Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer

Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials

Maine Blueberry Advisory Committee Research Report

The 1990 edition of the Maine Blueberry Advisory Committee Research Reports was prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers with the Maine Agricultural Experiment Station and Maine Cooperative Extension Service at the University of Maine, Orono. Projects in this report include: 1. Biology and action thresholds of secondary blueberry pests 2. Control of blueberry maggot 3. Control of secondary blueberry pests 4. Application of steam as a method of controlling secondary pest insects on lowbush blueberry: a feasibility study 5. Pollination of the lowbush blueberry by native bees 6. Nitrogen-phosphorus study 7. Potassium study 8. Multiple cropping of wild stands 9. Phosphorus dose/response curve 10. Improvement in the color and texture of the canned blueberry 11. The effect of fertilization and irrigation on blueberry fruit quality 12. Investigation of preprocess changes (chemical, microbiological, and/or physical) that could lead to the development of a simple and inexpensive method to measure preprocess berry spoilage 13. The effect of postharvest handling on the dietary fiber and ellagic acid content of lowbush blueberries 14. Determination of pesticide residue levels in freshly harvested and processed lowbush blueberries 15. Evaluation of Defoliating Diseases 16. Vacuum Sanitation for Disease Control 17. Evaluation and modification of commercial herbicide applications 18. Evaluation of the suitability of remote sensing to evaluate plant cover in lowbush blueberry fields 19. Evaluation of Sethoxydin (POAST) in lowbush blueberry fields 20. Seedling pruning study 21. Evaluation of norflurazon (SOLICAM) with or without hexazinone (VELPAR) for bunchberry control 22. Selective wiper and mechanical control of dogbane and bracken fern 23. Evaluation of norflurazon (SOLICAM) in fall vs spring for oatgrass control 24. Evaluation of sulfonyl urea herbicides for bunchberry control 25. Evaluation of postemergence applications of DPX-L5300 for bunchberry control 26. Effect of time of application and formulation of hexazinone (VELPAR) on blueberry and bunchberry 27. Investigations of lowbush blueberry fruit-bud cold hardiness 28. The economics of investing in irrigation for lowbush blueberries 29. Effects of irrigation on lowbush blueberry yield and quality 30. Groundwater and surface water development for blueberry irrigation 31. Design, fabrication and testing of an experimental sterilizer for blueberry field

1993 Progress Reports

The 1993 Progress Reports which contain Blueberry Tax Supported Weed Management and Pruning Project Reports, and CSRS Supported Weed Management and Pruning Project Reports, pertain to and report on research conducted in 1992. They were prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: Progress Reports 1. Effects of Irrigation on Low bush Blueberry Yield and Quality 2. Economics of Investing in Irrigation for Lowbush Blueberries 3. Diammonium Phosphate Study 4. Phosphorus Dose/Response Curve 5. Winter Injury Protection by Potassium 6. Multiple Cropping of Wild Stands 7. Effect of Boron on Lowbush Blueberry Fruit Set and Yield 8.Determination of Pesticide Residue Levels in Freshly Harvested and Processed Lowbush Blueberries 9. Effects of Calcium Salts and Citric Acids on the Quality of Canned Lowbush Blueberries- missing 10. Investigation of PreProcess Changes- missing 11. The Effect of Fertilization and Irrigation on Blueberry Fruit Control - missing 12. Pollination Ecology of Lowbush Blueberry in Maine 13. Control of Secondary Blueberry Pests 14. Control of Blueberry Maggot 15. Biology and Action Thresholds of Secondary Blueberry Pests 16. Cold-Hardiness of Native Lowbush Blueberries 17. Design, Fabrication, and Testing of an Experimental Sterilizer for Blueberry Fields 18. Canned Product Quality - Heat Resistant Molds 19. Sanitation for Disease Control Blueberry Tax Supported Weed Management and Pruning Project Reports 20. Evaluation of Postemergence Applications of Tribenuron Methyl for Bunchberry Control 21. Comparison of Poast and Select for Suppression of Bunchgrass 22. Effect of Time of Fall Pruning on Growth and Productivity of Blueberries. and Evaluation of Infrared Burner to Prune Blueberries 23. Evaluation of Velpar impregnated DAP for weed control 24. Thresholds of Dogbane and Bracken Fern for Mechanical and Chemical Control in Lowbush Blueberry Fields 25. Effect of Time and Rate of Application of Clopyralid for Control of Vetch in Lowbush Blueberries 26. Hexazinone Ground Water Survey 27. Composting Blueberry Processing Waste 28. Hexazinone Movement in a Blueberry Soil in Maine CSRS Supported Weed Management and Pruning Project Reports 29. Evaluation of the Suitability of Remote Sensing to Evaluate Plant Cover in Lowbush Blueberry Fields 30. Obstruction Removal in Lowbush Blueberry Fields 31. Evaluation of Pressurized Rope Wick Wick Master Wiper for Treating Weeds Growing Above Lowbush Blueberries 32. Evaluation of Infrared Burner for Weed Control 33. Blueberry Extension Education Program Base Miscellaneous 34. Comparison of N, NP, and NPK Fertilizers to Correct Nitrogen and Phosphorus Deficienc

1993-94 Progress Report

The 1993 edition of the Progress Reports was prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: 1. Effects of irrigation on lowbush blueberry yield and quality 2. The Economics of investigating irrigation for lowbush blueberries 3. Phosphorus dose/response curve 4. Winter injury protection by potassium 5. Multiple cropping of wild stands 6. Effect of Boron and Calcium on lowbush blueberry fruit set and yield 7. Comparison of N, NP, and NPK fertilizers to correct nitrogen and phosphorus deficiency 8. Determination of pesticide residue levels in freshly harvested and processed lowbush blueberries 9. Effects of calcium salts and citric acid on the quality of canned lowbush blueberries 10. Investigation of preprocess changes (chemical, microbiological, and/or physical) that can lead to the development of a simple and inexpensive method to measure preprocess berry spoilage 11. The effect of fertilization and irrigation in blueberry fruit quality 12. Pollination Ecology of lowbush blueberry in Maine 13. Current importance of insects in lowbush blueberry fields 14. Application of heat as a method of controlling secondary pest insects on lowbush blueberry: a feasibility study 15. Control of blueberry maggot 16. Control of secondary blueberry pest insects 17. Biology and action thresholds of secondary blueberry pest insects 18. Cold-hardiness of native lowbush blueberry 19. Design, fabrication, and testing of an experimental sterilizer for blueberry fields 20. Canned Product Quality--Heat-resistant molds 21. Sanitation for disease control 22. Evaluation of Velpar® impregnated DAP and Pronone® for weed control 23. Evaluation of postemergence applications of tribenuron methyl for bunchberry control 24. Evaluation of postemergence applications of a tank mix of tribenuron methyl and hexazinone for bunchberry control 25. Thresholds of dogbane and bracken fem by mechanical and chemical control in lowbush blueberry fields 26. Effect of time of application of clopyralid for control of vetch and effect on flowering in lowbush blueberries 27. Effect of time of fall pruning on growth and productivity of blueberries and evaluation of infrared burner to prune blueberries 28. Evaluation of infrared burner for selective seedling weed control 29. Evaluation of pressurized rope wick Wick Master wiper for treating weeds growing above lowbush blueberries 30. Blueberry Extension Education Program Base 31. Blueberry ICM program for Hancock County 32. Composting blueberry processing waste 33. Hexazinone ground water survey 34. Investigations of Lowbush Blueberry Fruit bud Cold-hardiness 35. Design, Fabrication, and Testing of an Experimental Sterilizer for Blueberry Field

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies

Simulation-based mastery learning compared to standard education for discussing diagnostic uncertainty with patients in the emergency department: a randomized controlled trial.

BACKGROUND: Diagnostic uncertainty occurs frequently in emergency medical care, with more than one-third of patients leaving the emergency department (ED) without a clear diagnosis. Despite this frequency, ED providers are not adequately trained on how to discuss diagnostic uncertainty with these patients, who often leave the ED confused and concerned. To address this training need, we developed the Uncertainty Communication Education Module (UCEM) to teach physicians how to discuss diagnostic uncertainty. The purpose of the study is to evaluate the effectiveness of the UCEM in improving physician communications. METHODS: The trial is a multicenter, two-arm randomized controlled trial designed to teach communication skills using simulation-based mastery learning (SBML). Resident emergency physicians from two training programs will be randomly assigned to immediate or delayed receipt of the two-part UCEM intervention after completing a baseline standardized patient encounter. The two UCEM components are: 1) a web-based interactive module, and 2) a smart-phone-based game. Both formats teach and reinforce communication skills for patient cases involving diagnostic uncertainty. Following baseline testing, participants in the immediate intervention arm will complete a remote deliberate practice session via a video platform and subsequently return for a second study visit to assess if they have achieved mastery. Participants in the delayed intervention arm will receive access to UCEM and remote deliberate practice after the second study visit. The primary outcome of interest is the proportion of residents in the immediate intervention arm who achieve mastery at the second study visit. DISCUSSION: Patients\u27 understanding of the care they received has implications for care quality, safety, and patient satisfaction, especially when they are discharged without a definitive diagnosis. Developing a patient-centered diagnostic uncertainty communication strategy will improve safety of acute care discharges. Although use of SBML is a resource intensive educational approach, this trial has been deliberately designed to have a low-resource, scalable intervention that would allow for widespread dissemination and uptake. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT04021771). Registration date: July 16, 2019

Onchocerca volvulus bivalent subunit vaccine induces protective immunity in genetically diverse collaborative cross recombinant inbred intercross mice

This study tests the hypothesis that an Onchocerca volvulus vaccine, consisting of two recombinant antigens (Ov-103 and Ov-RAL-2) formulated with the combination-adjuvant Advax-2, can induce protective immunity in genetically diverse Collaborative Cross recombinant inbred intercross mice (CC-RIX). CC-RIX lines were immunized with the O. volvulus vaccine and challenged with third-stage larvae. Equal and significant reductions in parasite survival were observed in 7 of 8 CC-RIX lines. Innate protective immunity was seen in the single CC-RIX line that did not demonstrate protective adaptive immunity. Analysis of a wide array of immune factors showed that each line of mice have a unique set of immune responses to vaccination and challenge suggesting that the vaccine is polyfunctional, inducing different equally-protective sets of immune responses based on the genetic background of the immunized host. Vaccine efficacy in genetically diverse mice suggests that it will also be effective in genetically complex human populations

Comparative evaluation of 11 commercialized rapid diagnostic tests for detecting Trypanosoma cruzi antibodies in serum banks in areas of endemicity and nonendemicity

Chagas disease is one of the main public health issues in Latin America. Increasingly during the past few decades, Trypanosoma cruzi infection has been detected in North America, Europe, and the Western Pacific, mainly as a result of population movement. The limited availability of rapid serological diagnostic tests hinders rapid diagnosis and early treatment in areas of endemicity and nonendemicity. In collaboration with 11 national reference laboratories (NRLs) from different geographical areas, we evaluated the performances of commercialized serological rapid diagnostic tests (RDT) for T. cruzi infection. Eleven commercialized T. cruzi infection RDTs were evaluated on a total of 474 samples extensively tested with at least three different techniques for Chagas disease, maintained at controlled low temperatures, and stored in the serum banks of the 11 NRLs. We measured the sensitivity, specificity, and concordance of each RDT and provided an additional questionnaire to evaluate its ease of use. The selected RDTs in this study were performed under controlled laboratory conditions. Out of the 11 RDTs, we found 8 of them to be useful, with the cassette format favored over the strip. We did not observe significant differences in RDT performances in the different regions. Overall, the performance results were lower than those disclosed by the manufacturers. The results of this evaluation validate the possibility of using RDTs to diagnose Chagas disease, thereby decreasing the time to treatment at a primary health care facility for patients who are willing to be treated. Further studies should be conducted in the laboratory and in the field to confirm these data, expressly to evaluate reproducibility in resource-limited settings, or using whole blood in clinical settings in areas of endemicity and nonendemicity

Path dependence in energy systems and economic development

Energy systems are subject to strong and long-lived path dependence, owing to technological, infrastructural, institutional and behavioural lock-ins. Yet, with the prospect of providing accessible cheap energy to stimulate economic development and reduce poverty, governments often invest in large engineering projects and subsidy policies. Here, I argue that while these may achieve their objectives, they risk locking their economies onto energy-intensive pathways. Thus, particularly when economies are industrializing, and their energy systems are being transformed and are not yet fully locked-in, policymakers should take care before directing their economies onto energy-intensive pathways that are likely to be detrimental to their long-run prosperity

Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an