bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B27: B-cell lymphoma response to anti-CD20 antibodies based therapies is tightly modulated by FOXO1-mediated MS4A1 gene transcription
Authors: Zerrouqi Abdessamad , Pyrzynska Beata , Dwojak Michal , Miazek Nina , Zapala Piotr , Golab Jakub , Winiarska Magdalena
Published: February 2019

No remission or early relapse remains a major clinical concern in diffuse large B cell lymphoma (DLBCL) with a third of patients failing to respond to current regimens or relapsing with resistant disease. Genome and transcriptome sequencing studies have identified FOXO1 as one of the recurrent target for somatic mutations in DLBCL associated with patient short survival. These mutations enhance FOXO1 nuclear localization and activity on target genes. Herein, we determine the role FOXO1 (wild type and mutated) on the expression of the rituximabtarget, CD20. The effect of active mutated FOXO1 on CD20 expression was determined upon inhibition of AKT, exogenous expression of active myristolated AKT, and mutated FOXO1 at its N-terminal region. FOXO1 binding activity to CD20 promoter was assessed using various assays combined with an in silico analysis of a publicly available ChipSeq data. Our results show that the activation of FOXO1 using AKT inhibitors (MK2206 and GDC0068) led to a significant decrease of CD20 transcript and protein levels, which resulted in a significant resistance to rituximab mediated complement dependent cytotoxicity (CDC). Consistently, the overexpression of either wild-type or mutated FOXO1 repressed CD20 expression. Unlike the activity of exogenous wild type FOXO1 that can be inhibited by AKT1, the activity of mutated FOXO1AAA (Thr24, Ser256 and Ser319 mutated to Ala and that cannot be phosphorylated) markedly inhibits CD20 expression. Furthermore, CD20 levels remained high and unchanged by the DNA binding defective mutant of FOXO1H215R, suggesting a FOXO1 mediated regulation of CD20 transcription through FOXO1 binding to CD20 promoter, as confirmed by ChIP, EMSA and the analysis of ChIPSeq data using antiFOXO1 antibody. These results show that FOXO1 mutants that are insensitive to AKT1 kinase activity, effectively suppress CD20 expression in comparison to wild type FOXO1, through a binding to CD20 promoter.

In summary, these results establish FOXO1 as an important determinant of cell response to complement-dependent rituximab induced cytotoxicity. In addition, our findings indicate that the genetic status of FOXO1 together with its transcriptional activity need careful attention while designing rituximab-based regimens for the therapy of specific B-lymphomas.

Supported by: National Science Center, Poland (NCN#2013/11/B/NZ5/03240), STREAM project (Horizon 2020,#692180).

Citation Format: Abdessamad Zerrouqi, Beata Pyrzynska, Michal Dwojak, Nina Miazek, Piotr Zapala, Jakub Golab, Magdalena Winiarska. B-cell lymphoma response to anti-CD20 antibodies based therapies is tightly modulated by FOXO1-mediated MS4A1 gene transcription [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B27.
Abstract B28: Validation and characterization of MiXeno humanized mouse models for immuno-oncology
Authors: Zhang Lan , Zhang Juan , Qiao Meng , Yan Xuefei , Ding Jian , Chen Fei , An Xiaoyu , Yang WenQing , Shi Qian
Published: February 2019

Despite the unprecedented success of immune checkpoint blockade therapy in patients with various cancer types, a lack of effective preclinical mouse models remains a major challenge for the development of novel immunotherapeutics. Different strategies to humanize immunodeficient mouse model systems have been reported, including replenishment with human hematopoietic stem cells (HSC) or human PBMC, as well as the development of chimeric models harboring human immune checkpoint targets in immunocompetent mice. CrownBio has successfully established a number of human PBMC-humanized xenograft models known as MiXeno for in vivo immunotherapy evaluation. Our MiXeno platform is a rapid and simple strategy for model humanization. However, aspects such as the optimal PBMC injection route and cell number, the PBMC donor dependence and specificity, and the impact of donor HLA type on the engraftment of immune or tumor cells, etc., require fine tuning. After comparative studies for cell titration and immune cell reconstitution, the optimal inoculation conditions and protocols were established for each model. Immune cell constitution and tumor cell engraftment were synchronized so that graft versus host disease (GvHD) can be managed. Models were also characterized by immunophenotyping. MiXeno is proven as a valid alternative to other humanized mouse models, and has a broad spectrum of applications in immuno-oncology including the evaluation of human specific immuno-modulatory drugs in vivo.

Citation Format: Lan Zhang, Juan Zhang, Meng Qiao, Xuefei Yan, Jian Ding, Fei Chen, Xiaoyu An, WenQing Yang, Qian Shi. Validation and characterization of MiXeno humanized mouse models for immuno-oncology [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B28.
Abstract B31: Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration
Authors: Heaster Tiffany M. , Yu Jiaquan , Beebe David J. , Skala Melissa C.
Published: February 2019

Macrophages are key regulators of tumor progression, and can be targeted for cancer treatment. However, reprogramming macrophages for anti-tumor activity is challenging due to their plasticity. Standard assessment of macrophage function (e.g., ELISA) lacks the sensitivity to capture cell-level heterogeneity in living macrophages. Therefore, single cell imaging and analysis tools are needed to study heterogeneous macrophage behavior within the tumor microenvironment. Macrophages adapt their metabolism to alter both phenotype and function. Thus, we propose the combination of optical metabolic imaging (OMI) and microdevice co-culture to observe cellular level macrophage heterogeneity in response to tumor stimuli. OMI enables noninvasive, dynamic imaging of intact, living samples by measuring autofluorescence from the metabolic co-enzymes NAD(P)H and FAD. Cellular level redox balance is evaluated with the optical redox ratio, defined as the ratio of NAD(P)H to FAD intensity. Additionally, NAD(P)H and FAD fluorescence lifetimes report on metabolic enzyme binding activities. Three-layer microdevices consisting of murine PyVMT breast carcinoma cells, collagen (200 micron thickness), and RAW 264.7 macrophages, respectively, were designed to monitor tumor-mediated macrophage polarization and migration. Metabolic changes with macrophage migration were measured with OMI at 24, 48, and 72 hours after culture. Redox ratio and NAD(P)H mean lifetime increased over time in co-cultured macrophages (p <0.05). Macrophage mono-cultures exhibited lower redox ratio and NAD(P)H lifetime (p<0.05) than in co-culture, consistent with the metabolism of naïve and cytokine-stimulated M2-like macrophages, respectively. Phenotype and function of co-cultured macrophages were confirmed with polymerase chain reaction (PCR) gene expression analysis and immunostaining. Furthermore, volumetric imaging visualized macrophage migration distance-dependent changes in NAD(P)H autofluorescence intensity. These results demonstrate that OMI and microdevice co-culture can capture dynamic changes in macrophage metabolism throughout 3D tumor-stimulated polarization and migration. Overall, this approach could enhance our understanding of macrophage metabolism and function, thus revealing novel therapeutic targets within the tumor microenvironment.

Citation Format: Tiffany M. Heaster, Jiaquan Yu, David J. Beebe, Melissa C. Skala. Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B31.
Abstract B44: Regulation of macrophage activation by vascular niche in glioblastoma
Authors: Wang Qirui , Gong Yanqing Anna , Fan Yi
Published: February 2019

Spatiotemporal regulation of tumor immunity remains largely unexplored. Here we identify a vascular niche that controls alternative macrophage activation in glioblastoma (GBM). We show that tumor-promoting macrophages are spatially proximate to GBM-associated endothelial cells (ECs), permissive for angiocrine-induced macrophage polarization. We identify ECs as a major source for interleukin (IL)-6 expression in GBM microenvironment. Furthermore, we reveal that colony stimulating factor-1 (CSF-1) and angiocrine IL-6 induce robust arginase-1 expression and macrophage alternative activation, mediated through peroxisome proliferator-activated receptor (PPAR)-γ-dependent transcriptional activation of hypoxia-inducible factor (HIF)-2α. Finally, utilizing a genetic murine GBM model, we show that EC-specific knockout of IL-6 inhibits macrophage alternative activation and improves survival in the GBM-bearing mice. These findings illustrate a vascular niche-dependent mechanism for alternative macrophage activation and cancer progression, and suggest that targeting endothelial IL-6 may offer a selective and efficient therapeutic strategy for GBM, and possibly other solid malignant tumors.

Note: This abstract was not presented at the conference.

Citation Format: Qirui Wang, Yanqing Anna Gong, Yi Fan. Regulation of macrophage activation by vascular niche in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B44.
Abstract B67: Regulation of a novel cell surface protein in macrophage activity in tumor microenvironment
Authors: Ray Rashmi , Rai Vivek
Published: February 2019

Inflammatory cells and their mediators are an essential component of the tumor microenvironment. Tumor associated macrophages (TAMs) represent a predominant population of inflammatory cells present in the solid tumor and tumor microenvironment. TAMs are associated with tumor progression and metastasis and the infiltration of TAMs or the enrichment of TAM-associated genes relates to poor prognosis and disease outcome in most human tumor types. However, the stimulus and triggers for the tumor cells-macrophage interaction remain unclear. Autotaxin, an ectoenzyme generates smallest phospholipid, lyophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Autotaxin is also known to play important roles in breast cancer, ovarian cancer and many other cancers. LPA is involved in numerous biological processes encompassing cell growth, cell proliferation, cell migration, cancer and metastasis. LPA exerts its functions on different cell types via its different G-protein coupled receptors (GPCRs). More progress has been made in recent years in dissecting the mechanisms of LPA generation and how it directly acts on its target cells. Recently we have shown that LPA converts monocytes into macrophages both in mice and humans. Here, we show that cancer cells in tumor growth are associated with tumor associated macrophages via a signature paracrine link. Our studies identify an unknown signaling link between tumor cells and macrophages. Furthermore, we have functionally characterized these macrophages and the suppression of this paracrine network leads to decrease in tumor growth and its progression. Our preliminary data also shows that blocking of this paracrine link decreases the secretion of proangiogenic factor such as TGF-b, TNF-a, MMP-9, and VEGF. This study suggests that suppression of this paracrine network can act as a new therapeutic approach to control cancer and metastasis. New insights into the role of LPA in regulating immune responses via cancer cells should be explored in the near future.

Citation Format: Rashmi Ray, Vivek Rai. Regulation of a novel cell surface protein in macrophage activity in tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B67.
Abstract B72: Secretory autophagy in tumor-associated fibroblasts alter effector function of natural killer cells against HNSCC
Authors: Enders Jonathan David , New Jacob , Aliani Rana , Thomas Sufi Mary
Published: February 2019

Tumor-associated fibroblasts (TAFs) are the most abundant cell type in the microenvironment of head and neck squamous cell carcinoma (HNSCC). We and others previously reported that secreted factors from TAFs increase the proliferation, migration, and invasion of HNSCC. Further studies revealed that HNSCC-secreted factors induce secretory autophagy in TAFs. However, the contribution of TAF autophagy to immune-evasion in the HNSCC microenvironment is unknown. Natural killer (NK) cells are an essential arm of anti-tumor immunity; thus, our study set out to determine the role of TAF autophagy in suppressing NK cell effector functions against HNSCC. To address this, we treated the NK cell line NK-92MI with conditioned media from primary HNSCC TAFs or normal fibroblasts derived from cancer-free subjects and assessed changes in IFN-γ production and cytotoxicity, measures of NK cell activation. We then assessed the role of TAF autophagy in mediating this effect by repeating the studies using conditioned media from TAFs whose autophagy had either been inhibited by chloroquine treatment or knocked down by siRNA. Finally, we assessed the mechanisms by which autophagy in the TAF affects NK cell function. Our data demonstrate HNSCC tumor cells orchestrate a complex mechanism of NK cell inhibition through the modulation of TAFs in the microenvironment. Treatment with TAF-conditioned media induced IFN-γ mRNA expression in NK-92MI cells. Interestingly, TAF-conditioned media also reduced NK cell-mediated cytotoxicity as compared to conditioned media from normal fibroblasts. Knockdown of key regulators in the secretory autophagy pathway by siRNA abrogated release of TAF-secreted factors, including hepatocyte growth factor (HGF). HGF induced NK-92MI expression of IFN-γ mRNA, which could be abrogated by an inhibitor of the HGF receptor, c-MET. In conclusion, these data describe a previously undefined effect of TAFs on NK cell function in the HNSCC microenvironment.

Citation Format: Jonathan David Enders, Jacob New, Rana Aliani, Sufi Mary Thomas. Secretory autophagy in tumor-associated fibroblasts alter effector function of natural killer cells against HNSCC [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B72.
Abstract IA06: Enhancing combination immunotherapy and adoptive cell therapy of cancer via lymph node-targeted vaccines
Authors: Irvine Darrell J.
Published: February 2019

Lymph node targeting is achieved clinically is sentinel lymph node mapping in cancer patients, where small-molecule dyes are efficiently delivered to lymph nodes by binding to serum albumin. To mimic this process in vaccine delivery, we synthesized amphiphile-vaccines (lipid-polymer conjugates of peptides, proteins, or molecular adjuvants) designed to non-covalently bind vaccine antigens and adjuvants to endogenous albumin. These amphiphile conjugates both protect peptide antigens from premature degradation and greatly increase their delivery to lymph nodes. Such “albumin-hitchhiking” amphiphiles elicited as much as 30-fold amplified cellular immune responses and antitumor immunity against multiple antigens, and further enable mucosal delivery of therapeutic vaccines through albumin-mediated transport across epithelial barriers via the neonatal Fc receptor. When combined with complementary immunotherapy agents, these lymph node-targeted vaccines are capable of eradicating large established tumors in several mouse models, providing a blueprint for curative immunotherapies. We have further demonstrated that amph-vaccines can be used to deliver ligands for chimeric antigen receptor (CAR) T cells to lymph nodes, creating efficient booster vaccines for CAR T cells.

Citation Format: Darrell J. Irvine. Enhancing combination immunotherapy and adoptive cell therapy of cancer via lymph node-targeted vaccines [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA06.
Abstract IA07: Genetic engineering of therapeutic T cells using synthetic nanoparticles
Authors: Moffett Howell F. , Smith Tyrel T. , Stephan Matthias T.
Published: February 2019

Despite the obvious advantages afforded by targeted T-cell cancer therapies (compared with the blunt instruments of chemotherapy, radiotherapy, and surgery), the complexity and costs involved in producing genetically modified lymphocytes remain major obstacles to their implementation as standard of care. Work in our laboratory aims to obviate these problems by integrating materials science, immunology, and gene therapy to make cellular immunotherapy more effective, practical, and widespread. In this talk, I will highlight two examples: In the first segment, I will describe a new strategy to genetically imprint therapeutically desirable phenotypes in cultured T cells, simply by mixing them with a targeted mRNA-carrying nanoreagent. When they are added to a culture of cells, these engineered nanoparticles bind to targeted T cell populations and induce major biologic effects on the basis of transient “hit-and-run” gene therapy without the necessity of resorting to complicated protocols or complex ancillary equipment. Our approach provides significant advantages over those currently used to create cytoreagents (i.e., viral transfection and electroporation), which require specialized equipment and demanding production steps. In the second part of my presentation, I will introduce a new injectable reagent our group developed that that can quickly program tumor-recognizing capabilities into circulating T cells without the need for laboratory manipulations. We demonstrate that, once they are adapted with lymphocyte-targeting ligands, polymeric nanocarriers can selectively deliver leukemia-specific chimeric antigen receptor (CAR) genes into host T cells in situ. These nanoparticles are easy to manufacture and are stable, which simplifies long-term storage and reduces cost. This technology may therefore provide a practical, broadly applicable treatment that can generate antitumor immunity at the time of diagnosis in a variety of settings.

Citation Format: Howell F. Moffett, Tyrel T. Smith, Matthias T. Stephan. Genetic engineering of therapeutic T cells using synthetic nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA07.
Abstract IA12: Integrative genomics and immune contexture approach to immuno-oncology
Authors: Galon Jérôme
Published: February 2019

To date the anatomic extent of tumor (TNM classification) has been by far the most important factor to predict the prognosis of cancer patients. However, this classification provides limited prognostic information and does not predict response to therapy.

We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector-memory T-cells (Tem) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph nodes. We demonstrated the critical tumor-microenvironment parameters determining the dissemination to distant metastasis. We showed that the combination of immune parameters associating the nature, the density, the functional immune orientation, and the location of immune cells within the tumor was essential to accurately define the impact of the local host-immune reaction on patient prognosis. We defined these parameters as the “immune contexture.” We characterized the immune landscape within human tumors, and showed the importance of adaptive immune cells including cytotoxic T cells, Th1 cells, B cells, and T follicular-helper (Tfh) cells. We described the immunopenotype and antigenome associated with immune escape mechanisms and demonstrated mechanisms associated with preexisting and proliferating intratumoral T cells.

Based on the immune contexture, a standardized, simple, and powerful digital pathology-based immune stratification-system, termed Immunoscore, was delineated having a prognostic power superior to that of the currently used cancer staging system. Tumor invasion parameters were statistically dependent on the host-immune reaction. A worldwide Immunoscore consortium validated the prognostic value of Immunoscore, using a standardized assay. Recent data are supporting the significant role of Immunoscore within lung, liver, and brain metastases. Thus, tumor progression, invasion, and recurrence are dependent on preexisting immunity and on Immunoscore, and the role of the immune contexture in predicting response to immunotherapy will be discussed.

Citation Format: Jérôme Galon. Integrative genomics and immune contexture approach to immuno-oncology [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA12.
Abstract IA14: An atlas of the tumor immune ecosystem
Authors: Pe’er Dana
Published: February 2019

We created a comprehensive atlas of breast tumor-immune ecosystem by collecting a dataset of over 50,000 single immune cell transcriptomes from different types of human breast cancer, normal breast tissue, peripheral blood, and the lymph node using single-cell RNA-seq, and analyzed with novel computational clustering and normalization techniques. Our analyses revealed remarkably increased heterogeneity of intratumoral cells of both lymphoid and myeloid cell lineages, which occupy significantly expanded contiguous phenotypic space in comparison to normal breast tissue. The observed continuum of cell states is associated with their progressive cellular activation and differentiation and argues strongly against the notion of few discrete states of differentiation or activation of individual cell types shaping the tumor microenvironment. The substantial heterogeneity of cell states within major cell types and across patients is also driven by complex coexpression relationships between genes, and by extension their potential suitability as therapeutic cotargets.

Citation Format: Dana Pe’er. An atlas of the tumor immune ecosystem [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA14.
Abstract IA22: Fusobacterium nucleatum and colon cancer
Authors: Garrett Wendy S.
Published: February 2019

Cancer has largely been considered a disease of genetic and environmental factors; however, increasing evidence has demonstrated a role for the microbiota (the microorganisms associated with the human body) in shaping systemic and tumor microenvironment immunity and promoting tumor growth and spread. Herein, we discuss both human data from meta’omics analyses and data from mechanistic studies in cell culture and animal models that support that specific bacteria act as potentiators of colonic tumorigenesis, with a focus on Fusobacterium nucleatum.

Citation Format: Wendy S. Garrett. Fusobacterium nucleatum and colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA22.
Abstract PR05: Preventing the recurrence of breast cancer at the metastatic niche using resolution-phase macrophages
Authors: Gilon Odelya , Feuermann Yonatan David , Schif-Zuck Sagie , Weidenfeld Keren , Huth Palle Von , Sabo Edmond , Ariel Amiram , Barkan Dalit
Published: February 2019

Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy appears to arise from tumor cells that disseminated early in the course of the disease but did not develop into clinically apparent lesions. These long-term surviving, quiescent disseminated dormant tumor cells (QDTC) are resistant to conventional therapies that target actively dividing cells. The mechanisms responsible for maintaining the survival and outgrowth of QDTC remain largely unknown. Recently, we found that fibrotic-like microenvironment with extensive deposition of Type I collagen (Col-I) and fibroectin, established at the site of the residing QDTC, promoted the outbreak of QDTC. Therefore, we hypothesized that promoting resolution—the endogenous mechanism that terminates inflammation and fibrotic responses and actively directs tissue return to homeostasis—at the permissive site will “normalize” it and prevent metastatic outbreak. Here we demonstrate that soluble factors secreted by ex vivo generated pro-resolving CD11blow macrophages can inhibit the establishment of a fibrotic niche resulting in the inhibition of the metastatic outgrowth of QDTC. The inhibition of the fibrotic niche was due to inhibition of TGFβ1-induced differentiation of fibroblasts to myofibroblasts and myofibroblasts’ apoptosis. Interestingly, our data also demonstrate that the blockade of fibroblast differentiation to myofibroblasts is not mediated by inhibition of the canonical signaling of TGFβ1. Taken together our results demonstrate a pioneering conceptual approach to “normalize” the microenvironment that supports the outgrowth of QDTC by promoting the tissue resolution axis.

This abstract is also being presented as Poster B36.

Citation Format: Odelya Gilon, Yonatan David Feuermann, Sagie Schif-Zuck, Keren Weidenfeld, Palle Von Huth, Edmond Sabo, Amiram Ariel, Dalit Barkan. Preventing the recurrence of breast cancer at the metastatic niche using resolution-phase macrophages [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR05.
MicroRNA-653 Inhibits Thymocyte Proliferation and Induces Thymocyte Apoptosis in Mice with Autoimmune Myasthenia Gravis by Downregulating TRIM9
Authors: Cao Yu-Ling , Dong Wei  , Li Yu-Zhi  , Han Wei
Published: January 2019

Objectives: Myasthenia gravis (MG) is an organ-specific autoimmune neuromuscular disorder that occurs as a result of the impairment in neuromuscular junction and autoantibody attack on the postsynaptic receptors. Increasing evidence suggests that microRNAs (miRs) might be involved in the development of MG. Therefore, the present study aimed to investigate the regulatory function of miR-653 on MG and its relationship with tripartite motif 9 (TRIM9). Methods: The thymic tissues obtained from MG patients with thymic hyperplasia were prepared for establishing an MG mouse model in BALB/c mice. Afterwards, the miR-653 and TRIM9 expressions were determined in thymic tissues. A dual-luciferase reporter assay was carried out to validate whether miR-653 directly targets TRIM9. Finally, the thymocytes were exposed to mimics or inhibitors of miR-653, or siRNA against TRIM9 with the use of MTT assays and flow cytometry for the verification of the gain or loss function of miR-653 and TRIM9 on viability, cell cycle progression, and apoptosis of thymocytes. Results: There was a decrease in thymocyte miR-653 and an increase in TRIM9 in thymic tissues of MG mice. miR-653 was found to negatively regulate TRIM9. Overexpression of miR-653 or depletion of TRIM9 resulted in the inhibition of cell viability, suppression of cell cycle progression, and induction of apoptosis rate in thymocytes. Conclusion: The findings from the present study provided evidence that miR-653 impairs proliferation and promotes apoptosis of thymocytes of MG mice by suppressing TRIM9, indicating that miR-653 could be used as potential therapeutic target in the treatment of autoimmune MG.
B Cell-Based Cancer Immunotherapy
Authors: Wennhold Kerstin , Shimabukuro-Vornhagen Alexander , von Bergwelt-Baildon Michael
Published: February 2019

B cells are not only producers of antibodies, but also contribute to immune regulation or act as potent antigen-presenting cells. The potential of B cells for cellular therapy is still largely underestimated, despite their multiple diverse effector functions. The CD40L/CD40 signaling pathway is the most potent activator of antigen presentation capacity in B lymphocytes. CD40-activated B cells are potent antigen-presenting cells that induce specific T-cell responses in vitro and in vivo. In preclinical cancer models in mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. So far, there have been only few early-stage clinical studies involving B cell-based cancer vaccines. These trials indicate that B cell-based immunotherapy is generally safe and associated with little toxicity. Furthermore, these studies suggest that B-cell immunotherapy can elicit antitumor T-cell responses. Alongside the recent advances in cellular therapies in general, major obstacles for generation of good manufacturing practice-manufactured B-cell immunotherapies have been overcome. Thus, a first clinical trial involving CD40-activated B cells might be in reach.
Yield of Screening Tests for Systemic Vasculitis in Young Adults with Ischemic Stroke
Authors: Yoon Cindy W. , Park Hee-Kwon , Rha Joung-Ho
Published: February 2019

Systemic vasculitis, which can involve the brain, may be one of the causes of stroke in young adults; therefore, a test panel for systemic vasculitis is considered for some young stroke patients. However, little is known about this test’s yield as a screening test in young adults with ischemic stroke. We evaluated the yield of a panel for systemic vasculitis as a screening test in young patients with ischemic stroke. Consecutive patients aged 18–45 years with ischemic stroke between January 2010 and December 2017 were included. They all underwent screening tests for systemic vasculitis including rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, anticardiolipin antibody, lupus anticoagulant, anti-DNA antibody, and anti-Ro/SSA and La/SSB antibodies. Among 3,593 consecutive patients with acute ischemic stroke during the study period, 198 (5.5%) were aged 18–45 years. Only 4 patients (2.0%) were diagnosed with systemic vasculitis; 2 had systemic lupus erythematosus, 1 had Sjogren’s syndrome, and 1 had Churg-Strauss syndrome. Vasculitis panel screening in every young ischemic stroke patient is not of high yield unless a vasculitic process is highly suspected based on other systemic symptoms or signs of vasculitis. Screening should be targeted toward persons with clinical suspicion.
Intrascleral Fixation of an Intraocular Lens through the Pars Plana Prevents Corneal Endothelial Damage
Authors: Miyamoto Naomi , Yamakawa Momoko , Akimoto Masayuki
Published: February 2019

We report two cases of aphakia in whom an intraocular lens (IOL) was intrasclerally fixated through the pars plana to minimize further corneal endothelial damage. A modified lock-and-lead technique was used. A sclerotomy and scleral incision were made 2.5 mm from the limbus. A 24-G catheter needle was used for penetration of the leading haptic, and two ultrathin 30-G needles were used to bury the ends of the haptics. The scleral incision was sutured with 8-0 nylon. Corneal endothelial cells were preserved after surgery. Neither intra- nor postoperative complications were observed. Intrascleral fixation of an IOL through the pars plana effectively minimizes further damage to corneal endothelial cells in select cases.
Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease
Authors: Elgaz Sümeyye , Kuçi Zyrafete , Kuçi Selim , Bönig Halvard , Bader Peter
Published: February 2019

Acute graft-versus-host disease (aGvHD) continues to impact morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). First-line therapy for aGvHD still remains the use of high-dose corticosteroids. Unfortunately, 40–60% of patients with aGvHD exhibit steroid resistance, which is associated with a very poor prognosis. As no effective second-line therapy existed, in recent decades various treatment options were considered for the treatment of therapy-refractory GvHD. Based on their in vitro immunomodulatory properties, the use of mesenchymal stromal cells (MSCs) in the treatment of aGvHD has been introduced. However, most of the clinical data are generated from uncontrolled trials and case series, showing clinical responses to MSCs. Clinical results are more consistent in children despite the use of MSC preparations of various provenance and manufacturing protocols. While these data support the therapeutic principle, the great variability of outcomes strongly suggests that not all MSC preparations are equal and that the specific manufacturing protocols influence therapeutic success in vivo.
ПОШИРЕНІСТЬ УРОЛОГІЧНОЇ ПАТОЛОГІЇ ТА ПРОБЛЕМИ ОРГАНІЗАЦІЇ НАДАННЯ УРОЛОГІЧНОЇ ДОПОМОГИ НАСЕЛЕННЮ (ОГЛЯД НАУКОВОЇ ЛІТЕРАТУРИ)
Authors: Diachuk M. D.
Published: January 2019

Мета: виявлення сучасного стану розробки проблеми організації медичної допомоги пацієнтам урологічного профілю та перспективи подальших досліджень.

Матеріали і методи. При виконанні дослідження використано бібліографічний метод та метод контент-аналізу.

Результати. Незважаючи на тягар медико-соціальних проблем, пов’язаних із хворобами сечостатевої системи, дослідження з цієї тематики є вкрай нечисленні. Вони присвячені вивченню масштабів поширення патології, провідних чинників впливу, удосконаленню технологій лікування, вирішенню питань боротьби з окремими хворобами сечостатевої системи, насамперед із сечокам’яною хворобою, інфекціями та хронічними хворобами нирок, та організації медичної допомоги окремим категоріям населення, переважно в регіональному контексті.

Залишаються невирішеними питання медико-організаційного характеру. Це вимагає комплексного підходу з урахуванням широкого спектра патології, багатьох чинників впливу, сучасних стратегій розвитку урологічної служби, інтегративних тенденцій, профілактичних концепцій, пацієнторієнтованого підходу тощо.

Висновки. Аналіз наукової літератури виявив недостатню розробку проблеми скорочення урологічної патології, її негативних наслідків, засвідчив необхідність наукового обґрунтування удосконалення системи надання урологічної допомоги населенню за умов реформування охорони здоров’я.
Prevalência de hipovitaminose D e hiperparatireoidismo secundário em mulheres na pós-menopausa
Authors: Baroncini Camila Varotto , Regalado Thalles Pereira , Borba Victória Zeghbi Cochensk , Moreira Carolina Aguiar
Published: February 2019

Introdução: A vitamina D e o paratormônio (PTH) são os principais moduladores do metabolismo mineral, contribuindo para homeostase do cálcio e fósforo. Considera-se como insuficientes níveis séricos abaixo de 30 ng/mL de 25-hidroxi-vitamina D [25(OH)D] e deficientes quando abaixo de 20 ng/mL. Tal deficiência também ocasiona aumento da secreção de PTH e, assim, há aumento da desmineralização óssea. Este estudo visa avaliar os níveis séricos de 25(OH)D em mulheres na pós-menopausa e correlacioná-los com as concentrações de PTH e a densidade mineral óssea (DMO). Materiais e métodos: Foram coletados dados clínicos, laboratoriais e densitométricos de 114 mulheres na pós-menopausa que participaram de estudo clínico prévio. As pacientes incluídas apresentavam diagnóstico de osteopenia ou osteoporose sem tratamento prévio. A análise estatística foi realizada pelo software Statistica - Statsoft®. Resultados: As pacientes foram classificadas em osteoporóticas 82,9% (n=92) e osteopênicas 17,1% (n = 19). A média dos valores de 25(OH)D encontrada foi 26,21 ± 9,69 ng/mL. Identificou-se deficiência (16,05 ± 2,81 ng/mL) em 32,4% das pacientes (n = 37) e insuficiência (24,71 ± 3,18 ng/mL) em 33,3% (n = 38). Os valores de PTH apresentaram média de 53,7 ± 20,1 pg/mL. Destes, 25% (n = 29) apresentaram-se acima dos valores de referência. Os valores séricos de PTH correlacionaram-se negativamente com os valores séricos de 25(OH)D (p < 0,01; rho = -0.2971). Houve uma correlação negativa do T-score de colo de fêmur em duas situações: histórico de fraturas e no diagnóstico de fraturas de coluna (p < 0,01). Conclusão: Neste grupo de mulheres pós-menopausadas houve uma alta prevalência de hipovitaminose D, a qual se correlacionou negativamente com o PTH, não sendo observado relação com as estações do ano. Houve uma correlação entre a história de fraturas e a DMO, evidenciando que a DMO de fêmur pode predizer risco de fraturas em outros sítios.
Racial Differences in Sudden Cardiac Death
Authors: Zhao Di , Post Wendy S. , Blasco-Colmenares Elena , Cheng Alan , Zhang Yiyi , Deo Rajat , Pastor-Barriuso Roberto , Michos Erin D. , Sotoodehnia Nona , Guallar Eliseo
Published: February 2019

Background:

Blacks have a higher incidence of out-of-hospital sudden cardiac death (SCD) in comparison with whites. However, the racial differences in the cumulative risk of SCD and the reasons for these differences have not been assessed in large-scale community-based cohorts. The objective of this study is to compare the lifetime cumulative risk of SCD among blacks and whites, and to evaluate the risk factors that may explain racial differences in SCD risk in the general population.

Methods:

This is a cohort study of 3832 blacks and 11 237 whites participating in the Atherosclerosis Risk in Communities Study (ARIC). Race was self-reported. SCD was defined as a sudden pulseless condition from a cardiac cause in a previously stable individual, and SCD cases were adjudicated by an expert committee. Cumulative incidence was computed using competing risk models. Potential mediators included demographic and socioeconomic factors, cardiovascular risk factors, presence of coronary heart disease, and electrocardiographic parameters as time-varying factors.

Results:

The mean (SD) age was 53.6 (5.8) years for blacks and 54.4 (5.7) years for whites. During 27.4 years of follow-up, 215 blacks and 332 whites experienced SCD. The lifetime cumulative incidence of SCD at age 85 years was 9.6, 6.6, 6.5, and 2.3% for black men, black women, white men, and white women, respectively. The sex-adjusted hazard ratio for SCD comparing blacks with whites was 2.12 (95% CI, 1.79–2.51). The association was attenuated but still statistically significant in fully adjusted models (hazard ratio, 1.38; 95% CI, 1.11–1.71). In mediation analysis, known factors explained 65.3% (95% CI 37.9–92.8%) of the excess risk of SCD in blacks in comparison with whites. The single most important factor explaining this difference was income (50.5%), followed by education (19.1%), hypertension (22.1%), and diabetes mellitus (19.6%). Racial differences were evident in both genders but stronger in women than in men.

Conclusions:

Blacks had a much higher risk for SCD in comparison with whites, particularly among women. Income, education, and traditional risk factors explained ≈65% of the race difference in SCD. The high burden of SCD and the racial–gender disparities observed in our study represent a major public health and clinical problem.
Urine Haptoglobin and Haptoglobin-Related Protein Predict Response to Spironolactone in Patients With Resistant Hypertension
Authors: Martin-Lorenzo Marta , Martinez Paula J. , Baldan-Martin Montserrat , Lopez Juan A. , Minguez Pablo , Santiago-Hernandez Aranzazu , Vazquez Jesus , Segura Julian , Ruiz-Hurtado Gema , Vivanco Fernando , Barderas Maria G. , Ruilope Luis M. , Alvarez-Llamas Gloria
Published: February 2019

Resistant hypertension prevalence is progressively increasing, and prolonged exposure to suboptimal blood pressure control results in higher cardiovascular risk and end-organ damage. Among various antihypertensive agents, spironolactone seems the most effective choice to treat resistant hypertension once triple therapy including a diuretic fails. However success in blood pressure control is not guaranteed, adverse effects are not negligible, and no clinical tools are available to predict patient’s response. Complementary to our previous study of resistant hypertension metabolism, here we investigated urinary proteome changes with potential capacity to predict response to spironolactone. Twenty-nine resistant hypertensives were included. A prospective study was conducted and basal urine was collected before spironolactone administration. Patients were classified in responders or nonresponders in terms of blood pressure control. Protein quantitation was performed by liquid chromatography–mass spectrometry; ELISA and target mass spectrometry analysis were performed for confirmation. Among 3310 identified proteins, HP (haptoglobin) and HPR (haptoglobin-related protein) showed the most significant variations, with increased levels in nonresponders compared with responders before drug administration (variation rate, 5.98 and 7.83, respectively). Protein-coordinated responses were also evaluated by functional enrichment analysis, finding oxidative stress, chronic inflammatory response, blood coagulation, complement activation, and regulation of focal adhesions as physiopathological mechanisms in resistant hypertension. In conclusion, protein changes able to predict patients’ response to spironolactone in basal urine were here identified for the first time. These data, once further confirmed, will support clinical decisions on patients’ management while contributing to optimize the rate of control of resistant hypertensives with spironolactone.
Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II–Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity
Authors: Guimarães Drielle D. , Cruz Josiane C. , Carvalho-Galvão Alynne , Zhuge Zhengbing , Marques Stefanne M. , Naves Lara M. , Persson A. Erik G. , Weitzberg Eddie , Lundberg Jon O. , Balarini Camille M. , Pedrino Gustavo R. , Braga Valdir A. , Carlström Mattias
Published: February 2019

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)–induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment–induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT
1
Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT
1
Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.
The Practice of Khulʿ in Germany: Pragmatism versus Conservativism
Authors: Jaraba Mahmoud
Published: February 2019

In this article, I examine how Muslim women who ae religiously-married in Germany might initiate no-fault divorce in the absence of a German registered civil marriage. Because there is no Muslim state authority to consult, local imams and Islamic leaders can resort to a community-led practice known as khulʿ (divorce initiated by the woman) to dissolve an Islamic marriage (nikāḥ) that is not recognized by civil authorities. In this article, which is the culmination of three years of fieldwork in Germany, I analyze and interpret the views and practices of two groups of religious actors - conservatives and pragmatists - towards khulʿ in cases of nikāḥ. I find that conservatives only permit a woman to divorce through khulʿ with her husband’s consent, whereas pragmatists use Muslim minority jurisprudence (fiqh al-aqalliyyāt al-Muslima) to argue that the husband’s consent is not essential to legitimize a khulʿ pronouncement.
Arresting Alternatives
Authors: Rauhala Marika
Published: February 2019

Ancient Greek descriptions of ecstatic and mystic rituals, here broadly labeled as Bacchantic worship, regularly include elements of moral corruption and dissolution of social unity. Suspicions were mostly directed against unofficial cult groups that exploited Dionysiac experiences in secluded settings. As the introduction of copious new cults attests, Greek religion was receptive to external influences. This basic openness, however, was not synonymous with tolerance, and pious respect for all deities did not automatically include their worshippers. This article reconsiders the current view of ancient religious intolerance by regarding these negative stereotypes as expressions of prejudice and by investigating the social dynamics behind them. Prejudices against private Bacchantic groups are regarded as part of the process of buttressing the religious authority of certain elite quarters in situations where they perceive that their position is being threatened by rival claims. It is suggested that both the accentuation and alleviation of prejudice is best understood in relation to the relative stability of the elite and the religious control it exerted.
The (Ancient Greek) Subject Supposed to Believe
Authors: Eidinow Esther
Published: February 2019

This article discusses the challenges facing scholars exploring the nature of belief in ancient Greek religion. While recent scholarship has raised questions about individual religious activities, and work on ritual, the body, and the senses has broadened our methodological palette, the nature and dynamics of generally held “low intensity” beliefs still tend to be described simply as “unquestioned” or “embedded” in society. But examining scholarship on divine personifications suggests that ancient beliefs were — and our perceptions of them are — more complex. This article first explores the example of Tyche (“Chance”), in order to highlight some of the problems that surround the use of the term “belief.” It then turns to the theories of “ideology” of Slavoj Žižek and Robert Pfaller and argues that these can offer provocative insights into the nature and dynamics of ritual and belief in ancient Greek culture.