Elevated international normalized ratio is correlated with large volume transfusion in pediatric trauma patients.

BACKGROUND: Pediatric trauma patients may benefit from a balanced transfusion strategy, however, determining when to activate massive transfusion protocols remains uncertain. The purpose of this study was to explore whether certain scoring systems can predict the need for large volume transfusion. METHODS: We conducted a retrospective review of pediatric trauma patients who presented to our center and required a transfusion of packed red blood cells. Baseline laboratory and clinical data were used to calculate Trauma Associated Severe Hemorrhage (TASH) score and a previously reported composite of acidosis and coagulopathy. RESULTS: We identified 518 pediatric trauma patients who presented to our center between January 1, 2013 and December 31, 2018. These patients were less than 18 years of age (mean 9.6 years) and had an injury severity score ranging from 1 to 50 (mean 11.3). Forty-three patients (8.3%) received a transfusion within 24 hours of presentation, ranging from 4 to 139 mL/kg of packed red blood cells (mean 23.1 mL/kg). Transfusion volume was associated with acidosis and coagulopathy scores (r = 0.37, p = 0.033) and international normalized ratio (INR) (r = 0.34, p = 0.03) but not TASH (p = 0.72). Patients with INR≥1.3 received a higher mean volume of packed red cells compared to those with normal values (34 versus 18 mL/kg, p = 0.046). CONCLUSION: Pediatric trauma patients who undergo transfusion of packed red blood cells are likely to require large volume transfusion if their baseline INR is ≥1.3. These patients may benefit from a balanced transfusion strategy, such as utilization of massive transfusion protocols or whole blood.

PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila Cancer Res; 76(16); 4708-19. ©2016 AACR.

Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma.

Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC- overexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.

Senescence of the cellular immune response in Drosophila melanogaster.

Immune system effectiveness generally declines as animals age, compromising disease resistance. In Drosophila, expression of a variety of immune-related genes elevates during ageing; however how this is linked to increasing pathogen susceptibility in older flies has remained unclear. We investigated whether changes in the Drosophila cellular immune response might contribute to immunosenescence. Experiments studied fly cohorts of different ages and compared the numbers and activity of the circulating haemocytes involved in pathogen defence. In female wildtype Samarkand and Oregon R flies the haemocyte population fell by 31.8% and 10.2% respectively during the first four weeks of adulthood. Interestingly we detected no such decline in male flies. The impact of ageing on the phagocytic activity of haemocytes was investigated by injecting flies with fluorescently labelled microbes or latex beads and assessing the ability of haemocytes to engulf them. For all immune challenges the proportion of actively phagocytosing haemocytes decreased as flies aged. Whilst 24.3%±1.15% of haemocytes in one-week-old flies phagocytosed Escherichia coli bacteria or Beauveria bassiana fungal spores, this decreased to 16.7%±0.99% in four-week-old flies. This clear senescence of the Drosophila cellular immune response may underpin increased disease susceptibility in older flies.