bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA14: Targeting focal adhesion kinase to awaken responses to immunotherapy in pancreatic cancer
Authors: Denardo David G. 
Published: November 2016

Abstract
Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells.
We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy.
Citation Format: David G. Denardo. Targeting focal adhesion kinase to awaken responses to immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA14.
Abstract IA16: Cancer as a disease of the symbiont/metaorganism
Authors: Trinchieri Giorgio 
Published: November 2016

Abstract
Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and non-immune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. The commensal microbiota not only may affect the development, progression, and immune evasion of cancer but also have important effects on the response to cancer immune- and chemotherapy. Myeloid cells are a major component of the tumor microenvironment where they play a dual role inducing antitumor immune responses but mostly promoting immune evasion, tumor progression, and metastases formation. Myeloid cells respond to environmental factors including signals derived from commensal microbes that modulate their function and reactivity, thus impacting the response to cancer therapy.
Citation Format: Giorgio Trinchieri. Cancer as a disease of the symbiont/metaorganism [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA16.
Abstract IA18: Gut microbiota-host immunomodulatory interactions
Authors: Geva-Zatorsky Naama , Alvarez David , Hudak Jason E. , Mans Nicola C. Reading , Erturk-Hasdemir Deniz , Dasgupta Suryasarathi , Andrian Ulrich von , Kasper Dennis 
Published: November 2016

Abstract
Adaptive co-evolution has formed a complex network of inextricable bonds between the resident microbes and the mammalian host. These symbiotic microbes are now believed to have critical impacts on human health. One of the most common gut symbionts, Bacteroides fragilis, produces an outersurface polysaccharide (PSA) that possesses immunomodulatory effects on the host. We adapted a metabolic labeling approach to study the microbiota communication with the host in real-time. We labeled PSA and detected B. fragilis in vivo associated with immune cells and organs. We extended this labeling approach to commensals from diverse phyla in order to study their effects on the host. This method has the potential to enhance our understanding of microbiota colonization as well as to define a set of characteristics of protective cells whose stimulation by previously undiscovered commensal-derived molecules may represent an important new approach to the treatment and prevention of diseases.
Citation Format: Naama Geva-Zatorsky, David Alvarez, Jason E. Hudak, Nicola C. Reading Mans, Deniz Erturk-Hasdemir, Suryasarathi Dasgupta, Ulrich von Andrian, Dennis Kasper. Gut microbiota-host immunomodulatory interactions [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA18.
Abstract IA22: Targeting inducible T cell co-stimulator (ICOS) promotes effector T cell function and antitumor response
Authors: Mayes Patrick A. , Yadavilli Sapna , Liu Yao-Bin , Bi Meixia , Zhang Tianqian , Sendeyo Kelhia , Willoughby Jane , Seestaller-Wehr Laura , Hahn Ashleigh , Bhattacharya Sabyasachi , DeYoung M. Phillip , Blackwell Christina , Shi Hong , Killian David , Adam Michael , Zhang Shu-Yun , Jing Junping , Hopson Chris , Marodon Gilles , Cragg Mark S. , Hoos Axel 
Published: November 2016

Abstract
Cancer immunity is regulated by co-stimulatory mechanisms that when triggered may mount effective anticancer responses. Robust antitumor responses, including complete cures, have been achieved by modulating patients' immune systems. Antibodies targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand-1 (PD-L1) have demonstrated impressive activity in select patients; however, most cancers remain non-responsive to this class of agents. Inducible T cell co-stimulator (ICOS) is a T cell restricted co-stimulatory receptor belonging to the CD28/CTLA immunoglobulin super family whose expression is highly induced on CD4+ and CD8+ T cells upon T cell receptor (TCR) activation. Here we describe the development of a humanized monoclonal antibody (H2L5 IgG4PE) with specific, high-affinity binding to human ICOS capable of delivering agonistic activity and stimulating effector CD4+ and cytotoxic CD8+ T cell activation, expansion, and function. We show that the antibody isotype and FcγR-mediated crosslinking are critical features required for optimal activity of the H2L5 antibody. In mouse tumor models antibody-induced ICOS agonism elicited potent T cell activation and antitumor responses alone and synergistically in combination with other agents, including an anti-PD1 antibody. The first-in-class ICOS agonist antibody described here offers a promising next-generation immunotherapy agent to enhance the magnitude and duration of antitumor responses in patients whose tumors are already sensitive to current immunotherapy approaches as well as potentially expanding the population of patients and range of tumor types that respond to immunotherapy. A phase I clinical trial has been initiated to test H2L5 IgG4PE (GSK3359609) alone and in combination with anti-PD1 and other anticancer agents in patients with solid tumors (www.clinicaltrials.gov; NCT02723955).
Citation Format: Patrick A. Mayes, Sapna Yadavilli, Yao-Bin Liu, Meixia Bi, Tianqian Zhang, Kelhia Sendeyo, Jane Willoughby, Laura Seestaller-Wehr, Ashleigh Hahn, Sabyasachi Bhattacharya, M. Phillip DeYoung, Christina Blackwell, Hong Shi, David Killian, Michael Adam, Shu-Yun Zhang, Junping Jing, Chris Hopson, Gilles Marodon, Mark S. Cragg, Axel Hoos. Targeting inducible T cell co-stimulator (ICOS) promotes effector T cell function and antitumor response [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA22.
Abstract IA25: Synergistic innate and adaptive integrin-targeted immunotherapy
Authors: Wittrup Karl Dane 
Published: November 2016

Abstract
We have determined that antitumor antibodies, when combined with extended systemic exposure to IL-2, strongly polarize an inflammatory tumor microenvironment and generate a vaccinal effect that significantly potentiates adoptive T cell therapies (1). We have broadened this approach by delivering activating Fc domains to tumors via a small peptide that targets RGD-binding integrins (i.e. alpha V beta 3 and alpha 5 beta1). Combining integrin-targeted Fc-mediated effector functions with extended IL-2 exposure leads to ablation of established syngeneic tumors, with formation of protective immunity against subsequent tumor rechallenge. The therapeutic index of this protocol is excellent in wild-type mice, with mild transient reversible toxicities attributable primarily to IL-2 exposure. These results provide a strong case for using tumor-opsonizing agents such as monoclonal antibodies or Fc fusions to synergize with T-cell directed immunotherapies.Reference1. Zhu EF, Gai SA, Opel CF, Kwan BH, Surana R, Mihm MC, Kauke MJ, Moynihan KD, Angelini A, Williams RT, Stephan MT, Kim JS, Yaffe MB, Irvine DJ, Weiner LM, Dranoff G, Wittrup KD. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell 2015;27(4):489-501.
Citation Format: Karl Dane Wittrup. Synergistic innate and adaptive integrin-targeted immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA25.
Abstract IA28: Cancer epigenetic and metabolic mechanisms controlling immunotherapy and chemotherapy
Authors: Zou Weiping 
Published: November 2016

Abstract
We have studied the cross-talk between immune cell subsets and tumor/stem cells in the human tumor microenvironment and its impact on tumor immunity and therapy. Our prior research efforts demonstrate that the tumor microenvironment is comprised of immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor-specific immunity and promote tumor growth in a highly effective manner. These studies have helped define the nature of immune responses in the tumor microenvironment; provide original insights into designing immune therapies to target the immune suppressive mechanisms, including Tregs and inhibitory B7 family members (e.g. PD-L1/PD-1); and treat patients with cancer. Using several human cancers as our models, we demonstrate that Th22 cells and myeloid derived suppressor cells (MDSCs) and macrophages regulate tumor EMT and stemness via epigenetic mechanisms. Furthermore, we found that histone modification and DNA methylation repress the tumor production of Th1-type chemokines and subsequently determine effector T cell trafficking to the tumor microenvironment—affecting tumor progression, therapeutic efficacy of checkpoint blockade and adoptive T cell transfusion, and patient outcome. Thus, epigenetic mechanisms determine tumor immune phenotype (hot vs cold) and tumor biological phenotype (EMT/stem-like vs non EMT/stem like) and shape immunotherapy response. In addition to immunotherapy, we found that effector T cells affect chemoresistance. CD8+ T cells abolish ovarian cancer cisplatin-resistance by altering glutathione and cystine metabolism in fibroblasts. CD8+ T cell-derived IFNγ controls fibroblast glutathione and cysteine through up-regulation of gamma-glutamyl transpeptidase and transcriptional repression of system xc− cystine and glutamate antiporter via the JAK/STAT1 pathway. Thus, effector T cells play a role in cancer chemoresistance. Selective epigenetic reprogramming may alter T cell landscape in cancer and enhance clinical efficacy of cancer immunotherapy and chemotherapy.
Citation Format: Weiping Zou. Cancer epigenetic and metabolic mechanisms controlling immunotherapy and chemotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA28.
Abstract PR14: Automatic identification of cell niches and immune interactions important for clinical outcomes using multiparameter imaging and deep neural networks
Authors: Bhate Salil S. , Samusik Nikolay , Goltsev Yury , Nolan Garry P. 
Published: November 2016

Abstract
Multiparameter cytometry, for example with CyTOF, has enabled the interrogation of immune phenotypes in unprecedented detail in many clinical contexts. But cytometry is incapable of answering a question of critical importance to many tissue context studies, and especially understanding how local interactions between tumor cells and immune cells correlate to clinical outcomes. This becomes especially relevant to understanding the subtleties of how different immunotherapeutic approaches operate in vivo.
We recently developed a multiparameter immunofluorescence technique, termed CODEX, which allows the capture of spatial information for protein and RNA expression in tissue sections. This spatial information enables us to establish not only cell-types according to traditional phenotypic surface marker expression, but also to potentially surmise specific tissue states driving clinical responses. To make sense of the high-dimensional data afforded by CODEX, we apply here state-of-the-art deep neural networks (DNNs). These networks, which have achieved superhuman classification accuracy in many diverse domains, automatically identify cells, cell niches and regions (at multiple scales) that are capable of distinguishing healthy and diseased samples. This is done in an unbiased way, with only ‘healthy’ vs. ‘disease’ labels as additional input alongside the imaging data.
We first train DNNs to successfully classify multiparameter tissue images from independent replicates across conditions. Having achieved a high accuracy of classification, we set the network output to highlight cells and regions deemed to be most relevant to classify each condition. Applying this methodology to healthy and mrl (lupus) spleens stained for 30 markers, our neural network is able to successfully identify a not previously observed enrichment of cell confluences (niches) consisting of CD8 T-cells and conventional dendritic cells enriched in MRL samples, as well as other novel niches completely unpredicted by prior knowledge.
Our DNN enables the systematic and unbiased discovery of specific immune interactions in any tissue type. Applying our technique to the analysis of samples from immunotherapy recipients could enable the discovery of key factors in the tumor microenvironment that distinguish positive responders as well as the subsequent identification of targets for perturbation.
Citation Format: Salil S. Bhate, Nikolay Samusik, Yury Goltsev, Garry P. Nolan. Automatic identification of cell niches and immune interactions important for clinical outcomes using multiparameter imaging and deep neural networks [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR14.
Wide Variation in Reported Rates of Stroke Across Cohorts of Patients With Atrial Fibrillation
Authors: Quinn Gene R. , Severdija Olivia N. , Chang Yuchiao , Singer Daniel E. 
Published: November 2016

Background:

Oral anticoagulants decrease ischemic stroke rates in patients with atrial fibrillation (AF) but increase the risk of bleeding. For the average patient with AF, the threshold of annual ischemic stroke rate where the benefit of anticoagulation outweighs the bleeding risk (net clinical benefit) has been shown to be ≈1% to 2%. Guideline recommendations for oral anticoagulants in AF are based on the CHA
2
DS
2
-VASc stroke risk point scores, assuming that those scores translate to fixed stroke rates. However, the relationship between stroke point scores and annual stroke rates may vary substantially across populations. We sought to comprehensively assess the reported rates of stroke in patients with AF and the relationship of stroke rates to stroke risk point scores.

Methods:
A systematic review of cohort studies and randomized controlled trials enrolled patients with nonvalvular AF not treated with oral anticoagulants.

Results:

Of the 3552 studies screened, we identified 34 studies eligible for analysis. Overall stroke rates in cohort studies were highly heterogeneous (Q=5706.54,
P
<0.001; I
2
= 99.6%) and ranged from 0.45% to 9.28% per year, despite being of similar objective study quality. The mean North American stroke rate was less than one-third that of the mean European stroke rate (
P
<0.0001). However, a random effects regression indicated that between-study variability was not significantly accounted for by cohort region, prospective versus retrospective design, calendar year of study, or outcome event cluster. At a CHA
2
DS
2
-VASc score of 1, 76% of cohorts reported ischemic stroke rates <1% per year and only 18% of cohorts reported a stroke rate >2% per year. At a CHA
2
DS
2
-VASc score of 2, 27% of cohorts reported stroke rates below 1% per year, 40% reported stroke rates between 1 and 2% per year, and 33% reported stroke rates >2% per year.

Conclusions:

Substantial variation exists across cohorts in overall stroke rates and rates corresponding to CHA
2
DS
2
-VASc point scores. These variations can affect the point score threshold for recommending oral anticoagulants in AF. The majority of cohorts did not observe stroke rates that would indicate a clear expected net clinical benefit for anticoagulating AF patients with CHA
2
DS
2
-VASc scores of 1 or 2.
Causes of Extreme Ridges That Induce California Droughts
Authors: Teng Haiyan , Branstator Grant 
Published: November 2016

Abstract
California droughts are often caused by high-amplitude and persistent ridges near and off the west coast of North America without apparent connections with ENSO. Here with a hierarchy of climate models, it is demonstrated that extreme ridges in this region are associated with a continuum of zonal wavenumber-5 circumglobal teleconnection patterns that originate from midlatitude atmospheric internal dynamics. Although tropical diabatic heating anomalies are not essential to the formation and maintenance of these wave patterns, certain persistent heating anomalies may double the probability of ridges with amplitudes in the 90th percentile occurring on interannual time scales. Those heating anomalies can be caused by either natural variability or possibly by climate change, and they do not necessarily depend on ENSO. The extreme ridges that occurred during the 2013/14 and 2014/15 winters could be examples of ridges produced by heating anomalies that are not associated with ENSO. This mechanism could provide a source of subseasonal-to-interannual predictability beyond the predictability provided by ENSO.
Utility of multiparametric MRI in Caesarean section scar characterization and preoperative prediction of scar dehiscence: a prospective study
Authors: Kumar Ishan , Verma Ashish , Matah Manjari , Satpathy Gayatri 
Published: November 2016

Background Post-Caesarean uterine scar rupture during vaginal birth after Caesarean section (VBAC) is a potentially life-threatening complication. Prediction of scar dehiscence and scar rupture is vital in treatment planning and selecting candidates of trial of labor after a Caesarean section (CS). Purpose To assess the accuracy of magnetic resonance imaging (MRI) for evaluation of post-Caesarean uterine scar and to predict scar dehiscence during repeat CS. Material and Methods Thirty patients with a history of at least one previous CS underwent pelvic MRI for assessment of uterine scar during a subsequent gestation, all of whom underwent lower segment Caesarean section (LSCS) subsequently due to one of the established indications of CSs. Thickness, T1, T2 signal intensity ratio (SER), and apparent diffusion coefficient (ADC) value of scar site were charted. The lower uterine segment was assessed and graded intraoperatively and findings were correlated with MRI findings. Results A total of 30 participants were included in this study, of which nine were classified as having an abnormal scar (of various grades) based on surgical observations. T2 SER with a cutoff value of 0.935 showed the highest sensitivity of 100% and scar thickness value of 3.45 mm showed highest specificity of 91% in prediction of abnormal scar. On drawing a receiver operating characteristic (ROC) curve, T2 signal intensity ratio showed the highest area under the curve (AUC) closely followed by scar thickness values. Conclusion MRI derived parameters may be utilized for differentiation of an abnormal post-Caesarean uterine scar from a normal one. Both scar thickness and T2 SER measured on MRI can be used to predict scar dehiscence. However, T2 SER can serve as a more standardized and objective criterion.
Post herpes zoster SUNCT like syndrome: Insights from two case reports
Authors: Mathew Thomas , Srinivas Meghana , Badachi Sagar , Nadig Raghunandan 
Published: November 2016

Background SUNCT like syndrome secondary to post herpes zoster infection has not been reported in literature. Case We are reporting two cases of SUNCT like syndrome secondary to post herpes zoster infection of the V1 distribution of the trigeminal nerve. Treatment with pregabalin and lamotrigine achieved complete symptomatic relief in both patients. Conclusion SUNCT like syndrome can occur after herpetic infection of the trigeminal nerve. Unlike primary SUNCT syndrome, post-herpetic SUNCT like syndrome seems to respond well to pharmacological treatment and has a good prognosis.