Chronic undernutrition impairs renal mitochondrial respiration accompanied by intense ultrastructural damage in juvenile rats.

This study investigated whether chronic undernutrition alters the mitochondrial structure and function in renal proximal tubule cells, thus impairing fluid transport and homeostasis. We previously showed that chronic undernutrition downregulates the renal proximal tubules (Na++K+)ATPase, the main molecular machine responsible for fluid transport and ATP consumption. Male rats received a multifactorial deficient diet, the so-called Regional Basic Diet (RBD), mimicking those used in impoverished regions worldwide, from weaning to a juvenile age (3 months). The diet has a low content (8 %) of poor-quality proteins, low lipids, and no vitamins compared to control (CTR). We investigated citrate synthase activity, mitochondrial respiration (oxygraphy) in phosphorylating and non-phosphorylating conditions with different substrates/inhibitors, potential across the internal membrane (Δψ), and anion superoxide/H2O2 formation. The data were correlated with ultrastructural alterations evaluated using transmission electron microscopy (TEM) and focused ion beam scanning electron microscopy (FIB-SEM). Citrate synthase activity decreased (∼50 %) in RBD rats, accompanied by a similar reduction in respiration in non-phosphorylating conditions, maximum respiratory capacity, and ATP synthesis. The Δψ generation and its dissipation after carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone remained unmodified in the survival mitochondria. H2O2 production increased (∼100 %) after Complex II energization. TEM demonstrated intense matrix vacuolization and disruption of cristae junctions in a subpopulation of RBD mitochondria, which was also demonstrated in the 3D analysis of FIB-SEM tomography. In conclusion, chronic undernutrition impairs mitochondrial functions in renal proximal tubules, with profound alterations in the matrix and internal membrane ultrastructure that culminate with the compromise of ATP supply for transport processes.

GammaTile® (GT) as a brachytherapy platform for rapidly proliferating glioblastomas: from case series to clinical trials.

PURPOSE: Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 (131Cs) brachytherapy platform for such aggressive tumors. METHODS: We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30 days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement. RESULTS: There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2 days (range: 1-5 days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347 days (11.6 months), median progression free survival of ≥ 320 days (10.6 months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347 days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively. CONCLUSION: Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design.

Dosimetric evaluation and treatment planning considerations for GammaTile permanent brain implants - a pilot, institutional experience.

PURPOSE: GammaTile® (GT) is a brachytherapy platform that received Federal Drug Administration (FDA) approval as brain tumor therapy in late 2018. Here, we reviewed our institutional experience with GT as treatment for recurrent glioblastomas and characterized dosimetric parameter and associated clinical outcome. METHODS AND MATERIALS: A total of 20 consecutive patients with 21 (n = 21) diagnosis of recurrent glioblastoma underwent resection followed by intraoperative GT implant between 01/2019 and 12/2020. Data on gross tumor volume (GTV), number of GT units implanted, dose coverage for the high-risk clinical target volume (HR-CTV), measured by D90 or dose received by 90% of the HR-CTV, dose to organs at risk, and six months local control were collected. RESULTS: The median D90 to HR-CTV was 56.0 Gy (31.7-98.7 Gy). The brainstem, optic chiasm, ipsilateral optic nerve, and ipsilateral hippocampus median Dmax were 11.2, 5.4, 6.4, and 10.0 Gy, respectively. None of the patients in this study cohort suffered from radiation necrosis or adverse events attributable to the GT. Correlation was found between pre-op GTV, the volume of the resection cavity, and the number of GT units implanted. Of the resection cavities, 7/21 (33%) of the cavity experienced shrinkage, 3/21 (14%) remained stable, and 11/21 (52%) of the cavities expanded on the 3-months post-resection/GT implant MRIs. D90 to HR-CTV was found to be associated with local recurrence at 6-month post GT implant, suggesting a dose response relationship (p = 0.026). The median local recurrence-free survival was 366.5 days (64-1,098 days), and a trend towards improved local recurrence-free survival was seen in patients with D90 to HR-CTV ≥ 56 Gy (p = 0.048). CONCLUSIONS: Our pilot, institutional experience provides clinical outcome, dosimetric considerations, and offer technical guidance in the clinical implementation of GT brachytherapy.

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice.

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.

Top-down effects of foraging decisions on local, landscape and regional biodiversity of resources (DivGUD).

Foraging by consumers acts as a biotic filtering mechanism for biodiversity at the trophic level of resources. Variation in foraging behaviour has cascading effects on abundance, diversity, and functional trait composition of the community of resource species. Here we propose diversity at giving-up density (DivGUD), i.e. when foragers quit exploiting a patch, as a novel concept and simple measure quantifying cascading effects at multiple spatial scales. In experimental landscapes with an assemblage of plant seeds, patch residency of wild rodents decreased local α-DivGUD (via elevated mortality of species with large seeds) and regional γ-DivGUD, while dissimilarity among patches in a landscape (ß-DivGUD) increased. By linking theories of adaptive foraging behaviour with community ecology, DivGUD allows to investigate cascading indirect predation effects, e.g. the ecology-of-fear framework, feedbacks between functional trait composition of resource species and consumer communities, and effects of inter-individual differences among foragers on the biodiversity of resource communities.

Early Effects of Extracellular Vesicles Secreted by Adipose Tissue Mesenchymal Cells in Renal Ischemia Followed by Reperfusion: Mechanisms Rely on a Decrease in Mitochondrial Anion Superoxide Production.

Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O2•-) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administered during reperfusion can suppress the exacerbated mitochondrial O2•- formation after I/R. We used Wistar rats subjected to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R + EVs group) or saline (I/R group) in the kidney subcapsular space. The third group consisted of false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and used immediately. Amplex Red™ was used to measure mitochondrial O2•- formation and MitoTracker™ Orange to evaluate inner mitochondrial membrane potential (Δψ). In vitro studies were carried out on human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxic conditions. Administration of EVs restored O2•- formation to SHAM levels in all mitochondrial functional conditions. The gene expression of catalase and superoxide dismutase-1 remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs favor long-term recovery of renal structures and functions after I/R rely on a decrease of mitochondrial O2•- formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.

On the importance of quality assurance (QA) for COMS eye plaque Silastic inserts: A guide to measurement methods, typical variations, and an example of how QA intercepted a manufacturing aberration.

PURPOSE: Eye plaques are widely used for ocular melanoma and provide an effective alternative to enucleation with adequate tumor control. A COMS plaque utilizes a Silastic insert for precise positioning of the radioactive seeds with respect to the scleral surface of the eye; however, due to manufacturing variability, the insert may unintentionally increase or decrease the distance between the sources and tumor. The purpose of this work is to provide guidance in measuring and identifying outliers in Silastic inserts. The importance of regular quality assurance (QA) is illustrated in an experience where a systematic problem was detected and the manufacturer's 22-mm mold was corrected. METHODS: A detailed description of the molds and manufacturing process used to produce Silastic inserts is provided, including photographs of the process steps. The variability in Silastic insert production was evaluated by measuring the thickness of 124 Silastic inserts. An estimate of how the observed Silastic thickness discrepancies impact the dose to the tumor and critical eye structures was performed using homogeneous dose calculations. A standard QA protocol was developed to guide the clinical user. RESULTS: Thickness of the measured Silastic inserts ranged from 1.22 to 2.67 mm, demonstrating variation from the 2.25 mm standard. Six of the 22-mm inserts were outliers (Δthickness >3 standard deviations) and were excluded from the statistics. The outliers were investigated with the help of the manufacturer, who discovered that a systematic error was accidentally introduced into the 22-mm mold. CONCLUSIONS: Due to manufacturing errors or variability, the Silastic inserts used in COMS eye plaques may be thicker or thinner than the design standard. Such variations may impact tumor control or increase the risk of normal tissue side effects. A standardized QA program is recommended to detect variations and communicate unusual findings to the manufacturer.

Identification of genes from the general phenylpropanoid and monolignol-specific metabolism in two sugarcane lignin-contrasting genotypes.

The phenylpropanoid pathway is an important route of secondary metabolism involved in the synthesis of different phenolic compounds such as phenylpropenes, anthocyanins, stilbenoids, flavonoids, and monolignols. The flux toward monolignol biosynthesis through the phenylpropanoid pathway is controlled by specific genes from at least ten families. Lignin polymer is one of the major components of the plant cell wall and is mainly responsible for recalcitrance to saccharification in ethanol production from lignocellulosic biomass. Here, we identified and characterized sugarcane candidate genes from the general phenylpropanoid and monolignol-specific metabolism through a search of the sugarcane EST databases, phylogenetic analysis, a search for conserved amino acid residues important for enzymatic function, and analysis of expression patterns during culm development in two lignin-contrasting genotypes. Of these genes, 15 were cloned and, when available, their loci were identified using the recently released sugarcane genomes from Saccharum hybrid R570 and Saccharum spontaneum cultivars. Our analysis points out that ShPAL1, ShPAL2, ShC4H4, Sh4CL1, ShHCT1, ShC3H1, ShC3H2, ShCCoAOMT1, ShCOMT1, ShF5H1, ShCCR1, ShCAD2, and ShCAD7 are strong candidates to be bona fide lignin biosynthesis genes. Together, the results provide information about the candidate genes involved in monolignol biosynthesis in sugarcane and may provide useful information for further molecular genetic studies in sugarcane.

GammaTile®: Surgically targeted radiation therapy for glioblastomas.

Glioblastoma is the most common primary malignant neoplasm of the central nervous system in adults. Standard of care is resection followed by chemo-radiation therapy. Despite this aggressive approach, >80% of glioblastomas recur in proximity to the resection cavity. Brachytherapy is an attractive strategy for improving local control. GammaTile® is a newly US FDA-cleared device which incorporates 131Cs radiation emitting seeds in a resorbable collagen-based carrier tile for surgically targeted radiation therapy to achieve highly conformal radiation at the time of surgery. Embedding encapsulated 131Cs radiation emitter seeds in collagen-based tiles significantly lowers the technical barriers associated with traditional brachytherapy. In this review, we highlight the potential of surgically targeted radiation therapy and the currently available data for this novel approach.

Comparability of three output prediction models for a compact passively double-scattered proton therapy system.

The purpose of this study was to investigate comparability of three output prediction models for a compact double-scattered proton therapy system. Two published output prediction models are commissioned for our Mevion S250 proton therapy system. Model A is a correction-based model (Sahoo et al., Med Phys, 2008;35(11):5088-5097) and model B is an analytical model which employs a function of r = (R'-M')/M' (Kooy et al., Phys Med Biol, 2005;50:5487-5456) where R' is defined as depth of distal 100% dose with straggling and M' is the width between distal 100% dose and proximal 100% dose with straggling instead of the theoretical definition due to more accurate output prediction. The r is converted to ((R-0.31)-0.81 × M)/(0.81 × M) with the vendor definition of R (distal 90% dose) and M (distal 90% dose-to-proximal 95% dose), where R' = R-0.31 (g cm-2 ) and M' = 0.81 × M (g cm-2 ). In addition, a quartic polynomial fit model (model C) mathematically converted from model B is studied. The outputs of 272 sets of R and M covering the 24 double scattering options are measured. Each model's predicted output is compared to the measured output. For the total dataset, the percent difference between predicted (P) and measured (M) outputs ((P-M)/M × 100%) were within ±3% using the three different models. The average differences (±standard deviation) were -0.13 ± 0.94%, -0.13 ± 1.20%, and -0.22 ± 1.11% for models A, B, and C, respectively. The p-values of the t-test were 0.912 (model A vs. B), 0.061 (model A vs. C), and 0.136 (model B vs. C). For all the options, all three models have clinically acceptable predictions. The differences between models A, B, and C are statistically insignificant; however, model A generally has the potential to more accurately predict the output if a larger dataset for commissioning is used. It is concluded that the models can be comparably used for the compact proton therapy system.

Comparison of Gamma Knife (GK) and Linear Accelerator (LINAC) radiosurgery of brain metastasis resection cavity: a systematic review and proportional meta-analysis.

PURPOSE: Stereotactic radiosurgery (SRS) to the resection cavity is essential in the treatment of brain metastasis (BM) amenable to surgical resection. The two most common platforms for SRS delivery include Gamma Knife (GK) and LINAC. Here we collated the available peer-reviewed literature and performed a meta-analysis on clinical outcomes after GK or LINAC resection cavity SRS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include all studies evaluating each post-operative SRS modality. Local control, overall survival, radiation necrosis, and leptomeningeal disease were evaluated from the available data. A proportional meta-analysis was performed via R using the metafor package to pool the outcomes of studies and a moderator effect to assess the significance between groups. RESULTS: We identified 21 GK studies (n = 2009) and 28 LINAC studies (n = 2219). The radiosurgery doses employed were comparable between GK and LINAC studies. The pooled estimate of 1-year local control, 1-year overall survival, and risk of leptomeningeal disease were statistically comparable between GK and LINAC (81.7 v 85.8%; 61.4 v 62.7%; 10.6 v 12.5%, respectively). However, the risk of radiation necrosis (RN) was higher for LINAC resection cavity SRS (5.4% vs. 10%, p = 0.036). The volume of the resection cavity was a significant modifying factor for RN in both modalities (p = 0.007) with a 0.5% and 0.7% increase in RN risk with every 1 cm3 increase in tumor volume for GK and LINAC, respectively. CONCLUSIONS: Our meta-analysis suggests that GK and LINAC SRS of resection cavity achieve comparable 1-year local control and survival. However, resection cavity treated with GK SRS was associated with lowered RN risk relative to those treated with LINAC SRS.

Preoperative Versus Postoperative Radiosurgery of Brain Metastases: A Meta-Analysis.

OBJECTIVE: While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval]. RESULTS: We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5-17.6 cm3). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9-13.7] and 17.5% [15.1-19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6-6.2], relative to post-SRS, 12.3% [8.9-15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1-9.6] and 8.9% [6.3-11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8-64.6] and 60.5% [56.9-64.0] for pre- and post-SRS studies (P = 0.974). CONCLUSIONS: This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM.

The role of male quality in sequential mate choice: pregnancy replacement in small mammals?

Females mainly increase their reproductive success by improving the quality of their mates and need to be discriminative in their mate choices. Here, we investigate whether female mammals can trade up sire quality in sequential mate choice during already progressed pregnancies. A male-induced pregnancy termination (functional 'Bruce effect') could thus have an adaptive function in mate choice as a functional part of a pregnancy replacement. We used bank voles (Myodes glareolus) as a model system and exchanged the breeding male in the early second trimester of a potential pregnancy. Male quality was determined using urine marking values. Females were offered a sequence of either high- then low-quality male (HL) or a low- then high-quality male (LH). The majority of females bred with high-quality males independent of their position in the sequence, which may indicate a pregnancy replacement in LH but not in HL. The body size of the second male, which could have been related to the coercion of females by males into remating, did not explain late pregnancies. Thus, pregnancy replacement, often discussed as a counterstrategy to infanticide, may constitute adaptive mate choice in female mammals, and female choice may induce pregnancy replacement in mammals.

Nutritional composition, phenolic compounds and biological activities of selected unconventional food plants.

This review highlights the nutritional content, phytochemical compounds, and biological properties of three unconventional food plants consumed in the Amazon: ora-pro-nóbis (Pereskia aculeata Mill.), taioba (Xanthosoma sagittifolium), and vitória-régia (Victoria amazonica). These plants show significant nutritional, functional, and economic potential, which can enhance the intake of daily nutrients, energy, and bioactive compounds. Ora-pro-nóbis is a rich source of caftaric acid, quercetin, and isorhamnetin; taioba contains syringic acid, caffeic acid, and quercetin; and vitória-régia shows cinnamic acid, caffeic acid, and sinapic acid in its composition. These compounds confer antioxidant, anticancer, antimicrobial, anti-inflammatory, analgesic, and antiproliferative properties on these plants. These unconventional plants can be exploited by the food industry as food and supplements and therapeutic plants to develop valuable products for food, cosmetics, pharmaceutical, and medical applications.

Radiation dermatitis in the hairless mouse model mimics human radiation dermatitis.

Over half of all people diagnosed with cancer receive radiation therapy. Moderate to severe radiation dermatitis occurs in most human radiation patients, causing pain, aesthetic distress, and a negative impact on tumor control. No effective prevention or treatment for radiation dermatitis exists. The lack of well-characterized, clinically relevant animal models of human radiation dermatitis contributes to the absence of strategies to mitigate radiation dermatitis. Here, we establish and characterize a hairless SKH-1 mouse model of human radiation dermatitis by correlating temporal stages of clinical and pathological skin injury. We demonstrate that a single ionizing radiation treatment of 30 Gy using 6 MeV electrons induces severe clinical grade 3 peak toxicity at 12 days, defined by marked erythema, desquamation and partial ulceration, with resolution occurring by 25 days. Histopathology reveals that radiation-induced skin injury features temporally unique inflammatory changes. Upregulation of epidermal and dermal TGF-ß1 and COX-2 protein expression occurs at peak dermatitis, with sustained epidermal TGF-ß1 expression beyond resolution. Specific histopathological variables that remain substantially high at peak toxicity and early clinical resolution, including epidermal thickening, hyperkeratosis and dermal fibroplasia/fibrosis, serve as specific measurable parameters for in vivo interventional preclinical studies that seek to mitigate radiation-induced skin injury.

Supercritical Technology as an Efficient Alternative to Cold Pressing for Avocado Oil: A Comparative Approach.

Avocado oil is rich in nutrients beneficial to human health, such as monounsaturated fatty acids, phenolic compounds, tocopherol, and carotenoids, with numerous possibilities for application in industry. This review explores, through a comparative approach, the effectiveness of the supercritical oil extraction process as an alternative to the conventional cold-pressing method, evaluating the differences in the extraction process steps through the effect of temperature and operating pressure on bioactive quality and oil yield. The results reveal that supercritical avocado oil has a yield like that of mechanical cold pressing and superior functional and bioactive quality, especially in relation to α-tocopherol and carotenoids. For better use and efficiency of the supercritical technology, the maturation stage, moisture content, fruit variety, and collection period stand out as essential factors to be observed during pre-treatment, as they directly impact oil yield and nutrient concentration. In addition, the use of supercritical technology enables the full use of the fruit, significantly reducing waste, and adds value to the agro-industrial residues of the process. It produces an edible oil free of impurities, microorganisms, and organic solvents. It is a green, environmentally friendly technology with long-term environmental and economic advantages and an interesting alternative in the avocado market.

Early experience and perioperative risk of GammaTile for upfront brain metastases: Report from a prospective multicenter study.

Background: GammaTile (GT), a form of brachytherapy utilizing cesium-131 seeds in a bioresorbable collagen tile, has gained popularity for the treatment of recurrent intracranial tumors and more recently for newly diagnosed metastases. This study reports early experience utilizing GT in upfront brain metastases with a focus on clinical applications and perioperative safety. Methods: The STaRT Registry (NCT04427384) was queried for all patients receiving GT for upfront metastases from August 2021 to August 2023. Data regarding patient demographics, procedure details, and adverse events (AEs) were extracted and analyzed. Results: Twenty-eight patients, median age 65 years (range 28-81), with 30 treated metastases were reported from 6 institutions. Patients had 2.8 metastases on average (range 1-15) at the time of surgery; however, most patients had a single metastasis (60.7%). The mean diameter of treated metastases was 3.4 cm (range 1.5-4.7). A median of 4.0 tiles (range 1-10) were used per tumor. The median follow-up was 3.0 months (range 1.0-11.2) with 6 attributed AEs (21.4%), including 1 grade ≥ 3 (infection). In the immediate postoperative period (<14 days), 2 patients reported pain or headache, and 1 reported facial edema. One patient developed seizures on postoperative day 8 requiring medication. At 1-month follow-up, there was 1 superficial wound infection, in a previously colonized patient, requiring surgical intervention without explantation of tiles. At 3-month follow-up, 1 patient reported facial pain not requiring treatment. There were no symptomatic hematomas. Conclusions: GT demonstrates a favorable safety profile in upfront brain metastases with a 3.6% rate of serious AEs (grade ≥ 3) within 90 days of the procedure.

So many choices, so little time: Food preference and movement vary with the landscape of fear.

Spatial and temporal variation in perceived predation risk is an important determinant of movement and foraging activity of animals. Foraging in this landscape of fear, individuals need to decide where and when to move, and what resources to choose. Foraging theory predicts the outcome of these decisions based on energetic trade-offs, but complex interactions between perceived predation risk and preferences of foragers for certain functional traits of their resources are rarely considered. Here, we studied the interactive effects of perceived predation risk on food trait preferences and foraging behavior in bank voles (Myodes glareolus) in experimental landscapes. Individuals (n = 19) were subjected for periods of 24 h to two extreme, risk-uniform landscapes (either risky or safe), containing 25 discrete food patches, filled with seeds of four plant species in even amounts. Seeds varied in functional traits: size, nutrients, and shape. We evaluated whether and how risk modifies forager preference for functional traits. We also investigated whether perceived risk and distance from shelter affected giving-up density (GUD), time in patches, and number of patch visits. In safe landscapes, individuals increased time spent in patches, lowered GUD and visited distant patches more often compared to risky landscapes. Individuals preferred bigger seeds independent of risk, but in the safe treatment they preferred fat-rich over carb-rich seeds. Thus, higher densities of resource levels remained in risky landscapes, while in safe landscapes resource density was lower and less diverse due to selective foraging. Our results suggest that the interaction of perceived risk and dietary preference adds an additional layer to the cascading effects of a landscape of fear which affects biodiversity at resource level.

The Distant Molecular Effects on the Brain by Cancer Treatment.

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Novel intraocular shielding device for eye plaque brachytherapy using magnetite nanoparticles: A proof-of-concept study using radiochromic film and Monte Carlo simulations.

PURPOSE: Eye plaque brachytherapy is a mainstay treatment for uveal melanomas despite potential toxicities to normal tissues. This work proposes a nanoparticle ferrofluid as a novel intraocular shielding device. With a modified magnetic plaque, the shielding particles are drawn to the tumor surface, attenuating dose beyond the tumor while maintaining prescription dose to the target. METHODS AND MATERIALS: Ferromagnetic nanoparticles suspended in a silicone polymer were synthesized to provide a high-density shielding medium. The ferrofluid's half-value layer (HVL) was quantified for 125I photons using radiochromic film and Monte Carlo methods. A magnetic COMS plaque was created and evaluated in its ability to attract ferrofluid over the tumor. Two ferrofluid shielding mediums were evaluated in their ability to attenuate dose at adjacent structures with in vitro measurements using radiochromic film, in addition to Monte Carlo studies. RESULTS: The shielding medium's HVL measured approximately 1.3 mm for an 125I photon spectrum, using film and Monte Carlo methods. With 0.8 mL of shielding medium added to the vitreous humor, it proved to be effective at reducing dose to normal tissues of the eye. Monte Carlo-calculated dose reductions of 65%, 80%, and 78% at lateral distances 5, 10, and 18 mm from a tumor (5-mm apical height) in a modeled 20-mm COMS plaque. CONCLUSIONS: The magnitude of dose reduction could reduce the likelihood of normal tissue side effects for plaque brachytherapy patients, including patients with normal tissues close to the plaque or tumor. Additional studies, safety considerations, and preclinical work must supplement these findings before use.