bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Analysis of the Capsid Gene of Genotype GII.2 Noroviruses
Authors: Iritani Nobuhiro , Vennema Harry , Siebenga J. Joukje , Siezen Roland J. , Renckens Bernadet , Seto Yoshiyuki , Kaida Atsushi , Koopmans Marion 
Published: May 2008

ABSTRACT

Noroviruses (NoVs) are considered to be a major cause of acute nonbacterial gastroenteritis in humans. The NoV genus is genetically diverse, and genotype GII.4 has been most commonly identified worldwide in recent years. In this study we analyzed the complete capsid gene of NoV strains belonging to the less prevalent genotype GII.2. We compared a total of 36 complete capsid sequences of GII.2 sequences obtained from the GenBank (
n
= 5) and from outbreaks or sporadic cases that occurred in The Netherlands (
n
= 10) and in Osaka City, Japan (
n
= 21), between 1976 and 2005. Alignment of all capsid sequences did not show fixation of amino acid substitutions over time as an indication for genetic drift. In contrast, when strains previously recognized as recombinants were excluded from the alignment, genetic drift was observed. Substitutions were found at five informative sites (two in the P1 subdomain and three in the P2 subdomain), segregating strains into five genetic groups (1994 to 1997, 1999 to 2000, 2001 to 2003, 2004, and 2005). Only one amino acid position changed consistently between each group (position 345). Homology modeling of the GII.2 capsid protein showed that the five amino acids were located on the surface of the capsid and close to each other at the interface of two monomers. The data suggest that these changes were induced by selective pressure, driving virus evolution. Remarkably, this was observed only for nonrecombinant genomes, suggesting differences in behavior with recombinant strains.
Mechanistic Studies of a T20-Dependent Human Immunodeficiency Virus Type 1 Variant
Authors: Baldwin Chris , Berkhout Ben 
Published: May 2008

ABSTRACT
We previously described a T20-dependent human immunodeficiency virus type 1 variant from a patient on T20 therapy (3). This virus carries two mutations in the gp41 domain of the envelope protein (Env) that was proposed to undergo a premature conformational switch to the 6-helix bundle structure. The T20 peptide can rescue this hyperfusogenic Env protein by preventing the premature switch and preserving an earlier prefusion conformation, thus restoring virus infectivity and replication. In this study, we set out to critically test this mechanistic explanation with alternative effectors that may control the Env switch, including other fusion inhibitors and antibodies that target gp41.
Targeting CUB Domain-Containing Protein 1 with a Monoclonal Antibody Inhibits Metastasis in a Prostate Cancer Model
Authors: Siva Amara C. , Wild Martha A. , Kirkland Richard E. , Nolan Mary Jean , Lin Bing , Maruyama Toshiaki , Yantiri-Wernimont Ferda , Frederickson Shana , Bowdish Katherine S. , Xin Hong 
Published: May 2008

Abstract
Through a whole-cell panning approach, we previously identified a panel of antibodies that bound to prostate cancer cell surface antigens. One such antigen, CUB domain-containing protein 1 (CDCP1), was recognized by monoclonal antibody 25A11 and is a single transmembrane molecule highly expressed in several metastatic cancers as well as on CD34+CD133+ myeloid leukemic blast cells. We show CDCP1 expression on prostate cancer cell lines by real-time quantitative PCR (RT-qPCR), flow cytometry, and immunohistochemistry and on prostate cancer patient samples by RT-qPCR and immunohistochemical staining. In cell-based assays, antibody 25A11 inhibited prostate cancer cell migration and invasion in vitro. Further characterization showed that CDCP1 is internalized on antibody binding. When 25A11 was coupled to the cytotoxin saporin either directly or via a secondary antibody, both resulted in prostate cancer cell killing in vitro. In vivo targeting studies with an anti-CDCP1 immunotoxin showed significant inhibition of primary tumor growth as well as metastasis in a mouse xenograft model. These data provide support for continued evaluation of anti-CDCP1 therapy for potential use in cancer in primary and metastatic disease. [Cancer Res 2008;68(10):3759–66]
Rap1GAP Promotes Invasion via Induction of Matrix Metalloproteinase 9 Secretion, Which Is Associated with Poor Survival in Low N-Stage Squamous Cell Carcinoma
Authors: Mitra Raj S. , Goto Mitsuo , Lee Julia S. , Maldonado Diana , Taylor Jeremy M.G. , Pan Quintin , Carey Thomas E. , Bradford Carol R. , Prince Mark E. , Cordell Kitrina G. , Kirkwood Keith L. , D'Silva Nisha J. 
Published: May 2008

Abstract
The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G1-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P &lt; 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P &lt; 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P &lt; 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P &lt; 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs. [Cancer Res 2008;68(10):3959–69]
Activation of Estrogen Receptor-α by the Anion Nitrite
Authors: Veselik David J. , Divekar Shailaja , Dakshanamurthy Sivanesan , Storchan Geoffrey B. , Turner Jasmine M.A. , Graham Kelly L. , Huang Li , Stoica Adriana , Martin Mary Beth 
Published: May 2008

Abstract
In this study, the ability of nitrite and nitrate to mimic the effects of estradiol on growth and gene expression was measured in the human breast cancer cell line MCF-7. Similar to estradiol, treatment of MCF-7 cells with either 1 μmol/L nitrite or 1 μmol/L nitrate resulted in ∼4-fold increase in cell growth and 2.3-fold to 3-fold increase in progesterone receptor (PgR), pS2, and cathepsin D mRNAs that were blocked by the antiestrogen ICI 182,780. The anions also recruited estrogen receptor-α (ERα) to the pS2 promoter and activated exogenously expressed ERα when tested in transient cotransfection assays. To determine whether nitrite or nitrate was the active anion, diphenyleneiodonium was used to inhibit oxidation/reduction reactions in the cell. The ability of diphenyleneiodonium to block the effects of nitrate, but not nitrite, on the induction of PgR mRNA and the activation of exogenously expressed ERα suggests that nitrite is the active anion. Concentrations of nitrite, as low as 100 nmol/L, induced a significant increase in PgR mRNA, suggesting that physiologically and environmentally relevant doses of the anion activate ERα. Nitrite activated the chimeric receptor Gal-ER containing the DNA-binding domain of GAL-4 and the ligand-binding domain of ERα and blocked the binding of estradiol to the receptor, suggesting that the anion activates ERα through the ligand-binding domain. Mutational analysis identified the amino acids Cys381, His516, Lys520, Lys529, Asn532, and His547 as important for nitrite activation of the receptor. [Cancer Res 2008;68(10):3950–8]
Deletion of the WNT Target and Cancer Stem Cell Marker CD44 in Apc(Min/+) Mice Attenuates Intestinal Tumorigenesis
Authors: Zeilstra Jurrit , Joosten Sander P.J. , Dokter Maarten , Verwiel Eugène , Spaargaren Marcel , Pals Steven T. 
Published: May 2008

AbstractMutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active β-catenin/TCF–mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts. The expression of CD44 is dramatically increased in aberrant crypt foci in both humans and tumor-susceptible ApcMin/+ mice, suggesting a role for CD44 in intestinal tumorigenesis. To study this role, we crossed C57BL/6J-Cd44−/− mice with C57BL/6J-ApcMin/+ mice. Compared with C57BL/6J-Cd44+/+/ApcMin/+ mice, C57BL/6J-Cd44−/−/ApcMin/+ mice showed an almost 50% reduction in the number of intestinal adenomas. This reduction was primarily caused by a decrease in the formation of aberrant crypts, implying the involvement of CD44 in tumor initiation. The absence of CD44 in the normal (nonneoplastic) crypts of Cd44−/−/ApcMin/+ mice did not alter the proliferative capacity and size of the intestinal stem cell and transit-amplifying compartments. However, compared with Cd44+/+/ApcMin/+ mice, Cd44−/−/ApcMin/+ showed an increase in the number of apoptotic epithelial cells at the base of the crypt which correlated with an increased expression of the proapoptotic genes Bok and Dr6. Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt. [Cancer Res 2008;68(10):3655–61]
Protein Kinase D3 (PKD3) Contributes to Prostate Cancer Cell Growth and Survival Through a PKCε/PKD3 Pathway Downstream of Akt and ERK 1/2
Authors: Chen Jun , Deng Fan , Singh Shivendra V. , Wang Qiming J. 
Published: May 2008

Abstract
Protein kinase D (PKD) is a family of novel diacylglycerol/phorbol ester targets that regulate many important cellular functions including cell growth and survival. We now provide experimental evidence to indicate that PKD3 contributes to prostate cancer cell growth and survival. Expression of PKD3 as well as PKD1 was significantly higher in human prostate tumors compared with normal tissues as revealed by immunohistochemistry. Moreover, PKD3 exhibited a marked increase in nuclear localization in tumor tissues, which correlated with tumor grade. Isoforms of PKD were differentially expressed and localized between normal and human prostate cancer cells. Increased protein expression and nuclear accumulation of PKD3 were observed in the more aggressive androgen-independent PC3 and DU145 cells compared with the less aggressive androgen-dependent LNCaP cells. Overexpression of wild-type PKD3 in LNCaP cells blocked phorbol 12-myristate 13-acetate (PMA)-induced apoptosis in association with inhibition of PMA-induced down-regulation of Akt activity, and prolonged extracellular signal-regulated kinase (ERK)1/2 activation. Overexpression of wild-type PKD3 also promoted S phase entry, whereas depletion of endogenous PKD3 resulted in G0-G1 phase cell cycle arrest and inhibition of PC3 cell proliferation. In PC3 and DU145 cells, PKCε regulated PKD3 kinase activity and nuclear localization. Moreover, ectopical expression of PKD3 increased, whereas depletion of endogenous PKD3 reduced basal Akt and ERK1/2 activities. Further analysis showed that up-regulation of Akt activity induced by PKD3 required phosphatidylinositol-3-OH kinase and p38. In summary, our data indicate that PKD3 contributes to growth and survival of prostate cancer cells and may represent a novel therapeutic target for prostate cancer. [Cancer Res 2008;68(10):3844–53]
Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment
Authors: Augustine Christina K. , Yoshimoto Yasunori , Gupta Mukur , Zipfel Patricia A. , Selim M. Angelica , Febbo Phillip , Pendergast Ann Marie , Peters William P. , Tyler Douglas S. 
Published: May 2008

Abstract
Malignant transformation in melanoma is characterized by a phenotype “switch” from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin–expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma. [Cancer Res 2008;68(10):3777–84]
Inhibition of Photocarcinogenesis by Platelet-Activating Factor or Serotonin Receptor Antagonists
Authors: Sreevidya Coimbatore S. , Khaskhely Noor M. , Fukunaga Atsushi , Khaskina Polina , Ullrich Stephen E. 
Published: May 2008

AbstractThe UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT2A) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT2A to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT2A receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT2A receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT2A receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT2A receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression. [Cancer Res 2008;68(10):3978–84]
UVA-Induced Cell Cycle Progression Is Mediated by a Disintegrin and Metalloprotease/Epidermal Growth Factor Receptor/AKT/Cyclin D1 Pathways in Keratinocytes
Authors: He Yu-Ying , Council Sarah E. , Feng Li , Chignell Colin F. 
Published: May 2008

Abstract
UVA (315–400 nm), which constitutes ∼95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer. [Cancer Res 2008;68(10):3752–8]
Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors
Authors: Nagano Satoshi , Perentes Jean Yannis , Jain Rakesh K. , Boucher Yves 
Published: May 2008

Abstract
The success of tumor oncolytic virotherapy is limited by the poor penetration of virus in tumors. Interstitial collagen fibers and the narrow spacing between cancer cells are major barriers hindering the movement of large viral particles. To bypass the cellular barrier, we tested the hypothesis that the void space produced by cancer cell apoptosis enhances the initial spread and efficacy of oncolytic herpes simplex virus (HSV). In mice with mammary tumors, apoptosis was induced by doxycycline-regulated expression/activation of CD8/caspase-8, paclitaxel, or paclitaxel plus tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). In both collagen-poor and collagen-rich tumors, apoptosis or necrosis increased the initial intratumoral spread of HSV. Compared with the isolated pattern of HSV infection generally located in the center of control tumors, apoptosis induction and a single i.t. injection of virus produced an interconnected and diffuse pattern of infection, which extended from the tumor center to the periphery. This interconnected pattern of viral infection correlated with the formation of void spaces and channel-like structures in apoptosis-rich tumor areas. We also show that the i.t. injection of HSV after caspase-8 activation or paclitaxel-TRAIL pretreatment retards tumor growth, whereas HSV administration before tumor cell death induction did not improve therapeutic efficacy. Hence, our findings show that the induction of cancer cell death before the injection of oncolytic HSV enhances intratumoral virus delivery/penetration and antitumor efficacy. [Cancer Res 2008;68(10):3795–802]
Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities
Authors: Natsume Akito , In Mika , Takamura Hiroyuki , Nakagawa Tomoaki , Shimizu Yukiko , Kitajima Kazuko , Wakitani Masako , Ohta So , Satoh Mitsuo , Shitara Kenya , Niwa Rinpei 
Published: May 2008

AbstractEnhancement of multiple effector functions of an antibody may be a promising approach for antibody therapy. We have previously reported that fucose removal from Fc-linked oligosaccharides greatly enhances antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies. Here, we report a unique approach to enhance complement-dependent cytotoxicity (CDC), another important effector function of antitumor antibodies, by using engineered constant region of human IgG1/IgG3 chimeric isotypes. We systematically shuffled constant domains of IgG1 and IgG3 to generate a comprehensive set of mixed chimeric isotypes of anti-CD20 antibodies. Among these, the variant 1133, consisting of the CH1 and the hinge each from IgG1 and the Fc from IgG3, was unexpectedly found to exhibit markedly enhanced CDC that exceeded wild-type levels. However, it lacked protein A–binding capacity, an important feature for the industrial production. To eliminate this deficiency, a portion in COOH-terminal CH3 domain of 1133 was substituted with IgG1, resulting in full recovery of protein A binding without compromising the enhanced CDC and ADCC activities. The CDC-enhancing effect using a chimeric isotype was also shown in CD52 antigen/antibody system. The ADCC activity of the variants was also maximized by the absence of fucose from its carbohydrate structure, a phenomenon that has previously been observed for wild-type antibodies. Enhanced cytotoxicity of a variant was confirmed in a cynomolgus monkey model. These findings suggest that the variant antibodies with IgG1/IgG3 chimeric constant regions and nonfucosylated oligosaccharides that possess dual-enhanced cytotoxic functions may be an improvement for the next generation of therapeutic antitumor antibodies. [Cancer Res 2008;68(10):3863–72]
Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells
Authors: Contessa Joseph N. , Bhojani Mahaveer S. , Freeze Hudson H. , Rehemtulla Alnawaz , Lawrence Theodore S. 
Published: May 2008

Abstract
Receptor tyrosine kinases (RTK) are therapeutic targets for the treatment of malignancy. However, tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades. Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell. We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling. Using the N-linked glycosylation inhibitor, tunicamycin, we show that expression levels of several RTKS (EGFR, ErbB2, ErbB3, and IGF-IR) are exquisitely sensitive to inhibition of N-linked glycosylation. Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments. Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines, two cell lines resistant to epidermal growth factor receptor–targeted therapies, we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells. In comparison, experiments in nontransformed cells showed neither a reduction in RTK-dependent signaling nor an enhancement in radiosensitivity, suggesting the potential for a therapeutic ratio between tumors and normal tissues. This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies. [Cancer Res 2008;68(10):3803–9]