bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-90: DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease.
Authors: Gardner Thomas A. , Fletcher James W. , Ko Song-Chu , Low Philip S. , Ratliff Timothy L. 
Published: August 2014

Abstract
Objectives: Currently, the absence of an effective prostate cancer targeted imaging agent limits the ability to correctly clinically stage prostate cancer. The conjugation of a high affinity PSMA-targeting ligand, 2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to technetium 99m (99mTc) has generated a new prostate cancer imaging agent termed DUPA-99mTc. The objective of this phase 0 clinical trial was to confirm the preclinical data demonstrating high affinity localization to human prostate cancer cells and tissues.
Methods: Nine men with advanced and metastatic prostate cancer confirmed by CT scan and/or bone scan were enrolled in the Phase 0 trial to investigate both the biologic efficacy and toxicity of the DUPA-99mTc agent. Dosimetry studies of images, blood and urine at 5 and 20 mCi doses were obtained at baseline, 5 min, 1, 2, 4, 8 and 24 hours.
Results: Nine men with documented prostate cancer were enrolled. Seven of the nine subjects were evaluable. One patient did not receive a full iv dose and another received poorly labeled DUPA-99mTc (70%). The remaining seven patients, who received DUPA-99mTc in excess of 95% labeled product, demonstrated localization to all cancerous areas seen on pre-enrollment images (CT and Bone Scans) plus additional lesions in several of the patients. Two men who had biopsy-confirmed locally recurrent prostate cancer had scans prior to resection, and tissue was monitored intra-operatively and ex-vivo to confirm the higher 99mTc counts in malignant tissue compared to normal tissue. No significant toxicity was demonstrated with administration of the DUPA-99mTc in any subject.
Conclusions: DUPA-99mTc compound can be reliably administered to men with prostate cancer without toxicities and with equal or superior imaging compared to conventional CT and bone scans. A Phase I/II trial will be conducted to confirm the performance of this imaging agent in a larger patient population.
Citation Format: Thomas A. Gardner, James W. Fletcher, Song-Chu Ko, Philip S. Low, Timothy L. Ratliff. DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-90. doi:10.1158/1538-7445.AM2013-LB-90
Abstract LB-92: RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells.
Authors: Campeau Eric , Jahagirdar Ravi , Wu Jin , Gesner Emily M. , Kharenko Olesya , Yu Raymond , Attwell Sarah , Hansen Henrik C. , Wagner Gregory S. , McLure Kevin G. , Young Peter R. 
Published: August 2014

Abstract
Current treatment of acute myeloid leukemia (AML) often includes a combination of intravenous cytarabine (Ara-C) and an anthracycline such as idarubicin. Bromodomain and extra-terminal domain (BET) proteins contain two bromodomains that bind to acetylated lysines in histones and regulate gene transcription by an epigenetic mechanism. Here we describe a novel small molecule BET inhibitor, RVX-2135, which selectively binds recombinant BET bromodomains of BRD2, BRD3, and BRD4 but not non-BET bromodomains. RVX-2135 inhibited BRD2, BRD3, and BRD4 dual bromodomains binding to acetylated histones in vitro with sub to low micromolar IC50 values. In the human AML cell line MV4-11, RVX-2135 displaced BET proteins from chromatin and significantly reduced expression of c-MYC and BCL-2 mRNAs, with IC50s of 4 and 5 μM, respectively. RVX-2135 inhibited proliferation of cultured MV4-11 cells with an IC50 value of 6 μM, and induced cell cycle arrest and apoptosis. In vivo, nude mice bearing MV4-11 xenografts were treated orally with RVX-2135 at doses of 75 and 120 mg/kg b.i.d, and showed tumor growth inhibition of 77 and 92% respectively. There was a corresponding inhibition of c-MYC and BCL-2 mRNA expression in the xenograft tumors. In combination therapy in vitro, RVX-2135 synergized with idarubicin and cytarabine, with Chou-Talalay's combination indices of 0.17 and 0.18, respectively. The synergistic effect also translated into increased apoptosis when cytarabine was combined with RVX-2135. Similar data were seen with BET inhibitors from different chemical scaffolds, suggesting that this may represent a promising new class of drugs for AML.
Citation Format: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young. RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2013-LB-92
Abstract PR11: Doxorubicin enhances nucleosome turnover around active gene promoters
Authors: Yang Fan , Kemp Christopher J. , Henikoff Steven 
Published: August 2014

Abstract
Doxorubicin (also known as Adriamycin) is a DNA intercalator that is among the most commonly used anti-cancer drugs. Doxorubicin causes DNA double-strand breaks in rapidly dividing cells, although whether it also affects general chromatin properties is unknown. Here, we use a metabolic labeling strategy for directly measuring nucleosome turnover to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around promoters of active genes. Consistent with a direct action of doxorubicin, enhancement of nucleosome turnover around promoters gradually increases with time of exposure to the drug. Interestingly, enhancement occurs both in wild-type cells and in cells lacking the p53 tumor suppressor gene or the master regulator of the DNA damage response, Atm, suggesting that doxorubicin action on nucleosome dynamics is independent of the DNA damage checkpoint. In addition, another anthracycline intercalator, aclarubicin, shows similar effects on enhancing nucleosome turnover around promoters. Our results suggest that anthracycline intercalation promotes nucleosome turnover by its effect on DNA topology, with possible implications for cancer chemotherapies that combine traditional DNA intercalators with targeted epigenetic drugs.
This abstract is also presented as Poster A48.
Citation Format: Fan Yang, Christopher J. Kemp, Steven Henikoff. Doxorubicin enhances nucleosome turnover around active gene promoters. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR11.
Abstract B51: Tumor ER stress transmission to infiltrating myeloid cells in vivo require IRE1alpha and TLR4
Authors: Rodvold Jeffrey J. , Hiramatsu Nobuhiko , Chiu Kevin T. , Mahadevan Navin R. , Lin Jonathan , Zanetti Maurizio 
Published: August 2014

Abstract
The unfolded protein response (UPR) facilitates tumor outgrowth through evoking a variety of cell intrinsic processes that promote cancer survival, angiogenesis, and chemoresistance. The UPR can be transmitted from stressed cancer cells to receiver myeloid cells in vitro through a process termed transmissible endoplasmic reticulum stress (TERS) in which receiver cells undergo a UPR and acquire tumor promoting pro-inflammatory (IL-6, TNF-alpha, IL-23) and immune-suppressive (Arg1) characteristics. Here, we confirmed that CD11b+ myeloid cells isolated from subcutaneous murine melanoma tumors in C57BL/6 mice display the TERS signature. In light of the fact that TERS signaling in myeloid receiver cells is partly TLR4-dependent, we interrogated subcutaneous tumors in TLR4 mice. We found that these tumors had delayed onset, reduced growth kinetics, and improved survival over tumors growing in wildtype mice. Most significantly, isolated CD11b+ cells from TLR4-/- tumors did not undergo a UPR nor upregulate inflammatory genes when compared to splenic controls, though, interestingly, still upregulated Arg1. Next, we probed individual signaling arms of the UPR in relation to TERS production. We utilized a panel of novel transgenic cell lines in which specific arms of the UPR can be conditionally activated and found that activated inositol requiring enzyme-1alpha (IRE1alpha) transmitted stress to myeloid cells. The remaining two UPR arms (PERK and ATF6) had little transmitting potential, if any. Bone marrow derived myeloid cells treated with TERS generated from IRE1alpha KO mouse embryonic fibroblasts (MEFs) had a markedly reduced UPR than those treated to wildtype MEF TERS. Subcutaneous tumors consisting of IRE1alpha KO TERS-conditioned myeloid dendritic cells and melanoma cancer cells had delayed onset and grew at reduced rate compared to tumor mixtures in which wildtype MEF TERS was used. Based on these data, we probed a patient melanoma for its co-localization of stress, myeloid infiltrate, and inflammation. Together, these data identify a novel signaling mechanism dependent on IRE1alpha and TLR4 used by stressed tumor cells to co-opt infiltrating myeloid cells to become tumor promoting.
Citation Format: Jeffrey J. Rodvold, Nobuhiko Hiramatsu, Kevin T. Chiu, Navin R. Mahadevan, Jonathan Lin, Maurizio Zanetti. Tumor ER stress transmission to infiltrating myeloid cells in vivo require IRE1alpha and TLR4. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B51.
Abstract B26: Identification of molecular and functional differences in tumor-associated macrophage subsets
Authors: Arwert Esther N. , Harney Allison S. , Entenberg David , Wang Yarong , Pollard Jeffrey W. , Condeelis John S. 
Published: August 2014

Abstract
During breast cancer metastasis motile tumor cells migrate within the primary tumor to blood vessels and enter the bloodstream which leads these cells to other organs where they can found a new metastasis. These cancer cells have to navigate from their primary site to the blood vessel, and make their way through the extra cellular matrix of the basement membranes of mammary ducts and blood vessels. Cancer cells are not acting alone during the metastatic process. Tumor associated macrophages (TAMs) play an important role during breast cancer development and metastasis.
The on-going research aims to gain a better understanding of the origin, location and flexibility in function of different TAM subsets, including the metastasis-assisting macrophages. Using high-resolution multi-photon live-imaging we have identified different TAM subsets based on location and phenotype. For example TAMs can be found at the outside of the tumor (cortical), around tumor blood vessels (perivascular) or in fast moving cell streams (streaming). All these different TAM subsets perform different functions. Cortical TAMs are suggested to be immunosuppressive, while streaming TAMs appear to guide motile cancer cells towards blood vessels, and perivascular macrophages seem to attract the streams and mediate cancer cell intravasation.
Currently, there are no (surface) markers to differentiate these unique TAM subsets and little is known about the underlying molecular mechanisms relevant for the differentiation of monocytes into any of these subtypes. The current research is using single-cell laser capture dissection, high-resolution multi-photon live-imaging and lineage tracing experiments to elucidate some aspects of the interplay between cancer cells and macrophages
Citation Format: Esther N. Arwert, Allison S. Harney, David Entenberg, Yarong Wang, Jeffrey W. Pollard, John S. Condeelis. Identification of molecular and functional differences in tumor-associated macrophage subsets. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B26.
Abstract PR13: microRNAs: Master regulators of human tumor dormancy
Authors: Almog Nava , Ma Lili , Christine Briggs , Rietman Edward , Beheshti Afshin , Abdollahi Amir 
Published: August 2014

Abstract
Tumor dormancy refers to a critical stage in cancer progression in which tumors remain small and occult for a prolonged period until they eventually progress and become clinically apparent. Although escape from tumor dormancy has long been recognized as an important problem in the treatment of cancer, the molecular and cellular regulators underlying this transition remain poorly understood. We have previously generated and characterized in vivo models of human tumor dormancy. In these models dormancy of micro-tumors is angiogenesis dependent and the spontaneous escape of the tumors from dormancy requires a stable transcriptional reprogramming.
We show here that dormant tumors undergo a stable microRNA switch during their transition to the fast-growing angiogenic phenotype and report the identification of a consensus set of dormancy-associated microRNAs (DmiRs). Loss of DmiR expression is associated with the spontaneous transition of dormant tumors to rapid growth. The expression pattern of two DmiRs was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR580, 588 or 190) led to phenotypic reversal of fast-growing tumors towards prolonged tumor dormancy. Transcriptional reprogramming of tumors via DmiR over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF, TGF alpha or Bv8 and decreased tumor recruitment of pro-angiogenic bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR expressing tumors.
We further investigated the transcriptional targets of mir-190 which exerts the strongest tumor inhibiting effect and show that mir-190 affects mRNA levels of a very large set of genes in both direct and indirect ways. Many of the genes affected by mir-190 are related to the transcription process, are associated with tumor suppressors and with the interferon pathway.
The identification of tumor dormancy associated microRNAs, along with improved understanding of their mechanistic actions could lead to the development of novel means to revert the malignant tumor phenotype to a dormant state. This work may also provide promising targets for early detection or prevention of cancer.
This abstract is also presented as Poster C97.
Citation Format: Nava Almog, Lili Ma, Briggs Christine, Edward Rietman, Afshin Beheshti, Amir Abdollahi. microRNAs: Master regulators of human tumor dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR13.
Abstract B65: IgG4 subclass antibodies impair antitumor immunity in melanoma.
Authors: Karagiannis Panagiotis , Gilbert Amy E. , Josephs Debra H. , Ali Niwa , Dodev Tihomir , Saul Louise , Roberts Luke , Beddowes Emma , Koers Alexander , Ferreira Silvia , Geh Jenny L.C. , Healy Ciaran , Harries Mark , Hobbs Carl , Blower Philip J. , Mitchell Tracey , Fear David , Spicer James F. , Lacy Katie E. , Nestle Frank O. , Karagiannis Sophia N. 
Published: August 2014

Abstract
Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 type immune responses in a range of inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. We found that CD22+ B cells and IgG4+ infiltrating cells accumulated in melanoma lesions. When compared to B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Consistent with modified Th2-biased inflammation and in situ production of IgG4, we detected IL-10 and IL-4 cytokine mRNA in melanoma lesions. Tumor cells enhanced IL-10, IL-4 and VEGF secretion and production of IgG4 by B cells ex vivo. Despite accumulation in tumors, and in contrast to IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro and in vivo. Furthermore, treatment with IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions by blocking of FcgammaRI against tumors, providing a novel perspective on tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.
Citation Format: Panagiotis Karagiannis, Amy E. Gilbert, Debra H. Josephs, Niwa Ali, Tihomir Dodev, Louise Saul, Luke Roberts, Emma Beddowes, Alexander Koers, Silvia Ferreira, Jenny L.C. Geh, Ciaran Healy, Mark Harries, Carl Hobbs, Philip J. Blower, Tracey Mitchell, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4 subclass antibodies impair antitumor immunity in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B65.
Practice Patterns and Trends in the Use of Medical Therapy in Patients Undergoing Percutaneous Coronary Intervention in Ontario
Authors: Garg Pallav , Wijeysundera Harindra C. , Yun Lingsong , Cantor Warren J. , Ko Dennis T. 
Published: August 2014

Background

Clinical guidelines emphasize medical therapy as the initial approach to the management of patients with stable coronary artery disease (
CAD
). However, the extent to which medical therapy is applied before and after percutaneous coronary intervention (
PCI
) in contemporary clinical practice is uncertain. We evaluated medication use for patients with stable
CAD
undergoing
PCI
, and assessed whether the
COURAGE
study altered medication use in the Canadian healthcare system.

Methods and Results

A population‐based cohort of 23 680 older patients >65 years old) with stable
CAD
undergoing
PCI
in Ontario between 2003 and 2010 was assembled. Optimal medical therapy (
OMT
) was defined as prescription for a β‐blocker, statin, and either angiotensin‐converting enzyme inhibitor or angiotensin
II
receptor blocker in the 90 days before
PCI
, and the same medications plus thienopyridine 90 days following
PCI
. Prior to
PCI
, 8023 (33.9%) patients were receiving
OMT
, 11 891 (50.2%) were on suboptimal therapy, and 3766 (15.9%) were not prescribed any medications of interest. There was significant improvement in medical therapy following
PCI
(
OMT
: 11 149 [47.1%], suboptimal therapy: 11 591 [48.9%], and none: 940 [4.0%],
P
<0.001). Utilization rate of
OMT
reduced significantly after the publication of
COURAGE
(34.9% before versus 32.8% after,
P
<0.001). Similarly, the rate of
OMT
following
PCI
was lower in the period after publication of
COURAGE
(47.3% before versus 46.9% after,
P
<0.001).

Conclusions

OMT
was prescribed in about 1 in 3 patients prior to
PCI
and less than half after
PCI
. In contrast to the anticipated impact of
COURAGE
, we found lower rates of medication use in
PCI
patients after its publication.
Seasonal Drought in the Greater Horn of Africa and Its Recent Increase during the March–May Long Rains
Authors: Lyon Bradfield 
Published: August 2014

Abstract
This paper provides a review of atmospheric circulation and sea surface temperature (SST) conditions that are associated with meteorological drought on the seasonal time scale in the Greater Horn of Africa (the region 10°S–15°N, 30°–52°E). New findings regarding a post-1998 increase in drought frequency during the March–May (MAM) “long rains” are also reported. The period 1950–2010 is emphasized, although rainfall and SST data from 1901–2010 are used to place the recent long rains decline in a multidecadal context. For the latter case, climate model simulations and isolated basin SST experiments are also utilized.
Climatologically, rainfall exhibits a unimodal June–August (JJA) maximum in west-central Ethiopia with a generally bimodal [MAM and October–December (OND) maxima] distribution in locations to the south and east. Emphasis will be on these three seasons. SST anomalies in the tropical Pacific and Indian Oceans show the strongest association with drought during OND in locations having a bimodal annual cycle, with weaker associations during MAM. The influence of the El Niño–Southern Oscillation (ENSO) phenomenon critically depends on its ability to affect SSTs outside the Pacific. Salient features of the anomalous atmospheric circulation during drought events in different locations and seasons are discussed. The post-1998 decline in the long rains is found to be driven strongly (although not necessarily exclusively) by natural multidecadal variability in the tropical Pacific rather than anthropogenic climate change. This conclusion is supported by observational analyses and climate model experiments, which are presented.
Impact of Sea Spray on Air–Sea Fluxes. Part I: Results from Stochastic Simulations of Sea Spray Drops over the Ocean
Authors: Mueller James A. , Veron Fabrice 
Published: August 2014

Abstract
The contributions of sea spray drops to the total air–sea exchanges of momentum, heat, and mass remain an open question. A number of factors obscure any simple quantification of their contribution; the per drop contribution to the fluxes is a particularly important factor that cannot be calculated easily, as are the number of drops formed. To estimate the per droplet fluxes, the authors first calculate the low order statistics from a large number of drop trajectories, which are simulated with a recently developed Lagrangian stochastic model adapted for the heavy drop transport and evaporation within the marine boundary layer. This paper describes the results from simulations of sea spray drops over the ocean, and as one of two parts, summarizes new estimations for the spray-mediated fluxes on a per drop basis. The results suggest that common simplifications in previous sea spray models, such as the residence time in the marine boundary layer, may not be appropriate.