tbuckley/cabot-search huggingface dataset:
Abstract B22: Necuparanib inhibits pancreatic cancer progression and invasion in a 3D tumor and stromal cell co-culture system
Authors: Amanda MacDonald, Michelle Priess, Jennifer Curran, Silva Krause
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is one of the most aggressive types of cancer, with only about 5% of patients surviving 5 years past the initial diagnosis. Despite advances with new chemotherapy combinations, overall survival outcomes are still dismal due to the cancer's complex pathology. Novel multi-targeted agents or therapeutic combinations able to disrupt the aggressive fibrotic microenvironment and restrict tumor proliferation are a current focus in the field. Necuparanib (formerly M402) is a heparan sulfate-like molecule that binds and inhibits multiple heparin-binding growth factors, chemokines, and adhesion molecules in cancer progression and metastasis and as such has been shown to modulate multiple pathways in tumors. In order to further explore how necuparanib affects the tumor and its microenvironment, a 3-dimensional (3D) culture system mimicking pancreatic cancer was developed containing a co-culture of human pancreatic tumor cells and pancreatic stellate cells, the most abundant stromal cell in the pancreas. Morphological and histological assessment of the 3D tumor spheroids demonstrated that necuparanib inhibits a) pancreatic tumor cell growth, b) pancreatic tumor cell invasion, and c) pancreatic stellate cell growth. Necuparanib's activity in these assays was shown to be dose-dependent. Moreover, using a negative control for necuparanib engineered to lack the ability to bind growth factors, we established that necuparanib's activity is growth factor binding dependent. The ability to inhibit both tumor and stromal cells demonstrates that necuparanib is a very promising multi-targeting agent for difficult-to-treat cancers such as desmoplastic pancreatic tumors. These studies aid in our understanding of the key biological targets and pathways responsible for necuparanib's anti-tumor effects and support the current Phase 2 safety and efficacy study being performed in patients with metastatic pancreatic cancer. Citation Format: Amanda MacDonald, Michelle Priess, Jennifer Curran, Silva Krause. Necuparanib inhibits pancreatic cancer progression and invasion in a 3D tumor and stromal cell co-culture system. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B22.
­­LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation
Authors: Julia Zinngrebe, Eva Rieser, Lucia Taraborrelli, Nieves Peltzer, Torsten Hartwig, Hongwei Ren, Ildikó Kovács, Cornelia Endres, Peter Draber, Maurice Darding, Silvia von Karstedt, Johannes Lemke, Balazs Dome, Michael Bergmann, Brian J. Ferguson, Henning Walczak
Journal: The Journal of Experimental Medicine (2016)

The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.
Efficacy and Safety of FCR (Fludarabine, Cyclophosphamide, Rituximab) Followed by Yttrium-90 Ibritumomab Tiuxetan in Relapsed Follicular Lymphoma (FL) Patients
Authors: Francesco Pisani, Carlo Ludovico Maini, Rosa Sciuto, Laura Dessanti, Antonio Spadea, Andrea Mengarelli, Mariella D’Andrea, Sandra Rea, Luisa Romano, Maria Concetta Petti
Journal: Blood (2008)
Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy for Diagnosis of Intra-Abdominal Lymphoma without Accessible Peripheral Lymphadenopathy
Authors: Kota Fukumoto, Sou Nakaji, Yasuhito Suehara, Manabu Fujisawa, Keisuke Seike, Masafumi Fukaya, Hiroki Sugihara, Masami Takeuchi, Kosei Matsue
Journal: Blood (2014)
Why a Hospital Needs a Waterfall
Authors: Bonnie Salomon
Journal: Annals of Internal Medicine (2016)

Ad Libitum18 October 2016Why a Hospital Needs a WaterfallBonnie Salomon, MDBonnie Salomon, MDFrom Northwestern Lake Forest Hospital, Deerfield, Illinois.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-0978 Audio Reading - “Why a Hospital Needs a Waterfall” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Why a Hospital Needs a Waterfall," by B. Salomon. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Northwestern is spending about $400 million to replace the aging Lake Forest Hospital.…Rivals seem to think some of the hospital's features are excessive.—Chicago Tribune, 24 April 2016It's easy in Aprilto walk along rosy pathsinhaling fragrance deepinto healthy lungs. Much harderafter frost, with stiff jointswe make our terminal way.So, of course, a hospitalneeds a waterfall.There must be the slap of beauty,the memory of hope in this placefor healing, where suffering cascades downas a rush of water, blendinginside this placid pond. Author, Article, and Disclosure InformationAffiliations: From Northwestern Lake Forest Hospital, Deerfield, Illinois.Current Author Address: Bonnie Salomon, MD, Northwestern Lake Forest Hospital, 139 Riverside Drive, Deerfield, IL 60015; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Why a Hospital Needs a Waterfall” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Why a Hospital Needs a Waterfall," by B. Salomon. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 18 October 2016Volume 165, Issue 8Page: 598KeywordsAgingInhalationInterleukinsLungsMemory ePublished: 18 October 2016 Issue Published: 18 October 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 1703: Involvement of Adam17 in Neointima Formation after Vascular Injury; Potential Role of Tyrosine Phosphorylation on its Activity
Authors: Akinari Hinoki, Sadaharu Higuchi, Keita kimura, Kunie Eguchi, Michael V Autieri, Laura J Sommerville, Gerald D Frank, Satoru Eguchi
Journal: Circulation (2008)

Angiotensin II (AngII) and its G protein-coupled receptor, AngII type-1 receptor (AT 1 ), play critical roles in mediating cardiovascular diseases such as hypertension and atherosclerosis. It is widely believed that AngII promotes these diseases by inducing vascular remodeling that involves hypertrophy and hyperplasia of vascular smooth muscle cells (VSMCs). We and others have shown that the EGF receptor transactivation pathway is the key signaling mechanism by which AngII induces VSMC growth. Recently, we have further reported that production of HB-EGF via a metalloprotease, ADAM17, leads to EGF receptor transactivation by AngII in vitro. Here, we hypothesised that tyrosine phosphorylation of ADAM17 is essential for ADAM17 activation by the AT 1 receptor in VSMCs, and that ADAM17 is a critical target of intervention for prevention of vascular remodeling in vivo. Our result revealed that not only a forced expression of dominant-negative (dn) ADAM17-E406A by adenovirus but also the tyrosine phosphorylation incapable ADAM17-Y702F mutant markedly inhibited AngII-induced EGF receptor transactivation compared to the stimulated control in vector-infected VSMCs. The neointimal cells appeared 14 days after balloon injury are strongly positive for ADAM17 immunostaining. Moreover, we observed marked inhibition of intimal hyperplasia in dnADAM17 adenovirus treated carotid artery after the balloon injury. We also confirmed marked expression of dnADAM17 in the artery after the virus infection. Taken together, these results suggest the involvement of ADAM17 in neointima formation. ADAM17 may be activated at the lesion by an upstream tyrosine kinase in response to AngII and other hormonal factors. This research has received full or partial funding support from the American Heart Association, AHA National Center.
Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer
Authors: Filippo Pietrantonio, Claudio Vernieri, Giulia Siravegna, Alessia Mennitto, Rosa Berenato, Federica Perrone, Annunziata Gloghini, Elena Tamborini, Sara Lonardi, Federica Morano, Benedetta Picciani, Adele Busico, Chiara Costanza Volpi, Antonia Martinetti, Francesca Battaglin, Ilaria Bossi, Alessio Pellegrinelli, Massimo Milione, Chiara Cremolini, Maria Di Bartolomeo, Alberto Bardelli, Filippo de Braud
Journal: Clinical Cancer Research (2016)

Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples.Results:RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC. Clin Cancer Res; 23(10); 2414-22. ©2016 AACR.
A Comprehensive Diagnostic Approach Improves the Diagnostic Accuracy of Invasive Fungal Disease (IFD) in Adult Haemato-Oncology Patients Undergoing HSCT or High Dose Chemotherapy- Results of the King's Prospective Aspergillosis Study (NCT00816088)
Authors: M. Mansour Ceesay, Lisa Berry, Sujal R Desai, Joanne Cleverely, Christopher Kibbler, Jim Wade, Melvyn Smith, Ghulam J. Mufti, Antonio Pagliuca
Journal: Blood (2011)
Opposite effects of M1 and M2 macrophage subtypes on lung cancer progression.
Authors: Yi-Jing Hsiao, Kang-Yi Su, Hsuan-Yu Chen, Sung-Liang Yu
Journal: Journal of Clinical Oncology (2015)

e19148 Background: Macrophages in tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Our study sought to investigate the impacts of different macrophage on lung cancer cells and the association with the survival of lung cancer patients. Methods: THP-1 monocytic cells were polarized into different macrophage subtypes M0, M1, M2a, and M2c. The transcriptomic profiling was analyzed by expression microarray for identifying M1/M2 associated gene signatures. We definitized the M1 relative genes were protective and M2 were risky genes, which were used to predict outcome in a published microarray data of lung cancers. After coculture with macrophages, the phenotypes of A549 cells were evaluated in vitro and in vivo. Results: Three gene signatures were identified based on the published patient cohorts (n = 443), including an M1-specific gene signature, M2-specific gene signature and M1/M2 combination gene signature. Patients with a high-risk gene signature exhibited shorter, median overall survival than patients with a low-risk gene signature (M1-specific: P = 0.0020, M2-specific: P = 0.0035, M1/M2 combination: P = 0.0005, log rank test). A multivariate Cox proportional hazards regression with covariates of age, gender and stage was used to evaluate the independent prognostic factors. The results indicated that gene signatures from M1/M2 gene expression profiles correlated with extended overall survival in this published cohort. Furthermore, we found that M2a/M2c subtypes promoted A549 invasion but M1 subtype suppressed xenograft tumor growth and angiogenesis. M1 also enhanced the sensitivity of A549 to cisplatin, decreased tube formation activity and cell viability of A549 by inducing apoptosis and senescence. Different macrophage subtypes mainlyregulated genes involved in immune response, cytoskeletal remodeling, coagulation, and apoptosis pathways in A549 cells, a pattern that correlated with the altered behaviors of A549. Conclusions: Our results demonstrate that different macrophages alter cellular functions and gene expression profiles of A549 cells, and are associated with patient’s survival. These results suggest that M1/M2 polarization may be a target of future immune-modulating therapies.
Abstract 2088: PU.1 enrichment to intronic enhancers is required for meis1 gene expression in both hematopoiesis and leukemogenesis
Authors: Yajun Li, Bo Li, Qiang Li, Lixia Zhang, Ping Li
Journal: Cancer Research (2015)

Abstract Hematopoiesis is a tightly regulated process with multiple transcription factors (TFs) involved sequentially. Aberrant expression of the lineage specific transcription factors may disturb normal differentiation of hematopoietic cells and result in leukemia. Myeloid Ectropic viral Integration Site 1 (MEIS1), induces and maintains MLL transformation, and plays a rate-limiting regulatory role in MLL leukemogenesis. Meis1 gene is identified as the downstream targets of PU.1, another important hematopoietic transcription factor, which is inversely correlated with worse prognosis. Though multiple regulatory elements have been identified throughout the Meis1 locus, little is known about how PU.1 plays its role on Meis1 gene expression. To gain insight into the transcriptional regulatory role of PU.1 during myeloid differentiation, we isolated the hematopoietic stem/progenitor cells (HSPC, Lin-kit+CD34+ cells) and matured myeloid cells (Lin+Gr1+cells) from bone marrows of C57 mice, performed ChIP sequencing assay, and analyzed PU.1 enrichment and histone modifications. The ChIP seq data was then confirmed with an induced differentiation model of mouse MLL-ENL leukemia cells. In addition to DNaseI hypersensitivity, the PU.1 binding elements were also characterized with H3K4me1 and H3K27ac modification. We studied the transcriptional activation role of one common PU.1 binding elements with luciferase assay. Insertion of PU.1 binding elements before the promoter increased the luciferase reporter activity, suggesting that the PU.1 binding region be the enhancer element of Meis1 gene. The association between PU.1 enrichment and Meis1 gene expression was studied in further with PU.1 knocking down assay in the MLL leukemia cells. Bioinformatics analysis results suggest that there were other transcription factors, including HOXA9 and MEIS1 itself enriched around the PU.1 binding sites. Our results suggest that PU.1 enrichment to the intronic enhancers of Meis1 gene is required for the proper expression during hematopoiesis. PU.1 together with histone modification and many other TFs, including MEIS1 itself, contributed to the hematopoietic expression of Meis1 gene. (The work is supported by National Natural Science Foundation of China (Grant number 81100380) to Y.L.) Citation Format: Yajun Li, Bo Li, Qiang Li, Lixia Zhang, Ping Li. PU.1 enrichment to intronic enhancers is required for meis1 gene expression in both hematopoiesis and leukemogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2088. doi:10.1158/1538-7445.AM2015-2088
Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status
Authors: Seung-jae Kim, Zhenlong Chen, Abdul B Essani, Hatem A Elshabrawy, Michael V Volin, Giamila Fantuzzi, Iain B McInnes, Joshua F Baker, Patricia Finn, George Kondos, Suncica Volkov, William Swedler, Shiva Arami, Nadera Sweiss, Shiva Shahrara
Journal: Annals of the Rheumatic Diseases (2016)

Studies were performed to uncover the significance of obesity in rheumatoid arthritis (RA) and preclinical models.Preclinical arthritis models were used to examine the impact of obesity on disease onset and remission. Conditioned media from RA adipose tissues were used to investigate the mechanism contributing to joint neutrophil influx and M1 macrophage differentiation observed in early and remission phases of arthritis.We report that mice fed with high fat diet (HFD) have an earlier onset of collagen-induced arthritis (CIA) compared with mice on regular diet. However, the differences in CIA joint swelling between the two diet groups are lost once disease is established. We found that early arthritis triggered by obesity is due to elevated joint MIP2/interleukin-8 levels detected in CIA as well as in the RA and mouse adipose tissues and the effect of this chemokine on neutrophil recruitment. Although active disease progression is similarly affected in both diet groups, arthritis resolution is accelerated in lean mice while joint inflammation is sustained in obese mice. We document that HFD can prolong toll-like receptor (TLR)4-induced arthritis by increasing joint monocyte migration and further remodelling the recruited cells into M1 macrophages. Consistently, we show that adipose condition media can transform RA and wild-type naïve myeloid cells into M1 macrophages; however, this function is impaired by TLR4 blockade or deficiency.We conclude that despite established disease being unaffected by obesity, the early and the resolution phases of RA are impacted by obesity through different mechanisms.
THE EFFECTS OF ALTITUDE TRAINING ON BLOOD GENE EXPRESSION PROFILES IN ORDER TO COMPARE AND DIFFERENTIATE FROM A PREVIOUSLY IDENTIFIED “MOLECULAR SIGNATURE” OF RHUEPO DOPING
Authors: J Shurlock, G Wang, Y Pitsiladis
Journal: British Journal of Sports Medicine (2016)

Aims Current testing methods for the abuse of recombinant human erythropoietin for performance enhancement are inadequate. Recently ‘omics’ technologies have been used, successfully, to demonstrate a ‘molecular signature’ of rHuEPO administration. The same technologies can be applied in altitude-trained individuals in an attempt to differentiate rHuEPO administration and altitude training at a gene expression level. This approach has the potential to improve current doping detection methods, such as the Athlete Biological Passport (ABP). The aim of this project was to assess the effects of altitude training on blood gene expression profiles in order to compare and differentiate from a previously identified “molecular signature” of rHuEpo doping. Methods 20 endurance trained individuals participated in the study. 12 individuals (5 Female, 7 Male) trained at ∼2320 m altitude (Sierra Nevada, Spain) for 17 days and 8 individuals (3 Female, 5 Male) trained at sea-level (London, England). Blood samples were taken for haematological and gene expression analysis at baseline, during, and post-48hr, 1 week, 2 weeks and 4 weeks-post altitude exposure. Gene expression was analysed using Affymetrix QuantiGene Plex Assay, focussing on a subset of 50 target genes. Results 28 of the target genes were identified as significant by the overall F-test (FDR adjusted P value &lt;0.05). Two trends towards significantly differential expression were identified. 20 genes were found to be trending towards under expression 1-week after altitude exposure (FDR&gt;0.06). 13 genes were found to be trending towards over expression during altitude exposure (FDR&gt;0.07). There were no significant changes in the measured haematological parameters. Conclusions This study gives an insight into the gene expression signature of altitude exposure in endurance-trained athletes. Altitude exposure cannot currently be confidently differentiated from rHuEPO doping, using gene expression profiles alone. These findings add to the evidence supporting the use of “Omics” technologies, alongside current anti-doping strategies.
High Herpesvirus-Specific T Cell Counts Are Associated with near-Zero Likelihood of Malignancy Relapse and a Low Likelihood of Infections Due to Any pathogen.
Authors: Mette Hoegh-Petersen, Sarah Sy, Alejandra Ugarte-Torres, Tyler S Williamson, Adnan Mansoor, Yiping Liu, Stephanie Liu, Kevin Fonseca, Faisal Khan, James A Russell, Jan Storek
Journal: Blood (2010)
GW26-e2233 Noninvasive Renal Denervation for Resistant Hypertension Using High-intensity Focused Ultrasound
Authors: Shunkang Rong, Hui Zhu, Dichuan Liu, Jun Qian, Kun Zhou, Que Zhu, Yonghong Jiang, Dengqing Zhang, Changming Deng, Gang Yang, Qi Zhou, Han Lei, Tongchuan He, Zhibiao Wang, Jing Huang
Journal: Journal of the American College of Cardiology (2015)
Incompatibilities of HA-1 and 3 Polymorphic Adhesion Molecules Including CD62L, CD31 codon563 and CD31 codon125 Induce Graft-Versus-Leukemia Effect Rather Than GVHD Resulting in Long-Term Survival in HLA Identical SCT.
Authors: Nahoko Kuba, Shintaro Shiobara, Tatsuo Hurukawa, Jyunichi Tsukada, Sinji Nakao, Mine Harada
Journal: Blood (2005)
A Single Nucleotide Polymorphism and Its Haplotype of ZNF42 Transcriptional Modulator Gene Predisposes Individuals to High-Risk Acute Myelogenous Leukemia (AML).
Authors: Il-Kwon Lee, Jeong-Hwa Choi, Yu Ra Lee, Yeo-Kyeoung Kim, Hee Nam Kim, Kyeong-Soo Park, Je-Jung Lee, Myung Geun Shin, Chan Choi, Hoon Kook, Tai Ju Hwang, Moo Rim Park, Deog Yeon Jo, Jong Ho Won, Hyeoung-Joon Kim
Journal: Blood (2005)