bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA06: Molecular basis of T cell exhaustion: Insights for immunotherapy
Authors: Wherry E. John
Published: November 2016

T cell exhaustion is common during chronic infections, cancer and prevents optimal immunity. Exhausted CD8 T cells (TEX) are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. In addition, it has become clear that TEX co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at re-invigorating TEX. Our work has recently defined transcriptional networks of T cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes) in controlling the sustainability and terminal differentiation of TEX populations. We have found a key role for T-bet in sustaining a progenitor pool of TEX during chronic infection, while the related transcription factor Eomes governs terminal differentiation. One key observation from these studies is that a key surrogate of reinvigoration of TEX responses is a population of EomesHi PD-1Hi TEX. The use of this subset of CD8 T cells as a biomarker is explored. Moreover, our recent work has investigated the question of durability of response to PD-1 pathway blockade. These studies have lead to the discovery that the epigenetic landscape of TEX is highly distinct from effector or memory CD8 T cells defining TEX as a unique and distinct lineage of cells. Moreover, we have now defined the epigenetic and transcriptional network changes that occur in TEX upon PD-1 blockade and the effects of these changes on long-term durability of TEX reinvigoration. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.

Citation Format: E. John Wherry. Molecular basis of T cell exhaustion: Insights for 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 IA06.
Abstract IA11: Emerging insights into stromal cell function inimmune homeostasis and inflammation
Authors: Turley Shannon
Published: November 2016

Stromal cells reside in all bodily organs and have long been viewed as chief structural determinants of tissue organization, function, and regeneration. It is becoming increasingly clear that lymphoid organs contain a developmentally related network of highly specialized myofibroblasts known as fibroblastic reticular cells (FRCs). Our understanding of lymph node and spleen FRC function in immune homeostasis and inflammatory disease is incomplete; however, emerging evidence suggests that these cells are of central importance in immunity and tolerance. Likewise, the precise impact of inflammation on stromal cell numbers, activation, gene expression, and function in situ remains unclear. Using genetic and molecular approaches that target specific subsets of stromal cells in vivo we have begun to examine the identity, plasticity, and immunological functions of FRCs in healthy, inflamed, and malignant tissues. We are systematically defining gene expression and molecular elements that control the activation of FRCs across multiple lymphoid and non-lymphoid organs. Additional studies examining the spatial contexture and molecular interactions between fibroblastic reticular cells and immunocytes have identified previously unknown and functionally significant cross-talk between these compartments in health and inflammatory disease settings. New findings from this work will be presented.

Citation Format: Shannon Turley. Emerging insights into stromal cell function inimmune homeostasis and inflammation [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 IA11.
Abstract IA14: Targeting focal adhesion kinase to awaken responses to immunotherapy in pancreatic cancer
Authors: Denardo David G.
Published: November 2016

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

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

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

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

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

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

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.
The Effect of Growth Hormone on Lipid Accumulation or Maturation in Adipocytes
Authors: Zhang Yuchao , Yu Hongsheng , Gao Peng , Chen Jicui , Yu Cong , Zong Chen , Lu Sumei , Li Xia , Ma Xiaoli , Liu Yuantao , Wang Xiangdong
Published: November 2016

Background: Adipogenesis of adipocytes includes two stages: initiation and maturation. Growth hormone (GH) secretion is decreased in obese subjects and GH levels are inversely correlated with abdominal fat mass. The effects of growth hormone (GH) on lipids accumulation or maturation of adipocytes remains elusive. Methods: In the present study, effect of GH on lipid accumulation in vitro and in vivo was examined. cDNA microarray, quantitative real time-PCR (qPCR) and western blotting was used to analyze the expression of genes related to adipocyte lipid accumulation or degradation in pre- or mature 3T3-F442A adipocytes treated with GH and in epididymal adipose tissue of C57BL/6 mice administrated with GH. Level of adiponectin in supernatants of cultured F442A adipocytes was determined by enzyme-linked immune-sorbent assay. Results: We found that in 3T3-F442A especially 6 days post initiation of adipogenesis, GH intervention resulted in decreased expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP, while the expression of UCP1 was markedly enhanced. cDNA microarray analysis and qPCR showed that the expression of SOCS2 and Adipor2 was increased under GH-treatment in mature 3T3-F442A adipocytes. GH treatment increased the mRNA expression of adiponectin and UCP1 in mature adipocytes. The above results were confirmed by in vivo study. Conclusions: GH potentially negatively modulates the maturation and accumulation of lipid in adipocytes.
MicroRNA-129 in Human Cancers: from Tumorigenesis to Clinical Treatment
Authors: Gao Yanping , Feng Bing , Han Siqi , Lu Lu , Chen Yitian , Chu Xiaoyuan , Wang Rui , Chen Longbang
Published: November 2016

Emerging evidence has shown that microRNAs (miRNAs) play essential roles in regulating human cancers development and progression. However, the underlying mechanisms remain to be further explored. MiRNAs are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that moderate gene expression primarily at post-transcriptional level. There is a growing body of literature that recognizes the importance of microRNA (miR)-129 during the development of cancers. Aberrant expression of miR-129 has been detected in various types of human cancers and the validated target genes are involved in cancer-related biological processes such as DNA methylation, cell proliferation, apoptosis, cell cycle, and metastasis. In this review, we summarized the roles of miR-129 family members and their target genes in tumorigenesis and clinical treatment of human cancers, highlighting the potential roles of miR-129 as biomarkers for cancer diagnosis and prognosis, and promising tools for cancer treatment.
Clinical Significance of an Alloantibody against the Kell Blood Group Glycoprotein
Authors: Mattaloni Stella Maris , Arnoni Carine , Céspedes Rosario , Nonaka Claudia , Trucco Boggione Carolina , Luján Brajovich Melina Eliana , Trejo Andrea , Zani Néstor , Biondi Claudia Silvia , Castilho Lilian , Cotorruelo Carlos Miquel
Published: November 2016

Background: Kell null (K0) individuals can produce anti-Ku, an antibody against many epitopes in the Kell glycoprotein, after transfusion and/or pregnancy. Since sensitized K0 patients are rare, little is known about anti-Ku clinical relevance and in particular about its association to hemolytic disease of the fetus and newborn. Case Report: This work describes a case of neonatal hyperbilirubinemia due to immune-mediated erythrocyte destruction by an alloantibody directed against the Kell glycoprotein. Serologic and molecular approaches identified an anti-Ku alloantibody in maternal serum. A homozygous IVS3 + 1g>a point mutation (KEL*02N.06 allele) was found to be responsible for the lack of Kell antigen expression in the mother's red blood cell and subsequent alloimmunization after a previous pregnancy. Even though in most cases Kell antibodies are clinically severe and may cause suppression of erythropoiesis, in our case the newborn had a moderate anemia and hyperbilirubinemia that was successfully treated with phototherapy without requiring exchange transfusion. Serological and molecular studies performed in the proband's family members allowed us to provide them with proper counseling regarding alloimmunization after transfusion and/or pregnancy. Conclusions: This case enlarges the understanding of the clinical significance of alloantibodies against Kell blood group antigens.
Primary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Stomach
Authors: Khuri Safi , Gilshtein Hayim , Sayidaa Sa’d , Bishara Bishara , Kluger Yoram
Published: November 2016

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) is a tumor of small round cells arising in skeletal tissues. These tumors rarely arise in the stomach. We present a 31-year-old healthy female patient who was admitted to our surgical ward due to upper gastrointestinal hemorrhage. Upper endoscopy revealed a large ulcerated bleeding mass originating from the lesser curvature. Biopsy revealed tumor cell immunoreactivity positive for CD99, vimentin, and Ki67 (an index of proliferation). These findings were compatible with gastric ES/PNET. The fluorescence in situ hybridization analysis result for the EWSR1 gene rearrangement (11: 22 translocation) was positive. The patient refused neoadjuvant treatment and thus underwent an operation during which a mass at the lesser curvature of the stomach was found. The mass was adhering to the pancreatic tail and to the mesentery of the transverse and descending colon. Total gastrectomy, distal pancreatectomy, splenectomy, and left adrenalectomy were done. The patient refused adjuvant treatment. She is free of disease 3 years after surgery.
Nephrotic-Range Proteinuria and Peripheral Edema in a Child: Not Only Idiopathic Nephrotic Syndrome
Authors: Dolcemascolo Valentina , Vivarelli Marina , Colucci Manuela , Diomedi-Camassei Francesca , Piras Rossella , Alberti Marta , Emma Francesco
Published: November 2016

Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury due to thrombotic microangiopathy (TMA) mainly occurring in renal and cerebral microvessels. Although the most common cause of HUS in children is Shiga toxin-producing Escherichia coli, atypical forms in which Shiga toxin is not the trigger may occur. Research over the last few years has shown that complement dysregulation secondary to mutations of genes coding for proteins involved in the regulation of the alternative pathway of complement account for most forms of atypical HUS (aHUS). Among these, thrombomodulin (THBD) gene mutations, representing 3–5% of all alternative pathway complement component abnormalities, correlate with early disease onset and rapid evolution to end-stage renal failure. aHUS onset is generally sudden, but occasionally the only manifestations of renal TMA are arterial hypertension, proteinuria, and a progressive increase in serum creatinine. Nephrotic syndrome at disease onset is exceptional. We describe the case of an adolescent female who presented with peripheral edema due to nephrotic-range proteinuria with bioptic evidence of TMA. Study of the alternative complement pathway showed a heterozygous missense THBD gene mutation (P501L variant) consistent with aHUS diagnosis. One year later she developed clinical signs of hemolytic anemia. Eculizumab, an anti-C5 monoclonal antibody, was started with rapid improvement. This case report highlights the phenotypic variability in aHUS due to THBD gene mutation. Early diagnosis by renal biopsy followed by genetic screening is required to optimize management in such a rare disease with a severe prognosis.
Blood-Based Oxidative Stress Markers and Cognitive Performance in Early Old Age: The HAPIEE Study
Authors: Horvat Pia , Kubinova Ruzena , Pajak Andrzej , Tamosiunas Abdonas , Schöttker Ben , Pikhart Hynek , Peasey Anne , Kozela Magdalena , Jansen Eugene , Singh-Manoux Archana , Bobak Martin
Published: November 2016

Background/Aims: Oxidative stress is involved in Alzheimer disease pathology, but its impact on cognitive function in community-dwelling older adults remains unknown. We estimated associations between serum oxidative stress markers and cognitive function in early old age. Methods: Subjects aged 45-69 years recruited in urban centers in Central and Eastern Europe had memory, verbal fluency, and processing speed assessed at baseline (2002-2005) and 3 years later. Derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and total thiol levels (TTLs) were measured at baseline in a subsample. Linear regression was used to estimate associations of biomarkers with cognitive test scores cross-sectionally (n = 4,304) and prospectively (n = 2,882). Results: Increased d-ROM levels were inversely associated with global cognition and verbal fluency cross-sectionally and in prospective analysis; observed effects corresponded to 3-4 years' higher age. TTL was inconsistently associated with memory. BAP was not related to cognitive function. Conclusion: This study found modest evidence for a relationship between serum d-ROMs and cognitive function in a population sample of older adults.
Bilateral Ocular Decompression Retinopathy after Ahmed Valve Implantation for Uveitic Glaucoma
Authors: Flores-Preciado Javier , Ancona-Lezama David Arturo , Valdés-Lara Carlos Andrés , Díez-Cattini Gian Franco , Coloma-González Itziar
Published: November 2016

Case Report: We report the case of a 29-year-old man who underwent Ahmed valve implantation in both eyes as treatment for uveitic glaucoma, subsequently presenting with bilateral ocular decompression retinopathy in the postoperative period. Discussion: Ocular decompression retinopathy is a rare complication of filtering surgery in patients with glaucoma; however, the course is benign in most cases, with spontaneous resolution of bleedings and improvement of visual acuity.
Sófocles na Irlanda: The Cure at Troy e The Burial at Thebes, de Seamus Heaney
Authors: Mutran Munira H.
Published: November 2016

Este artigo apresenta uma breve reflexão sobre o uso do mito na literatura e a ocorrência constante de reescrituras da tragédia grega na Irlanda. Como o estudo das interações entre o texto fonte e o novo texto depende do conhecimento em que a tragédia foi recriada, momentos significativos da história irlandesa foram esboçados com o objetivo de situar The Cure at Troy e The Burial at Thebes, de Seamus Heaney, e ilustrar alguns aspectos da transposição de Filoctetes e Antigona, de Sófocles, para a Irlanda.
A noção mítica de justiça nas relações de poder na tragédia Ifigênia em Áulida de Eurípides
Authors: Torrano Jaa
Published: November 2016

A análise hermenêutica da tragédia Ifigênia em Áulida de Eurípides verifica que nas relações de poder confundem-se e distinguem-se quatro pontos de vista consubstanciados em quatro graus conexos e necessários de verdade, de ser e de conhecimento, descritos como humano, heroico, numinoso e divino. Ao mesmo tempo essa análise nos mostra tanto a dinâmica dessa unidade quádrupla como estrutura básica do teatro de Eurípides quanto as refrações da justiça no interior dessa unidade múltipla.
Hécuba e As Troianas: ecos da Guerra do Peloponeso em Eurípides
Authors: Franciscato Maria Cristina Rodrigues da Silva
Published: November 2016

O presente artigo trabalha com as tragédias Hécuba e As Troianas de Eurípides, relacionando-as ao contexto histórico em que foram criadas. Investiga possíveis relações entre elas e episódios da Guerra do Peloponeso, sobretudo entre As Troianas, apresentada na Dionísia de 415 a.C., e a conquista e destruição da ilha de Melos no inverno de 416-415 a.C.
O alazôn, o outro e o amigo do outro: teatro da desconfiança na tribuna grega
Authors: Torres Milton L.
Published: November 2016

O alazôn aparece com frequência nas comédias de Aristófanes como uma figura de bloqueio que, por meio de seu maior estatuto social, rigidez, vanglória e impostura, tenta impedir a concretização da utopia cômica. O termo também é empregado, na antiguidade grega, para o cavalo de raça (Pólux, Onomástico 1.195), devido à forma imponente com que este sustenta a crina. Além da comédia, a retórica grega também faz uso abundante do termo, geralmente aplicado a um adversário. Uma vez que o desempenho do orador é comparado à disposição do cavalo no hipódromo (Ésquines, Contra Timarco 1.176) e que a algazarra do tribunal ateniense é comparável à do teatro (Platão, República 492b), sugere-se que o topos da alazoneia serve para estigmatizar um personagem (no teatro) ou um orador (na tribuna) como aproveitador, inimigo do bem comum e representante de interesses alheios aos da pólis. Nesse processo, é possível que seu emprego na comédia e na oratória reforce mutuamente o estigma, promovendo uma desconfiança generalizada no orador/alazôn e nas pessoas com ele relacionadas.
Hypertension-Linked Pathophysiological Alterations in the Gut
Authors: Santisteban Monica M. , Qi Yanfei , Zubcevic Jasenka , Kim Seungbum , Yang Tao , Shenoy Vinayak , Cole-Jeffrey Colleen T. , Lobaton Gilberto O. , Stewart Daniel C. , Rubiano Andres , Simmons Chelsey S. , Garcia-Pereira Fernando , Johnson Richard D. , Pepine Carl J. , Raizada Mohan K.
Published: November 2016

Rationale:

Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension.

Objective:

Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension.

Methods and Results:

Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat and chronic angiotensin II infusion rat models. The increase in blood pressure in spontaneously hypertensive rat was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut–neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin-converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology.

Conclusions:

A dysfunctional sympathetic–gut communication is associated with gut pathology, dysbiosis, and inflammation and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with the current pharmacotherapy, may be a novel strategy for hypertension treatment.
Diagnostic and Prognostic Utility of Circulating Cytochrome
c
in Acute Myocardial Infarction
Authors: Marenzi Giancarlo , Cosentino Nicola , Boeddinghaus Jasper , Trinei Mirella , Giorgio Marco , Milazzo Valentina , Moltrasio Marco , Cardinale Daniela , Sandri Maria Teresa , Veglia Fabrizio , Bonomi Alice , Kaech Max , Twerenbold Raphael , Nestelberger Thomas , Reichlin Tobias , Wildi Karin , Shrestha Samyut , Kohzuharov Nikola , Sabti Zaid , Cipolla Carlo M. , Mueller Christian , Bartorelli Antonio L.
Published: November 2016

Rationale:

In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin, functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients.

Objective:

To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome
c
.

Methods and Results:

We prospectively assessed cytochrome
c
serum levels at hospital presentation in 2 cohorts: a diagnostic cohort of patients presenting with suspected AMI and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic end point, and prognostic prediction of in-hospital mortality was the primary prognostic end point. Serum cytochrome
c
had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals 0.44–0.58;
P
=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome
c
was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with nondetectable cytochrome
c
(6% versus 1%;
P
<0.001). This result was mainly driven by the high mortality rate observed in ST-segment–elevation AMI patients with detectable cytochrome
c
, as compared with those with nondetectable cytochrome
c
(11% versus 1%;
P
<0.001). At multivariable analysis, cytochrome
c
remained a significant independent predictor of in-hospital mortality (odds ratio 3.0; 95% confidence interval 1.9–5.7;
P
<0.001), even after adjustment for major clinical confounders (odds ratio 4.01; 95% confidence interval 1.20–13.38;
P
=0.02).

Conclusions:

Cytochrome
c
serum concentrations do not have diagnostic but substantial prognostic utility in AMI.
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.
Blood Pressure Reduction and Secondary Stroke Prevention
Authors: Katsanos Aristeidis H. , Filippatou Angeliki , Manios Efstathios , Deftereos Spyridon , Parissis John , Frogoudaki Alexandra , Vrettou Agathi-Rosa , Ikonomidis Ignatios , Pikilidou Maria , Kargiotis Odysseas , Voumvourakis Konstantinos , Alexandrov Anne W. , Alexandrov Andrei V. , Tsivgoulis Georgios
Published: November 2016

Current recommendations do not specifically address the optimal blood pressure (BP) reduction for secondary stroke prevention in patients with previous cerebrovascular events. We conducted a systematic review and metaregression analysis on the association of BP reduction with recurrent stroke and cardiovascular events using data from randomized controlled clinical trials of secondary stroke prevention. For all reported events during each eligible study period, we calculated the corresponding risk ratios to express the comparison of event occurrence risk between patients randomized to antihypertensive treatment and those randomized to placebo. On the basis of the reported BP values, we performed univariate metaregression analyses according to the achieved BP values under the random-effects model (Method of Moments) for those adverse events reported in ≥10 total subgroups of included randomized controlled clinical trials. In pairwise meta-analyses, antihypertensive treatment lowered the risk for recurrent stroke (risk ratio, 0.73; 95% confidence interval, 0.62–0.87;
P
<0.001), disabling or fatal stroke (risk ratio, 0.71; 95% confidence interval, 0.59–0.85;
P
<0.001), and cardiovascular death (risk ratio, 0.85; 95% confidence interval, 0.75–0.96;
P
=0.01). In metaregression analyses, systolic BP reduction was linearly related to the lower risk of recurrent stroke (
P
=0.049), myocardial infarction (
P
=0.024), death from any cause (
P
=0.001), and cardiovascular death (
P
<0.001). Similarly, diastolic BP reduction was linearly related to a lower risk of recurrent stroke (
P
=0.026) and all-cause mortality (
P
=0.009). Funnel plot inspection and Egger statistical test revealed no evidence of publication bias. The extent of BP reduction is linearly associated with the magnitude of risk reduction in recurrent cerebrovascular and cardiovascular events. Strict and aggressive BP control seems to be essential for effective secondary stroke prevention.
Virtually Virtual? The New Frontiers of Diplomacy
Authors: Pilegaard Jess
Published: November 2016

Much excitement surrounds diplomatic neologisms such as e-diplomacy, digital diplomacy and even virtual diplomacy. This article reviews existing writing on the subject, with special focus on some of the ‘first movers’ in the new wave of information and communication technology (ict)-enabled diplomacy, namely the United States, the United Kingdom and Canada. On this basis, the article suggests a rough typology of ict-enabled diplomacy, ranging from (new) public diplomacy to more advanced forms of digital diplomacy. The article subsequently explores a number of empirical examples of advanced forms of digital diplomacy — that is, ict-enabled diplomatic practices that are not necessarily grounded in a specific time and physical space. The article offers a few concluding thoughts on the possibilities and limits of digital diplomacy.
Begonia titoevangelistae (sect. Baryandra, Begoniaceae) a new species from Catanduanes Island, the Philippines
Authors: TANDANG DANILO N. , RUBITE ROSARIO R. , ANGELES JR. RAUL T. , GUZMAN MARGARET C. DE
Published: November 2016

Begonia titoevangelistae from Nahulugan Falls, Gigmoto, Catanduanes Island is described as a new species endemic to the Philippines. It resembles Begonia neopurpurea but is distinguished by the variegated leaves where the veins and midrib are dark green to almost black contrasting with light green interveins in the adaxial surface. In the abaxial surface, the veins are maroon contrasting with cream interveins, and its wide obliquely ovate leaf is elongated with shallowly undulate and minutely lobed leaf margin and long acuminate apex. Based on International Union for the Conservation of Nature red list criteria, B. titoevangelistae was assessed to be critically endangered, since it consists of one population with 300 individuals on a 100 m area around the waterfalls, which is being developed into a tourist spot.
Two new species of Sida (Malvaceae: Malvoideae) for Brazil
Authors: BOVINI MASSIMO G.
Published: November 2016

Two new species of Sida (Malvaceae) found in the state of Minas Gerais, southeastern Brazil are described and illustrated: S. oblonga and S. carrascoana, which belong to the sections Cordifoliae and Muticae, respectively. Both are compared to related species, and have their conservation status evaluated.
The harvestman genus Taracus Simon 1879, and the new genus Oskoron (Opiliones: Ischyropsalidoidea: Taracidae)
Authors: SHEAR WILLIAM A. , WARFEL JOSEPH G.
Published: November 2016

The ischyropsalidoid genus Taracus Simon 1879 is reviewed and all previously named species are redescribed. Taracus nigripes Goodnight & Goodnight, 1943 is synonymized with T. packardi Simon 1879, and T. malkini Goodnight & Goodnight 1945 with Oskoron spinosus (Banks) 1894; the type locality of T. gertschi Goodnight & Goodnight 1942 is corrected from “eastern Oregon” to Rose Lake, Idaho, based on original labelling. The following new species of Taracus are described: T. carmanah (Vancouver Island), T. marchingtoni (Oregon), T. taylori, T. spesavius (both Nevada), T. timpanogos (Utah), T. audisioae, T. ubicki, and T. fluvipileus (all California). A new genus Oskoron is based upon O. spinosus (Banks) 1894, originally described in Taracus, and also includes two new species, O. brevichelis (Oregon, Washington) and O. crawfordi (Washington). New locality records extend the known distribution of Taracus to the Canadian provinces of Alberta and British Columbia and the US states of Montana, Wyoming, Utah, Nevada and New Mexico. Schönhofer’s (2013) proposal of a family Taracidae for Taracus, Hesperonemastoma Gruber 1970 and Crosbycus Roewer 1914 is discussed.
Causes of Extreme Ridges That Induce California Droughts
Authors: Teng Haiyan , Branstator Grant
Published: November 2016

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.