Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor.

Synovial sarcoma is a soft-tissue sarcoma and a rare type of cancer. Unfortunately, effective chemotherapies for synovial sarcomas have not been established. In this report, we show that synovial sarcoma cell lines have reduced repair activity for DNA damage induced by ionizing radiation (IR) and a topoisomerase II inhibitor (etoposide).

A rare polymorphic variant of NBS1 reduces DNA repair activity and elevates chromosomal instability.

Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia.

Up-regulation of PSF1 promotes the growth of breast cancer cells.

PSF1 is a subunit of the GINS complex that functions along with the MCM2-7 complex and Cdc45 in eukaryotic DNA replication. Although mammalian PSF1 is predominantly expressed in highly proliferating cells and organs, little is known about the roles of PSF1 in mature cells or cancer cells. We found that PSF1 was expressed at relatively high levels in breast tumor cells, but at low levels in normal breast cells.

Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth.

Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%.

The SYT-SSX fusion protein down-regulates the cell proliferation regulator COM1 in t(x;18) synovial sarcoma.

Chromosomal translocations are frequently associated with soft-tissue sarcomas. Fusion proteins generated by such translocations often play critical roles in tumorigenesis. Therefore, it is important to understand the function of the fusion protein to develop therapeutic interventions.

Microtubule bundle formation and cell death induced by the human CLASP/Orbit N-terminal fragment.

Previously we have identified the Drosophila orbit gene whose hypomorphic mutations cause abnormal chromosome segregation (Inoue et al., 2000). The orbit encodes Orbit/Mast, a 165-kDa microtubule-associated protein (MAP) with GTP-binding motifs.

An interventional approach to block brain damage caused by Shiga toxin-producing Escherichia coli infection, by use of a combination of phosphodiesterase inhibitors.

We tested the combination of phosphodiesterase (PDE) 3 and PDE4 inhibitors as an interventional approach to prevent the development of brain damage after Shiga toxin (Stx)-producing Escherichia coli (STEC) infection, using mice with protein calorie malnutrition. The combination consisted of pentoxifylline and rolipram; the dose of each inhibitor was 7.5 mg/kg.

Functionally active CD8alphabeta+ TCRgammadelta intestinal intraepithelial lymphocytes in athymic nu/nu mice.

Murine intestinal intraepithelial lymphocytes (IEL) encompass a high proportion of TCRgammadelta cells. A vast majority of these TCRgammadelta IEL express CD8alpha, but not CD8beta (CD8alphaalpha homodimer), and are considered to develop in intestinal epithelial layers independently of a functional thymus. Here we show that TCRgammadelta cells expressing both CD8alpha and CD8beta (CD8alphabeta heterodimer) appear in athymic nu/nu mice, although their appearance is random.

Highly biased type 1 immune responses in mice deficient in LFA-1 in Listeria monocytogenes infection are caused by elevated IL-12 production by granulocytes.

LFA-1 (CD11a/CD18) plays a key role in various inflammatory responses. Here we show that the acquired immune response to Listeria monocytogenes is highly biased toward type 1 in the absence of LFA-1. At the early stage of listeriosis, numbers of IFN-gamma producers in the liver and spleen of LFA-1(-/-) mice were markedly increased compared with heterozygous littermates and Valpha14(+)NKT cell-deficient mice, and NK cells were major IFN-gamma producers.

Increased resistance of LFA-1-deficient mice to lipopolysaccharide-induced shock/liver injury in the presence of TNF-alpha and IL-12 is mediated by IL-10: a novel role for LFA-1 in the regulation of the proinflammatory and anti-inflammatory cytokine balance.

Challenge with low doses of LPS together with D-galactosamine causes severe liver injury, resulting in lethal shock (low dose LPS-induced shock). We examined the role of LFA-1 in low dose LPS-induced shock. LFA-1(-/-) mice were more resistant to low dose LPS-induced shock/liver injury than their heterozygous littermates, although serum levels of TNF-alpha and IL-12 were higher in these mice.

Neutrophilia in LFA-1-deficient mice confers resistance to listeriosis: possible contribution of granulocyte-colony-stimulating factor and IL-17.

LFA-1 (CD11a/CD18) plays a crucial role in various inflammatory responses. In this study, we show that LFA-1(-/-) mice are far more resistant to Listeria monocytogenes infection than LFA-1(+/-) mice. Consistent with this, we found the following: 1) the numbers of granulocytes infiltrating the liver were markedly higher in LFA-1(-/-) mice than in LFA-1(+/-) mice, 2) increased antilisterial resistance in LFA-1(-/-) mice was abrogated by depletion of granulocytes, and 3) the numbers of granulocytes in peripheral blood, and the serum levels of both G-CSF and IL-17 were higher in LFA-1(-/-) mice than in LFA-1(+/-) mice.

Critical role of NK cells rather than V alpha 14(+)NKT cells in lipopolysaccharide-induced lethal shock in mice.

Although macrophages play a central role in the pathogenesis of septic shock, NK1(+) cells have also been implicated. NK1(+) cells comprise two major populations, namely NK cells and V alpha 14(+)NKT cells. To assess the relative contributions of these NK1(+) cells to LPS-induced shock, we compared the susceptibility to LPS-induced shock of beta(2)-microglobulin (beta(2)m)(-/-) mice that are devoid of V alpha 14(+)NKT cells, but not NK cells, with that of wild-type (WT) mice.