text:
57 results for Articles
Livestock Breeding
breeding research
Livestock Breeding Articles
Ground-Truth Data 'Absolutely' Adds Value to Top-Shelf Cannabis
Esensia's craft cannabis operation uses senses and sensors to navigate an industry sea change, while staying true to its roots. ...
Global warming to result in widespread crop loss to insects
Rice, corn and wheat loss rates could rise by up to 25% with every 1˚C increase to global temperatures as insects start to eat and breed more, new research has found. Led by researchers at Washington University, the ...
By The Institute of Environmental Management and Assessment (IEMA)
Catastrophic cost of Foot and Mouth Disease
Foot and Mouth disease has never completely disappeared. Although it has been almost 20 years since the last major outbreak of Foot and Mouth disease in the UK, which cost the industry more than £8 Billion, it does not mean that the disease is not still a very real risk to the economy. ...
By Addfield Environmental Systems Ltd.
Introducing Dr. Beatrice Amyotte, Small Fruit Germplasm Development Program
The berry breeding program at the Agriculture and AgriFood Canada (AAFC) Kentville Research and Development Centre in Kentville, Nova Scotia, is now the Small Fruit Germplasm Development Program. The new approach to plant breeding will allow the fruit industry to be more involved in the release of new Canadian varieties of strawberries, raspberries, blackberries and grapes that are developed ...
By Vineland Research and Innovations Centre Inc
Transgenic fish are ready for us. Are we ready for them?
After decades of regulatory and legal challenges, AquaBounty aims to bring genetically engineered salmon to U.S. and Canadian markets next year. On a hill above the cold waters around Prince Edward Island, technicians painstakingly create fertilized Atlantic salmon eggs that include growth-enhancing DNA from two other fish species. The eggs will be shipped to ponds in the high rainforest of ...
By Ensia
Field of genes: Uncovering EGRINs (Environmental Gene Regulatory Influence Networks) in Rice that Function During High-temperature and Drought Stress
Heat and drought stress greatly restrict crop productivity, but most of what we know about a plant's response to these stresses comes from controlled laboratory studies. This factor, along with the complex nature of these responses, has hampered efforts to breed and engineer crops with improved stress tolerance. Plants respond to fluctuating environments through the altered expression of ...
By H Smith Plastics LTD
Global Tows a Humpback Whale to its resting place - Case Study
Sometimes urgent jobs send Global halfway around the world. Other times the call comes right from its own neighborhood. Such was the case in August of 2016 when the company was called upon to remove a humpback whale that had stranded and later died in the shallows beside the Fauntleroy ferry dock in West Seattle. This is actually the second whale removal Global has performed in the area ...
By Global Diving & Salvage, Inc.
A call to conserve crops' wild cousins
Wild cousins aren't always appreciated at family gatherings. But when it comes to crops, the opposite is often true: Plant breeding has historically relied on genes from plants growing in the wild as a source of diversity that can be introduced into crop plants to produce new crop varieties that are more resilient, nutritious and productive than those currently cultivated. As human ...
Ontario Horticulture Research Priority Report 2016
Sector Consultation The Ontario Fruit and Vegetable Growers Association partnered with Vineland to host a research strategy workshop in November 2014 with the goal of defining the top five research priorities for each crop group. Grower organizations were invited to nominate two representatives to participate on their behalf and a number of researchers from relevant fields were invited to ...
Lowara pumps drive livestock operations
Animal output processed for safe disposal, reuse and renewable energy Xylem scope Xylem Lowara have installed several different types of pumps in this process cycle. Ranging from the DLV submersible pump fitted with Vortex impeller used in the pressurization of wastewater obtained from the separation of the digestate. Various high efficiency e-range pumps ...
By LOWARA - a Xylem brand
Welcome to the wild world of rhino conservation
From fake horns to relocation, today's wildlife protectors enlist new — and often problematic — strategies to save endangered species. In 1909, after completing his second term as U.S. president, Theodore Roosevelt led an ambitious expedition across east Africa to shoot specimens for America's most famous ...
A Decade After Asian Tsunami, New Forests Protect the Coast
The tsunami that struck Indonesia in 2004 obliterated vast areas of Aceh province. But villagers there are using an innovative microcredit scheme to restore mangrove forests and other coastal ecosystems that will serve as a natural barrier against future killer waves and storms. On the day that the Indian Ocean tsunami hit his village a decade ago, fisherman Hajamuddin was at sea. It was ...
By Wetlands International
Investing in people and evidence for sustainable farming
Evaluation of farming systems, new ideas and learning with practitioners should be part of a transformed agriculture. Food security is difficult to pin down. It can be explained simply as access to enough food. But behind that simplicity lies an interconnected web of factors — from food prices to ...
By SciDev.Net
Intellectual property and Freedom To Operate in the flax breeding world: Canada in the global context
Through one-on-one in-depth interviews of Canadian public sector flax breeders, this study explores issues around Intellectual Property (IP) and Freedom To Operate (FTP) in flax breeding from a Canadian perspective. The results are supported by a scan of flax breeding efforts worldwide, an in-depth patent analysis (using Patent Lens and the US Patent and Trademark Office (USPTO) databases) and a ...
By Inderscience Publishers
Molecular mapping of wheat leaf rust resistance gene Lr42
Leaf rust, caused by Puccinia triticina Eriks., is an important foliar disease of wheat (Triticum aestivum L.) worldwide. Leaf rust resistance gene Lr42 from Aegilops tauschii Coss. has been used as a source of rust resistance in breeding programs. To identify molecular markers closely linked to Lr42, a segregating population of near-isogenic lines contrasting for the presence of Lr42 was ...
By Soil Science Society of America (SSSA)
Combining ability and heterosis for forage yield among elite alfalfa core collection accessions with different fall dormancy responses
Understanding genetic parameters of populations that are being considered for inclusion into plant-breeding programs provides critical knowledge to enhance economic traits of interest. The objective of this study was to determine the genetic parameters influencing forage yield for nine populations selected from the USDA National Plant Germplasm System alfalfa (Medicago sativa L.) core collection ...
Mapping quantitative trait loci for long coleoptile in Chinese wheat landrace wangshuibai
Wheat (Triticum aestivum L.) cultivars with long coleoptiles can be sown deeply for better seedling establishment in drought environments. A population of 139 recombinant inbred lines (RILs) from a cross between a long-coleoptile Chinese landrace, Wangshuibai, and short-coleoptile U.S. wheat cultivar, Wheaton, were characterized for coleoptile length and plant height. Heritabilities for ...
Climatic and genotypic effects for grain yield in maize under stress conditions
Climate change is expected to affect agriculture. Yield stability across environments is a critical breeding goal when dealing with unstable climate and input reductions in farming systems. The objective of this study was to determine climatic and genetic factors contributing to genotype (G), environment (E), and genotype x environment (GE) variability for maize (Zea mays L.) grain yield under ...
Validation of molecular markers associated with net blotch resistance and their utilization in barley breeding
With the advancement of molecular marker technology and computer software, mapping quantitative trait loci (QTL) for complex traits in agricultural crops is frequent; however, exploitation of these QTL in practical breeding programs is limited. Here we report the validation of molecular markers linked to net blotch resistance QTL and their utilization in a barley (Hordeum vulgare L.) breeding ...
Ancestral landraces of common bean from the South of Europe and their agronomical value for breeding programs
Selection among breeding lines has been widely used to identify important cultivars and favorable alleles for adaptation, and resistance to abiotic and biotic stress. The objective of this work was to study the variability among common bean breeding lines selected from ancestral landraces, to evaluate the reaction of these lines to anthracnose (ANT) rust, common bacterial blight (CBB), halo ...

redpajama_set_name: RedPajamaCommonCrawl


text:
search filter All ContentAll JournalsBlood Advances
About Blood Advances
Lymphoid Neoplasia| March 4, 2020
Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk
Mariko Witalis,
Mariko Witalis
1Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada;
2Molecular Biology Department, University of Montréal, Montréal, QC, Canada;
Jinsam Chang,
Jinsam Chang
Ming-Chao Zhong,
Ming-Chao Zhong
Yasser Bouklouch,
Yasser Bouklouch
3Department of Experimental Medicine, McGill University, Montréal, QC, Canada;
Vincent Panneton,
Vincent Panneton
4Department of Microbiology, Infectious Diseases, and Immunology, University of Montréal, Montréal, QC, Canada;
Joanna Li,
Joanna Li
5Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada;
Thorsten Buch,
Thorsten Buch
6Institute of Laboratory Animal Science, University of Zürich, Zürich, Switzerland; and
Seok Jin Kim,
Seok Jin Kim
7Samsung Medical Center, Sungkyunkwan University, Seoul, Korea
Won Seog Kim,
Won Seog Kim
Young Hyeh Ko,
Young Hyeh Ko
André Veillette,
André Veillette
Woong-Kyung Suh
Blood Adv (2020) 4 (5): 868–879.
https://doi.org/10.1182/bloodadvances.2019001114
Mariko Witalis, Jinsam Chang, Ming-Chao Zhong, Yasser Bouklouch, Vincent Panneton, Joanna Li, Thorsten Buch, Seok Jin Kim, Won Seog Kim, Young Hyeh Ko, André Veillette, Woong-Kyung Suh; Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk. Blood Adv 2020; 4 (5): 868–879. doi: https://doi.org/10.1182/bloodadvances.2019001114
AITL-like tumors in mice continuously require key Tfh factors, such as Bcl6 and SAP.
Molecular pathways crucial for Tfh identity and T-B collaboration could be promising therapeutic targets for AITL.
Lymphoid Neoplasia
angioimmunoblastic lymphadenopathy, mice, neoplasms, tumor progression, lymphocyte function-associated antigen-1, t-lymphocytes, b-lymphocytes
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell–B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage–defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule–associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive non-Hodgkin lymphoma representing 15% to 20% of peripheral T-cell lymphomas.1 Patients have generalized lymphadenopathy, hypergammaglobulinemia, and autoimmune hemolytic anemia with poor prognosis (5-year survival rate, ∼33%).2,3 Typically, tumors display oligoclonal expansion of T cells and an effacement of lymph node architecture with prominent arborization of endothelial venules.1,4,5 Gene expression profiling, immunohistochemical studies, and xenograft experiments established that neoplastic cells in AITL are derived from CD4+ T follicular helper (Tfh) cells.6-9 However, the actual Tfh tumor cell content in the AITL tumor mass is kept low throughout disease progression, with concomitant expansion of bystander B cells and other reactive immune cells.5,6,10 Currently, chemotherapy is the most common treatment of AITL, but its limited efficacy demands more effective therapeutic options.3
The etiology of AITL has not been fully elucidated; however, genome sequencing of AITL tumor samples has uncovered heterogeneous somatic mutations with a few recurrent genes. The most frequently mutated genes include epigenetic modifiers (IDH2, TET2, and DNMT3A), genes encoding the small GTPase RhoA, and components of T-cell receptor/costimulatory signaling, including the Src-related protein tyrosine kinase Fyn.10-13 Importantly, activating mutations in T-cell signaling components were found in ∼50% of AITL patients, suggesting that hyperactivation of T cells during germinal center (GC) reactions may play an important role in the malignant transformation of Tfh cells and tumor growth.12,13
Tfh cells are a subset of CD4+ T cells whose differentiation is driven by the transcription factor Bcl6.14,15 Excessive Tfh cell activity can lead to pathologies such as autoimmunity, as well as Tfh-driven lymphomas.15,16 Directly or indirectly, Bcl6 suppresses other lineage-committing transcription factors and promotes the expression of Tfh signature genes, such as those encoding CXCR5, PD-1, and SAP, as well as key cytokines such as IL-21.17-19 Tfh cells have a unique ability to migrate into B-cell follicles, forming transient yet stable T-cell–B-cell (T-B) conjugates during GC reactions. These processes are supported by signaling lymphocytic activation molecule (SLAM) family receptors and their adaptor protein, SLAM-associated protein (SAP),20-24 as well as LFA-1.25 After repeated interaction with T cells, GC B cells that have received sufficient T-cell help and B-cell receptor signaling downregulate Bcl6 and upregulate IRF4 to differentiate into antibody-secreting plasma cells.26,27
Mice possessing 1 copy of the sanroque allele of Roquin (Roquinsan), a dominant negative point mutation, spontaneously develop AITL-like disease.16 The sanroque mutation increases the stability of an array of mRNA species, such as those coding for ICOS, OX40, and IFN-γ in CD4+ T cells, because of the disruption of Roquin-mediated mRNA degradation machinery.28 Mice homozygous for this sanroque mutation (Roquinsan/san) have hyperactive Tfh cells, spontaneous GC reactions, and lupus-like autoimmune disease, combined with AITL-like disease within 4-months of age.29 Heterozygous Roquinsan/+ mice do not develop lupus-like disease, but still have hyperactive GC reactions and present with AITL-like disease (∼50% incidence rates at 6 months of age).16 Although ROQUIN gene mutations have not been discovered in AITL patients,30 hyperactivation of T cells and Tfh cells are shared features of tumors arising in Roquinsan/+ mice and AITL patients.
In this study, the AITL-like tumors in Roquinsan/+ mice accumulated B cells with features of early-stage plasma cells. This B-cell expansion coincided with highly proliferative CD4+CXCR5+PD-1+ Tfh-like cells equipped with Bcl6, SAP, and high-affinity LFA-1. Importantly, acute abrogation of Bcl6 or SAP function or inhibition of high-affinity LFA-1 led to partial or full tumor regression. Taken together, these data suggest that AITL-like tumors in Roquinsan/+ mice are driven by Tfh-like CD4+ cells that continuously interact with B cells in a manner resembling GC T-B interactions.
Mice with the Roquinsan allele16,29 were provided by C. Vinuesa (Australian National University) and bred with other lines of mice to make composite mouse lines. UBC-CreERT2 (Jax 008085)31 and CD4-CreERT2 mice32 were used for tamoxifen-inducible ubiquitous or CD4+ cell–specific knockout models. Bcl6 conditional knockout mice were provided by T. Takemori (RIKEN, Japan).33 SAP conditional knockout (Sh2d1af)34 and SAPR78A mice (Sh2d1aR78A)35 were previously described. All mice had been backcrossed on the C57BL/6J background for more than 10 generations before the composite lines were generated. Mice were maintained in the animal facility at the Institut de Recherches Cliniques de Montréal (IRCM) in a specific pathogen-free environment, and all experiments were performed in compliance with animal use protocols approved by the IRCM Animal Care Committee.
Antibodies and chemicals
All antibodies, streptavidin conjugates, and reagents used for flow cytometry were from ThermoFisher unless otherwise stated: B220 (RA3-6B2), Bcl6 (K112-91; BD Biosciences), CD4 (GK1.5), CD16/CD32 (2.4G2; BioXCell), CD95 (BD Biosciences), CD138 (281-2; BioLegend or BD Biosciences), CXCR5 (SPRCL5), GL7, ICAM-1 (YN1/1.7.4), IRF4 (3E4), Ki-67 (SolA15), PD-1 (J43; BD Biosciences), SAP (1A9; BD Biosciences or produced by the André Veillette laboratory), streptavidin-APC, and streptavidin-PE-Cy. Dead cells were stained with 7-aminoactinomycin D (BD Biosciences) or a fixable viability dye. Fixation and permeabilization kits (BD Biosciences and ThermoFisher) were used to perform intracellular staining. Tamoxifen was purchased from Millipore Sigma, isoflurane from CDMV, and lovastatin from Selleck Chemicals. Anti-LFA1 (CD11a; M17/A) was purchased from BioXCell.
Single-cell suspensions of lymph nodes were prepared by mechanical dissociation via a 70-μm nylon mesh filter (BD Biosciences), in phosphate-buffered saline or staining buffer with 1% bovine serum albumin (Wisent). Cells were first blocked with anti-CD16/CD32 and then stained with primary antibodies, followed by streptavidin conjugates. For intracellular stains, cells were fixed and permeabilized with Cytofix/Cytoperm solution (BD Biosciences) or Fix/Perm Buffer (ThermoFisher), according to the manufacturer's instructions. ICAM-1 binding assay was performed as described in the supplemental Methods. Samples were acquired using LSR Fortessa (BD Biosciences) and analyzed by using FlowJo, version 10 (Treestar).
Tumor monitoring and treatment
Tumors in cervical, axillary, brachial, and inguinal lymph nodes were palpated and monitored by in vivo sonographic imaging (VEVO 770; Visual Sonics), using the RMV 707B scanhead. A minimum of 5 cross-sectional ultrasound images were taken, and the largest diameter and cross-sectional surface area were chosen (∼5- to 12-mm diameter; ∼13- to 77-mm2 cross-sectional surface area). To induce Cre recombinase activity, oral gavage was performed for 5 consecutive days (200 μg/g of body weight per day in corn oil). Lovastatin was administered through intraperitoneal injections (2 mg/kg, every other day for 2 weeks). ELISA, human AITL histology, as well as genomic DNA preparation and PCR are described further in the supplemental Methods.
Data were analyzed using Prism 7.0 (GraphPad Software). When comparing 2 groups, an unpaired Student t test was performed. When comparing 3 groups, 1-way analysis of variance was used. For time courses of tumor regression, 2-way analysis of variance was used. For comparing tumor incidence rates, Fisher's exact test was used. P < .05 was considered statistically significant.
Signs of elevated helper T-cell activities in Roquinsan/+ tumor-bearing mice
A longitudinal study of AITL patient biopsy samples revealed that B-cell follicles in tumorous lymph nodes gradually disappear, leading to a complete disruption of T-B-cell boundaries.5,36 This hallmark feature of AITL has been recapitulated in lymph node tumors spontaneously developing in Roquinsan /+ mice.16 As with human AITL, rather than a disproportionate expansion of T cells, it is an expansion of B cells that contributes to most of the tumor mass.16 Although it has been presumed that this B-cell expansion is driven by the hyperactive helper functions of neoplastic CD4+ cells, the different B-cell populations in Roquinsan /+ tumor-bearing mice during progression have not been well characterized.16 Thus, we phenotyped B-cell populations in tumor-free, nontumorous, and tumorous lymph nodes of Roquinsan /+ mice (6-13 months old; Figure 1A).
An increase in plasmablasts in tumor lymph nodes of Roquinsan/+mice. (A) Pictogram illustrating differences between tumor-free and -bearing mice, as well as providing a pictorial explanation of tumor-free, nontumorous (non-tumor), and tumorous (tumor) lymph nodes. (B-D) Representative flow cytometric analyses and frequencies of B-cell populations using the surface markers Fas and GL7 (n = 10 tumor-free; n = 11 nontumorous; and n = 15 tumorous samples). (E-F) Representative flow cytometry plots and histograms comparing the frequency of plasmablasts (n = 5 tumor-free, n = 6 nontumorous; and n = 9 tumorous samples). (G-I) Expression profile of Bcl6 and IRF4 in GL7hiFas+ B cells as depicted through representative flow cytometry plots and frequencies (n = 5 tumor-free; n = 5 nontumorous; and n = 9 tumorous samples). Error bars in panels C-D,F,H-I represent the standard error of the mean (SEM). Data are pooled from at least 2 independent experiments. *P < .05; **P < .01; ***P < .001; ****P < .0001. ns, not significant.
Consistent with mild spontaneous GC reactions, there was a greater frequency of GC B cells (B220+GL7hiFas+) in nontumorous than in tumor-free lymph nodes (Figure 1B-C). Interestingly, in tumors, the frequency of typical GC B cells was reduced, as confirmed by flow cytometric analysis of B220+GL7hiFas+ (Figure 1B-C) and B220+Bcl6+Fas+ (supplemental Figure 1B) cell populations. We reasoned that this reduction could be related to a rapid transition of GC B cells into the plasma cell lineage, reflecting hyperactive helper T-cell activities during tumor growth. Consistent with this, we observed an increase of CD138+B220int plasmablasts in tumors (Figure 1E-F). Furthermore, we found that B220+GL7hiFas+ cells in tumors had an increased subset of cells that express high levels of IRF4 and reduced Bcl6 (Figure 1G-I), a population reported to be the immediate precursor of plasma cells.26,27 The B220+GL7hiFas− cells that accumulated in tumorous lymph nodes were almost exclusively IRF4hi Bcl6−. We also confirmed that tumor-bearing mice have elevated IgG2c and IgG1 titers (supplemental Figure 2A-B), consistent with previous data.16 This hypergammaglobulinemia is a shared feature between human AITL and our mouse model.2 Thus, tumor-bearing Roquinsan /+ mice have signs of ongoing T-B-cell cross talk within tumors, despite a lack of conventional GCs.
Persistent activity of Bcl6 is essential for tumor progression
When heterogeneous human AITL tumor cell populations were xenografted into immunodeficient mice, after repeated rounds of serial transplantation, putative neoplastic CD4+ T cells persisted, whereas CD8+ T and B cells gradually disappeared.8 Importantly, the enriched T-lineage cells were mostly Bcl6+, suggesting that sustained expression of Bcl6 in CD4+ tumor cells may be necessary for AITL tumor progression. Similar to this observation, we found that consecutive sections of AITL patient biopsy samples had staining patterns where CD3 and Bcl6 cells overlapped (Figure 2A). Multicolor immunofluorescence imaging confirmed a predominant expression of Bcl6 in CD4+ cells in AITL, whereas Bcl6 expression was restricted within the GC in human tonsils (supplemental Figure 3A-B). In fact, Bcl6 positivity is now considered a reliable diagnostic tool, especially for AITL patients with bone marrow involvement.37,38 In Roquinsan /+ tumors, the conventional CD4+CXCR5+PD-1+ Tfh cell population was decreased with reduced PD-1 expression (Figure 2B-D).16 However, this difference was less pronounced when we gated on CD4+CXCR5+Bcl6+ cells (supplemental Figure 4A-B) and high levels of Bcl6 in CD4+CXCR5+PD-1+ cells were maintained, regardless of tumor status (Figure 2E-F). Because this CD4+CXCR5+PD-1+ population expresses the highest levels of Bcl6 and is also highly proliferative (Figure 2G), we suspect that these cells represent the neoplastic cells driving tumor growth by interacting with B cells. Based on these, we predicted that acute ablation of Bcl6 activity halts AITL-like tumor growth. To test this idea, we generated mice expressing a CD4-driven tamoxifen-inducible Cre recombinase and conditioned Bcl6 genes on the Roquinsan/+ background (Roquinsan/+; Cd4-CreERT2+/−; Bcl6f/f; Figure 2H). Upon exposure to Cre recombinase activity, the conditioned Bcl6 gene loses exons 7 to 9 (encoding Zn-finger domains) and thereby its capacity to drive GC B or Tfh differentiation.33,39 We confirmed that our Cd4-CreERT2 system efficiently removed the floxed Bcl6 DNA segment specifically in CD4-expressing cells (supplemental Figure 5A). Under the same conditions, the Bcl6 antibody (clone K112-91) detected intact levels of Bcl6 in Cre-experienced Tfh-like cells (supplemental Figure 5B), suggesting that the deleted allele still produced a nonfunctional truncated version of Bcl6. Once these mice developed full-size tumors, we followed tumor growth by palpation and sonographic imaging after administration of tamoxifen. Notably, tamoxifen treatment alone in control tumor-bearing mice (Roquinsan/+; Cd4-CreERT2+/−) reduced tumor size within the first week after treatment (Figure 2I), perhaps because of a general anticancer effect of tamoxifen.40 However, tumors grew back after the initial shrinkage at 2 weeks after treatment. In contrast, Roquinsan/+; Cd4-CreERT2+/−; Bcl6f/f mice showed continued tumor regression (Figure 2I-J). Mice that showed tumor regression had no recurrence in primary or distal lymph nodes up to 12 weeks after tamoxifen treatment (Figure 2I). Therefore, we concluded that persistent Bcl6 activity is indispensable for the continued growth of AITL-like tumors in Roquinsan/+ mice.
Disruption of functional Bcl6 gene in growing AITL-like tumors leads to tumor regression. (A) Exemplary immunohistochemistry sections of AITL patient samples depicting CD3 and Bcl6 expression. (B) Representative flow cytometric plots showing subsets of CD4 cells based on expression of PD-1 and CXCR5. (C) Comparing frequencies of CD4+CXCR5+PD-1+ cells between tumor-free, nontumorous (non-tumor), and tumorous (tumor) samples (n = 11 tumor-free; n = 15 nontumorous; and n = 21 tumorous samples). (D) MFI of CXCR5 and PD-1 on CD4+CXCR5+PD-1+ cells (n = 11 tumor-free; n = 15 nontumorous; and n = 21 tumorous samples). Bcl6 expression in CXCR5−PD1−, CXCR5+PD-1−, and CXCR5+PD-1+ cells from tumor samples (E) and Bcl6 MFI of CD4+CXCR5+PD-1+ cells (F) (n = 9 tumor-free; n = 12 nontumorous; and n = 13 tumorous). (G) Representative histogram and frequency of Ki-67 levels in tumor CD4+ subsets (n = 21 tumorous). (H) Roquinsan/+ mice were bred with a CD4-specific, tamoxifen-inducible Cre-recombinase to target the Bcl6 gene (Roquinsan/+; Cd4-CreERT2+/−; Bcl6f/f). Representative time course (I) and sonograms (J) demonstrating tumor regression in mice with Bcl6 gene deletion (n = 5 Roquinsan/+; Cd4-CreERT2+/−; Bcl6+/+; n = 6 Roquinsan/+; Cd4-CreERT2+/−; Bcl6f/f). Error bars in panels C-G,I represent the SEM. Data are pooled from at least 2 independent experiments. *P < .05; **P < .01; ***P < .001; ****P < .0001.
SAP is critical for tumor progression
Next, we sought to identify key mechanisms downstream of the Bcl6-dependent Tfh program that support AITL-like tumor growth in Roquinsan/+ mice. As a master regulator of Tfh cell differentiation, Bcl6 has many direct or indirect target genes, ∼50% of which are distinct from those identified in B cells.17,19 Relevant to its role in Tfh differentiation, Bcl6 overexpression in human CD4+ T cells leads to upregulation of SAP, along with CXCR5 and PD-1.18 SAP has been shown to be crucial for the formation of T-B conjugates during early and late stages of the GC reaction.20,22 This is the likely reason that SAP deficiency drastically reduced tumor incidence in Roquinsan/+ mice.16 Consequently, we predicted that sustained expression of SAP is critical for AITL-like tumor growth. We found increased frequencies of SAPhi cells among CD4+ T cells (Figure 3A) and Tfh-like cells from tumors in Roquinsan/+ mice, although we observed no differences in SAP median fluorescence intensity (MFI) among Tfh-like cells (Figure 3B). Notably, SAPhi CD4+ T cells from tumors had more Ki-67+ cells when compared with SAPhi CD4+ T cells from nontumorous or tumor-free lymph nodes (Figure 3C). Within tumors, SAPhi CD4+ T cells were more proliferative than SAPlo CD4+ T cells (Figure 3D). These results suggest that tumor cells require high levels of SAP expression for their growth. To directly test this idea, we generated Roquinsan/+; Cd4-CreERT2+/−; Sh2d1af/for Sh2d1af/y mice (the Sh2d1a gene is X-linked; Figure 3E). As expected, abrogation of SAP protein expression in CD4+ T cells by administration of tamoxifen (supplemental Figure 5E) led to durable tumor regression until 12 weeks after treatment (Figure 3F-G). Similar results were obtained when the Sh2d1a gene was deleted ubiquitously by using a UBC-CreERT2 system in growing tumors (supplemental Figure 6). Despite similar tumor regression kinetics caused by abrogation of functional Bcl6 or SAP, the 2 Tfh signature proteins appear to have distinct roles in AITL-like tumor maintenance. First, acute disruption of Bcl6 gene function does not cause immediate loss of SAP protein (supplemental Figure 5C). Second, Bcl6 disruption leads to a small but clear reduction of CXCR5 expression levels among Tfh-like cells without grossly affecting their total frequency (supplemental Figure 5D). In contrast, abrogation of SAP expression leads to a clear twofold reduction in the percentage of Tfh-like cells without affecting CXCR5 levels (supplemental Figure 5F).
Abrogation of SAP expression from AITL-like tumors leads to tumor regression. (A) Increased expression of the SLAM adaptor protein, SAP in CD4 cells from AITL-like tumors (n = 5 tumor-free; n = 8 nontumorous [non-tumor]; and n = 12 tumorous [tumor] samples). (B) Frequency and MFI of SAP in CXCR5+PD-1+ cells from tumor-free, nontumorous, and tumor samples (n = 5 tumor-free; n = 8 nontumorous; and n = 12 tumorous samples). (C) SAPhi CD4 cells from tumors are more proliferative, as depicted through increased frequencies of Ki-67+ cells (n = 4 tumor-free; n = 7 nontumorous; and n = 11 tumorous samples). (D) SAPhi CD4+ tumor cells are more proliferative than SAPlo as shown in representative histogram and frequencies. (E) Roquinsan/+ mice were bred with a CD4 specific tamoxifen-inducible Cre recombinase and conditional Sh2d1a allele (Roquinsan/+; Cd4-CreERT2+/−; Sh2d1af/y or f/f). Representative time course (F) and sonograms (G) demonstrating tumor regression in mice with CD4-specific abrogation of SAP (n = 5 Roquinsan/+; Cd4-CreERT2+/−; Sh2d1a+/+; n = 9 Roquinsan/+; Cd4-CreERT2+/−; Sh2d1af/y or f/f). In panel F, we reused CD4-CreERT2 control data shown in Figure 2I to perform statistical analysis for different time points. Error bars in panels A-D,F represent the SEM. Data are pooled from at least 2 independent experiments. *P < .05; **P < .01; ***P < .001; ****P < .0001.
Selective abrogation of SAP-Fyn signaling pathway does not greatly alter AITL-like disease
SAP promotes the production of cytokines such as IL-4 by activating the Src family protein kinase Fyn.35 When SAP-Fyn interactions were abrogated by the SAP R78A point mutation, the ability of SAP to activate Fyn was abolished.35 However, this SAP R78A mutant retained the ability to promote Tfh maturation and GC reactions.24,41 Interestingly, a few Fyn mutations with disrupted autoinhibitory mechanisms have been discovered in human AITL tumors, suggesting a positive role for Fyn kinase in AITL tumorigenesis.12,13 Although SAP-deficient Roquinsan/+ mice had dramatically reduced tumor incidence (no tumors developed in the 16 mice monitored),16 the contributions of the SAP-Fyn signaling pathway to disease incidence and severity have not been evaluated. To address these questions, we generated cohorts of Roquinsan/+ mice possessing the Sh2d1a+/y or Sh2d1aR78A/y genotype. Although there was some trend toward reduced tumor incidence, a substantial portion (9 of 29) of SAP R78A mutant mice still developed tumors (Figure 4A). Also, there was no difference in the number and size of tumors. Furthermore, the percentages of CD4+CXCR5+PD-1+ Tfh-like cells in tumors within wild-type or mutant SAP mice were similar (Figure 4B). We observed no differences in Bcl6 levels but found increased Ki-67+ populations in SAP-R78A tumors, compared with the number in SAP-wild-type tumors (Figure 4C). SAP-R78A tumors also recapitulated the phenotype of B-cell populations in SAP-wild-type tumors (Figure 4D-E). Last, there was no difference in the adhesive capacities of CD4+ T cells derived from the 2 groups of tumors, as judged by an ICAM-1 binding assay (supplemental Figure 7). These results indicate that SAP mostly uses Fyn-independent pathways, such as T-B-cell conjugation, to promote AITL-like disease.
Loss of SAP-Fyn signaling pathway does not greatly alter AITL-like disease. (A) Abrogation of downstream signaling between SAP and Fyn kinase does not prevent tumor incidence, but may have a partial effect (n = 17 Roquinsan/+; Sh2d1a+/y and n = 29 Roquinsan/+; Sh2d1aR78A/y). (B-E) Tumors from Roquinsan/+; Sh2d1a+/y or Roquinsan/+; Sh2d1aR78A/y show comparable T-B-cell expression patterns and frequencies (n = 3 Roquinsan/+; Sh2d1a+/y tumors and n = 7 from Roquinsan/+; Sh2d1aR78A/y tumors). Error bars in panels B-E represent the SEM. Data are pooled from at least 2 independent experiments. **P < .01.
Evidence of LFA-1–dependent T-B-cell cross talk in AITL-like tumor progression
Because ongoing T-B-cell cross talk was evident in growing AITL-like tumors, we wanted to test for upregulation of adhesion molecules on CD4+ and B220+ cells in tumors. It has been reported that Tfh cells express high levels of LFA-1 and that disruption of LFA-1 activity severely compromises Tfh cell survival and GC reactions.25 Interestingly, using an ICAM-1 binding assay, we found that CD4+ T cells from tumors had elevated levels of functional or high-affinity LFA-1 compared with tumor-free Roquinsan/+ mice, whereas nontumor CD4+ T cells had intermediate levels of active LFA-1 (Figure 5A). In addition, tumor samples contained B cells that expressed relatively higher levels of ICAM-1 compared with their counterparts in tumor-free mice, although the difference in absolute MFI was not very strong (Figure 5B), suggesting that B cells in tumor-bearing mice have a better capacity to engage with T cells. Among B-cell subsets, regardless of tumor progression, ICAM-1 levels were highest in B220+GL7hiFas+ GC B-like cells, the known partner of Tfh cells in GCs (Figure 5C). Accordingly, we tested whether repeated injection of LFA-1–blocking antibodies could reduce tumor size. However, we could not detect clear regression of AITL-like tumors. We reasoned that macromolecules, such as antibodies, may not infiltrate tumor lymph nodes because of their highly disorganized lymph node architecture. Therefore, we decided to test small-molecule inhibitors for LFA-1. A cholesterol-lowering drug, lovastatin, has been reported to inhibit LFA-1 allosterically.42,43 We validated this inhibitory effect of lovastatin in vitro using Tfh cells isolated from Peyer's patches, with minimal change to cell viability (Figure 5D). Importantly, when we administered lovastatin to tumor-bearing Roquinsan/+ mice, we observed a full regression (>60% reduction in area) or partial regression (25% to 60% reduction in area) in 6 of 13 tumors (Figure 5E-F). However, the impact of lovastatin on tumor growth may involve mechanisms other than LFA-1 inhibition, such as alteration of cholesterol metabolism, warranting further study. Because absence of SAP in murine natural killer cells diminishes high-affinity LFA-1,44 we tested whether acute loss of SAP expression would lead to a drastic disappearance of high-affinity LFA-1 in CD4+ T cells. However, both in vitro and in vivo tamoxifen-induced abrogation of SAP expression did not affect active LFA-1 levels (supplemental Figure 8). Together, these data suggest that LFA-1 and ICAM-1 serve as adhesion molecules that promote T-B-cell cross talk and growth of AITL-like tumors in Roquinsan/+ mice.
Elevated high-affinity LFA-1 and ICAM-1 levels in Roquinsan/+tumors. (A) Tumor samples have increased frequency of high-affinity LFA-1. Representative flow cytometric analyses and frequency of high-affinity LFA-1 expression on CD4+ cells from recombinant ICAM-1 binding assay (10 μg/mL of murine recombinant ICAM-1; n = 5 tumor-free; n = 4 nontumorous [non-tumor]; and n = 4 tumorous [tumor] samples). (B) Concomitant increased expression of ICAM-1 on B220+ cells in Roquinsan/+ tumors as shown in representative flow cytometric analyses and frequencies. (B-C) MFI of ICAM-1 on B-cell subsets (n = 5 tumor-free; n = 5 nontumorous; and n = 7 tumorous samples). (D) Incubating wild-type Peyer's patch cells with Lovastatin during ICAM-1 binding assay verifies reduction in high-affinity LFA-1 levels on CD4+ T cells with minimal differences in cell viability (n = 5, wild type). (E) Left graph shows a time course of change in tumor size after treatment with lovastatin (2 mg/kg, intraperitoneal, every other day for 2 weeks) compared with the untreated control group. Lovastatin-treated mice were further subgrouped based on the following criteria: no response (<25% reduction in area or growth), partial response (25% to 60% reduction in area), or full response (>60% reduction in area) at the final time point (week 6). The right graph further compares each response type with the untreated control group. (F) Exemplary regressed tumor is shown in sonograms. Error bars in panels A-E represent the SEM. Data are pooled from at least 2 independent experiments. *P < .05; **P < .01; ***P < .001; ****P < .0001.
We report evidence that CD4+ and B220+ cells in AITL-like tumors intimately influence each other and resemble Tfh-GC B-cell interactions in physiological GCs. First, there is an accumulation of B220+GL7hi Fas+ populations with signs of plasma cell commitment (Bcl6loIRF4hi), a product of successful Tfh-GC B collaboration. Second, AITL-like tumor progression relies heavily on continued expression of the Tfh lineage–defining transcription factor Bcl6 and high levels of SAP, a key element of T-B-cell conjugation. In addition, CD4+ T cells from tumor-bearing mice had increased active LFA-1, an adhesion molecule highly expressed on Tfh cells, as well as elevated levels of its binding partner ICAM-1 on B cells. Last, we found that tumor CD4+ T cells can drive tumor growth without Fyn-mediated SAP signaling mechanisms, consistent with previous studies that T-B-cell collaboration during GC reactions is SAP-Fyn independent.
It is intriguing that Bcl6 plays critical roles in both GC-derived T- and B-cell malignancies. Dysregulated Bcl6 expression is important in the development and progression of GC-derived B-cell lymphomas.45-48 In B-cell lymphomas, the oncogenic effects of persistent Bcl6 is most likely mediated by its ability to suppress cell cycle inhibitor p21 and p53.46 In contrast, BCL6 mutations have not been discovered in human AITL, but sustained expression of Bcl6 appears to be critical for maintaining malignant CD4+ cell populations in xenografted human AITL samples8 and our mouse model. Considering that ∼50% of Bcl6 target genes in Tfh cells are distinct from those regulated in GC B cells,17 Bcl6 may play different roles in T-cell lymphoma generation and progression than in B-cell lymphomas.
The association between Bcl6 and SAP has been well established in Tfh cells. Both in mouse and human Tfh cells, Bcl6 expression levels correlate highly with SAP levels and B-cell helper functions.18,49,50 High levels of SAP in Tfh cells appear to promote T-B-cell conjugation by inhibiting negative signals provided by SLAMF6.23 Analogous to this, Bcl6-expressing Tfh-like cells in tumor lymph nodes had higher levels of SAP expression, along with an expansion of B cells progressing into the plasma cell lineage. However, we found that acute disruption of Bcl6 activity does not lead to a drastic change in SAP expression level in CD4+ T cells. Because tumor regression becomes evident 2 weeks after tamoxifen treatment, we predict that these differences may be greater at later stages. However, we have not pursued this possibility, as newly generated T cells from the thymus may complicate the interpretation. Despite this, our data suggest that SAP is not an immediate downstream component of Bcl6. Further mechanistic studies are needed to identify proximal components of Bcl6-regulated genes relevant to AITL tumor progression.
There have been a handful of human AITL patients reported with somatic mutations in the FYN gene. These Fyn mutations disrupt autoinhibitory mechanisms and suggest that hyperactive Fyn could drive AITL tumor initiation and progression. Previous work has shown that Roquinsan/+ mice cannot develop tumors in SAP-deficient mice.16 However, specific roles for SAP-Fyn signaling in AITL-like tumor incidence and progression have not been clarified. In this study, we could not find clear differences in tumor incidence rates, severity, or characteristics, indicating that SAP-Fyn signaling has a very limited role in tumorigenesis and maintenance. Although it remains possible that persistently hyperactive Fyn activity through other upstream signals (such as T-cell receptor [TCR]) may drive tumor progression, it is not the main mechanism of how SAP drives AITL-like disease in our mouse model.
There are several mouse models of AITL that have provided insights into the pathogenesis of human AITL. An early study using transplantation of human AITL cells into immunodeficient mice confirmed that neoplastic CD4+ T cells express high levels of Bcl6.8 Studies using genetically engineered mouse models confirmed the relevance of the most prevalent somatic mutations discovered in human AITL. A recurrent RHOA G17V mutation is present in ∼60% to 70% of AITL patients and is often associated with loss-of-function mutations in TET2.10,12,13,51 Several recent mouse models support a 2-hit model of AITL tumorigenesis that requires both TET2 deficiency and expression of RhoA G17V. Loss of TET2 in hematopoietic progenitor cells is shown to predispose mice to both lymphoid and myeloid malignancies, but an additional RhoA G17V mutation in T cells is essential to initiate Tfh-driven lymphomas.51-54 These studies also showed that combining TET2-deficiency with the RhoA G17V mutation synergistically elevates Tfh differentiation, as well as PI3K-mTORC1 and TCR signaling pathways, which leads to AITL-like disease. Although spleen and swollen lymph nodes (<2 mm in diameter) in these mouse models share histological features with human AITL, they do not phenocopy the hypergammaglobulinemia and palpable lymphadenopathy seen in humans. In contrast, Roquinsan/+ mice give rise to easily detectable tumors with most of the pathological features of human AITL. The gross change in the size of tumor lymph nodes provides a unique opportunity to test the impact of gene deletion or drug treatment in a preclinical setting. Despite these advantages, it should be noted that ROQUIN gene mutations have not been detected in human AITL.30 Also, it remains unclear whether T cells in Roquinsan/+ mice transform into tumor cells in response to elevated TCR or cytokine signaling, as is often shown in peripheral T-cell lymphomas.13,55 Therefore, our findings made in Roquinsan/+ mice should be further validated in more relevant disease models. In this context, patient-derived xenograft models using human AITL cell lines with defined causative mutations may provide further insights.56,57
In summary, our data suggest that ongoing T-B-cell cross talk is a driving force for the progression of Tfh-derived T-cell lymphomas. Importantly, this may apply not only to AITL but also to other peripheral T-cell lymphomas with features of Tfh origin. Therefore, we propose that future therapies for AITL focus on T-cell signaling components that mediate T-B-cell interactions.
The authors will share renewable materials, data sets, and protocols upon e-mail request to the corresponding author.
The authors thank C. Vinuesa (Australian National University, Canberra, Australia) for the Roquinsan/+ mice, T. Takemori (RIKEN, Yokohama City, Japan) for Bcl6 cko, I. King (McGill University) for assistance with the ICAM-1 binding assay, and the IRCM Flow Cytometry Core Facility and IRCM Animal Facilities for their services.
This work was supported by operating grants from the Cancer Research Society (W.-K.S.) and Canadian Institutes of Health Research (CIHR) grants MT-14429, MOP-82906, and FDN-143338 (A.V.). A.V. holds the Canada Research Chair on Signaling in the Immune System. M.W. and J.L. received CIHR Master's Awards, and M.W. and V.P. received Fonds de Recherche du Québec–Santé (FRQS) Doctoral Scholarships.
Contribution: W.-K.S. conceptualized the study; M.W., J.C., M.-C.Z., Y.B., V.P., J.L., T.B., and A.V. developed experimental tools; M.W. performed the experiments; M.W. and W.-K.S. analyzed the data and prepared the figures; M.W. and W.-K.S. wrote the manuscript with input from J.C., Y.B., V.P., J.L., T.B., M.-C.Z., A.V., S.J.K., W.S.K., and Y.H.K.; and all authors approved the final version of the manuscript.
Conflict-of-interest disclosure: A.V. has a contract with Bristol Myers-Squibb to study the mechanism of action of anti-SLAMF7 monoclonal antibody elotuzumab in multiple myeloma. The remaining authors declare no competing financial interests.
Correspondence: Woong-Kyung Suh, IRCM, 110 Ave des Pins Ouest, Montréal, QC H2W IR7, Canada; e-mail: woong-kyung.suh@ircm.qc.ca.
Bellei
Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project
Mounier
Brière
Groupe d'Etude des Lymphomes de l'Adulte
Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials
No survival improvement for patients with angioimmunoblastic T-cell lymphoma over the past two decades: a population-based study of 1207 cases
Dogan
Pathology and clinical features of angioimmunoblastic T-cell lymphoma after successful treatment with thalidomide
Attygalle
Kyriakou
Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression
Am J Surg Pathol
de Leval
Thielen
The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells
Roncador
García Verdes-Montenegro
Tedoldi
Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma mice model
Leuk Res
Distinct features of angioimmunoblastic T-cell lymphoma with bone marrow involvement
Am J Clin Pathol
Sakata-Yanagimoto
Somatic RHOA mutation in angioimmunoblastic T cell lymphoma
Nat Genet
A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma
Palomero
Couronné
Khiabanian
Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas
Vallois
Dobay
Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas
T follicular helper cell differentiation, function, and roles in disease
Linterman
Follicular Helper T Cells
Annu Rev Immunol
Ellyard
Rodriguez-Pinilla
Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice
Hatzi
BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms
J Exp Med
Locci
Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation
J Immunol
Genome-wide Analysis Identifies Bcl6-Controlled Regulatory Networks during T Follicular Helper Cell Differentiation
Cell Reports
Klauschen
Schwartzberg
SAP-controlled T-B cell interactions underlie germinal centre formation
T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction
M-C
Veillette
Critical role of SAP in progression and reactivation but not maintenance of T cell-dependent humoral immunity
Mol Cell Biol
The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development
Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84
Fontés
The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance
Fujii
Shiroguchi
T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate
715.E4
Gadzinsky
Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction
e536.
Roquin--a multifunctional regulator of immune homeostasis
Genes Immun
Angelucci
A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity
Travert
ROQUIN/RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma
Ruzankina
Pinzon-Guzman
Asare
Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss
Cell Stem Cell
Sledzińska
Hemmers
TGF-β signalling is required for CD4+ T cell homeostasis but dispensable for regulatory T cell function
PLoS Biol
Kaji
Ishige
Hikida
Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory
SAP expression in T cells, not in B cells, is required for humoral immunity
Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation
Al-Jehani
Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10
Suzumiya
Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma
Hum Pathol
Nishizawa
BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma
Int J Hematol
Leung Soo
T Follicular Helper Cell-Derived IL-4 Is Required for IgE Production during Intestinal Helminth Infection
Bogush
Dudko
Polotsky
Tjulandin
Davydov
Tamoxifen non-estrogen receptor mediated molecular targets
Oncol Rev
The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis
J Biol Chem
Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation
Weitz-Schmidt
Welzenbach
Kallen
Improved Lymphocyte Function-associated Antigen-1 (LFA-1) Inhibition by Statin Derivatives: Molecular Basis Determined by X-Ray Analysis and Monitoring of LFA-1 Conformational Changes In Vitro and Ex Vivo
Pérez-Quintero
The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells
Dalla-Favera
Germinal centres and B cell lymphomagenesis
Nat Rev Immunol
Phan
BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells
Nat Immunol
Béguelin
Gearhart
EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis
The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells
Monticelli
Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150)
Suryani
Early commitment of naïve human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12
Immunol Cell Biol
Ambesi-Impiombato
RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis
RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice
Nagae
Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice
Blood Cancer J
Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis
J Clin Invest
Crispatzu
Admirand
Herling
T-cell receptor signaling in peripheral T-cell lymphoma: a review of patterns of alterations in a central growth regulatory pathway
Curr Hematol Malig Rep
Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
Horwitz
Porcu
Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
The full-text version of this article contains a data supplement.
Supplement File 1- pdf file
Blood Advance Talks
Submit to Blood Advances
Advertising in Blood Advances


text:
Unorganized South East Algoma District is an unorganized area in the Canadian province of Ontario, comprising a small unincorporated portion in the southeasternmost corner of the Algoma District. It comprises a small strip of land which lies between the territory of the Sagamok First Nation and the Algoma District's boundary with the Sudbury District, as well as several small islands within the North Channel of Lake Huron, such as Eagle, Fréchette, Fox, Hotham, Middleton, North and South Benjamin Islands.

The division comprises  (increased from 41.71 km2 in the 2001 census), and had a reported population of zero in the Canada 2006 Census.

The division includes the historic Fort La Cloche trading post and a small portion of La Cloche Provincial Park.

Demographics
Population trend:
 Population in 2011: 0
 Population in 2006: 0
 Population in 2001: 0
 Population in 1996: 0
 Population in 1991: 0

See also
List of townships in Ontario

References

Geography of Algoma District
Algoma South East

redpajama_set_name: RedPajamaWikipedia


text:
Hans Thoolen on Human Rights Defenders
share information on human rights defenders, comment on events, support the HRDs
Posts Tagged '#WelcomingEurope'
How anti-illegal migrants rules in the EU threaten human rights defenders
An African at a temporary camp for immigrants seeking entry to Europe, in Melilla (Spanish autonomous city in North Africa), 12 October 2005 (EPA/Chema Moya)
Lizan Nijkrake published on 25 March 2019 an excellent piece under the title "Should it be a crime to help illegal immigrants?" She describes how European defenders of migrants are being prosecuted for aiding illegal immigrants. EU states had a choice to exempt humanitarian aid from criminal charges but most didn't take it. And those who did are not always following the rules.
Take the UK as an example: The United Kingdom's Institute for Race Relations, which has been tracking criminal cases, reported that 81 people were prosecuted for assisting immigrants in 2018, compared with 20 in 2017. "Things escalated in 2018," says Anya Edmond-Pettitt, a researcher at the Institute of Race Relations. "People got charged with serious crimes, linked to terrorism and membership of a criminal organization."
Why is this happening?
In 2002, the EU adopted a directive that requires all EU member states to impose sanctions on citizens who intentionally help illegal immigrants secure unauthorized entry into, transit across or residence within in the EU — thus making it illegal to offer aid in the form of free rides or overnight stays. The directive says its objective is to "combat the aiding of illegal immigration" to further the EU's goal of creating "an area of freedom, security and justice." But in a study for the European Parliament, the Centre for European Policy Studies (CEPS), a Brussels-based think tank, concluded that the EU rules are not in line with the United Nations Protocol against the Smuggling of Migrants by Land, Sea and Air.
The UN protocol stipulates that assisting a migrant can be a crime only when there is a clear aim of making money or other material gains. While the EU directive says offering overnight stays is illegal only if it is done for profit, CEPS reported last December that 13 out of 28 member states have criminalized free sleepovers. Out of 28 EU countries, CEPS says that only four have laws that adhere fully to UN protocol: Germany, Ireland, Luxembourg and Portugal.
The EU directive allows member states to exempt individuals from sanctions for helping illegal immigrants enter or move across EU territory if done for reasons of "humanitarian assistance," such as giving food, shelter and first aid to people in need. Nine member states have included some types of exemption in their national laws, according to the European Commission.
But the CEPS said states should be required to make such an exception. "And even in the European nations that have exempted humanitarian acts, we still see prosecutions happening, for example in Italy," said CEPS researcher Lina Vosyliūtė.
Lizan Nijkrake's piece gives concrete examples of how the laws and the application in practice are affecting those who try to help.
But no change is expected any time soon. The European Commission has consistently said there's no need to change the law. In early 2018, Nijkrake wrote that it should be left to judges in the countries themselves to decide on a case-by-case basis whether or not to prosecute citizens. It has noted that few people have been convicted. While most of those charged have been acquitted, in the case involving Van Gestel and Berghe (in Belgium), seven of the defendants were convicted and given suspended sentences of 12 to 24 months.
More than 170 organizations have launched an initiative, "We are a welcoming Europe – let us help!" (#WelcomingEurope), with the goal of securing a million signatures on a citizens' petition that calls for migration policy reforms, including the decriminalization of deeds of solidarity.
https://news-decoder.com/2019/03/25/eu-immigrants/
Later also: https://www.infomigrants.net/en/post/17319/amnesty-international-accuses-france-of-intimidating-people-who-help-migrants
Posted in EU | Leave a Comment »
Tags: #WelcomingEurope, Brussels, Centre for European Policy Studies (CEPS), CEPS, EU directive, Europe, huma rights defenders, human trafficking, illegal migrants, Lizan Nijkrake, Sea and Air, United Nations Protocol against the Smuggling of Migrants by Land
Shocking: Aluízio Palmar being sued by his torturer in Brazil
Remembering Russian activists Stanislav Markelov and Baburova
Annual reports 2019: Azerbaijan in review – muted hope for 2020
Palestinian and Israeli human rights defenders stand together: Mohammed Khatib and Jonathan Pollak
Colombia: 21 January 2020 civil society begins a much-needed Patriotic March
Manusher Jonno Foundation honours 10 unsung rights defenders in Bangladesh
New national Human Rights Commission in Myanmar: OLD wine in a new bottle
24 January, Day of the Endangered Lawye: ABA focuses on Pakistan
FIDH website partner in Observatory for HRDs
Martin Ennals Award for Human Rights Defenders THE award for Human Rights Defenders
OMCT website partner in Observatory for HRDs
True Heroes Films (THF) visualisation for human rights defenders


text:
"""Print bcl2fastq output directory for MUX according to collection: gisds.runcomplete
"""

#--- standard library imports
#
from argparse import ArgumentParser
from os.path import abspath, dirname, join, realpath
from sys import path

#--- project specific imports
#
# add lib dir for this pipeline installation to PYTHONPATH
LIB_PATH = abspath(join(dirname(realpath(__file__)), "..", "lib"))
if LIB_PATH not in path:
    path.insert(0, LIB_PATH)
from mongodb import mongodb_conn

__author__ = "LIEW Jun Xian"
__email__ = "liewjx@gis.a-star.edu.sg"
__copyright__ = "2016 Genome Institute of Singapore"
__license__ = "The MIT License (MIT)"

def main():
    """
    Main function
    """
    instance = ArgumentParser(description=__doc__)
    instance.add_argument("-m", "--mux", required=True, help="MUX_ID to generate OUT_DIR")
    args = instance.parse_args()

    for document in mongodb_conn(False).gisds.runcomplete.find(
            {"analysis.per_mux_status.mux_id": args.mux}):
        if "analysis" in document:
            last_out_dir = ""
            for analysis in document["analysis"]:
                if analysis["Status"].upper() != "FAILED":
                    if "per_mux_status" in analysis:
                        for mux in analysis["per_mux_status"]:
                            if mux["mux_id"] == args.mux:
                                last_out_dir = analysis["out_dir"].replace("//", "/")
            print(last_out_dir)

if __name__ == "__main__":
    main()

redpajama_set_name: RedPajamaGithub


Family First NZ says that a mother had to appeal all the way to the Court of Appeal after voluntarily admitting using a few light smacks over the past couple of years, and that it sends a warning to all parents about what they admit to authorities regarding smacking. The mother was acquitted in the Court of Appeal.
"Despite the sales pitch from police and CYF, and Prime Minister John Key declaring that a smack is ok and wouldn't result in prosecution, this mother's experience proves that this is not the case and may actually result in assault convictions, loss of reputation, ruined career, financial hardship, and having to appeal all the way to the Court of Appeal in order to gain some common sense," says Bob McCoskrie, National Director of Family First NZ.
"When a relative reported the mother for asking her partner to smack their 8 year old on the bottom, mum unfortunately admitted that over the past 2-3 years, she had smacked her son on a couple of occasions. The court acknowledged that mum had sought help and assistance many times – but said that the fact that the mother was not angry but that the smack was a 'considered decision' was an aggravating factor!
When they appealed to the High Court, the partner was discharged without conviction. However, because of mum's admission that she had used smacking in the past, her conviction was upheld in the High Court, because, according to the judgement, 'it cannot be said it was a one-off incident in response to an extreme, highly unusual situation' – despite her son presenting 'unusual and difficult challenges'.
She then appealed to the Court of Appeal and won an acquittal. They acknowledged that mum had 'sought appropriate expert assistance … and had utilised a range of non-physical measures to address the child's behaviour' and that the actions were at 'the lower end of the scale'. They also held that the prior incidents were overstated by the District Court judge.
"The warning to all good parents from this case is that they need to be careful what they admit – even if their actions of a smack are deemed reasonable and appropriate in the circumstances. The outcome of the anti-smacking law is only just coming home to roost," says Mr McCoskrie.


Hi Friends, Recently I came across with drop in keyword ranking and website traffic. Is their any Google update in last week.
What Google Maccabees Update is all about?
Hello, everyone please tell me what is Maccabees Update in SEO?
What is maccabees update? anyone can explain me in detail ?
Any recent update in Google ?
Is there any Google update released in this week? because my website keyword ranking down day by day..
Google latest alghoritm update who was hit?
Google has just released some major unnamed update many webmasters including me report serious change in rankings! Have you also got hot?
What is the latest update effects ranking of website?
Any new Google update June 2015?
Checking my website rankings yesterday I noticed it had dropped from ranking high for 2 of my primary keywords. Was there a new update released?
Google May update 2015 did anybody get hit?


Now visitors to http://www.ushorse.biz have opportunities to buy top equestrian products at great prices from 250 companies like Ariat, Cashel, Cavallo, Irideon, Kerrits, Mountain Horse, Outback Trading Company, Ovation, Perris Leather, Tailored Sportsman, Toklat, Troxel, and many more.
Check out our new shopping portal!
UShorse.biz is now offering terrific prices on over 9,000 top products for both the horse and rider.
UShorse.biz is now offering members and visitors terrific prices on over 9,000 top products for both the horse and rider. Everything equestrians need for impeccable care and turned out presentation in any discipline. Products for dogs have been included as well!
The cornerstone of USHorse.biz is dedication to helping equestrian businesses by offering affordable promotion and custom websites. But USHorse.biz is not going to stop there, now equestrians can find some of the best prices on high quality products on the Internet. The site offers product previews and highlights, sweepstakes and giveaways of all the products equestrians love.
USHorse.biz is partnering with Equestrian Collections, the leader in equestrian Internet shopping in the United States, which provides the shopping engine and service. For the month of May offerings include specials for trail riding, fly protection, schooling apparel, rain gear and plus size riding apparel. So stay tuned, because USHorse.biz is here to offer the best in services to members and visitors.
USHorse.biz is dedicated to offering affordable business tools for equestrian businesses. Custom website design, hosting, monthly updates and promotion only $99.95 per month, or the promotion of existing websites in the USHorse.biz newsletter, with a reach of 60,000 equestrians nationwide, for only $29.95 per month.


text:
Home » Archive » Uncategorized » Explosion Leads to Power Outage Downtown
Explosion Leads to Power Outage Downtown
by Contributing Editor January 23, 2023 January 23, 2023
About 500 Los Angeles Department of Water and Power customers in downtown Los Angeles and more than 3,200 customers in El Sereno are without power Monday.
An explosion damaged four electrical vaults in downtown Los Angeles caused power outages in that area and led to street closures on 3rd Street between Omar Street and Central Avenue.
LA DWP crews were responding to the explosions downtown.
There were 3,265 customers without power in the El Sereno neighborhood. Power was expected to be restored at 8:30 a.m., according to the LA DWP.
Tagged: Downtown, Explosion, leads, outage, power


Children seven (7) years of age or under require adult supervision in the water at a ratio not to exceed five (5) children to one (1) adult. Children six (6) years of age and over must change in the change room of their gender. Family change rooms are available at some facilities.
Fun, socials, & programs for cultural gatherings, parents, playschools, youth, seniors, you name it!
Summerside Community League of Edmonton represents residents of Sunset Valley, Fields of Summerside, Orchards of Ellerslie, Walker Lakes and Lake Summerside residents.
At our events, we are often asked what a community league is. There are 155 community leagues in Edmonton so wherever you live in the City, you will at some point come into contact with a community league either through events, community sports, hall rentals, etc. A community league is the primary speaking body for the community. Any resident within the boundaries of the community may become a member. Summerside Community League's boundaries are from 50th Street to Gateway Blvd and from Ellerslie Road south to 41st Avenue SW.
A league's members are responsible for electing a Board of Directors. Summerside Community League's annual general meeting is held in October each year. All area residents who have purchased a $25 community league membership are eligible to vote and volunteer for board roles.
A community league acts on behalf of its members. A league may be able to assume that it's position likely represents the majority views of the community. We encourage communication with members so that we can accurately reflect the community's views.
Represent the community at large on matters of interest to the appropriate order of government and other organizations (e.g. Traffic issues, new developments, crime prevention, etc.).
Provide recreation and social programs such as soccer, basketball, family events, etc.
Develop amenities such as a community hall, rink, playground, etc. for the benefit of its members.
I hope this helps you understand what the role of the community league and how the league can work for you.


text:
This is a list of nicknames in the sports of American football and Canadian football.

Players

 "A-Train" – Mike Alstott, running back
 "All Day" – Adrian Peterson, running back
 "The Assassin" - Jack Tatum, Oakland Raiders, safety
 "Avatar" – Jimmy Graham, tight end
 "Bad Moon" - Andre Rison, many teams, wide receiver
 "Baggadonuts" - Frank Winters, Green Bay Packers, center
 "The Bearded Pony" - Andrew Luck, Indianapolis Colts, named for his amazing beard and the fact that he plays for the Colts.
 "Beast Mode" – Marshawn Lynch, Seattle Seahawks, named for his violent running style and unusual ability to break tackles
 "Big Dick Nick" - Nick Foles, Philadelphia Eagles quarterback
 "Big Phil" - Phil Loadholt,  Minnesota Vikings offensive tackle
 "Blood" - John McNally, Green Bay Packers, running back
 "Boob" - Bernard Darling, Green Bay Packers, center
 "Boomer"- Bob Brown, tackle
 "Broadway Joe" - Joe Namath, New York Jets, quarterback
 "Buckets" - Charles Goldenberg, Green Bay Packers, guard/running back
 "The Bus" - Jerome Bettis, Pittsburgh Steelers, running back
 "Captain Comeback" - Roger Staubach, Dallas Cowboys, quarterback
 "The Claymaker" – Clay Matthews III
 "Cool Brees" – Drew Brees
 "The Cowboy" – Justin Smith
 "Crazy Legs" – Elroy Hirsch, running back/wide receiver
 "Curly"  - Earl Louis Lambeau, Green Bay Packers, founder, halfback and coach
 "Danimal" – Dan Hampton
 "Danny Dimes" - Daniel Jones, New York Giants, quarterback
 "Deacon" - David Jones, Los Angeles Rams, defensive end
 "The Diesel" - John Riggins, Washington Redskins, running back
 "Dirty Dozen" = 1975 Dallas Cowboys team
 "The Dodger" – Roger Staubach, quarterback
 "The Dome Patrol" – the New Orleans Saints football team's linebacker corps of the late 1980s and the early 1990s. The Dome Patrol was rated by NFL Network as the #1 linebacker corps of all-time.
 "Easy E" – Eli Manning, quarterback, named for his relaxed demeanor even in pressure situations
 "Edge" - Edgerrin James, running back
 "Famous Jameis" - Jameis Winston, Tampa Bay Buccaneers, quarterback
 "Fatso"- Art Donovan, defensive tackle
 "The Freak" - Jevon Kearse, Tennessee Titans, defensive end
 "The Fridge" – William Perry (American football), defensive tackle
 "The Ghost" - Dave Casper, Tight End who participated in two famous Oakland Raiders Plays:  "Ghost to the Post" & "Holy Roller (American football)"
 "Golden Boy" - Paul Hornung, Green Bay Packers, half back/kicker
 "The Gray Ghost of Gonzaga" - Tony Canadeo, halfback
 "Greasy"- Earle Neale, coach
 "The Gunslinger" – Brett Favre, quarterback
 "The Hangman"- Chris Hanburger- linebacker
 "Highway 63" - Gene Upshaw, Hall of Fame Guard who won two Super Bowls with the Oakland Raiders
 "The Hogs" – 1980s/1990s Washington Redskins offensive line
 "The Intellectual Assassin" - Ron Mix, offensive tackle
 "Joe Cool" - Joe Montana, quarterback
 "Johnny Football" - Johnny Manziel, quarterback
 "The Juice" – O. J. Simpson, running back
 "JJ "Swatt" – J. J. Watt, Houston Texans, named for his ability to bat down passes at the line of scrimmage
 "Jug" - Francs Louis Earp, Green Bay Packers, center
 "The Kraken" - Greg Hardy defensive end
 "Legatron" – Greg Zuerlein, St. Louis Rams
 "Legion of Boom™" – defensive backfield of the Seattle Seahawks (Richard Sherman, Kam Chancellor, Earl Thomas), named for their hard-hitting and physical style of play
 "The Lion"- Leo Nomellini, defensive tackle
 "The Manster" – Randy White, defensive tackle
 "Mean Joe" - Joe Greene, Pittsburgh Steelers, defensive end
 "Megatron" – Calvin Johnson, wide receiver
 "The Minister of Defense" - Reggie White, Philadelphia Eagles, Green Bay Packers, defensive end
 "The Missile" - Qadry Ismail, wide receiver
 "Minitron" - Julian Edelman, wide receiver
 "MJD" - Maurice Jones-Drew, running back
 "The Muscle Hamster" – Doug Martin, running back
 "The New York Sack Exchange" - the New York Jets defensive line during the early 1980s
 "Night Train" – Dick Lane, a reference to his fear of flying and resultant travel to road games on night trains.
 "The No Fly Zone" – defensive backfield of the Denver Broncos
 "Orange Crush" – the 3–4 defense of the Denver Broncos during the late 1970s and early 1980s
 "Optimus Grimes" - Brent Grimes Cornerback
 "The Pocket Hercules" – Maurice Jones-Drew, running back
 "Pot Roast" – Terrance Knighton, defensive tackle
 "Primetime" – Deion Sanders, cornerback
 "Purple Jesus" - Adrian Petersen, Minnesota Vikings, running back
 "The Purple People Eaters" - the Minnesota Vikings defensive line during the 1970s
 "The Refrigerator" - William Perry, Chicago Bears, nose tackle
 "Robo-sack" - Rob Johnson, quarterback known for a reputation of being sacked frequently
 "Robo-QB" - Todd Marinovich - quarterback
 "Rocket" - Raghib Ismail - wide receiver
 "Shady" – LeSean McCoy, running back
 "The Sheriff" – Peyton Manning, quarterback a reference to Manning's pre-snap routine, which is one of the most recognizable in the NFL.
 "Showtime" - Patrick Mahomes, quarterback
 "The Silver Rush" - the Detroit Lions defensive line during the early 1980s
 "Smoking" – Jay Cutler, quarterback
 "Snacks"  – Damon Harrison, Defensive Tackle.
 "The Snake" - Kenny Stabler, Hall of Fame quarterback who won Super Bowl XI with the Oakland Raiders
 "Steel Curtain" – the Pittsburgh Steelers defensive line during the 1970s
 "The Stork" - Ted Hendricks, Hall of Fame Linebacker who won Super Bowls with the Baltimore Colts and Oakland Raiders
 "Swede" - Chester Johnston, Green Bay Packers, running back
 "Sweetness" – Walter Payton, running back
 "Tiny" - Paul Engebretsen, Green Bay Packers, guard
 "Too Tall" - Edward Lee Jones, Dallas Cowboys, defensive end
 "The Toolbox" - Ed West, Green Bay Packers, tight end
 "The Tyler Rose" – Earl Campbell, an allusion to his hometown Tyler, Texas
 "White Shoes" – Billy Johnson, wide receiver
 "World" - Jerry Rice, San Francisco 49ers, wide receiver

Teams
This is a list of nicknames of professional and college football teams. Many are merely abbreviations or diminutives of the team's name; otherwise, the origin of the nickname (if known) is noted.  An asterisk (*) after a nickname indicates that the name is pejorative, insulting, or has at least a negative intent, and is often used by opponents or detractors (including fans when the team is performing poorly).
Note on abbreviations: CFL – Canadian Football League; NFL – National Football League; NCAA – National Collegiate Athletic Association

American football

By nickname
 "Ain'ts*" – New Orleans Saints, NFL; rhyming play on the non-standard English negative ain't
 "America's Team" – Dallas Cowboys, by sports media
 "B.I.L.L.S.*" – Buffalo Bills, by detractors, acronyms for "Boy I Love Losing Super Bowls", in reference to the team's failure to win the Super Bowl in four straight tries during the early 1990s
 "Big Blue (Wrecking Crew)" – New York Giants, NFL; from the color of their jerseys, influenced by the nickname of IBM
 "The Black and Gold" – Pittsburgh Steelers, NFL; from their uniform colors
 "Black and Blue Division" – NFC North, NFL; from the division's rugged style of play in the 20th century (also "Frostbite Division")
 "The Blue Giants" – Used for New York Giants because of the team color
 "Bolts" – Los Angeles Chargers, NFL; from the lightning bolt design on their helmets
 "Bucs/Buckies" – Tampa Bay Buccaneers, NFL; abbreviation of team name
 "The Bungles" – Cincinnati Bengals, NFL; mainly used by detractors
 The Cardiac Cats – Carolina Panthers, coined in 2003 due to their frequent 4th-quarter comebacks and/or losses
 "Cheeseheads" – Nickname used for residents of Wisconsin in reference to the state's large dairy industry.  Sometimes employed derogatorily by neighboring states, the moniker was  embraced by residents, particularly Green Bay Packers fans, and has become synonymous with Wisconsin's football culture. (While the state is presently known for cheese production, the Packers team itself was originally named for the Indian meat packing company in Green Bay, WI.)
 "Cheatriots" -New England Patriots,NFL; Used by detractors as a reference to the Patriots cheating allegations during Bill Belichick and Tom Brady era
 "The Chefs" – Kansas City Chiefs, NFL; origin Snickers candy bar commercial; however, the NFL has licensed official "Kansas City Chief Head Chef Cookie Jars"
 "The Chesapeake Watershed Region Indigenous Persons" – Washington Redskins, NFL; translation of team name into politically correct terms It was later changed to "Potomac Drainage Basin Indigenous Persons" (see below) since the Baltimore Ravens also share the Chesapeake Bay region.
 "Clowns" - Cleveland Browns, NFL; used by detractors.
 The Cowgirls - Dallas Cowboys, by detractors.
 "Da Raidahs" – Las Vegas Raiders, NFL; The way Chris Berman of ESPN says, "The Raiders", a spoof of Raiders team owner Al Davis' accent.
 "Dawgs" – Cleveland Browns, NFL; according to Hanford Dixon, then a cornerback with the original Art Modell-owned Browns, he gave his defensive teammates this nickname to inspire them before the 1985 season
 "DeadSkins" – Washington Redskins, NFL; rhyming play on team name; used by detractors or disgruntled fans.
 "Detroit Lie-downs" – Detroit Lions, NFL;  so called because they just lie down and let other teams run over them.
 "The Dirty Birds" – Atlanta Falcons, NFL; team dubbed themselves by this name during their race to Super Bowl XXXIII
 "The Dolts" – Indianapolis Colts, NFL; rhyming play on name with a term for "idiot"; by detractors
 "The Donks" – Denver Broncos, used by detractors.
 "The Empire" - Used by detractors to refer to either the Dallas Cowboys, due to their reputation of having a large fanbase, plentiful funds, and several Super Bowl rings, and the New England Patriots, due to their own reputation of also being one of the most hated teams in the NFL and being the de facto villain for the league, and because of their recent Super Bowl dynasty. The "role" of the Emperor is usually filled by Jerry Jones or Bill Belichick.
 "The Flaming Thumbtacks" – Tennessee Titans, NFL; a humorous interpretation of their team logo, actually a flaming stylized letter "T"
 "The Fins" – Miami Dolphins, NFL; play on abbreviation of name with the appendages of a dolphin
 "The Fish" – Miami Dolphins, NFL; while the mascot and team logo of bottlenose dolphins are not fish, but mammals.  The rhyme detractors used when they played in the Orange Bowl was, "squish the fish in the Orange Dish." Now rarely used due to the Florida Marlins, who are also called "The Fish".
 "The Forty-Whiners/The Whiners" – San Francisco 49ers, used by detractors.
 "G-Men" – New York Giants, NFL; initial of team name, possibly a play on the term for a government (e.g., FBI) agent
 "Goats" – Los Angeles Rams, NFL; when playing poorly
 "Honolulu Blue Wrecking Crew" – Detroit Lions, NFL; from a primary color of the uniform
 "The Houston No-Wins" – Houston Texans, NFL; rhyming play on name when team is performing poorly
 "Iggles" – Philadelphia Eagles, NFL; reference to how some Philadelphians pronounce "Eagles"
 "Jags" – Jacksonville Jaguars, NFL; abbreviation of team name
 "Gang Green" – New York Jets, NFL; used by supporters (reference to medical condition that is difficult to overcome)(Green Bay Packers), NFL; used by supporters since the mid-1970s; also the name of the unofficial team mascot who is given home field credentials.
 "Jest" – New York Jets, NFL; humorous misspelling of team name; used when team is performing poorly
 "Jints" – New York Giants, NFL; used occasionally by local media, as eye dialect for the team's name. Also used for the baseball team while it was in New York.
 "Jokeland (Faders/Traitors)"* – Las Vegas Raiders, by detractors
 "Lambs" – Los Angeles Rams, NFL; a lamb being a soft, cuddly, meek baby sheep (as opposed to a ram, being an aggressive full-grown male sheep); rhyming nickname used by detractors when team performs poorly
 "Monsters of the Midway" – Chicago Bears, NFL; originally applied to the University of Chicago "Maroons", a strong (former) college football team; "Midway" refers to the Midway Plaisance, a long, green swath of boulevard space bordering the southern end of the campus. The University discontinued its football program in 1939, and the Bears adopted the nickname.
 "'Niners" – San Francisco 49ers, NFL; abbreviation of team name
 "The Oilers" – Tennessee Titans, NFL; a reference of the team's name before it moved to Tennessee, the Houston Oilers
 "The Tennessee Titanics"* – NFL, reference given to the team after their 0–6 start in 2009 including a 59–0 loss to the Patriots, this after going 13–3 in 2008
 "The Pack" – Green Bay Packers, NFL; abbreviation of name, and a play on the collective term for a group of animals such as dogs or wolves
 "Pats" – New England Patriots, NFL; abbreviation of team name
 "The Patsies" – New England Patriots, NFL; play on nickname "Pats" (above) and the term patsy, "a person who is easily manipulated or victimized"
 "The Potomac Drainage Basin Indigenous Persons" – Washington Redskins, NFL; translation of team name into politically correct terms, popularized by NFL columnist and Washington, D.C. resident Gregg Easterbrook in his weekly column Tuesday Morning Quarterback.
 "Seagulls" – Seattle Seahawks, term often said by detractors when Seahawks are playing poorly.
 "The Silver and Black" – Las Vegas Raiders, NFL; from the colors of the uniforms
 "Sinners" – New Orleans Saints, NFL; "sinner" is often a paired opposite of "saint"; used by detractors, but also as a result of New Orleans Saints Bounty Scandal
 "'Skins" – Washington Redskins, NFL; abbreviation of team name
 "'Stillers" – Pittsburgh Steelers, NFL; how native Pittsburghers (Picksbergers) pronounce the name of their team
 "Tennessee Traitors " * – Tennessee Titans, NFL; derisive nickname of the former Houston Oilers, usually aimed at owner Bud Adams by former Oilers fans
 "Vikes" – Minnesota Vikings, NFL; abbreviation of team name

Canadian football
 "Als" – Montreal Alouettes, CFL; abbreviation of name
 "Argos" – Toronto Argonauts, CFL; abbreviation of name
 "The Blue and Gold" – Winnipeg Blue Bombers, CFL; after the team colours
 "The Boatmen" – Toronto Argonauts, CFL; in reference to the team's foundation by the Argonaut Rowing Club of Toronto, which in turn was derived from Jason and the Argonauts, mythical heroes and boatmen who are the namesake of both the rowing club and the CFL team
 "Bombers" – Winnipeg Blue Bombers, CFL; abbreviation of team name
 "The Double Blue" – Toronto Argonauts, CFL; in reference to the team colours, Oxford blue and Cambridge blue
 "Esks" or "Eskies" – Edmonton Eskimos, CFL; abbreviation of team name
 "'Gades" – Ottawa Renegades, CFL; abbreviation of team name
 "Jolly Green Giants" – Saskatchewan Roughriders for the colour of the team's uniforms and size of the players
 "Leos" – BC Lions, CFL; "Leo" is a common nickname for "lion" (from Latin, leo)
 "Roughies or Green Riders" – Saskatchewan Roughriders, CFL; Green Riders to differentiate team from the now defunct Ottawa team of the same name. Roughies - abbreviation of team name
 "Stamps" – Calgary Stampeders, CFL; abbreviation of team name
 "Tabbies" - Hamilton Tiger-Cats Tabby is a type of domestic cat with stripes
 "Ti-cats" – Hamilton Tiger-Cats, CFL; telescoping of team name

See also

 Nickname
 List of NFL nicknames
 List of baseball nicknames
 List of basketball nicknames
 List of hockey nicknames
 List of athletes by nickname
 Lists of nicknames – nickname list articles on Wikipedia
 American football
 Canadian football

References

Nicknames
Nicknames
Nicknames in American football
Canadian football


Microsoft made a massive push to the cloud in 2014, and as a result Office 365 is taking off. We're seeing it in how Okta customers are using Okta to connect to Office 365 in increasing numbers. This eGuide provides some data from the Okta Application Network on the trends we are seeing around Office 365. It also describes the most important things to consider for Identity and Mobility Management during deployment. Office 365 is unlike any other cloud app in it's complexity, and it is best for IT to plan and deploy solutions around Identity and Mobility Management in concert with their Office 365 roll-out to get maximum user adoption.


text:
10 Best Things to Do in Gatineau (Canada)
January 2, 2023 by Tiffany
Gatineau is a small city with a lot of personality that is right across the river from Canada's capital city. Gatineau is a smaller city, but it has all the fun things to do, sights to see, and entertainment that a big city does.
Gatineau (Canada)
Tourists often go to Ottawa instead of the city, but there is so much to see and do in the city. It's a good idea to cross the river and stay here for a few days. Gatineau is full of parks, has a lively nightlife, a lot of attractions, and some fun events that happen every year. If you are in the area, you shouldn't miss the chance to explore the city and see what it has to offer.
Let's look at Gatineau's best things to do:
1. Check out Canada's most popular museum.
The Canadian Museum of History is the best thing to see in the city, so don't miss it. The museum looks at the history of the country and the many different cultures that live there.
It is both a museum and a major research center. The people who work there know a lot about Canada's archaeology, history, folk culture, and other things. It is also one of the oldest places of culture in all of North America.
The Grand Hall, the Fort People's Hall, and the Canada Hall are the three permanent galleries at the museum. There is also a big IMAX theater there.
2. Bring your children to the Children's Museum
The Canadian Children's Museum is a part of the Canadian Museum of History that is just for kids. It is a great interactive museum that gets more than 500,000 people a year.
The museum was made just for kids younger than 14 years old. Its main show is called "The Great Adventure," and it takes people on an interactive trip through many countries around the world.
See also 10 Best Things to Do in Trois-Rivières (Quebec, Canada)
Kids can go to Nigeria, India, Japan, Mexico, and Indonesia without ever getting on an airplane. There are cafes, cargo ships, desert treks, and market bazaars, so the kids can learn about cultures from around the world in a hands-on way.
3. Go to the park for a day
Gatineau Park is a great place to spend a day, and it's also one of the biggest outdoor playgrounds in Canada. There are so many things to do here all year long that it's a paradise for anyone who loves being outside.
In the winter, you can go to the park and ski or snowshoe. In the summer, you can spend the day at a beach, hiking, mountain biking, or canoeing in Gatineau Park.
When fall comes, the park is full of beautiful colors that will make any photographer drool. You can also climb rocks, watch birds, or sleep in a tent outside under the stars.
4. Play poker
Or you can play blackjack, baccarat, craps, or roulette. Or, you can put your money in one of the Casino du Lac-1,800 Leamy's slot machines.
The government runs the Casino du Lac-Leamy, which has more than 65 tables where you can try your luck 24 hours a day. There are also restaurants, bars, and an amphitheater on site.
The name of the casino comes from the fact that it was built on an old quarry on the shore of Lac Leamy. Every year, more than three million people visit the casino.
5. Go skiing
The beautiful Laurentian Mountains are right next to the Gatineau Hills. Not only tourists, but also people who live in Gatineau and other nearby cities like to ski on the hills.
In Gatineau Hills, there are more than 190 km of cross-country ski trails. If you like skiing downhill, go to the Camp Fortune alpine ski center or the Vorlage ski hill.
See also 10 Best Small Towns to Visit in Canada
When you go to the city in the fall, you should also go to Gatineau Hills to see how the leaves change color. It's really something to see.
6. Enjoy a festival
Gatineau has many festivals and events all year long, but the Gatineau Hot Air Balloon Festival is one of the most well-known. This festival takes place over the weekend of Labor Day and is a lot of fun.
The Rendez-vous des saveurs de l'Outaouais, which comes right after this festival, is a great place for foodies who want to try delicious food and wine. In the summer, you should go to Parc du Lac-Beauchamp for the annual Wonders of Sand sandcastle competition.
Saint Jean-Baptiste Day, also known as Fête nationale du Québec, is the biggest party of the year. Hotels, museums, and arenas all host shows and exhibitions as part of the June festival.
7. Wine and dine
Gatineau is a French-speaking city with a lot of French charm, so it shouldn't be a surprise that it has some great bars and restaurants. You can eat delicious French food that is cooked just right and goes well with a great bottle of wine.
You can sip a cocktail, a bottle of craft beer, or a glass of wine while listening to live jazz, funk, or rock and roll. Gatineau has great nightlife, and the Vieux-Hull area is the place to be.
If you don't like French food, there are lots of other kinds of food to try in the city. A lot of people eat real Italian food and food from other parts of the world.
8. Go back to the past
Visit L'auberge Symmes, or Symmes Inn, to learn about life in Gatineau in the 1900s. This inn was built by Charles Symmes in 1831, and in 2003, it became a museum.
See also Where to Stay in Banff, One of the Best-kept Secrets in North America
The National Heritage Site used to be a hotel where people from Montreal stayed before boarding a ship on the Ottawa River. It is right next to the river and Lake Deschênes.
The Ottawa River and the rivers that flow into it are the main focus of the museum. There are guided tours in both French and English that last about an hour.
9. Go to the beach.
From June to September, people can swim and do other things on the beach at Leamy Lake. The lake is, of course, open all year, but if you go in the summer, there are lifeguards on duty.
Many people come to Leamy Lake beach to swim, but it's also a great place to lay out and soak up the sun. On-site, there are restrooms, change rooms, and places to eat.
If this beach gets too crowded, there are other ones in Gatineau. You can buy a day pass that lets you go to Leamy Lake Beach and other beaches nearby. This is a great thing.
10. Look at old airplanes
Vintage Wings of Canada is the place to go if you've ever wanted to see old airplanes. At the Gatineau-Ottawa Executive Airport, the museum is in a hangar that is 2,100 square meters in size.
There are both military and civilian planes on display, like the North American Aviation P-51 Mustang and the Fairchild PT-19. Even planes are for sale at Vintage Wings of Canada.
Almost all of the planes at Vintage Wings of Canada work or are being fixed up, and all of them are flown in parades and air shows today. You can also rent one of these old cars to fly in.
10 Best Things to Do in Mississauga (Ontario, Canada)
10 Best Things to Do in Markham (Ontario, Canada)