The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs.

PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.

Chromosomal instability (CIN) has been recognized as a hallmark of human cancer and is caused by continuous chromosome missegregation during mitosis. Proper chromosome segregation requires a physical connection between spindle microtubules and centromeric DNA and this attachment occurs at proteinaceous structures called kinetochore. Several centromere proteins such as CENP-A and CENP-H are the fundamental components of the human active kinetochore, and inappropriate expression of the centromere proteins could be a major cause of CIN. We have previously shown that CENP-A was overexpressed in primary human colorectal cancer. In this study, we show that CENP-H was also up-regulated in all of 15 primary human colorectal cancer tissues as well as in CIN tumor cell lines. Surprisingly, transient transfection of CENP-H expression plasmid into the diploid cell line HCT116 remarkably induced aneupoidy. Moreover, CENP-H stable transfectant of mouse embryonic fibroblast/3T3 cell lines showed aberrant interphase micronuclei, characteristic of chromosome missegregation. In these CENP-H overexpressed cells, CENP-H completely disappeared from the centromere of mitotic chromosomes, which might be the cause of the chromosome segregation defect. These results suggest that the aberrant expression and localization of a kinetochore protein CENP-H plays an important role in the aneuploidy frequently observed in colorectal cancers. (Cancer Res 2005; 65(11): 4683-9)

Concentrations of persistent organochlorine pesticides such as DDTs, hexachlorocyclohexanes (HCHs), chlordane compounds (CHLs), hexachlorobenzene (HCB), and polychlorinated biphenyls (PCBs), were determined in a wide variety of foodstuffs and human tissues collected from Shanghai and its vicinity in China in 2000-2001. Among the organochlorines analyzed, DDT and its metabolites were prominent compounds in most of the foodstuffs. In particular, mussels contained noticeable residues of DDTs (34,000 ng/g lipid weight), which are one to three orders greater than those reported levels in bivalves from other Asian countries. Concentrations of HCHs, CHLs, HCB, and PCBs in foodstuffs were generally low, suggesting small amounts of inputs into the environment. Temporal trends examined by comparing the results of previous studies of organochlorine levels in Chinese foodstuffs in 1970s and 1992 revealed a greater amounts of declines of DDTs and HCHs residues and the average daily intakes during the past 30 years. In contrast, very high concentrations of DDTs and HCHs were detected in human tissues from Shanghai, with the maximum values as high as 19,000 ng/g lipid weight (mean: 7,600 ng/g) and 17,000 ng/g (mean: 7,400 ng/g), respectively. Considering that foodstuffs are a main source of human exposure to contaminants, the greater concentrations of DDTs and HCHs in Chinese people might be due to past extensive usage of these compounds as agricultural pesticides. Continuous monitoring and epidemiological studies of organochlorine pesticides in humans are warranted in China. To our knowledge, this is the first report to present the residue levels of persistent organochlorine pesticides and PCBs in human tissues of China.

No abstract

No abstract

The trans-endothelial migration of activated leukocytes into inflamed tissue is an important mechanism in the pathogenesis of inflammatory diseases. Endothelial cells play a key role in this step by up-regulating the synthesis and secretion of chemokines and the cell surface expression of adhesion molecules (CAMs) 2 (1). The adhesion molecules ICAM-1 and VCAM-1 bind leukocytes expressing the major integrins lymphocyte function associated antigen-1 (LFA-1) and the VLA-4 (very late activation antigen-4), respectively, and are induced on endothelial cells by inflammatory stimuli (2, 3). Both are required for the attachment of circulating leukocytes to the endothelium and mediate not only transcellular migration but also the induction of intracellular signals resulting in transient junctional disruption (1) and the paracellular passage of leukocytes across the endothelial monolayer.Lysophosphatidic acid (LPA), a pleiotropic proinflammatory lipid mediator, is elevated in multiple disease states. High concentrations of the lipid have been detected in the bronchoalveolar lavage fluid of preclinical animal models of allergic asthma (4). LPA plays a role in regulating the secretion of pro-and anti-inflammatory mediators by airway epithelial cells and in modulating airway epithelial barrier integrity (5). Additionally, synovial fluid obtained from rheumatoid arthritis patients contain significant amounts of LPA and the LPA-synthesizing enzyme autotaxin driving cytokine secretion by and migration of resident synoviocytes (6, 7). The lipid mediator has also been implicated in the initiation of neuropathic pain (8). Blood platelets also store LPA and are an important source of the lipid. Serum and plasma contain nanomolar levels of LPA and de novo generation or release from platelet stores during inflammation may result in higher LPA levels at disease loci. LPA engages a family of at least five closely related G protein-coupled receptors LPA1-5 (9). It has been reported that HUVECs express LPA1 and LPA3 receptors and are responsive to LPA with induced expression of chemokines and cell adhesion molecules (CAMs) (10 -12). In vitro and in vivo studies employing Rho kinase inhibitors, isoform-specific LPA receptor inhibitors, and targeted receptor deletions link LPA acting through the LPA1 receptor, to the downstream activation of Rho kinase (8,13,14).Rho kinase, a serine/threonine kinase, was initially characterized as a mediator of the formation of RhoA-induced stress fibers and focal adhesions (15). Activation of the Rho kinase pathway leads to the phosphorylation of downstream substrates including the 20-kDa myosin light chain (MLC) (16), the myosin phosphatase subunit (MYPT-1) (17), and CPI-17A (18), which have been postulated to control a variety of fundamental cellular functions such as proliferation, survival, contraction, migration, and the transcriptional regulation of gene expression. However, abnormal activation of the pathway has been * This work was supported by Pfizer, Inc.

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.