tbuckley/cabot-search huggingface dataset:
Abstract 5931: <i>PDGFRα+</i> pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells <i>in vivo</i>
Authors: Gediminas Greicius, Zahra Kabiri, Kristmundur Sigmundsson, Chao Liang, Ralph Bunte, Manvendra K. Singh, David M. Virshup
Journal: Cancer Research (2018)

Abstract Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem cells. However, in vivo, Paneth cell and indeed, all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. PdgfRα is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα+ cells blocked intestinal crypt formation, demonstrating for the first time that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem cell niche. Mice with Rspo3 excision in the PdgfRα+ cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation, and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα. [G.G. and Z.K. contributed equally to this work.] Citation Format: Gediminas Greicius, Zahra Kabiri, Kristmundur Sigmundsson, Chao Liang, Ralph Bunte, Manvendra K. Singh, David M. Virshup. PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5931.
Abstract 13332: Ideal Cardiovascular Health Metrics Are Associated With Disability Independently of Vascular Conditions
Authors: Saravana Devulapalli, Hazem Shoirah, Mandip S Dhamoon
Journal: Circulation (2015)

Background: Individuals with disability comprise the largest health care consumer group in the US. Vascular and non-vascular conditions contribute independently to disability, but it is unclear whether vascular risk factors are associated with disability independently of vascular events. We examined whether the American Heart Association’s 7 ideal cardiovascular health (CVH) metrics were independently associated with disability in a nationally representative cohort. Methods: Adults age&gt;=20 years from the National Health and Nutrition Examination Survey 2005-2012 were included. Ideal CVH was calculated as a composite of 7 measures, each scored from 0-2. Primary predictors were number of ideal CVH metrics and score of CVH metrics. The outcome was a dichotomous score from 20 activities of daily living (ADL) and instrumental ADLs. Unadjusted and adjusted weighted logistic models estimated associations between ideal CVH and disability. Secondarily, interactions were tested and each disability item was tested separately. Results: The total cohort included 22692 participants; mean age was 46.9 years. Cardiac disease and stroke were present in 6.6% and 2.8%; 90.3% had poor physical activity and 89.9% poor diet. Among 3975 individuals with full data on all 7 CVH metrics, the mean number of ideal CVH metrics was 3.12 (95% CI 3.05-3.20) and ideal CVH score was 7.6 (7.5-7.7). In fully adjusted models, the OR for disability was 0.90 (95% CI 0.83-0.98) per point increase in ideal CVH score, and 0.84 (0.73-0.97) per additional number of ideal CVH metrics. There were significant interactions with ideal CVH measures for cardiac disease (p =0.007 for ideal CVH score and 0.01 for number of ideal CVH indicators) and stroke (p= 0.12 and 0.11 respectively). Among those with cardiac disease and stroke, there was a paradoxical trend for increased odds of disability for increasing values of CVH. For the majority of disability items, there was an inverse relationship with ideal CVH metrics. Conclusions: Both ideal CVH score and number of ideal CVH metrics were strongly and significantly associated with reduced odds of disability independently of vascular and non-vascular conditions. Poorer CVH may cause subclinical vascular disease resulting in disability.
The Lupus-Associated Fcγ Receptor IIb-I232T Polymorphism Results in Impairment in the Negative Selection of Low-Affinity Germinal Center B Cells Via c-Abl in Mice
Authors: Jyun‐Pei Jhou, I‐Shing Yu, Haw Hwai, Chih‐Shan Chen, Pei‐Lung Chen, Shiang‐Jong Tzeng
Journal: Arthritis & Rheumatology (2018)

Fcγ receptor IIb (FcγRIIb) is an essential negative regulator of B cells that blocks B cell receptor (BCR) signaling and triggers c-Abl-dependent apoptosis of B cells. FcγRIIb-deficient mice display splenomegaly with expansion of B cells, leading to lupus. FcγRIIb-I232T is a hypofunctional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of the FcγRIIb-I232T polymorphism, we investigated the role of FcγRIIb in the deletion of low-affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity.We generated FcγRIIb232T/T mice to mimic human FcγRIIb-I232T carriers and immunized mice with chicken gamma globulin (CGG)-conjugated NP, a T cell-dependent antigen, to examine the response of GC B cells.Compared to wild-type (WT) mice, FcγRIIb232T/T mice showed increased numbers of low-affinity NP-specific IgG and NP-specific B cells and plasma cells; additionally, the expression of a somatic mutation (W33L) in their VH 186.2 genes encoding high-affinity BCR was reduced. Notably, FcγRIIb232T/T mice had a higher number of GC light zone B cells and showed less apoptosis than WT mice, despite having equivalent follicular helper T cell numbers and function. Moreover, phosphorylation of c-Abl was reduced in FcγRIIb232T/T mice, and treatment of WT mice with the c-Abl inhibitor nilotinib during the peak of GC response resulted in reduced affinity maturation reminiscent of FcγRIIb232T/T mice.Our findings provide evidence of a critical role of FcγRIIb/c-Abl in the negative selection of GC B cells in FcγRIIb232T/T mice. Importantly, our findings indicate potential benefits of up-regulating FcγRIIb expression in B cells for treatment of systemic lupus erythematosus.
A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody
Authors: SylvainGalvani, MagaliTrayssac, NathalieAugé, Jean-ClaudeThiers, DenisCalise, Hans-WilliKrell, FedericoSallusto, NassimKamar, LionelRostaing, MogensThomsen, AnneNègre-Salvayre, RobertSalvayre
Journal: Circulation (2011)

Background—Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy. Methods and Results—Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling me...
Abstract 17822: Cardiac Biomarkers are Elevated in Children During Chemotherapy Regardless of Anthracycline Status
Authors: Kimberly Y Lin, Jason L Freedman, Jill Ginsberg, Elizabeth Goldmuntz, Robert E Shaddy
Journal: Circulation (2014)

Introduction: Conflicting evidence exists as to whether measuring cardiac biomarkers can help identify children at risk of developing anthracycline-mediated cardiomyopathy (ACM). The newest generations of assays can detect minute cardiac perturbations. Hypothesis: We hypothesized that exposure to anthracyclines in children causes an increase in highly- and ultra-sensitive troponin I (hsTnI and usTnI), B-type natriuretic peptide (BNP), and NT pro-BNP levels during therapy. Methods: Cardiac biomarkers were sampled at baseline, early (within 24 hours), and late (3-7 days) after every 100-150 mg/m2 of anthracycline administered, and within 30 days of the end of all chemotherapy. Biomarkers measured include TnI by fourth (“highly-sensitive”) and fifth (“ultra-sensitive”) generation assays, BNP, and NT pro-BNP. Non-parametric testing was performed to determine if peak values of each biomarker vary between anthracycline exposed and non-exposed (control) individuals. Results: Twenty-six patients (54% male, mean age 11.2 ± 6.3 yrs) with a variety of malignancies were enrolled and categorized by target cumulative anthracycline dose: Control (0mg/m 2 ), low dose (&lt;100mg/m 2 ), middle dose (100-299mg/m 2 ), high dose (≤300mg/m 2 ). Mean peak biomarker levels are presented in Table 1. No significant differences were seen in peak values of hsTnI (p=0.51), usTnI (p=0.24), BNP (p=0.07) or NT pro-BNP (p=0.57) between control subjects and those receiving anthracyclines. Conclusions: Next generation cardiac biomarkers did not distinguish anthracycline subjects from controls while on treatment for various malignancies in this small pediatric cohort. Further study is needed to verify this finding in larger numbers of children with an assessment for differences between subgroups with different cumulative anthracycline exposures, and with follow up to determine whether such biomarkers predict long term cardiotoxicity.
Reducing the need for carbon dioxide monitoring in the investigation of paediatric sleep disordered breathing
Authors: Federica Trucco, Andrew Bush, Hui-Leng Tan
Journal: European Respiratory Journal (2018)

There is increasing interest in the use of home sleep studies to diagnose paediatric sleep disordered breathing (SDB) as they are potentially more cost-effective, convenient and representative of the child's typical nights' sleep [1–3]. One concern is that most home sleep study equipment does not include measurement of carbon dioxide. Overnight cardiorespiratory polygraphy without CO2 monitoring is adequate in children investigated for uncomplicated obstructive sleep apnoea <http://ow.ly/P7Fs30lpKFj>
Short-Term Treatment With Anti-CD3 Antibody Reduces the Development and Progression of Atherosclerosis in Mice
Authors: SabineSteffens, FabienneBurger, GrazianoPelli, YannDean, GregElson, MarieKosco-Vilbois, LucienneChatenoud, FrançoisMach
Journal: Circulation (2006)

Background— Atherosclerosis is a chronic inflammatory disease of the large arteries that is the primary cause of heart disease and stroke. Anti-CD3–specific antibodies suppress immune responses by antigenic modulation of the CD3 antibody/T-cell receptor complex. Their unique capacity to restore self-tolerance in a mouse model of diabetes and, importantly, in patients with recent-onset type 1 diabetes involves transforming growth factor-β–dependent mechanisms via expansion and/or activation of regulatory T cells. We hypothesized that treatment with anti-CD3–specific antibodies might inhibit atherosclerosis development and progression in mice. Methods and Results— Low-density lipoprotein receptor–deficient mice were fed a high-cholesterol diet for 13 or 24 weeks. Anti-CD3 antibody was administered on 5 consecutive days beginning 1 week before or 13 weeks after the high-cholesterol diet was initiated, respectively. Control mice were injected in parallel with phosphate-buffered saline. Anti-CD3 antibody thera...
Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency
Authors: Xiao-Fei Kong, Ruben Martinez-Barricarte, James Kennedy, Federico Mele, Tomi Lazarov, Elissa K. Deenick, Cindy S. Ma, Gaëlle Breton, Kimberly B. Lucero, David Langlais, Aziz Bousfiha, Caner Aytekin, Janet Markle, Céline Trouillet, Fabienne Jabot-Hanin, Cecilia S. Lindestam Arlehamn, Geetha Rao, Capucine Picard, Théo Lasseau, Daniela Latorre, Sophie Hambleton, Caroline Deswarte, Yuval Itan, Katia Abarca, Dewton Moraes-Vasconcelos, Fatima Ailal, Aydan Ikinciogullari, Figen Dogu, Ibtihal Benhsaien, Alessandro Sette, Laurent Abel, Stéphanie Boisson-Dupuis, Bernd Schröder, Michel C. Nussenzweig, Kang Liu, Frédéric Geissmann, Stuart G. Tangye, Philippe Gros, Federica Sallusto, Jacinta Bustamante, Jean-Laurent Casanova
Journal: Nature Immunology (2018)
Abstract 3601: Targeting USP7/PTEN axis regulates the metastatic competency of bone marrow-resident melanoma cells
Authors: Monika Vishnoi, Debasish Boral, Haowen N. Liu, Marc L. Sprouse, Wei Yin, Michael A. Davies, Isabella C. Glitza Oliva, Dario Marchetti
Journal: Cancer Research (2018)

Abstract Recurrence is the major cause of melanoma death due to cell dissemination from primary/metastatic tumor (CTCs). During asymptomatic periods, these cells reside in bone marrow (bone-marrow resident tumor [BMRT cells]) and remain quiescent. We hypothesized that disseminated tumor cells survive in bone marrow (BM) during these periods and evolve to metastatic potency during disease progression. First, we isolated CTC-enriched, Lin-neg population from clinically advanced melanoma patients and performed biomarker expression and mutational profiling to confirm presence of putative CTCs. Lin-neg CTC population contained unique transcriptomics signature with elevated melanoma markers expression (BAGE, MAGEA1, B4GALNT1, S100A3). Further, downstream IPA analysis demonstrated that an upregulation of transcripts for genes involved in cell survival and pro-development functions with concomitant decrease in cell proliferative and inflammation properties. Second, we implanted Lin-neg population in murine xenograft models and isolated HLA+/ Melan-A+ cells population from blood and BM at endpoint. Expression of human (HLA-ABC) and melanoma markers (Melan-A, S100, NG2, CD146) on BMRTCs and CTCs was confirmed by employing: (a) immunofluorescence staining, (b) single-cell DEPArrayTM and CellSearchTM capture, (c) genomic profiling, and (d) organ-site colonization of CTCs with concomitant to BMRTCs in BM. Third, we discovered distinct transcriptomic signature of BMRTCs vs CTCs by differential gene expression profiling. Subsequent pathway analysis showed top five altered canonical pathways in BMRTCs: protein ubiquitination pathway, EIF2, actin cytoskeleton, systemic lupus erythematosus and hypoxia signaling. Of note, a strikingly elevated expression of PTEN in BMRTCs was detected. Fourth, because PTEN binds to USP7, a key component of protein ubiquitination pathway, we evaluated USP7/PTEN axis in CTC-driven BMRTCs modulated metastatic competency. The use of two clinically approved USP7 inhibitors to study their effects on the proliferative capacity of BMRTCs led to a significant reduction of CTCs at metastatic sites. This study provides critical insights to identify biomarkers of melanoma recurrence during the asymptomatic periods of the disease, fostering application of USP7 inhibitors for innovative melanoma therapies for patients with metastasis undetectable disease and/or yet to develop metastasis. Citation Format: Monika Vishnoi, Debasish Boral, Haowen N. Liu, Marc L. Sprouse, Wei Yin, Michael A. Davies, Isabella C. Glitza Oliva, Dario Marchetti. Targeting USP7/PTEN axis regulates the metastatic competency of bone marrow-resident melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3601.
Abstract LB-091: Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2
Authors: BEIQIN YU, DONGSHENG GU, XIAOLI ZHANG, BINGYA LIU, JINGWU XIE
Journal: Cancer Research (2018)

Abstract Gastric cancer is the third leading cause of cancer-related mortality worldwide. Currently, there are no specific therapeutic options to cure gastric cancer, and chemotherapy is frequently used. Some patients respond initially to chemotherapy but all patients eventually succumb to the disease. Thus, identifying molecular mechanisms responsible for chemotherapy resistance may help design novel strategies to sensitize cancer cells to chemotherapy. In this study, we revealed that treatment with chemotherapeutic reagents CDDP and 5Fu induced expression of GLI1, GLI2 and PTCH1 in gastric cancer cell lines, suggestive of hedgehog (Hh) signaling activation. GLI1 knockdown sensitized gastric cancer cells to CDDP and 5Fu treatment whereas ectopic GLI1 expression desensitized cancer cells to these treatments. Further analyses indicate elevated Hh signaling is associated with an increase in putative cancer stem cell marker expression, such as ABCG2. We found that GLI1 protein binds to the promoter of ABCG2 through a Gli-binding consensus site. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, resulted in an increase of drug sensitivity both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance. Citation Format: BEIQIN YU, DONGSHENG GU, XIAOLI ZHANG, BINGYA LIU, JINGWU XIE. Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-091.
Abstract 1356: NSMCE2 enables rescue of collapsed replication forks to prevent mitotic DNA damage
Authors: Kelvin W. Pond, Christelle DeRenty, Mary K. Yagle, Nathan Ellis
Journal: Cancer Research (2018)

Abstract Background: Replication forks that are persistently blocked cannot restart, even after DNA damage is repaired. These forks are termed collapsed forks. In order to fully duplicate the genome, collapsed forks must be rescued by activation of nearby dormant origins of replication. Homologous recombination (HR) is essential in collapsed-fork rescue. Cells deficient in the SUMO E3 ligase NSMCE2 exhibit mitotic defects, are sensitive to DNA damaging agents, and have defects in HR. Thus, NSMCE2 regulates HR during replication stress, but the molecular mechanisms are poorly understood. In yeasts, hypomorphic NSMCE2 (MMS21) alleles accumulate HR intermediates during replication stress. We therefore hypothesized that NSMCE2 regulates RAD51 function during collapsed fork rescue. Results: It was previously shown that sumoylation of the BLM helicase results in recruitment of RAD51 to stalled forks. Consistent with data in yeast, we found that BLM sumolyation is dependent on NSMCE2. However, contrary to our expectation, we found that the amount of RAD51 protein that accumulated at collapsed forks was over two times greater in NSMCE2-deficient cells than in normal cells. In contrast, the levels of BLM, RPA, single-stranded DNA, and γH2AX at stalled forks is reduced by half. Consistent with the low levels of γH2AX, the double-strand breaks and sister chromatid exchanges that accumulate during collapsed fork rescue were also greatly diminished in NSMCE2-deficient cells. Thus, despite the over-accumulation of RAD51 to sites of collapsed replication forks, cells are unable to perform HR efficiently, indicating that RAD51 is unable to complete its function there. In NSMCE2-deficient cells, the hyper-accumulated RAD51 at collapsed forks persists into mitosis where excess under-replicated DNA causes mitotic DNA damage. Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests that NSMCE2 is required for the remodeling of collapsed forks that normally leads to the rescue of collapsed forks, namely, the unloading of RAD51, DNA breakage, repair by HR, and completion of DNA synthesis. We suggest that the excess accumulation of RAD51 that is observed in a substantial number of cancers is not sufficient to demonstrate that the cells are HR proficient. The identification of NSMCE2 as a controller of HR-mediated fork rescue also highlights NSMCE2's potential as a new therapeutic target for combinatorial therapy of HR-dependent cancers. Citation Format: Kelvin W. Pond, Christelle DeRenty, Mary K. Yagle, Nathan Ellis. NSMCE2 enables rescue of collapsed replication forks to prevent mitotic DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1356.