PDCD2 functions in cancer cell proliferation and predicts relapsed leukemia

PDCD2 is an evolutionarily conserved eukaryotic protein with unknown function. The Drosophila PDCD2 ortholog Zfrp8 has an essential function in fly hematopoiesis. Zfrp8 mutants exhibit marked lymph gland hyperplasia that results from increased proliferation of partially differentiated hemocytes, suggesting Zfrp8 may participate in cell growth. Based on the above observations we have focused on the role of PDCD2 in human cancer cell proliferation and hypothesized that aberrant PDCD2 expression may be characteristic of human malignancies. We report that PDCD2 is highly expressed in human acute leukemia cells as well as in normal hematopoietic progenitors. PDCD2 knockdown in cancer cells impairs their proliferation, but not viability relative to parental cells, supporting the notion that PDCD2 overexpression facilitates cancer cell growth. Prospective analysis of PDCD2 in acute leukemia patients indicates PDCD2 RNA expression correlates with disease status and is a significant predictor of clinical relapse. PDCD2’s role in cell proliferation and its high expression in human malignancies make it an attractive, novel potential molecular target for new anti-cancer therapies.     

Effect of hyperthermia and anoxia on glucocorticoid and mineralocorticoid receptor expression in neonatal rat hippocampus

Brief periods of neonatal asphyxia are frequently observed. Within the CNS, the hippocampus is known to be particularly vulnerable to the damaging effects of hypoxia/ischaemia. The hippocampus contains the highest concentration of both mineralocorticoid (MR) and glucocorticoid (GR) receptors and the balance between MR/GR activation influences cell birth and death. MR occupation appears to promote prosurvival actions, while GR overactivation favours neurodegeneration. It has been widely recognized that core body temperature is a critical determinant of the severity of hypoxic–ischemic brain injury; indeed, hyperthermia exacerbates the degree of damage. Therefore, the aim of the present investigation was to study the effect of elevated body temperature in newborn rats under control conditions or during neonatal exposure to a critical anoxia, on changes of MR and GR mRNA expression in the rat hippocampus. 2-day-old rats were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 °C (typical for the rat neonates), or elevated to a level typical for febrile (39 °C) adults. Control rats were exposed to atmospheric air under the respective thermal conditions. The changes in MR and GR mRNA expression in hippocampus were examined 24 h after exposure. Our data show that hyperthermia with or without added anoxia, causes induction of MR mRNA expression in neonatal rat hippocampus without any effect on GR mRNA expression. We suggest this elevation of MR plays an important role in modulating the survival of neurons in the injured hippocampus.     

Improving PTSD/Substance Abuse Treatment in the VA: A Survey of Providers

We surveyed 205 Veterans Affairs (VA) staff on treatment of posttraumatic stress disorder (PTSD), substance use disorder (SUD), and the combination (PTSD/SUD). The survey was anonymous and VA‐wide. PTSD/SUD was perceived as more difficult to treat than either disorder alone; gratification in the work was stronger than difficulty (for PTSD, SUD, and PTSD/SUD); and difficulty and gratification appeared separate constructs. Respondents endorsed views that represent expert treatment for the comorbidity; however, there was also endorsement of “myths.” Thus, there is a need for more training, policy clarifications, service integration, and adaptations for veterans returning from Iraq and Afghanistan. Limitations are described. (Am J Addict 2010;19:257–263)     

Nonadditive effects of PAHs on Early Vertebrate Development: mechanisms and implications for risk assessment.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants. Traditionally, much of the research has focused on the carcinogenic potential of specific PAHs, such as benzo(a)pyrene, but recent studies using sensitive fish models have shown that exposure to PAHs alters normal fish development. Some PAHs can induce a teratogenic phenotype similar to that caused by planar halogenated aromatic hydrocarbons, such as dioxin. Consequently, mechanism of action is often equated between the two classes of compounds. Unlike dioxins, however, the developmental toxicity of PAH mixtures is not necessarily additive. This is likely related to their multiple mechanisms of toxicity and their rapid biotransformation by CYP1 enzymes to metabolites with a wide array of structures and potential toxicities. This has important implications for risk assessment and management as the current approach for complex mixtures of PAHs usually assumes concentration addition. In this review we discuss our current knowledge of teratogenicity caused by single PAH compounds and by mixtures and the importance of these latest findings for adequately assessing risk of PAHs to humans and wildlife. Throughout, we place particular emphasis on research on the early life stages of fish, which has proven to be a sensitive and rapid developmental model to elucidate effects of hydrocarbon mixtures.     

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m⁻², cisplatin 60 mg m⁻² on day 1 and capecitabine 1000 mg m⁻² daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43–82), disease stabilisation of 25% (95% CI: 11–47) and a disease control rate (CR+PR+SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.     

Cleaning frequency and the microbial load in ice-cream

This study investigates the efficacy of a 62 h cleaning frequency in the manufacturing of ice-cream. Various product and product contact surfaces were sampled progressively throughout the time period between cleaning cycles, and analyzed for microbial growth. The coliform and standard plate counts (SPC) of these samples did not vary significantly over time after 0, 24, 48, or 62 h from Cleaning in Place (CiP). Data for product contact surfaces were significant for the SPC representing sample locations. Some of the variables in cleaning practices had significant influence on microbial loads. An increase in the number of flavors manufactured caused a decrease in SPC within the 24 h interval, but by the 48 h interval the SPC increased. More washouts within the first 24 h interval were favorable, as indicated by decreased SPC. The more frequently the liquefier was sanitized within the 62 h interval, the lower the SPC. This study indicates that food safety was not compromised and safety practices were effectively implemented throughout the process.