bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY15-02: Constructing and deconstructing cancer using mouse models and RNAi
Authors: Lowe Scott W. 
Published: May 2019

Abstract
Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the inappropriate expansion of aberrantly proliferating cells. Such mutations can involve activation of oncogenes or inactivation of tumor-suppressor genes, each contributing one or more new capabilities to the developing cancer cell. However, cancer is not an inevitable consequence of oncogenic mutations; instead, cells acquiring such mutations can be eliminated or kept in check by innate tumor-suppressor programs that can be activated in these damaged cells. Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior. We previously showed that apoptosis and cellular senescence are potent barriers to oncogene-driven tumorigenesis and that each contributes to the antitumor action of many chemotherapeutic drugs. Thus, not only do mutations that disrupt apoptosis and senescence promote tumor progression but, depending on the particular lesion, they can also reduce the efficacy of cancer therapy. To facilitate our research, we have recently developed new mouse cancer models based on the genetic manipulation of stem and progenitor cells ex vivo followed by transplantation of the altered cells into the appropriate organ of syngeneic recipient mice. This approach allows us to rapidly study the impact of many genes and gene combinations on tumorigenesis in a “mosaic” setting where tumor-initiating cells are embedded in normal tissues. Furthermore, we have developed powerful methods for using RNAi to suppress gene function in vivo in either a stable and reversible manner. Current efforts in the laboratory strive to integrate mosaic mouse models, RNA interference, and cancer genomics to identify new components of tumor suppressor gene networks and characterize their impact on tumorigenesis and treatment response. In addition, we are developing new RNAi interference methods to explore the role of tumor suppressor genes in tumor maintenance, and the cell death mechanisms involved in tumor regression.
Citation Format: Scott W. Lowe. Constructing and deconstructing cancer using mouse models and RNAi [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-02
Abstract SY18-01: Targeting the p53-MDM2 interaction for cancer therapy
Authors: Vassilev Lyubomir T. 
Published: May 2019

Abstract
The p53 tumor suppressor is tightly controlled by MDM2 which binds p53 and negatively modulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may offer a novel approach to cancer therapy. Recently developed potent and selective small-molecule MDM2 antagonists, the nutlins, interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 with nutlins stabilized p53 and activated the p53 pathway.
Although half of human tumors retain wild-type p53, the function of the tumor suppressor could be compromised by defective signaling in the pathway. Using nutlin-3a to probe downstream p53 signaling we find that the cell cycle arrest function of p53 is preserved in all tested cancer cell lines expressing wild-type p53 but many have compromised ability to undergo p53-dependent apoptosis. The p53 transcription target and potent CDK inhibitor, p21, has been shown to inhibit the apoptotic response to genotoxic p53 activation. Although it is strongly upregulated by MDM2 antagonists in all tested cancer cell lines, p21 does not affect the apoptotic outcome of nutlin treatment, suggesting that it does not play anti-apoptotic role during non-genotoxic p53 activation. MDM2 controls p53 stability and activity through a feedback mechanism by which both proteins mutually regulate their cellular levels. Nutlins disrupt this regulatory circuit leading to upregulation of both p53 and MDM2. They selectively block the p53-MDM2 interaction but do not affect MDM2 E3 ligase activity that is elevated in the presence of the drug. MDMX, a known p53 inhibitor and MDM2 ubiqutination target decreased with the increase of MDM2, suggesting that MDM2 contributes to antitumor activity of nutlins at least in part by facilitating MDMX degradation. Elevated MDM2 contributes to the apoptotic outcome of nutlin treatment also by interfering with the maturation of subsets of microRNAs. Nutlin-3a doses that shrink xenograft tumors activated p53 signaling in mouse tissues but caused only mild changes in bone marrow, thymus and spleen. These results suggest that p53 activation by MDM2 antagonists may provide an acceptable safety window for cancer therapy. A member of the nutlin family of MDM2 antagonists is currently undergoing Ph I clinical testing in patients with solid and hematological malignancies.
Citation Format: Lyubomir T. Vassilev. Targeting the p53-MDM2 interaction for cancer therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY18-01
Abstract SY20-03: Novel radiotracers for clinical molecular imaging in oncology
Authors: Larson Steven M. 
Published: May 2019

Abstract
In cancer, molecular imaging (MI) can be thought of as imaging the key molecules and molecular based events that are fundamental to promoting and maintaining the malignant state. Although MI is multimodality, the focus of this discussion will be on the use of positron emitting radiotracers for Positron Emission Tomography (PET), an imaging methodogy that can bridge the divide between discovery in the laboratory and application in clinical medicine. Modern PET incorporates CT into the same gantry and as PET/CT has rapidly penetrated clinical oncology, providing improved tumor staging and the detection of recurrence.. F[18]-2-flouro-2-deoxy-D-glucose (FDG) and PET is being used to imaging more tha 1 million cancer patients per year in the US along. The biologic basis for the successful use of FDG-PET/CT is as follows. Many cancers exhibit a characteristic biochemical phenotype, which is altered in comparison to tissues from which the neoplasm originated. In particular, tumor tissues often exhibit the “Warburg Effect” which is an accelerated aerobic glyolysis. The reasons behind the Warburg effect are thought to relate to a need for carbon backbones for tumor growth, as well as to control.altered REDOX state within the cell. Other metabolic markers useful in functional imaging of cancer include radiolabeled nucleosides like [F-18]-Fluorothymidine (FLT) for proliferation, and radiolabeled amino acids, like [C-11] methionine for imaging amino acid transport. Molecular imaging in oncology is increasingly being applied for evaluation of treatment response,to radiation and chemotherapy, using FDG, FLT, and F-18 misonidazole (FMISO) a nitroimidazole which is taken up in hypoxic tissues. Molecular imaging is also applied clinically for drug discovery, and a large number of targeted agents have been radiolabeled and are being studied in man. At MSKCC our group has used PET imaging to study targeting at both a basic and clinical level with a variety of drugs and monoclonal antibodies, includine antibodyA33, which recognizes the epithelial marker A33, and antibody cG250 which recognizes carbonic anydrase IX, a marker of clear cell lung cancer and hypoxia. Finally, endocrine responsive maligancies form a fascinating group for which specific receptor directed agents, and natural substrates, may open a window on the biology of human disease including lesion by lesion heterogeneity. In this regard, [F-18]FDHT, an agent targeting androgen receptor, in prostate cancer and [I-124] NaI, for sodium iodide symporter in thyroid cancer, are giving new information about the behavior of human tumors studied in situ.
Citation Format: Steven M. Larson. Novel radiotracers for clinical molecular imaging in oncology [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY20-03
Abstract SY30-03: First impressions of the multiple myeloma genome
Authors: Golub Todd R. 
Published: May 2019

Abstract
Multiple myeloma is a malignancy of mature B-lymphoid cells whose pathogenesis remains obscure. To address this, we undertook a large-scale effort to characterize the genomes of multiple myleoma tumor samples and their matched normal DNAs. Funded by the Multiple Myeloma Research Foundation, this sequencing effort is one of the largest cancer genome sequencing projects completed to date, representing 29 patients (22 whole genomes and 17 whole exomes) sequenced to an average of 30X coverage. Improvements in mutation-calling algorithms yielded a mutation rate of ~ 10-6, with a mutation validation rate of 97%, indicating that the false-positive rate of mutations in this dataset is extremely low. Highlights of novel and biologically important findings from this dataset will be presented, and include: 1) mutations in the transcription factor IRF4; 2) mutations in histone methyltransferases; 3) mutations in genes involved in protein translation; 4) mutations in genes involved in blood coagulation; and 5) an activating mutation in BRAF, for which small-molecule inhibitors are in clinical development. These results suggest that sequencing of the multiple myeloma genome will provide new insights into the pathogenesis of multiple myeloma, and moreover suggest that while mutations in particular genes may be rare, they may result in the aberrant activity of common pathways. This in turn suggests that the sequencing of large numbers of cancer genomes may be required to develop a full understanding of the biological consequences of somatic mutations.
Citation Format: Todd R. Golub. First impressions of the multiple myeloma genome [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY30-03
Abstract SY31-04: Metabolic regulation of tumor cells survival
Authors: Mak Tak W. 
Published: May 2019

Abstract
Today's targeted therapeutics exert their anti-cancer effects mainly by blocking molecular signals that promote tumor cell proliferation, obstruct cell death, hamper cellular differentiation, or facilitate angiogenesis. However, the molecular pathways that underlie these cellular processes are multifaceted and often redundant, allowing tumor cells to escape these drugs. Another approach may be to target tumor cell metabolism. In the 1920s, Warburg noted that cancers exhibit increased rates of glycolysis even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the ‘Warburg effect’. The switch from oxidative phosphorylation to glycolysis that underlies the Warburg effeect represents an alteration to tumor cell metabolism that permits cancer cells to adapt and thrive in conditions that kill normal cells Such adaptations may include upregulated or altered molecular pathways to increase energy production, expansion of the cell's biosynthetic capacity, and/or adoption of an enhanced redox state to cope with elevated levels of deleterious reactive oxygen species. Understanding the energy sources and metabolic pathways utilized by cancer cells to survive should allow the exploitation of this knowledge to design more effective anti-cancer drugs.
Citation Format: Tak W. Mak. Metabolic regulation of tumor cells survival [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-04
Abstract 1599: Oral epithelium as a surrogate tissue for assessing smoking-induced molecular alterations in lungs
Authors: Bhutani Manisha , Pathak Ashutosh K , Fan You Hong , Liu Diane D , Lee J. Jack , Tang Hongli , Kurie Jonathan M , Morice Rodolfo C , Kim Edward S , Hong Waun K , Mao Li 
Published: May 2019

Abstract
Background: Because lungs and oral cavity are both exposed to tobacco-carcinogens, we hypothesized that the oral epithelium undergoes molecular alterations similar to those in other airway areas and therefore may be used as a surrogate tissue to assess tobacco-induced molecular alterations in lungs.
Methods: Promoter methylation of p16 and FHIT genes was analyzed in 127 chronic smokers enrolled in a prospective randomized placebo-controlled chemoprevention trial with 1,774 samples from oral and bronchial brushes (baseline and 3-months after intervention) using methylation-specific PCR (MSP). Methylation patterns in oral tissues were correlated with bronchial methylation indices (methylated sites/total sites per subject).
Results: At baseline, promoter methylation was observed in 23%, 17%, and 35% of the bronchial tissues for p16, FHIT, and any of the two genes, respectively, which is comparable to 19%, 15%, and 31% observed in the oral tissues. Among the 125 individuals with available baseline data from both oral and bronchial tissues, strong correlations were observed between tissues from the two organ sites (P &lt; 0.0001 for both p16 and FHIT genes). Among the 39 individuals with oral tissue methylation in any of the two genes, the mean bronchial methylation index was 0.53 (±0.29) compared to only 0.27 (±0.26) for the 86 cases without oral tissue methylation (P &lt; 0.0001). Similar correlations were also observed in samples obtained at 3 months after chemopreventive intervention.
Conclusions: Oral epithelium may be used as a surrogate tissue to assess tobacco-induced molecular damages in lungs, which has potential implications in lung cancer prevention trials.
Abstract 2100: Inhibition of androgen-independent growth of LNCaP xenograft tumors in immunodeficient mice by a combination of atorvastatin (Lipitor) and celecoxib (Celebrex)
Authors: Zheng Xi , Cui Xiao-Xing , Huang Mou-Tuan , Liu Yue , Paulino Raphael , Rabson Arnold , Reddy Bandaru , Conney Allan H. 
Published: May 2019

Abstract
Epidemiological studies indicate that statins and non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of prostate cancer. In the present study, we assessed the effects of Lipitor and Celebrex alone or in combination on androgen-independent growth of human prostate cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. In the in vitro studies, LNCaP cells were cultured in medium supplemented with charcoal-stripped fetal bovine serum to mimic androgen-deprivation treatment. We found that treatment of LNCaP cells cultured in androgen-depleted medium with Lipitor or Celebrex alone resulted in growth inhibition and apoptosis. A combination of Lipitor and Celebrex had more potent effects on growth inhibition and apoptosis than either agent alone. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously with LNCaP cells in Matrigel. After 4-6 weeks, mice with LNCaP tumors (about 0.6 cm wide and 0.6 cm long) were surgically castrated and received daily i.p injections with vehicle, Lipitor (10 μg/g body weight/day), Celebrex (10 μg/g/day) or a combination of Lipitor (5 μg/g/day) and Celebrex (5 μg/g/day) for 42 days. In the vehicle control group, LNCaP tumors regressed initially in response to castration and then re-grew in 2 weeks after castration to develop androgen-independent tumors. Treatment of the mice with Lipitor or Celebrex alone suppressed the re-growth of LNCaP tumors after castration. A combination of low doses of Lipitor and Celebrex had a more potent effect for inhibiting the androgen-independent growth of LNCaP tumors than a higher dose of either agent alone. The results from our study indicate that a combination of Lipitor and Celebrex may be an effective strategy for the prevention of prostate cancer progression from androgen-dependence to an androgen-independent stage.
Abstract 2102: Nanochemoprevention: Introducing a novel concept in cancer chemoprevention with a proof of principle for superior activity of green tea polyphenol epigallocatechin-3-gallate encapsulated in PLGA/PVA nanoparticles
Authors: Siddiqui Imtiaz A , Adhami Vaqar M , Bin Hafeez Bilal , Asim Mohammad , Khwaja Sabih I , Bharali Dhruba , Mousa Shaker A , Mukhtar Hasan 
Published: May 2019

Abstract
Despite extensive efforts that have been put to prevent cancer through chemoprevention, lack of delivery of desired levels of bioactive agents thus limiting their bioavailability, remains a challenging issue for effective clinical outcome. Thus, there is a strong unmet need in the biomedical technology community to find novel tools for making chemoprevention a success. Because most biological processes including those that are cancer-related occur at nanoscale, nanoparticulate technology has emerged as a potential tool to diagnose and treat cancer. We considered that nanoparticulate technology can prove to be very useful in cancer chemoprevention by allowing for effective and targeted delivery of chemopreventive agents. This delivery system could overcome many biological, biophysical and biomedical barriers that the body stages. Here, for the first time we introduce a concept of ‘nanochemoprevention’. To demonstrate the proof of principle we selected green tea polyphenol epigallocatechin-3-gallate (EGCG) with which we have considerable experience. We encapsulated EGCG in Poly (DL-lactide-co-glycolide acid) (PLGA)/Polyvinyl alcohol (PVA) nanoparticles, hereafter referred to as nano-EGCG, and evaluated it for cytotoxic response against human prostate cancer (PCa) PC3, DU145, 22Rν1 and LNCaP cells. MTT assay showed that treatment of cells with PLGA/PVC nanoparticles alone had negligible effect on cell growth. Interestingly, nano-EGCG, compared to EGCG in PBS, produced remarkably superior effects. For PC3 cells, the IC50 value at 24 hours of nano-EGCG was 3.75 μM compared to 40 μM of EGCG in PBS; 3.75 μM of EGCG in PBS had no effect. These differential effects were persistent at 48 and 72 hours. Similar effects of nano-EGCG were observed in 22Rν1, LNCaP and DU145, other human PCa cells. EGCG in PBS treatment to cells is known to result in induction of apoptosis and inhibition of colony formation which is considered essential for its chemopreventive effects. Next series of experiments were conducted to determine the effect of nano-EGCG on apoptosis and colony formation potential of PC3 cells. Treatment of the cells for 48 hours with nano-EGCG led to significant induction of PARP cleavage in a dose dependent manner and modulation of bax and bcl2 ratio that favored apoptosis. Further, nano-EGCG treatment also led to a dramatic increase in the levels of annexin V, an early marker of apoptosis. We then performed a 2-dimensional colony formation assay to evaluate the effect of nano-EGCG on the cellular growth pattern of PC3 cells and observed a marked decrease in colony number. Validation of these cell culture data to animal model systems could pave way for developing new avenues for cancer chemoprevention.
Abstract 3696A: The detection and prediction of circulating tumor cells in breast cancer patients
Authors: Molloy Tim , Helgason Helgi H , Bosma Astrid , van't Veer Laura J. 
Published: May 2019

Abstract
The detection of circulating tumor cells (CTC) in the blood of cancer patients is a promising tool for risk stratification, treatment tailoring, and monitoring of the disease state. The current study aims to develop a QPCR-based detection platform for the semi-quantitation of tumor cell load in the peripheral blood of breast cancer patients by combining gene expression data from 4 tumor marker genes into a single index-score. From a cohort of 131 individuals, CTC index-score positivity, indicating tumor cell presence, was observed in 14 out of 16 (88%) metastatic patients, 16 out of 87 (18%) non-metastatic stage I-III patients, and 0 out of 28 (0%) healthy female controls. A previous study demonstrated that CTC index-score positivity in metastatic patients correlated to a significantly shorter time to disease progression. This CTC detection platform demonstrates high specificity (100%) and sensitivity (88%), and can be an effective clinical tool providing valuable prognostic information.
This CTC detection assay was subsequently compared to a CTC prediction assay developed using microarray expression data from the primary tumors of the patients from the same cohort. From 73 patients, a CTC predictive tumor profile was developed with the ability to distinguish those patients with a positive CTC QPCR index-score from those with a negative index-score with an average 83% internal cross-validation accuracy. When a small independent test set was assayed, those patients classified on the basis of their tumor gene expression as having a positive CTC QPCR score had a shorter interval to metastasis development (mean = 29.6 months) versus those predicted to have a negative score (mean = 51.4 months).
When the QPCR-based and microarray-based CTC assays were compared directly, and each in combination with the “70-gene prognosis signature” for distant metastasis prediction, the CTC predictive microarray assay was superior to the CTC QPCR assay both alone and in combination with the 70-gene profile for time interval to metastasis. This study demonstrates that a microarray model predictive of tumor cell dissemination has prognostic value and seems independent of other metastasis-predictive microarray profiles.