High variability in short and long-term recovery kinetic of blood cell count and blood chemistry in a partial body irradiation mouse model.

PURPOSE: In the aftermath of a nuclear disaster or accident, survivors will suffer from radiation-induced normal tissue damage. Recovery after radiation exposure is dictated by several factors, one of which is degree of shielding at time of exposure. This study aims to characterize the short and late term changes in kinetics and magnitude of pancytopenia and blood chemistry in a model of heterogeneous radiation exposure, or partial body irradiation (PBI), compared to whole body irradiation (WBI). MATERIALS AND METHODS: Male C57BL/6 mice, 8-10 weeks of age, were WBI at 6 different doses (6, 6.1. 6.15, 6.2, 6.5, and 7.5 Gy) to establish the LD50. To determine the effect of shielding on blood cell counts and chemistry, animals were either WBI at 6 Gy (LD2230) or 6 Gy PBI with one leg shielding (LD030). Complete blood counts and chemistry were measured at 1, 5-, 10-, 20-, 30- and 120-days post-irradiation. RESULTS AND CONCLUSIONS: Irradiated animals had significant depletion of white blood cells, red blood cells and platelets up to 10 days post-irradiation. Separation between PBI and WBI were observed at 10- and 20-days post-irradiation at which point PBI animals showed sign of recovery while overall cell count remains depleted in WBI animals up to 30 days post-irradiation. In addition, significant changes were found in parameters indicative of hematopoietic injury including hemoglobin count, hematocrit count and white blood cell population. Significant changes were observed in kidney function with changes to blood urea nitrogen and calcium concentration at 5-days post-irradiation. At 10-days post-irradiation. liver function changes differentiated WBI from PBI animals. Long-term, irradiated animal's chemistry values and many blood counts were not significantly different from Sham. In conclusion, partial shielding ensured complete survival and demonstrated a different recovery kinetics of blood and chemistry parameters after irradiation compared to survivors of whole body irradiation and no single hemopoietic parameter was able to consistently differentiate irradiated from Sham animals. This seems to indicate that there is no single robust hemopoietic parameter to differentiate those exposed from those who were not due to the inherent variability in individual responses. Furthermore, there were no significant long-term effects on these blood parameters between survivors of WBI and PBI except that shielding accelerated recovery.

Acknowledging and overcoming barriers to entry into radiation science for women.

PURPOSE: Radiation science is a unique field that brings together various disciplines to understand nature, develop new technologies, and cure diseases. Our field is a prime example of advancement through a diverse pool of competencies. Similarly, studies show that the power of diversity requires proportionate representation of sex and gender, minorities, or other groups. Nevertheless, women are still underrepresented in the radiation sciences, although disparities and underlying mechanisms were first described decades ago. This review summarizes barriers to entry and retention and suggests strategies for overcoming disparities in our field. We also highlight a concerted effort by young professionals to promote the underrepresented and underserved within the radiation science community. CONCLUSION: The radiation science community should avoid losing diverse perspectives among its ranks due to sex bias or gender disparity among others. Through targeted efforts, we can cultivate change and harness the talent of researchers, practitioners, and other professionals for the benefit of scientific progress, health-care improvement, and societal advancement overall.

Cognitive and Imaging Differences After Proton and Photon Whole Brain Irradiation in a Preclinical Model.

PURPOSE: Compared with photon cranial radiation therapy (X-CRT), proton cranial radiation therapy (P-CRT) offers potential advantages in limiting radiation-induced sequalae in the treatment of pediatric brain tumors. This study aims to identify cognitive, functional magnetic resonance and positron emission tomography imaging markers and molecular differences between the radiation modalities. METHODS AND MATERIALS: Juvenile rats received a single faction of 10 Gy (relative biological effectiveness-weighted dose) delivered with 6 MV X-CRT or at the midspread out Bragg peak of a 100 MeV P-CRT beam. At 3, 6, and 12 months post-CRT, executive function was measured using 5-choice serial reaction time task. At ∼12 months post-CRT, animals were imaged with 18F-Flurodeoxy-glucose positron emission tomography imaging followed by functional ex vivo magnetic resonance imaging and stained for markers of neuroinflammation. RESULTS: Irradiated animals had cognitive impairment with a higher number of omissions and lower incorrect and premature responses compared with sham (P ≤ .05). The accuracy of the animals' X-CRT was less than that of sham (P ≤ .001). No significant difference in rates of cognitive change were found between the radiation modalities. At 12 months post-CRT, glucose metabolism was significantly higher than sham in X-CRT (P = .04) but not P-CRT. Using diffusion tensor imaging, P-CRT brains were found to have higher white matter volume and fiber lengths compared with sham (P < .03). Only X-CRT animals had higher apparent diffusion coefficient values compared with sham (P = .04). P-CRT animals had more connectomic changes compared with X-CRT. Correlative analysis identified several imaging features with cognitive performance. Furthermore, microgliosis (P < .05), astrogliosis (P < .01), and myelin thinning (P <.05) were observed in both radiation modalities, with X-CRT showing slightly more inflammation. CONCLUSIONS: Both P-CRT and X-CRT lead to neurocognitive changes compared with sham. Although no significant difference was observed in neuroinflammation between the irradiated groups, differences were found in late-term glucose metabolism and brain connectome. Our results indicate that despite relative biological effectiveness weighting of the proton dose there are still differential effects which warrants further investigation.

Cross-Sectional Characterization of Local Brain Network Connectivity Pre and Post Breast Cancer Treatment and Distinct Association With Subjective Cognitive and Psychological Function.

Objective: We aimed to characterize local brain network connectivity in long-term breast cancer survivors compared to newly diagnosed patients. Methods: Functional magnetic resonance imaging (fMRI) and subjective cognitive and psychological function data were obtained from a group of 76 newly diagnosed, pre-treatment female patients with breast cancer (mean age 57 ± 7 years) and a separate group of 80, post-treatment, female breast cancer survivors (mean age 58 ± 8; mean time since treatment 44 ± 43 months). The network-based statistic (NBS) was used to compare connectivity of local brain edges between groups. Hubs were defined as nodes with connectivity indices one standard deviation or more above network mean and were further classified as provincial (higher intra-subnetwork connectivity) or connector (higher inter-subnetwork connectivity) using the participation coefficient. We determined the hub status of nodes encompassing significantly different edges and correlated the centralities of edges with behavioral measures. Results: The post-treatment group demonstrated significantly lower subjective cognitive function (W = 3,856, p = 0.004) but there were no group differences in psychological distress (W = 2,866, p = 0.627). NBS indicated significantly altered connectivity (p < 0.042, corrected) in the post-treatment group compared to the pre-treatment group largely in temporal, frontal-temporal and temporal-parietal areas. The majority of the regions projecting these connections (78%) met criteria for hub status and significantly less of these hubs were connectors in the post-treatment group (z = 1.85, p = 0.031). Subjective cognitive function and psychological distress were correlated with largely non-overlapping edges in the post-treatment group (p < 0.05). Conclusion: Widespread functional network alterations are evident in long-term survivors of breast cancer compared to newly diagnosed patients. We also demonstrated that there are both overlapping and unique brain network signatures for subjective cognitive function vs. psychological distress.

Differentiation of Heterogeneous Radiation Exposure Using Hematology and Blood Chemistry.

In the aftermath of a nuclear incident, survivors will suffer the deleterious effects from acute radiation exposure. The majority of those affected would have received heterogeneous radiation exposure, reflected in hematological metrics and blood chemistry. Here, we investigated the acute and long-term changes in kinetics and magnitude of pancytopenia and blood chemistry in rats irradiated using varying degrees of body shielding. We hypothesized that, although a single blood count may not be able to differentiate the degree of radiation exposure, a combination of measurements from complete blood cell counts (CBCs) and blood chemistry tests is able to do so. Male Sprague Dawley rats, 8-10 weeks of age, received single-dose 7.5 Gy (160 kVp, 25 mA, 1.16 Gy/min) whole-body irradiation (WBI, LD100/30) or partial-body irradiation (PBI), as follows: one leg shielded (1LS, LD0/30), two legs shielded (2LS, LD0/30) or the upper half of the body shielded (UHS, LD0/30). Animal morbidity and weights were measured. Blood was drawn at 1, 5, 10, 20 and 30 days postirradiation (n = 4-11). For kidney and liver function measurements, CBC and blood chemistry analyses were performed. WBI animals on average survived 9 ± 0.4 days postirradiation. In contrast, all PBI animals survived the 30-day study period. CBC analysis revealed that both white blood cell (WBC) and platelet counts were most affected after irradiation. While WBC counts were significantly lower in all irradiated groups on days 1, 5 and 10, platelets were only significantly lower on days 5 and 10 postirradiation. In addition, on day 5 postirradiation both WBC and platelet counts were able to differentiate WBI (non-survivors) from PBI 2LS and UHS animals (survivors). Using four blood parameters (platelets, percentage lymphocytes, percentage neutrophils and percentage monocytes) on day 5 after 7.5 Gy irradiation and a linear discrimination analysis (LDA), we were able to predict the degree of body exposure in animals with a 95.8% accuracy. Alkaline phosphatase (ALP) was significantly lower in all groups on days 5 and 10 postirradiation compared to baseline. Furthermore, ALP was significantly higher in the UHS than WBI animals. The AST:ALT ratio was significantly higher than baseline in all irradiated groups on day 1 postirradiation. In conclusion, four CBC parameters, on day 5 after receiving a 7.5 Gy dose of radiation, can be employed in a LDA to differentiate various degrees of exposure (shielding). The characterization presented in this work paves the way for further studies in differences caused by heterogeneous body exposure to radiation and a new metric for biodosimetry.

A comprehensive preclinical assessment of late-term imaging markers of radiation-induced brain injury.

BACKGROUND: Cranial radiotherapy (CRT) is an important part of brain tumor treatment, and although highly effective, survivors suffer from long-term cognitive side effects. In this study we aim to establish late-term imaging markers of CRT-induced brain injury and identify functional markers indicative of cognitive performance. Specifically, we aim to identify changes in executive function, brain metabolism, and neuronal organization. METHODS: Male Sprague Dawley rats were fractionally irradiated at 28 days of age to a total dose of 30 Gy to establish a radiation-induced brain injury model. Animals were trained at 3 months after CRT using the 5-choice serial reaction time task. At 12 months after CRT, animals were evaluated for cognitive and imaging changes, which included positron emission tomography (PET) and magnetic resonance imaging (MRI). RESULTS: Cognitive deficit with signs of neuroinflammation were found at 12 months after CRT in irradiated animals. CRT resulted in significant volumetric changes in 38% of brain regions as well as overall decrease in brain volume and reduced gray matter volume. PET imaging showed higher brain glucose uptake in CRT animals. Using MRI, irradiated brains had an overall decrease in fractional anisotropy, lower global efficiency, increased transitivity, and altered regional connectivity. Cognitive measurements were found to be significantly correlated with six image features that included myelin integrity and local organization of the neural network. CONCLUSIONS: These results demonstrate that CRT leads to late-term morphological changes, reorganization of neural connections, and metabolic dysfunction. The correlation between imaging markers and cognitive deficits can be used to assess late-term side effects of brain tumor treatment and evaluate efficacy of new interventions.

Image-based Classification of Tumor Type and Growth Rate using Machine Learning: a preclinical study.

Medical images such as magnetic resonance (MR) imaging provide valuable information for cancer detection, diagnosis, and prognosis. In addition to the anatomical information these images provide, machine learning can identify texture features from these images to further personalize treatment. This study aims to evaluate the use of texture features derived from T1-weighted post contrast scans to classify different types of brain tumors and predict tumor growth rate in a preclinical mouse model. To optimize prediction models this study uses varying gray-level co-occurrence matrix (GLCM) sizes, tumor region selection and different machine learning models. Using a random forest classification model with a GLCM of size 512 resulted in 92%, 91%, and 92% specificity, and 89%, 85%, and 73% sensitivity for GL261 (mouse glioma), U87 (human glioma) and Daoy (human medulloblastoma), respectively. A tenfold cross-validation of the classifier resulted in 84% accuracy when using the entire tumor volume for feature extraction and 74% accuracy for the central tumor region. A two-layer feedforward neural network using the same features is able to predict tumor growth with 16% mean squared error. Broadly applicable, these predictive models can use standard medical images to classify tumor type and predict tumor growth, with model performance, varying as a function of GLCM size, tumor region, and tumor type.

In Vitro and In Vivo Characterization of a Preclinical Irradiation-Adapted Model for Ewing Sarcoma.

PURPOSE: Radiation therapy (RT) is a viable therapeutic option for Ewing sarcoma (ES) patients. However, little progress has been made to elucidate the mechanisms of radioresistance. This study establishes a novel ES irradiation-adapted model designed to assess molecular and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) alterations secondary to RT. METHODS AND MATERIALS: Radiation-adapted cell lines (RACLs) were created in vitro by exposing ES human cell lines to fractionated doses of radiation. Assays to assess migration or invasion potential and RNA expression were performed on the RACLs. Orthotopic intratibial in vivo investigations were performed with irradiation-sensitive and irradiation-adapted ES cells to generate tumors. Transplanted mice were imaged using 18F-FDG PET followed by fractionated RT directed at the primary tumor. Mice were monitored for tumor regression and change in metabolic activity using 18F-FDG PET imaging. Protein expression analyses were performed on the RACLs and orthotopic tumors. RESULTS: Exposure to fractionated doses of radiation caused a significant increase in migratory and invasive properties in the RACLs when compared with nonirradiated wild-type ES cells. RACL transcriptomic and proteomic analysis suggests enhanced activation of the mammalian target of rapamycin-AKT pathway when compared with wild-type ES cells. Irradiation-adapted tumors demonstrated significantly less tumor regression (P = .03) than wild-type tumors. Wild-type tumors also had decreased expression of lactate dehydrogenase A protein and significantly lower metabolic activity after RT compared with irradiation-adapted tumors (P = .03). CONCLUSIONS: We developed novel in vitro and in vivo irradiation-adapted ES models. In vitro investigations revealed increased migratory and invasive phenotypes in the RACLs. In vivo investigations demonstrated increased metabolic activity and significantly decreased sensitivity to RT in the irradiation-adapted tumors as demonstrated by growth response curves and 18F-FDG PET activity. Investigations of the RACLs identified possible radiosensitizing-dependent targets in lactate dehydrogenase A and the mammalian target of rapamycin-AKT pathway.

Preoperative weight loss with glucagon-like peptide-1 receptor agonist treatment predicts greater weight loss achieved by the combination of medical weight management and bariatric surgery in patients with type 2 diabetes: A longitudinal analysis.

We examined the relationship between weight changes after preoperative glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and weight changes from the start of medical weight management (MWM) until 12 months after bariatric surgery in patients with type 2 diabetes in a retrospective cohort study. A total of 45 patients (64.4% women, median [interquartile range] age 49 [45-60] years) were included. The median (interquartile range) weight loss from start of MWM until 12 months post-surgery was 17.9% (13.0%-29.3%). GLP-1RA treatment during MWM resulted in 5.0% (1.9%-7.7%) weight loss. Weight loss during GLP-1RA treatment predicted weight loss from the start of MWM until 12 months post-surgery, but not postoperative weight loss after adjustment. The proportion of weight loss from start of MWM to 12 months post-surgery attributed to GLP-1RA treatment was negatively associated with that attributed to surgery, after adjustment. In conclusion, weight change after GLP-1RA treatment predicted the weight loss achieved by a combination of MWM and bariatric surgery, but not weight loss induced by surgery only. Failure to lose weight after GLP-1RA treatment should not be considered a barrier to undergoing bariatric surgery.

Imaging Radiation-Induced Gastrointestinal, Bone Marrow Injury and Recovery Kinetics Using 18F-FDG PET.

Positron emission tomography using 18F-Fluro-deoxy-glucose (18F-FDG) is a useful tool to detect regions of inflammation in patients. We utilized this imaging technique to investigate the kinetics of gastrointestinal recovery after radiation exposure and the role of bone marrow in the recovery process. Male Sprague-Dawley rats were either sham irradiated, irradiated with their upper half body shielded (UHBS) at a dose of 7.5 Gy, or whole body irradiated (WBI) with 4 or 7.5 Gy. Animals were imaged using 18F-FDG PET/CT at 5, 10 and 35 days post-radiation exposure. The gastrointestinal tract and bone marrow were analyzed for 18F-FDG uptake. Tissue was collected at all-time points for histological analysis. Following 7.5 Gy irradiation, there was a significant increase in inflammation in the gastrointestinal tract as indicated by the significantly higher 18F-FDG uptake compared to sham. UHBS animals had a significantly higher activity compared to 7.5 Gy WBI at 5 days post-exposure. Animals that received 4 Gy WBI did not show any significant increase in uptake compared to sham. Analysis of the bone marrow showed a significant decrease of uptake in the 7.5 Gy animals 5 days post-irradiation, albeit not observed in the 4 Gy group. Interestingly, as the metabolic activity of the gastrointestinal tract returned to sham levels in UHBS animals it was accompanied by an increase in metabolic activity in the bone marrow. At 35 days post-exposure both gastrointestinal tract and bone marrow 18F-FDG uptake returned to sham levels. 18F-FDG imaging is a tool that can be used to study the inflammatory response of the gastrointestinal tract and changes in bone marrow metabolism caused by radiation exposure. The recovery of the gastrointestinal tract coincides with an increase in bone marrow metabolism in partially shielded animals. These findings further demonstrate the relationship between the gastrointestinal syndrome and bone marrow recovery, and that this interaction can be studied using non-invasive imaging modalities.

An Update on the Registration of Biosimilars in Malaysia.

BACKGROUND: Because of its structure and complex manufacturing process, every biotherapeutic product (BTP; medicinal products made by or derived from living organisms and produced by biotechnology) adheres to stringent quality assurance and control requirements, in addition to extensive nonclinical and clinical study data. Similarly, copy products of original biotherapeutics (termed as "biosimilars") are subjected to equally strict regulatory control. BTPs have been registered in Malaysia since the 1990s; however, registration of biosimilars started only in 2008. METHODS: This research aims to compare evaluation practice on biosimilar and novel BTPs at the Biological Product Registration Section in Malaysia. Evaluation activities were studied in terms of evaluation questions, evaluation timeline, nonclinical and clinical requirements, and local requirements on product label (including package insert). Six biosimilar product dossiers and 6 novel BTP dossiers evaluated in 2013-2015 were sampled. Parameters for comparison were determined and analyzed using data collection forms. Specific to the biosimilar products, the evaluation practice on labels and package inserts were dissected and described in a qualitative arm of this research. RESULTS: Generally, the registration requirements of novel BTPs and biosimilar products are in agreement with international regulatory practices. However, some labeling and package insert requirements, and registration conditions are unique to the Malaysian regulatory context. CONCLUSIONS: Study findings revealed some similarities and differences in current evaluation practice (timeline and requirements) for biosimilar versus novel BTPs. The findings of this research also provide an insight on current evaluation practice on biosimilar product labeling.

Tonotopic and localized pathways from primary auditory cortex to the central nucleus of the inferior colliculus.

Descending projections from the cortex to subcortical structures are critical for auditory plasticity, including the ability for central neurons to adjust their frequency tuning to relevant and meaningful stimuli. We show that focal electrical stimulation of primary auditory cortex in guinea pigs produces excitatory responses in the central nucleus of the inferior colliculus (CNIC) with two tonotopic patterns: a narrow tuned pattern that is consistent with previous findings showing direct frequency-aligned projections; and a broad tuned pattern in which the auditory cortex can influence multiple frequency regions. Moreover, excitatory responses could be elicited in the caudomedial portion along the isofrequency laminae of the CNIC but not in the rostrolateral portion. This descending organization may underlie or contribute to the ability of the auditory cortex to induce changes in frequency tuning of subcortical neurons as shown extensively in previous studies.

Three-dimensional brain reconstruction of in vivo electrode tracks for neuroscience and neural prosthetic applications.

The brain is a densely interconnected network that relies on populations of neurons within and across multiple nuclei to code for features leading to perception and action. However, the neurophysiology field is still dominated by the characterization of individual neurons, rather than simultaneous recordings across multiple regions, without consistent spatial reconstruction of their locations for comparisons across studies. There are sophisticated histological and imaging techniques for performing brain reconstructions. However, what is needed is a method that is relatively easy and inexpensive to implement in a typical neurophysiology lab and provides consistent identification of electrode locations to make it widely used for pooling data across studies and research groups. This paper presents our initial development of such an approach for reconstructing electrode tracks and site locations within the guinea pig inferior colliculus (IC) to identify its functional organization for frequency coding relevant for a new auditory midbrain implant (AMI). Encouragingly, the spatial error associated with different individuals reconstructing electrode tracks for the same midbrain was less than 65 µm, corresponding to an error of ~1.5% relative to the entire IC structure (~4-5 mm diameter sphere). Furthermore, the reconstructed frequency laminae of the IC were consistently aligned across three sampled midbrains, demonstrating the ability to use our method to combine location data across animals. Hopefully, through further improvements in our reconstruction method, it can be used as a standard protocol across neurophysiology labs to characterize neural data not only within the IC but also within other brain regions to help bridge the gap between cellular activity and network function. Clinically, correlating function with location within and across multiple brain regions can guide optimal placement of electrodes for the growing field of neural prosthetics.