bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA07: Multiple myeloma as a model of bone metastasis.
Authors: Ghobrial Irene 
Published: August 2015

Abstract
The process of cell metastasis is characterized by a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. Multiple myeloma (MM) represents one of the best models to examine bone metastasis as it is characterized by the presence of multiple myelomatous “omas” throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. We will examine intrinsic factors of clonal heterogeneity that mediate cell dissemination, as well as factors present in the bone marrow niche that are permissive for oncogenic proliferation. In addition, we will discuss advances that have been discovered in the complex process of invasion-metastasis in MM, and potential therapeutic agents that target the different steps of cell dissemination and progression.
Citation Format: Irene Ghobrial. Multiple myeloma as a model of bone metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA07.
Abstract IA14: Preclinical models for targeting oncogenic Ras signaling in cancer.
Authors: Shannon Kevin 
Published: August 2015

Abstract
Somatic RAS mutations occur in 30% of human cancers, and are common in both melanoma and hematopoietic cancers. Importantly, whereas KRAS mutations predominate in epithelial cancers, NRAS is mutated much more often in melanoma and hematopoietic cancers. The most obvious therapeutic strategy for cancers with RAS mutations – developing specific inhibitors of the mutant protein – is extremely challenging due to the very high affinity of Ras for GTP, structural considerations of the Ras/GTPase activating protein (Ras/GAP) molecular switch, and the loss of normal enzymatic activity as a consequence of oncogenic RAS mutations. Given these issues, most recent drug discovery efforts have focused on inhibiting downstream biochemical targets of mutant Ras such as Raf, MEK, and Akt with many compounds undergoing clinical evaluation. We have exploited strains of mice that recapitulate endogenous expression of cancer-associated RAS alleles or NF1 inactivation to model human hematologic cancers and to conduct biologic and preclinical studies. In particular, we have deployed the MOL4070LTR retrovirus as an insertional mutagen to generate genetically heterogeneous transplantable myeloid and lymphoid leukemias characterized by hyperactive Ras signaling. We utilize cohorts of mice that are engrafted with the same primary leukemias for preclinical testing. In this presentation, I will focus on three biologic and therapeutic questions related to NRAS in tumorigenesis: (1) loss of the normal NRAS allele in cancers with oncogenic NRAS mutations; (2) responses of primary Nras mutant leukemias to MEK and PI3 kinase inhibitors; and, (3) potential strategies for selectively targeting oncogenic N-Ras in cancer.
Note: This abstract was presented as part of the Joint Session: Clinical Science Interactions between Melanoma and Hematologic Malignancies with the AACR Special Conference on Advances in Melanoma: From Biology to Therapy held September 20-23, 2014 in Philadelphia, PA.
Citation Format: Kevin Shannon. Preclinical models for targeting oncogenic Ras signaling in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA14.
Abstract IA17: Adoptive T cell therapy with CAR modified T cells: We have a Model A Ford, can we build a Ferrari?
Authors: Brentjens Renier 
Published: August 2015

Abstract
Recently published reports support the novel approach of treating cancer with patient derived T cells genetically modified to express artificial T cell receptors, termed chimeric antigen receptors (CARs), targeted to tumor associated antigens. To this end, initial clinical trial outcomes of patients with relapsed B cell acute lymphoblastic leukemia (B-ALL) treated with T cells genetically modified to express a CAR specific to the CD19 antigen demonstrate that this approach is a very promising therapeutic intervention which potentially may dramatically alter the standard of care in this disease. In contrast far more modest clinical responses were seen in patients with relapsed low grade B cell malignancies including chronic lymphocytic leukemia (CLL) and B cell non-Hodgkins lymphomas (NHL). The etiologies of discordant clinical outcomes between B-ALL and CLL/NHL patients treated with CD19 targeted CAR T cells remains a subject of conjecture although the tumor microenvironment is a strong focus for further investigation. To this end, we will present novel data on a next generation of CAR T cells, termed “armored CAR” T cells genetically designed to enhance persistence, anti-tumor efficacy, and an ability to overcome an immune suppressive tumor microenvironment through further genetic modification. Promising preclinical studies utilizing various “armored CAR” T cell approaches and their role in future clinical trials will be discussed as well as the relevance of these findings to the extrapolation of this technology from hematologic tumors to far more prevalent solid tumor malignancies.
Note: This abstract was presented as part of the Joint Session: Clinical Science Interactions between Melanoma and Hematologic Malignancies with the AACR Special Conference on Advances in Melanoma: From Biology to Therapy held September 20-23, 2014 in Philadelphia, PA.
Citation Format: Renier Brentjens. Adoptive T cell therapy with CAR modified T cells: We have a Model A Ford, can we build a Ferrari? [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA17.
Abstract IA22: An oncogenic enhancer drives NOTCH1-induced leukemia.
Authors: Ferrando Adolfo 
Published: August 2015

Abstract
Most genetic abnormalities found in cancer are located in intergenic regions and their role in cancer development remains poorly understood. Here we report the identification of a long range enhancer driving NOTCH1-induced transformation in T-ALL. Using genome wide ChIPseq mapping of NOTCH1 binding and functional epigenetic marks in T-ALL we identified a NOTCH1-occupied enhancer located in a gene desert island in 8q24, +1,427 kb 3' from the MYC locus. This regulatory element named N-Me for NOTCH-bound MYC enhancer activates MYC reporter constructs in T-ALL cells and directly interacts with MYC promoter sequences via long range chromatin loops. Notably, high resolution aCGH analysis revealed recurrent focal duplications at chromosome 8q24 encompassing this enhancer in 8/160 (5%) T-ALL cases. Functional characterization of N-Me in T-cell development and transformation using N-Me knockout and conditional knockout mice revealed a major role for this enhancer during thymocyte development and in T-ALL. Thus N-Me null animals showed a marked and selective reduction in thymus size and cellularity and were completely resistant to NOTCH1-induced transformation. Moreover, secondary deletion of N-Me in established NOTCH1 induced leukemias from tamoxifen-inducible N-Me conditional knockout mice induced profound antileukemic effects with extended survival and almost complete suppression of leukemia initiating cell activity. Altogether, these results identify N-Me as a major downstream effector NOTCH1 critically required for MYC expression in T-cell development and leukemia.
Citation Format: Adolfo Ferrando. An oncogenic enhancer drives NOTCH1-induced leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA22.
Abstract IA23: Integrating chemical and functional genomics for leukemia discovery.
Authors: Stegmaier Kimberly 
Published: August 2015

Abstract
Characterization of the genomic landscapes of cancer with new technologies, such as massively parallel sequencing, has catapulted our understanding of human malignancies. However, many questions remain about the true genetic dependencies in human cancer, and for most malignancies, therapeutic impact has lagged behind the unraveling of the DNA code. In principle, the integration of functional and chemical genomics offers a powerful approach to decipher the mechanisms of cancer and inform therapeutics. We have applied such as integrative approach to the identification of new targeted strategies to induce the differentiation of acute myeloid leukemia (AML) cells. Targeting PML-RARα, the fusion protein present in the majority of patients diagnosed with acute promyelocytic leukemia (APL), demonstrated feasible the use of targeted differentiation therapy in this AML subtype. Emerging data support a role not only for transcription factor-directed therapy, but also for kinase-directed therapy, to induce AML differentiation. In a recent clinical trial the FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib induced differentiation in patients with FLT3-ITD-positive AML, leading to responses in the majority of patients receiving the drug. Moreover, newer agents targeting chromatin regulators (e.g., DOT1L and BRD4) have been demonstrated to induce AML differentiation in vitro and in vivo, lending additional support to the potential of differentiation therapy for this disease. We have applied chemical and functional genomic screens for small-molecule and shRNA inducers of a complex gene expression signature of differentiation. Two high priority metabolic targets emerged at the intersection of these screens and have been validated in AML cells in vitro and in vivo with chemical and genetic perturbagens.
Citation Format: Kimberly Stegmaier. Integrating chemical and functional genomics for leukemia discovery. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA23.
Abstract IA31: Harnessing death for life.
Authors: Vandenberg Cassandra , Cory Suzanne , Bilardi Rebecca , Anstee Natasha , Bouillet Phillipe , Strasser Andreas 
Published: August 2015

Abstract
Impaired apoptosis is a critical step in the development of cancer and a major impediment to effective therapy. Bcl-2, the oncoprotein activated by chromosome translocation in human follicular lymphoma, inhibits cells from undergoing apoptosis in response to many cytotoxic agents. Several close relatives (Bcl-xL, Bcl-w, Mcl-1 and A1) are also anti-apoptotic but others (Bax and Bak) are instead pro-apoptotic, despite strong sequence and structural homology. More distant pro-apoptotic family members, the ‘BH3-only proteins’, are largely unrelated, apart from the signature BH3 (Bcl-2 homology region 3) domain that is essential for their killing function.
Using mouse models, we have shown that over-expression of Bcl-2 or Mcl-1, or loss of the BH3-only protein Bim, exacerbates a variety of lymphoid and myeloid neoplasias. Our recent preclinical studies suggest that small molecules mimicking BH3 domains will be effective cancer therapeutics.
Citation Format: Cassandra Vandenberg, Suzanne Cory, Rebecca Bilardi, Natasha Anstee, Phillipe Bouillet, Andreas Strasser. Harnessing death for life. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA31.
Abstract IA40: Patient-derived tumorgrafts from primary peripheral T-cell lymphoma represent innovative models to design patients' tailored therapies.
Authors: Inghirami Giorgio 
Published: August 2015

Abstract
Peripheral T-cell Lymphoma (PTCL) are a heterogeneous group of tumors with a dismal clinical outcome. The poor response of PTCL patients to conventional treatments is in part due to the lack of known pathogenetic mechanisms and reliable/reproducible in vitro or in vivo models. To overcome some of these limitations, we have constructed a library of Patient Derived Tumografts (PDT) from Anaplastic Large Cell Lymphoma patients in highly immunocompromised mice (NSG). Engraftment lymphoma were serially propagated and interrogated by using massive parallel sequencing platforms [RNAseq and WES], and by additional genomic and immunophenotype strategies. Our data demonstrate conserved similarities between PDT and their corresponding primary lymphoma and the presence of novel recurrent somatic lesions. Co-clinical trials of PDT bearing mice showed responses to therapies analogous to those seen in donor patients and could predict alternative and more successful therapeutic strategies.
ALCL PDT represent informative models to discover patient restricted/pathogenetic lesions and to design more efficient and/or tailored therapies for naïve and chemorefractory PTCL individuals.
Citation Format: Giorgio Inghirami. Patient-derived tumorgrafts from primary peripheral T-cell lymphoma represent innovative models to design patients' tailored therapies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA40.
Abstract PR03: Delineating the roles of lysine 27 methylation-associated epigenetic modulators in T cell leukemia.
Authors: Ntziachristos Panagiotis , Welstead Grant , Trimarchi Thomas , Bakogianni Sofia , Xu Luyao , Vlierberghe Pieter Van , Prinjha Rab , Ferrando Adolfo , Jaenisch Rudolf , Mullighan Charles , Iannis Aifantis 
Published: August 2015

Abstract
The cure rate for childhood acute lymphoblastic leukemia (ALL) has dramatically improved, yet up to 25% of patients experience disease recurrence. T cell ALL (T-ALL) represents 15% of pediatric and 25% of adult ALL and it is classified as a high-risk type of ALL. The aim of the hitherto studies is to specifically block the effects of cancer inducing oncogenes. Recently, we identified inactivating mutations of the polycomb repressive complex 2 (PRC2), the “writer” of Histone 3 lysine 27 methylation, in primary samples from human patients revealing a tumor suppressor role for the complex in T-ALL. Extending our work on the H3K27me3 mark, we now show the oncogenic role for the Jumonji d3 (JMJD3) demethylase. Functionally, genomic ablation of the JMJD3 modulator as well as targeting with a specific inhibitor, GSKJ4, leads to apoptosis and cell cycle arrest of T-ALL lines and primary cells. Genetic ablation of JMJD3 leads to slower initiation of the disease with significantly improved survival rates of the mice. Surprisingly, UTX acts as a tumor suppressor in the context of the same disease, as part of different transcriptional complexes, and we found that it is genetically inactivated in T-ALL patients. Importantly, in light of recent developments on novel epigenetic inhibitors against JMJD3, these findings pave the way to specific pharmacological targeting of T cell leukemia.
Citation Format: Panagiotis Ntziachristos, Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Pieter Van Vlierberghe, Rab Prinjha, Adolfo Ferrando, Rudolf Jaenisch, Charles Mullighan, Aifantis Iannis. Delineating the roles of lysine 27 methylation-associated epigenetic modulators in T cell leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr PR03.
PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex
Authors: Liu Pengda , Gan Wenjian , Chin Y. Rebecca , Ogura Kohei , Guo Jianping , Zhang Jinfang , Wang Bin , Blenis John , Cantley Lewis C. , Toker Alex , Su Bing , Wei Wenyi 
Published: August 2015

Abstract
mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical SIN1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the SIN1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate AKT in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.
Significance: The SIN1-PH domain interacts with the mTOR kinase domain to suppress mTOR activity, and PtdIns(3,4,5)P3 binds the SIN1-PH domain to release its inhibition on the mTOR kinase domain, leading to mTORC2 activation. Cancer patient–derived SIN1-PH domain mutations gain oncogenicity by loss of suppressing mTOR activity as a means to facilitate tumorigenesis. Cancer Discov; 5(11); 1194–209. ©2015 AACR.
See related commentary by Yuan and Guan, p. 1127.
This article is highlighted in the In This Issue feature, p. 1111
Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings
Authors: Nemes Laszlo , Jimenez-Yuste Victor , Rusen Luminita , Cid Ana , Charnigo Robert , Baumann James , Smith Lynne , Korth-Bradley Joan , Rendo Pablo , Lopez Rafael Parra 
Published: August 2015

SummaryThis prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1–139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5 % of bleeding episodes resolved after one infusion. LETE incidence was 0.06 % and 0.19 % in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).
Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133
+
Circulating Angiogenic Cells
Authors: DeJarnett Natasha , Yeager Ray , Conklin Daniel J. , Lee Jongmin , O’Toole Timothy E. , McCracken James , Abplanalp Wes , Srivastava Sanjay , Riggs Daniel W. , Hamzeh Ihab , Wagner Stephen , Chugh Atul , DeFilippis Andrew , Ciszewski Tiffany , Wyatt Brad , Becher Carrie , Higdon Deirdre , Ramos Kenneth S. , Tollerud David J. , Myers John A. , Rai Shesh N. , Shah Jasmit , Zafar Nagma , Krishnasamy Sathya S. , Prabhu Sumanth D. , Bhatnagar Aruni 
Published: August 2015

Objectives—
Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells.

Approach and Results—

In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31
+
/AC133
+
, AC133
+
, CD34
+
/AC133
+
, and CD34
+
/45
dim
/AC133
+
cells) and positively associated with road segment distance (CD31
+
/AC133
+
, AC133
+
, and CD34
+
/AC133
+
cells), traffic intensity (CD31
+
/AC133
+
and AC133
+
cells), and distance-weighted traffic intensity (CD31
+
/34
+
/45
+
/AC133
+
cells).

Conclusions—

Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133
+
. This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.