bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of gefitinib in tamoxifen‐resistant and hormone‐insensitive breast cancer: A phase II study
Authors: Gutteridge Eleanor , Agrawal Amit , Nicholson Robert , Cheung Kwok Leung , Robertson John , Gee Julia 
Published: September 2009

AbstractEstrogen receptor (ER)‐positive acquired tamoxifen‐resistant (TAM‐R) MCF‐7 breast cancer cell lines exhibit epidermal growth factor receptor (EGFR) expression/signaling and are growth‐inhibited by gefitinib (IRESSA). We examined the effect of gefitinib on ER‐positive TAM‐R and ER‐negative hormone‐insensitive breast cancer in a Phase II study. Fifty‐four patients with breast cancer [ER‐positive/acquired TAM‐R (n = 28); ER‐negative (n = 26)] received oral gefitinib 500 mg/day. Tumor biopsies were taken pre‐ (n = 28) and 8 weeks post‐treatment (n = 14 matched samples). Gefitinib was well tolerated and the clinical benefit rate (objective response or stable disease >24 weeks) was 33.3% overall (n = 18/54), and 53.6 and 11.5% in ER‐positive/TAM‐R and ER‐negative patients, respectively. Pretreatment ER and progesterone receptor‐positivity were associated with response (p < 0.001 and 0.016, respectively) and longer progression‐free survival (PFS; p= 0.001 and 0.013, respectively). All patients expressed EGFR, but high pretreatment levels predicted poorer outcome (p = 0.005) and shorter PFS (p = 0.012) with gefitinib. In patients with clinical benefit, reduced Ki67 staining during treatment (p = 0.024) was commonly observed, and those with >10% decline in EGFR phosphorylation demonstrated parallel decreases in ERK1/2 MAPK phosphorylation. Acquired tamoxifen resistance appears in part mediated through EGFR signaling and can be blocked with gefitinib.
Hospicells (ascites‐derived stromal cells) promote tumorigenicity and angiogenesis
Authors: Pasquet Marlene , Golzio Muriel , Mery Eliane , Rafii Arash , Benabbou Nadia , Mirshahi Pezhman , Hennebelle Isabelle , Bourin Philippe , Allal Ben , Teissie Justin , Mirshahi Massoud , Couderc Bettina 
Published: September 2009

AbstractThe microenvironment is known to play a dominant role in cancer progression. Cells closely associated with tumoral cells, named hospicells, have been recently isolated from the ascites of ovarian cancer patients. Whilst these cells present no specific markers from known cell lineages, they do share some homology with bone marrow‐derived or adipose tissue‐derived human mesenchymal stem cells (CD9, CD10, CD29, CD146, CD166, HLA‐1). We studied the role of hospicells in ovarian carcinoma progression. In vitro, these cells had no effect on the growth of human ovarian carcinoma cell lines OVCAR‐3, SKOV‐1 and IGROV‐1. In vivo, their co‐injection with adenocarcinoma cells enhanced tumor growth whatever the tumor model used (subcutaneous and intraperitoneally established xenografts in athymic mice). In addition, their injection increased the development of ascites in tumor‐bearing mice. Fluorescent macroscopy revealed an association between hospicells and ovarian adenocarcinoma cells within the tumor mass. Tumors obtained by coinjection of hospicells and human ovarian adenocarcinoma cells presented an increased microvascularization indicating that the hospicells could promote tumorigenicity of ovarian tumor cells in vivovia their action on angiogenesis. This effect on angiogenesis could be attributed to the increased HIF1α and VEGF expression associated with the presence of the hospicells. Collectively, these data indicate a role for these ascite‐derived stromal cells in promoting tumor growth by increasing angiogenesis.
Therapy for minimal residual tumor disease: β‐Galactosylceramide inhibits the growth of recurrent HPV16‐associated neoplasms after surgery and chemotherapy
Authors: Šímová Jana , Indrová Marie , Bieblová Jana , Mikyšková Romana , Bubeník Jan , Reiniš Milan 
Published: September 2009

AbstractNatural killer T (NKT) cells are potent modulators of antitumor immunity. Their protective effects can be achieved upon their activation by glycolipid ligands presented in the context of the CD1d molecule. These CD1d‐binding glycolipid antigens have been described as potent therapeutic agents against tumors, infections, as well as autoimmune diseases. Immunoregulatory and therapeutic effects of glycolipid ligands depend on their structure and modes of administration. Therefore, more studies are needed for optimization of the particular therapeutic settings. This study was focused on the tumor‐inhibitory effects of 12 carbon acyl chain β‐galactosyl ceramide (C12 β‐D‐Galactosyl Ceramide; β‐GalCer(C12)) on the growth of human papillomavirus type 16 (HPV16)‐associated neoplasms transplanted in syngeneic mice. Treatment of tumor‐bearing mice with β‐GalCer(C12) 3–14 days after tumor cell transplantation significantly inhibited the growth of the major histocompatability complex (MHC) Class I‐positive (TC‐1), as well as MHC Class I‐deficient (TC‐1/A9) HPV16‐asssociated tumors. Moreover, administration of β‐GalCer(C12) after surgical removal of TC‐1 tumors inhibited the growth of tumor recurrences. Similar results were obtained in the treatment of tumors after chemotherapy. β‐GalCer(C12) treatment turned out to be also synergistic with immunotherapy based on administration of IL‐12‐producing cellular vaccines. These results suggest that β‐GalCer(C12), whose antitumor effects have so far not been studied in detail, can be effective for the treatment of minimal residual tumor disease as well as an adjuvant for cancer immunotherapy.
Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy
Authors:   The MARIE‐GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk
Published: September 2009

AbstractMenopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone‐ and xenobiotic‐mediated signal transduction playing a crucial role in regulating gene expression. Therefore, variations within these genes may influence HT‐associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population‐based case‐control studies. Thirty‐three polymorphisms selected on the basis of known or putative functional relevance located inESR1, ESR2, PGR, PXRandARwere genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen–progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log‐additive and codominant modes of inheritance. We observed an increased risk for women carrying shortAR_(CAG) alleles of <22 repeats associated with combined estrogen–progestagen therapy compared with those with long alleles (≥22 repeats) (pinteraction= 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2PXRpolymorphisms with reduction of risk effects in carriers of the minorPXR_rs6785049_G andPXR_rs1054191_A alleles (pinteraction= 0.04 and 0.05, respectively). Variants in bothESR1andESR2modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the majorESR1_rs910416_T allele (pinteraction< 0.01) and in homozygotes for the minorESR2_rs1271572_T, majorESR2_rs4986938_G and minorESR2_rs928554_G alleles (pinteraction= 0.02, 0.05, 0.02, respectively). Risk effect modification byESR1_rs910416 andAR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT‐associated postmenopausal breast cancer risk.
Mismatch repair system decreases cell survival by stabilizing the tetraploid G1 arrest in response to SN‐38
Authors: Bhonde Mandar Ramesh , Hanski Marie‐Luise , Stehr Jenny , Jebautzke Britta , Peiró‐Jordán Roser , Fechner Henry , Yokoyama Kazunari Kazushige , Lin Weei‐Chin , Zeitz Martin , Hanski Christoph 
Published: September 2009

AbstractThe role of the mismatch repair (MMR) system in correcting base–base mismatches is well established; its involvement in the response to DNA double strand breaks, however, is less clear. We investigated the influence of the essential component of MMR, the hMLH1 protein, on the cellular response to DNA‐double strand breaks induced by treatment with SN‐38, the active metabolite of topoisomerase I inhibitor irinotecan, in a strictly isogenic cell system (p53wt, hMLH1+/p53wt, hMLH1−). By using hMLH1 expressing clones or cells transduced with the hMLH1‐expressing adenovirus as well as siRNA technology, we show that in response to SN‐38‐induced DNA damage the MMR proficient (MMR+) cells make: (i) a stronger G2/M arrest, (ii) a subsequent longer tetraploid G1 arrest, (iii) a stronger activation of Chk1 and Chk2 kinases than the MMR deficient (MMR−) counterparts. Both Cdk2 and Cdk4 kinases contribute to the basal tetraploid G1 arrest in MMR+ and MMR− cells. Although the Chk1 kinase is involved in the G2/M arrest, neither Chk1 nor Chk2 are involved in the enhancement of the tetraploid G1 arrest. The long‐lasting tetraploid G1 arrest of MMR+ cells is associated with their lower clonogenic survival after SN‐38 treatment, the abrogation of the tetraploid G1 arrest resulted in their better clonogenic survival. These data show that the stabilization of the tetraploid G1 arrest in response to double strand breaks is a novel function of the MMR system that contributes to the lesser survival of MMR+ cells.
The nuclear architectural protein HMGA1a triggers receptor‐mediated endocytosis
Authors: Wu Wuwei , Wan Wei , Li Alexander D.Q. 
Published: September 2009

AbstractHigh mobility group proteins A (HMGA), nuclear architectural factors, locate in the cell nuclei and mostly execute gene‐regulation function. However, our results reveal that a HMGA member (HMGA1a) has a unique plasma membrane receptor; this receptor specifically binds to HMGA‐decorated species, effectively mediates endocytosis, and internalizes extracellular HMGA‐functionalized cargoes. Indeed, dyes or nanoparticles labeled with HMGA1a protein readily enter Hela cells. Using a stratagem chemical cross‐linker, we covalently bonded the HMGA receptor to the HMGA1a‐GFP fusion protein, thus capturing the plasma membrane receptor. Subsequent Western blots and SDS–PAGE gel revealed that the HMGA receptor is a 26‐kDa protein. Confocal live‐cell microscopic imaging was used to monitor the whole endocytic process, in which the internalized HMGA1a‐decorated species are transported by motor proteins on microtubules and eventually arrive at the late endosomes/lysosomes. Cell viability assays also suggested that extracellular HMGA1a protein directly influences the survival ability of Hela cells in a dose‐dependent manner, implying versatility of HMGA1a protein and its potent role to suppress cancer cell survivability and to regulate growth. J. Cell. Biochem. 108: 791–801, 2009. © 2009 Wiley‐Liss, Inc.
Attenuating Smac mimetic compound 3‐induced NF‐κB activation by luteolin leads to synergistic cytotoxicity in cancer cells
Authors: Bai Lang , Chen Wenjie , Wang Xia , Ju Wei , Xu Shanling , Lin Yong 
Published: September 2009

AbstractSmac mimetics are potential anticancer therapeutics selectively killing cancer cells through autocrine tumor necrosis factor (TNF)‐mediated apoptosis pathway. Our recent study reveal that the Smac mimetic compound 3 (SMC3)‐activated NF‐κB protects cancer cells against apoptosis, thus blunting SMC3's anticancer activity. Based on our previous observations that the nutrient flavonoid luteolin potently blocks TNF‐induced NF‐κB activation in cancer cells, we investigated if the combination of SMC3 and luteolin would achieve a synergistic anticancer activity. The results show that luteolin had no effect on autocrine TNF but it effectively blocked SMC3‐induced nuclear factor kappa B (NF‐κB) activation and expression of anti‐apoptotic NF‐κB targets. When SMC3 and luteolin were combined in treating cancer cells derived from lung and liver tumors, the activation of TNF‐dependent apoptosis was markedly sensitized and a synergistic cytotoxic effect was achieved. In addition, the SMC3 and luteolin co‐treatment had marginal effect on immortalized normal human bronchial epithelial cells. The results suggest that combination of SMC3 and luteolin is an effective approach for improving the anticancer value of SMC3, which has implications in cancer prevention and therapy. J. Cell. Biochem. 108: 1125–1131, 2009. © 2009 Wiley‐Liss, Inc.
Impaired cell cycle regulation of the osteoblast‐related heterodimeric transcription factor Runx2‐Cbfβ in osteosarcoma cells
Authors: San Martin Inga A. , Varela Nelson , Gaete Marcia , Villegas Karina , Osorio Mariana , Tapia Julio C. , Antonelli Marcelo , Mancilla Edna E. , Pereira Barry P. , Nathan Saminathan S. , Lian Jane B. , Stein Janet L. , Stein Gary S. , van Wijnen Andre J. , Galindo Mario 
Published: September 2009

AbstractBone formation and osteoblast differentiation require the functional expression of the Runx2/Cbfβ heterodimeric transcription factor complex. Runx2 is also a suppressor of proliferation in osteoblasts by attenuating cell cycle progression in G1. Runx2 levels are modulated during the cell cycle, which are maximal in G1 and minimal beyond the G1/S phase transition (S, G2, and M phases). It is not known whether Cbfβ gene expression is cell cycle controlled in preosteoblasts nor how Runx2 or Cbfβ are regulated during the cell cycle in bone cancer cells. We investigated Runx2 and Cbfβ gene expression during cell cycle progression in MC3T3‐E1 osteoblasts, as well as ROS17/2.8 and SaOS‐2 osteosarcoma cells. Runx2 protein levels are reduced as expected in MC3T3‐E1 cells arrested in late G1 (by mimosine) or M phase (by nocodazole), but not in cell cycle arrested osteosarcoma cells. Cbfβ protein levels are cell cycle independent in both osteoblasts and osteosarcoma cells. In synchronized MC3T3‐E1 osteoblasts progressing from late G1 or mitosis, Runx2 levels but not Cbfβ levels are cell cycle regulated. However, both factors are constitutively elevated throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 stabilizes Runx2 protein levels in late G1 and S in MC3T3‐E1 cells, but not in ROS17/2.8 and SaOS‐2 osteosarcoma cells. Thus, proteasomal degradation of Runx2 is deregulated in osteosarcoma cells. We propose that cell cycle control of Runx2 gene expression is impaired in osteosarcomas and that this deregulation may contribute to the pathogenesis of osteosarcoma. J. Cell. Physiol. 221: 560–571, 2009. © 2009 Wiley‐Liss, Inc.
p38SJ, a novel DINGG protein protects neuronal cells from alcohol induced injury and death
Authors: Amini Shohreh , Merabova Nana , Khalili Kamel , Darbinian Nune 
Published: September 2009

AbstractEthanol induces neuronal cell injury and death by dysregulating several signaling events that are controlled, in part, by activation of MAPK/ERK1/2 and/or inactivation of its corresponding phosphatase, PP1. Recently, we have purified a novel protein of 38 kDa in size, p38SJ, from a callus culture ofHypericum perforatum, which belongs to an emerging DINGG family of proteins with phosphate binding activity. Here, we show that treatment of neuronal cells with p38SJ protects cells against injury induced by exposure to ethanol. Furthermore, pre‐treatment of neuronal cells with p38SJ diminishes the level of the pro‐apoptotic protein Bax and some events associated with apoptosis such as caspase 3 cleavage. In addition, by inducing stress, alcohol can elevate production of reactive oxygen species (ROS) that leads to a decrease in the activity of superoxide dismutase (SOD). Our results showed that p38SJ restores the activity of SOD in the ethanol treated neuronal cells. These observations provide a novel biological tool for developing new approaches for preventing neuronal cell death induced by ethanol and possibly treatment of neurological disorders associated with alcohol abuse. J. Cell. Physiol. 221: 499–504, 2009. © 2009 Wiley‐Liss, Inc.
LG4–5 domains of laminin‐211 binds α‐Dystroglycan to allow myotube attachment and prevent anoikis
Authors: Munoz Jesus , Zhou Yanwen , Jarrett Harry W. 
Published: September 2009

AbstractPoly(2‐hydroxyethyl methacrylate) (PolyHEMA) prevents cell attachment was used here to study anoikis, the process where cells die when unattached or attached to an inappropriate matrix, in mouse C2C12 myotubes. A method was developed to efficiently embed proteins into PolyHEMA and the effect on cultured myotubes was determined. Myotubes grown on PolyHEMA‐coated plates fail to attach to the surface and remain as rounded, suspended cells, undergo dramatic increases in apoptosis and necrosis, and the number of viable cells decreases. Incorporation of merosin (laminin‐211) or the short laminin globular (LG4–5) modules of the laminin‐α2 chain C‐terminus (called 2E3) that binds α‐dystroglycan diminishes both apoptosis and necrosis and increases viability while bovine serum albumin had a much lesser effect, showing the specificity of this effect for these matrix proteins. One sarcolemma receptor for laminin‐binding is α‐dystroglycan. An antibody which binds α‐dystroglycan but which does not block laminin‐binding (VIA4) had little effect on apoptosis or viability on merosin or 2E3 embedded plates while another antibody (IIH6) which specifically blocks binding dramatically decreased viability and increased apoptosis. When merosin or 2E3 are added to culture media rather than embedded on plates these can also increase viability and decrease apoptosis even though the cells remain in suspension, though the effect is not as great as found for the embedded proteins where the cells attach. Thus, we conclude that the binding of a small LG4–5 modules of laminin‐211 to α‐dystroglycan is important in preventing anoikis and that attachment plus binding is necessary for maximal cell survival. J. Cell. Physiol. 222:111–119, 2010. © 2009 Wiley‐Liss, Inc.
Thyroid follicular neoplasms: Can sonography distinguish between adenomas and carcinomas?
Authors: Seo Hyung Suk , Lee Dong Hoon , Park Sung Hye , Min Hye Sook , Na Dong Gyu 
Published: September 2009

AbstractPurposeThe purpose of this study was to determine whether sonography (US) can usefully differentiate thyroid follicular adenoma (FA) and follicular carcinoma (FC).MethodsThis retrospective study included 60 pathologically proven FAs and 66 FCs in 123 consecutive patients (17 males and 106 females) with a mean age of 47 ± 13 years, (17–73 years) who underwent thyroid surgery. We analyzed US features of each nodule, including maximum diameter, echogenicity, composition, presence of calcification, margins, and presence of halo. The frequencies of each US feature were compared by using the χ2 test or Fisher's exact test between FAs and FCs. The relative risk of malignancy was evaluated by logistic regression analysis.ResultsIsohypoechoic echogenicity, predominantly solid or mixed echotexture, and presence of microcalcifications or rim calcifications were associated with FC (p < 0.05). Logistic regression analysis demonstrated that predominantly solid or mixed echotexture and microcalcifications or rim calcifications were associated with significant increases in relative risk for FC (odds ratio 8.1 and odds ratio 13.5, respectively, p < 0.01).ConclusionsThe US features of isohypoechoic echogenicity, predominantly solid or mixed echotexture, and microcalcifications or rim calcifications are more common in FC than in FA. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2009
Computational approaches to identifying and characterizing protein binding sites for ligand design
Authors: Henrich Stefan , Salo‐Ahen Outi M. H. , Huang Bingding , Rippmann Friedrich F. , Cruciani Gabriele , Wade Rebecca C. 
Published: September 2009

AbstractGiven the three‐dimensional structure of a protein, how can one find the sites where other molecules might bind to it? Do these sites have the properties necessary for high affinity binding? Is this protein a suitable target for drug design? Here, we discuss recent developments in computational methods to address these and related questions. Geometric methods to identify pockets on protein surfaces have been developed over many years but, with new algorithms, their performance is still improving. Simulation methods show promise in accounting for protein conformational variability to identify transient pockets but lack the ease of use of many of the (rigid) shape‐based tools. Sequence and structure comparison approaches are benefiting from the constantly increasing size of sequence and structure databases. Energetic methods can aid identification and characterization of binding pockets, and have undergone recent improvements in the treatment of solvation and hydrophobicity. The “druggability” of a binding site is still difficult to predict with an automated procedure. The methodologies available for this purpose range from simple shape and hydrophobicity scores to computationally demanding free energy simulations. Copyright © 2009 John Wiley & Sons, Ltd.
Cuprizone induces similar demyelination in male and female C57BL/6 mice and results in disruption of the estrous cycle
Authors: Taylor Lorelei C. , Gilmore Wendy , Ting Jenny P.‐Y. , Matsushima Glenn K. 
Published: September 2009

AbstractMultiple sclerosis is a demyelinating neurological disease that is influenced by gender, primarily reflected in greater susceptibility to disease development in women than in men. Cuprizone intoxication, an animal model that is used to study demyelination and remyelination, has been extensively characterized in male C57BL/6 mice. Here, we have undertaken a comprehensive characterization of the morphological and cellular processes that occur in female C57BL/6J mice during cuprizone‐induced demyelination and subsequent remyelination and compared them with age‐matched male mice. We find that the pattern of demyelination and remyelination is similar between genders and that there is little or no difference in the loss or repopulation of mature oligodendrocytes or accumulation of reactive glia. Furthermore, examination of αERKO and βERKO mice suggests that estrogen receptors do not affect the outcome for demyelination or remyelination. Interestingly, we found that cuprizone treatment disrupts estrous cyclicity in female mice, possibly interfering with potential hormone influences on demyelination and remyelination. Therefore, cuprizone‐induced demyelination in C57BL/6J mice may have limitations as a model for the study of sex differences. © 2009 Wiley‐Liss, Inc.