bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis C Virus Triggers Mitochondrial Permeability Transition with Production of Reactive Oxygen Species, Leading to DNA Damage and STAT3 Activation
Authors: Machida Keigo , Cheng Kevin T.-H. , Lai Chao-Kuen , Jeng King-Song , Sung Vicky M.-H. , Lai Michael M. C. 
Published: June 2006

ABSTRACTHepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinomas and non-Hodgkin's B-cell lymphomas. Previously, we reported that HCV infection causes cellular DNA damage and mutations, which are mediated by nitric oxide (NO). NO often damages mitochondria, leading to induction of double-stranded DNA breaks (DSBs) and accumulation of oxidative DNA damage. Here we report that HCV infection causes production of reactive oxygen species (ROS) and lowering of mitochondrial transmembrane potential (ΔΨm) in in vitro HCV-infected cell cultures. The changes in membrane potential could be inhibited by BCL-2. Furthermore, an inhibitor of ROS production, antioxidantN-acetyl-l-cysteine (NAC), or an inhibitor of NO, 1400W, prevented the alterations of ΔΨm. The HCV-induced DSB was also abolished by a combination of NO and ROS inhibitors. These results indicated that the mitochondrial damage and DSBs in HCV-infected cells were mediated by both NO and ROS. Among the HCV proteins, core, E1, and NS3 are potent ROS inducers: their expression led to DNA damage and activation of STAT3. Correspondingly, core-protein-transgenic mice showed elevated levels of lipid peroxidation and oxidatively damaged DNA. These HCV studies thus identified ROS, along with the previously identified NO, as the primary inducers of DSBs and mitochondrial damage in HCV-infected cells.
Induction of Lactoferrin Gene Expression in Myeloid or Mammary Gland Cells by Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax: Implications for Milk-Borne Transmission of HTLV-1
Authors: Moriuchi Masako , Moriuchi Hiroyuki 
Published: June 2006

ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia, is transmitted vertically via breastfeeding. We have previously demonstrated that lactoferrin, a major milk protein, enhances HTLV-1 replication, at least in part by upregulating the HTLV-1 long terminal repeat promoter. We now report that HTLV-1 infection can induce lactoferrin gene expression. Coculture with HTLV-1-infected MT-2 cells increased the levels of lactoferrin mRNA in myeloid-differentiated HL-60 cells, as well as MCF-7 cells, models of two probable sources (neutrophils and mammary epithelium) of lactoferrin in breast milk. MT-2 cell coculture could be replaced with cell-free culture supernatants of MT-2 cells to exert the same effect. Furthermore, extracellularly administered Tax protein also induced lactoferrin gene expression at physiologically relevant concentrations. In transient-expression assays, Tax transactivated the lactoferrin gene promoter in HL-60 or MCF-7 cells. Experiments with Tax mutants, as well as site-directed mutants of the lactoferrin promoter reporters, indicated that the NF-κB transactivation pathway is critical for Tax induction of the lactoferrin gene promoter activity in myeloid-differentiated HL-60 cells, but not in MCF-7 cells. These results suggest that HTLV-1 infection may be able to induce expression of lactoferrin in a paracrine manner in the lactic compartment. Our findings, in conjunction with our previous study, implicate that mutual interaction between HTLV-1 and lactoferrin would benefit milk-borne transmission of this virus.
Neuropilin-1 Is Involved in Human T-Cell Lymphotropic Virus Type 1 Entry
Authors: Ghez David , Lepelletier Yves , Lambert Sophie , Fourneau Jean-Marie , Blot Vincent , Janvier Sébastien , Arnulf Bertrand , van Endert Peter M. , Heveker Nikolaus , Pique Claudine , Hermine Olivier 
Published: June 2006

ABSTRACTHuman T-cell lymphotropic virus type 1 (HTLV-1) is transmitted through a viral synapse and enters target cells via interaction with the glucose transporter GLUT1. Here, we show that Neuropilin-1 (NRP1), the receptor for semaphorin-3A and VEGF-A165 and a member of the immune synapse, is also a physical and functional partner of HTLV-1 envelope (Env) proteins. HTLV-1 Env and NRP1 complexes are formed in cotransfected cells, and endogenous NRP1 contributes to the binding of HTLV-1 Env to target cells. NRP1 overexpression increases HTLV-1 Env-dependent syncytium formation. Moreover, overexpression of NRP1 increases both HTLV-1 and HTLV-2 Env-dependent infection, whereas down-regulation of endogenous NRP1 has the opposite effect. Finally, overexpressed GLUT1, NRP1, and Env form ternary complexes in transfected cells, and endogenous NRP1 and GLUT1 colocalize in membrane junctions formed between uninfected and HTLV-1-infected T cells. These data show that NRP1 is involved in HTLV-1 and HTLV-2 entry, suggesting that the HTLV receptor has a multicomponent nature.
A Distinct p53 Protein Isoform Signature Reflects the Onset of Induction Chemotherapy for Acute Myeloid Leukemia
Authors: Anensen Nina , Oyan Anne Margrete , Bourdon Jean-Christophe , Kalland Karl Henning , Bruserud Oystein , Gjertsen Bjorn Tore 
Published: July 2006

Abstract
Purpose: The antioncogene protein product p53 has not been studied previously in cancer patients during in vivo chemotherapy. This study examined the early p53 protein and gene expression during induction chemotherapy in acute myeloid leukemia (AML).
Experimental Design: Leukemic cells were collected from five AML patients during their first 18 hours of induction chemotherapy and examined for p53 protein and gene expression by one- and two-dimensional gel immunoblot and high-density gene expression arrays.
Results: Up-regulation of p53 protein expression was detected in AML patients posttreatment in vivo. One- and two-dimensional gel immunoblots showed two main forms of p53, denominated αp53 and Δp53, both recognized by various NH2-terminal directed antibodies. As a response to treatment, we detected rapid accumulation of αp53, with significantly altered protein expression levels already after 2 hours. The accumulation of αp53 was accompanied by increased transcription of putative p53 target genes and subsequent cytopenia in the patients.
Conclusion: Up-regulation of the p53 protein and target genes seems to be a prominent feature in induction chemotherapy of AML. The rapid shift from a shorter p53 protein form (Δ) toward the full-length protein (α) underscores the complexity of p53 protein modulation in patients undergoing chemotherapy.
Signaling via ErbB2 and ErbB3 Associates with Resistance and Epidermal Growth Factor Receptor (EGFR) Amplification with Sensitivity to EGFR Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cells
Authors: Erjala Kaisa , Sundvall Maria , Junttila Teemu T. , Zhang Na , Savisalo Mika , Mali Pekka , Kulmala Jarmo , Pulkkinen Jaakko , Grenman Reidar , Elenius Klaus 
Published: July 2006

Abstract
Purpose: The epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) has shown antitumor activity in clinical trials against cancers, such as non–small cell lung cancer and head and neck squamous cell carcinoma (HNSCC). Research on non–small cell lung cancer has elucidated factors that may predict response to gefitinib. Less is known about molecular markers that may predict response to gefitinib in HNSCC patients.
Experimental Design: We analyzed possible associations of responsiveness to gefitinib with molecular markers of the EGFR/ErbB receptor family signaling pathway using 10 established HNSCC lines in vitro. IC50 of gefitinib sensitivity was determined using clonogenic survival assays. ErbB signaling was assessed by Western and real-time reverse transcription-PCR analyses of EGFR, ErbB2, ErbB3, and ErbB4 expression levels as well as by phosphorylation analysis of pEGFR, pErbB2, pErbB3, pAkt, and pErk. EGFR sequences encoding kinase domain and EGFR gene copy numbers were determined by cDNA sequencing and real-time PCR, respectively. Finally, responsiveness to gefitinib was compared with responsiveness to the anti-EGFR antibody cetuximab (Erbitux).
Results: Expression levels of pErbB2 (P = 0.02) and total ErbB3 protein (P = 0.02) associated with resistance to gefitinib. Combining gefitinib with pertuzumab (Omnitarg), an antibody targeting ErbB2 heterodimerization, provided additional growth-inhibitory effect over gefitinib alone on relatively gefitinib-resistant HNSCC cell lines. The same markers did not predict resistance to cetuximab. In contrast, a similar trend suggesting association between EGFR gene copy number and drug sensitivity was observed for both gefitinib (P = 0.0498) and cetuximab (P = 0.053). No activating EGFR mutations were identified.
Conclusions: EGFR amplification may predict sensitivity to gefitinib in HNSCC. However, other EGFR/ErbB receptor family members than EGFR may contribute to resistance to gefitinib. ErbB2 and ErbB3 may have potential as predictive markers and as therapeutic targets for combination therapy in treatment of HNSCC with gefitinib.
Captopril, an Angiotensin-Converting Enzyme Inhibitor, Promotes Growth of Immunogenic Tumors in Mice
Authors: Wysocki Piotr J. , Kwiatkowska Eliza P. , Kazimierczak Urszula , Suchorska Wiktoria , Kowalczyk Dariusz W. , Mackiewicz Andrzej 
Published: July 2006

Abstract
Purpose: Antitumor potential of angiotensin-converting enzyme inhibitors has been shown in different preclinical settings, which always involved immunocompromised organisms or nonimmunogenic tumor models. In our study, we wanted to evaluate the effect of captopril on growth of immunogenic tumors in immunocompetent animals.
Experimental Design: We used different murine tumor models to evaluate the effect of captopril on tumor take and survival of tumor-bearing immunocompetent and immunocompromised mice. We used an orthotopic renal cell cancer model and highly immunogenic tumor model, which were based on kidney subcapsular injection of RenCa cells or s.c. injection of MethA cells, respectively. To show the influence of captopril on antigen-specific immune responses, we have used two model antigens (green fluorescent protein and β-galactosidase).
Results: Captopril decreased survival of RenCa-bearing, immunocompetent mice in a dose-dependent manner and in adjuvant setting. In nephrectomized mice, captopril shortened their survival. Captopril promoted formation of immunogenic MethA sarcoma tumors but had no effect on nonimmunogenic melanoma cells (B78-H1). Treatment of immunocompromised mice bearing MethA tumors or RenCa kidney tumors with captopril did not affect tumor formation nor survival, respectively. Captopril-treated mice immunized with AdLacZ or AdGFP vectors did not generate or generated decreased numbers of antigen-specific CD8+ T cells, respectively. However, they showed B-cell responses represented by infiltration of MethA tumors with activated B cells and dramatically increased serum level of β-galactosidase-specific antibodies.
Conclusions: Our results show a novel role of captopril in tumor biology and the tumor-promoting properties of captopril seem to be associated with its immunomodulatory potential.
Humanization of the Bispecific Epidermal Growth Factor Receptor × CD3 Diabody and Its Efficacy as a Potential Clinical Reagent
Authors: Asano Ryutaro , Sone Yukiko , Makabe Koki , Tsumoto Kouhei , Hayashi Hiroki , Katayose Yu , Unno Michiaki , Kudo Toshio , Kumagai Izumi 
Published: July 2006

AbstractPurpose: Bispecific antibodies (BsAb) have been exploited as both cancer immunodiagnostics and cancer therapeutics and show promise in clinical trials of cancer imaging and therapy. For development of BsAbs as clinical reagents, we have focused on construction of small recombinant BsAbs, called bispecific diabodies. Here, we constructed and characterized a humanized bispecific diabody.Experimental Design: We have reported significant antitumor activity of an anti-epidermal growth factor receptor (EGFR) × anti-CD3 bispecific diabody (Ex3) in in vitro cytotoxicity assays and in vivo. We humanized the Ex3 diabody (hEx3) by grafting the complementarity-determining region and compared its biological properties with those of Ex3. We also tested its physiologic stability and ability to alter survival in xenografted mice.Results: The final yield of hEx3 was 10 times that of Ex3, and refolded hEx3 and Ex3 showed identical binding profiles in EGFR-positive cell lines and EGFR-transfected Chinese hamster ovary cells. hEx3 showed dose-dependent cytotoxicity to EGFR-positive cell lines, which could be specifically inhibited by parental monoclonal antibody IgGs against EGFR or CD3 antigens. The heterodimeric structure was retained in PBS for 6 months, and growth inhibition was maintained after incubation under physiologic conditions. Coadministration of hEx3 with T-LAK cells and interleukin-2 prolonged the survival of nude mice with human colon carcinoma.Conclusions: The humanized diabody hEx3 is an attractive molecule for cancer therapy and may provide important insights into the development of EGFR-based cancer-targeting reagents.
Positron Emission Tomography Using [18F]Galacto-RGD Identifies the Level of Integrin αvβ3 Expression in Man
Authors: Beer Ambros J. , Haubner Roland , Sarbia Mario , Goebel Michael , Luderschmidt Stephan , Grosu Anca Ligia , Schnell Oliver , Niemeyer Markus , Kessler Horst , Wester Hans-Jürgen , Weber Wolfgang A. , Schwaiger Markus 
Published: July 2006

Abstract
Purpose: The integrin αvβ3 plays a key role in angiogenesis and tumor cell metastasis and is therefore an important target for new therapeutic and diagnostic strategies. We have developed [18F]Galacto-RGD, a highly αvβ3-selective tracer for positron emission tomography (PET). Here, we show, in man, that the intensity of [18F]Galacto-RGD uptake correlates with αvβ3 expression.
Experimental Design: Nineteen patients with solid tumors (musculoskeletal system, n = 10; melanoma, n = 4; head and neck cancer, n = 2; gliobastoma, n = 2; and breast cancer, n = 1) were examined with PET using [18F]Galacto-RGD before surgical removal of the tumor lesions. Snap-frozen specimens (n = 26) were collected from representative areas with low and intense standardized uptake values (SUV) of [18F]Galacto-RGD. Immunohistochemistry was done using the αvβ3-specific antibody LM609. Intensity of staining (graded on a four-point scale) and the microvessel density of αvβ3-positive vessels were determined and correlated with SUV and tumor/blood ratios (T/B).
Results: Two tumors showed no tracer uptake (mean SUV, 0.5 ± 0.1). All other tumors showed tracer accumulation with SUVs ranging from 1.2 to 10.0 (mean, 3.8 ± 2.3; T/B, 3.4 ± 2.2; tumor/muscle ratio, 7.7 ± 5.4). The correlation of SUV and T/B with the intensity of immunohistochemical staining (Spearman's r = 0.92; P &lt; 0.0001) as well as with the microvessel density (Spearman's r = 0.84; P &lt; 0.0001) were significant. Immunohistochemistry confirmed lack of αvβ3 expression in normal tissue (benign lymph nodes, muscle) and in the two tumors without tracer uptake.
Conclusions: Molecular imaging of αvβ3 expression with [18F]Galacto-RGD in humans correlates with αvβ3 expression as determined by immunohistochemistry. PET with [18F]Galacto-RGD might therefore be used as a new marker of angiogenesis and for individualized planning of therapeutic strategies with αvβ3-targeted drugs.
A Phase I Study of Ultra Low Dose Interleukin-2 and Stem Cell Factor in Patients with HIV Infection or HIV and Cancer
Authors: Shah Manisha H. , Freud Aharon G. , Benson Don M. , Ferkitich Amy K. , Dezube Bruce J. , Bernstein Zale P. , Caligiuri Michael A. 
Published: July 2006

AbstractPurpose: Ultra low doses of interleukin-2 (IL-2) can activate the high-affinity IL-2 receptor constitutively expressed on CD56bright natural killer (NK) cells, the CD34+ NK cell precursor, and CD4+CD25+ regulatory T cells (Tregs) in vivo. We have previously shown synergy between IL-2 and stem cell factor (SCF) in the generation of CD56bright NK cells from CD34+ hemopoietic progenitor cells in vitro and showed synergistic NK cell expansion in an in vivo preclinical model. To determine the safety, toxicity, and immune modulation of this combination of cytokines in vivo, we conducted a first-in-man phase I study.Experimental Design: A phase I dose escalation study was conducted using IL-2 at 900,000 or 650,000 IU/m2/d for 8 weeks with 5 or 10 μg/kg/d of SCF given thrice a week for 8 weeks in patients with HIV infection and/or cancer.Results: Ten of 13 patients completed therapy; four experienced the dose-limiting toxicities of grade 3 fatigue or urticaria. The maximum tolerated doses of IL-2 and SCF in combination is 650,000 IU/m2/d of IL-2 and 5 μg/kg/d thrice a week of SCF. NK cells were expanded over 2-fold on therapy; Tregs were expanded nearly 6-fold from baseline.Conclusions: Administration of IL-2 with SCF is safe and well tolerated and leads to expansion of lymphocyte subsets in patients with HIV or HIV and cancer; however, the changes in NK cell and Treg expansion seen with this cytokine combination were no different than those seen with a similar dose of IL-2 alone.
Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1α activity and vascular endothelial growth factor expression in small cell lung cancer cells
Authors: Litz Julie , Krystal Geoffrey W. 
Published: July 2006

Abstract
Vascular endothelial growth factor (VEGF) is one of the most important mediators of tumor angiogenesis. In addition to hypoxia, peptide growth factors are known to regulate VEGF expression but the effect of stem cell factor (SCF), the ligand for c-Kit, on VEGF expression has not been characterized. We therefore studied the effect of SCF-mediated c-Kit activation on VEGF expression by the H526 small cell lung cancer (SCLC) cell line. SCF treatment doubled VEGF mRNA expression and VEGF secretion in the absence of other exogenous growth factors, an effect efficiently blocked by imatinib. The increase in VEGF mRNA occurred within the first 2 hours of treatment and was not caused by alterations in mRNA stability. The phosphatidylinositol 3-kinase inhibitor LY294002 blocked the increase in VEGF mRNA, implicating c-Kit-mediated activation of phosphatidylinositol 3-kinase in the phenomenon. VEGF promoter-reporter transfections indicated that a SCF-mediated increase in VEGF promoter activity paralleled the increase in VEGF mRNA, documenting that SCF mediated its effects through enhanced VEGF transcription. Mutation of the core hypoxia-inducible factor (HIF)-1 binding element in the VEGF promoter significantly blunted SCF-responsiveness. SCF increased nuclear levels of the HIF-1α transcription factor, which correlated well with increased HIF-1α binding to a consensus hypoxia-responsive element. SCF-mediated effects on HIF-1α expression were additive with those produced by CoCl2, a hypoxia-mimetic agent. These data indicate that activation of c-Kit by SCF leads to a predominantly HIF-1α-mediated enhancement of VEGF expression and that inhibition of c-Kit signaling with imatinib could result in inhibition of tumor angiogenesis. [Mol Cancer Ther 2006;5(6):1415–22]
Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer
Authors: Giovannetti Elisa , Mey Valentina , Nannizzi Sara , Pasqualetti Giuseppe , Del Tacca Mario , Danesi Romano 
Published: July 2006

Abstract
Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16INK4. Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment. Indeed, the inactivation of p53 may explain the relative resistance to 5-fluorouracil, whereas Bcl-2 overexpression is associated with reduced sensitivity to gemcitabine. However, the future challenge of pancreas cancer chemotherapy relies on the identification of molecular markers that help in the selection of drugs best suited to the individual patient. Recent pharmacogenetic studies focused on genes encoding proteins directly involved in drug activity, showing the role of thymidylate synthase and human equilibrative nucleoside transporter-1 as prognostic factor in 5-fluorouracil- and gemcitabine-treated patients, respectively. Finally, inhibitors of signal transduction and angiogenesis are under extensive investigation, and several prospective trials have been devoted to this area. Pharmacogenetics is likely to play a central role in the personalization of treatment, to stratify patients based on their likelihood of response to both standard agents (i.e., gemcitabine/nucleoside transporters) and targeted treatments (i.e., epidermal growth factor receptor gene mutations and/or amplification and tyrosine kinase inhibitors), Thus, molecular analysis should be implemented in the optimal management of the patient affected by pancreatic adenocarcinoma. [Mol Cancer Ther 2006;5(6):1387–95] [Mol Cancer Ther 2006;5(6):1387-95]
Constitutively active receptor tyrosine kinases as oncogenes in preclinical models for cancer therapeutics
Authors: Kellar Kristen A. , Lorenzi Matthew V. , Ho Ching Ping , You Dan , Wen Mei-Li , Ryseck Rolf P. , Oppenheimer Simone , Fink Brian E. , Vite Gregory D. , Rowley Bruce R. , Yu Chiang , Bol David K. , Lee Francis Y. , Wong Tai W. 
Published: July 2006

AbstractReceptor tyrosine kinases (RTK) remain an area of therapeutic interest because of their role in epithelial tumors, and experimental models specific to these targets are highly desirable. Chimeric receptors were prepared by in-frame fusion of the CD8 extracellular sequence with the cytoplasmic sequences of RTKs. A CD8HER2 fusion protein was shown to form disulfide-mediated homodimers and to transform fibroblasts and epithelial cells. CD8RTK fusion proteins transform rat kidney epithelial cells and impart phenotypes that may reflect signaling specificity inherent in the native receptors. Transgenic expression of CD8HER2 and CD8Met in mice resulted in the formation of salivary and mammary gland tumors. The transgenic tumors allow the derivation of allograft tumors and cell lines that are sensitive to inhibition by small molecule kinase inhibitors. This approach provides excellent cell and tumor models for the characterization of signaling properties of diverse RTKs and for the evaluation of rationally designed antagonists targeting these kinases. [Mol Cancer Ther 2006;5(6):1571–6]