bluuebunny/crossref_metadata_2025 huggingface dataset:
CFD-Based Transient Ignition Probability Modeling of Gas Leaks in Enclosures
Authors: Kumaresh Govindan Radhakrishnan , Fossan Ingar , Venkatraman Marutha Muthu , Giljarhus Knut Erik , Spangelo Øystein , Jensen Stian
Published: August 2015

Risk management of loss of containment at facilities processing or storing liquid flammable fluids is crucial in order to ensure safe operations. To control the risk, an extensive set of safety functions are in general implemented in design, for example systems that minimize the occurrence for initiating events (e.g., spontaneous leak of flammable material due to fatigue) and measures that reduce explosion loads arising in case of delayed ignition of the dispersed fluid mixed with air. Effective ventilation of the released fluid that potentially generates an explosive atmosphere (gas and/or droplets generated from the liquid phase) is one of the crucial barrier elements to mitigate the explosion hazard. Hence, the gas explosion hazard in enclosed modules with poor ventilation is of particular concern as a flammable mixture may accumulate even for small release rates. This may result in both high likelihood of ignition and considerable explosion loads in case of ignition due to the big amount of chemical energy taking part in the combustion process relative to the size of the enclosure. Computational fluid dynamics (CFD) methods are increasingly being used to characterize the consequences of leaks of flammable fluid in complex geometries, both modeling of the initial gas dispersion process and the resulting explosion and fire loads following from the combustion process in case of ignition. This paper presents an advanced methodology based on the CFD tool OpenFOAM for detailed assessment of the transient gas dispersion process and the associated likelihood of ignition for leaks of flammable fluid inside enclosures. The objective is to understand how to optimize the design of safety functions that affect the fire and explosion risk picture. This custom made tool, denoted cloudIgnitionFoam, accounts for the transient gas leak behavior based on real-time gas detection, subsequent initiation of emergency shutdown (ESD) and blow down systems and computes ignition probability based on the transient history of the dispersed gas cloud. The consistent methodology based on the CFD technology available in OpenFOAM and its ability to present the results in detail leverages the risk-based decision process. Measures that can be assessed quantitatively includes number and types of gas detectors and their optimal positioning, ignition source isolation, gas detection system voting philosophy, capacity of depressurization system and structural integrity of explosion barriers.
Representations of a rational number as a sum of odd powers
Authors: Reynya M. A.
Published: August 2015

In this paper, we substantially generalize one of the results obtained in our earlier paper [M. A. Reynya, Symmetric homogeneous Diophantine equations of odd degree, Int. J. Number Theory 28 (2013) 867–879]. We present a solution to a problem of Waring type: if [Formula: see text] is a symmetric form of odd degree [Formula: see text] in [Formula: see text] variables, then for any [Formula: see text], [Formula: see text], the equation [Formula: see text] has rational parametric solutions, that depend on [Formula: see text] parameters.
b-Chromatic sum of a graph
Authors: Lisna P. C. , Sunitha M. S.
Published: August 2015

A b-coloring of a graph G is a proper coloring of the vertices of G such that there exists a vertex in each color class joined to at least one vertex in each other color classes. The b-chromatic number of a graph G, denoted by [Formula: see text], is the maximum integer [Formula: see text] such that G admits a b-coloring with [Formula: see text] colors. In this paper we introduce a new concept, the b-chromatic sum of a graph [Formula: see text], denoted by [Formula: see text] and is defined as the minimum of sum of colors [Formula: see text] of [Formula: see text] for all [Formula: see text] in a b-coloring of [Formula: see text] using [Formula: see text] colors. Also obtained the b-chromatic sum of paths, cycles, wheel graph, complete graph, star graph, double star graph, complete bipartite graph, corona of paths and corona of cycles.
Micro photosynthetic power cell for power generation from photosynthesis of algae
Authors: Shahparnia Mehdi , Packirisamy Muthukumaran , Juneau Philippe , Zazubovich Valter
Published: August 2015

Devices such as solar and fuel cells have been studied for many decades and noticeable improvements have been achieved. This paper proposes a Micro Photosynthetic Power Cell (μPSC) as an alternative energy-harvesting device based on photosynthesis of blue-green algae. The effect of important biodesign parameters on the performance of the device, such as no-load performance and voltage–current (V–I) characteristics, were studied. Open-circuit voltage as high as 993 mV was measured while a peak power of 175.37 μW was obtained under an external load of 850 Ω. The proposed μPSC device could produce a power density of 36.23 μW/cm2, voltage density of 80 mV/cm2 and current density of 93.38 μA/cm2 under test conditions.
Pre-break-up palaeostress state along the East Greenland margin
Authors: Guarnieri Pierpaolo
Published: August 2015

This paper describes intraplate deformation and the palaeostress state along the East Greenland margin during the Paleocene between 65 and 55 myr ago, prior to the onset of the NE Atlantic spreading. It is shown that the pre-break-up deformation is the result of dip-oblique/strike-slip tectonics in the SE and compressive tectonics in the north. The reduced palaeostress tensors derived from inversion of the fault-slip data show that the maximum horizontal stress σ
1
is compressive and the orientations of σ
1
change from ENE–WSW in the south to NNE–SSW in the north. The reconstructed palaeostress trajectory map demonstrates that the σ
1
orientations reflect the plate motion path and define small circles whereas the trends of the minimum horizontal stress σ
3
converge and cluster around an area in the Arctic that is interpreted as the rotation pole of Greenland. The intraplate deformation, folding and uplift that affected the Greenland and European margins, the Barents Sea and the North Sea during the Paleocene can be explained by the counter-clockwise rotation of Greenland. The present paper calculates the pole of rotation of Greenland using the kinematics of brittle faults along the plate margin and the palaeostress derived from inversion of fault-slip data analysis as an indicator of motion path.
Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro
Authors: Meir Michael , Flemming Sven , Burkard Natalie , Bergauer Lisa , Metzger Marco , Germer Christoph-Thomas , Schlegel Nicolas
Published: August 2015

Recent data suggest that neurotrophic factors from the enteric nervous system are involved in intestinal epithelial barrier regulation. In this context the glial cell line-derived neurotrophic factor (GDNF) was shown to affect gut barrier properties in vivo directly or indirectly by largely undefined processes in a model of inflammatory bowel disease (IBD). We further investigated the potential role and mechanisms of GDNF in the regulation of intestinal barrier functions. Immunostaining of human gut specimen showed positive GDNF staining in enteric neuronal plexus and in enterocytes. In Western blots of the intestinal epithelial cell lines Caco2 and HT29B6, significant amounts of GDNF were detected, suggesting that enterocytes represent an additional source of GDNF. Application of recombinant GDNF on Caco2 and HT29B6 cells for 24 h resulted in significant epithelial barrier stabilization in monolayers with immature barrier functions. Wound-healing assays showed a significantly faster closure of the wounded areas after GDNF application. GDNF augmented cAMP levels and led to significant inactivation of p38 MAPK in immature cells. Activation of p38 MAPK signaling by SB-202190 mimicked GDNF-induced barrier maturation, whereas the p38 MAPK activator anisomycin blocked GDNF-induced effects. Increasing cAMP levels had adverse effects on barrier maturation, as revealed by permeability measurements. However, increased cAMP augmented the proliferation rate in Caco2 cells, and GDNF-induced proliferation of epithelial cells was abrogated by the PKA inhibitor H89. Our data show that enterocytes represent an additional source of GDNF synthesis. GDNF contributes to wound healing in a cAMP/PKA-dependent manner and promotes barrier maturation in immature enterocytes cells by inactivation of p38 MAPK signaling.
Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox
Authors: DiStasi Matthew R. , Mund Julie A. , Bohlen H. Glenn , Miller Steven J. , Ingram David A. , Dalsing Michael C. , Unthank Joseph L.
Published: August 2015

The present study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors associated with oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities including diabetes and hyperlipidemia were used as a preclinical model. Arterial occlusion was induced by distal femoral artery ligation in lean and DIO mice. Proximal collateral arteries were identified as the site of major (∼70%) vascular resistance to calf perfusion by distal arterial pressures, which decreased from ∼80 to ∼30 mmHg with ligation in both lean and DIO mice. Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice as evidenced by increased perfusion (147 ± 48% vs. 49 ± 29%) and collateral diameter (151 ± 30% vs. 44 ± 17%). Vascular mRNA expression of p22phox, Nox2, Nox4, and p47phox were all increased in DIO mice. Treatment of DIO mice with either apocynin or Nox2ds-tat or with whole body ablation of either Nox2 or p47phox ameliorated the impairment in both collateral growth and hindlimb perfusion. Multiparametric flow cytometry analysis demonstrated elevated levels of circulating monocytes in DIO mice without impaired mobilization and demargination after femoral artery ligation. These results establish collateral resistance as the major limitation to calf perfusion in this preclinical model, demonstrate than monocyte mobilization and demarginatin is not suppressed, implicate Nox2-p47phox interactions in the impairment of vascular compensation to arterial occlusion in DIO mice, and suggest that selective Nox component suppression/inhibition may be effective as either primary or adjuvant therapy for claudicants.
Cigarette smoke has sensory effects through nicotinic and TRPA1 but not TRPV1 receptors on the isolated mouse trachea and larynx
Authors: Kichko Tatjana I. , Kobal Gerd , Reeh Peter W.
Published: August 2015

Cigarette smoke (CS) exposes chemosensory nerves in the airways to a multitude of chemicals, some acting through the irritant receptors TRPV1 and TRPA1 but potentially also through nicotinic acetylcholine receptors (nAChR). Our aim was to characterize the differences in sensory neuronal effects of CS, gas phase, and particulate matter as well as of typical constituents, such as nicotine and reactive carbonyls. Isolated mouse trachea and larynx were employed to measure release of calcitonin gene-related peptide (CGRP) as an index of sensory neuron activation evoked by CS, by filtered CS gas phase essentially free of nicotine, and by dilute total particulate matter (TPM) containing defined nicotine concentrations. With CS stimulation of the superfused trachea, TRPV1 null mutants showed about the same large responses as wild-type mice, whereas both TRPA1−/− and double knockouts exhibited 80% reduction; the retained 20% response was abolished by mecamylamine (10 μM), indicating a distinct contribution of nAChRs. These phenotypes were accentuated by using TPM to stimulate the immersed trachea; 50% of response was retained in TRPA1−/− and abolished by mecamylamine. In contrast, the gas phase acted like a sheer TRPA1 agonist, consistent with its composition, among other compounds, of volatile reactive carbonyls like formaldehyde and acrolein. In the trachea, the gas phase and CS were equally effective in releasing CGRP, whereas the larynx showed much larger CS than gas phase responses. Thus nicotinic receptors contribute to the sensory effects of cigarette smoke on the trachea, which are dominated by TRPA1. How this translates to human perception affords future research.
Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53
Authors: Zhang Shengliang , Zhou Lanlan , Hong Bo , van den Heuvel A. Pieter J. , Prabhu Varun V. , Warfel Noel A. , Kline Christina Leah B. , Dicker David T. , Kopelovich Levy , El-Deiry Wafik S.
Published: August 2015

The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling. Cancer Res; 75(18); 3842–52. ©2015 AACR.
Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells
Authors: Kwak Yeonui , Cho Hanna , Hur Wooyoung , Sim Taebo
Published: August 2015

Uncontrolled activation of FGFRs induces the progression of various cancers. It was recently reported that FGFR2-activating mutants are implicated in about 12% of endometrial carcinomas. AZD4547, a potent pan-FGFR inhibitor, is currently being evaluated in clinical trials for several FGFR-driven cancers. However, AZD4547 has not been examined yet against FGFR2 mutant–driven endometrial cancers. Thus, we evaluated the activity of AZD4547 against four different endometrial cancer cells, including AN3-CA, MFE296, MFE280, and HEC1A, where all but HEC1A cells express distinctive FGFR2 mutations. We found that AZD4547 exhibits potent antiproliferative activity (EC50 = 31 nmol/L) against AN3-CA cells harboring FGFR2-K310R/N550K mutant. Analysis using a phospho-kinase array revealed that AZD4547 blocks FGFR2 downstream signaling, such as p38, ERK1/2, JNK, p70S6K, and PLCγ. Moreover, oral administration of AZD4547 (30 mg/kg, every day) remarkably delayed tumor growth in a mouse xenograft model of AN3-CA cells. Unbiased reporter gene assay showed that AZD4547 antagonizes the aFGF-induced activation of several transcription factors, including EGR1, ELK-1/SRF, AP-1, and NFκB. Genome-wide transcriptome analysis revealed that AZD4547 perturbs a number of transcriptions, and EGR1 was identified as one of the major targets of AZD4547. The significance of the FGFR2–EGR1 axis in endometrial cancer progression has not been reported. In addition, using kinome-wide inhibition profiling analysis, we first identified potential new target kinases of AZD4547, including MAP4K3, MAP4K5, IRR, RET, and FLT3. Our study demonstrated that AZD4547 exhibits its therapeutic activity against endometrial cancer cells by perturbing various regulatory mechanisms related to FGFR signaling. Mol Cancer Ther; 14(10); 2292–302. ©2015 AACR.
Abstract A07: Loss of Rpl22 promotes tumor progression through regulation of angiogenesis and dissemination.
Authors: Rao Shuyun , Stadanlick Jason E. , Cai Kathy Q. , David Wiest L.
Published: August 2015

Mutations in ribosomal proteins (RP) often cause bone marrow syndromes associated with increased risk for cancer development. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia (T-ALL). Indeed, loss of one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFκB-dependent manner. Moreover, mice lacking both Rpl22 alleles exhibited significantly increased thymic tumor size, which was associated with poor survival and markedly enhanced angiogenesis relative to Rpl22 heterozygous mice or wild type. The increased angiogenesis in the mediastinal mass was linked to upregulation of VEGFA and downregulation of S1P1. Loss of S1P1 is sufficient to block egress of lymphoma cells from thymus. Rpl22-deficient thymic lymphoma lines also exhibit enhanced growth upon adaptation to growth in vitro, and this is reversed by ectopic expression of Rpl22. Rpl22 expression also represses the expression of proteins that promote traversal of the cell cycle. Collectively, the increased tumor growth and angiogenesis, and the blockade of thymic egress contribute to the enlarged mediastinal masses observed in Rpl22-deficient mice. Rpl22-mutant T-ALL are a molecularly distinct subtype exhibiting increased aggression and treatment resistance. Accordingly, our identification of a number of signaling pathways controlled by Rpl22 may enable the development of novel strategies, such as targeting angiogenesis, in such cases of T-ALL.

Citation Format: Shuyun Rao, Jason E. Stadanlick, Kathy Q. Cai, Wiest L. David. Loss of Rpl22 promotes tumor progression through regulation of angiogenesis and dissemination. [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 A07.
Abstract A33: Role for the tumor suppressor phf6 in hematopoiesis.
Authors: Moore Finola E. , Esain Virginie , Lobbardi Riadh , Blackburn Jessica S. , North Trista E. , Langenau David M.
Published: August 2015

Plant Home domain Finger 6 (PHF6) is a tumor suppressor of unknown function for blood malignancies such as T-cell Acute Lymphoblastic Leukemia (T-ALL), Acute Myeloid leukemia (AML), and Chronic Myeloid Leukemia (CML). PHF6 contains two zinc finger-like PH domains and interacts with the Nucleosome Remodeling and Deacetylation (NuRD) complex, suggesting a role in chromatin remodeling. Although PHF6 loss-of-function mutations are found in nearly 40% of T-ALL patients, little is known about how PHF6 mutations contribute to blood development and leukemogenesis. To understand the function of PHF6, beginning with its role in hematopoiesis, we have undertaken developmental studies in zebrafish to discover how loss of phf6 affects blood development and to determine which pathways are regulated by phf6. Zebrafish will be used to study hematopoiesis due to the remarkable conservation of molecular pathways that regulate blood development, genetic tractability, and ability to observe embryonic development over a short window of time. RNA in situ hybridization studies of zebrafish embryos showed that phf6 is expressed broadly during zebrafish development, and especially in the dorsal aorta, a site analogous to the aorta-gonad-mesonephros (AGM) in mammals, from which hematopoietic stem cells (HSCs) arise. Further, phf6 is highly expressed in lymphocytes of adult zebrafish, reminiscent of the expression patterns found in human and mouse. To determine the effect of phf6 loss on hematopoiesis, phf6 expression was knocked down by morpholino injection. We find that phf6 morphants have increased numbers of HSCs by RNA in situ hybridization of runx1/cmyb in the AGM and caudal hematopoietic tissue ((CHT) analogous to mammalian fetal liver), sites of HSC emergence and migration. Later in development, phf6 morphants demonstrate increased lymphocytes by RNA in situ hybridization of rag1 at the thymus. Similar phenotypes were observed in homozygous phf6-null mutants generated by TALEN-mediated knockout. Phf6-null mutant zebrafish survive to Mendelian ratios and are fertile as adults. In total, we found a new role for phf6 in regulation of HSC formation.

Citation Format: Finola E. Moore, Virginie Esain, Riadh Lobbardi, Jessica S. Blackburn, Trista E. North, David M. Langenau. Role for the tumor suppressor phf6 in hematopoiesis. [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 A33.
Abstract A45: Osteoblastic niche supports the growth of quiescent multiple myeloma cells.
Authors: Chen Zheng , Orlowski Robert Z. , Wang Michael , Kwak Larry , McCarty Nami
Published: August 2015

The heterogeneity of multiple myeloma (MM) contributes to variable responses to therapy. In this study, we aim to correlate the heterogeneity of MM to the presence of quiescent cells using the PKH26 dye. We tracked the rare quiescent cells in different niches of the bone marrow by allowing the cells to cycle in vivo. Surprisingly, quiescent PKH+ MM cells prefer to reside within the osteoblastic niches of the bone marrow (PKH+/OS) rather than the vascular niches or the spleen. These cells (PKH+/OS) displayed enhanced stem-like properties by forming colonies in semi-solid medium. PKH+ cells were highly tumorigenic, as compared to PKH- cells, and were resistant to a variety of drugs. However, the levels of drug resistance were somewhat similar regardless of where the PKH+ cells were isolated. Our data indicate that osteoblastic niches support the growth of quiescent PKH+ cells and allow them to have stem-like functions.

Citation Format: Zheng Chen, Robert Z. Orlowski, Michael Wang, Larry Kwak, Nami McCarty. Osteoblastic niche supports the growth of quiescent multiple myeloma cells. [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 A45.
Abstract B14: Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis.
Authors: Roderick Justine R. , Hermance Nicole C. , Zelic Matija , Polykratis Apostolos , Pasparakis Manolis , Kelliher Michelle A.
Published: August 2015

The serine/threonine kinase RIPK1 is recruited to the TNF receptor 1 to mediate pro-inflammatory signaling and to regulate TNF-induced apoptosis and necroptosis. The kinase activity of RIPK1 is required for RIPK3 activation and induction of necroptosis, an inflammatory form of cell death. Although Ripk3-/- mice are viable, a RIPK1 deficiency results in postnatal lethality. To identify the lineages and cell types that depend on RIPK1 for survival, we generated conditional Ripk1 mice. Tamoxifen administration to adult RosaCreERT2Ripk1fl/fl mice results in lethality due to cell death in the intestinal and hematopoietic lineages. Similarly, Ripk1 deletion in cells of the hematopoietic lineage stimulates pro-inflammatory cytokine and chemokine production and hematopoietic cell death, resulting in bone marrow failure. The cell death reflects cell intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. We demonstrate that a RIPK3 deficiency partially rescues hematopoiesis in Vav-iCre Ripk1fl/fl mice, revealing that RIPK1 mediates survival by preventing RIPK3-mediated necroptosis. However, Vav-iCre Ripk1fl/fl Ripk3-/- progenitors remain TNF sensitive in vitro and fail to repopulate irradiated mice. These genetic studies reveal that a hematopoietic RIPK1 deficiency triggers both apoptotic and necroptotic death that is partially prevented by a RIPK3 deficiency. Thus, in contrast to in vitro studies, RIPK1 functions in hematopoietic cells to negatively regulate RIPK3 and prevent inflammation.

Citation Format: Justine R. Roderick, Nicole C. Hermance, Matija Zelic, Apostolos Polykratis, Manolis Pasparakis, Michelle A. Kelliher. Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis. [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 B14.
Abstract B21: Identifying mechanisms of resistance to BET bromodomain inhibition.
Authors: Centore Richard C. , Hatton Charlie , Bryant Barbara , Sims Robert J.
Published: August 2015

BET (bromodomain and extra terminal domain) family members are key transcriptional regulators that play an important role driving oncogene expression in hematologic malignancies. Several BET inhibitors (BETi) have recently entered clinical trials, including the optimized BET inhibitor CPI-0610. Understanding mechanisms of resistance to BET inhibition represents an important challenge and will likely provide insight into mechanisms of BET sensitivity. Here, we have developed a model of BETi resistance in AML using the BET inhibitor, CPI-203. Resistant cells demonstrate half-maximal growth inhibition at a concentration of CPI-203 that is greater than 10-fold that of parental cells. When challenged with CPI-203, parental cells undergo apoptosis, a phenomenon that correlates with strong suppression of MYC and the anti-apoptotic gene, BCL2. In resistant cells, transcription of MYC and BCL2 is maintained in the presence of BETi, and the apoptotic effect is severely blunted. Interestingly, withdrawal of BETi from the resistant cells triggers apoptosis, suggesting an acquired dependency on BET inhibition in these cells. To further understand the molecular mechanisms responsible for maintenance of MYC expression in resistant cells, we performed gene expression profiling and functionally interrogated transcriptional co-regulators that may facilitate BET-escape. Despite inhibition of BET proteins, MYC transcription in resistant cells remained dependent on acetyl-lysine signaling and non-BET chromatin adaptors. In summary, our work models resistance to a novel therapy and sheds light on additional targets that may allow cancer cells to bypass BETi-induced cell death.

Citation Format: Richard C. Centore, Charlie Hatton, Barbara Bryant, Robert J. Sims, III. Identifying mechanisms of resistance to BET bromodomain inhibition. [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 B21.
Abstract B37: The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells.
Authors: Trendowski Matthew
Published: August 2015

Background/Aim: Sonodynamic therapy (SDT) is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the efficacy of ultrasound's preferential damage to neoplastic cells. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Cytochalasin B is a cytokinesis inhibitor that preferentially enlarges and multinucleates malignant cells, making them much more sensitive to ultrasonic irradiation.

Materials and Methods: The present study investigated the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood cell populations. Cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm2).

Results: Cytochalasin B preferentially damages U937 cells both before and after sonication. This agent also reduces rapid proliferation as the clonogenicity of U937 cells was considerably reduced following treatment.

Conclusion: Cytochalasin B may have profound therapeutic applications when combined with SDT.

Citation Format: Matthew Trendowski. The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells. [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 B37.
Abstract IA07: Multiple myeloma as a model of bone metastasis.
Authors: Ghobrial Irene
Published: August 2015

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

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

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

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

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

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

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

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

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