bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computed tomography, anatomical description and three‐dimensional reconstruction of the lower jaw of Eusthenopteron foordi Whiteaves, 1881 from the Upper Devonian of Canada
Authors: Porro Laura B. , Rayfield Emily J. , Clack Jennifer A. 
Published: August 2015

AbstractThe cranial anatomy of the iconic early tetrapod Eusthenopteron foordi is probably the best understood of all fossil fishes. In contrast, the anatomy of the lower jaw – crucial for both phylogenetics and biomechanical analyses – has been only superficially described. Computed tomography data of three Eusthenopteron skulls were segmented using visualization software to digitally separate bone from matrix and individual bones from each other. Here, we present a new description of the lower jaw of Eusthenopteron based on microcomputed tomography data, including the following: detailed description of sutural morphology and the mandibular symphysis; confirmed occurrence of pre‐ and intercoronoid fossae on the dorsal aspect of the lower jaw; and the arrangement of the submandibular bones. Furthermore, we identify a novel dermal ossification, the postsymphysial, present on the anteromedial aspect of the lower jaw in Eusthenopteron and describe its distribution in other stem tetrapod taxa. Sutural morphology is used to infer load regimes and, along with overall skull and lower jaw morphology, suggests that Eusthenopteron may have used biting along with suction feeding to capture and consume large prey. Finally, visualization software was used to repair and reconstruct the lower jaw, resulting in a three‐dimensional digital reconstruction.
Current Account Adjustment in the Eurozone: Lessons From a Flexible Price Model
Authors: Zwick Christoph 
Published: August 2015

AbstractThis paper discusses the desired size of the internal devaluation in the Eurozone for a scenario of current account adjustment induced by shifts in relative demand. Based on Obstfeld and Rogoff, I develop a four‐region model of the world economy consisting of the Eurozone‐core, Eurozone‐periphery, United States and Asia. In contrast to most of the existing literature, this model structure enables studying the impact of global current account adjustment on the rebalancing process in the Eurozone. In addition, the model allows for movements of factors of production between tradable and non‐tradable sectors. The results point to the important impact of sectoral reallocation and increases in Asian demand on the size of the internal devaluation as well as on the implied length of the adjustment period.
Relationships between community social capital and injury in Canadian adolescents: a multilevel analysis
Authors: Vafaei Afshin , Pickett William , Alvarado Beatriz E 
Published: August 2015

BackgroundCharacteristics of social environments are potential risk factors for adolescent injury. Impacts of social capital on the occurrence of such injuries have rarely been explored.MethodsGeneral health questionnaires were completed by 8910 youth aged 14 years and older as part of the 2010 Canadian Health Behaviour in School-Aged Children study. These were supplemented with community-level data from the 2006 Canada Census of Population. Multilevel logistic regression models with random intercepts were fit to examine associations of interest. The reliability and validity of variables used in this analysis had been established in past studies, or in new analyses that employed factor analysis.ResultsBetween school differences explained 2% of the variance in the occurrence of injuries. After adjustment for all confounders, community social capital did not have any impact on the occurrence of injuries in boys: OR: 1.01, 95% CI 0.80 to 1.29. However, living in areas with low social capital was associated with lower occurrence of injuries in girls (OR 0.78, 95% CI 0.63 to 0.96). Other factors that were significantly related to injuries in both genders were younger age, engagement in more risky behaviours, and negative behavioural influences from peers.ConclusionsAfter simultaneously taking into account the influence of community-level and individual-level factors, community levels of social capital remained a relatively strong predictor of injury among girls but not boys. Such gender effects provide important clues into the social aetiology of youth injury.
Hypoxia Drives Breast Tumor Malignancy through a TET–TNFα–p38–MAPK Signaling Axis
Authors: Wu Min-Zu , Chen Su-Feng , Nieh Shin , Benner Christopher , Ger Luo-Ping , Jan Chia-Ing , Ma Li , Chen Chien-Hung , Hishida Tomoaki , Chang Hong-Tai , Lin Yaoh-Shiang , Montserrat Nuria , Gascon Pedro , Sancho-Martinez Ignacio , Izpisua Belmonte Juan Carlos 
Published: August 2015

Abstract
Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor–initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38–MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα–p38–MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET–TNFα–p38–MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy. Cancer Res; 75(18); 3912–24. ©2015 AACR.
Abstract A11: GIFT4-reprogrammed leukemic B cells for CLL immunotherapy.
Authors: Deng Jiusheng , Cohen Jonathon , Pennati Andrea , Wu Yuanqiang , Yuan Shala , Flowers Christopher , Galipeau Jacques 
Published: August 2015

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of typically CD5 positive B cells. Recently, we have developed a novel GM-CSF and IL-4 Fusion Transgene (named GIFT4), and found that GIFT4 protein triggers a robust anti-tumor B cell response (Deng et al. Cancer Research 2014). Considering CLL B cells broadly express the IL-4 receptor, we tested the immune function of human GIFT4 on CLL B cells, and discovered that GIFT4 protein possess a unique pharmaceutical property and reprograms leukemic B cells into anti-CLL effectors with T-helper features. We showed that GIFT4 protein led to hyper-phosphorylation of STAT5 in primary human CLL cells, which involed cluster of JAK1, JAK2 and JAK3 signaling. GIFT4 treated CLL B-cells up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86. Inhibition of JAK signaling with specific inhibitors suppressed the expression of the co-stimulatory molecules. GIFT4-reprogrammed CLL cells secreted IL-1β, IL-6, ICAM1 and substantial IL-2. GIFT4-CLL B cells further propelled the expansion of IFN-γ-producing autologous cytotoxic T cells and NK cells in vitro. Administration of GIFT4 protein in immune deficient NSG mice decreased the survival of primary CLL cells from patients in murine circulation. Altogether, our data demonstrate that GIFT4 has potent anti-CLL immune function by reprograming leukemic B cells into anti-CLL helper cells. We propose that the newly bio-engineered fusokine GIFT4 could serve as a potential therapeutic for CLL treatment, and GIFT4-reprogrammed leukemic B cells could provide an entirely novel B-cell driven therapeutic strategy for the potential personalized cellular immunotherapy for individuals with CLL.
Citation Format: Jiusheng Deng, Jonathon Cohen, Andrea Pennati, Yuanqiang Wu, Shala Yuan, Christopher Flowers, Jacques Galipeau. GIFT4-reprogrammed leukemic B cells for CLL immunotherapy. [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 A11.
Abstract A12: Combination of the anti-CD38 monoclonal antibody daratumumab and all-trans retinoic acid.
Authors: Nijhof Inger S. , Lokhorst Henk M. , Kessel Berris van , Doshi Parul , Sasser Kate , Mutis Tuna , Donk Niels WCJ van de 
Published: August 2015

Abstract
Background: Daratumumab (DARA) is an anti-CD38 monoclonal antibody (mAb) with lytic activity on multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). In current clinical phase I/II trials, DARA induced anti-MM activity; however, the depth of the response varied between patients. Further improvement of DARA-treatment can be achieved by modulating the mechanisms hampering DARA responsiveness.
Results: In a sub-analysis of 16 MM patients treated with DARA monotherapy (GEN501 trial), we observed that response to DARA was associated with baseline CD38 expression levels on the MM cells (R2= 0.40; P= 0.009). We also observed a significant decrease of CD38 expression on MM cells during DARA-treatment (median MFI decreased from 900 to 83).
Consistent with this idea, in vitro experiments with isogenic MM cell lines expressing different levels of CD38 have revealed that the level of CD38 expression correlates with DARA-mediated ADCC and CDC. Similarly, in bone marrow samples from 125 and 56 MM patients, we observed a significant correlation between CD38 expression and DARA-mediated ADCC (Pearson R= 0.34; P= 0.&lt;0001) as well as CDC (Pearson R= 0.35; P= 0.0038) respectively. Altogether, this suggested that upregulation of CD38 expression, before and during DARA-treatment, may improve the anti-MM activity of DARA.
Indeed, all-trans retinoic acid (ATRA) induced a ~5-fold increase in CD38 expression both in 4 MM cell lines and primary MM cells from 5 DARA-naive patients, which resulted in synergistic improvement of DARA-mediated ADCC and CDC. The synergy between ATRA and DARA was observed not only in DARA-naive patients, but also in 2 DARA-treated patients, whose residual MM cells had lower CD38 expression following therapy.
Conclusion: Our results provide evidence that CD38 expression levels may predict response to DARA. Furthermore, we show that ATRA increases CD38 expression on MM cells, resulting in enhanced DARA-mediated lysis of MM cells. Our results provide the preclinical rationale for further evaluation of DARA combined with ATRA in MM patients.
Citation Format: Inger S. Nijhof, Henk M. Lokhorst, Berris van Kessel, Parul Doshi, Kate Sasser, Tuna Mutis, Niels WCJ van de Donk. Combination of the anti-CD38 monoclonal antibody daratumumab and all-trans retinoic acid. [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 A12.
Abstract A15: In vivo efficacy of a CD38-specific engineered toxin body.
Authors: Robinson Garrett L. , Rajagopalan Sangeetha , Brieschke Brigitte , Erdman Jennifer , Neill Jane , Flores Rodney , Foree Julia , Null William , Liu Jensing , Higgins Jack P. , Willert Erin K. 
Published: August 2015

Abstract
The cell surface glycoprotein CD38 is highly expressed on the surface of several B cell lineage cancers, such as the plasma cell malignancy multiple myeloma, some lymphomas and chronic lymphocytic leukemia (CLL), where it is a marker of unfavorable prognosis. CD38 is a transmembrane receptor and ectoenzyme that is absent or expressed at a low level on most resting leukocytes under normal conditions, making this an appealing target for directed therapy for hematological malignancies. Recent clinical trials with antibodies to CD38 have shown promise in multiple myeloma. While these antibodies rely on the recruitment of an immune response for cytotoxicity, we have developed an engineered toxin body (ETB) comprising a CD38 binding scFv and a modified Shiga-like Toxin A subunit capable of specifically recognizing and directly killing CD38 expressing cells. The CD38 targeted ETB has a different mechanism of action than current treatments for multiple myeloma (such as immunomodulatory agents, protease inhibitors and chemotherapies). Our CD38 targeted ETB has shown to be well tolerated in mice and displays dose dependent efficacy in a CD38 positive tumor setting. The CD38 targeted ETB significantly reduced tumor burden and increased survival over a 40-fold dose range in a disseminated Daudi xenograft, early treatment model. In this setting, the mean tumor burden at day 28 was reduced to 29% of control for the lowest dose group (0.05 mg/kg) and less than 1% of control for the two higher doses (0.5 and 2 mg/kg). Median survival of the control, untreated group was 34 days; the low dose group had extended median survival to 59.5 days and, at the day 60 study end, 90 or 100% of mice were alive in the higher two dosing groups. Our results show that the CD38 targeted ETB is a promising targeted therapeutic agent against CD38 positive cancer cells and is currently under further development.
Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney Flores, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert. In vivo efficacy of a CD38-specific engineered toxin body. [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 A15.
Abstract A27: Risk of hematopoietic cancer associated mortality among workers in the poultry slaughtering and processing industries.
Authors: Bangara Saritha , Felini Martha J. , Aryal Subhash , Sterling David , Johnson Eric S. 
Published: August 2015

Abstract
Objectives: Previous occupational cohort studies among poultry workers have revealed an excess risk of cancer-related mortality, including deaths due to hematopoietic malignancies. However, specific occupational and non-occupational exposures contributing to this excess risk have yet to be identified. Poultry workers are particularly at high risk since an average of 175,000 chickens are killed daily in poultry plants in the United States. This brings poultry workers into intimate contact with their blood, organs, and secretions, which may harbor transmissible oncogenic viruses. Moreover, they are exposed to potentially carcinogenic chemicals that are emitted during packaging and preparation. Hence, our study was conducted to provide preliminary evidence of which specific poultry related and non-poultry related occupational tasks increase the risk of mortality from hematopoietic cancer among poultry workers.
Methods: A pilot case-cohort study was conducted using a combined cohort of 30,411 highly exposed poultry workers and 16,408 control subjects. Exposures pertaining to poultry and non-poultry related tasks were self-reported through telephone interviews from controls and next-of-kin for cases. Hematopoietic cancer mortality risk was assessed using logistic regression odds ratios (OR) and proportional hazard ratios (HR).
Results: One hundred fifty-two cases of hematopoietic cancer occurred in this cohort between January 1, 1990 and December 31, 2003. Since this is a feasibility study, exhaustive attempts were not made to identify study subjects and their next of kin. Thus, we report here on the first 52 (69%) of the 75 cases whose next-of-kin were traced. Similarly, of the first 214 controls that were traced, 152 (71%) completed interviews. Preliminary analysis is currently underway to identify the specific task exposures contributing to this excess risk.
Conclusion: We expect the results of our study will confirm known risk factors related to hematopoietic cancers, and uncover new risk exposures that have yet to be appreciated in the general population due to their low level exposures. Using high-risk unique populations offers an opportunity to better understand molecular mechanisms that investigators may explore to aid in future drug development.
Citation Format: Saritha Bangara, Martha J. Felini, Subhash Aryal, David Sterling, Eric S. Johnson. Risk of hematopoietic cancer associated mortality among workers in the poultry slaughtering and processing industries. [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 A27.
Abstract A39: Initial characterization of genetically engineered mice carrying a conditional allele of a splicing factor gene (U2AF1) commonly mutated in myeloid disorders.
Authors: Varmus Harold 
Published: August 2015

Abstract
Putative “driver” mutations in genes encoding splicing factors---including recurrent mutations in U2AF1, which encodes a component of the U2 auxiliary factor to regulate pre-mRNA splicing---have been identified in myeloid dysplasias, related neoplasms, and lung adenocarcinomas. To study the functional impact of U2AF1 mutations, we have created transgenic mice carrying a conditional mutant allele, MG-S34F, at the endogenous U2AF1 locus. We have crossed the MG-S34F mice with mice carrying a Mx1-Cre transgene, and demonstrated efficient Cre-mediated recombination and expression of U2AF1-S34F in bone marrow cells two weeks after treatment with poly IC. Bone marrow cells from compound transgenic mice had a modest but statistically significant reduction in their ability to form monocyte and granulocyte colonies in culture. A small cohort of mice is also being followed for long-term hematologic defects after exposing these mice to low doses of N-ethyl-N-nitrosourea (ENU). While U2AF1-S34F expression coupled with ENU treatment has not produced myeloid leukemia after 3 months, a low ratio of U2AF1-S34F to wild-type U2AF1 RNA in blood cells implies that expression of U2AF1-S34F affects normal hematopoiesis or survival of blood cells in mice. We are now expanding our mouse cohort to study the hematologic defects apparently induced by U2AF1-S34F in greater detail.
Citation Format: Dennis Liang Fei, Harold Varmus. Initial characterization of genetically engineered mice carrying a conditional allele of a splicing factor gene (U2AF1) commonly mutated in myeloid disorders. [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 A39.
Abstract A40: Megakaryocyte endomitosis requires Pak2 to regulate actin and microtubule networks.
Authors: Kosoff Rachelle E. , Chernoff Jonathan 
Published: August 2015

Abstract
Megakaryocytes mature and differentiate into polyploid cells in the bone marrow, and migrate from the osteoblastic niche to the vascular niche by means of an SDF-1α gradient, culminating in the release of platelets into circulation. Failure to do so results in myeloproliferative disorders, which can manifest as thrombocytopenia. Many chemotherapeutic agents are known to induce thrombocytopenia and other platelet disorders. Regulation of megakaryocyte differentiation and polyploidization is controlled by MAPK associated proteins, and cytoskeleton regulating proteins. p21-activated kinase 2 (Pak2) is known to regulate these two pathways, but nothing is currently known about the role of Pak2 in megakaryocyte biology. In our study, we sought to demonstrate that Pak2 is essential for proper megakaryocyte differentiation, maturation and polyploidization, in vivo and in vitro. Inducible deletion of Pak2fl/fl results in 100% lethality within 20 days of cre induction, specifically in hematopoietic tissues (Mx1-cre). Peripheral blood analysis demonstrates thrombocytopenia (reduced platelet counts), along with increased neutrophil count (neutrophilia) and decreased lymphocyte count. Bone marrow histology and analysis by flow cytometry demonstrates altered megakaryocyte differentiation, observed by elevated megakaryocyte(Mk) precursors in the bone marrow (Lin-ckit+Sca1- CD150+CD41+), elevated mature bone marrow Mks (CD41+), increased number of polyploid cells(&gt;8N) and hyperplastic megakaryocytes. In vitro culture of bone marrow derived Pak2-null megakaryocytes demonstrates elevated polyploidization, altered β1-tubulin structure and reduced platelet formation. Additionally, cre activation in platelets and megakaryocytes using a PF4-cre driver (platelet factor 4) recapitulates the enhanced polyploidization phenotype observed in the Mx1-cre model. Ultimately, we demonstrate that Pak2 signals through LIMK, cofilin, and myosin light chain 2 (MLC2) to regulate megakaryocyte cytoskeleton during differentiation and polyploidization.
In summary, Pak2 is an important regulator of megakaryocyte maturation and platelet formation in vivo via regulation of proteins involved in cytoskeletal dynamics.
Citation Format: Rachelle E. Kosoff, Jonathan Chernoff. Megakaryocyte endomitosis requires Pak2 to regulate actin and microtubule networks. [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 A40.
Abstract B09: Exploiting oncogene-induced DNA replicative stress as synthetic lethal approach to target myeloma.
Authors: Cottini Francesca , Hideshima Teru , Richardson Paul , Anderson Kenneth , Tonon Giovanni 
Published: August 2015

Abstract
This abstract is being presented as a short talk. A full abstract is printed in the Proffered Abstracts section (PR04) of the Conference Proceedings.
Citation Format: Francesca Cottini, Teru Hideshima, Paul Richardson, Kenneth Anderson, Giovanni Tonon. Exploiting oncogene-induced DNA replicative stress as synthetic lethal approach to target myeloma. [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 B09.