Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration.

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

Training Hematologists/Oncologists for the Academic-Community Hybrid: Creating a Fellowship Framework for the Future.

PURPOSE: Conventional hematology/oncology fellowship training is designed to foster careers in academic practice through intensive exposure to clinical and laboratory research. Even so, a notable proportion of graduating fellows opt to pursue a clinically focused career outside the realm of academic medicine. Given the corresponding shortage of oncologists in nonurban and rural settings, improving the representation of hematologists/oncologists in the community setting is a national priority. METHODS: We reviewed current national challenges and changing models of cancer care delivery in the context of the traditional academic training model along with trends in practice patterns for recent hematology/oncology graduates. We defined the Academic-Community hybrid (ACH) and how it supports the evolution in contemporary models of cancer care. We then drew on the authors' experiences to formulate an innovative goal-concordant training paradigm for fellows seeking careers in the ACH model. RESULTS: The ACH hematology/oncology fellowship training pathway emphasizes and optimizes professional development domains including clinical care, patient safety and quality improvement, business and operations, cancer care equity and community access, healthy policy and alignment with professional organizations, and medical education. CONCLUSION: This novel hematology/oncology training model provides a paradigm for optimizing preparedness for practice in an increasingly complex cancer care delivery environment while addressing workforce shortages and health disparities.

Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration.

Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of known regeneration associated transcription factors, including Jun, Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1α, Pparγ, Ascl1a, Srf, and Ctcf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of novel candidate transcription factors alone or in combination promotes axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis highlights that transcription factor interaction and chromatin architecture play important roles as a regulator of axon regeneration.

Cohort Profile: The Assessing Economic Transitions (ASSET) Study-A Community-Based Mixed-Methods Study of Economic Engagement among Inner-City Residents.

The Assessing Economic Transitions (ASSET) study was established to identify relationships between economic engagement, health and well-being in inner-city populations given that research in this area is currently underdeveloped. This paper describes the objectives, design, and characteristics of the ASSET study cohort, an open prospective cohort which aims to provide data on opportunities for addressing economic engagement in an inner-city drug-using population in Vancouver, Canada. Participants complete interviewer-administered surveys quarterly. A subset of participants complete nested semi-structured qualitative interviews semi-annually. Between April 2019 and May 2022, the study enrolled 257 participants ages 19 years or older (median age: 51; 40% Indigenous, 11.6% non-Indigenous people of colour; 39% cis-gender women, 3.9% transgender, genderqueer, or two-spirit) and 41 qualitative participants. At baseline, all participants reported past daily drug use, with 27% currently using opioids daily, and 20% currently using stimulants daily. In the three months prior to baseline, more participants undertook informal income generation (75%) than formal employment (50%). Employed participants largely had casual jobs (42%) or jobs with part-time/varied hours (35%). Nested qualitative studies will focus on how inner-city populations experience economic engagement. The resulting evidence will inform policy and programmatic initiatives to address socioeconomic drivers of health and well-being.

GSK-3ß inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line.

Neuroblastoma is the most common extracranial solid tumor of childhood. While survival rates are high for localized disease, treatment response remains poor for a subset of patients with large tumors or disseminated disease. Thus, there remains much room for improvement in treatment strategies for this disease. Using in vitro and in vivo systems, we present glycogen synthase kinase-3ß (GSK-3ß) inhibition as a potential mechanism to treat neuroblastoma. Using the specific GSK-3ß inhibitor SB415286, we demonstrate that GSK-3ß inhibition decreases the viability of Neuro-2A cells, as determined by cell proliferation assay and clonogenic survival. Moreover, we show that GSK-3ß inhibition induces apoptosis in neuroblastoma cells, as determined by Annexin V staining and confirmed with DAPI staining. Using flow cytometry, we are able to demonstrate that SB415286 induces the accumulation of cells in the G2/M phase of the cell cycle. Finally, we show that these in vitro results translate into delayed tumor growth in vivo using a heterotopic tumor model in nude mice treated with SB415286. These findings suggest that GSK-3ß is a potential molecular target for the treatment of neuroblastoma.

Effectiveness of odor-baited trap trees for plum curculio (Coleoptera: Curculionidae) monitoring in commercial apple orchards in the northeast.

The plum curculio, Conotrachelus nenuphar (Herbst), is a key pest of pome and stone fruit in eastern and central North America. For effective management of this insect pest in commercial apple (Malus spp.) orchards in the northeastern United States and Canada, one of the greatest challenges has been to determine the need for and timing of insecticide applications that will protect apple fruit from injury by adults. In a 2004-2005 study, we assessed the efficacy and economic viability of a reduced-risk integrated pest management strategy involving an odor-baited trap tree approach to determine need for and timing of insecticide use against plum curculio based on appearance of fresh egg-laying scars. Evaluations took place in commercial apple orchards in seven northeastern U.S. states. More specifically, we compared the trap-tree approach with three calendar-driven whole-block sprays and with heat-unit accumulation models that predict how long insecticide should be applied to orchard trees to prevent injury by plum curculio late in the season. Trap tree plots received a whole-plot insecticide spray by the time of petal fall, and succeeding sprays (if needed) were applied to peripheral-row trees only, depending on a threshold of one fresh plum curculio egg-laying scar out of 25 fruit sampled from a single trap tree. In both years, level of plum curculio injury to fruit sampled from perimeter-row, the most interior-row trees and whole-plot injury in trap tree plots did not differ significantly from that recorded in plots subject to conventional management or in plots managed using the heat-unit accumulation approach. The amount of insecticide used in trap tree plots was reduced at least by 43% compared with plots managed with the conventional approach. Advantages and potential pitfalls of the bio-based trap tree approach to plum curculio monitoring in apple orchards are discussed.

Double-hit monomorphic B-cell lymphoma after liver transplantation.

We report the first case of double-hit (MYC and BCL-6) monomorphic post-transplant lymphoproliferative disorder in a patient status post liver transplantation. Our patient is a 71-year-old man with a past medical history of Budd-Chiari syndrome complicated by cirrhosis and hepatocellular carcinoma. He underwent a deceased donor liver transplantation 2 years prior to presentation and was maintained on tacrolimus and mycophenolate mofetil for immunosuppression. He presented with a 3-week history of classical B-symptoms. Initial workup was notable for elevated lactate dehydrogenase. Abdomen ultrasound revealed multiple hypoechoic lesions, raising suspicion for a post-transplant lymphoproliferative disorder. Biopsy showed pleomorphic large neoplastic cells throughout, consistent with a diagnosis of diffuse large B-cell lymphoma. Cytogenetics then revealed rearrangements in both MYC and BCL-6, consistent with double-hit lymphoma. His immunosuppressive regimen was subsequently tapered and he was started on DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab) regimen.

Toward the Integration of an Attract-and-Kill Approach with Entomopathogenic Nematodes to Control Multiple Life Stages of Plum Curculio (Coleoptera: Curculionidae).

Efforts to reduce insecticide inputs against plum curculio, Conotrachelus nenuphar, a key pest of apples in eastern North America, include perimeter-row insecticide sprays applied after the whole-orchard petal fall spray to manage dispersing adults and, more recently, insecticide sprays confined to odor-baited trap trees. Entomopathogenic nematodes (EPNs) are virulent to ground-dwelling stages of C. nenuphar, and may be applied to the ground underneath trap-tree canopies. Here, we (1) compared the efficacy of the odor-baited trap tree approach with grower-prescribed (=grower standard) sprays to manage C. nenuphar populations over a six-year period in seven commercial apple orchards in New England; and (2) assessed the performance of the EPN Steinernema riobrave at suppressing ground-dwelling stages of C. nenuphar. In addition, the performance of S. riobrave was compared against that of S. carpocapsae and S. feltiae in one year. Across the six years, percent fruit injury on trap tree plots averaged 11.3% on odor-baited trap trees and 1.4% on unbaited trees in grower standard plots, highlighting the ability of trap trees to aggregate C. nenuphar activity and subsequent injury. Mean percentage injury on fruit sampled from interior trees, the strongest measure of treatment performance, in trap tree plots did not differ significantly from that recorded on interior trees in grower standard spray plots (0.95 vs. 0.68%, respectively). Steinernema riobrave consistently reduced C. nenuphar populations as indicated by the significantly lower number of adult C. nenuphar that emerged from the soil, when compared to water control. Steinernema carpocapsae and S. riobrave performed similarly well, and both EPN species outperformed S. feltiae. Our combined findings indicate that an IPM approach that targets multiple life stages of C. nenuphar has the potential to manage this pest more sustainably in a reduced-spray environment.

Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors.

A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.

Reducing the energy density of an entrée decreases children's energy intake at lunch.

BACKGROUND: Strategies need to be developed to reduce preschool children's energy intake. OBJECTIVE: To test the effect of reducing the energy density of an entrée on children's ad libitum energy intake. SUBJECTS: Subjects were 2- to 5-year-old children (37 boys and 40 girls) in a university day-care facility. INTERVENTION: In this within-subjects crossover study, children were served a test lunch once per week for 6 weeks. Two versions of a macaroni and cheese entrée were formulated to differ in energy density while maintaining similar palatability. Each version was served to children three times. The higher-energy-density entrée had 2.0 kcal/g and the other entrée was 30% lower in energy density. Lunch, consumed ad libitum, also included broccoli, applesauce, and milk. MAIN OUTCOME MEASURES: Food intake and energy intake were measured. STATISTICAL ANALYSES: A mixed linear model tested effect of energy density of the entrée on food intake and energy intake. Results are reported as mean+/-standard error. RESULTS: Decreasing the energy density of the entrée by 30% significantly (P<0.0001) reduced children's energy intake from the entrée by 25% (72.3+/-8.3 kcal) and total lunch energy intake by 18% (71.8+/-7.9 kcal). Children consumed significantly more of the lower-energy-density entrée (10.1+/-4.2 g; P<0.05). Children's sex-specific body mass index-for-age percentiles did not affect the relationship between energy density of the entrée and children's intakes. CONCLUSIONS: Decreasing the energy density of a lunch entrée resulted in a reduction in children's energy intake from the entrée and from the total meal. Reducing the energy density of foods may be an effective strategy to moderate children's energy intake.

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR.

Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo.

Cyclooxygenase-2 (COX-2) is expressed within neovascular structures that support many human cancers. Inhibition of COX-2 by celecoxib delays tumor growth and metastasis in xenograft tumor models as well as suppresses basic fibroblast growth factor 2 (FGF-2)-induced neovascularization of the rodent cornea. The present studies were undertaken to evaluate possible mechanisms of the antiangiogenic and anticancer effects of celecoxib. Prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were increased in rat corneas implanted with slow-release pellets containing FGF-2 (338.6 ng of PGE(2)/g and 17.53 ng of TXB(2)/g) compared with normal rat corneas (63.1 ng of PGE(2)/g and 2.0 ng of TXB(2)/g). Celecoxib at 30 mg/kg/day p.o. inhibited angiogenesis (78.6%) and prostaglandin production by 78% for PGE(2) (72.65 ng/g) and 68% for TXB(2) (5.55 ng/g). Decreased prostaglandin production in corneas was associated with a 2.5-fold cellular increase in apoptosis and a 65% decrease in proliferation. Similar reductions in proliferation were observed in neovascular stroma (65-70%) of celecoxib-treated (dietary 160 ppm/day) xenograft tumors as well as in tumor cells (50-75%). Apoptosis was also increased in the tumor cells (2.2-3.0-fold) in response to celecoxib. Thus, the antitumor activity of celecoxib may be attributable, at least in part, to a direct effect on host stromal elements, such as the angiogenic vasculature.

Inclusion of Specialist and Generalist Stimuli in Attract-and-Kill Programs: Their Relative Efficacy in Apple Maggot Fly (Diptera: Tephritidae) Pest Management.

Investigating the chemical ecology of agricultural systems continues to be a salient part of integrated pest management programs. Apple maggot fly, a key pest of apple in eastern North America, is a visual specialist with attraction to host fruit-mimicking cues. These cues have been incorporated into red spherical traps used for both monitoring and behaviorally based management. Incorporating generalist or specialist olfactory cues can potentially increase the overall success of this management system. The primary aim of this study was to evaluate the attractiveness of a generalist olfactory cue, ammonium carbonate, and the specialist olfactory cue, a five-component apple volatile blend, when included as a component of a red attracticidal sphere system. Secondly, we assessed how critical it was to maintain minimal deviation from the optimal, full-round specialist visual stimulus provided by red spheres. Finally, attracticidal spheres were deployed with specialist olfactory cues in commercial apple orchards to evaluate their potential for effective management of apple maggot. Ammonium carbonate did not increase residency, feeding time, or mortality in the laboratory-based trials. Field deployment of specialist olfactory cues increased apple maggot captures on red spheres, while the generalist cue did not. Apple maggot tolerated some deviation from the optimal visual stimulus without reducing captures on red spheres. Attracticidal spheres hung in perimeter trees in orchards resulted in acceptable and statistically identical levels of control compared with standard insecticide programs used by growers. Overall, our study contributes valuable information for developing a reliable attract-and-kill system for apple maggot.

Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development.

More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.

Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.

Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.

Evaluating electrophysiological and behavioral responses to volatiles for improvement of odor-baited trap tree management of Conotrachelus nenuphar (Coleoptera: Curculionidae).

Plum curculio, Conotrachelus nenuphar (Herbst), one of the most important pests of apple in eastern and central North America, is usually managed in New England apple orchards by multiple full-block insecticide applications. Efforts to reduce insecticide inputs against plum curculio include using an "attract and kill" approach: odor-baited trap trees deployed in the perimeter row of apple orchards. The standard approach is based on baiting apple trees with two olfactory stimuli, the fruit volatile benzaldehyde and the aggregation pheromone of plum curculio, grandisoic acid. We attempted to improve attraction, aggregation, and retention of adult plum curculios within specific baited trap tree canopies within apple orchards using an additional host plant volatile found to be highly stimulating in electroantennogram studies, trans-2-hexenal. We also attempted to increase aggregation using increased release rates of grandisoic acid. We found that trans-2-hexenal did not provide increased aggregation when deployed as an additional attractant within trap trees or when conversely deployed as a "push" component or repellent in perimeter trees lateral to the baited trap tree. Although increasing the release rate of grandisoic acid 5× actually appeared to increase overall aggregation within trap trees, it was not significantly different than that obtained using the standard dose. Therefore, we believe that the standard olfactory stimuli are sufficient to provide aggregation within trap trees, but that other means should be used to manage them after their arrival.

Exploratory Analysis in Time-Varying Data Sets: a Healthcare Network Application.

We introduce a new method for exploratory analysis of large data sets with time-varying features, where the aim is to automatically discover novel relationships between features (over some time period) that are predictive of any of a number of time-varying outcomes (over some other time period). Using a genetic algorithm, we co-evolve (i) a subset of predictive features, (ii) which attribute will be predicted (iii) the time period over which to assess the predictive features, and (iv) the time period over which to assess the predicted attribute. After validating the method on 15 synthetic test problems, we used the approach for exploratory analysis of a large healthcare network data set. We discovered a strong association, with 100% sensitivity, between hospital participation in multi-institutional quality improvement collaboratives during or before 2002, and changes in the risk-adjusted rates of mortality and morbidity observed after a 1-2 year lag. The proposed approach is a potentially powerful and general tool for exploratory analysis of a wide range of time-series data sets.

Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature.

Despite wide margins and high dose irradiation, unresectable malignant glioma (MG) is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA(2)) is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX) and lysophosphatidic acid (LPA) receptors are downstream from cPLA(2) and highly expressed in MG. Using the ATX and LPA receptor inhibitor, α-bromomethylene phosphonate LPA (BrP-LPA), we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC) and mouse brain microvascular cells bEND.3 with 5 µmol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND.3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG.

Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia.

PURPOSE: Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL. EXPERIMENTAL DESIGN: Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily. RESULTS: Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6-44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA. CONCLUSIONS: Dasatinib as a single agent has activity in relapsed and refractory CLL.

Reducing the energy density of multiple meals decreases the energy intake of preschool-age children.

BACKGROUND: The energy density (ED) of an entrée affects children's energy intake at a meal consumed ad libitum. However, the effects in children of changing the ED of meals over multiple days are unknown. OBJECTIVE: We aimed to test the effect of reducing the ED of multiple meals on the ad libitum energy intake of preschool-age children over 2 d. DESIGN: In this crossover study, 3- to 5-y-old children (n = 10 boys, 16 girls) were served manipulated breakfasts, lunches, and afternoon snacks 2 d/wk for 2 wk. Foods and beverages served at these meals during 1 wk were lower in ED than were those served during the other week. ED reductions were achieved by decreasing fat and sugar and by increasing fruit and vegetables. Dinner and an evening snack were sent home with children, but these meals did not vary in ED. The same 2-d menu was served in both conditions. RESULTS: Children consumed a consistent weight of foods and beverages over 2 d in both conditions, and therefore their energy consumption declined by 389 +/- 72 kcal (14%) in the lower-ED condition, a significant decrease (P < 0.0001). Differences in energy intake were significant at breakfast on day 1, and they accumulated at manipulated meals over 2 d (P < 0.01). Intake of the nonmanipulated meals was similar between conditions. CONCLUSIONS: Children's energy intake is influenced by the ED of foods and beverages served over multiple days. These results strengthen the evidence that reducing the ED of the diet is an effective strategy for moderating children's energy intake.