bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B9: Abnormalities in cellular and humoral immunity in breast cancer patients resistant to endocrine therapy.
Authors: Zavadova Eva , Konopasek Bohuslav , Vocka Michal , Miskovicova Michaela , Spacek Jan , Fucikova Terezie , Petruzelka Lubos 
Published: August 2014

Abstract
Defects in the immune response correlated with poor prognosis and therefore in recent years, research focused on a precise description of the status and function of the immune system and its possible effect in cancer patients.
Although more than 2/3 of treated patients respond to the endocrine therapy, most patients with metastatic breast cancer will develop resistance.. It appears that other factor contributing to the resistance may be a transforming factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates production of vascular endothelial growth factor /VEGF.
The purpose of the study was to monitor immune responses in patients with hormone receptor positive breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, CD8, HLA-DR) as well as humoral immunity. TGF beta, and VEGF production was monitored and we analyzed the changes during hormonal treatment.
Methods: 85 patients included in the research project were implemented routine cancer treatment with endocrine therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF beta, VEGF were measured by ELISA and anti-tumor cellular immunity (CD4, CD8, antigen presenting cells ) were measured by flow cytometry.
Results In patients with resistance to endocrine therapy mainly depression in cellular immunity was found. Immunglobulin plasma level was decreased as well (mainly IgG4 subtype). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections) TGF beta as well as VEGF plasma level were increased. Significant increase of autoantibodies production was found, particularly in those, involved into blood coagulation process/anti phospholipide and anti cardiolipin autoantibodies.
Conclusion Correlation of these factors with resistance to hormonal therapy, and the state of anticancer immunity could help in the future with the prediction of resistance to hormonal therapy and contribute to the selection of targeted immune therapy in cancer patients.
Dedication: This project was supported by grant IGA NT11168-3/2010.
Citation Format: Eva Zavadova, Bohuslav Konopasek, Michal Vocka, Michaela Miskovicova, Jan Spacek, Terezie Fucikova, Lubos Petruzelka. Abnormalities in cellular and humoral immunity in breast cancer patients resistant to endocrine therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B9.
Abstract B90: Eribulin mesylate alters immune homeostasis in mice bearing syngeneic tumors.
Authors: Albu Diana I. , Kumar Namita , Kusnetzov Galina , Xu Shanqin , Littlefield Bruce , Woodall-Jappe Mary 
Published: August 2014

Abstract
Numerous studies indicate that certain tumor-infiltrating macrophage subsets can support neoplastic growth. Recent reports showed that spleen can serve as an important reservoir for macrophages and neutrophils that replicate in situ, then migrate to support tumor growth. Eribulin mesylate (Halaven®) is a microtubule-dynamics inhibitor approved for third line clinical use in patients with heavily pretreated metastatic breast cancer based upon statistically significant increase in median overall survival (OS) compared to treatment of physician's choice. In an effort to understand whether eribulin has additional effects beyond its anti-mitotic activity, the current study addressed the effects of eribulin mesylate on immune cells. Using the subcutaneous syngeneic murine tumor model Lewis lung carcinoma (LLC), we found that the tumor shrinking effect of eribulin correlated with increased extramedullary hematopoiesis observed in the spleens of treated mice. Eribulin was also found to inhibit the proliferation of M2 tumor-associated macrophages (TAMs) in the spleens of LLC-bearing mice. Early effects of eribulin were studied using the CT-26 colon tumor isograft model and included increased differentiation and death of CD4+ and CD8+ effector T cells. Furthermore, eribulin caused increased CD25 expression on CD4+ Foxp3- T cells but not on CD4+ Foxp3+ T regulatory cells. Finally, frequencies of exhausted CD8+ T cells were reduced following eribulin treatment. Taken together, these results suggest that eribulin-mediated modulation of immune homeostasis especially in the spleen, may contribute to its anti-tumor effect.
Citation Format: Diana I. Albu, Namita Kumar, Galina Kusnetzov, Shanqin Xu, Bruce Littlefield, Mary Woodall-Jappe. Eribulin mesylate alters immune homeostasis in mice bearing syngeneic tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B90.
Abstract B97: The role of JNK isoforms in adenovirus-induced autophagy: Implications for cancer immunotherapy using oncolytic adenoviruses.
Authors: Klein Sarah R. , Jiang Hong , Piya Sujan , Lu Zhimin , Gomez-Manzano Candelaria , Fueyo Juan 
Published: August 2014

Abstract
Glioblastoma multiforme is the most common and lethal form of primary brain tumor in adults. Targeted immunotherapy using recombinant oncolytic viruses is a promising strategy for the treatment of brain tumors. Delta-24-RGD is a highly selective and potent oncolytic adenovirus that induces autophagy in malignant gliomas. Data from our ongoing clinical trial suggested Delta-24-RGD initiated an anti-tumor immune response in patients. Importantly, autophagy promotes the presentation of viral antigens for activation of immune cells; therefore, we sought to elucidate the molecular mechanisms by which adenoviruses induce autophagy. Adenoviral replication induced phosphorylation of JNK that was required for autophagy. Our results indicated that JNK regulates autophagy through Bcl-2 phosphorylation and consequent dissociation of Bcl-2 and beclin 1. Contrary to starvation-induced autophagy, adenovirus-mediated autophagy was facilitated by both JNK1 and JNK2 isoforms of JNK. Moreover, our data indicated that adenoviral antigens were presented at the cell surface, which was ablated upon down-regulation of JNK or autophagy. We propose a JNK/autophagy-dependent mechanism for the immune presentation of viral antigens that can be leveraged when developing recombinant adenoviruses for the advancement of anti-tumor immunotherapy. Thus, we developed a genetically-modified Delta-24 adenovirus expressing an EGFRvIII epitope that is aberrantly expressed in gliomas. The majority (&gt;80%) of cells infected with Delta-24-FvIII presented the fiber-bound EGFRvIII epitope on their surface, an effect that was diminished upon inhibition of autophagy. Our data demonstrated that oncolytic adenoviruses can be modified to present cancer antigens for an anti-tumor immune response that may be enhanced by positively regulating autophagy.
Citation Format: Sarah R. Klein, Hong Jiang, Sujan Piya, Zhimin Lu, Candelaria Gomez-Manzano, Juan Fueyo. The role of JNK isoforms in adenovirus-induced autophagy: Implications for cancer immunotherapy using oncolytic adenoviruses. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B97.
Abstract IA10: Tipping the balance from a procarcinogenic to anticancer response in pancreatic cancer.
Authors: Jaffee Elizabeth 
Published: August 2014

Abstract
Pancreatic cancer remains a “death sentence”, with the poorest survival rates reported for solid tumors. Escalating this problem is the fact that pancreatic cancer is among the most resistant cancers to traditional forms of therapy. But in this new era of targeted therapies, there is reason to hope that significant progress will be made in the development of new treatments in the near future.
Until recently, barriers to immunotherapy clinical successes for pancreatic cancer have been due to a lack of understanding of the immune pathways within the pancreatic tumor microenvironment that hinder successful immune responses. Recent advances in our understanding of its immunobiology has identified new targets for developing cancer specific vaccines and new targets for modulating the tumor microenvironment to allow more potent activation and improved access of vaccine induced immune responses. We are just learning that non-neoplastic cells, including cancer-associated myofibroblasts, regulatory T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are hijacked by pre-invasive and invasive cancer cells to create a tolerogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this tolerogenic polarization within the tumor microenvironment with the goal of tipping the balance in favor of an anticancer immune response. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease.
This presentation will provide new data in pre-clinical and clinical studies demonstrating mechanisms that convert procarcinogenic inflammatory responses into anticancer immunity.
Citation Format: Elizabeth Jaffee. Tipping the balance from a procarcinogenic to anticancer response in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA10.
Abstract IA12: Translation of an OX40 agonist: Putting a foot on an immunologic gas pedal.
Authors: Weinberg Andrew D. 
Published: August 2014

Abstract
Our group has focused on using agonists to the TNF-receptor, OX40, to enhance anti-tumor immunity/activity. OX40 agonists have T cell costimulatory activity and are known to increase CD4 and CD8 T cell proliferation, effector function, and memory T cell survival. Injecting OX40 agonists into cancer-bearing hosts leads to increased anti-tumor immunity, which has been observed in several different mouse tumor models. The OX40 agonist anti-tumor activity is dependent on both CD4 and CD8 T cells and mice cured via OX40 agonists are immune to tumor rechallenge, suggesting an enhanced tumor-specific memory T cell response. The preclinical data led to the development of a mouse anti-human OX40 agonist Ab that was recently tested in a phase I clinical trial. The phase I trial treated metastatic cancer patients from several different tumor types, which included melanoma, renal cell carcinoma, ovarian cancer, lung cancer, colon cancer, and prostate cancer. A dose escalation of the human OX40 Ab was well-tolerated and showed increased signs of T cell proliferation in both CD4/FoxP3neg and CD8 T cells (via Ki-67 staining) that peaked at the 0.4 mg/kg dose level. We also found that OX40-induced proliferating CD8 T cells showed increased levels of immune activation, as these cells had increased levels of CD38 and HLA-DR on their surface. One round of treatment led to regression of at least one metastatic lesion in 12/30 patients treated, however there were no partial or complete responses by RECIST criteria. In a select group of patients we were able to assess anti-tumor immune responses pre- and post-anti-OX40 treatment. We found in 3 of 4 patients that the anti-tumor immune responses were increased following anti-OX40 administration. In summary, OX40 agonist stimulation enhances anti-tumor immunity in cancer-bearing hosts and this activity was translated to late stage cancer patients. The human OX40 agonist used in these clinical studies was a mouse Ab. Hence it could only be administered once and had a relatively short half-life in vivo, therefore humanized versions of the OX40 agonists will be tested in future clinical trials.
Citation Format: Andrew D. Weinberg. Translation of an OX40 agonist: Putting a foot on an immunologic gas pedal. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA12.
Abstract IA7: Regulation of myeloid-derived suppressor cells in tumor micro-environment.
Authors: Gabrilovich Dmitry 
Published: August 2014

Abstract
Myeloid-derived suppressor cells (MDSC) is a major factor responsible for tumor escape. These cells accumulate in large numbers in tumor-bearing hosts and are characterized by their myeloid origin, immature state, and, most importantly, by their potent ability to suppress different aspects of immune responses, primarily T-cell proliferation and cytokine production. This heterogeneous group of cells, consists of immature myeloid cells (IMC) with morphological and phenotypic characteristics, similar to that of monocytes (M-MDSC) and polymorphonuclear neutrophils (PMN-MDSC). However, MDSC have a distinct gene expression profile and a number of biochemical, and functional, differences from monocytes (Mon) and neutrophils (PMN). In tumor-bearing hosts, there is a constant influx of myeloid cells from the bone marrow to other peripheral organs. Soluble growth factors and certain cytokines produced by tumor cells modulate, expand and differentiate these immature myeloid cells by interacting with the receptors on their surface and converting them to a suppressive phenotype. Recently, “two-signal” model of MDSC accumulation was proposed. This model suggests that accumulation of MDSC can be separated into two processes governed by different signal transduction pathways. One pathway is predominantly responsible for MDSC expansion and the second one for driving MDSC activation. The fate of MDSC remains poorly understood. We found, contrary to our initial expectations, that MDSC, in tumor-bearing mice and cancer patients, have a substantially lower survival than their control counterparts, Mon and PMN. We have identified possible mechanism of this phenomenon and suggested that it can be used for selective elimination of MDSC in tumor-bearing hosts.
Citation Format: Dmitry Gabrilovich. Regulation of myeloid-derived suppressor cells in tumor micro-environment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA7.
DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation
Authors: Bakhoum Samuel F. , Kabeche Lilian , Murnane John P. , Zaki Bassem I. , Compton Duane A. 
Published: August 2014

Abstract
Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here, we show that activation of the DNA-damage response (DDR) during mitosis selectively stabilizes kinetochore–microtubule (k-MT) attachments to chromosomes through Aurora-A and PLK1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or CHK2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, the DDR during mitosis inappropriately stabilizes k-MTs, creating a link between s-CIN and w-CIN.
Significance: The genome-protective role of the DDR depends on its ability to delay cell division until damaged DNA can be fully repaired. Here, we show that when DNA damage is induced during mitosis, the DDR unexpectedly induces errors in the segregation of entire chromosomes, thus linking structural and numerical chromosomal instabilities. Cancer Discov; 4(11); 1281–9. ©2014 AACR.
See related commentary by Jelluma and Kops, p. 1256
This article is highlighted in the In This Issue feature, p. 1243
Cardiac-Specific Overexpression of Human Stem Cell Factor Promotes Epicardial Activation and Arteriogenesis After Myocardial Infarction
Authors: Xiang Fu-Li , Liu Yin , Lu Xiangru , Jones Douglas L. , Feng Qingping 
Published: August 2014

Background—
The adult epicardium is a potential source of cardiac progenitors after myocardial infarction (MI). We tested the hypothesis that cardiomyocyte-specific overexpression of membrane-associated human stem cell factor (hSCF) enhances epicardial activation, epicardium-derived cells (EPDCs) production, and myocardial arteriogenesis post MI.

Methods and Results—

Wild-type and the inducible cardiac-specific hSCF transgenic (hSCF/tetracycline transactivator) mice were subjected to MI. Wilms tumor-1 (Wt1)–positive epicardial cells were higher in hSCF/tetracycline transactivator compared with wild-type mice 3 days post MI. Arteriole density was significantly higher in the peri-infarct area of hSCF/tetracycline transactivator mice compared with wild-type mice 5 days post MI. In cultured EPDCs, adenoviral hSCF treatment significantly increased cell proliferation and growth factor expression. Furthermore, adenoviral hSCF treatment in wild-type cardiomyocytes significantly increased EPDC migration. These effects of hSCF overexpression on EPDC proliferation and growth factor expression were all abrogated by ACK2, a neutralizing antibody against
c-kit
. Finally, lineage tracing using ROSA
mTmG
;Wt1
CreER
mice showed that adenoviral hSCF treatment increased Wt1
+
lineage–derived EPDC migration into the infarcted myocardium 5 days post MI, which was inhibited by ACK2.

Conclusions—
Cardiomyocyte-specific overexpression of hSCF promotes epicardial activation and myocardial arteriogenesis post MI.
Diagnostic Concordance of Echocardiography and Cardiac Magnetic Resonance–Based Tissue Tracking for Differentiating Constrictive Pericarditis From Restrictive Cardiomyopathy
Authors: Amaki Makoto , Savino John , Ain David L. , Sanz Javier , Pedrizzetti Gianni , Kulkarni Hemant , Narula Jagat , Sengupta Partho P. 
Published: August 2014

Background—
Variations in longitudinal deformation of the left ventricle have been suggested to be useful for differentiating chronic constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). We assessed left ventricular mechanics derived from cardiac magnetic resonance (CMR) cine–based and 2-dimensional echocardiography–based tissue tracking to determine intermodality consistency of diagnostic information for differentiating CP from RCM.

Methods and Results—

We retrospectively identified 92 patients who underwent both CMR and 2-dimensional echocardiography and who had a final diagnosis of CP (n=28), RCM (n=30), or no structural heart disease (n=34). Global longitudinal strain from long-axis views and circumferential strain from short-axis views were measured on 2-dimensional echocardiographic and CMR cine images using the same offline software. Logistic regression models with receiver operating characteristics curves, continuous net reclassification improvement, and the integrated discrimination improvement (IDI) were used for assessing the incremental predictive performance. Global longitudinal strain was higher in patients with CP than in those with RCM (
P
<0.001), and both techniques were found to have similar diagnostic value (area under the curve, 0.84 versus 0.88 for CMR and echocardiography, respectively). For echocardiography, the addition of global longitudinal strain to respiratory septal shift and early diastolic mitral annular velocity resulted in improved continuous net reclassification improvement (
P
<0.001 for both) and integrated discrimination improvement (
P
=0.005 and 0.024) for both models. Similarly, for CMR, the addition of global longitudinal strain to septal shift and pericardial thickness resulted in improved continuous net reclassification improvement (
P
<0.001 for both) and integrated discrimination improvement (
P
=0.003 and <0.001).

Conclusions—
CMR and echocardiography tissue tracking–derived left ventricular mechanics provide comparable diagnostic information for differentiating CP from RCM.
Transoral Resection of Stylopharyngeus Calcification
Authors: Kamil Rebecca J. , Gonik Nathan J. , Lee Jimmy S. , Shifteh Keivan , Smith Richard V. 
Published: August 2014

Background: Eagle syndrome is often considered in the work-up of odynophagia and neck pain. Classically, this is manifested by ossification or calcification of the stylohyoid ligament or styloid process. There are no reported cases of stylopharyngeal calcification leading to these symptoms. Case: We describe a patient with a suspected submucosal pharyngeal foreign body who was found to have a calcified stylopharyngeus muscle and tendon during surgery. The patient experienced full resolution of symptoms after transoral robotic resection. This diagnosis was initially missed because the radiology was inconsistent with Eagle syndrome. Conclusion: This is the first report of isolated stylopharyngeal calcification, and this unique manifestation of a stylohyoid complex syndrome should be considered in patients with symptoms of Eagle syndrome without styloid elongation.