bluuebunny/crossref_metadata_2025 huggingface dataset:
Mosasaur tooth marks on the ammonite Placenticeras from the Upper Cretaceous of Alberta, Canada
Authors: Hewitt R. A. , Westermann G. E. G.
Published: June 2010

Mosasaur tooth marks were found in the body chamber and phragmocone of the Campanian ammonite Placenticeras meeki Boehm from the Bearpaw Formation of the St. Mary River area near Lethbridge. They imply that the shell wall of the ammonite buckled around point loads and did not break into fragments like the shell of Nautilus. The complex septal sutures provided a strong but marginally flexible support for the shell wall. The shells were probably attacked near the surface, perhaps during initial postmortem drift of corpses.
Polymetamorphism in the Archean Hemlo – Heron Bay greenstone belt, Superior Province: P–T variations and implications for tectonic evolution
Authors: Pan Yuanming , Fleet Michael E.
Published: June 2010

The tectono-metamorphic history of the late Archean (2800–2600 Ma) Hemlo – Heron Bay greenstone belt in the Superior Province has been delineated from textural relationships, mineral chemistry, and P–T paths in metapelites, cordierite–orthoamphibole rocks, and metabasites from the White River exploration property, Hemlo area, Ontario. An early low-temperature, medium-pressure metamorphism (about 500 °C and 6–6.5 kbar (1 kbar = 100 MPa)) is indicated by the occurrence of relict kyanite and staurolite porphyroblasts and zoned garnet porphyroblasts in metapelites and the presence of zoned calcic amphiboles in metabasites. This early metamorphism appears to have been coeval with the previously documented D1 deformation that is associated with, for example, low-angle thrusts. A second regional metamorphism predominates in the Hemlo – Heron Bay greenstone belt and is generally of relatively low grade, at about 510–530 °C and 3.2–3.5 kbar, over most of the study area and increases to medium grade (550–650 °C and 4–5 kbar) towards the southern margin with the Pukaskwa Gneissic Complex and along the central axis enclosing the Hemlo Shear Zone. The second regional metamorphism was contemporaneous with the D3 deformation and was probably related to plutonism. This type of polymetamorphism in the Hemlo – Heron Bay greenstone belt may be equivalent to those in Phanerozoic subduction complexes and therefore supports the arc–arc accretion model for the development of the southern Superior Province. Although the Hemlo – Heron Bay greenstone belt most likely represents a single tectonic environment (an oceanic island arc), the restricted occurrence of the relict kyanite and staurolite indicates that the central portion of this Archean greenstone belt probably was at a deeper crustal level at the time of the first metamorphic event.
Hadrosaurid and lambeosaurid bone beds from the Upper Cretaceous Two Medicine Formation of Montana: taphonomic and biologic implications
Authors: Varricchio David J. , Horner John R.
Published: June 2010

Numerous dinosaur bone beds have been found in the Upper Cretaceous Two Medicine Formation. Taphonomy and size-frequency profiles for the most common skeletal elements of six predominantly hadrosaurid and (or) lambeosaurid assemblages were compared. All six localities are single, highly concentrated bone horizons within silty mudstones. Most are monospecific with some degree of skeletal association, parautochthonous, and likely the result of mass mortality. Four are associated with small lacustrine or waterhole environments and may be the result of drought-related mortality. Within the Two Medicine Formation drought was apparently a common mechanism for generating fossil assemblages.Both hadrosaurids and lambeosaurids appear to have been gregarious. Lack of association between small (total length < 3 m) and larger individuals suggests either that juvenile growth rates were as rapid as large ungulates or less likely, that juveniles had a period of noninteraction with adults, perhaps dwelling in strictly juvenile groups. In Maiasaura peeblesorum, reproduction appears to have been synchronous among herd members and seasonal. Additionally, mortality was high for juveniles and dropped off rapidly as animals approached adult size.
Crustal velocity structure in the eastern Insular and southernmost Coast belts, Canadian Cordillera
Authors: Zelt B. C. , Ellis R. M. , Clowes R. M.
Published: June 2010

Seismic refraction data recorded along a 330 km cross-strike profile through the eastern Insular and southernmost Coast belts of the Canadian Cordillera are interpreted using an iterative combination of traveltime inversion and amplitude forward modelling. The resultant model is characterized by large lateral variations in velocity. The most significant of these variations is a decrease in upper and middle crustal velocities to the east of the surface trace of the Harrison fault, which likely represents the transition from crust of the Insular superterrane to that of the Intermontane superterrane. This interpretation is consistent with some present geological models that place the possible (probable) location of the suture between the two superterranes less than 20 km east of the Harrison fault. Velocities at the base of the upper crust average 6.4 and 6.2 km/s west and east of the fault, respectively. Mid-crustal velocities average 6.6–6.9 km/s to the west and 6.35–6.45 km/s to the east of the fault. Lower crustal velocities also decrease slightly to the east. Other features of the velocity model include (i) a thin near-surface layer with velocities between 2.5 and 6.1 km/s; (ii) upper crustal thickness of 12.5 km, thinning to 8 km at the eastern boundary of the Western Coast Belt (WCB); (iii) high velocity (6.6–6.9 km/s) mid-crustal layer west of the Harrison fault extending to 21 km depth; (iv) high-velocity (6.75–7.1 km/s) lower crustal layer; (v) low-velocity gradient upper mantle with depth to Moho at 34–37 km beneath most of the Coast Belt, decreasing to 30 km beneath the eastern Insular Belt, a depth much less than previous estimates. The inferred crustal velocity structure beneath the WCB is consistent with the three-layer electrical conductivity structure for this area derived from magnetotelluric surveys. The association of high resistivities with the upper crust suggests that the upper 8–12 km represents the massive cover of plutonic rocks which characterizes the WCB. Middle and lower crustal velocities beneath the WCB are consistent with Wrangellian velocities found beneath Vancouver Island, suggesting Wrangellia may extend at depth eastward as far as the Harrison fault.
GENERALIZED SECOND LAW OF THERMODYNAMICS IN WORMHOLE GEOMETRY
Authors: BOKHARI ASHFAQUE H. , AKBAR M.
Published: June 2010

In this paper, the generalized second law (GSL) of thermodynamics is studied at the apparent horizon of the evolving wormhole. It is shown that the GSL holds at the apparent horizon of the evolving wormhole together with the assumption that the horizon temperature is equal to the temperature of the phantom energy.
Hydrogenases from Methanogenic Archaea, Nickel, a Novel Cofactor, and H2 Storage
Authors: Thauer Rudolf K. , Kaster Anne-Kristin , Goenrich Meike , Schick Michael , Hiromoto Takeshi , Shima Seigo
Published: June 2010

Most methanogenic archaea reduce CO2 with H2 to CH4. For the activation of H2, they use different [NiFe]-hydrogenases, namely energy-converting [NiFe]-hydrogenases, heterodisulfide reductase-associated [NiFe]-hydrogenase or methanophenazine-reducing [NiFe]-hydrogenase, and F420-reducing [NiFe]-hydrogenase. The energy-converting [NiFe]-hydrogenases are phylogenetically related to complex I of the respiratory chain. Under conditions of nickel limitation, some methanogens synthesize a nickel-independent [Fe]-hydrogenase (instead of F420-reducing [NiFe]-hydrogenase) and by that reduce their nickel requirement. The [Fe]-hydrogenase harbors a unique iron-guanylylpyridinol cofactor (FeGP cofactor), in which a low-spin iron is ligated by two CO, one C(O)CH2-, one S-CH2-, and a sp2-hybridized pyridinol nitrogen. Ligation of the iron is thus similar to that of the low-spin iron in the binuclear active-site metal center of [NiFe]- and [FeFe]-hydrogenases. Putative genes for the synthesis of the FeGP cofactor have been identified. The formation of methane from 4 H2 and CO2 catalyzed by methanogenic archaea is being discussed as an efficient means to store H2.
Eukaryotic Chromosome DNA Replication: Where, When, and How?
Authors: Masai Hisao , Matsumoto Seiji , You Zhiying , Yoshizawa-Sugata Naoko , Oda Masako
Published: June 2010

DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of the basic machinery of DNA replication from prokaryotes to eukaryotes. However, the need for replication of a substantially longer segment of DNA in coordination with various internal and external signals in eukaryotic cells has led to more complex and versatile regulatory strategies. The replication program in higher eukaryotes is under a dynamic and plastic regulation within a single cell, or within the cell population, or during development. We review here various regulatory mechanisms that control the replication program in eukaryotes and discuss future directions in this dynamic field.
Scaling Laws for Plasma Concentrations and Tolerable Doses of Anticancer Drugs
Authors: Dawson Thomas H.
Published: June 2010

General scaling laws are developed for projecting measurements of the plasma concentrations of anticancer drugs from laboratory animals to humans and among humans of different sizes. Associated scaling laws for critical drug doses are established from these laws. Broad categories of single and periodic i.v. bolus dosings are considered. Validity of the relations is shown using measurement from the literature for several well-known cytotoxic agents. The scaling theory is also shown to apply to novel anticancer drugs now available or presently under development, as represented by the p.o. administered prodrug capecitabine, the gene silencing inhibitor zebularine, and the blood vessel inhibitor bevacizumab. Scaling considerations for the modern practice of combination chemotherapy are also discussed. Cancer Res; 70(12); 4801–8. ©2010 AACR.
E6-Associated Protein Is Required for Human Papillomavirus Type 16 E6 to Cause Cervical Cancer in Mice
Authors: Shai Anny , Pitot Henry C. , Lambert Paul F.
Published: June 2010

High-risk human papillomaviruses (HPV) cause certain anogenital and head and neck cancers. E6, one of three potent HPV oncogenes that contribute to the development of these malignancies, is a multifunctional protein with many biochemical activities. Among these activities are its ability to bind and inactivate the cellular tumor suppressor p53, induce expression of telomerase, and bind to various other proteins, including Bak, E6BP1, and E6TP1, and proteins that contain PDZ domains, such as hScrib and hDlg. Many of these activities are thought to contribute to the role of E6 in carcinogenesis. The interaction of E6 with many of these cellular proteins, including p53, leads to their destabilization. This property is mediated at least in part through the ability of E6 to recruit the ubiquitin ligase E6-associated protein (E6AP) into complexes with these cellular proteins, resulting in their ubiquitin-mediated degradation by the proteasome. In this study, we address the requirement for E6AP in mediating acute and oncogenic phenotypes of E6, including induction of epithelial hyperplasia, abrogation of DNA damage response, and induction of cervical cancer. Loss of E6AP had no discernible effect on the ability of E6 to induce hyperplasia or abrogate DNA damage responses, akin to what we had earlier observed in the mouse epidermis. Nevertheless, in cervical carcinogenesis studies, there was a complete loss of the oncogenic potential of E6 in mice nulligenic for E6AP. Thus, E6AP is absolutely required for E6 to cause cervical cancer. Cancer Res; 70(12); 5064–73. ©2010 AACR.
Cyclin E Deregulation Impairs Mitotic Progression through Premature Activation of Cdc25C
Authors: Bagheri-Yarmand Rozita , Nanos-Webb Angela , Biernacka Anna , Bui Tuyen , Keyomarsi Khandan
Published: June 2010

The cyclin E–cyclin-dependent kinase 2 (CDK2) complex accelerates entry into the S phase of the cell cycle and promotes polyploidy, which may contribute to genomic instability in cancer cells. The effect of low molecular weight isoforms of cyclin E (LMW-E) overexpression on mitotic progression and its link to genomic instability were the focus of this study. Here, we show that full-length cyclin E (EL) and LMW-E overexpression impairs the G2-M transition differently by targeting dual-specificity phosphatase Cdc25C activity. We identify Cdc25C as an interaction partner and substrate for cyclin E/CDK2 kinase. Specifically, the cyclin E/CDK2 complex phosphorylates Cdc25C on Ser214, leading to its premature activation, which coincides with higher cyclin B/CDK1 and Polo-like kinase 1 (PLK1) activities in an S-phase–enriched population that result in faster mitotic entry. Whereas EL overexpression leads to hyperactivation of Cdc25C, cyclin B/CDK1, and PLK1 in a G2-M–enriched population, LMW-E overexpression causes premature inactivation of Cdc25C and PLK1, leading to faster mitotic exit. In addition, LMW-E–overexpressing cells showed a reduction in the mitotic index in the presence of a spindle poison and faster degradation of cyclin B, suggesting an increased rate of mitotic slippage and adaptation to the spindle checkpoint. Lastly, downregulation of Cdc25C inhibits LMW-E–mediated chromosome missegregation, anaphase bridges, and centrosome amplification. These results suggest that the high levels of LMW-E isoforms found in breast cancer may contribute to cellular transformation and genomic instability by impairing mitotic progression involving Cdc25C. Cancer Res; 70(12); 5085–95. ©2010 AACR.
High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of Bcl-2 Gene
Authors: Esposito Francesco , Tornincasa Mara , Chieffi Paolo , De Martino Ivana , Pierantoni Giovanna Maria , Fusco Alfredo
Published: June 2010

We have previously described a mechanism through which the high-mobility group A1 (HMGA1) proteins inhibit p53-mediated apoptosis by delocalizing the p53 proapoptotic activator homeodomain-interacting protein kinase 2 from the nucleus to the cytoplasm. By this mechanism, HMGA1 modulates the transcription of p53 target genes such as Mdm2, p21waf1, and Bax, inhibiting apoptosis. Here, we report that HMGA1 antagonizes the p53-mediated transcriptional repression of another apoptosis-related gene, Bcl-2, suggesting a novel mechanism by which HMGA1 counteracts apoptosis. Moreover, HMGA1 overexpression promotes the reduction of Brn-3a binding to the Bcl-2 promoter, thereby blocking the Brn-3a corepressor function on Bcl-2 expression following p53 activation. Consistently, a significant direct correlation between HMGA1 and Bcl-2 overexpression has been observed in human breast carcinomas harboring wild-type p53. Therefore, this study suggests a novel mechanism, based on Bcl-2 induction, by which HMGA1 overexpression contributes to the escape from apoptosis leading to neoplastic transformation. Cancer Res; 70(13); 5379–88. ©2010 AACR.
The Polycomb Group Protein Bmi-1 Is Essential for the Growth of Multiple Myeloma Cells
Authors: Jagani Zainab , Wiederschain Dmitri , Loo Alice , He Dan , Mosher Rebecca , Fordjour Paul , Monahan John , Morrissey Michael , Yao Yung-Mae , Lengauer Christoph , Warmuth Markus , Sellers William R. , Dorsch Marion
Published: June 2010

Bmi-1 is a member of the Polycomb group family of proteins that function in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. Bmi-1 was first identified through its ability to accelerate c-Myc–induced lymphomagenesis. Subsequent studies have further supported an oncogenic role for Bmi-1 in several cancers including those of the breast, lung, prostate, and brain. Using a stable and inducible shRNA system to silence Bmi-1 gene expression, we show a novel role for Bmi-1 in regulating the growth and clonogenic capacity of multiple myeloma cells both in vitro and in vivo. Moreover, to elucidate novel gene targets controlled by Bmi-1, global transcriptional profiling studies were performed in the setting of induced loss of Bmi-1 function. We found that the expression of the proapoptotic gene Bim is negatively regulated by Bmi-1 and that Bim knockdown functionally rescues the apoptotic phenotype induced upon loss of Bmi-1. Therefore, these studies not only highlight Bmi-1 as a cancer-dependent factor in multiple myeloma, but also elucidate a novel antiapoptotic mechanism for Bmi-1 function involving the suppression of Bim. Cancer Res; 70(13); 5528–38. ©2010 AACR.
Downregulation of Gadd45β Expression by Hepatitis C Virus Leads to Defective Cell Cycle Arrest
Authors: Higgs Martin R. , Lerat Hervé , Pawlotsky Jean-Michel
Published: June 2010

Members of the Gadd45 family play central roles in the cellular response to genotoxic stress and have been implicated in several human cancers, including hepatocellular carcinomas. Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of primary hepatocellular tumors, although the underlying mechanisms are unclear. Here, we show a novel link between diminished Gadd45β expression and HCV infection. Inhibited Gadd45β expression was observed in both nontumoral and tumoral tissues from infected individuals, and in cell lines harboring a HCV replicon and the infectious HCV strain JFH1. Decreased Gadd45β expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame. Mechanistically, hypermethylation of the Gadd45β promoter in the presence of HCV is responsible for this defect. Diminished Gadd45β expression leads to aberrant cell cycle arrest and diminished DNA excision repair. Together, these results provide a novel insight into the mechanisms involved in HCV-associated hepatocellular carcinomas, showing that reduced Gadd45β expression may play a contributory role to this process, and providing evidence that HCV may interfere with epigenetic gene expression by altering promoter methylation. Cancer Res; 70(12); 4901–11. ©2010 AACR.
FoxM1 Mediates Resistance to Herceptin and Paclitaxel
Authors: Carr Janai R. , Park Hyun Jung , Wang Zebin , Kiefer Megan M. , Raychaudhuri Pradip
Published: June 2010

Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In human breast cancer samples, overexpression of the oncogenic transcription factor FoxM1 has been suggested to be a marker of poor prognosis. In this study, we report that FoxM1 overexpression confers resistance to the human epidermal growth factor receptor 2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin-destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by small interfering RNA or an alternate reading frame (ARF)–derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer. Cancer Res; 70(12); 5054–63. ©2010 AACR.
High Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer
Authors: Jiang Tao , Chen Ning , Zhao Fei , Wang Xiao-Jun , Kong Beihua , Zheng Wenxin , Zhang Donna D.
Published: June 2010

Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor Nrf2 was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC-derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs, whereas it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2–derived xenografts to chemotherapeutic treatments using both cell culture and severe combined immunodeficient mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy. Cancer Res; 70(13); 5486–96. ©2010 AACR.
Cancer Stem Cells and Self-renewal
Authors: O'Brien Catherine Adell , Kreso Antonija , Jamieson Catriona H.M.
Published: June 2010

The cancer stem cell (CSC) or cancer-initiating cancer (C-IC) model has garnered considerable attention over the past several years since Dick and colleagues published a seminal report showing that a hierarchy exists among leukemic cells. In more recent years, a similar hierarchical organization, at the apex of which exists the CSC, has been identified in a variety of solid tumors. Human CSCs are defined by their ability to: (i) generate a xenograft that histologically resembles the parent tumor from which it was derived, (ii) be serially transplanted in a xenograft assay thereby showing the ability to self-renew (regenerate), and (iii) generate daughter cells that possess some proliferative capacity but are unable to initiate or maintain the cancer because they lack intrinsic regenerative potential. The emerging complexity of the CSC phenotype and function is at times daunting and has led to some confusion in the field. However, at its core, the CSC model is about identifying and characterizing the cancer cells that possess the greatest capacity to regenerate all aspects of the tumor. It is becoming clear that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and CSC maintenance will lead to a better understanding of the mechanisms driving tumor growth. This review will address some of the main controversies in the CSC field and emphasize the importance of focusing first and foremost on the defining feature of CSCs: dysregulated self-renewal capacity. Clin Cancer Res; 16(12); 3113–20. ©2010 AACR.
The Difficulty of Targeting Cancer Stem Cell Niches
Authors: LaBarge Mark A.
Published: June 2010

Normal stem cell niches typically are identified by their distinctive anatomical features and by association with tissue-specific stem cells. Identifying cancer stem cell (CSC) niches presents a special problem because there are few if any common anatomical features among tumors, and the physical phenotypes that reportedly describe the CSCs as entities may be subject to the host's microenvironment, sex, and tumor stage. Irrespective of a niche's location, the occupant's phenotype, or the precise molecular composition, all niches must do basically the same thing: maintain the activities in a stem cell that define it as such. Therefore, a potentially successful strategy, both for elaborating a molecular and cellular portrait of a CSC niche, and for therapeutically targeting them, is to identify components in the tumor microenvironment that are required for maintaining the functions of self-renewal, differentiation, and quiescence in the face of cytotoxic therapeutic regimens. Clin Cancer Res; 16(12); 3121–9. ©2010 AACR.
Targeting Wnt Signaling: Can We Safely Eradicate Cancer Stem Cells?
Authors: Takahashi-Yanaga Fumi , Kahn Michael
Published: June 2010

The Wnt signaling pathways have been conserved throughout evolution and regulate cell proliferation, morphology, motility, and fate during embryonic development. These pathways also play important roles throughout adult life to maintain homeostasis of tissues including skin, blood, intestine, and brain by regulating somatic stem cells and their niches. Aberrant regulation of the Wnt pathway leads to neoplastic proliferation in these same tissues. It has been suggested that Wnt signaling is also involved in the regulation of cancer stem cells (CSC), because there are many similarities in the signaling pathways that regulate normal adult stem cells and CSC. In this Perspective, we have focused on the Wnt/β-catenin signaling pathway, which is the most intensively studied and best characterized Wnt signaling pathway. We provide an overview on the function of the Wnt/β-catenin signaling pathway in CSC, and the possibility of the development of novel therapeutics to target this pathway. Clin Cancer Res; 16(12); 3153–62. ©2010 AACR.
Development of an Integrated Genomic Classifier for a Novel Agent in Colorectal Cancer: Approach to Individualized Therapy in Early Development
Authors: Pitts Todd M. , Tan Aik Choon , Kulikowski Gillian N. , Tentler John J. , Brown Amy M. , Flanigan Sara A. , Leong Stephen , Coldren Christopher D. , Hirsch Fred R. , Varella-Garcia Marileila , Korch Christopher , Eckhardt S. Gail
Published: June 2010

Background: A plethora of agents is in early stages of development for colorectal cancer (CRC), including those that target the insulin-like growth factor I receptor (IGFIR) pathway. In the current environment of numerous cancer targets, it is imperative that patient selection strategies be developed with the intent of preliminary testing in the latter stages of phase I trials. The goal of this study was to develop and characterize predictive biomarkers for an IGFIR tyrosine kinase inhibitor, OSI-906, that could be applied in CRC-specific studies of this agent.

Methods: Twenty-seven CRC cell lines were exposed to OSI-906 and classified according to IC50 value as sensitive (≤1.5 μmol/L) or resistant (>5 μmol/L). Cell lines were subjected to immunoblotting and immunohistochemistry for effector proteins, IGFIR copy number by fluorescence in situ hybridization, KRAS/BRAF/phosphoinositide 3-kinase mutation status, and baseline gene array analysis. The most sensitive and resistant cell lines were used for gene array and pathway analyses, along with shRNA knockdown of highly ranked genes. The resulting integrated genomic classifier was then tested against eight human CRC explants in vivo.

Results: Baseline gene array data from cell lines and xenografts were used to develop a k-top scoring pair (k-TSP) classifier, which, in combination with IGFIR fluorescence in situ hybridization and KRAS mutational status, was able to predict with 100% accuracy a test set of patient-derived CRC xenografts.

Conclusions: These results indicate that an integrated approach to the development of individualized therapy is feasible and should be applied early in the development of novel agents, ideally in conjunction with late-stage phase I trials. Clin Cancer Res; 16(12); 3193–204. ©2010 AACR.
Biobehavioral, Immune, and Health Benefits following Recurrence for Psychological Intervention Participants
Authors: Andersen Barbara L. , Thornton Lisa M. , Shapiro Charles L. , Farrar William B. , Mundy Bethany L. , Yang Hae-Chung , Carson William E.
Published: June 2010

Purpose: A clinical trial was designed to test the hypothesis that a psychological intervention could reduce the risk of cancer recurrence. Newly diagnosed regional breast cancer patients (n = 227) were randomized to the intervention-with-assessment or the assessment-only arm. The intervention had positive psychological, social, immune, and health benefits, and after a median of 11 years the intervention arm was found to have reduced the risk of recurrence (hazard ratio, 0.55; P = 0.034). In follow-up, we hypothesized that the intervention arm might also show longer survival after recurrence. If observed, we then would examine potential biobehavioral mechanisms.

Experimental Design: All patients were followed; 62 recurred. Survival analyses included all 62. Upon recurrence diagnosis, those available for further biobehavioral study were accrued (n = 41, 23 intervention and 18 assessment). For those 41, psychological, social, adherence, health, and immune (natural killer cell cytotoxicity, T-cell proliferation) data were collected at recurrence diagnosis and 4, 8, and 12 months later.

Results: Intent-to-treat analysis revealed reduced risk of death following recurrence for the intervention arm (hazard ratio, 0.41; P = 0.014). Mixed-effects follow-up analyses with biobehavioral data showed that all patients responded with significant psychological distress at recurrence diagnosis, but thereafter only the intervention arm improved (P values < 0.023). Immune indices were significantly higher for the intervention arm at 12 months (P values < 0.017).

Conclusions: Hazards analyses augment previous findings in showing improved survival for the intervention arm after recurrence. Follow-up analyses showing biobehavioral advantages for the intervention arm contribute to our understanding of how improved survival was achieved. Clin Cancer Res; 16(12); 3270–8. ©2010 AACR.
Continuous Docetaxel Chemotherapy Improves Therapeutic Efficacy in Murine Models of Ovarian Cancer
Authors: De Souza Raquel , Zahedi Payam , Moriyama Eduardo H. , Allen Christine J. , Wilson Brian C. , Piquette-Miller Micheline
Published: June 2010

Ovarian cancer is known as the silent killer for being asymptomatic until late stages. Current first-line treatment consists of debulking surgery followed by i.v. chemotherapeutics administered intermittently, which leads to insufficient drug concentrations at tumor sites, accelerated tumor proliferation rates, and drug resistance, resulting in an overall median survival of only 2 to 4 years. For these reasons, more effective treatment strategies must be developed. We have investigated a localized, continuous chemotherapy approach in tumor models of human and murine ovarian cancers using the antineoplastic agent docetaxel. We show here that continuous docetaxel therapy is considerably more efficacious than intermittent therapy, resulting in a greater decrease in tumor burden and ascites fluid accumulation. Immunohistochemical analyses show that continuous chemotherapy abrogates tumor cell proliferation and angiogenesis to the tumor microenvironment, leading to greater tumor cell death than intermittent docetaxel therapy. Overall, our results show greater therapeutic advantages of continuous over intermittent chemotherapy in the treatment of ovarian cancer. Mol Cancer Ther; 9(6); 1820–30. ©2010 AACR.
Cyclooxygenase-Deficient Pancreatic Cancer Cells Use Exogenous Sources of Prostaglandins
Authors: Omura Noriyuki , Griffith Margaret , Vincent Audrey , Li Ang , Hong Seung-Mo , Walter Kimberly , Borges Michael , Goggins Michael
Published: June 2010

Genes that are differentially expressed in pancreatic cancers and under epigenetic regulation are of considerable biological and therapeutic interest. We used global gene expression profiling and epigenetic treatment of pancreatic cell lines including pancreatic cancer cell lines, pancreatic cancer–associated fibroblasts, and cell lines derived from nonneoplastic pancreata. We examined expression and epigenetic alterations of cyclooxygenase-1 (COX-1) and COX-2 in pancreatic cancers and normal pancreas and performed proliferation, knockdown, and coculture experiments to understand the role of stromal sources of prostaglandins for pancreatic cancers. We identify COX-1 as a gene under epigenetic regulation in pancreatic cancers. We find that COX-1 expression is absent in many pancreatic cancer cells and some of these cancers also lack COX-2 expression. Suspecting that such cancers must rely on exogenous sources of prostaglandins, we show that pancreatic cancer stromal cells, such as fibroblasts expressing COX-1 and COX-2, are a likely source of prostaglandins for pancreatic cancer cells deficient in COX. Knocking down the prostaglandin transporter multidrug resistance–associated protein-4 in fibroblasts suppresses the proliferation of cocultured pancreatic cancer cells lacking COX. Pancreatic cancers that lack COX can use exogenous sources of prostaglandins. Blocking multidrug resistance–associated protein-4 may be a useful therapeutic strategy to deplete COX-deficient pancreatic cancers of prostaglandins. Mol Cancer Res; 8(6); 821–32. ©2010 AACR.
Cancer-Associated Fibroblasts Derived from EGFR-TKI–Resistant Tumors Reverse EGFR Pathway Inhibition by EGFR-TKIs
Authors: Mink Sheldon R. , Vashistha Surabhi , Zhang Wenxuan , Hodge Amanda , Agus David B. , Jain Anjali
Published: June 2010

Epidermal growth factor receptor (EGFR) plays a critical role in oncogenesis, which makes it an attractive target for pharmacologic inhibition. Yet, EGFR inhibition with tyrosine kinase inhibitors (TKI) does not result in a measurable and sustainable clinical benefit in a vast majority of tumors. This emphasizes the need for further investigations into resistance mechanisms against EGFR-TKIs. We previously reported the generation of an in vivo adenocarcinoma model of EGFR-TKI–acquired resistance that was devoid of the known mechanisms of resistance. Using this same xenograft model, we now show that the tumor stroma plays an important role in limiting responsiveness to EGFR-TKIs. EGFR-TKI–resistant tumors display increased surface expression of CD44hi/CD24lo and markers of epithelial to mesenchymal transition (EMT), SNAI1, and N-cadherin. An in vivo green fluorescent protein–tagging approach reveals that the tumor stroma of the EGFR-TKI–resistant tumors is distinct in that 24% of its cancer-associated fibroblast (CAF) population is composed of EMT-derived tumor cells that represent the in vivo escape from EGFR-TKIs. We further show that EMT subpopulation–harboring CAFs isolated from the EGFR-TKI–resistant tumors are tumorigenic and express the biomarker of gefitinib resistance, epithelial membrane protein-1. Finally, we provide evidence that paracrine factors secreted from the EGFR-TKI–resistant CAFs mitigate the EGFR-TKI–mediated blockade of pEGFR and pMAPK in cocultured tumor cells, regardless of their EGFR mutational status. This is the first demonstration that the tumor stroma is modified with acquisition of EGFR-TKI resistance and that it further contributes in promoting drug resistance. Mol Cancer Res; 8(6); 809–20. ©2010 AACR.
Meat Processing and Colon Carcinogenesis: Cooked, Nitrite-Treated, and Oxidized High-Heme Cured Meat Promotes Mucin-Depleted Foci in Rats
Authors: Santarelli Raphaëlle L. , Vendeuvre Jean-Luc , Naud Nathalie , Taché Sylviane , Guéraud Françoise , Viau Michelle , Genot Claude , Corpet Denis E. , Pierre Fabrice H.F.
Published: June 2010

Processed meat intake is associated with colorectal cancer risk, but no experimental study supports the epidemiologic evidence. To study the effect of meat processing on carcinogenesis promotion, we first did a 14-day study with 16 models of cured meat. Studied factors, in a 2 × 2 × 2 × 2 design, were muscle color (a proxy for heme level), processing temperature, added nitrite, and packaging. Fischer 344 rats were fed these 16 diets, and we evaluated fecal and urinary fat oxidation and cytotoxicity, three biomarkers of heme-induced carcinogenesis promotion. A principal component analysis allowed for selection of four cured meats for inclusion into a promotion study. These selected diets were given for 100 days to rats pretreated with 1,2-dimethylhydrazine. Colons were scored for preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF). Cured meat diets significantly increased the number of ACF/colon compared with a no-meat control diet (P = 0.002). Only the cooked nitrite-treated and oxidized high-heme meat significantly increased the fecal level of apparent total N-nitroso compounds (ATNC) and the number of MDF per colon compared with the no-meat control diet (P < 0.05). This nitrite-treated and oxidized cured meat specifically increased the MDF number compared with similar nonnitrite-treated meat (P = 0.03) and with similar nonoxidized meat (P = 0.004). Thus, a model cured meat, similar to ham stored aerobically, increased the number of preneoplastic lesions, which suggests colon carcinogenesis promotion. Nitrite treatment and oxidation increased this promoting effect, which was linked with increased fecal ATNC level. This study could lead to process modifications to make nonpromoting processed meat. Cancer Prev Res; 3(7); 852–64. ©2010 AACR.
Morphogenesis of the Medaka Cerebellum, with Special Reference to the Mesencephalic Sheet, a Structure Homologous to the Rostrolateral Part of Mammalian Anterior Medullary Velum
Authors: Ishikawa Yuji , Yamamoto Naoyuki , Yasuda Takako , Yoshimoto Masami , Ito Hironobu
Published: June 2010

We have examined cerebellar morphogenesis after neural tube stage in medaka (Oryzias latipes), a ray-finned fish, by conventional histology and immunohistochemistry using anti-proliferating cell nuclear antigen (PCNA) and anti-acetylated tubulin antibodies. Our results indicate that the medaka cerebellum is formed in 4 successive stages: (1) formation and enlargement of the cerebellar primordia; (2) rostral midline fusion of the left/right halves of the cerebellar primordia; (3) formation of the cerebellar matrix zones in the midline and caudalmost regions of the primitive cerebellum, and (4) growth and differentiation of the cerebellum. Our results also show that cerebellar morphogenesis is different from that in mammals in 3 important points: the developmental origins of the primordia, directions along which cerebellar fusion proceeds, and number, locations and duration of the cerebellar matrix zones. During the course of this study, an alar-derived membranous structure between the cerebellum and the midbrain in the adult medaka brain was identified as the structure homologous to the rostrolateral part of the mammalian anterior medullary velum. We have named this structure in the adult teleostean brains as the ‘mesencephalic sheet’. The present study indicates that there exists both conserved and divergent patterns in cerebellar morphogenesis in vertebrates.
Retinal Ganglion Cell Topography of Five Species of Ground-Foraging Birds
Authors: Dolan Tracy , Fernández-Juricic Esteban
Published: June 2010

Birds that forage on the ground have been studied extensively in relation to behavioral trade-offs between foraging and scanning for predators; however, we know little about the topography of their retinas, which can influence how they gather visual information. We characterized the density of retinal ganglion cells across the retina and estimated visual acuity of four Passeriformes (European starling Sturnus vulgaris, brown-headed cowbird Molothrus ater, house sparrow Passer domesticus, house finch Carpodacus mexicanus) and one Columbiforme (mourning dove Zenaida macroura) that forage on the ground. We used cresyl violet to stain retinal ganglion cells and estimated visual acuity based on cell density and eye size. All species contained a single area centralis, where cell densities were >20,000 cells/mm2. The proportion of the retina that fell in each of five cell density ranges varied between species. European starlings and house finches had the largest area of high cell density, mourning doves had the smallest. The largest proportion of the retina (>35%) of brown-headed cowbird and house sparrow was in the second-lowest cell density range. Considering the 25th percentile of highest cell densities, house finches and European starlings showed the highest cell densities and mourning doves the lowest. Estimated visual acuity increased from house finch, house sparrow, brown-headed cowbird, European starling to mourning dove, and was associated with both retinal area and cell density. Our findings suggest that these ground foragers do not have highly specialized retinas in relation to other types of foragers (e.g. tree foragers), probably because foraging on seeds and insects from the ground is not as visually demanding; however, the studied species showed variability in retinal topography that may be related to foraging techniques, eye size constraints, and size of the area centralis.
The CBV-ASPECT Score as a Predictor of Fatal Stroke in a Hyperacute State
Authors: Kim Joon-Tae , Park Man-Seok , Choi Kang-Ho , Nam Tai-Seung , Choi Seong-Min , Lee Seung-Han , Kim Byeong-Chae , Kim Myeong-Kyu , Cho Ki-Hyun
Published: June 2010

Background: Many parameters of multimodal computed tomography (CT) have been assessed to predict clinical outcome and recanalization after thrombolysis. However, an early predictor of fatal stroke has not been clearly identified. Therefore, this study was conducted to identify early predictors related to fatal stroke. Methods: We retrospectively analyzed subjects with acute ischemic stroke within 6 h of onset between March 2007 and January 2009. Early fatal stroke was defined as death or coma within 1 week of the initial ischemic stroke. Multimodal CT images were scored according to previous studies, such as the Alberta Stroke Program Early CT Score (ASPECTS), collateral score (CS) and clot burden score (CBS). Results: A total of 68 patients were analyzed in this study. Twenty-two patients (32.4%) fell into a coma or died within 1 week of the initial stroke. Patients with fatal stroke had a lower CS, CBS and ASPECTS in the cerebral blood volume (CBV) and time-to-peak maps than those with nonfatal stroke. The initial NIHSS score, CBV-ASPECTS, age and diabetes mellitus were associated with fatal infarct in multivariate logistic regression analysis. Conclusions: Our study demonstrated that initially low CBV-ASPECTS on perfusion CT could predict early fatal stroke and that a CBV-ASPECTS threshold of <4 with a modest sensitivity and specificity could be considered as an early predictor of fatal stroke.
The Onset of Multiple Sclerosis in Greece: A Single-Center Study of 1,034 Consecutive Patients
Authors: Koutsis G. , Evangelopoulos M.E. , Andreadou E. , Mandellos D. , Karachalios G. , Potagas C. , Karantoni E. , Karouli M. , Chrysovitsanou C. , Vassilopoulos D. , Sfagos C.
Published: June 2010

Background/Aims: The onset of multiple sclerosis (MS) in Greece has not been systematically studied. We sought to provide data on the onset of MS in Greece with detailed information regarding initial symptoms, and to confirm the prognostic significance of demographic and clinical factors at onset. Methods: We studied 1,034 consecutive patients with MS and independently assessed 265 patients ‘seen at onset’. We used the MS severity score and survival analysis (time to reach an Expanded Disability Status Scale score of 4.0) to evaluate the prognostic significance of factors at onset. Results: Female-to-male ratio was 1.9:1 and mean age at onset was 30.7 ± 9.9 years. MS was primary progressive in 9.6%. Initial symptoms were optic neuritis in 20.1%, brainstem dysfunction in 14.7%, dysfunction of long tracts in 49.3%, cerebral dysfunction in 1% and a combination of symptoms in 14.9%. In ‘seen at onset’ patients, detailed data on initial symptoms are presented. Female gender, earlier age at onset, ‘bout onset’ and onset with optic neuritis were associated with less severe disease and longer time to disability. Conclusion: The onset of MS in Greece is similar to Western populations. Initial symptoms are within the expected spectrum. Prognostic significance of factors at onset is as previously identified.
A Rare Instance of ‘Cardio-Respiratory Pacing’: Permanent Pacemaker Insertion for Symptomatic Bradycardia in a Quadriplegic Man Dependent on Diaphragmatic Pacing by Phrenic Nerve Stimulators
Authors: Krishnan Unni , Ramrakha Punit S. , Money-Kyrle Andrew
Published: June 2010

Patients with high spinal cord injury may present with significant cardiac dysautonomia. There is a dearth of data regarding electromechanical interference to cardiac pacemakers from phrenic nerve stimulators which are used in such patients for respiratory support. We report an instance of bipolar lead permanent pacemaker insertion for ventricular standstill in a man with quadriplegia following C2 fracture and the measures we adopted to minimise electromagnetic interference with phrenic nerve stimulators. To the best of our knowledge, this is the first reported instance of successful pacemaker insertion in a quadriplegic patient on long-term diaphragmatic pacing.
Therapeutic Effect of Direct Hemoperfusion with a Polymyxin B-Immobilized Fiber Column in the Treatment of HIV-Negative Severe Pneumocystis Pneumonia
Authors: Tachikawa Ryo , Tomii Keisuke , Murase Kimihiko , Ueda Hiroyuki , Harada Yuka , Kida Yoko , Ishihara Kyosuke
Published: June 2010

Background: Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been shown to improve oxygenation in cases of diffuse alveolar damage, but little is known about its effectiveness in treating pneumocystis pneumonia (PCP) in HIV-negative immunosuppressed patients. Objectives: This study was aimed at investigating the effect of PMX-DHP in treating non-HIV-related PCP. Methods: Between October 2005 and September 2008, 6 patients with non-HIV-related PCP were treated with 2 sessions of PMX-DHP at an attending physician’s discretion when severe hypoxemia developed despite conventional treatments including high-dose corticosteroid, whereas 9 patients in a similar condition were treated without PMX-DHP. Changes in oxygenation and radiographic findings in the PMX-DHP group and adverse events associated with PMX-DHP were investigated retrospectively, as were the outcomes for both treatment groups. Results: There was an improvement in PaO2/FiO2 during each PMX-DHP session, from 148.8 ± 52.5 to 188.2 ± 79.3 mm Hg (p = 0.02). After 2 sessions of PMX-DHP, an improvement in PaO2/FiO2, from 131.8 ± 37.4 to 213.3 ± 87.3 mm Hg, was observed (p = 0.04), but no significantly different improvement was detected on the following day. The radiographic findings improved in 4 patients during PMX-DHP. The in-hospital mortality was similarly high in both groups (50% in the PMX-DHP group vs. 67% in the non-PMX-DHP group). No significant adverse events associated with PMX-DHP were observed except for advanced thrombocytopenia in 1 patient. Conclusion: PMX-DHP may serve as an adjunct in the treatment of non-HIV-related PCP, temporarily alleviating severe hypoxemia even in cases refractory to conventional treatments.
Lakī and Kurdish
Authors: Shahsavari Faramarz
Published: June 2010

This paper aims at verifying the traditional set of phonetic changes, defined by D. N. Mackenzie as the main distinctive feature of the Kurdish dialects, with regard to Lakī having yet no clear affiliation in the Iranian dialectology. It is usually considered to be a dialect of Kurdish, sometimes a transitional dialect between Kurdish and Luri, and even a separate idiom.
The Dialect of Jowshaqan Part One: Phonology, Morphology and Syntax
Authors: Borjian Habib
Published: June 2010

This article presents the grammar of Jowshaqani, a Central Iranian dialect. Like other members of this group, Jowshaqani has its own peculiarities; for instance, it has a rich inventory of personal pronouns distinguished by gender in the 3rd person singular, as do verb endings: nen ate “he comes”, néna atea “she comes”, etc. The past tenses of transitive verbs are inflected ergatively, with the agential affixes, which float through the sentence yielding complex syntactic structures.