Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation.

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.

Proteomic profiling of cerebrospinal fluid identifies prostaglandin D2 synthase as a putative biomarker for pediatric medulloblastoma: A pediatric brain tumor consortium study.

The aims of this study were to demonstrate the feasibility of centrally collecting and processing high-quality cerebrospinal fluid (CSF) samples for proteomic studies within a multi-center consortium and to identify putative biomarkers for medulloblastoma in CSF. We used 2-DE to investigate the CSF proteome from 33 children with medulloblastoma and compared it against the CSF proteome from 25 age-matched controls. Protein spots were subsequently identified by a combination of in-gel tryptic digestion and MALDI-TOF TOF MS analysis. On average, 160 protein spots were detected by 2-DE and 76 protein spots corresponding to 25 unique proteins were identified using MALDI-TOF. Levels of prostaglandin D2 synthase (PGD2S) were found to be six-fold decreased in the tumor samples versus control samples (p<0.00001). These data were further validated using ELISA. Close examination of PGD2S spots revealed the presence of complex sialylated carbohydrates at residues Asn(78) and Asn(87) . Total PGD2S levels are reduced six-fold in the CSF of children with medulloblastoma most likely representing a host response to the presence of the tumor. In addition, our results demonstrate the feasibility of performing proteomic studies on CSF samples collected from patients at multiple institutions within the consortium setting.

TGFß Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFß Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFß), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFß-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFß treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

Evaluation of thyrotoxicosis during pregnancy with color flow Doppler sonography.

OBJECTIVE: To determine whether color flow Doppler sonography (CFDS) is useful in differentiating Graves vs non-Graves thyrotoxicosis during pregnancy, when nuclear imaging is contraindicated. METHODS: Ten pregnant women with thyrotoxicosis were divided into Graves, and non-Graves, disease groups and were evaluated by CFDS for thyroid volume, vascularity, and inferior thyroid artery (ITA) flow velocity. Each patient was matched with a euthyroid woman of the same pregnancy duration. RESULTS: Of the 10 patients, 3 were diagnosed with Graves disease, 4 with gestational toxicosis, and 3 with destructive thyroiditis. Those in the Graves disease group had a greater thyroid gland volume (18.9+/-1.5 cm3 vs 12.1+/-2.4 cm3; P<0.05), greater thyroid vascularity, and greater ITA flow velocity than those in the non-Graves disease group (92+/-13 cm/s vs 20.4+/-2.4 cm/s; P<0.05). There was no significant difference in the corresponding values between the patients with gestational toxicosis and those with destructive thyroiditis or between them and their healthy controls. CONCLUSION: Thyroid evaluation by CFDS is useful for the differential diagnosis of thyrotoxicosis in pregnant women.

Primary school health education: a practical project for a small hospital community health department.

A pilot project in a rural district of Tamil Nadu, India in which health is taught as a subject in primary schools by hospital-based staff is described.

Predictors of postoperative outcome for acetabular fractures.

BACKGROUND: The outcomes of surgically treated acetabular fractures are dependent on many factors. The purpose of this retrospective study is to evaluate these factors in a group of patients operated on by a single surgeon in one institute. METHODS: One hundred and eighteen patients, treated surgically for their displaced acetabular fracture and who had completed two years follow-up, were evaluated clinically with Modified Postel Merle d'Aubigné score and radiologically with Matta's radiological outcome grading. The effect of age (≤ 55 or >55 years), gender, fracture displacement (≤ 20mm or >20mm), hip dislocation, delay in surgery (≤ 2 weeks or >2 weeks), associated injury and length of follow-up (≤ 5 years or >5 years) on the functional outcome was evaluated. RESULTS: There were 99 (83.9%) males and 19 (16.1%) females with mean age of 38.75 years (16 to 65 years). The mean duration of follow-up was 3.95 years (range 2 to 14 years). The mean Modified Postel Merle d'Aubigné score was 15.7 ± 2.2 (range, 8 to 18). The clinical outcome was excellent in 27 (22.9%), good in 52 (44.2%), fair in 20 (16.9%), and poor in 19 (16.1%, 10 patients who underwent THR for secondary arthritis were considered as poor outcome) patients. The Modified Postel Merle d'Aubigné score was significantly affected by quality of reduction (P=0.0001), presence of associated injuries (P=0.0001), initial fracture displacement of >20mm (P=0.018), joint dislocation (P=0.015) and delay in surgery (P=0.001). However, age, gender, fracture type and length of follow-up did not have any effects on the clinical outcome. CONCLUSION: Poor reduction, associated injuries, fracture displacement of >20mm, joint dislocation and late surgery definitely carry poor prognosis in predicting the outcome of surgically treated acetabular fractures.