Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice

Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (> 1000 mg/dL) during therapy is associated with increased frequency of symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no pre-clinical studies investigating impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine if fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced with fenofibrate throughout treatment, with the most pronounced 4.5-fold decrease at week 3 (p<1x10-6). Both frequency (33% versus 74%, p=0.006) and severity (median necrosis score of 0 versus 75; p=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (p=0.65) nor on the antileukemic properties of dexamethasone (p=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL).We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Factors Affecting Dietary Practices in a Mississippi African American Community

This study examined the practices, personal motivation, and barriers of African American communities in Mississippi regarding their dietary practices. We selected the Metro Jackson Area comprised of Hinds, Madison and Rankin Counties because it is a combination of urban and rural communities. The sample consisted of 70 participants from seven sites. A total of seven focus groups responded to six questions to assess practices, personal motivation, and barriers to dietary practices: (1) Where in your community can you access fresh fruits and vegetables? (2) How many meals a day should a person eat? (3) What would you consider to be a healthy breakfast, lunch and dinner? (4) What would you consider to be a healthy snack? (5) What do you consider to be your motivations for eating healthy? (6) What do you consider to be your barriers to eating healthy? Each of the seven focus groups consisted of 6 to 12 participants and provided details of their dietary practices. The focus group interviews were digitally‐recorded. The recorded interviews were transcribed. The majority of the participants stated that there is a limited availability of fresh fruits/vegetables in rural areas because of a shortage of grocery stores. When they do find fruits, they are priced very high and are unaffordable. Even though health conditions dictate food frequency and portion size, community members feel that individuals should eat three good balanced meals per day with snacks, and they should adhere to small portion sizes. While the desire to attain overall good health and eliminate associative risks for heart disease (e.g., diabetes, obesity) are personal motivations, the cost of food, transportation, age, and time required for food preparation were seen as barriers to healthy eating. Decisions regarding meal choice and meal frequency can have an impact on long‐term health outcomes. Health promotion programs should become an integral part of academic‐ community collaborative agreements

Perception of Policy and Environmental Action to Promote Healthy Behaviors in African American Communities

The present study aimed to examine the perceptions of African American communities regarding the involvement of political leaders in facilitating policy and environmental change promoting healthy eating and physical activity. We selected the Metro Jackson Area comprised of Hinds, Madison and Rankin Counties because it is a combination of urban and rural communities. The sample consisted of 70 participants from seven sites. A total of seven focus groups were asked to respond to one question to assess political leaders’ involvement in healthy living: “When you think about your political leaders that you have in the Jackson, Mississippi area, do any of them promote healthy eating and physical activity?” Focus groups consisted of six to 12 participants and were asked to comment on their participation in physical activity. The focus group interviews were digitally recorded. The recorded interviews were transcribed by a professional transcriptionist. Community members could not recollect much participation from political leaders in the health prevention/intervention efforts. In each of the counties, there was evidence that there was some involvement by local politicians in health promotion issues, but not on a large scale. In conclusion, making healthy foods and products available in neighborhood stores has long been associated with healthy behaviors and positive health outcomes. This can make a difference in the Mississippi communities where supermarkets are not accessible and health disparities abound

Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models.

IntroductionCombination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule.MethodsUsing the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts.ResultsThe addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied.ConclusionsWhen discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase