity ,Adrenal Hyperplasia, Congenital ,JCEM Online: Advances in Genetics ,business.industry ,Biochemistry (medical) ,Hyperandrogenism ,nutritional and metabolic diseases ,medicine.disease ,Cross-Sectional Studies ,Obesity, Abdominal ,Female ,Metabolic syndrome ,Tomography, X-Ray Computed ,business ,Body mass index - Abstract
Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in normal children, potentially increasing their risk of cardiovascular disease (CVD). Abdominal adiposity, in particular visceral adipose tissue (VAT), is strongly associated with metabolic syndrome and CVD. However, it remains unknown whether VAT is increased in CAH.The objective of the study was to determine whether adolescents and young adults with classical CAH have more VAT and sc adipose tissue (SAT) than matched controls and whether VAT and SAT are associated with biomarkers of metabolic syndrome, inflammation, and hyperandrogenism in CAH.This was a cross-sectional study at a tertiary center.CAH subjects (n = 28; 15.6 ± 3.2 y; 15 females) were matched for age, sex, ethnicity, and body mass index to healthy controls (n = 28; 16.7 ± 2.3 y; 15 females).VAT and SAT, using computed tomography imaging and serum biomarkers associated with CVD risk, were measured. Data are reported as mean ± SD.Both VAT (43.8 ± 45.5 cm(2)) and SAT (288.1 ± 206.5 cm(2)) were higher in CAH subjects than controls (VAT 26.4 ± 29.6 cm(2) and SAT 226.3 ± 157.5 cm(2); both P.001). The VAT to SAT ratio was also higher in CAH subjects (0.15 ± 0.07) than controls (0.12 ± 0.06; P.05). Within CAH, measures of obesity (waist to height ratio, fat mass) and inflammation (plasminogen activator inhibitor-1, high-sensitivity C-reactive protein, leptin) correlated strongly with VAT and SAT. In addition, homeostasis model assessment of insulin resistance, and low-density lipoprotein correlated with abdominal adiposity. There were no sex differences for VAT or SAT in CAH subjects.CAH adolescents and young adults have increased abdominal adiposity, with a higher proportion of proinflammatory VAT than SAT. An improved understanding of the mechanism of obesity in CAH may lead to targeted prevention and therapeutics in this high-risk population.
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- 2015
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48. Glutaminase activity determines cytotoxicity of l-asparaginases on most leukemia cell lines
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Steven D. Mittelman, Erika Tarasco, Maristella Maggi, Claudia Scotti, Jean Hugues Parmentier, and Vassilios I. Avramis
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Cancer Research ,Asparaginase ,Leukemia ,Helicobacter pylori ,Glutaminase ,Hematology ,Biology ,medicine.disease ,Glutaminase activity ,Molecular biology ,Article ,Glutamine ,chemistry.chemical_compound ,Oncology ,chemistry ,Biochemistry ,Cell culture ,Cell Line, Tumor ,medicine ,Humans ,Asparagine ,Cytotoxicity - Abstract
L-Asparaginase (ASNase) is a front-line chemotherapy for acute lymphoblastic leukemia (ALL), which acts by deaminating asparagine and glutamine. To evaluate the importance of glutaminase activity, we exploited a recently developed mutant of Helicobacter pylori ASNase (dm HpA), with amino acid substitutions M121C/T169M. The mutant form has the same asparaginase activity as wild-type but lacks glutaminase activity. Wild-type and dm HpA were compared with the clinically used ASNases from Escherichia coli (l-ASP) and Erwinia chrysanthemi (ERWase). Asparaginase activity was similar for all isoforms, while glutaminase activity followed the rank order: ERWase>l-ASP>wild-type HpA>dm HpA. Cytotoxic efficacy of ASNases was tested on 11 human leukemia cell lines and two patient-derived ALL samples. Two cell lines which we had previously shown to be asparagine-dependent were equally sensitive to the asparaginase isoforms. The other nine lines and the two patient-derived samples were more sensitive to isoforms with higher glutaminase activities. ERWase was overall the most effective ASNase on all cell lines tested whereas dm HpA, having the lowest glutaminase activity, was the least effective. These data demonstrate that asparaginase activity alone may not be sufficient for ASNase cytotoxicity, and that glutaminase activity may be required for full anti-leukemic efficacy.
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- 2015
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49. Salsalate treatment improves glycemia without altering adipose tissue in nondiabetic obese hispanics
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Xia Sheng, Steven D. Mittelman, Joyce M. Richey, Hooman Allayee, Lauren E. Gyllenhammer, Tanya L. Alderete, Michael I. Goran, Jonathan Tucci, Fred R. Sattler, and Edward Grant
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medicine.medical_specialty ,Nutrition and Dietetics ,Adiponectin ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Medicine (miscellaneous) ,Adipokine ,Adipose tissue ,Inflammation ,Placebo ,3. Good health ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Adipocyte ,Internal medicine ,Salsalate ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
Author(s): Alderete, Tanya L; Sattler, Fred R; Richey, Joyce M; Allayee, Hooman; Mittelman, Steven D; Sheng, Xia; Tucci, Jonathan; Gyllenhammer, Lauren E; Grant, Edward G; Goran, Michael I | Abstract: ObjectiveSalsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.MethodsA randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P l 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P l 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P l 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P l 0.01).ConclusionsFindings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.
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- 2015
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50. Adipose Tissue Inflammation in Breast Cancer Survivors: Effects of a 16-week Combined Aerobic and Resistance Exercise Training Intervention
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Wendy J. Mack, Fred R. Sattler, Kyuwan Lee, Steven D. Mittelman, Nathalie Sami, Jean-Hugues Parmentier, Darcy V. Spicer, and Christina M. Dieli-Conwright
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0301 basic medicine ,Oncology ,Cancer Research ,Aging ,Biopsy ,Adipose tissue ,Pilot Projects ,White adipose tissue ,Systemic inflammation ,Cardiovascular ,Body composition ,0302 clinical medicine ,Absorptiometry, Photon ,Cancer Survivors ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Rehabilitation ,Middle Aged ,Photon ,Postmenopause ,Local ,030220 oncology & carcinogenesis ,Body Composition ,Disease Progression ,Female ,Adiponectin ,medicine.symptom ,Adult ,medicine.medical_specialty ,Adipose tissue macrophages ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Subcutaneous Fat ,Inflammation ,Breast Neoplasms ,Article ,03 medical and health sciences ,Breast cancer ,Clinical Research ,Internal medicine ,Breast Cancer ,medicine ,Humans ,Oncology & Carcinogenesis ,Obesity ,Absorptiometry ,Nutrition ,6.7 Physical ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Prevention ,Macrophages ,Evaluation of treatments and therapeutic interventions ,Resistance Training ,medicine.disease ,030104 developmental biology ,Neoplasm Recurrence ,Physical therapy ,Neoplasm Recurrence, Local ,business - Abstract
PURPOSE:Obesity is a leading modifiable contributor to breast cancer mortality due to its association with increased recurrence and decreased overall survival rate. Obesity stimulates cancer progression through chronic, low-grade inflammation in white adipose tissue, leading to accumulation of adipose tissue macrophages (ATMs), in particular, the pro-inflammatory M1 phenotype macrophage. Exercise has been shown to reduce M1 ATMs and increase the more anti-inflammatory M2 ATMs in obese adults. The purpose of this study was to determine whether a 16-week exercise intervention would positively alter ATM phenotype in obese postmenopausal breast cancer survivors. METHODS:Twenty obese postmenopausal breast cancer survivors were randomized to a 16-week aerobic and resistance exercise (EX) intervention or delayed intervention control (CON). The EX group participated in 16weeks of supervised exercise sessions 3 times/week. Participants provided fasting blood, dual-energy X-ray absorptiometry (DXA), and superficial subcutaneous abdominal adipose tissue biopsies at baseline and following the 16-week study period. RESULTS:EX participants experienced significant improvements in body composition, cardiometabolic biomarkers, and systemic inflammation (all p 
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- 2017
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