bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Weekly Docetaxel and Bevacizumab in Mesenchymal Chondrosarcoma: A New Theranostic Method Combining Xenografted Biopsies with a Mathematical Model
Authors: Gorelik Boris , Ziv Irit , Shohat Revital , Wick Michael , Hankins W. David , Sidransky David , Agur Zvia 
Published: October 2008

AbstractThe paucity of clinical treatment data on rare tumors, such as mesenchymal chondrosarcoma (MCS), emphasizes the need in theranostic tools for these diseases. We put forward and validated a new theranostic method, combining tumor xenografts and mathematical models, and used it to suggest an improved treatment schedule for a particular MCS patient. Growth curves and gene expression analysis of xenografts, derived from a patient's lung metastasis, served for creating a mathematical model of MCS progression and adapting it to the xenograft setting. The pharmacokinetics and pharmacodynamics of six drugs were modeled, with model variables being adjusted by patient-specific chemosensitivity tests. The xenografted animals were treated by various monotherapy and combination schedules, and the MCS xenograft model was computer simulated under the same treatment scenario. The mathematical model for xenograft growth was then up-scaled to retrieve the MCS patient's tumor progression under different treatment schedules. An average accuracy of 87.1% was obtained when comparing model predictions with the observed tumor growth inhibition in the xenografted animals. Simulation results suggested that a regimen containing bevacizumab applied i.v. in combination with once-weekly docetaxel would be more efficacious in the MCS patient than all other simulated schedules. Weekly docetaxel in the patient resulted in stable metastatic disease and relief of pancytopenia due to tumor infiltration. We suggest that the advantage of weekly docetaxel on the triweekly regimen is directly related to the angiogenesis rate of the tumor. Further validation of this conclusion, and the theranostic method we provide, may facilitate personalization of solid cancer pharmacotherapy. [Cancer Res 2008;68(21):9033–40]
Just Say No to ATOH: How HIC1 Methylation Might Predispose Medulloblastoma to Lineage Addiction
Authors: Briggs Kimberly J. , Eberhart Charles G. , Watkins D. Neil 
Published: October 2008

Abstract
Hypermethylated in cancer-1 (HIC1) is a tumor suppressor frequently targeted for promoter hypermethylation in medulloblastoma, an embryonal tumor of the cerebellum. Recently, we showed that HIC1 is a direct transcriptional repressor of ATOH1, a proneural transcription factor required for normal cerebellar development, as well as for medulloblastoma cell viability. Because demethylating agents can induce reexpression of silenced tumor suppressors, restoring HIC1 function may present an attractive therapeutic avenue in medulloblastoma by exploiting an apparent addiction to ATOH1. [Cancer Res 2008;68(21):8654–6]
Modulation of Orphan Nuclear Receptor Nur77-Mediated Apoptotic Pathway by Acetylshikonin and Analogues
Authors: Liu Jie , Zhou Wen , Li Shao-Shun , Sun Zhe , Lin Bingzhen , Lang Yuan-Yuan , He Jia-You , Cao Xihua , Yan Tingdong , Wang Li , Lu Jiongming , Han Young-Hoon , Cao Yu , Zhang Xiao-kun , Zeng Jin-Zhang 
Published: October 2008

Abstract
Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that orphan nuclear receptor Nur77 migrates from the nucleus to the mitochondria, where it binds to Bcl-2 to induce apoptosis. Here, we report that certain shikonin derivatives could modulate the Nur77/Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of acetylshikonin resulted in the identification of a derivative 5,8-diacetoxyl-6-(1′-acetoxyl-4′-methyl-3′-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH2-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction. [Cancer Res 2008;68(21):8871–80]
Conspirators in a Capital Crime: Co-deletion of p18INK4c and p16INK4a/p14ARF/p15INK4b in Glioblastoma Multiforme
Authors: Solomon David A. , Kim Jung-Sik , Jean Walter , Waldman Todd 
Published: October 2008

Abstract
Glioblastoma multiforme (GBM) is one of the most dreaded cancer diagnoses due to its poor prognosis and the limited treatment options. Homozygous deletion of the p16INK4a/p14ARF/p15INK4b locus is among the most common genetic alterations in GBM. Two recent studies have shown that deletion and mutation of another INK4 family member, p18INK4c, also drives the pathogenesis of GBM. This minireview will discuss the known roles for p18INK4c in the initiation and progression of cancer and suggest opportunities for future studies. [Cancer Res 2008;68(21):8657–60]
Milk Fat Globule EGF-8 Promotes Melanoma Progression through Coordinated Akt and Twist Signaling in the Tumor Microenvironment
Authors: Jinushi Masahisa , Nakazaki Yukoh , Carrasco Daniel R. , Draganov Dobrin , Souders Nicholas , Johnson Matthew , Mihm Martin C. , Dranoff Glenn 
Published: October 2008

AbstractThe pathogenesis of malignant melanoma involves the interplay of tumor cells with normal host elements, but the underlying mechanisms are incompletely understood. Here, we show that milk fat globule EGF-8 (MFG-E8), a secreted protein expressed at high levels in the vertical growth phase of melanoma, promotes disease progression through coordinated αvβ3 integrin signaling in the tumor microenvironment. In a murine model of melanoma, MFG-E8 enhanced tumorigenicity and metastatic capacity through Akt-dependent and Twist-dependent pathways. MFG-E8 augmented melanoma cell resistance to apoptosis, triggered an epithelial-to-mesenchymal transition (EMT), and stimulated invasion and immune suppression. In human melanoma cells, MFG-E8 knockdown attenuated Akt and Twist signaling and thereby compromised tumor cell survival, EMT, and invasive ability. MFG-E8–deficient human melanoma cells also showed increased sensitivity to small molecule inhibitors of insulin-like growth factor I receptor and c-Met. Together, these findings delineate pleiotropic roles for MFG-E8 in the tumor microenvironment and raise the possibility that systemic MFG-E8 blockade might prove therapeutic for melanoma patients. [Cancer Res 2008;68(21):8889–98]
Zerumbone Down-regulates Chemokine Receptor CXCR4 Expression Leading to Inhibition of CXCL12-Induced Invasion of Breast and Pancreatic Tumor Cells
Authors: Sung Bokyung , Jhurani Sonia , Ahn Kwang Seok , Mastuo Yoichi , Yi Tingfang , Guha Sushovan , Liu Mingyao , Aggarwal Bharat B. 
Published: October 2008

Abstract
CXC chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is now known to be expressed in various tumors including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and melanoma. This receptor mediates homing of tumor cells to specific organs that express the ligand CXCL12 for this receptor. Thus, agents that can down-regulate CXCR4 expression have potential against cancer metastasis. In this study, we report the identification of zerumbone, a component of subtropical ginger (Zingiber zerumbet), as a regulator of CXCR4 expression. This sesquiterpene down-regulated the expression of CXCR4 on HER2-overexpressing breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 by zerumbone was found to be not cell type specific as its expression was abrogated in leukemic, skin, kidney, lung, and pancreatic cancer cell lines. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of mRNA expression, inhibition of nuclear factor-κB activity, and suppression of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by zerumbone correlated with the inhibition of CXCL12-induced invasion of both breast and pancreatic cancer cells. An analogue of zerumbone, α-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 down-regulation. Overall, our results show that zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of cancer metastasis. [Cancer Res 2008;68(21):8938–44]
Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth InhibitionIn vivo
Authors: Fournier Pierrick G.J. , Daubiné Florence , Lundy Mark W. , Rogers Michael J. , Ebetino Frank H. , Clézardin Philippe 
Published: October 2008

AbstractBisphosphonates bind avidly to bone mineral and are potent inhibitors of osteoclast-mediated bone destruction. They also exhibit antitumor activity in vitro. Here, we used a mouse model of human breast cancer bone metastasis to examine the effects of risedronate and NE-10790, a phosphonocarboxylate analogue of the bisphosphonate risedronate, on osteolysis and tumor growth. Osteolysis was measured by radiography and histomorphometry. Tumor burden was measured by fluorescence imaging and histomorphometry. NE-10790 had a 70-fold lower bone mineral affinity compared with risedronate. It was 7-fold and 8,800-fold less potent than risedronate at reducing, respectively, breast cancer cell viability in vitro and bone loss in ovariectomized animals. We next showed that risedronate given at a low dosage in animals bearing human B02-GFP breast tumors reduced osteolysis by inhibiting bone resorption, whereas therapy with higher doses also inhibited skeletal tumor burden. Conversely, therapy with NE-10790 substantially reduced skeletal tumor growth at a dosage that did not inhibit osteolysis, a higher dosage being able to also reduce bone destruction. The in vivo antitumor activity of NE-10790 was restricted to bone because it did not inhibit the growth of subcutaneous B02-GFP tumor xenografts nor the formation of B16-F10 melanoma lung metastases. Moreover, NE-10790, in combination with risedronate, reduced both osteolysis and skeletal tumor burden, whereas NE-10790 or risedronate alone only decreased either tumor burden or osteolysis, respectively. In conclusion, our study shows that decreasing the bone mineral affinity of bisphosphonates is an effective therapeutic strategy to inhibit skeletal tumor growth in vivo. [Cancer Res 2008;68(21):8945–53]
Moderate Expression of Prostate-Specific Membrane Antigen, a Tissue Differentiation Antigen and Folate Hydrolase, Facilitates Prostate Carcinogenesis
Authors: Yao Veronica , Parwani Anil , Maier Christoph , Heston Warren DeWayne , Bacich Dean John 
Published: October 2008

Abstract
Increased expression of PSMA, a differentiation antigen with folate hydrolase activity, is an independent marker of prostate cancer progression. Mice expressing moderate levels of human PSMA in their prostate develop PIN-like lesions by 9 months. The aim of this study was to determine whether PSMA is involved in prostate carcinogenesis and progression and, if so, the possible mechanism by which PSMA may exert its effects. Using prostates from PSMA-transgenic mice, we developed a tissue recombinant model that exhibits small atypical glands with features of adenocarcinoma. This was not observed in tissue recombinants that were composed of prostate tissues from the wild-type siblings. Cells from PSMA-transgenic tissue recombinants have the ability to form colonies in semisolid agar. PSMA may facilitate this phenotype by increasing the invasive ability of cells. Ectopic PSMA expression on PC-3 cells increased the invasive capacity of cells in in vitro invasion assays, which could be competed out by folic acid. These results suggest PSMA facilitates the development of prostate cancer, and the invasive ability of these cells may be modulated by folate levels. These findings show a novel mechanism that may contribute to the known role of folate in cancer prevention, and may lead to the use of PSMA inhibitors as novel chemopreventive agents for prostate cancer. Moreover, our model should prove useful for further dissecting pathways involved in prostate carcinogenesis and progression. [Cancer Res 2008;68(21):9070–7]
A Novel Association between p130Cas and Resistance to the Chemotherapeutic Drug Adriamycin in Human Breast Cancer Cells
Authors: Ta Huy Q. , Thomas Keena S. , Schrecengost Randy S. , Bouton Amy H. 
Published: October 2008

Abstract
Resistance to chemotherapy remains a major obstacle for the treatment of breast cancer. Understanding the molecular mechanism(s) of resistance is crucial for the development of new effective therapies to treat this disease. This study examines the putative role of p130Cas (Cas) in resistance to the cytotoxic agent Adriamycin. High expression of Cas in primary breast tumors is associated with the failure to respond to the antiestrogen tamoxifen and poor prognosis, highlighting the potential clinical importance of this molecule. Here, we show a novel association between Cas and resistance to Adriamycin. We show that Cas overexpression renders MCF-7 breast cancer cells less sensitive to the growth inhibitory and proapoptotic effects of Adriamycin. The catalytic activity of the nonreceptor tyrosine kinase c-Src, but not the epidermal growth factor receptor, is critical for Cas-mediated protection from Adriamycin-induced death. The phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) is elevated in Cas-overexpressing cells treated with Adriamycin, whereas expression of the proapoptotic protein Bak is decreased. Conversely, Cas depletion in the more resistant T47D and MDA-MB-231 cell lines increases sensitivity to Adriamycin. Based on these data, we propose that Cas activates growth and survival pathways regulated by c-Src, Akt, and ERK1/2 that lead to the inhibition of mitochondrial-mediated apoptosis in the presence of Adriamycin. Because Cas is frequently expressed at high levels in breast cancers, these findings raise the possibility of resensitizing Cas-overexpressing tumors to chemotherapy through perturbation of Cas signaling pathways. [Cancer Res 2008;68(21):8796–804]
The Anaplastic Lymphoma Kinase Controls Cell Shape and Growth of Anaplastic Large Cell Lymphoma through Cdc42 Activation
Authors: Ambrogio Chiara , Voena Claudia , Manazza Andrea D. , Martinengo Cinzia , Costa Carlotta , Kirchhausen Tomas , Hirsch Emilio , Inghirami Giorgio , Chiarle Roberto 
Published: October 2008

Abstract
Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin's lymphoma that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. The proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filament assembly in a pattern similar to T-cell receptor–stimulated cells. NPM-ALK formed a complex with the guanine exchange factor VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity, and in turn, Cdc42 regulated the shape and migration of ALCL cells. In vitro knockdown of VAV1 or Cdc42 by short hairpin RNA, as well as pharmacologic inhibition of Cdc42 activity by secramine, resulted in a cell cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cell growth through Cdc42. [Cancer Res 2008;68(21):8899–907]
ERRγ Mediates Tamoxifen Resistance in Novel Models of Invasive Lobular Breast Cancer
Authors: Riggins Rebecca B. , Lan Jennifer P-J. , Klimach Uwe , Zwart Alan , Cavalli Luciane R. , Haddad Bassem R. , Chen Li , Gong Ting , Xuan Jianhua , Ethier Stephen P. , Clarke Robert 
Published: October 2008

Abstract
One-third of all estrogen receptor (ER)–positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ERα and increased expression of the estrogen-related receptor γ (ERRγ). Knockdown of ERRγ in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRγ blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRγ-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRγ/AP1 signaling in the development of TAM resistance and suggest that expression of ERRγ may be a marker of poor TAM response. [Cancer Res 2008;68(21):8908–17]
Eastern Mediterranean chameleons (Chamaeleo chamaeleon, Ch. africanus) are distinct
Authors: Dimaki Maria , Hundsdörfer Anna , Fritz Uwe 
Published: October 2008

AbstractBased on mitochondrial 16S rRNA sequences, we suggest that the founder individuals of the introduced Greek population of Chamaeleo africanus originated in the Nile Delta region of Egypt. In Ch. chamaeleon, we discovered in the eastern Mediterranean new 16S rRNA haplotypes, being highly distinct from previously published western Mediterranean haplotypes. Eastern Mediterranean haplotypes were found in samples from northern Syria, Cyprus, Crete, Samos, Malta and Tunisia. The occurrence of an eastern Mediterranean haplotype in Tunisia and of distinct haplotypes in Morocco could argue for a phylogeographic break in northwestern Africa.
Seed dispersal, habitat selection and movement patterns in the Amazonian tortoise, Geochelone denticulata
Authors: Stevenson Pablo , Guzmán Adriana 
Published: October 2008

AbstractThe Amazonian tortoise Geochelone denticulata may play an important role in forest dynamics due to its highly frugivorous diet, ability to disperse viable seeds, and predilection for resting in forest gaps for thermoregulation. The purpose of our study was to evaluate the species' effectiveness as a seed disperser. We measured dispersal quantity (abundance of seeds in feces, frequency of droppings, and population density of the disperser) and dispersal quality (movement patterns, habitat use, germination rates of dispersed seeds, and recruitment probabilities of seedlings) in a SW Amazonian forest, in Peru. Population density was calculated by mark-recapture and line-transect methods. Eight individuals were radio-tracked to monitor habitat use. Diet was described from fecal samples, which were washed to count seeds and for germination experiments. Seedling survival in different environmental conditions was monitored for three plant species. Population densities with mark-recapture estimates (0.15-0.31 individuals/ha) were much higher than with line transects estimates (0.0025 individuals/ha). Diet included fruit of 55 different plant species. Dispersed seeds had high germination rates (average 76%). In spite of their low activity, we documented long seed dispersal distances (average 89.6 m). Tortoises showed a marked preference for the open-canopy swampy forest, where long term recruitment was not favorable for seedlings of the species examined. However, the high solar radiation in this forest type promoted survival of pioneer seedlings in the short term. In conclusion, while G. denticulata did not perform a very efficient role in terms of the quantity of seed dispersal, the species can be considered efficient in many aspects of dispersal quality.
Thermal preference of the yellow-margined box turtle (Cuora flavomarginata) (Testudines: Geoemydidae) inhabiting a mesic lowland forest, northern Taiwan
Authors: Chen Tien-Hsi , Lue Kuang-Yang 
Published: October 2008

AbstractThermal preference of free-living yellow-margined box turtle, Cuora flavomarginata, was studied in a mesic forested habitat using a combination of radiotransmitters and temperature dataloggers attached to individual turtles. Patterns of mean weekly shell surface temperature variation of selected individuals were highly related to seasonal change of environmental temperature, with a peak temperature of 24.5-25.1°C in males and 26.0-27.0°C in females during June and July. Minimum shell surface temperature occurred in late January (4.5-7.6°C). Despite a small sample size, there were significantly intersexual differences in mean weekly shell surface temperature during nesting season. Individual females of C. flavomarginata tended to maintain higher shell surface temperature during nesting season (May-July). This difference was mostly pronounced during the day. There were no obviously intersexual differences prior to and after nesting season. Our results do not support the previous predictions that gravid C. flavomarginata may select higher environmental temperatures prior to nesting season.