Radioresistance of Brain Tumors

Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation

Experimental investigation of nonequilibrium and separation scaling in double-wedge and double-cone geometries

Experiments were performed in the Hypervelocity Expansion Tube (HET) and the T5 hypervelocity shock tunnel to investigate geometric and gas composition effects on a double-wedge and double-cone geometry. The high-speed flow over the models results in a complex shock boundary-layer interaction which is known to be sensitive to thermal and chemical nonequilibrium. High-speed shadowgraph and surface heat flux measurements are obtained for both geometries. Surface heat flux measurements of the laminar boundary layer for the double-wedge show good agreement between both facilities with proper nondimensionalization. High-speed shadowgraph imaging is used to study the flowfield startup processes. The shock interactions and separation location exhibit no transient processes once the nozzle reservoir reaches a steady stagnation pressure level in T5. Two of the primary shock-shock interaction types are identified for the double-cone. Augmented heat flux is observed for the Edney Type V interactions with the highest peak heating observed with the nitrogen test gas. However, transient heat flux measurements during the nozzle startup indicate that the peak heat flux is not captured by the thermocouples for the air case due to the highly local nature of heating in this shock configuration. The boundary-layer separation scaling based on triple-deck theory for a double-wedge is applied to the double-cone geometry. The pressure correlation for the double-cone is found to be in agreement with historical results. No significant response of the separation length to the gas composition, apart from changes in the freestream condition, are observed for the current experiments. In purely laminar interactions no dependence of the scaled separation on Reynolds number is observed. Reattachment heat flux indicates transitional behavior of the separated boundary layer for the high Reynolds number conditions. A consistent decrease in scaled separation length is found for transitional interactions

Biologically effective dose correlates with linear tumor volume changes after upfront single-fraction stereotactic radiosurgery for vestibular schwannomas.

Vestibular schwannomas (VSs) are benign, slow-growing tumors. Management options include observation, surgery, and radiation. In this retrospective trial, we aimed at evaluating whether biologically effective dose (BED) plays a role in tumor volume changes after single-fraction first intention stereotactic radiosurgery (SRS) for VS. We compiled a single-institution experience (n = 159, Lausanne University Hospital, Switzerland). The indication for SRS was decided after multidisciplinary discussion. Only cases with minimum 3 years follow-up were included. The Koos grading, a reliable method for tumor classification was used. Radiosurgery was performed using Gamma Knife (GK) and a uniform marginal prescription dose of 12 Gy. Mean BED was 66.3 Gy (standard deviation 3.8, range 54.1-73.9). The mean follow-up period was 5.1 years (standard deviation 1.7, range 3-9.2). The primary outcome was changes in 3D volumes after SRS as function of BED and of integral dose received by the VS. Random-effect linear regression model showed that tumor volume significantly and linearly decreased over time with higher BED (p < 0.0001). Changes in tumor volume were also significantly associated with age, sex, number of isocenters, gradient index, and Koos grade. However, the effect of BED on tumor volume change was moderated by time after SRS and Koos grade. Lower integral doses received by the VSs were inversely correlated with BED in relationship with tumor volume changes (p < 0.0001). Six (3.4%) patients needed further intervention. For patients having uniformly received the same marginal dose prescription, higher BED linearly and significantly correlated with tumor volume changes after SRS for VSs. BED could represent a potential new treatment paradigm for patients with benign tumors, such as VSs, for attaining a desired radiobiological effect. This could further increase the efficacy and decrease the toxicity of SRS not only in benign tumors but also in other SRS indications

Predicting treatment related imaging changes (TRICs) after radiosurgery for brain metastases using treatment dose and conformality metrics.

Purpose: Treatment-related imaging changes (TRICs) after stereotactic radiosurgery (SRS) involves the benign transient enlargement of radiographic lesions after treatment. Identifying the radiation dose volumes and conformality metrics associated with TRICs for different post-treatment periods would be helpful and improve clinical decision making. Methods: 367 metastases in 113 patients were treated using Gamma Knife SRS between 1/1/2007-12/31/2009. Each metastasis was measured at each imaging follow-up to detect TRICs (defined as ≥ 20% increase in volume). Fluctuations in small volume lesions (less than 108 mm Results: From 0-6 months, all measures correlated with the incidence of TRICs (p Conclusions: All metrics except KARE were associated with TRICs from 0-12 months only. Additional patient and treatment factors may become dominant at greater times after SRS

Parasitic chytrids could promote copepod survival by mediating material transfer from inedible diatoms

Diatoms form large spring blooms in lakes and oceans, providing fuel for higher trophic levels at the start of the growing season. Some of the diatom blooms, however, are not grazed by filter-feeding zooplankton like Daphnia due to their large size. Several of these large diatoms are susceptible to chytrid infections. Zoospores of chytrids appeared to be excellent food for Daphnia, both in terms of size, shape, and quality (PUFAs and cholesterol). Thus, zoospores of chytrids can bridge the gap between inedible diatoms and Daphnia. In order to examine the effects of diatoms and chytrids on the survival of copepods, we performed one grazing and one survival experiment. The grazing experiment revealed that the diatom, Asterionella formosa, was not grazed by the copepod, Eudiaptomus gracilis, even after being infected by the chytrid Zygorhizidium planktonicum. However, carbon and nitrogen concentrations were significantly reduced by E. gracilis only when A. formosa was infected by Z. planktonicum, indicating that the chytrids might facilitate material transfer from inedible diatoms to the copepods. The survival experiment revealed that E. gracilis lived shorter with A. formosa than with the cryptophyta Cryptomonas pyrenoidifera. However, the survival of E. gracilis increased significantly in the treatment where A. formosa cells were infected by Z. planktonicum. Since E. gracilis could not graze A. formosa cells due to their large colonial forms, E. gracilis may acquire nutrients by grazing on the zoospores, and were so able to survive in the presence of the A. formosa. This provides new insights into the role of parasitic fungi in aquatic food webs, where chytrids may improve copepod survival during diatom blooms.

CYP2D6 drug-gene and drug-drug-gene interactions among patients prescribed pharmacogenetically actionable opioids

Purpose When codeine and tramadol are used for pain management, it is imperative that nurses are able to assess for potential drug-gene and drug-drug-gene interactions that could adversely impact drug metabolism and ultimately pain relief. Both drugs are metabolized through the CYP2D6 metabolic pathway which can be affected by medications as well the patient's own pharmacogenotype. The purpose of this brief report is to identify drug-gene and drug-drug-gene interactions in 30 adult patients prescribed codeine or tramadol for pain. Methods We used three data sources: (1) six months of electronic health record data on the number and types of medications prescribed to each patient; (2) each patient's CYP2D6 pharmacogenotype, and (3) published data on known CYP2D6 gene-drug and drug-drug-gene interactions. Results Ten patients (33%) had possible drug-gene or drug-drug-gene interactions. Five patients had CYP2D6 drug-gene interactions indicating they were not good candidates for codeine or tramadol. In addition, five patients had potential CYP2D6 drug-drug-gene interactions with either codeine or tramadol. Conclusion Our findings from this exploratory study underscores the importance of assessing and accounting for drug-gene and drug-drug-gene interactions in patients prescribed codeine or tramadol

Medication Exposure Patterns in Primary Care Patients Prescribed Pharmacogenetically Actionable Opioids

Current approaches to assessing medication exposure fail to capture the complexity of the phenomenon and the context in which it occurs. This study’s purpose was to develop a typology of subgroups of patients who share common patterns of medication exposure. To create the typology, we used an exemplar sample of 30 patients in a large public healthcare system who had been prescribed the pharmacogenetically actionable opioids codeine or tramadol. Data related to medication exposure were drawn from large data repositories. Using a person-oriented qualitative approach, eight subgroups of patients who shared common patterns of medication exposure were identified. The subgroups had one of five opioid prescription patterns (i.e., singular, episodic, switching, sustained, multiplex), and one of three types of primary foci of medical care (i.e., pain, comorbidities, both). The findings reveal medication exposure patterns that are dynamic, multidimensional, and complex, and the typology offers an innovative approach to assessing medication exposure

Bringing dogs onto campus : inclusions and exclusions of animal bodies in organisations

Since the early years of the 20th century, work organizations have largely been places where animal bodies are absent or invisible. Recently, US and UK universities have facilitated therapy dog visits to improve students' wellbeing. In this article we analyse data on therapy dog visits to a UK university library as a starting point for thinking about other than human animals in organizations and the gendered dimensions of their inclusion and exclusion. Rather than focusing solely on the benefits of these encounters for students, we put the experiences of the dogs and their guardians centre stage, along with those of the library staff and the students. Drawing on observations of visits to a UK university library in 2015–2016, and a total of 16 interviews with library staff, guardians and students, we explore the instrumental rationale for the programme and the efforts to control any potential disruption of normative organizational expectations