bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract SY09-02: Molecular mechanisms in prostate cancer in African Americans
Authors: Li Yirong , Zhang David , Ren Qinghu , Ye Fei , Daniels Garrett , Wu Xinyu , Osman Iman , Melamed Jonathan , Dynlacht Brian , Lee Peng
Published: August 2012

African American men have long been known to have the highest rates of prostate cancer (PCa) in the world. In addition, age adjusted mortality rates from PCa patients are two times worse among African Americans (AA) than Caucasians (CA). The reasons for the disparity in PCa risk, incidence, clinical progression, and disease-specific death are still controversial. In addition to socioeconomic and environmental factors, such as diet, access to care, and screenings, a biologically more aggressive cancer is proposed as one important explanation for the racial disparity observed in AA men. Androgens and the androgen receptor pathway are well established key regulators of aggressive PCa behavior.

Using a novel proteomic pathway analysis comparing the distinct signal pathway and network proteins different between AA and CA PCa, we identified a number of markers including stem/progenitor cell and EMT related proteins that are overexpressed in PCa among AA. Our ongoing study indicates a novel link among Notch, WNT and androgen receptor (AR) pathways.

In contrast to increase in epithelial AR, our data revealed a decrease in the expression of the stromal AR in AA PCa compared to CA PCa. Androgen and its receptor inhibit proliferation of prostate stromal cells through transcriptional suppression of cyclin B1. Mechanistically, the negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR negative stromal cells or AR positive stromal cells under androgen depleted condition. Upon stimulation with androgen in AR positive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to recruitment of the SMRT/HDAC3 co-repressor complex and repression of cyclin B1. Furthermore, the switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as cytoplasm to nucleus translocation of E2F4.

In summary, our study revealed an association between distinct epithelial and stromal AR expression and PCa racial disparity as well as the molecular mechanism involved in regulating AR expression in epithelial and stromal prostate cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY09-02. doi:1538-7445.AM2012-SY09-02
Abstract SY10-03: Cell of origin in pediatric medulloblastomas
Authors: Kawauchi Daisuke , Robinson Giles , Uziel Tamar , Elisson David W. , Gilbertson Richard J. , Roussel Martine F.
Published: August 2012

Medulloblastoma is the most common malignant brain tumor in children with a median age of 3 to 7 years old. Human medulloblastomas are molecularly classified into four major subgroups including two with constitutive activation of developmental signaling pathways Sonic Hedgehog/Patched defining the SHH-subgroup and Wnt for the WNT-subgroup, subgroup 3 with amplification or overexpression of c-MYC and subgroup 4 with as yet undefined genetic anomalies. To date, all medulloblastomas regardless of their subgroup are treated with the same therapeutic regimen with different outcome. If children with WNT-subgroup tumors fair well, those with subgroup 3 medulloblastoma, the most aggressive form of the disease have a dismal prognosis.

Most mouse models of medulloblastoma developed to date mimic the human SHH-subgroup. However, we recently developed two new mouse models that faithfully recapitulate the human WNT-subgroup and subgroup 3 (MYC). The SHH-subgroup and subgroup 3 medulloblastomas were derived from cerebellar granule progenitors in the external granule layer which sustain mutations in the SHH pathway associated with MYCN overexpression, or C-MYC amplification, respectively. In contrast, the WNT-subgroup medulloblastoma with mutations in β-Catenin originate from the lower rhombic lip, the germinal neuroepithelium surrounding the floor of the 4th ventricle, suggesting that each subgroup may originate from specific neuronal precursors within the developing cerebellum.

Mouse subgroup 3 medulloblastomas, but not SHH- or WNT-subgroup tumors can be passaged indefinitely as neurospheres that express markers characterizing stem cells, including Lgr5, Oct4, Nanog, and Sox2 and induce secondary medulloblastomas with similar characteristics as the primary tumors, after orthotopic transplant into the cortices of recipient mice.

These novel medulloblastoma mouse models should significantly advance our efforts to develop new therapeutic modalities for this deadly childhood cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY10-03. doi:1538-7445.AM2012-SY10-03
Abstract SY12-02: Epstein-Barr virus (EBV) and cancer: Opportunities for etiologic research and prevention
Authors: Hildesheim Allan
Published: August 2012

Infections are known to cause approximately one in every five cancers. Helicobacter pylori (H. pylori), human papillomavirus (HPV), and hepatitis (B & C) infections each account for approximately 5% of cancers each year. Understanding the role of these infections in cancer etiology has led to numerous promising approaches to primary and secondary prevention, including prophylactic vaccination (HPV & HBV), screening (HPV), and treatment (H. pylori & HCV). EBV is a ubiquitous infection that establishes lifelong latency. Infection with EBV has been shown to be linked to the development of a subset of various forms of lymphoma, nasopharyngeal carcinomas, salivary gland cancers, and gastric cancers, totaling approximately 200,000 new cases each year worldwide. In addition, in countries where first infection with EBV tends to occur in late childhood or early adulthood, EBV is responsible for infectious mononucleosis (150,000 cases per year in the US alone), a condition that is typically benign but associated with prolonged morbidity. Despite our knowledge that EBV is associated with the development of various cancers, little attention has been placed to date on potential measures to prevent diseases associated with this common infection. In this presentation, our understanding of the link between EBV infection and cancer is summarized, and the potential for applying our knowledge to cancer prevention efforts discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY12-02. doi:1538-7445.AM2012-SY12-02
Abstract SY13-02: In vivo cancer theranostics
Authors: Pomper Martin G.
Published: August 2012

A theranostic agent enables diagnosis and treatment concurrently. Although a relatively new concept to pharmaceutics, theranostics have been used in nuclear medicine for over 50 years - dating back to the iodine-131 thyroid scan. Today we most frequently associate theranostics with nanotechnology since nanomedicines tend to present an appropriate platform for complex, multifunctional capability such as simultaneous or sequential imaging and therapy. Unlike low molecular weight agents, nanomedicines can carry sufficient information to enable local control of imaging and therapeutic species. But not all theranostics are nanomedicines - they may also be multifunctional genes or suitably functionalized small molecules or serve as biomarkers themselves. Introduction to theranostics with examples of existing and emerging theranostic agents as well as their clinical potential and application will be discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY13-02. doi:1538-7445.AM2012-SY13-02
Abstract SY13-03: Molecular imaging for advanced practice in oncology
Authors: Larson Steven M.
Published: August 2012

Positron Emission Tomography (PET) with 2-flouro-2-D-oxyglucose (FDG) has been the poster child for MI and several million studies are performed for oncology indications in the US alone. FDG takes advantage of the Warburg effect, which is the aerobic glycolysis that is a common feature of many malignant tumors. The incorporation of high resolution CT into the same gantry with a high resolution PET scanner, has given a further boost to PET imaging of tumors and in fact, PET CT is the most rapidly growing clinical imaging modality in the US today. Tumors for which staging, monitoring treatment response are common place include, Lung, Lymphoma, Thyroid, head and neck, melanoma, colorectal cancers.

But MI with PET/CT is potentially much more than FDG PET imaging, and several 100 tracers for specific molecular imaging have been developed in the last decade. Examples include amino acid tracers, like F-18 FACBC, nucleoside analogs, like F-18 FLT, and Na 124I to imaging iodide metabolism, Androgen receptor imaging (AR) with F-18 FDHT, and Estrogen receptor imaging with F-18 FES. In addition to small molecules, positron emitting tracers like 124I-, 68 Ga and 89 Zr are widely used for radiolabeling of antibodies and peptides, opening the entire universe of ligand receptor binding for human tumors. Radiolabeled drugs are being developed and examples include F-18 desatinib, a src family tyrosine kinase inhibitor and 124I-PUH71, a heat-shock protein 90 inhibitor. These radiolabeled drugs should facilitate the study of intratumoral pharmacology of human cancers. In addition radiolabeled nanoparticles are being developed and promise specialized targeting properties, and to serve as carriers for drugs to improve therapeutic index. In summary, MI with PET is rapidly evolving as a major frontier for development of the knowledge of tumor biology and pharmacology needed to optimize treatment of the individual oncology patient.

References

Schoder H, Grimm J and Larson SM: Molecular Imaging Section 6 in DeVita VT Lawrence TS and Rosenberg SA: Cancer Principles and Practice of Oncology 8th Edition Volume 1 p 746

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY13-03. doi:1538-7445.AM2012-SY13-03
Abstract SY14-02: p53-mediated senescence impairs the apoptotic response to chemotherapy in breast cancer
Authors: Lozano Guillermina , Jackson James G.
Published: August 2012

Studies on the role of p53 mutation in human breast cancer response to chemotherapy are controversial. Using MMTV-Wnt1 murine breast tumor model, we show that tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin treated p53-mutant tumors failed to arrest proliferation leading to abnormal mitoses and cell death, while p53 wild-type tumors underwent arrest and senescence with expression of senescence-associated cytokines that led to autocrine/paracrine activity and mitogenic potential. Wild-type p53 could still mediate arrest and inhibit drug response even in the context of a heterozygous p53 point mutation or absence of p21. Thus, we show wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY14-02. doi:1538-7445.AM2012-SY14-02
Abstract SY17-01: Intratumor diversity in breast cancer
Authors: Polyak Kornelia
Published: August 2012

Tumor heterogeneity is a major challenge toward understanding and clinical management of cancers. Intratumor diversity for hereditary traits is the diver of tumor evolution including disease progression and therapeutic resistance. We have been investigating intratumor genetic and phenotypic heterogeneity during breast tumor progression and treatment. We found high degree of genetic and phenotypic heterogeneity within and between distant metastases of the same patient. The degree of intratumor heterogeneity was influenced by treatment and it was associated with clinical characteristics. We also characterized the dependency of distinct cell populations in human breast tumors on specific genes and signaling pathways by performing a large-scale loss-of-function screen. Using this approach, we identified genes required for cell growth or proliferation in specific subsets of breast cancer cells. Our results highlight the differences between distinct breast cancer cell types and identify cell type-specific targets that may lead to more effective breast cancer therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY17-01. doi:1538-7445.AM2012-SY17-01
Abstract SY18-01: Hypoxia, metabolism, and tumor progression
Authors: Simon M. Celeste
Published: August 2012

Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- cells deprived of serum lipids undergo mTORC1-dependent apoptosis associated with elevated reactive oxygen species (ROS), a persistent unfolded protein response (UPR), and a failure to fully activate autophagy. Of note, UPR activation and cell death can be reversed by the addition of unsaturated fatty acids or ROS inhibitors. Our data suggest that cancer cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance protein and lipid synthesis due to a critical limitation in desaturated fatty acids.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY18-01. doi:1538-7445.AM2012-SY18-01
Abstract SY19-01: Integrating proteomic, transcriptional, epigenomic, and interactome data reveals the signaling changes induced by oncogenic mutations
Authors: Fraenkel Ernest
Published: August 2012

Proteomic technologies, next-generation sequencing and RNAi screens are providing increasingly detailed descriptions of the molecular changes that occur in diseases. However, it is difficult to assemble these data into a coherent picture that could lead to new therapeutic insights for several reasons. Despite their power, each of these methods still only captures a small fraction of the cellular response. Moreover, when different assays are applied to the same problem, they often provide apparently conflicting answers. We have developed powerful new approaches to integrate these data to identify small, functionally coherent pathways that underlie cellular behavior. In this talk, I will demonstrate how these methods can be applied to understand how oncogenic mutations alter signaling and transcription.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY19-01. doi:1538-7445.AM2012-SY19-01
Abstract SY19-02: Novel models and treatments targeting the HER-AKT pathway in cancers that overexpress HER2
Authors: Itani Soulaiman , Korkola James , Gray Joe , Tomlin Claire
Published: August 2012

Dynamic treatments targeting the HER-AKT pathway in cancers that overexpress HER2 Soulaiman Itani*, James Korkola**, Joe Gray**, Claire Tomlin* The mixed performance of TKI treatment for HER2-amplified breast cancers has inspired further research of the HER-PI3K signaling pathway. This in turn has produced new insight into the feedback that allows this pathway to survive the inhibition of HER2, and the role of additional mutations in the pathway. Based on this insight, we created an Ordinary Differential Equation (ODE) model for the pathway. The model was based on mass action kinetics, catalytic, and Michaelis-Menten models of chemical reactions, and was able to give several correct predictions about the response of different cell lines to overstimulation, their sensitivity to treatment, and their basal activity levels. The modeling also emphasized the importance of dynamic treatments, where the dosing and mixture of the drugs changes over time to drive the cancer first to susceptible states and then to death. Dynamic treatments are inspired by the steering of dynamic systems: To make a wide left turn, you go right first. Our novel dynamic treatment scheme was designed, tested, and was shown in experiment to increase the apoptosis of HER2 amplified cancers from 11% to 50%. The experiments tested the treatment on five cell lines, SKBR3, BT747, HCC1954, JIMT1, and MDAMB361. The cell lines were serum starved, then pretreated for two days with a drug that activates AKT, and then treated with Lapatinib. The pretreatment increased the efficacy of Lapatinib, which is nonintuitive since these drugs have opposite effects on AKT. Dynamic treatments focus on the idea of using the cancer's strongest asset, its adaptability, against it. *UC Berkeley **Oregon Health and Science University

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY19-02. doi:1538-7445.AM2012-SY19-02
Abstract SY22-02: Mammalian functional genetic signatures identify efficacy landscapes of combination chemotherapy
Authors: Lauffenburger Douglas A. , Pritchard Justin R. , Hemann Michael T.
Published: August 2012

Many current cancer treatments involve the administration of multi-drug regimens. However, no clear consensus exists to explain how drugs interact to create combinatorial effects. Here we will describe recent studies using RNAi-based functional signatures in mammalian cells to test specific hypotheses underlying combination drug mechanisms. We find that while potently synergistic drug combinations reinforce the cytotoxic action of one component in a manner that highlights drug-specific genetic dependencies, clinically used multi-drug regimens minimize the effect of genetic diversity and thus homogenize response across distinct subpopulations. We confirmed this finding in spontaneously arising lymphomas, where standard combination therapy reduced the variation in drug response between different tumors. Thus, we suggest that commonly used chemotherapeutic drug combinations are intrinsically “de-personalized” and function by homogenizing therapeutic response across randomized patient cohorts.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY22-02. doi:1538-7445.AM2012-SY22-02
Abstract SY23-01: Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues
Authors: Shibata Yoshiyuki , Kumar Pankaj , Layer Ryan , Willcox Smaranda , Gagan Jeffrey R. , Griffith Jack D. , Dutta Anindya
Published: August 2012

DNA in normal mammalian somatic cells is either in long chromosomes or in mitochondria. Furthermore, other than in specialized tissues like B and T cells, the genomic DNA in normal tissues is usually considered to be an exact copy of germ-line DNA. We hypothesized that errors in DNA replication may lead to the production of extra-chromosomal DNA and/or changes in copy number of segments of the DNA in normal somatic tissue. We have identified tens of thousands of short double-stranded and single-stranded extrachromosomal circular DNA (microDNA) that are derived from unique, non-repetitive sequences of chromosomes in normal mouse brain, heart and liver as well as mouse and human cell lines. MicroDNAs are 200-400 bases long and high in GC content. Short direct repeats are often present at the start and end of the corresponding chromosomal sequence suggesting that microDNAs are produced by replication slippage, homologous recombination or microhomology mediated repair. Several of the microDNAs overlap with nucleosome-occupied DNA, explaining how such short double-stranded DNA can be bent into a circle. The genomic sources of the microDNAs are enriched in the 5′ region of genes, exons and CpG islands. Ultrahighthroughput sequencing of adult brain DNA targeted to chromosomal loci that are enriched sources of microDNA, reveals a small fraction of genomic DNA molecules with micro-deletions that may be generated by the excision of microDNAs. We have thus identified a new DNA entity in somatic cells and provide evidence that deletions may occur in different genomic loci in somatic tissues, leading to genetic variability between normal somatic cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY23-01. doi:1538-7445.AM2012-SY23-01
Abstract SY27-01: Cutting both ways: Why FADD, FLIP, and Caspase-8 are required for embryonic development
Authors: Green Douglas R.
Published: August 2012

Caspase-8 has two opposing biological functions - it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T lymphocyte activation, and resistance to necrosis induced by Tumor Necrosis Factor-α (TNF) and related family ligands. We found that development of caspase-8-deficient mice is completely rescued by ablation of Receptor Interacting Protein Kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand, and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-Like Inhibitory Protein Long (FLIPL), and this complex is required for the protective function.

Caspase-8 homodimers and caspase-8-FLIP heterodimers are activated on the oligomerized adapter molecule, FADD. Therefore, while the FADD-caspase-8-FLIP complex protects against RIPK3-dependent necrosis, the FADD-caspase-8 complex does not, and necrosis ensues. In the absence of RIPK3, FADD-caspase-8 instead induces apoptosis. This idea has several ramifications. Knock-outs of FADD, or FLIP show identical embryonic lethality, but while the FADD KO is fully rescued by ablation of RIPK3, the FLIP KO is not. Our in vitro studies suggest that in the FLIP, RIPK3 DKO mouse, sensitive cell populations die by apoptosis rather than necrosis. Indeed, we found that unlike caspase-8 or FADD KO embryos, FLIP RIPK3 DKO embryos at e9.5 show focal regions of apoptosis.

Another prediction from the in vitro studies is even more striking_that lethality in the FLIP RIPK3 DKO mouse should be rescued by ablation of FADD. We have now generated the FADD FLIP RIPK3 TKO mouse, and these animals are developmentally normal. In addition to providing strong genetic evidence for a model of FADD-caspase-8-FLIP interaction with RIPK1-RIPK3, these studies involve an effect that has not been previously seen to our knowledge_two lethal genotypes (one KO, one DKO) when combined into a TKO, result in normal development. We think that's pretty cool.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY27-01. doi:1538-7445.AM2012-SY27-01
Abstract SY27-04: The signaling pathway of necrosome
Authors: Wang Xiaodong
Published: August 2012

Understanding Cell Death Xiaodong Wang, Ph.D. National Institute of Biological Sciences, Beijing Programmed cell death is a critical part of normal being in metazoan animals. Program cell death happens in two forms, apoptosis and necrosis. Apoptotic death is executed by a group of intracellular cysteine proteases, caspases, which are activated by apoptosis trigger. In contrast to apoptosis, the molecular mechanism of necrosis execution is poorly understood. Our laboratory has been using necrosis induced by TNF-α to study the biochemical pathway of necrosis. The programmed necrosis induced by TNF-α family of cytokines requires the activities of the receptor interacting serine-threonine kinases RIP1 and RIP3. Such form of cell death has now recognized to have important roles in animal development, tissue damage response, and innate immunity against microbes. How RIP kinases cause cell death is not known. In this meeting, I plan to discuss our recent progress in dissecting the molecular pathway downstream of RIP3 activation using a combination of tools from chemical biology, biochemistry and live cell imaging. We are able to map a necrotic pathway with discrete biochemical steps leading to the characteristic changes associated with necrosis. Moreover, we have identified a necrosis execution step that seems to be the convergent point of multiple necrosis pathways including necrosis induced by reactive oxygen species (ROS) and calcium overload.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY27-04. doi:1538-7445.AM2012-SY27-04
Abstract SY28-04: Targeting the tumor extracellular matrix with armed antibodies
Authors: Neri Dario
Published: August 2012

Antibodies can be used to deliver bioactive molecules (drugs, cytokines, photosensitizers, radionuclides, etc.) to the tumor environment, thus sparing normal tissues.

The targeting of modified sub-endothelial extracellular matrix components using armed antibodies is particularly attractive, because of:

(i) the abundance and stability of some of these antigens (e.g., splice isoforms of fibronectin and tenascin-C); (ii) the dependence of cancer on new blood vessels (iii) accessibility of these structures from the blood-stream (iv) the fact that some of these antigens are very aboundant in many different cancer types, while being virtually undetectable in most normal adult tissues.

Advanced preclinical and clinical data on armed antibodies will be presented in this lecture.

References:

Neri & Bicknell (2005) Nature Rev. Cancer, 5: 436-446

Neri & Supuran (2011) Nature Rev. Drug Discov.: 10: 767-777

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY28-04. doi:1538-7445.AM2012-SY28-04
Abstract SY29-01: mTOR, metabolism, and cell growth control
Authors: Blenis John , Csibi Alfredo , Kim Sang Gyun , Choo Andrew , Buel Gwen , Jang Young Jin , Hoffman Gregory
Published: August 2012

The mTOR complex 1 (mTORC1) is a ser/thr protein kinase complex and critical regulator of cellular metabolism, protein synthesis, autophagy and cell growth. This signaling system is normally carefully controlled by the integration of inputs from growth factors, nutrients, cellular energy status, oxygen availability and stress. A variety of loss-of-function or gain-of-function alterations in key mTORC1 regulatory proteins, very often results in inappropriate regulation of this signaling system. Uncontrolled mTORC1 activation contributes on its own or in combination with other pathways to metabolic diseases ranging from diabetes and obesity, cardiac hypertrophy, neurodegeneration, aging, benign tumor syndromes to highly malignant cancers. Mechanistically, uncontrolled mTORC1 activation leads to a constant positive input into anabolic processes and suppression of many catabolic processes. As a result, these cells require increased energy and carbon sources to meet their high metabolic needs for cell growth. To meet this demand, we have found in cells that are PTEN or TSC1/2 null, that activated mTORC1 uses distinct mechanisms to increase glutamine consumption (glutaminolysis) by elevating the expression of glutaminase and the activity of glutamate dehydrogenase. Furthermore, under nutrient-rich conditions, these tumor cells sense the increased energy production and in a positive feedback loop, promote more mTORC1 assembly via an AMP kinase (AMPK)-dependent, and a novel AMPK-independent mechanism. This acquired addiction to glutamine provides a novel therapeutic strategy for treating patients with activated mTORC1. Indeed, by acutely blocking the ability of energetically stressed cells with hyperactive mTORC1 to metabolize glutamine, we can selectively kill some tumor cells without damaging normal cells. We anticipate that these studies will lead to the development of “synthetic-lethal” drugs useful in the treatment of patients with diseases linked to inappropriate activation of mTORC1. Research supported by NIH RO1-GM51405 and the LAM Foundation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY29-01. doi:1538-7445.AM2012-SY29-01
Abstract SY31-03: Inflammatory mechanisms of cancer-related fatigue
Authors: Bower Julienne
Published: August 2012

Fatigue is one of the most common and disabling side effects of cancer treatment and may persist for months or years after successful treatment completion, causing significant impairment in quality of life. Basic research on neural-immune signaling has demonstrated that proinflammatory cytokines signal the central nervous system to trigger a constellation of behavioral changes that include fatigue as well depression, sleep disturbance, and cognitive impairment. This presentation will review the evidence linking proinflammatory cytokines and fatigue in cancer patients and survivors. In addition, we will consider host factors that influence inflammation and associated symptoms of fatigue, focusing on genetic mechanisms. There is considerable variability in the experience of post-treatment fatigue that cannot be explained by treatment exposure, suggesting that host factors play an important role in symptom severity and persistence. Single nucleotide polymorphisms (SNPs) that influence quantitative gene expression have been identified in the promoter regions of several genes that encode proinflammatory cytokines and examined individually in relation to breast cancer susceptibility and prognosis as well as behavioral symptoms. Here, we will present findings linking SNPs in the promoter regions of three proinflammatory cytokine genes (IL-1β -511 C>T (rs16944), IL6 -174 G>C (rs1800795), and TNF -308 G>A (rs1800629)) to fatigue in breast cancer survivors. Further, we will consider how alterations in glucocorticoid signaling pathways may contribute to persistent cancer-related fatigue.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-03. doi:1538-7445.AM2012-SY31-03
Abstract SY31-04: Impact of cytokines on neurocircuits relevant to anxiety, depression, and fatigue in cancer patients
Authors: Miller Andrew
Published: August 2012

Clues have been revealed regarding the brain regions that may be targeted by cytokines to change behavior and cognition. Mounting data indicate that activation of the inflammatory response and the release of inflammatory cytokines can lead to changes in behavior including depression, anxiety, fatigue and cognitive dysfunction. Given the association of immune system activation with a host of medical illnesses including cancer, such cytokine-induced behavioral changes may contribute to the high rate of depression, anxiety, fatigue and other behavioral alterations observed in cancer patients. Using the anti-viral cytokine, interferon (IFN)-alpha, work by our group and others has demonstrated that cytokines can access the brain and alter the function of the basal ganglia as measured by brain imaging techniques including both functional magnetic resonance imaging (fMRI) and positron emission tomography as well as in vivo microdialysis in non-human primates. The basal ganglia are key brain structures involved in the regulation of motor activity and motivation. Cytokine-induced alterations in basal ganglia function in turn have been associated with motor slowing and fatigue and appear to involve fundamental alterations in presynaptic dopamine function. In addition, cytokines appear to activate areas of the brain including the dorsal anterior cingulate cortex that are triggered in behavioral states of anxiety, arousal and alarm. Thus, the constellation of effects of cytokines on the brain includes the inhibition of brain circuits involved in exploratory behavior in addition to the activation of circuits that lead to a sense of danger. Taken together, these cytokine effects on behavior and cognition may subserve competing evolutionary survival priorities during infection and/or wounding to conserve energy resources for fighting pathogens while at the same time increasing vigilance against predators who may attack during states of vulnerability. Chronic or excessive inflammation and activation of these brain circuits during illnesses such as cancer, however, may lead to the development of behavioral pathologies in vulnerable individuals. Such behavioral alterations may be uniquely targeted by therapies focused on the immune system.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-04. doi:1538-7445.AM2012-SY31-04
Mirror-Image Asymmetry in Monozygotic Twins with Kabuki Syndrome
Authors: Riess A. , Dufke A. , Riess O. , Beck-Woedl S. , Fode B. , Skladny H. , Klaes R. , Tzschach A.
Published: August 2012

Kabuki syndrome (OMIM 147920) is a rare disorder characterised by moderate intellectual disability, growth retardation, microcephaly and characteristic facial dysmorphic features which comprise long palpebral fissures, eversion of the lateral third of the eyelids and arched eyebrows with lateral sparseness. Mutations in MLL2 are the most frequent cause of this disorder. More than 100 MLL2 point mutations have been reported, but large intragenic deletions comprising one or more exons have not yet been identified. We report on a pair of monozygotic twin brothers in whom a deletion of 2 neighbouring exons was detected. The twins had the characteristic facial features of Kabuki syndrome, and they suffered from microcephaly, cleft lip and palate and congenital heart disease. Cleft lip and palate were left-sided in the first twin and right-sided in the second twin, i.e. they represented a mirror-image asymmetry. The intragenic deletion in these brothers broadens the spectrum of MLL2 mutations, and they provide a rare example of mirror-image asymmetry of congenital malformations in monozygotic twins.
5q31 Microdeletions: Definition of a Critical Region and Analysis of LRRTM2, a Candidate Gene for Intellectual Disability
Authors: Kleffmann W. , Zink A.M. , Lee J.A. , Senderek J. , Mangold E. , Moog U. , Rappold G.A. , Wohlleber E. , Engels H.
Published: August 2012

Microdeletions including 5q31 have been reported in only few patients to date. Apart from intellectual disability/developmental delay (ID/DD) of varying degrees, which is common to all reported patients, the clinical spectrum is wide and includes short stature, failure to thrive, congenital heart defects, encephalopathies, and dysmorphic features. We report a patient with a 0.9-Mb de novo deletion in 5q31.2, the smallest microdeletion in 5q31 reported thus far. His clinical presentation includes mild DD, borderline short stature, postnatal microcephaly, and mild dysmorphic signs including microretrognathia. Together with data from 7 reported overlapping microdeletions, analysis of our patient enabled the tentative delineation of a phenotype map for 5q31 deletions. In contrast to the mild phenotype of small microdeletions affecting only 5q31.2, carriers of larger microdeletions which also include subbands 5q31.1 and/or 5q31.3 seem to be more severely affected with congenital malformations, growth anomalies, and severe encephalopathies. A 240-kb smallest region of overlap in 5q31.2 is delineated which contains only 2 genes, CTNNA1 and LRRTM2. We propose LRRTM2 as the most promising candidate gene for ID/DD due to its expression pattern, function as a key regulator of excitatory development, and interaction with Neurexin 1. However, sequence analysis of LRRTM2 in 330 patients with ID/DD revealed no relevant alterations, excluding point mutations in LRRTM2 as a frequent cause of ID/DD in patients without microdeletions.
Development and Validation of a Simplified Chinese Version of EORTC QLQ-CR38 to Measure the Quality of Life of Patients with Colorectal Cancer
Authors: Kong Danli , Yang Zheng , Wang Yajing , Meng Qiong , Tang Xueliang , Cun Yingli , Wan Chonghua
Published: August 2012

Objectives: This study aimed to develop and validate the simplified Chinese version of the EORTC Quality of Life Questionnaire for Colorectal Cancer, QLQ-CR38. Methods: It was developed by the strict translation procedure of EORTC translation guidelines, including translation, back translation, a pilot test and a cultural adaptation. Three instruments (QLQ-CR38, Quality of Life Instruments for Cancer Patients-Colorectal Cancer, and Functional Assessment of Cancer Therapy-Colorectal) were used on a sample of 110 patients with colorectal cancer at the time of their admission to the hospital and 1–2 days after hospitalization, and a subsample of patients was measured a third time at discharge. The psychometric properties were evaluated by correlational analysis, multi-trait scaling analysis, factor analysis, and t tests. Results: Multi-trait scaling analysis and correlation analysis among domains and items of the three instruments showed good construct validity and criterion-related validity. Cronbach’s α and the test-retest reliability coefficients were greater than 0.70 for all domains (except chemotherapy side effects, 0.44 and 0.60, respectively). All domains had statistically significant changes after treatment with the standardized response mean ranging from 0.44 to 2.47. Conclusions: The simplified Chinese version of QLQ-CR38 has good validity, reliability, and responsiveness and can be used to measure the quality of life of Chinese patients with colorectal cancer.
Identification and Characterization of the Sex-Determiner Transformer-2 Homologue in Chinese Shrimp, Fenneropenaeus chinensis
Authors: Li S. , Li F. , Wen R. , Xiang J.
Published: August 2012

The transformer-2 gene, encoding a protein (Tra-2) which directs sex-specifically alternative splicing of doublesex (dsx) pre-mRNA in combination with the transformer (Tra) protein, has been proved to play important roles on sex differentiation and sex development in Drosophila melanogaster. In the present study, a tra-2 homologue (FcTra-2) was cloned and characterized in the Chinese shrimp, Fenneropenaeus chinensis. A FcTra-2 genomic DNA sequence with a length of 8,871 bp was obtained and verified to consist of 7 exons and 6 introns. Three alternatively spliced mRNA transcripts, designated as FcTra-2a, FcTra-2b and FcTra-2c, were isolated and characterized. Sequence analysis showed that FcTra-2 included a RNA recognition motif and a linker region, which shared high sequence identities with Tra-2 from other species and 2 arginine/serine rich regions. Further studies were performed on the isoform FcTra-2c, since it exhibited a significantly higher expression level in ovary than in other tissues. In early developmental stages of the shrimp, FcTra-2c was detected to suddenly increase its expression level at the mysis stage. In juvenile stage, FcTra-2c displayed a significantly higher expression level in female Chinese shrimp than in males. These data indicated that FcTra-2 might be involved in female sex determination in Chinese shrimp.
Sex-Biased miRNA Expression in Atlantic Halibut (Hippoglossus hippoglossus) Brain and Gonads
Authors: Bizuayehu T.T. , Babiak J. , Norberg B. , Fernandes J.M.O. , Johansen S.D. , Babiak I.
Published: August 2012

The role of miRNA in fish sexual development is not elucidated yet. We profiled miRNAs in gonads and brains of Atlantic halibut using SOLiD sequencing technology. We found tissue- and sexually dimorphic expression of several miRNAs, including miR-29a, miR-34, miR-143, miR-145, miR-202-3p, miR-451, and miR-2188. miR-9 and miR-202 were abundant in brain and gonads, respectively. In the next step, we selected some miRNAs showing differential expression patterns between sexes and performed RT-qPCR on 3 age groups: juveniles, 3-year-, and 5-year-olds. In brains, miR-451 was significantly down-regulated in juveniles compared to adults. let-7a, miR-143, and miR-202-3p were up-regulated in gonads of mature males compared to immature females at the same age. We investigated the effect of suppressing aromatase cytochrome P450 enzyme on miRNA expression at the onset of sex differentiation through masculinization with Fadrozole or 17-α-methyltestosterone. We found significant differences in miRNA expression between masculinized individuals and untreated controls. miR-202-3p was significantly down-regulated in female juveniles compared to male juveniles. The expression levels of let-7a and miR-451 were restored after termination of the masculinization treatment. Our data give a first insight into miRNA involvement in sexual development in teleosts.
WRF-Fire: Coupled Weather–Wildland Fire Modeling with the Weather Research and Forecasting Model
Authors: Coen Janice L. , Cameron Marques , Michalakes John , Patton Edward G. , Riggan Philip J. , Yedinak Kara M.
Published: August 2012

A wildland fire-behavior module, named WRF-Fire, was integrated into the Weather Research and Forecasting (WRF) public domain numerical weather prediction model. The fire module is a surface fire-behavior model that is two-way coupled with the atmospheric model. Near-surface winds from the atmospheric model are interpolated to a finer fire grid and are used, with fuel properties and local terrain gradients, to determine the fire’s spread rate and direction. Fuel consumption releases sensible and latent heat fluxes into the atmospheric model’s lowest layers, driving boundary layer circulations. The atmospheric model, configured in turbulence-resolving large-eddy-simulation mode, was used to explore the sensitivity of simulated fire characteristics such as perimeter shape, fire intensity, and spread rate to external factors known to influence fires, such as fuel characteristics and wind speed, and to explain how these external parameters affect the overall fire properties. Through the use of theoretical environmental vertical profiles, a suite of experiments using conditions typical of the daytime convective boundary layer was conducted in which these external parameters were varied around a control experiment. Results showed that simulated fires evolved into the expected bowed shape because of fire–atmosphere feedbacks that control airflow in and near fires. The coupled model reproduced expected differences in fire shapes and heading-region fire intensity among grass, shrub, and forest-litter fuel types; reproduced the expected narrow, rapid spread in higher wind speeds; and reproduced the moderate inhibition of fire spread in higher fuel moistures. The effects of fuel load were more complex: higher fuel loads increased the heat flux and fire-plume strength and thus the inferred fire effects but had limited impact on spread rate.
A Study of the Impacts of Vertical Diffusion on the Structure and Intensity of the Tropical Cyclones Using the High-Resolution HWRF System
Authors: Gopalakrishnan Sundararaman G. , Marks Frank , Zhang Jun A. , Zhang Xuejin , Bao Jian-Wen , Tallapragada Vijay
Published: August 2012

The Hurricane Weather Research and Forecasting (HWRF) system was used in an idealized framework to gain a fundamental understanding of the variability in tropical cyclone (TC) structure and intensity prediction that may arise due to vertical diffusion. The modeling system uses the Medium-Range Forecast parameterization scheme. Flight-level data collected by a NOAA WP-3D research aircraft during the eyewall penetration of category 5 Hurricane Hugo (1989) at an altitude of about 450–500 m and Hurricane Allen (1980) were used as the basis to best match the modeled eddy diffusivities with wind speed. While reduction of the eddy diffusivity to a quarter of its original value produced the best match with the observations, such a reduction revealed a significant decrease in the height of the inflow layer as well which, in turn, drastically affected the size and intensity changes in the modeled TC. The cross-isobaric flow (inflow) was observed to be stronger with the decrease in the inflow depth. Stronger inflow not only increased the spin of the storm, enhancing the generalized Coriolis term in the equations of motion for tangential velocity, but also resulted in enhanced equivalent potential temperature in the boundary layer, a stronger and warmer core, and, subsequently, a stronger storm. More importantly, rapid acceleration of the inflow not only produced a stronger outflow at the top of the inflow layer, more consistent with observations, but also a smaller inner core that was less than half the size of the original.