tbuckley/cabot-search huggingface dataset:
Abstract 1710: DKN-01, a therapeutic DKK1 neutralizing antibody, has immune modulatory activity in nonclinical tumor models
Authors: Michael Haas, Heidi Heath, Yinyuan Wu, Xinjun Zhang, Cynthia Sirard, Xi He, Walter Newman, Michael Kagey
Journal: Cancer Research (2018)

Abstract Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt signaling modulator DKK1 is expressed in a variety of tumor types and elevated levels frequently correlate with poor survival. DKK1 promotes tumor growth by stimulating proliferation, metastasis, and angiogenesis, and has been implicated in contributing to an immune suppressive tumor microenvironment. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and selectivity. It is currently being evaluated clinically as a monotherapy and in combination in a variety of solid tumors. Here we describe further characterization of the mechanism of action of DKN-01 and demonstrate immune mediated anti-tumor activity in nonclinical models. A murine version of DKN-01 (mDKN-01) has efficacy in a syngeneic melanoma B16 tumor model. However, mDKN-01 is unable to impede B16 tumor growth in NSG immunodeficient mice, indicating that a functioning immune system is required for antibody activity. Furthermore, preliminary data suggest that mDKN-01 is targeting a myeloid derived suppressor cell population in the tumor microenvironment. These data support an immune mediated mechanism of action of DKN-01 and provide a rationale for clinical development in combination with immunotherapy agents. The first clinical study evaluating DKN-01 in combination with pembrolizumab has initiated enrollment in patients with relapse/refractory esophagogastric malignancies. Citation Format: Michael Haas, Heidi Heath, Yinyuan Wu, Xinjun Zhang, Cynthia Sirard, Xi He, Walter Newman, Michael Kagey. DKN-01, a therapeutic DKK1 neutralizing antibody, has immune modulatory activity in nonclinical tumor models [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 1710.
Early identification of rheumatoid arthritis: the risk of overtreatment in perspective
Authors: Annette van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2018)

With interest I read the Viewpoint of Landewe in which he discussed six domains in rheumatology in which progress has been made in the last decennia, and where the occurrence of overdiagnosis and subsequent overtreatment could be a disadvantageous side effect.1 I appreciate and agree with his concerns. Indeed, the burden of unnecessary treatment should be avoided for individual patients and for society as a whole, especially if expensive drugs (eg, biologics) are applied.

The Viewpoint is written from the general concept, referring to advances in rheumatoid arthritis (RA), spondyloarthritis and psoriatic arthritis. With respect to the paradigm ‘early diagnosis’, Landewe included a remark concerning the recent efforts to identify patients at risk for RA in the symptomatic phase that precedes the development of clinically evident arthritis.1 When discussing the risks of overtreatment as a drawback of early identification of RA, it is important to put the discussion in the correct context.

Arthralgia suspicious for progression to RA (or clinically suspect arthralgia, CSA) is …
CXCL14, a Brown Adipokine that Mediates Brown-Fat-to-Macrophage Communication in Thermogenic Adaptation
Authors: Rubén Cereijo, Aleix Gavaldà-Navarro, Montserrat Cairó, Tania Quesada-López, Joan Villarroya, Samantha Morón-Ros, David Sánchez-Infantes, Marion Peyrou, Roser Iglesias, Teresa Mampel, Jean-Valery Turatsinze, Décio L. Eizirik, Marta Giralt, Francesc Villarroya
Journal: Cell Metabolism (2018)
Abstract 4866: BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer
Authors: Dorothea Rudolph, Markus Reschke, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Andreas Gollner, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Kraut Norbert, Jürgen Moll
Journal: Cancer Research (2018)

Abstract MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept in cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development. While the tumor targeting activity of MDM2 inhibitors has been well documented, recent preclinical data with the tool compound Nutlin-3 have shown that p53 activation by local, intra-tumoral injections induces anti-tumor immunity (Cancer Res 2017, 77(9) 2292-2305). Here we present data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties that is suitable for intermittent dose schedules in syngeneic mouse models of cancer. Our data show that immune modulation contributes to efficacy of BI 907828 after oral administration in a Colon-26 syngeneic mouse model. Responding mice develop anti-tumor immunity that can control the tumor growth of a secondary tumor without any further treatment in a re-challenge study. A T cell depletion study shows a contribution of CD8+ T cells but not of CD4+ T cells to single-agent efficacy with BI 907828. Moreover, preclinical data in a Colon-26 syngeneic mouse model of cancer show synergistic efficacy for the combination of a PD-1 checkpoint inhibitor with BI 907828. In summary, BI 907828 is a novel, potent, orally bioavailable MDM2 inhibitor that shows synergistic efficacy in combination with a PD-1 checkpoint inhibitor in syngeneic mouse models of cancer. Citation Format: Dorothea Rudolph, Markus Reschke, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Andreas Gollner, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Kraut Norbert, Jürgen Moll. BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer [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 4866.
Serum Lipids and Lipoproteins in Chinese Men and Women
Authors: WenyingYang, JianzhongXiao, ZhaojunYang, LinongJi, WeipingJia, JianpingWeng, JumingLu, ZhongyanShan, JieLiu, HaomingTian, QiuheJi, DalongZhu, JiapuGe, LixiangLin, XiaohuiGuo, ZhigangZhao, QiangLi, ZhiguangZhou, GuangliangShan, JiangHe
Journal: Circulation (2012)

Background—Because of rapid change in lifestyle risk factors, cardiovascular disease has become the leading cause of death in China. We sought to estimate the national levels of serum lipids and lipoproteins among the Chinese adult population. Methods and Results—We conducted a cross-sectional study in a nationally representative sample of 46 239 adults aged ≥20 years. Fasting serum total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were measured by standard methods. The age-standardized estimates of total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were 4.72 (95% confidence interval, 4.70–4.73), 1.30 (1.29–1.30), 2.68 (2.67–2.70), and 1.57 (1.55–1.58) mmol/L, respectively, in the Chinese adult population. In addition, 22.5% (21.8–23.3%) or 220.4 million (212.1–228.8) Chinese adults had borderline high total cholesterol (5.18–6.21 mmol/L), and 9.0% (8.5–9.5%) or 88.1 million (83.4–92.8) had high total cholesterol (≥6.22 mmol/...
Hormone Therapy for Menopausal Symptoms
Authors: John Robbins
Journal: Annals of Internal Medicine (2018)

Letters7 August 2018Hormone Therapy for Menopausal SymptomsJohn Robbins, MD, MHSJohn Robbins, MD, MHSUniversity of California, Davis, Sacramento, California (J.R.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0238 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I believe that Reynolds and colleagues (1) fall into the frequent trap of considering only estrogen combined with medroxyprogesterone acetate (MPA) when thinking of hormone therapy. Reference 5 of their article shows that unopposed estrogen actually decreased the risk for breast cancer in long-term follow-up of the WHI (Women's Health Initiative) trial. All-cause mortality did not reach statistical significance with unopposed estrogen compared with placebo but seems to be significantly lower than when estrogen was combined with MPA.The use of MPA probably dates from the recommendations of the PEPI (Postmenopausal Estrogen/Progestin Interventions) trial (2). The authors ...References1. Reynolds EE, Bates C, Richardson M, Burns RB. Should this patient receive hormone therapy for her menopausal symptoms?: Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med. 2018;168:203-9. [PMID: 29404595]. doi:10.7326/M17-3320 LinkGoogle Scholar2. The Writing Group for the PEPI Trial.. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1996;275:370-5. [PMID: 8569016] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: University of California, Davis, Sacramento, California (J.R.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0238. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoShould This Patient Receive Hormone Therapy for Her Menopausal Symptoms? Eileen E. Reynolds , Carol Bates , Martha Richardson , and Risa B. Burns Hormone Therapy for Menopausal Symptoms Eileen E. Reynolds , Carol Bates , Martha Richardson , and Risa B. Burns Metrics 7 August 2018Volume 169, Issue 3Page: 203KeywordsBreast cancerConflicts of interestDisclosureEstrogensFallsHormonal therapyHormonesMortalityObstetrics and gynecologyUltrasound imaging ePublished: 7 August 2018 Issue Published: 7 August 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase−/− Mice Is Related to Decreased Endothelial Progenitor Cell Repair
Authors: UrsulaMayr, YipingZou, ZhongyiZhang, HermannDietrich, YanhuaHu, QingboXu
Journal: Circulation Research (2006)

Inducible NO synthase (iNOS) is expressed by macrophages and smooth muscle cells in atherosclerotic lesions. Previously, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of iNOS in the development of vein graft arteriosclerosis in iNOS−/− mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in iNOS−/− mice was increased 2-fold compared with that of wild-type controls. Neointimal lesions contained mainly MAC-1+ macrophages and α-actin+ smooth muscle cells (SMCs) in both vein grafts of iNOS−/− and iNOS+/+ mice. Immunofluorescence analysis revealed that increased iNOS expression in neointimal macrophages and SMCs of wild-type, but not iNOS−/−, mice coincided with increased vascular endothelial growth factor (VEGF) expression in vein grafts. When vein grafts were performed in iNOS−/−/TIE2-LacZ transgenic mice expressing LacZ gene only in endothelial cells, the number ...
Abstract 4142: Conformational dynamics of the chimeric kinase DNAJB1-PRKACA, the driver for fibrolamellar hepatocellular carcinoma
Authors: Michael D. Tomasini, Yingiie Wang, Adak Karamafrooz, James Hall, Susan S. Taylor, Thijs Beuming, Gianluigi Veglia, Sanford M. Simon
Journal: Cancer Research (2018)

Abstract In fibrolamellar hepatocellular carcinoma (FLC) there is a single common genetic alteration in all tumors: A deletion in one copy of chromosome 19 resulting in the fusion of the first exon of DNAJB1, encoding the J-domain of heat shock protein 40, with exons 2-10 of the catalytic subunit of protein kinase A, PRKACA [1]. This produces an enzymatically active chimeric protein. Expression of the chimera in mouse liver either by recreating the deletion by CRISPR/Cas9, or expression, in trans, by a transposon is sufficient to produce FLC [2]. We used molecular dynamics simulations, NMR, and SAXS to analyze the conformational dynamics of the native and chimeric kinase. The most significant differences were in the amino domain with the chimera in an ensemble of conformations. Some structures had the J-domain tucked under the large lobe of the kinase, similar to that reported in the crystal structure, and in others the J-domain was dislodged from the core of the kinase, swinging free in solution. These simulated dislodged states were captured experimentally both by NMR and small angle X-ray scattering. Modeling of the different conformations onto the RIIβ holoenzyme revealed no obvious steric interactions suggesting that the J-domain does not preclude formation of the holoenzyme. The flexible conformations appear to be independent of the nucleotide/substrate binding mode as they were observed in ATP, ADP, Apo, and ATP-PKI bound states. [1] Honeyman, J. N. et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343, 1010-1014 (2014). [2] Kastenhuber, E. R. et al. DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc. Natl. Acad. Sci. 201716483 (2017). doi:10.1073/pnas.1716483114 Citation Format: Michael D. Tomasini, Yingiie Wang, Adak Karamafrooz, James Hall, Susan S. Taylor, Thijs Beuming, Gianluigi Veglia, Sanford M. Simon. Conformational dynamics of the chimeric kinase DNAJB1-PRKACA, the driver for fibrolamellar hepatocellular carcinoma [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 4142.
Abstract 2036: Alternative activation of TGFβ signaling pathways in breast cancer tumors with different subtype is related to a differential expression of transcription factors that induce EMT
Authors: Victoria Ortega-Hernández, Wanda Fernandez, Pilar Carvallo
Journal: Cancer Research (2018)

Abstract Breast cancer is the leading cause of cancer death among women worldwide being distant metastases the main cause of disease. Patients with triple negative breast cancer tumors develop distant metastases earlier compared to luminal tumors. Epithelial-mesenchymal transition (EMT) induced by TGFβ signaling pathways, is the main mechanism to promote metastasis through the expression of the transcription factors TWIST, SNAIL, SLUG and ZEB1. Expression of EMT transcription factors has been studied in cancer cell lines however studies in breast cancer tumors with different subtype have not been reported. In addition, the molecular mechanism that induce EMT program is not known yet. In this study we evaluated the expression of the four transcription factors as well as the state of TGFβ/SMAD, ERK/MAPK and PI3K/AKT pathways in breast cancer cell lines HCC1937 (triple negative) and T47D (luminal) after TGFβ treatment. The same analysis was done by immunohistochemistry in 100 breast cancer tumors with different subtype. After TGFβ treatment T47D showed activation of ERK/MAPK and PI3K/AKT pathways and expression of only two transcription factors: SNAIL and SLUG. HCC1937 cells showed activation of TGFβ/SMAD and ERK/MAPK pathways and expression of TWIST, SLUG and ZEB1 but not SNAIL. Similar results were observed in breast cancer tumors, being TGFβ/SMAD pathway active in the majority of triple negative tumors, whereas an active state of PI3K/AKT was observed in luminal tumors. Active ERK/MAPK pathway was observed in both triple negative and luminal tumors. In relation to expression of transcription factors triple negative tumors with an active state of the TGFβ/SMAD pathway showed expression of transcription factors TWIST, SNAIL and SLUG, whereas those tumors with an active state of ERK/MAPK pathway showed only ZEB1 expression. Luminal tumors with an active PI3K/AKT pathway frequently showed ZEB1 expression. Our results showed that expression of a specific EMT transcription factor induced by TGFβ is related to the tumor subtype and depends on the activated signaling pathway. These results suggest different mechanisms of EMT induction by TGFβ in relation to breast cancer tumor subtype. Citation Format: Victoria Ortega-Hernández, Wanda Fernandez, Pilar Carvallo. Alternative activation of TGFβ signaling pathways in breast cancer tumors with different subtype is related to a differential expression of transcription factors that induce EMT [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 2036.
Abstract 4688: Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment
Authors: David Yoonsuk Oh, Serena S. Kwek, Serghei Mangul, Siddharth S. Raju, Sasha Targ, Arun Burra, Eric Chow, Dvir Aran, Sima Porten, Maxwell V. Meng, Terence W. Friedlander, Chun Jimmie Ye, Lawrence Fong
Journal: Cancer Research (2018)

Abstract Bladder cancer can be responsive to immunotherapies such as anti-PD-1 and anti-PD-L1 checkpoint inhibitors, but overall response rates are low. Tumor-resident T cells demonstrate considerable heterogeneity as far as antigenic repertoire and phenotype. Whether the bladder tumor environment is enriched for specific types of T cells with a particular functional profile and antigenic specificity, and whether these tumor-specific populations are associated with treatment or response to immunotherapy, remains unclear. We performed single-cell RNA sequencing of CD4+ and CD8+ T cells from localized human bladder tumors and paired adjacent non-malignant bladder. We also assessed resected bladder tumors treated with neoadjuvant chemotherapy or atezolizumab (anti-PD-L1) as part of an ongoing phase II trial. We find both known and unexpected CD4+ T cell functional populations that are specific to the tumor microenvironment, including regulatory T cells and a novel population of cytotoxic CD4+ T cells. Furthermore, by combining whole-transcriptome data with paired T cell receptor identification on single cells, we find that tumor-specific CD4+ populations are clonally expanded and utilize an antigenic repertoire which is distinct from uninvolved bladder. These findings provide evidence for specialization of both phenotype and antigenic specificity of CD4+ T cells in the bladder tumor environment, and indicate that a limited number of tumor-specific antigens may drive in situ expansion and differentiation of specialized CD4+ subsets whose function may be critical to tumor control. Citation Format: David Yoonsuk Oh, Serena S. Kwek, Serghei Mangul, Siddharth S. Raju, Sasha Targ, Arun Burra, Eric Chow, Dvir Aran, Sima Porten, Maxwell V. Meng, Terence W. Friedlander, Chun Jimmie Ye, Lawrence Fong. Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment [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 4688.
Abstract 629: Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments
Authors: Jan H. Tavernier, Anje Cauwels, Sandra Van Lint, Franciane Paul, Geneviève Garcin, Alexander Van Parys, Nikolai Kley, Gilles Uzé
Journal: Cancer Research (2018)

Abstract An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN), for instance, has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its optimal clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. As conventional Dendritic Cells (cDC) are essential for IFN antitumor efficacy, we targeted type I IFN-derived “AcTaferon (AFN)” to Clec9A+ cDC. Clec9A-AFN therapy displayed strong antitumor activity in murine melanoma (B16), breast carcinoma (4T1) and lymphoma models (A20), as well as against human RL lymphoma in immunodeficient NSG mice reconstituted with a human immune system. In sharp contrast to wild-type IFN therapy, the antitumor efficacy of Clec9A-AFN was not accompanied by any detectable toxicity, assessed by body weight and several hematological parameters. Clec9A-AFN effects were lost in CD8-depleted or Batf3-/- mice, and depended on IFN signaling in cDCs but not in T lymphocytes. Combined with α-PDL1 immune checkpoint blockade, Treg-depleting anti-CTLA4 + anti-OX40 therapy, immunogenic chemotherapy, or low-dose TNF, complete tumor regressions and long-lasting tumor immunity (memory) were obtained, still without any adverse effects. Our findings thus indicate that DC-targeted AFN provides a highly efficient, off-the-shelf and safe cancer immunotherapy, with possible application in a broad range of malignancies. Citation Format: Jan H. Tavernier, Anje Cauwels, Sandra Van Lint, Franciane Paul, Geneviève Garcin, Alexander Van Parys, Nikolai Kley, Gilles Uzé. Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments [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 629.
Erratum: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
Authors: Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Seth Love, Patrick G Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Reinhard Heun, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Minerva M Carrasquillo, V Shane Pankratz, Steven G Younkin, Peter A Holmans, Michael O'Donovan, Michael J Owen, Julie Williams
Journal: Nature Genetics (2013)