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Objective: Surgeries for cancer of the esophagus are still associated with a high rate of postoperative morbidity. There are few reports of perioperative nutritional support for patients undergoing esophageal cancer surgery, and there is insufficient evidence to recommend routine use of immunonutrition in these patients. The aim of this study was to determine whether preoperative immunonutrition positively influences key clinical outcomes such as postoperative infectious complications, mortality, length of hospital stay, and short-term survival in this population. Design and Setting: We undertook a retrospective investigation of the effects of preoperative nutritional support on the postoperative course of esophageal cancer surgery at the Department of Gastroenterological Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan. Participants: Fifty-five patients who underwent esophagectomy for esophageal cancer were included in this study. Of the 55 patients, 26 patients consumed a liquid dietary supplement (IMPACT group) before surgery and 29 patients did not (STANDARD group). Intervention: Before surgery, the IMPACT group consumed 750 ml (3 packs)/day of Impact® for 5 consecutive days. Measurements: The analysis was based on postoperative complications, hospital mortality, length of hospital stay, and short-term survival. Results: Significantly fewer patients developed postoperative infections in the IMPACT group compared with the STANDARD group (p=.007): 4 of 21 patients in the IMPACT group and 10 of 29 patients in the STANDARD group. Either an infectious complication or another complication developed in 8 patients in the IMPACT group and 13 patients in the STANDARD group, with the result that 6 patients in the STANDARD group died of postoperative complications (p=.001). The duration of hospitalization was 34 days in the IMPACT group and 48 days in the STANDARD group; hence, hospitalization was significantly shorter in patients treated with Impact® (p=.008). The mean 6-month survival rates for the IMPACT group and the STANDARD group were 92% (24/26) and 72% (21/29), respectively (p=.028). Conclusion: Simple preoperative supplementation significantly improved outcome. Administration of the supplemental diet before esophageal surgery appeared to be an effective strategy in reducing infectious complications, mortality, and hospitalization, and improving short-term survival. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies.Methods: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied.Results: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status.Conclusion: GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL. [ABSTRACT FROM AUTHOR]

Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl+ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl+ stem cells is needed to cure leukemias caused by Bcr-Abl+ cells. Human Bcr-Abl+ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl+ sublines by selection in long-term hypoxic cultures (1.0% O2). Interestingly, HA-Bcr-Abl+ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher β-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl+ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl+ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl+ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl+ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment. [ABSTRACT FROM AUTHOR]

Galectins constitute a family of lectins that specifically exhibit the affinity for β-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC50 between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH2-terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy. [ABSTRACT FROM AUTHOR]

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl+) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl+ leukemias.Cell Death and Differentiation (2008) 15, 1712–1722; doi:10.1038/cdd.2008.107; published online 11 July 2008 [ABSTRACT FROM AUTHOR]

Bcr-Abl is the cause of Philadelphia-positive (Ph+) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph+ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-XL, greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph+ leukemic cells.Cell Death and Differentiation (2007) 14, 1667–1677; doi:10.1038/sj.cdd.4402168; published online 18 May 2007 [ABSTRACT FROM AUTHOR]

We report a 19-year-old woman with Behcet’s disease who suffered a subarachnoid hemorrhage and had bilateral peripheral middle cerebral artery aneurysms. After steroid therapy for 3 days, the smaller aneurysm disappeared. The larger aneurysm was excised and the artery reconstructed using a superficial temporary artery graft. Histological examination showed vasculitis restricted to the wall of the aneurysm. This is the first report of arterial reconstruction for an aneurysm associated with Behcet’s disease. Steroid therapy before the operation may facilitate repair of the arterial wall. [ABSTRACT FROM AUTHOR]

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.British Journal of Cancer (2006) 95, 601–606. doi:10.1038/sj.bjc.6603311 www.bjcancer.com Published online 8 August 2006 [ABSTRACT FROM AUTHOR]

Aim/hypothesis. An increased production of reactive oxygen species (ROS) could contribute to the development of diabetic nephropathy. NAD(P)H oxidase might be an important source of ROS production in kidney as reported in blood vessels. In this study, we show the increased expression of essential subunits of NAD(P)H oxidase, NOX4 and p22phox, in the kidney of diabetic rats. Methods. The levels of mRNA of both NOX4 and p22phox were evaluated in kidney from streptozotocin-induced diabetic rats and age-matched control rats at 4 and 8 weeks after onset of diabetes by Northern blot analysis. The localization and expression levels of these components and 8-hydroxy-deoxyguanosine (8-OHdG), which is a marker of ROS-induced DNA damage, were also evaluated by immunostaining. Results. The levels of both NOX4 and p22phox mRNA were increased in the kidney of diabetic rats as compared with control rats. Immunostaining analysis showed that the expression levels of NOX4 and p22phox were clearly increased in both distal tubular cells and glomeruli from diabetic rats. Both the localization and the expression levels of these components were in parallel with those of 8-OHdG. Interventive insulin treatment for 2 weeks completely restored the increased levels of these components in the diabetic kidney to control levels in parallel with those of 8-OHdG. Conclusions/interpretation. This study provides evidence that NAD(P)H oxidase subunits, NOX4 and p22phox, were increased in the kidney of diabetic rats. Thus, NAD(P)H-dependent overproduction of ROS could cause renal tissue damage in diabetes. This might contribute to the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Blastic natural killer cell leukemia/lymphoma (blastic NKL/L) is characterized by blastic morphology and a distinctive immunophenotype combining blastic features and cytologically resembling acute myeloid or lymphoid leukemia. The clinical, pathologic, and cytogenetic features of blastic NKL/L have not yet been systematically identified. We report herein a case of blastic NKL/L with skin lesion, adenopathy, and systemic lymphoadenopathy. The identified tumor cells were positive for CD4 and CD56, and negative for T-cell, B-cell, and myeloid markers. T-cell receptor beta, gamma, delta, and immunoglobulin heavy chain genes in the bone marrow cells showed germ-line configurations. Southern blot analysis with a terminal probe did not reveal any Epstein-Barr virus infection. Although patients diagnosed as blastic NKL/L have generally shown chemotherapy resistance and poor prognosis, our patient was treated with a combined chemotherapy, which is also used for acute lymphoblastic leukemia, and has maintained complete remission (CR) for more than 13 months. In addition to clinical investigations, we thoroughly analyzed his karyotype by using a combination of G-banding and a new technique, spectral karyotyping. The karyotype was described as 45, XY, der(1)t(1;20)(p32;q11.2), der(6) (1pter-->1p32:: 6p21.1-->6q13:: 7q11.2-->7qter), der(7) t(7;20)(q11.2;q11.2), t(13;14)(q14;q32), der(13)t(6;13) (p21.1; q14), -20. [ABSTRACT FROM AUTHOR]

This report concerns a case of aggressive-phase multiple myeloma (AGMM) with Burkitt's type translocation t(8;14)(q24;q32), detected by Giemsa-banding. Double-color fluorescence in situ hybridization identified the breakpoint on 8q24 at a comparatively centromeric site, which was at least 300 kb and possibly 600 kb distant from the c-myc coding region. The breakpoint on 8q24 of the present case was far removed from that seen in other B-cell neoplasms with t(8;14)(q24;q32). Despite the presence of t(8;14)(q24;q32), neither rearrangement nor overexpression of the c-myc gene was observed in this case. Although our case may be a special case of multiple myeloma, it nevertheless suggests that overexpression of c-myc is not mandatory in an AGMM patient with Burkitt's type translocation. t(8;14)(q24;q32) which was seen in our case represents one of the first to be mapped at more than 300 kb 5' of c-myc. It should also be noted that this result could mean that a centromeric boundary 5' of c-myc exists where the influence of the immunoglobulin (Ig) H enhancer on c-myc transcription is not effective. [ABSTRACT FROM AUTHOR]

A 38-year-old male presented with fever and hepatosplenomegaly. Cells that had infiltrated to the bone marrow were consistent immunophenotypically and genotypically with natural killer (NK) cells. Oligoclonal Epstein-Barr virus infection was detected in the bone marrow cells. The patient was diagnosed as a case of aggressive NK cell leukemia/lymphoma. Combined chemotherapy was not effective and death occurred shortly after presentation. Although the karyotype of this case was too complicated to be accurately identified only by G-banding, spectral karyotyping (SKY) analysis not only identified all chromosomal materials of unknown origin, but also detected the cryptic translocation on the apparently normal chromosome. Moreover, SKY analysis identified der(4)t(4;14)(q12;q11.2). The chromosomal band 14q11.2 is a recurring breakpoint in T-cell non-Hodgkin's lymphoma, and is also the locus of the delta chain of the T-cell receptor. To our knowledge, t(4;14)(q12;q11.2) in T-cell or NK-cell malignancies has not been previously reported. [ABSTRACT FROM AUTHOR]

The susceptibility of fourteen established cell lines to infection with Japanese encephalitis virus (JEV) was assayed using an indirect fluorescent antibody technique. In kinetic studies, the degree of binding and internalization of JEV allowed the identification of high susceptibility and low-susceptibility cells. Scatchard analysis showed that JEV specifically bound to high-susceptibility Vero cells with greater affinity than to low-susceptibility NRK cells. Microinjection of viral genomic RNA into NRK cells induced highly efficient production of viral antigen and infectious virions. A hemagglutinin-inhibiting monoclonal antibody against JEV (MAb 301) inhibited the binding of JEV to the Vero and NRK cells. JEV was found to bind to a 74K molecule present in the membrane fraction of Vero cells and this binding was inhibited by MAb 301. Importantly, the 74K molecule was not detected in the membrane faction of NRK cells. These results suggest that early events in the JEV-cell interaction influence the susceptibility of cells to infection, and in particular suggests that the 74K molecule may be a possible candidate or component of the cellular receptor for JEV. [ABSTRACT FROM AUTHOR]

To study the role of HIV-1 gp120 in loss of myelin in HIV encephalopathy, the binding of gp120 to various types of neural cells and its effects on myelination were examined in rat primary brain culture. Doublestaining of cultured cells with gp120 and specific antibodies for different neural cell types showed that gp120 bound to most of the galactocerebroside (GalC)-positive oligodendrocytes, a small population of type-2-like astrocytes and a few small neurons. Gp120 did not bind to type-1-like astrocytes, most neurons, or to macrophage/microglia. To assay myelination, cells were bathed in a myelination medium containing chick embryo extract and high glucose, with or without gp120. Seven days after the application, myelination in the culture was observed morphologically and by staining with anti-myelin basic protein (MBP) antibody, and was found to be significantly inhibited by the addition of gp120 (50-100 nM). The processes of oligodendrocytes were reduced in length and arborization relative to the control, but MBP production by oligodendrocytes was unaffected. These results show that gp120 can cause a functional disorder of oligodendrocytes and thus could underlie the diffuse loss of mylein sheaths of HIV encephalopathy. [ABSTRACT FROM AUTHOR]

Among all the neural cells in fetal rat brain culture developing neurons showed the highest rate of infection by Japanese encephalitis virus (JEV). JEV specifically bound to these cells as measured by immuno-staining. These results indicate that developing neurons are the major target of JEV, and that the initial specific binding of virus to these cells may be one of the reasons for the neurotropism of JEV. [ABSTRACT FROM AUTHOR]

The biogeochemistry of hypersaline environments is strongly influenced by changes in biological processes and physicochemical parameters. Although massive evaporation events have occurred repeatedly throughout Earth history, their biogeochemical cycles and global impact remain poorly understood. Here, we provide the first nitrogen isotopic data for nutrients and chloropigments from modern shallow hypersaline environments (solar salterns, Trapani, Italy) and apply the obtained insights to δ15N signatures of the Messinian salinity crisis (MSC) in the late Miocene. Concentrations and δ15N of chlorophyll a, bacteriochlorophyll a, nitrate, and ammonium in benthic microbial mats indicate that inhibition of nitrification suppresses denitrification and anammox, resulting in efficient ammonium recycling within the mats and high primary productivity. We also suggest that the release of 15N-depleted NH3(gas) with increasing salinity enriches ammonium 15N in surface brine (≈34.0‰). Such elevated δ15N is also recorded in geoporphyrins isolated from sediments of the MSC peak (≈20‰), reflecting ammonium supply sufficient for sustaining phototrophic primary production. We propose that efficient nutrient supply combined with frequent bottom-water anoxia and capping of organic-rich sediments by evaporites of the Mediterranean MSC could have contributed to atmospheric CO2 reduction during the late Miocene. [ABSTRACT FROM AUTHOR]