bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marked Activity of Irinotecan and Rapamycin Combination toward Colon Cancer Cells In vivo and In vitro Is Mediated through Cooperative Modulation of the Mammalian Target of Rapamycin/Hypoxia-Inducible Factor-1α Axis
Authors: Pencreach Erwan , Guérin Eric , Nicolet Céline , Lelong-Rebel Isabelle , Voegeli Anne-Claire , Oudet Pierre , Larsen Annette K. , Gaub Marie-Pierre , Guenot Dominique 
Published: February 2009

Abstract
Purpose: Despite recent progress, colon cancer is often resistant to combination chemotherapy, highlighting the need for development of novel therapeutic approaches. An attractive target is hypoxia-inducible factor-1α (HIF-1α), a key transcription factor with a pivotal role in tumor cell metabolism. One potential class of therapeutic agents targeting HIF-1α are mammalian target of rapamycin inhibitors such as rapamycin. A second class are topoisomerase I inhibitors, such as irinotecan, which are able to inhibit the accumulation of HIF-1α. We here investigated whether combination of rapamycin and irinotecan was active in human colon cancer models.
Experimental Design: Human metastatic tumors were xenografted in nude mice and treated with low doses of irinotecan alone, rapamycin alone, or combination of both drugs. The cellular effects of irinotecan and rapamycin were further characterized for HT-29 and HCT-116 colon cancer cells in vitro.
Results: In contrast to single-agent therapy, xenografted tumors treated with combination of irinotecan and rapamycin showed potent inhibition of the mammalian target of rapamycin/HIF-1α axis, which was accompanied by a dramatic reduction in tumor volume. In vitro experiments showed that exposure to low concentrations of the two drugs resulted in massive HT-29 cell death under hypoxic, but not normoxic, conditions, in full agreement with a cytotoxic effect mediated through HIF-1α rather than through induction of genotoxic lesions. HCT-116 cells were less sensitive to the combined treatment due to constitutive activation of phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways.
Conclusion: These results identify HIF-1α as a promising target and provide a rationale for clinical trials of low-dose irinotecan and rapamycin combination toward metastatic colon cancer.
Longitudinal Analysis and Prognostic Effect of Cancer-Testis Antigen Expression in Multiple Myeloma
Authors: Atanackovic Djordje , Luetkens Tim , Hildebrandt York , Arfsten Julia , Bartels Katrin , Horn Christiane , Stahl Tanja , Cao Yanran , Zander Axel R. , Bokemeyer Carsten , Kröger Nicolaus 
Published: February 2009

Abstract
Purpose: Reliable data on the persistence of tumor expression of cancer-testis (CT) antigens over time and consequent analyses of the effect of CT antigen expression on the clinical course of malignancies are crucial for their evaluation as diagnostic markers and immunotherapeutic targets.
Experimental Design: Applying conventional reverse transcription-PCR, real-time PCR, and Western blot, we did the first longitudinal study of CT antigen expression in multiple myeloma analyzing 330 bone marrow samples from 129 patients for the expression of four CT antigens (MAGE-C1/CT7, MAGE-C2/CT10, MAGE-A3, and SSX-2).
Results: CT antigens were frequently and surprisingly persistently expressed, indicating that down-regulation of these immunogenic targets does not represent a common tumor escape mechanism in myeloma. We observed strong correlations of CT antigen expression levels with the clinical course of myeloma patients as indicated by the number of bone marrow–residing plasma cells and peripheral paraprotein levels, suggesting a role for CT antigens as independent tumor markers. Investigating the prognostic value of CT antigen expression in myeloma patients after allogeneic stem cell transplantation, we found that expression of genes, such as MAGE-C1, represents an important indicator of early relapse and dramatically reduced survival.
Conclusions: Our findings suggest that CT antigens might promote the progression of multiple myeloma and especially MAGE-C1/CT7, which seems to play the role of a “gatekeeper” gene for other CT antigens, might characterize a more malignant phenotype. Importantly, our study also strongly supports the usefulness of CT antigens as diagnostic and prognostic markers as well as therapeutic targets in myeloma.
Phase I and Pharmacokinetic Study of Pegylated Liposomal CKD-602 in Patients with Advanced Malignancies
Authors: Zamboni William C. , Ramalingam Suresh , Friedland David M. , Edwards Robert P. , Stoller Ronald G. , Strychor Sandra , Maruca Lauren , Zamboni Beth A. , Belani Chandra P. , Ramanathan Ramesh K. 
Published: February 2009

Abstract
Purpose: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors.
Experimental Design: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone + hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated + released) CKD602 measured by liquid chromatography-tandem mass spectrometry.
Results: Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602.
Conclusions: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.
Monoclonal antibody 16D10 to the COOH-terminal domain of the feto-acinar pancreatic protein targets pancreatic neoplastic tissues
Authors: Benkoël Liliane , Bernard Jean-Paul , Payan-Defais Marie-José , Crescence Lydie , Franceschi Cécile , Delmas Mireille , Ouaissi Mehdi , Sastre Bernard , Sahel José , Benoliel Anne-Marie , Bongrand Pierre , Silvy Françoise , Gauthier Laurent , Romagné François , Lombardo Dominique , Mas Eric 
Published: February 2009

Abstract
We have shown that the 16D10 antigen located on the mucin-like COOH-terminal domain of the feto-acinar pancreatic protein (FAPP) is expressed at the surface of human pancreatic tumor cell lines such as SOJ-6 cell line. Furthermore, an in vivo study indicates that targeting this cell-membrane glycopeptide by the use of the monoclonal antibody (mAb) 16D10 inhibits the growth of SOJ-6 xenografts in nude mice. To validate the potential use of the mAb16D10 in immune therapy, this study examined the expression of 16D10 antigens at the surface of human pancreatic adenocarcinomas versus control tissues. We examined the reactivity of mAb16D10 and mAb8H8 with pancreatic ductal adenocarcinomas (PDAC) compared with controls by using immunohistochemistry and confocal laser scanning microscopy. mAb8H8 does react with control or nontumoral human pancreatic tissues. mAb16D10 has a strong and specific reactivity with PDAC and does not react with other cancers of epithelia or normal tissues tested. Notable, mAb16D10 mostly recognizes membrane of tumoral cells. Furthermore, mAb8H8 and mAb16D10 recognized a protein of 110 to 120 kDa in homogenates of nontumoral and tumoral human pancreatic tissues, respectively. This size correlates with that of FAPP or with that of the normal counterpart of FAPP, the so-called bile salt-dependent lipase. The results suggest that mAb16D10 presents a unique specificity against PDAC; consequently, it could be effective in immune therapy of this cancer. Furthermore, mAb16D10 and mAb8H8 pair might be useful for diagnosis purpose in discriminating tumoral from nontumoral human pancreatic tissues. [Mol Cancer Ther 2009;8(2):282–91]
Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy
Authors: Li Yunqing , Guessous Fadila , DiPierro Charles , Zhang Ying , Mudrick Tucker , Fuller Lauren , Johnson Elizabeth , Marcinkiewicz Lukasz , Engelhardt Matthew , Kefas Benjamin , Schiff David , Kim Jin , Abounader Roger 
Published: February 2009

AbstractThe tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells. We also assessed the experimental therapeutic effects of combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition. PTEN significantly inhibited HGF-induced proliferation, cell cycle progression, migration, and invasion of glioblastoma cells. PTEN attenuated HGF-induced changes of signal transduction proteins Akt, GSK-3, JNK, and mTOR as well as cell cycle regulatory proteins p27, cyclin E, and E2F-1. Combining PTEN restoration to PTEN-null glioblastoma cells with c-Met and HGF inhibition additively inhibited tumor cell proliferation and cell cycle progression. Similarly, combining a monoclonal anti-HGF antibody (L2G7) with the mTOR inhibitor rapamycin had additive inhibitory effects on glioblastoma cell proliferation. Systemic in vivo delivery of L2G7 and PTEN restoration as well as systemic in vivo deliveries of L2G7 and rapamycin additively inhibited intracranial glioma xenograft growth. These preclinical studies show for the first time that PTEN loss amplifies c-Met-induced glioblastoma malignancy and suggest that combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition is worth testing in a clinical setting. [Mol Cancer Ther 2009;8(2):376–85]
CNOB/ChrR6, a new prodrug enzyme cancer chemotherapy
Authors: Thorne Steve H. , Barak Yoram , Liang Wenchuan , Bachmann Michael H. , Rao Jianghong , Contag Christopher H. , Matin A. 
Published: February 2009

Abstract
We report the discovery of a new prodrug, 6-chloro-9-nitro-5-oxo-5H-benzo(a)phenoxazine (CNOB). This prodrug is efficiently activated by ChrR6, the highly active prodrug activating bacterial enzyme we have previously developed. The CNOB/ChrR6 therapy was effective in killing several cancer cell lines in vitro. It also efficiently treated tumors in mice with up to 40% complete remission. 9-Amino-6-chloro-5H-benzo(a)phenoxazine-5-one (MCHB) was the only product of CNOB reduction by ChrR6. MCHB binds DNA; at nonlethal concentration, it causes cell accumulation in the S phase, and at lethal dose, it induces cell surface Annexin V and caspase-3 and caspase-9 activities. Further, MCHB colocalizes with mitochondria and disrupts their electrochemical potential. Thus, killing by CNOB involves MCHB, which likely induces apoptosis through the mitochondrial pathway. An attractive feature of the CNOB/ChrR6 regimen is that its toxic product, MCHB, is fluorescent. This feature proved helpful in in vitro studies because simple fluorescence measurements provided information on the kinetics of CNOB activation within the cells, MCHB killing mechanism, its generally efficient bystander effect in cells and cell spheroids, and its biodistribution. The emission wavelength of MCHB also permitted its visualization in live animals, allowing noninvasive qualitative imaging of MCHB in mice and the tumor microenvironment. This feature may simplify exploration of barriers to the penetration of MCHB in tumors and their amelioration. [Mol Cancer Ther 2009;8(2):333–41]
Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells
Authors: Morales Cristina , García Maria J. , Ribas Maria , Miró Rosa , Muñoz Mar , Caldas Carlos , Peinado Miguel A. 
Published: February 2009

Abstract
Gene amplification is one of the most frequent manifestations of genomic instability in human tumors and plays an important role in tumor progression and acquisition of drug resistance. To better understand the factors involved in acquired resistance to cytotoxic drugs via gene amplification, we have analyzed the structure and dynamics of dihydrofolate reductase (DHFR) gene amplification in HT29 cells treated with methotrexate (MTX). Analysis of the DHFR gene amplification process shows that the amplicon exhibits a complex structure that is consistently reproduced in independent treatments. The cytogenetic manifestation of the amplification in advanced stages of the treatment may be in the form of double minutes or as a homogeneously stained region. To get insights into the mechanisms of resistance, we have also investigated the sensitization to MTX of MTX-resistant cells after drug withdrawal and reexposure to MTX. Passive loss of the DHFR amplicon by withdrawal of the drug results in MTX-sensitive cells exhibiting a substantial reduction of their capacity or even an incapacity to generate resistance when submitted to a second cycle of MTX treatment. On a second round of drug administration, the resistant cells generate a different amplicon structure, suggesting that the formation of the amplicon as in the first cycle of treatment is not feasible. These results indicate that DHFR gene amplification is a “wear and tear” process in HT29 cells and that MTX-resistant cells may become responsive to a second round of treatment if left untreated during a sufficient period of time. [Mol Cancer Ther 2009;8(2):424–32]
Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy
Authors: Kim Young H. , Choi Beom K. , Oh Ho S. , Kang Woo J. , Mittler Robert S. , Kwon Byoung S. 
Published: February 2009

AbstractChemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8+ T cells, the 4-1BB–dependent expansion and differentiation of which into IFN-γ–producing CD11c+CD8+ T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced ∼60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8+ T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs. [Mol Cancer Ther 2009;8(2):469–78
Encoding Emotions in Speech with the Size Code
Authors: Chuenwattanapranithi Suthathip , Xu Yi , Thipakorn Bundit , Maneewongvatana Songrit 
Published: February 2009

Abstract
Our current understanding of how emotions are expressed in speech is still very limited. Part of the difficulty has been the lack of understanding of the underlying mechanisms. Here we report the findings of a somewhat unconventional investigation of emotional speech. Instead of looking for direct acoustic correlates of multiple emotions, we tested a specific theory, the size code hypothesis of emotional speech, about two emotions – anger and happiness. According to the hypothesis, anger and happiness are conveyed in speech by exaggerating or understating the body size of the speaker. In two studies consisting of six experiments, we synthesized vowels with a three-dimensional articulatory synthesizer with parameter manipulations derived from the size code hypothesis, and asked Thai listeners to judge the body size and emotion of the speaker. Vowels synthesized with a longer vocal tract and lower F0 were mostly heard as from a larger person if the length and F0 differences were stationary, but from an angry person if the vocal tract was dynamically lengthened and F0 was dynamically lowered. The opposite was true for the perception of small body size and happiness. These results provide preliminary support for the size code hypothesis. They also point to potential benefits of theory-driven investigations in emotion research.
A Lagged Warm Event–Like Response to Peaks in Solar Forcing in the Pacific Region
Authors: Meehl Gerald A. , Arblaster Julie M. 
Published: February 2009

AbstractThe forced response coincident with peaks in the 11-yr decadal solar oscillation (DSO) has been shown to resemble a cold event or La Niña–like pattern during December–February (DJF) in the Pacific region in observations and two global coupled climate models. Previous studies with filtered observational and model data have indicated that there could be a lagged warm event or El Niño–like response following the peaks in the DSO forcing by a few years. Here, observations and two climate model simulations are examined, and it is shown that dynamical coupled processes initiated by the response in the tropical Pacific to peaks in solar forcing produce wind-forced ocean Rossby waves near 5°N and 5°S. These reflect off the western boundary, producing downwelling equatorial Kelvin waves that contribute to transitioning the tropical Pacific to a warm event or El Niño–like pattern that lags the peaks in solar forcing by a few years.
New Altimetric Estimates of Mode-1 M2 Internal Tides in the Central North Pacific Ocean
Authors: Zhao Zhongxiang , Alford Matthew H. 
Published: February 2009

AbstractNew estimates of mode-1 M2 internal tide energy flux are computed from an extended Ocean Topography Experiment (TOPEX)/Poseidon (T/P) altimeter dataset that includes both the original and tandem tracks, improving spatial resolution over previous estimates from O(500 km) to O(250 km). Additionally, a new technique is developed that allows separate resolution of northward and southward components. Half-wavelength features previously seen in unseparated estimates are shown to be due to the superposition of northward and southward wave trains. The new technique and higher spatial resolution afford a new view of mode-1 M2 internal tides in the central North Pacific Ocean. As with all altimetric estimates, only the coherent or phase-locked signals are detectable owing to the long repeat period of the tracks. Emanating from specific generation sites consistent with predictions from numerical models, internal tidal beams 1) are as narrow as 200 km and 2) propagate a longer distance than previously observed. Two northward internal tidal beams radiating from the Hawaiian Ridge, previously obscured by coarse resolution and the southward Aleutian beam, are now seen to propagate more than 3500 km across the North Pacific Ocean to reach the Alaskan shelf. The internal tidal beams are much better resolved than in previous studies, resulting in better agreement with moored flux estimates.
Programs, materials and techniques
Authors: Brown Virginia L. 
Published: February 2009

Interest in word analysis tests and techniques is widespread in the field of learning disabilities. Yet, the role that word analysis, as it is commonly considered, plays in learning to read is still ambiguous. Because of the controversial nature of this topic, this month's column presents a detailed, critical review of the Sipay Word Analysis Tests (SWAT). SWAT is an individually administered series of phonic-related tests designed to reinforce the basis for the development of remedial programs. Also included in this column are briefer descriptions of several programs, techniques, and materials of potential value to learning disabilities personnel and to parents. The Peabody Articulation Decks are a set of 10-card decks to be used with speech, language, classification, and association activities. Essentially a guide to organization, Planning Curriculum Development will appeal to persons charged with the design and implementation of curriculum projects. Teaching Interpersonal Social Skills is a notebook developed under Title III in San Diego County. It contains group problem-solving activities and individual behavior control techniques. Northcott's Curriculum Guide for young, hearing impaired children is recommended for some of the techniques and materials suggestions useful for the learning disabled student. Of interest to those who teach adolescents and young adults will be The Big-New-Mother Mind-Boggling Behavior Expander to teach the principles and applications of behavior modification. And finally, The Whole Kids Catalog for Adventure Seekers of All Ages is highly recommended. It includes several suggestions for special use with students labeled learning disabled.
Programs, materials, and techniques
Authors: Van Etten Carlene , Watson Bill 
Published: February 2009

High school counselors expend much effort assisting students in planning for their futures. Teachers present career and vocational units, take students on field trips, bring in guest speakers, and provide reading material about various occupations. When the pupil who is considering career planning also has a learning disability, the teacher and counselor must even more carefully plot exploration of possible jobs — in the elementary school curriculum as well as at the secondary level. Part of our efforts should also be directed toward earlier introduction of vocational information into the school curriculum. The last few years have, in fact, seen a move toward earlier introduction of career awareness activities and exploration of the world of work. This development seems a positive step in the direction of lessening the “I graduate in May, what am I going to do now?” problem. This column does not attempt to address itself to the current issue of whether the major emphasis in secondary programming should be on basic skills, with career education as a subunit, or on a career education as the primary teaching goal. We do feel, however, that career awareness must be at least a part of the total curriculum for the learning disabled student. Further, many varied, and careful opportunities for exploring career possibilities will more likely result in job selections which will minimize the effect of various learning disabilities in individual students. We have included examples of career awareness, career exploration, and planning materials. Materials for young children are reviewed here, as well as materials suitable for secondary programming. We have also included materials in a variety of formats. — C.V.E., B.W.