bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL03-03: The clinical significance of intratumor diversity in breast cancer
Authors: Polyak Kornelia 
Published: July 2012

Abstract
Intratumor diversity for hereditary traits is the driver of tumor evolution, including disease progression and therapeutic resistance. To investigate the role of intratumor genetic and phenotypic heterogeneity in breast tumor progression and in therapeutic responses, we performed immunoFISH (iFISH) analyses of distant metastases from the same patient and breast tumor biopsies before and after treatment. iFISH allows for the combined analysis of phenotypic markers (e.g., such as CD24 and CD44) and chromosomal copy number gains at the single-cell level. In each tumor we evaluated four distinct tumor cell populations (CD44+/CD24-, CD44-/CD24+, CD44+/CD24+, and CD44-/CD24- cells) for chromosomal gain at 8q24 and other commonly gained chromosomal regions. iFISH data was evaluated using ecological and evolutionary models. We found high degree of genetic heterogeneity within and between the four different cell subpopulations in some tumors, in some patients the distant metastases were highly divergent, and the degree of intratumor diversity was altered by treatment and was associated with clinical characteristics. Our findings demonstrate the power of analyzing tumors as ecosystems and indicate that numerical measures of intratumor diversity can be used as clinically useful biomarkers predicting the risk of progression and therapeutic resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL03-03. doi:10.1158/1538-7445.AM2011-PL03-03
Abstract SY01-01: Harnessing genetic dependencies in cancer therapy
Authors: Ashworth Alan 
Published: July 2012

Abstract
Many tumors harbor defects in their ability to maintain genomic integrity. This contributes to the mutational burden and likely fosters pathogenesis. We have been exploring therapeutic strategies to exploit these defects. We have used a synthetic lethal approach to target the defect in DNA repair by homologous recombination in tumors with a BRCA1 or BRCA2 mutation. This strategy using PARP inhibitors is showing considerable promise in the clinic. Here, I will describe the approach as well recent work defining determinants of sensitivity and resistance to PARP inhibitors. The application of the synthetic lethal approach to other cancer types will also be discussed. In addition, we have been using high- and medium-throughput RNAi screens to uncover new therapeutic targets for cancer as well as biomarkers of patients who might respond to specific treatments. In particular I will discuss the integration of genomic, gene expression, and RNAi data to generate functional maps of cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY01-01. doi:10.1158/1538-7445.AM2011-SY01-01
Abstract SY02-01: Pericellular proteolysis and the regulation of the 3-D cancer invasion program
Authors: Weiss Stephen J. 
Published: July 2012

Abstract
To initiate prometastatic programs, carcinoma cells must transmigrate multiple extracellular matrix barriers, including the subtending basement membrane and the underlying interstitial matrix before gaining access to vascular and/or lymphatic beds. Subsequently, the cells extravasate and embed themselves in distant tissues where they must reactivate proliferation programs (Ann Rev Cell Dev Biol 25:567, 2009). Current evidence suggests that proinvasive carcinoma cells engage a reversible epithelial-mesenchymal cell-like transition (EMT) that falls under the regulation of a growing number of transcription factors, including Snail1 or Snail2. In response to multiple stimuli, ranging from growth factors and hypoxia to inflammatory cytokines and loss-of-function p53 mutations, EMT-inducing transcription factors promote the mobilization of a complex mix of proteinases that propagate the proteolytic remodeling of the extracellular matrix in a fashion that supports tissue-invasive activity (PNAS 106:20318, 2009; J Cell Biol 185:11, 2009; Genes & Dev 20:2673, 2006). While the identity of proteases mobilized by invading cells to traverse matrix barriers remains controversial, increasing evidence supports a critical role for a subclass of membrane-anchored matrix metalloproteinases, termed the membrane-type MMPs (MT-MMPs). In an exocyst-regulated fashion, MT-MMP family members decorate the leading edge of migrating cancer and stromal cells alike in order to drive invasion through extracellular matrix barriers. Importantly, MT-MMP function is not restricted to invasion alone as membrane-anchored proteases play additional roles in regulating cell proliferation, survival and differentiation (Cell 114:33, 2003; Cell 125:577, 2006; Genes & Dev 22:1231, 2008; Blood 115:221, 2010). While the range of cellular activities that fall under the MT-MMP umbrella is, in some ways, perplexing, new evidence suggests that MT-MMP-dependent pericellular proteolysis indirectly controls nuclear architecture and function in a 3-D extracellular matrix-specific fashion. Understanding the interplay between EMT-inducing transcription factors, the activation of tissue-remodeling cell programs, and the impact of pericellular proteolysis on gene regulation and function should provide new insights into the control of neoplastic cell trafficking and metastatic activities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY02-01. doi:10.1158/1538-7445.AM2011-SY02-01
Abstract SY05-01: Biological and clinical activities of FDA-approved drugs that antagonize Hh signaling
Authors: Kim James , Tang Jean Y. 
Published: July 2012

Abstract
The inappropriate activity of the Hedeghog (Hh) signaling pathway noted in a variety of tumor types has prompted efforts to develop small molecule antagonists of Hh pathway signaling. The use of FDA-approved drugs as Hh pathway antagonists may avoid some of the expense and delay associated with de novo development of Hh pathway antagonists. We have identified two FDA-approved drugs, itraconazole and arsenic trioxide, as potent inhibitors of the Hh pathway in vitro and in vivo at the level of Smoothened (Smo) and Gli, respectively. In addition, both itraconazole and arsenic trioxide have inhibitory activity against a mutant Smoothened resistant to GDC-0449, a potent Smo antagonist. These preclinical studies have led to a pilot clinical trial (ID: NCT01108094) using itraconazole for patients with basal cell carcinoma, a skin tumor that is driven by the Hh pathway. We have treated 13 subjects with 200mg of itraconazole twice daily and found -32% (95% CI: -19 to -42%) reduction in tumor diameter in 1 month. These studies suggest that FDA-approved drugs show promise as Hh pathway antagonists for the treatment of Hh-dependent cancers and warrant further study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY05-01. doi:10.1158/1538-7445.AM2011-SY05-01
Abstract SY05-02: Hedgehog/wnt feedback supports regenerative proliferation of epithelial stem cells in bladder
Authors: Beachy Philip A. 
Published: July 2012

Abstract
Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury caused by bacterial infection or chemical agents. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show that proliferation within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal, Sonic hedgehog (Shh). Upon injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a model for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signaling pathways in cancer growth and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY05-02. doi:10.1158/1538-7445.AM2011-SY05-02
Abstract SY07-02: Polarity proteins in morphogenesis and metastasis
Authors: McCaffrey Luke Martin , Montalbano JoAnne , Macara Ian G. 
Published: July 2012

Abstract
Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. A conserved set of polarity proteins, called PAR proteins, drives cell polarization in many contexts, and in Drosophila these proteins can function as tumor suppressors. However, to date, only Par4 (LKB1) has been implicated in human cancers. To determine whether other polarity proteins might have tumor suppressor functions in mammals, we have used lentiviruses to deliver oncogenes and shRNAs to primary murine mammary cells, which are then implanted into the cleared fat pads of isogenic host mice. Using this system, we silenced expression of the PAR3 polarity protein in the context of oncogenic Notch (NICD) or Ras. Depletion of Par3 dramatically reduced tumor latency in both models, producing tumors that were highly invasive and metastatic. Notably, the NICD/shPAR3 tumors retained epithelial character, with no evidence of epithelial-mesenchymal transition in either the primary tumors or the lung metastases. We have identified an unexpected signaling pathway that drives invasion in these tumors. Importantly, PAR3 protein expression is significantly reduced in ∼50% of human breast cancers, as compared to matched normal tissue. Together, these data provide a link between cell polarity, tissue organization, and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY07-02. doi:10.1158/1538-7445.AM2011-SY07-02
Abstract SY08-02: Markers of caspase activation in cells and serum
Authors: Wells James A. 
Published: July 2012

Abstract
The final and hoped for outcome for treatment with cancer drugs is selective apoptosis of cancer cells. However, despite the low response rates to cancer drugs patients do not discover this until months after treatment has begun. Apoptosis is rapid process which is often induced within 24 hours of drug treatment. The hallmark of apoptosis is the activation of caspases, cysteine proteases that are specific for cleaving target proteins after aspartic acid. We have developed a novel proteomics technology that allows us to tag and enrich for caspase-cleaved proteins during apoptosis (Mahrus et al (2008) Cell, 134, 866-876. “Global Sequencing of Proteolytic Cleavage Sites in Apoptosis by Specific Labeling of Protein N Termini”). We have been characterizing the apoptotic products of caspase cleavage in a variety of cell lines and in human serum with the view that this information can be used to monitor apoptosis during cancer drug treatment. These and other studies in a variety of cancer cell lines showed that upwards of 1000 proteins are cleaved by caspases during apoptosis. However, in any given cell line we find there are fewer than 500 targets because of differences in expression patterns between cell types. Thus, while many targets are in common from one cell line to another, many are unique. We have developed single-reaction monitoring (SRM) methods to identify these products in serum. We are beginning to identify specific apoptotic products in leukemia patients treated with various cancer drugs. These studies and the prospects for using these as apoptotic markers to assist in cancer drug treatment will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY08-02. doi:10.1158/1538-7445.AM2011-SY08-02
Abstract SY11-01: Knockout mouse models for sirtuins: Genome integrity, metabolism, and cancer
Authors: Deng Chuxia , Kim Hyun-Seok , Vassilopoulos Athanassios , Wang Rui-Hong , Lahusen Tyler , Xiao Zhen , Xu Xiaoling , Li Cuiling , Veenstra Timothy D. , Ji Junfang , Wang Xin-Wei , Park Seong-Hoon , Gius David 
Published: July 2012

Abstract
In budding yeast, Sir2 is a NAD+-dependent histone deacetylase that plays a role in chromatin silencing, longevity and genomic stability. In mammals, sirtuins exist as a family of 7 members (SIRT1-7) that deacetylate histones and many nonhistone proteins. Currently, all sirtuins have been knocked out by gene targeting, and the mutant mice suffer various abnormalities in cell growth, apoptosis, neurological behavior, adaptation to calorie restriction, organ metabolism and function, and/or premature aging, highlighting critical roles of sirtuins in these biological processes. Of note, mice carrying mutations of SIRT1, SIRT2 or SIRT3 also developed cancers, predominantly in the mammary glands and the liver that are accompanied by genomic instability and/or abnormal energy metabolism. Our further analysis revealed distinct role of these siruins in maintaining genome integrity. SIRT1 mutant cells displayed altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage [1]; SIRT3 mutant cells had increased stress-induced superoxide levels and genomic instability [2]; and SIRT2 loss primarily affects mitotic functions. We found that SIRT2 plays a role in maintaining normal mitosis progression through modulating expression levels of several mitotic regulators, including Aurora-A and -B. Loss of SIRT2, consequently, causes centrosome amplification, aneuploidy, and mitotic catastrophe. SIRT2-deficient mice initially develop normally, however, suffer mammary tumors and hepatocellular carcinoma (HCC) when they become old. These data highlight how accurate maintenance of genomic integrity is critical for the suppression of tumorigenesis. Finally, we found that human breast cancer and HCC exhibit reduced levels of SIRT1-3. These results implicate SIRT1-3 as tumor suppressors in these organs.
References:
1. Wang RH, Sengupta K, Li C. et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008; 14: 312-323.
2. Kim HS, Patel K, Muldoon-Jacobs K. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010; 17: 41-52.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY11-01. doi:10.1158/1538-7445.AM2011-SY11-01
Lipid Effects of Peroxisome Proliferator-Activated Receptor-Δ Agonist GW501516 in Subjects With Low High-Density Lipoprotein Cholesterol
Authors: Olson Eric J. , Pearce Gregory L. , Jones Nigel P. , Sprecher Dennis L. 
Published: July 2012

Objective—
Peroxisome proliferator-activated receptor-δ–induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins.

Methods and Results—
GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (−7.3%), triglycerides (−16.9%), apoB (−14.9%), and free fatty acids (−19.4%). The exploratory study showed significant reductions in the concentration of very LDL (−19%), intermediate-density lipoprotein (−52%), and LDL (−14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL).

Conclusion—
GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.
Vascular Hypoxic Preconditioning Relies on TRPV4-Dependent Calcium Influx and Proper Intercellular Gap Junctions Communication
Authors: Rath Géraldine , Saliez Julie , Behets Gaëtane , Romero-Perez Miguel , Leon-Gomez Elvira , Bouzin Caroline , Vriens Joris , Nilius Bernd , Feron Olivier , Dessy Chantal 
Published: July 2012

Objective—
We investigated the impact of hypoxia-reoxygenation on endothelial relaxation and aimed to clarify the role of transient receptor potential cation channels V4 (TRPV4) and gap junctions in the protective effect associated with hypoxic preconditioning on the vascular function.

Methods and Results—
By mimicking ischemia-reperfusion in C57BL/6 male mice in vivo, we documented a reduced NO-mediated relaxation and an increased endothelium-derived hyperpolarization (EDH[F])-mediated relaxation. Hypoxic preconditioning, however, restored NO relaxation and further improved the EDH(F) response. We also examined specifically 2 major effectors of the EDH(F) pathway, transient receptor potential cation channels V4 and connexins. We found that in endothelial cells, expression and activity of transient receptor potential cation channels V4 were increased by hypoxic stimuli independently of preconditioning which was interestingly associated with an increase of structural caveolar component caveolin-1 at membrane locations. Gap junctions, however, seemed to directly support EDH(F)-driven preconditioning as connexin 40 and connexin 43 expression increased and as in vivo carbenoxolone treatment completely inhibited the EDH(F) pathway and significantly reduced the protection afforded by preconditioning for the concomitant NO-mediated relaxation.

Conclusion—
Our work provides evidence on how transient receptor potential cation channels V4 and connexins might participate in preserving vasorelaxation under hypoxia and restoring the NO-mediated pathway in hypoxic preconditioning conditions pointing out caveolae as a common signaling location.
Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure
Authors: Litteri Gaia , Carnevale Daniela , D’Urso Alessandra , Cifelli Giuseppe , Braghetta Paola , Damato Antonio , Bizzotto Dario , Landolfi Alessandro , Ros Francesco Da , Sabatelli Patrizia , Facchinello Nicola , Maffei Angelo , Volpin Dino , Colombatti Alfonso , Bressan Giorgio M. , Lembo Giuseppe 
Published: July 2012

Objective—

Emilin-1 is a protein of elastic extracellular matrix involved in blood pressure (BP) control by negatively affecting transforming growth factor (TGF)-β processing.
Emilin1
null mice are hypertensive. This study investigates how Emilin-1 deals with vascular mechanisms regulating BP.

Methods and Results—

This study uses a phenotype rescue approach in which Emilin-1 is expressed in either endothelial cells or vascular smooth muscle cells of transgenic animals with the
Emilin1

−/−

background. We found that normalization of BP required Emilin-1 expression in smooth muscle cells, whereas expression of the protein in endothelial cells did not modify the hypertensive phenotype of
Emilin1

−/−

mice. We also explored the effect of treatment with anti-TGF-β antibodies on the hypertensive phenotype of
Emilin1

−/−

mice, finding that neutralization of TGF-β in
Emilin1
null mice normalized BP quite rapidly (2 weeks). Finally, we evaluated the vasoconstriction response of resistance arteries to perfusion pressure and neurohumoral agents in different transgenic mouse lines. Interestingly, we found that the hypertensive phenotype was coupled with an increased arteriolar myogenic response to perfusion pressure, while the vasoconstriction induced by neurohumoral agents remained unaffected. We further elucidate that, as for the hypertensive phenotype, the increased myogenic response was attributable to increased TGF-β activity.

Conclusion—
Our findings clarify that Emilin-1 produced by vascular smooth muscle cells acts as a main regulator of resting BP levels by controlling the myogenic response in resistance arteries through TGF-β.
Vascular Endothelial Growth Factor–Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts
Authors: Li Xiao-Dong , Chen Jing , Ruan Cheng-Chao , Zhu Ding-Liang , Gao Ping-Jin 
Published: July 2012

Objective—
Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia–mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation.

Methods and Results—
In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal–regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis.

Conclusion—
These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases.