Towards Identifying Potent New Hits for Glioblastoma

Glioblastoma is a devastating disease of the brain and is the most common malignant primary brain tumour in adults. The prognosis for patients is very poor with median time of survival after diagnosis measured in months, due in part to the tumours being highly aggressive and often resistant to chemotherapies. Alongside the ongoing research to identify key factors involved in tumour progression in glioblastoma, medicinal chemistry approaches must also be used in order to rapidly establish new and better treatments for brain tumour patients. Using a computational similarity search of the ZINC database, alongside traditional analogue design by medicinal chemistry intuition to improve the breadth of chemical space under consideration, six new hit compounds (14, 16, 18, 19, 20 and 22) were identified possessing low micromolar activity against both established cell lines (U87MG and U251MG) and patient-derived cell cultures (IN1472, IN1528 and IN1760). Each of these scaffolds provides a new platform for future Page 1 of 29 MedChemComm development of a new therapy in this area, with particular promise shown against glioblastoma subtypes that are resistant to conventional chemotherapeutic agents

Fish Culture in Minnesota Farm Ponds

This paper presents the results of a three year research and extension project in fish farming in central Minnesota. Fifty-seven farm ponds were stocked with one or more of the following species: channel catfish, largemouth bass, rainbow trout, yellow bullheads, bluegill sunfish, and black crappie. Several stocking densities with and without supplemental feeding were tested. The results indicate that when intensively managed, ponds over 0.05 hectare in size and 1 meter in depth are suitable for the production of food fish. Production of harvestable-size fish is possible during a single season when large fingerlings are stocked in early spring. Trout and catfish demonstrated the highest growth rates. Average yields for different production methods ranged from 18 to 356 kg/ha in warm-water ponds and 114 to 880 kg/ha in cold-water ponds. Fish yields were higher in ponds with supplemental feeding than without feeding. Several harvesting methods were tested and analyzed for efficiency. The findings indicate the importance of proper site selection and pond design for the success of an aquaculture operation. Economic analysis revealed the profitability of trout culture, and relatively high production costs for warm water species. Ways to reduce these costs are suggested

Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma

Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote the theory that IDH1 mutations are an oncogenic event that drives tumorigenesis in general. Through bioinformatic analysis of more than 45,000 human pan-cancer samples from three independent datasets, we show here that IDH1 mutations are rare events in human cancer but are exclusively prevalent in WHO grade II and grade III (lower-grade) glioma. Interestingly, alterations in the tumor-suppressor gene TP53 (tumor protein p53) co-occur significantly with IDH1 mutations and show a tendency of exclusivity to IDH2 mutations. The co-occurrence of IDH1 mutation and TP53 alteration is widespread in glioma, particularly in those harboring IDH1R132H, IDH1R132G, and IDH1R132S, whereas co-occurrence of IDH1R132C and TP53 alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, TP53 status is an independent predictor of overall survival irrespective of histological and molecular subgroups in lower-grade glioma. Together, these results indicate tissue specificity of IDH1 hotspot mutation and TP53 alteration and the importance of TP53 status as a predictor of patient outcome in lower-grade glioma

Firing of a Cannon: Psychophysical Evaluation of Ergonomic Hazards

Musculoskeletal-related occupational illnesses and injuries comprise a large majority of military medical encounters and result in decreased combat readiness and degraded human performance. The United States of America has the most sophisticated and technologically advanced military in the world. Consequently, they are constantly challenged with the requirements of reducing health hazards associated with the use, maintenance and testing of new and evolving technology. Ensuring the well-being of personnel operating, maintaining or testing military equipment is paramount to mission success. Heavy artillery tasks when deployed to combat zones are notoriously dangerous. Our study to evaluate the ergonomic risk factors of a heavy artillery task was initiated because military personnel had experienced a high rate of injuries during routine heavy artillery training exercises after returning home from combat. A three day study was conducted that spanned a complete heavy artillery firing exercise. Twenty-five military personnel were interviewed about their prior injury experience during the first day, while the cannons were being set-up. The live-fire exercise was directly observed by the research team on days two and three, and video recordings were taken for subsequent analysis. Non-invasive verbal inquiry every 8 to 12 minutes was used to collect psychophysical measures of exertion, fatigue and pain using the Borg Scale. Human errors in executing the established SOP for firing the cannon were counted during the exercise and verified during the video analysis. Twenty-five personnel were evaluated during the study. Sixteen of 25 (64%) reported becoming injured during a routine training exercise after returning home from combat, and four (16%) were on limited duty because of an injury suffered prior to our study. Of the sixteen previously injured personnel, nine (56%) reported injuries that were related to their back. Ten of the sixteen (62%) previously injured personnel recalled becoming injured while lifting or moving cannon rounds. Personnel perceptions of exertion, fatigue and pain increased throughout each day over the course of both days. In addition, the number of errors committed by personnel also increased over the course of each day. The recommended crew size for firing the cannon was ten, but due to personnel on limited duty assignments or injured, crew sizes of only 6 and 7 personnel per cannon were observed. The small number of personnel per cannon limited task rotation and increased the workload for the operators. Battlerelated injuries are often considered to be the major source of disability for military personnel and soldiers are often considered at a low risk of injury while stationed in home port. Our study uncovered that the exposure profile during a routine training exercise led to degradations in performance and increased the risk of developing musculoskeletal disorders. Recommendations included maintaining the recommended crew size to allow for task rotation; reducing the rounds fired per exercise; proving aids to raise cannon rounds from the ground level; and a redesign of the loading tray task. A biomechanical analysis of the high-risk tasks involved in heavy artillery firing is warranted given the high rate of injuries suffered by military personnel