bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A96: Antigen-specific human CD4+ T cell clones as tools to characterize immunomodulatory receptor antibodies for immunotherapy
Authors: Li Sophie (Ying) , Le Saux Sabine , Shields Robert , de Waal Malefyt Rene
Published: June 2021

T-cell activation requires co-stimulatory signals that are provided by the interaction between Immuno-Modulatory Receptor (IMR) receptors and ligands expressed on the T cells and APC or tumor cells. Hence, an antigen (Ag)-specific human T-cell clone system was developed. It has been applied not only to study the biology of IMRs, but also to characterize the different biologics targeting those molecules as single agents or in combination to test improved efficacy. Data shown will include the establishment of alloreactive human CD4+ T-cell clones, FACS profiling IMRs of T-cell clones, engineering of different antigen presenting cells transfected with IMR ligands, and application of T-cell clones in characterization of anti-PD1 and anti-Lag3 antibodies

Citation Format: Sophie (Ying) Li, Sabine Le Saux, Robert Shields, Rene de Waal Malefyt. Antigen-specific human CD4+ T cell clones as tools to characterize immunomodulatory receptor antibodies for immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A96.
Abstract A99: Management of advanced melanoma: improved survival and barriers to access in a national cohort following the approvals of checkpoint blockade immunotherapies and targeted therapies
Authors: Dobry Allison , Zogg Cheryl , Hodi Stephen , Smith Timothy , Ott Patrick , Iorgulescu Bryan
Published: June 2021

Background: Immune checkpoint blockade (ICB) and BRAFV600-targeted therapy have demonstrated substantial clinical efficacy for patients with stage 4 melanoma in clinical trials; however, their impact on survival and barriers to treatment in the “real-life” setting remains unknown.

Methods: Patients who presented with cutaneous melanoma during 2004-2015 using the National Cancer Database, which comprises >70% of all newly-diagnosed cancers in the U.S., were evaluated for predictors of presenting with stage 4 disease and receiving ICB, and the associated unadjusted and risk-adjusted overall survival (OS).

Results: 17,975 patients presented with stage 4 metastatic cutaneous melanoma. Overall, patients who presented after the FDA’s initial approvals (starting in 2011) for ICB and BRAFV600-targeted therapy demonstrated a 31% relative improvement in 4-yr OS (p<0.001), compared to pre-2011. Following the initial approvals in 2011, improved OS was associated in risk-adjusted analyses with ICB (HR 0.57, 95CI: 0.52-0.63). ICB demonstrated improved median and 4-yr OS of 16.9 months (95CI: 15.6-19.3; vs. 7.7 months, 95CI: 7.2-8.4) and 32.4% (95CI: 29.5-35.3; vs. 21.0%, 95CI: 19.6-22.2, all p<0.001), respectively; improved OS was persistent in unadjusted and risk-adjusted landmark survival analyses. Uninsured patients and management in the community setting were less likely to receive ICB in multivariable analyses.

Conclusions: In a national “real-life” treatment population, we show that the wide availability of the novel treatment modalities ICB and BRAFV600-targeted therapy has significantly improved the survival of patients with stage 4 melanoma. Our findings additionally suggest that there are opportunities for expanding coverage and access to these novel immunotherapies in community practice.

Citation Format: Allison Dobry, Cheryl Zogg, Stephen Hodi, Timothy Smith, Patrick Ott, Bryan Iorgulescu. Management of advanced melanoma: improved survival and barriers to access in a national cohort following the approvals of checkpoint blockade immunotherapies and targeted therapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A99.
Abstract B35: Studies on photo-sensitivity of a glycol porphyrin derivative and its anti-tumor efficacy
Authors: Vosahlikova Sarka , Moserova Irena Kusova , Kralova Jarmila , Reinis Milan , Mikyskova Romana , Fucikova Jitka Palich
Published: June 2021

Photodynamic therapy (PDT) has attracted great attention in cancer treatment. Porphyrin derivative with ethylene glycol chains linked to meta position of meso-tetraphenylporphyrin, mTPP(EG)4, is one of assumed compounds that can be used for treatment of cancer in photodynamic therapy (PDT). The aim of the study is to demonstrate the photodynamic efficacy in vitro and in vivo as well as to analyze its therapeutic mechanism. The cell viability, cell surface exposure of immunogenic molecules, maturation and phagocytic capacity of PDT-treated tumor cells were monitored by flow cytometry. The kinetics of key components of ER stress-mediated apoptotic pathway was analyzed by Western blotting. Our first results indicate a new and attractive possibility of immunogenic cell death induction. Initiation of immunogenic cell death by PDT was successfully demonstrated in vitro on human and mouse tumor cell lines. The effects of mTPP(EG)4 were compared with the effects of mTPP(EG)4 without subsequent photoactivation, hypericin-mediated PDT, and high hydrostatic pressure. In vivo assays evaluated immunogenicity of mTPP(EG)4 in mice and assessed the ability of PDT treated cells to induce effective immunity against transplanted syngeneic tumors (mouse TRAMP-C2, TC-1 and B16). The results obtained in this study will provide a basis for possible further preclinical experiments with mTPP(EG)4 or other derivatives, testing their potential in PDT and development of new antitumor therapies.

Citation Format: Sarka Vosahlikova, Irena Kusova Moserova, Jarmila Kralova, Milan Reinis, Romana Mikyskova, Jitka Palich Fucikova. Studies on photo-sensitivity of a glycol porphyrin derivative and its anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B35.
Abstract B57: Integrating RNA expression and visual features for immune infiltrate prediction
Authors: Reiman Derek , Sha Lingdao , Ho Irvin , Tan Timothy , Lau Denise , Khan Aly A
Published: June 2021

Patient responses to cancer immunotherapy are shaped by their unique genomic landscape and tumor microenvironment. Clinical advances in immunotherapy are changing the treatment landscape by enhancing a patient’s immune response to eliminate cancer cells. While this provides potentially beneficial treatment options for many patients, only a minority of these patients respond to immunotherapy. In this work, we examined RNA-seq data and digital pathology images from individual patient tumors to more accurately characterize the tumor-immune microenvironment. Several studies implicate an inflamed microenvironment and increased percentage of tumor-infiltrating immune cells with better response to specific immunotherapies in certain cancer types. We developed NEXT (Neural-based models for integrating gene EXpression and visual Texture features) to more accurately model immune infiltration in solid tumors. To demonstrate the utility of the NEXT framework, we predicted immune infiltrates across four different cancer types and evaluated our predictions against expert pathology review. Our analyses demonstrate that integration of imaging features improves prediction of the immune infiltrate. Of note, this effect was preferentially observed for natural killer, macrophage, and CD8 T cells. In sum, our work effectively integrates both RNA-seq and imaging data in a clinical setting and provides a more reliable and accurate prediction of the immune composition in individual patient tumors.

Citation Format: Derek Reiman, Lingdao Sha, Irvin Ho, Timothy Tan, Denise Lau, Aly A Khan. Integrating RNA expression and visual features for immune infiltrate prediction [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B57.
Abstract B59: Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy
Authors: George Jason T. , Garber Haven R. , Molldrem Jeffrey J. , Levine Herbert
Published: June 2021

It is now well established that the host’s adaptive immune system plays an important role in identifying and eliminating cancer cells in much the same way that intracellular pathogens are cleared during an adaptive immune response to infection. From a therapeutic standpoint, the adaptive immune system is unique in that it can co-evolve alongside a developing tumor. However, tumor acquisition of immune evasive phenotypes, such as class-I MHC downregulation, remains a major limitation of successful T-cell immunotherapy. We propose a stochastic model that couples tumor and CD8+ T-cell adaptive immune compartments. This framework accurately models relevant empirical findings, including the growth-threshold conjecture of immune activation, and predicts experimental observations including “sneak-through,” wherein intermediate-growth threats are penalized relative to their slower- and faster-growing counterparts. We demonstrate that predicted optimal growth strategies depend on whether or not the threat may acquire an immune-evasive phenotype as well as the mode of immune detection. The model is able to accurately characterize age-dependent cancer incidence data as a function of decreasing T-cell turnover and repertoire diversity. Lastly, we quantify therapeutic efficacy of immunotherapy in the setting of an immune-evasive threat. Our model serves as a first attempt at modeling stochastic cancer evolution sculpted by an adaptive immune compartment.

Citation Format: Jason T. George, Haven R. Garber, Jeffrey J. Molldrem, Herbert Levine. Co-evolution between tumor cells and immune system in the setting of T-cell immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B59.
Abstract B68: Pre-existing immune memory to cancer-associated phosphopeptides in healthy donors
Authors: Lulu Amanda M. , Cummings Kara L. , Engelhard Victor H.
Published: June 2021

Identifying appropriate antigens is essential to developing effective cancer vaccines. Protein phosphorylation plays a major role in signal transduction pathways that are dysregulated and contribute to the malignant phenotype of cancer cells. Our lab has shown that phosphopeptides derived from these proteins can be presented by major histocompatibility complex Class-I molecules and represent a new class of cancer-associated neoantigens. We previously reported that healthy donors without evident prior cancer had unusually robust CD8 T-cell responses to a cohort of HLA-B7+ leukemia-associated phosphopeptides, suggesting that they might be due to pre-existing phosphopeptide specific memory T cells. To test this, we evaluated CD8+CD45RO+ memory T cells purified from the blood of healthy donors. These cells showed robust responses to 2-25% of HLA-A2+ and 0-23% of HLA-B7+ cancer-associated phosphopeptides. This demonstrates that healthy individuals with no evident cancer history have pre-existing immune memory to some cancer-associated phosphopeptides. We identified 3 “immunodominant” HLA-A2 associated phosphopeptides, in that memory responses were evident to them in the majority of analyzed donors. Such immunodominance suggests that these phosphopeptides result from signaling processes that occur commonly in transformation- or viral infection-related processes. In contrast, immunodominant phosphopeptides were not evident in the context of HLA-B7. While 2 donors showed pre-existing immune memory to a large number of shared targets, other donors showed memory to only small numbers of nonoverlapping phosphopeptides. This suggests that the mechanisms driving expression of these phosphopeptide antigens among healthy donors are much less common. We also found that responses to some phosphopeptides could be detected directly ex vivo. In some cases, the phosphopeptide targets of these ex vivo responses did not stimulate responses after 2 weeks in culture. These results suggest that some phosphopeptides in some donors may be the targets of ongoing immune responses composed of effector or effector memory cells that do not persist long-term in culture. These results provide evidence of regular, ongoing immune surveillance in healthy individuals to cancer-associated phosphopeptides.

Citation Format: Amanda M. Lulu, Kara L. Cummings, Victor H. Engelhard. Pre-existing immune memory to cancer-associated phosphopeptides in healthy donors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B68.
Abstract IA10: Metabolic regulation of cell proliferation
Authors: Vander Heiden Matthew G.
Published: June 2021

Complex regulatory mechanisms enable cell metabolism to match physiologic state. The major pathways cells use to turn nutrients into energy and to synthesize macromolecules have been elucidated; however, there remain many unanswered questions regarding how metabolism supports cell proliferation and how this varies in different cell types in both normal and disease states. We have found that acquisition of some amino acids, including aspartate and serine, can be limiting for cell proliferation and that both environmental and cell lineage factors can influence how cells obtain critical nutrients for proliferation. How metabolism influences tumor growth will be discussed, including how cancer cells and immune cells might compete for limiting nutrients.

Citation Format: Matthew G. Vander Heiden. Metabolic regulation of cell proliferation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA10.
Abstract IA15: Vascular reprogramming for enhancing cancer immunotherapy
Authors: De Palma Michele
Published: June 2021

Immune checkpoint blockade can reinvigorate the tumor-antagonizing functions of T cells and be potentially curative, but the majority of the tumors are either refractory or become resistant to the treatment. Among various parameters, the lack of pre-existing T-cell infiltrates may determine tumor refractoriness to immune checkpoint blockade and other cancer immunotherapies. Increasing data indicate that angiogenic blood vessels can limit the infiltration and functionality of T cells in tumors. For example, high intratumoral VEGFA levels make the tumor blood vessels dysfunctional and poorly permissive to T-cell extravasation, in part through the downregulation of T-cell adhesion molecules on the vascular endothelium. Besides VEGFA, angiopoietin-2 (ANGPT2) also induces abnormal tumor angiogenesis. Accordingly, combined blockade of VEGFA and ANGPT2 reprograms the tumor blood vessels to a form that is conducive to improved T-cell activation and trafficking and enhances tumor response to both immune checkpoint blockade (anti-PD-1) and agonistic CD40 antibodies in several genetically defined mouse cancer models. In my lecture I will discuss the applications, prospects, and current limitations of antiangiogenic immunotherapies.

Citation Format: Michele De Palma. Vascular reprogramming for enhancing cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA15.
Abstract IA22: Pharmacologic and physiologic processes that affect response to immunotherapy
Authors: McAllister Sandra S.
Published: June 2021

Immune checkpoint blockade therapy has revolutionized the treatment of many cancer types and has proven effective for ~10-20% of breast cancer patients in early clinical trials. For patients with triple-negative breast cancer, these responses represent an improvement over standard therapeutic strategies, offering hope that improving efficacy of immunotherapies will save patient lives. However, the reasons for resistance or lack of response to these therapies in breast cancer are unknown. First, we made preclinical observations that provide rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anticancer treatment. Using various preclinical breast cancer models, we showed that selective CDK4/6 inhibitors cause tumor regression by promoting antitumor immune responses. Genome-wide expression data from patient tumors in the NeoPalAna trial revealed similar antitumor immune signatures. The antitumor immunity occurs through processes that affect both tumor cells and the immune microenvironment. Hence, disease regression was further enhanced using a combination therapy regimen comprising a CDK4/6 inhibitor with immune checkpoint blockade. Second, we found that age-related changes to immune function present limitations to the application of immunotherapy in our triple-negative breast cancer (TNBC) preclinical models. While TNBC incidence is similar in young and old patients, it is not known whether age impacts response to immunotherapy in breast cancer. In fact, while over 50% of patients are over 65 years of age at diagnosis, elderly individuals are often excluded from clinical trials for various reasons. We found that aged mice (>12 months, corresponding to ~65-year old humans) had significantly reduced ability to respond to either anti-PD-L1 or anti-CTLA4 compared to young counterparts (8-10 weeks, corresponding to ~25-year old humans). Using high-content flow cytometric analyses and RNA-seq, we identified cellular and molecular mechanisms that correlate with response in young mice that are attenuated in old mice. Many of the differentially expressed genes that defined response in the young cohorts and resistance in the older cohorts were also predictors of response to immunotherapy in cancer patients. Our data suggested novel combination therapies that, when combined with checkpoint blockade, improved responses and survival in the old TNBC cohort. By studying pharmacologic and physiologic processes that improve responses, we hope to suggest new treatment strategies that ensure that breast cancer patients see the most benefit possible from checkpoint blockade therapy.

Citation Format: Sandra S. McAllister. Pharmacologic and physiologic processes that affect response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA22.
Abstract PR10: Heterogenous activation of multiple suppressive pathways by scRNAseq may underscore resistance to PD-1 therapy in metastatic castration-resistant prostate cancer
Authors: Wang Chaojie , Graff Julie , Xia Zheng , Moran Amy
Published: June 2021

Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease that, until recently, was thought to be resistant to checkpoint blockade. A recent clinical trial revealed that the PD-1 inhibitor, pembrolizumab, when given in combination with the androgen-deprivation therapy (ADT) drug enzalutamide, achieved an unprecedented 18% complete biochemical response rate in mCRPC patients. Though promising, ~80% of these patients failed to respond and the mechanisms of resistance remain unclear. The immunologic landscape of mCRPC is largely unknown. We hypothesize that mechanisms of resistance to anti-PD-1 therapy may reflect the heterogeneity of immune suppression in this disease. Revealing this heterogeneity is difficult to achieve because access to the metastatic disease is limited to core-needle biopsies of largely bone and lymph node disease. Therefore, to reveal pathways of resistance, we developed a protocol for isolating leukocytes and performing single-cell RNAseq from fresh core-needle biopsies taken from enzalutamide-resistant metastatic lesions prior to and after pembrolizumab treatment. The abundance of tumor-infiltrating leukocytes was on average less than 1% of total cells independent of biopsy location. Using our single-cell RNA sequencing data, we generated a leukocyte gene signature of enzalutamide mCRPC and used this to retrospectively deconvolute bulk RNA sequencing data from a cohort of 16 paired biopsies from enzalutamide-naive and -resistant patients. Computational approaches revealed the diverse leukocyte heterogeneity of mCRPC and multiple suppressive pathways beyond PD-1 within the tumor microenvironment. Importantly, the suppressive pathways were shared between metastatic biopsy locations (i.e., bone vs lymph node). To validate these targets in combination with ADT treatment, we developed orthotopic mouse models of mCRPC in immunocompetent mice. These strategies will identify new opportunities for clinical intervention to enhance antitumor responses in this patient population.

This abstract is also being presented as Poster A04.

Citation Format: Chaojie Wang, Julie Graff, Zheng Xia, Amy Moran. Heterogenous activation of multiple suppressive pathways by scRNAseq may underscore resistance to PD-1 therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR10.
Abstract PR20: A novel combination immunotherapy with a vaccine targeting tumor neoepitopes that mediates immune cascade in murine tumor models
Authors: Lee Karin L. , Palena Claudia , Lee John , Niazi Kayvan , Nguyen Andrew , Jones Frank , Rabizadeh Shahrooz , Soon-Shiong Patrick , Schlom Jeffrey , Hamilton Duane H.
Published: June 2021

Clinical successes utilizing checkpoint inhibitors demonstrate the potential of immune-based therapies for the treatment of cancer. Research suggests that these successes are a result of T cells recognizing nonsynonymous mutations uniquely expressed by a patient’s tumor. The advent of comparative tumor-normal DNA sequencing and tumor RNA sequencing for accurate prediction of presented somatic mutations has made it possible to rapidly identify these neoepitopes, allowing for the development of personalized cancer vaccines. However, such vaccines are often ineffective due to the immunosuppressive nature of the tumor microenvironment, and their clinical efficacies would be improved when used in an orchestrated combination approach with additional immune-oncology agents. In the present study, we investigated the combination of three immune-oncology agents, each targeting a unique mechanism of immune therapy, with a vaccine targeting tumor neoepitopes. We combined a neoepitope vaccine, delivered as a peptide or via a novel E2b-deleted adenovirus vehicle, with N-IL15 (previously called ALT-803), an IL-15 superagonist, to enhance the development of antigen-specific immunity; NHS-IL12, a tumor-targeting IL-12 molecule, to promote the maintenance and expansion of T cells within the tumor microenvironment; and PD-L1 blockade to decrease immune cell exhaustion within the tumor microenvironment. This combination therapy resulted in the regression of established tumors, which associated with the generation of robust immunity against neoepitopes contained in the vaccine. It also showed evidence of inducing a neoepitope cascade by causing development of T-cell responses to neoepitopes expressed by the tumor but not contained within the vaccine. This report is the first demonstration of an E2b-deleted adenovirus neoantigen vaccine generating robust immunity. Together, this study demonstrates the importance of a multifaceted, orchestrated treatment regimen to promote the generation of effective antitumor immunity.

This abstract is also being presented as Poster A18.

Citation Format: Karin L. Lee, Claudia Palena, John Lee, Kayvan Niazi, Andrew Nguyen, Frank Jones, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom, Duane H. Hamilton. A novel combination immunotherapy with a vaccine targeting tumor neoepitopes that mediates immune cascade in murine tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR20.
Environmental Cues and Mechanisms Underpinning Sex Change in Fish
Authors: Casas Laura , Saborido-Rey Fran
Published: June 2021

Fishes are the only vertebrates that undergo sex change during their lifetime, but even within this group, a unique reproductive strategy is displayed by only 1.5% of the teleosts. This lability in alternating sexual fate is the result of the simultaneous suppression and activation of opposing male and female networks. Here, we provide a brief review summarizing recent advances in our understanding of the environmental cues that trigger sex change and their perception, integration, and translation into molecular cascades that convert the sex of an individual. We particularly focus on molecular events underpinning the complex behavioral and morphological transformation involved in sex change, dissecting the main molecular players and regulatory networks that shape the transformation of one sex into the opposite. We show that histological changes and molecular pathways governing gonadal reorganization are better described than the neuroendocrine basis of sex change and that, despite important advances, information is lacking for the majority of hermaphrodite species. We highlight significant gaps in our knowledge of how sex change takes place and suggest future research directions.
Annually Recurring Erythema Annulare Centrifugum: A New Case Series with Review of the Literature
Authors: Maurelli Martina , Gisondi Paolo , Colato Chiara , Girolomoni Giampiero
Published: June 2021

Annually recurring erythema annulare centrifugum (AR-EAC) is a rare variant, characterized by typical annular plaques recurring in the same period of the year. We describe 5 new cases and present a review of the literature. Patients were 3 females and 2 males with an age range of 25–55 years. Multiple annular plaques were located at the thighs in 4 patients and the neck in one patient. In 1 patient, a single lesion was present. Plaques were recurring in summer in 3 cases; in 1 case, in spring; and another patient, in winter since 3–4 years. Lesions were self-healing in few days or weeks. Histologically, the epidermis presented mild acanthosis with patchy spongiosis, slight parakeratosis, and mild exocytosis. There was a perivascular lympho-histiocytic infiltrate of variable intensity in the superficial dermis, with occasional eosinophils. In 1 case, the inflammatory infiltrate reached the deep dermis. Mucin deposition was absent. Phenotyping studies in 1 case revealed a predominance of T cells, with a small B-cell component. Moreover, a moderate number of CD123+ plasmacytoid dendritic cells and CD1a+ dendritic cells were noted. Fourteen cases of AR-EAC have been published previously. Collectively, patients’ age ranged from 16 to 83 years, with a mean age of 47 years and a disease duration of 1–30 years. Lesions affected more frequently extremities and recurred most commonly in summer. Patients were all in good general health. Topical corticosteroids were the mainstay of treatment. AR-EAC is a benign disorder, the nature of which remains enigmatic.
Eosinophilic Granulomatosis with Polyangiitis Presenting with Myocarditis as an Initial Symptom: A Case Report and Review of the Literature
Authors: Kurihara Kanako , Tsugawa Jun , Ouma Shinji , Ogata Toshiyasu , Aoki Mikiko , Omoto Masatoshi , Kanda Takashi , Tsuboi Yoshio
Published: June 2021

A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression.
Falta Alguém em Nuremberg: uma representação liberal de Vargas e do Estado Novo no pós-45
Authors: Zon Julia Nogueira
Published: June 2021

Este artigo objetiva analisar o modo como foi representado o Estado Novo e Getúlio Vargas pelos setores liberais no período que compreende a segunda metade da década de 1940 no Brasil, tomando por fonte o livro Falta Alguém em Nuremberg, do jornalista David Nasser. Considerando que as representações políticas dificilmente constituem discursos imparciais, a análise busca atentar para os interesses que guiaram essas representações dentro de um contexto histórico marcado pelo processo de redemocratização, organização dos partidos políticos e emergência da classe trabalhadora no cenário político nacional. Partimos da proposta de apresentar de forma sucinta o debate historiográfico acerca do Estado Novo que serviu de guia para a realização do artigo. Dentro dessa perspectiva, investigamos como a representação negativa de Vargas dialogava com os novos interesses que se manifestavam pelos sujeitos e grupos políticos emergentes, uma vez que, com a democratização, a disputa partidária não podia ignorar o peso e a influência política que Vargas ainda exercia.
Prover e acumular: a estrutura e o perfil da posse de escravos em um contexto econômico de abastecimento (São Luiz do Paraitinga no primeiro quartel do XIX)
Authors: Lima Diego Alem de
Published: June 2021

O presente trabalho foi desenvolvido tendo como principal objetivo estabelecer uma análise acerca do uso e da posse da mão de obra escravizada em um contexto econômico de abastecimento durante o período colonial brasileiro, em uma vila paulista não diretamente relacionada com as atividades exportadoras da colônia: a pequena São Luiz do Paraitinga, localizada no médio Vale do Paraíba. A partir da rica documentação das Listas Nominativas de Habitantes disponíveis para o intervalo que compreende os anos de 1798 e 1818, bem como do instrumental teórico e metodológico da Demografia Histórica, buscamos acessar à faceta escravocrata do universo socioeconômico da pequena povoação partindo de uma temática pouco usual na miríade de trabalhos sobre a escravidão colonial: o universo dos pequenos proprietários de escravos. Assim sendo, mapeando ano a ano os longos Maços de População, fomos capazes de mapear centenas de trajetórias individuais que, em conjunto, pavimentaram o caminho para o aprofundamento das questões propostas: qual a importância demográfica do setor de pequenos proprietários de escravos? Quais as características sociais e demográficas desses indivíduos? E, aquela que talvez tenha sido a questão central, quais as características e o perfil da composição dessas escravarias? As respostas obtidas apontam para um quadro que difere em grande medida de alguns consensos pré-estabelecidos pela historiografia existente, e serão, a seguir, apresentadas.
Turismo Cultural y Policy Network: caracterización del modelo de negocio en la comuna de Camarones, Región de Arica y Parinacota, Chile
Authors: Acevedo-Mora Carlos
Published: June 2021

El presente artículo expone loa hallazgos una investigación destinada a estudiar la situación de la actividad turística cultural desde la perspectiva de los modelos de negocio de la red empresarial de la comuna de Camarones. Para tales efectos se exponen las distinciones del turismo cultural y sus variantes que son posibles de desarrollar en este territorio, así como también los conceptos modelos de negocios y sus componentes. La metodología de investigación empleada fue de tipo exploratorio cualitativo y las categorías de análisis se construyeron con base a las variables del modelo de negocios Canvas.  

 

Palabras clave: Red empresarial, Turismo Cultural, modelo de negocio, Bussines Model Canvas, comuna de Camarones-Chile
Comitês de Mortalidade Infantil e Fetal: importância, finalidade e funcionamento
Authors: Teixeira Mara Rúbia Campos , Magalhães Beatriz de Castro , Albuquerque Grayce Alencar
Published: June 2021

O objetivo do artigo foi refletir sobre a atuação dos Comitês de Mortalidade Infantil e Fetal em relação às ações implantadas como forma de superar os desafios e determinantes que contribuem para um maior número de óbitos dessas populações. Trata-se de uma revisão narrativa da literatura, que se deu por meio do levantamento de artigos e documentos oficiais referentes à operacionalização dos Comitês de Mortalidade Infantil e Fetal no Brasil. Os achados indicam que os Comitês de Mortalidade Infantil e Fetal devem ser, necessariamente, de forma efetiva, um pólo técnico/gerencial, cujas ações ou recomendações fluam com total respaldo das autoridades. Sobre sua atuação, os Comitês apontam dificuldades para reduzir os óbitos infantis e fetais, mediante obstáculos para acesso à saúde de qualidade, precarização das instituições de saúde, e deficiências nos processos de trabalho das equipes multidisciplinares, presentes nas redes de atenção. Conclui-se que há um quadro ainda preocupante no que se refere à ações resolutivas para a redução da mortalidade infantil e fetal, sendo a implantação dos Comitês de Mortalidade Infantil e Fetal, um avanço no sentido de promover meios de, a partir da compreensão dos fatores relacionados a óbitos evitáveis, implantar medidas efetivas para a sua redução.
Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease
Authors: McDermott Mary M. , Dayanidhi Sudarshan , Kosmac Kate , Saini Sunil , Slysz Joshua , Leeuwenburgh Christiaan , Hartnell Lisa , Sufit Robert , Ferrucci Luigi
Published: June 2021

Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.
Advances in Revascularization for Peripheral Artery Disease: Revascularization in PAD
Authors: Beckman Joshua A. , Schneider Peter A. , Conte Michael S.
Published: June 2021

Effective revascularization of the patient with peripheral artery disease is about more than the procedure. The approach to the patient with symptom-limiting intermittent claudication or limb-threatening ischemia begins with understanding the population at risk and variation in clinical presentation. The urgency of revascularization varies significantly by presentation; from patients with intermittent claudication who should undergo structured exercise rehabilitation before revascularization (if needed) to those with acute limb ischemia, a medical emergency, who require revascularization within hours. Recent years have seen the rapid development of new tools including wires, catheters, drug-eluting technology, specialized balloons, and biomimetic stents. Open surgical bypass remains an important option for those with advanced disease. The strategy and techniques employed vary by clinical presentation, lesion location, and lesion severity. There is limited level 1 evidence to guide practice, but factors that determine technical success and anatomic durability are largely understood and incorporated into decision-making. Following revascularization, medical therapy to reduce adverse limb outcomes and a surveillance plan should be put in place. There are many hurdles to overcome to improve the efficacy of lower extremity revascularization, such as restenosis, calcification, microvascular disease, silent embolization, and tools for perfusion assessment. This review highlights the current state of revascularization in peripheral artery disease with an eye toward technologies at the cusp, which may significantly impact current practice.
Activation of the Central Renin-Angiotensin System Causes Local Cerebrovascular Dysfunction
Authors: De Silva T. Michael , Modrick Mary L. , Grobe Justin L. , Faraci Frank M.
Published: June 2021

Background and Purpose:

Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model.

Methods:

C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H
2
O and H
2
O with 0.9% NaCl for 1 to 3 weeks.

Results:

In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal
Ren1
was markedly reduced while RAS components (eg,
Agt
and
Ace
) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (
Agtr1a
) promoter, DOCA increased GFP expression ≈3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles.

Conclusions:

These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.
The rise in preanalytical errors during COVID-19 pandemic
Authors: Mukhopadhyay Tapasyapreeti , Subramanian Arulselvi , Pandey Shivam , Madaan Nirupam , Trikha Anjan , Malhotra Rajesh
Published: June 2021

The COVID-19 pandemic has posed several challenges to clinical laboratories across the globe. Amidst the outbreak, errors occurring in the preanalytical phase of sample collection, transport and processing, can further lead to undesirable clinical consequences. Thus, this study was designed with the following objectives: (i) to determine and compare the blood specimen rejection rate of a clinical laboratory and (ii) to characterise and compare the types of preanalytical errors between the pre-pandemic and the pandemic phases. This retrospective study was carried out in a trauma-care hospital, presently converted to COVID-19 care centre. Data was collected from (i) pre-pandemic phase: 1st October 2019 to 23rd March 2020 and (ii) pandemic phase: 24th March to 31st October 2020. Blood specimen rejection rate was calculated as the proportion of blood collection tubes with preanalytical errors out of the total number received, expressed as percentage. Total of 107,716 blood specimens were screened of which 43,396 (40.3%) were received during the pandemic. The blood specimen rejection rate during the pandemic was significantly higher than the pre-pandemic phase (3.0% versus 1.1%; P < 0.001). Clotted samples were the commonest source of preanalytical errors in both phases. There was a significant increase in the improperly labelled samples (P < 0.001) and samples with insufficient volume (P < 0.001), whereas, a significant decline in samples with inadequate sample-anticoagulant ratio and haemolysed samples (P < 0.001). In the ongoing pandemic, preanalytical errors and resultant blood specimen rejection rate in the clinical laboratory have significantly increased due to changed logistics. The study highlights the need for corrective steps at various levels to reduce preanalytical errors in order to optimise patient care and resource utilisation.
Using Law as an Instrument of Domination and Violating the Right of Assembly: The Story behind the Palestinian NGOs’ Quest for Independence
Authors: Dodeen Mahmoud M.
Published: June 2021

This article explores the position of the successive executive powers that have ruled over the occupied Palestinian territory toward the right of association, analyzing the regulations and practical measures they introduced. The governance of these authorities was undemocratic, resulting in abuses of legislative power with a view to constraining the right to assembly and to dominating ngo s, starting with incorporation and ending with dissolution. Despite an ongoing struggle for operational independence, ngo s have been under the control of the Palestinian ruling political parties in the West Bank and the Gaza Strip since 2007. Throughout this period, elected formal oversight bodies have been lacking. While Fatah monopolizes government of the West Bank, Hamas takes exclusive possession of the administration of the Gaza Strip; each party has fought against the ngo s aligned with its rival. The ruling regimes have also exploited shortfalls and gaps in some regulations in order to undermine and weaken the role of ngo s in issues of public concern.
Redescription and Natural History of the Mexican harvestman Diguetinus raptator Roewer, 1912 (Opiliones: Globipedidae), type species of the genus
Authors: COKENDOLPHER JAMES C. , LUCIO-PALACIO CESAR RAZIEL , STARĘGA WOJCIECH
Published: June 2021

The taxonomy of the monotypic genus Diguetinus Roewer, 1912 is discussed with a redescription of the only named species. The redescription, illustrations, and photographs are based upon male and female type specimens as well as a pair of more recently collected specimens from a relatively nearby location; both in Jalisco, Mexico. The genitalia are illustrated for the first time. A distribution map is provided with all verified records from iNaturalist included from: Aguascalientes, Jalisco, Guanajuato, Querétaro, Michoacán, Estado de México, Ciudad de México, Hidalgo, and Puebla. All available knowledge on the natural history is presented including biogeography and distribution, local distribution and habitat use, influence of physical factors, and interspecific relations.
Some additional comments on the Ananteridae or ‘Ananteris group’ and description of a new species of Ananteris Thorell from Central Brazil (Scorpiones: Buthidae)
Authors: LOURENÇO WILSON R.
Published: June 2021

Some additional comments are proposed on the historical aspects of the subfamily Ananterinae (sensu Pocock 1900). The worldwide pattern of distribution of the elements associated with this subfamily is briefly discussed. The biogeographic patterns presented by extant and fossil elements of this subfamily confirm not only the characteristics of a group presenting a typical Gondwanian distribution, but may also correspond to older Pangaean patterns. One unexpected new species is described for the genus Ananteris Thorell from the State of Goiás in Central Brazil, Ananteris martensi sp. n., suggesting that the diversity levels of the Cerrados formations are most certainly higher than what is normally admitted.
Malgacheliodes martensi spec. nov. (Acari, Oribatida, Licnodamaeidae) from South Africa
Authors: ERMILOV SERGEY G. , HUGO-COETZEE ELIZABETH A. , KHAUSTOV ALEXANDER A.
Published: June 2021

The genus Malgacheliodes is recorded in South Africa for the first time. Malgacheliodes martensi spec. nov. is described from soil of Hogsback State Forest, Eastern Cape Province. Adults of the new species differ from those of Malgacheliodes guillaumeti by the presence of ribs and furrows in the aggenital region, bacilliform leg tracheae, rounded ventral keel on leg I femur and four pairs of notogastral setae (h1 absent); while its tritonymph differs from that of M. guillaumeti by the presence of five pairs of gastronotic setae (c1 absent). The generic diagnosis of Malgacheliodes is updated. The differences in morphology of the tritonymphal instar in Malgacheliodes and other genera of Licnodamaeidae are presented.
Martensopsalis, a new genus of Neopilionidae from New Caledonia (Opiliones: Eupnoi)
Authors: GIRIBET GONZALO , BAKER CAITLIN M. , BROUSTE DAMIEN
Published: June 2021

New Caledonia has an endemic opiliofauna with two named species of Triaenonychidae, 17 Troglosironidae and eight Zalmoxidae. The recent finding of Neopilionidae on Grande Terre was thus surprising, and required the formal description of a new genus, which we undertake here. Martensopsalis gen. nov. is characterized by a small unsclerotized body with a unique palp with a pointed basal apophysis on the ventral side of the femur and with a distal apophysis on the prolateral side of the patella. The distinct external morphology, simple penis and unique phylogenetic position justify the erection of the new genus with Martensopsalis dogny spec. nov. as its type species. In addition to the type locality we report several other localities of putative congeneric, yet undescribed species.