bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatocyte Growth Factor Activator Inhibitor Type 1 Regulates Epithelial to Mesenchymal Transition through Membrane-Bound Serine Proteinases
Authors: Cheng Haixia , Fukushima Tsuyoshi , Takahashi Nobuyasu , Tanaka Hiroyuki , Kataoka Hiroaki 
Published: February 2009

Abstract
Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-associated proteinase inhibitor that potently inhibits a variety of serine proteinases, including those that are membrane bound. Although HAI-1/SPINT1 is widely expressed by epithelial cells and cancer cells, its functional role is still unclear, particularly in cancer. Here, we show that stable knockdown of HAI-1/SPINT1 in the human pancreatic cancer cell line SUIT-2 induces an elongated spindle-like morphology associated with accelerated invasion, thereby mimicking an epithelial to mesenchymal transition (EMT). We found that HAI-1/SPINT1 knockdown significantly reduced the expression of E-cadherin and was accompanied by up-regulation of Smad-interacting protein 1 (SIP1), an E-cadherin transcriptional repressor. In addition, matrix metalloproteinase-9 (MMP-9) was up-regulated. Similar results were obtained in the HLC-1 lung carcinoma cell line. Moreover, a metastatic variant of SUIT-2 (S2-CP8) that showed loss of E-cadherin expression also showed a significantly reduced level of HAI-1/SPINT1. Engineered overexpression of HAI-1/SPINT1 in S2-CP8 resulted in reversion of E-cadherin expression and SIP1 down-regulation, which accompanied reestablishment of epithelial morphology in culture. The EMT caused by HAI-1/SPINT1 knockdown seemed to be mediated, at least partly, by membrane-bound serine proteinases, matriptase/ST14 and TMPRSS4, as knockdown of matriptase/ST14 or TMPRSS4 in HAI-1/SPINT1 knockdown SUIT-2 cells and HLC-1 cells resulted in reversion of SIP1 and/or MMP-9 expression levels. We suggest that interactions between HAI-1/SPINT1 and membrane-bound serine proteinases contribute to transcriptional and functional changes involved in EMT in certain carcinoma cells. [Cancer Res 2009;69(5):1828–35]
Dysfunctional Microvasculature as a Consequence of Shb Gene Inactivation Causes Impaired Tumor Growth
Authors: Funa Nina S. , Kriz Vitezslav , Zang Guangxiang , Calounova Gabriela , Åkerblom Björn , Mares Jaroslav , Larsson Erik , Sun Ying , Betsholtz Christer , Welsh Michael 
Published: February 2009

Abstract
Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis. [Cancer Res 2009;69(5):2141–8]
Oral Cancer Diagnosis by Mechanical Phenotyping
Authors: Remmerbach Torsten W. , Wottawah Falk , Dietrich Julia , Lincoln Bryan , Wittekind Christian , Guck Jochen 
Published: February 2009

Abstract
Oral squamous cell carcinomas are among the 10 most common cancers and have a 50% lethality rate after 5 years. Despite easy access to the oral cavity for cancer screening, the main limitations to successful treatment are uncertain prognostic criteria for (pre-)malignant lesions. Identifying a functional cellular marker may represent a significant improvement for diagnosis and treatment. Toward this goal, mechanical phenotyping of individual cells is a novel approach to detect cytoskeletal changes, which are diagnostic for malignant change. The compliance of cells from cell lines and primary samples of healthy donors and cancer patients was measured using a microfluidic optical stretcher. Cancer cells showed significantly different mechanical behavior, with a higher mean deformability and increased variance. Cancer cells (n ≈ 30 cells measured from each patient) were on average 3.5 times more compliant than those of healthy donors [Dnormal = (4.43 ± 0.68) 10−3 Pa−1; Dcancer = (15.8 ± 1.5) 10−3 Pa−1; P &lt; 0.01]. The diagnosis results of the patient samples were confirmed by standard histopathology. The generality of these findings was supported by measurements of two normal and four cancer oral epithelial cell lines. Our results indicate that mechanical phenotyping is a sensible, label-free approach for classifying cancer cells to enable broad screening of suspicious lesions in the oral cavity. It could in principle be applied to any cancer to aid conventional diagnostic procedures. [Cancer Res 2009;69(5):1728–32]
CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma
Authors: Tanemura Atsushi , Terando Alicia M. , Sim Myung-Shin , van Hoesel Anneke Q. , de Maat Michiel F.G. , Morton Donald L. , Hoon Dave S.B. 
Published: February 2009

Abstract
Purpose: The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.
Experimental Design: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARβ2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n = 122) was assessed.
Results: Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma.
Conclusions: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.
Phospho-p70S6K/p85S6K and cdc2/cdk1 Are Novel Targets for Diffuse Large B-Cell Lymphoma Combination Therapy
Authors: Zhao Merry Y. , Auerbach Aaron , D'Costa Anisha M. , Rapoport Aaron P. , Burger Angelika M. , Sausville Edward A. , Stass Sanford A. , Jiang Feng , Sands Amy M. , Aguilera Nadine , Zhao X. Frank 
Published: February 2009

Abstract
Purpose: This study aimed to identify and evaluate molecular targets for the development of a novel combination chemotherapy to treat refractory and recurrent diffuse large B-cell lymphoma (DLBCL).
Experimental Design: Lymphoma samples from 38 cases of primary and recurrent DLBCL were analyzed using real-time quantitative PCR of the RPS6KB1 and CDC2 genes, and immunohistochemistry for their gene products p70S6K/p85S6K and cdc2/cdk1. The Farage, Karpas422, Pfeiffer, and Toledo DLBCL cell lines were subsequently treated with rapamycin and UCN-01 alone or in combination. Cell proliferation, apoptosis, and cell cycle progression were analyzed after the drug treatment. In addition, the levels of several key protein kinases involved in the phosphoinositide 3′-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, apoptosis, and cell cycle progression were analyzed in the presence and absence of the drugs.
Results: Amplification of the RPS6KB1 and CDC2 genes was found in both primary and recurrent DLBCL. Moreover, the vast majority of these lymphomas (∼94%) were strongly positive for phospho-p70S6K and cdc2/cdk1 proteins. The combination of rapamycin and UCN-01 synergistically inhibited the DLBCL cell proliferation by inducing G1 arrest as well as apoptosis by suppressing the phosphorylation of p70S6K/p85S6K and CDC2 expression.
Conclusion: RPS6KB1 and CDC2 overexpression is common in DLBCL. Simultaneously targeting the RPS6KB1 and CDC2 products phospho-p70S6K/p85S6K and cdc2/cdk1 is very effective in inhibiting DLBCL proliferation and overcoming drug resistance. This work suggests that multilevel inhibition of the PI3K/Akt/mTOR pathway and double-block of cell cycle progression are effective strategies for DLBCL therapy.
Preclinical Studies of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytosine Arabinoside and Etoposide for Treatment of Acute Leukemias
Authors: Shiozawa Ken , Nakanishi Takeo , Tan Ming , Fang Hong-Bin , Wang Wen-chyi , Edelman Martin J. , Carlton David , Gojo Ivana , Sausville Edward A. , Ross Douglas D. 
Published: February 2009

AbstractPurpose: Vorinostat [suberoylanilide hydroxamic acid (SAHA)] is a potent histone deacetylase inhibitor with promising clinical efficacy as an anticancer agent. In this preclinical study, we evaluated combining cytosine arabinoside [1-β-d-arabinofuranosylcytosine (ara-C)] and/or etoposide with vorinostat for use in the treatment of acute leukemias.Experimental Design: Cell survival was examined in vitro in HL-60 human myeloid leukemia cells and K562 myeloid blast crisis chronic myelogenous leukemia cells, using the 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and/or fluorescein diacetate/propidium iodide assays. Drug interactions were analyzed by the combination index method (CalcuSyn) and by a novel statistical method that we developed (SynStat). Cell cycle phase distribution was measured by flow cytometry.Results: Cytotoxic antagonism resulted when vorinostat was combined concomitantly with ara-C; however, when vorinostat was given first followed by a drug-free interval before ara-C treatment, this sequential combination was mostly synergistic. Etoposide combined with vorinostat was additive to synergistic, and the synergism became more pronounced when etoposide was given after vorinostat. Cell cycle analyses revealed that the sequence-dependent interaction of vorinostat and ara-C or etoposide reflected the arrest of cells in G1 or G2 phase during vorinostat treatment and recovery into S phase after removal of vorinostat.Conclusions: These findings using two independent methods to assess drug combination effects provide a preclinical rationale for phase I trials of the sequential combination of vorinostat followed by ara-C and etoposide in patients with advanced or refractory leukemias. CalcuSyn findings were concordant with those of SynStat, validating the use of the latter in analyzing drug interactions.
Oncolytic Adenoviral Mutants with E1B19K Gene Deletions Enhance Gemcitabine-induced Apoptosis in Pancreatic Carcinoma Cells and Anti-Tumor Efficacy In vivo
Authors: Leitner Stephan , Sweeney Katrina , Öberg Daniel , Davies Derek , Miranda Enrique , Lemoine Nick R. , Halldén Gunnel 
Published: February 2009

Abstract
Purpose: Pancreatic adenocarcinoma is a rapidly progressive malignancy that is highly resistant to current chemotherapeutic modalities and almost uniformly fatal. We show that a novel targeting strategy combining oncolytic adenoviral mutants with the standard cytotoxic treatment, gemcitabine, can markedly improve the anticancer potency.
Experimental Design: Adenoviral mutants with the E1B19K gene deleted with and without E3B gene expression (AdΔE1B19K and dl337 mutants, respectively) were assessed for synergistic interactions in combination with gemcitabine. Cell viability, mechanism of cell death, and antitumor efficacy in vivo were determined in the pancreatic carcinoma cells PT45 and Suit2, normal human bronchial epithelial cells, and in PT45 xenografts.
Results: The ΔE1B19K-deleted mutants synergized with gemcitabine to selectively kill cultured pancreatic cancer cells and xenografts in vivo with no effect in normal cells. The corresponding wild-type virus (Ad5) stimulated drug-induced cell killing to a lesser degree. Gemcitabine blocked replication of all viruses despite the enhanced cell killing activity due to gemcitabine-induced delay in G1/S-cell cycle progression, with repression of cyclin E and cdc25A, which was not abrogated by viral E1A-expression. Synergistic cell death occurred through enhancement of gemcitabine-induced apoptosis in the presence of both AdΔE1B19K and dl337 mutants, shown by increased cell membrane fragmentation, caspase-3 activation, and mitochondrial dysfunction.
Conclusions: Our data suggest that oncolytic mutants lacking the antiapoptotic E1B19K gene can improve efficacy of DNA-damaging drugs such as gemcitabine through convergence on cellular apoptosis pathways. These findings imply that less toxic doses than currently practiced in the clinic could efficiently target pancreatic adenocarcinomas when combined with adenoviral mutants.
mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor
Authors: Lane Heidi A. , Wood Jeanette M. , McSheehy Paul M.J. , Allegrini Peter R. , Boulay Anne , Brueggen Joseph , Littlewood-Evans Amanda , Maira Sauveur-Michel , Martiny-Baron Georg , Schnell Christian R. , Sini Patrizia , O'Reilly Terence 
Published: February 2009

Abstract
Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK).
Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.
Results: RAD001 inhibited proliferation in vitro (IC50 values &lt;1 nmol/L to &gt;1 μmol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values &gt;10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.
Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
Transcription Deregulation at the15q25Locus in Association with Lung Adenocarcinoma Risk
Authors: Falvella Felicia S. , Galvan Antonella , Frullanti Elisa , Spinola Monica , Calabrò Elisa , Carbone Antonino , Incarbone Matteo , Santambrogio Luigi , Pastorino Ugo , Dragani Tommaso A. 
Published: February 2009

AbstractPurpose: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls.Experimental Design: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit α type 4], CHRNB4 (cholinergic receptor nicotinic β 4), CHRNA3 (cholinergic receptor nicotinic α 3), and CHRNA5 (cholinergic receptor nicotinic α 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung.Results: Expression analysis of the six candidate genes mapping in the lung cancer risk–associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n = 467) and healthy controls (n = 739). Analysis of a family-based series of nonsmoker lung cancer cases (n = 80) and healthy sib controls (n = 80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients.Conclusions: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.
Toxic and Chemopreventive Ligands Preferentially Activate Distinct Aryl Hydrocarbon Receptor Pathways: Implications for Cancer Prevention
Authors: Okino Steven T. , Pookot Deepa , Basak Shashwati , Dahiya Rajvir 
Published: February 2009

Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated regulatory protein that controls estrogen action through two distinct pathways. In one pathway, AhR acts as a transcription factor that induces the expression of the CYP1 family of estrogen-metabolizing genes; in the other pathway, AhR initiates the degradation of the estrogen receptor and suppresses estrogen signaling. The AhR ligand 3,3′-diindolylmethane (DIM) is a beneficial dietary constituent that prevents breast tumors in rodents and is associated with decreased breast cancer risk in humans. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic AhR ligand that is implicated in birth defects, infertility, and cancer. We analyzed MCF-7 cells to gain insight into how two AhR ligands can exert such fundamentally different health effects. We find that DIM and TCDD have differing abilities to activate the distinct AhR-controlled pathways. TCDD strongly induces AhR-dependent CYP1 gene expression, whereas DIM is a relatively weak CYP1 inducer. DIM strongly inhibits estrogen receptor-α expression and estrogen signaling, whereas TCDD has a notably weaker effect on these processes. Small interfering RNA knockdown of AhR confirms that the effects of DIM and TCDD are indeed AhR dependent. Our findings reveal that DIM and TCDD each elicit a unique pattern of change in pathways that control estrogen action; such patterns may determine if an AhR ligand has beneficial or adverse health effects.
Xiphinema iranicum n. sp. (Nematoda: Longidoridae) from north-western Iran
Authors: Pedram Majid , Robbins Robert , Ye Weimin , Niknam Gholamreza , Karegar Akbar 
Published: February 2009

AbstractXiphinema iranicum n. sp. is described from soil samples collected about the rhizosphere of Rosa sp. growing in a natural mountainous region close to Maragheh city, north-western Iran. The new species belongs to group 6 of the polytomous key to species identification and is unique by having a medium body length (3.8-4.3 mm), odontostyle length of 141-162 μm, odontophore length of 90-98 μm, mid-body diam. of 69-88 μm, presence of spines in the uterus and a hemispherical to conoid tail with a rounded terminus or minute bulge. It resembles X. ingens, X. aceri, X. aequum, X. smoliki, X. illyricum, X. macedonicum and X. vuittenezi but differs from X. aceri and X. aequum by having different tail shape, longer odontophore, lower ratio a, higher ratio c and lower ratio c′. Compared to X. ingens and X. smoliki, it differs by having lower ratio a, lower ratio b, spines in uterus vs crystalline bodies plus pseudo Z-organ in X. ingens and spines plus pseudo Z-organ in X. smoliki and also by the presence of rare males, and, finally, it can be distinguished from X. vuittenezi by body and odontostyle length, characters of juveniles and molecular differences. The new species has similar polytomous identification codes to X. illyricum and X. macedonicum but can be differentiated from both by longer body, higher ratio c, higher V, longer odontostyle and odontophore and larger body diam. at mid-body and anus level. Ribosomal gene 18S rDNA and ITS1 of X. iranicum n. sp., X. aceri, X. montenegrinum and X. macedonicum, all obtained from north-western Iran in the same survey, were sequenced to investigate the phylogenetic relationships with other sequenced Xiphinema species.
Additional data on Aorolaimus banoae (Rashid, Geraert & Sharma, 1987) from the Brazilian Atlantic forest
Authors: Silva Rosangela , Bessi Rosana , Inomoto Mário , Monteiro Ailton 
Published: February 2009

AbstractA population of the little-known species Aorolaimus banoae was collected in the municipality of Cananéia, São Paulo state, Brazil, in a remnant of the once far more extensive Brazilian Atlantic Forest. As the original description of this species was based on only three females and nine males, additional morphometric and morphological data, including SEM studies, are presented. It is suggested that A. banoae is a member of the original fauna associated with the coastal Atlantic forest.