tbuckley/cabot-search huggingface dataset:
Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis
Authors: Joel M. Kremer, Mark C. Genovese, Edward Keystone, Peter C. Taylor, Steven H. Zuckerman, Giacomo Ruotolo, Douglas E. Schlichting, Victoria L. Crotzer, Eric Nantz, Scott D. Beattie, William L. Macias
Journal: Arthritis & Rheumatology (2016)

Objective To assess the effects of baricitinib on lipid profiles in patients with moderate‐to‐severe rheumatoid arthritis. Methods Treatment with once‐daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4‐mg and 8‐mg baricitinib groups. Results Treatment with baricitinib resulted in dose‐dependent increases in serum lipid levels from baseline to week 12 (low‐density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high‐density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group‐wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A‐I, apolipoprotein B, and apolipoprotein CIII were observed with 4‐mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8‐mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL‐associated apolipoprotein CIII (–4.5% with 4‐mg baricitinib; –9.0% with 8‐mg baricitinib). Baricitinib reduced HDL‐associated serum amyloid A when administered at 4 mg (−36.0%) and 8 mg (−32.0%); a significant reduction in lipoprotein (a) was observed only with 8‐mg doses (−16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. Conclusion Baricitinib‐associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.
Membrane Type-Matrix Metalloproteinases (MT-MMPs) Are Expressed in Acute Myeloid Leukemia Cells and Are Upregulated by TNF-α.
Authors: Neeta Shirvaikar, Ali Jalili, Sara Ilnitsky, Loree Larratt, Imran Mirza, Anna Janowska-Wieczorek
Journal: Blood (2007)
Colette Denise Gina Le Doux
Authors: Lucy Williams
Journal: BMJ (2016)

Colette Denise Gina Le Doux was born in Gaillac, in the Tarn region of south-west France. Her father was invalided out of the Chasseurs Alpins after serious injury sustained at Verdun, and the family moved to Tunisia, where her father ran a business. Her idyllic childhood here came to an end, with the death of her beloved brother Pierre from septicaemia.

Colette decided to follow a cousin and came to school in England, attending a convent in Kidderminster in the Midlands, where she …
Therapeutic Targeting of the Bcl-6: p53 Axis with Histone Deacetylase Inhibitors in Diffuse Large B-Cell Lymphoma,
Authors: Jennifer E Amengual, Matko Kalac, Luigi Scotto, Patrick A Sleckman, Enrica Marchi, Changchun Deng, Danielle C Bongero, Salvia Jain, Jairo Baquero Buitrago, Owen A. O'Connor
Journal: Blood (2011)
Abstract 1925: Streamlined analysis and interpretation of RNA editing variants from melanoma cancer samples
Authors: Anika Joecker, Rupert Yip, Anne Arens, Bodil Oester, Douglas Basset, Bryant Macy
Journal: Cancer Research (2015)

Abstract Of special interest in a clinical setting is the identification and interpretation of somatic variants from the DNA of a tumor/normal matched pair. Studies have shown that a large proportion of variants present in DNA are not present in the RNA and vice versa due to RNA-Editing and other unknown molecular processes1. In addition, recent publications show that RNA-editing plays an important role in cancer2,3. These findings can have strong implications for clinical diagnostics where the correct identification and interpretation of somatic variants from tumor/normal matched samples is essential. We took a published Whole Trancriptome/Whole Exome Sequencing dataset of tumor and peripheral blood from two patients with uveal melanomas5. We looked for somatic variants present in the RNA, but absent in the DNA using CLC Cancer Research Workbench. A strong mutation signature for C-T, A-G changes was found, which result from Adenosine to Inosine changes, a typical RNA-Editing event, which was recently published to be common in human and is mediated by ADAR proteins. By running Ingenuity Variant Analysis directly from CLC Cancer Research Workbench we found RNA-Editing found in these two patients is highly associated with cancer and more specifically with Melanoma directly. Some of the variants directly associated with Melanoma were classified as likely pathogenic and were not described in COSMIC, but present in Ingenuity's large Knowledge Base. 1) Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Mingyao Li, Isabel X. Wang, Yun Li, Alan Bruzel, Allison L. Richards, Jonathan M. Toung, and Vivian G. Cheung. Science 1 July 2011: 333 (6038), 53-58. 2) RNA editing in RHOQ promotes invasion potential in colorectal cancer. Sae-Won Han et al. J Exp Med 2014 211:613-621. 3) A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Tim Hon Man Chan et al.Gut 2014;63:5 832-843 4) A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes.Genome Res. March 2014 24: 365-376 5) Harbour JW et al., “Frequent mutation of BAP1 in metastasizing uveal melanomas.”, Science, 2010 Nov 4;330(6009) Citation Format: Anika Joecker, Rupert Yip, Anne Arens, Bodil Oester, Douglas Basset, Bryant Macy. Streamlined analysis and interpretation of RNA editing variants from melanoma cancer samples. [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 1925. doi:10.1158/1538-7445.AM2015-1925
Co-Transplantation of Stromal Cells Enhances Engraftment Ability of MDS-Derived Hematopoietic Precursors in NOD/SCID-b2microglobulin-Deficient (b2mnull) Mice.
Authors: Daniella B. Kerbauy, Vladimir Lesnikov, Eileen Bryant, Nissa Abbasi-Shafer, Beverly Torok-Storb, H. Joachim Deeg
Journal: Blood (2005)
Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis
Authors: Julia Wilkerson, Kald Abdallah, Charles Hugh-Jones, Greg Curt, Mace Rothenberg, Ronit Simantov, Martin Murphy, Joseph Morrell, Joel Beetsch, Daniel J Sargent, Howard I Scher, Peter Lebowitz, Richard Simon, Wilfred D Stein, Susan E Bates, Tito Fojo
Journal: The Lancet Oncology (2016)
Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies
Authors: Satyajit Kosuri, Boglarka Gyurkocza, Sean Devlin, Molly Maloy, Cristi Ciolino, Taylor Borrill, Ann A. Jakubowski, Esperanza B Papadopoulos, H.R. Castro-Malaspina, Guenther Koehne, Miguel-Angel Perales, Sergio Giralt
Journal: Blood (2015)
Five-Year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma
Authors: Robert Chen, Ajay K. Gopal, Scott E. Smith, Stephen Ansell, Joseph D. Rosenblatt, Kerry J. Savage, Joseph M. Connors, Andreas Engert, Emily K Larsen, Dirk Huebner, Abraham Fong, Anas Younes
Journal: Blood (2015)
Abstract 4019: Examining mechanisms by which macrophages enhance intravasation in breast cancer
Authors: Serena Chiang, Zhenni Zhou, Jeffrey E. Segall
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common invasive malignancy and a leading cause of cancer-associated deaths in women worldwide. Metastasis is the major cause of morbidity and mortality in women afflicted with breast cancer. In the metastatic process, intravasation is an important step and largely dependent on interactions between tumor cells and stromal cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), an integral component of the TME, have been found to associate and co-migrate with tumor cells during intravasation. Invasive TAMs that co-migrate with tumor cells in response to epidermal growth factor display a unique transcriptome in comparison to the general TAM population found in the TME. Furthermore, intercellular signaling between tumor cells and TAMs generates a positive feedback loop that promotes tumor cell invasion and intravasation. Chemokines play a major role in cell migration and are an important component of the TME. In particular, chemokine (C-X-C motif) receptor 2 (CXCR2) has been shown to be important in tumor growth and angiogenesis. MIF and IL8, two ligands of CXCR2, correlate with poor outcome in breast cancer. Our objective is to elucidate the role of macrophage CXCR2 in tumor cell intravasation. We have used flow cytometry to characterize the basal expression of CXCR2 in a murine macrophage cell line, BAC-1.2F5 (BAC). We have also analyzed mRNA expression of CXCR2 in BAC and primary TAMs isolated from a murine model of breast cancer, the polyoma middle T oncoprotein (PyMT), by qRT-PCR. To test the functional significance of CXCR2 in intravasation, we have examined the effects of an inhibitor of CXCR2 on the ability of tumor cells to migrate through the endothelium using an in vitro transendothelial migration assay (iTEM). In this assay, MDA-MB-231 tumor cells, a human breast cancer cell line, are co-cultured with BAC cells and subsequently placed in an environment that is in contact with the basal surface of endothelial cells. We have observed that BAC cells produce CXCR2 mRNA and express surface CXCR2. We have also found elevated expression of CXCR2 in invasive TAMs as compared to the general TAM population. When MDA-MB-231 cells are co-cultured with BAC cells in the iTEM assay in the presence of SB265610, an inhibitor of CXCR2, we have found a significant reduction (p&amp;lt;10-4) in iTEM. Together, these results suggest that cellular signaling through macrophage CXCR2 is critical to tumor cell intravasation. Citation Format: Serena Chiang, Zhenni Zhou, Jeffrey E. Segall. Examining mechanisms by which macrophages enhance intravasation in breast cancer. [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 4019. doi:10.1158/1538-7445.AM2015-4019
Monoculture-Derived T Lymphocytes Providing Multiple Virus Specificity and Anti-Leukemia Activity for Recipients of Hematopietic Stem Cells or Umbilical Cord Blood Transplants
Authors: Barbara Savoldo, Kenneth Micklethwaite, Lawrence JN Cooper, Elizabeth J. Shpall, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner, CM Bollard, Gianpietro Dotti
Journal: Blood (2008)
Identification of Causative Genes and Mutations in Korean Familial Hemophagocytic Lymphohistiocytosis
Authors: Hoi Soo Yoon, KeunWook Bae, JeongA Park, Jae Hee Lee, Ho Joon Im, Hyung Nam Moon, Hack Ki Kim, Bin Cho, Tai Ju Hwang, Hoon Kook, Hee-Jo Baek, Dong Gyun Han, Mee Jeong Lee, Eun Sil Park, Ji Yoon Kim, Hong Hoe Koo, Ki Woong Sung, Keon Hee Yoo, Hee-Jin Kim, Jong Jin Seo
Journal: Blood (2008)
Monitoring Demands for Executive Control: Shared Functions between Human and Nonhuman Primates
Authors: Farshad A. Mansouri, Tobias Egner, Mark J. Buckley
Journal: Trends in Neurosciences (2016)

Fifteen years ago, an influential model proposed that the human dorsal anterior cingulate cortex (dACC) detects conflict and induces adaptive control of behavior. Over the years support for this model has been mixed, in particular due to divergent findings in human versus nonhuman primates. We here review recent findings that suggest greater commonalities across species. These include equivalent behavioral consequences of conflict and similar neuronal signals in the dACC, but also a common failure of dACC lesions to reliably abolish conflict-driven behavior. We conclude that conflict might be one among many drivers of adjustments in executive control and that the ACC might be just one component of overlapping distributed systems involved in context-dependent learning and behavioral control.
Fixed-Distance Model for Balloon Placement During Fluoroscopy-Free Resuscitative Endovascular Balloon Occlusion of the Aorta in a Civilian Population
Authors: Pierre Pezy, Alexandros N. Flaris, Nicolas J. Prat, François Cotton, Peter W. Lundberg, Jean-Louis Caillot, Jean-Stéphane David, Eric J. Voiglio
Journal: JAMA Surgery (2016)

<h3>Importance</h3> Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an innovative procedure in the treatment of noncompressible truncal hemorrhage. However, readily available fluoroscopy remains a limiting factor in its widespread implementation. Several methods have been proposed to perform REBOA without fluoroscopic guidance, and these methods were adapted predominantly from the military theater. <h3>Objective</h3> To develop a method for performing REBOA in a civilian population using a standardized distance from a set point of entry. <h3>Design, Setting, and Participants</h3> A retrospective study of whole-body computed tomographic (CT) scans from a cohort of 280 consecutive civilian trauma patients from University Hospitals of Lyon, France, was used to calculate the endovascular distances from both femoral arteries at the level of the upper border of the symphysis pubis to aortic zone I (descending thoracic aorta) and zone III (infrarenal aorta). These whole-body CT scans were performed between 2013 and 2015. Data were analyzed from July 16 to December 7, 2015. <h3>Main Outcomes and Measures</h3> Two segments (1 per zone) common to all CT scans were isolated, and their location, length, prevalence in the cohort, and predicted prevalence in the general population were calculated by inverting 99% certainty tolerance limits. <h3>Results</h3> Among the 280 trauma patients (140 men and 140 women) in this study, the mean (SD) height was 170.7 (8.7) cm, and the mean (SD) age was 38.8 (16.5) years. The common segment in zone I (414-474 mm) existed in all CT scans. The common segment in zone III (236-256 mm) existed in 99.6% and 97.9% of CT scans from the right and left femoral arteries, respectively. These segments are expected to exist in 98.7% (zone I) and 94.9% (zone III) of the general population. <h3>Conclusions and Relevance</h3> Target distances for blind placement of REBOA exist with more than 94% prevalence in a civilian population. These findings support the expanded use of REBOA in emergency department and prehospital settings. Validation for safety and efficacy on cadaveric and clinical models is necessary.
The Hsp90 Inhibitor 17-DMAG Increases SOCS3 and Regulates Cytokine Production, Migration and Cell Death in Chronic Lymphocytic Leukemia
Authors: Erin K Hertlein, Timothy L. Chen, Rainer Claus, Christoph Plass, Amy Lehman, David Jarjoura, Kami Maddocks, Jeffrey A. Jones, David M. Lucas, Amy J. Johnson, John C. Byrd
Journal: Blood (2012)
Abstract 4962: Inhibition of TGF-β-RUNX3 signaling by activated Shh is correlated with the development of TGF-β resistance in gastric cancer cells
Authors: Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Yoo Jin Na, Sang Cheul Oh
Journal: Cancer Research (2015)

Abstract Three members of the Runt-related (RUNX) family of genes, RUNX1, RUNX2, and RUNX3 transcription factors, are known as developmental regulators important in the inception and progression of a variety of human cancers. RUNX3 is a tumor suppressor in gastric cancer, and its expression is frequently inactivated by DNA methylation or its protein mislocalized in many cancer types, including gastric and breast cancer. In this study hypothesized that the relationship between Shh signaling and RUNX3 may be involved in the development of TGF-β resistance. Here, we was investigated a role and mechanism for RUNX3 reported a functionally important component in transforming growth factor-beta (TGF-beta) mediated signaling pathway. Cell proliferation, measured by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay that treat TGF-b in SHH overexpressed gastric cancer cell. The result showed that inhibit the proliferation by TGF-beta treatment in the control cells in a dose-dependent pattern but did not, SHH overexpressing gastric cancer cells. RT-PCR analysis showed that the expression of Runx3 in SHH overexpressing cells with TGF-beta. RUNX3 mRNA level not affected in control and SHH overexpressing cellls. When Shh overexpressing cells were treated with the proteasome inhiitors, MG132, level of Runx3 was decrease. RUNX3 are known to be primarily localized to the nucleus. Immunofluorescence indicate translocation of Runx3 from the nuleus to the cytoplasm in SHH overexpressing cells. On the other hand, treatment with SHH blocking antibody inhibited the moved from the nucleus to the cytoplasm in SHH overexpressing cells. These results indicate that suppression of TGF-β-RUNX3 signaling by activated Shh is correlated with the development of TGF-β resistance in gastric cancer. Citation Format: Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Yoo Jin Na, Sang Cheul Oh. Inhibition of TGF-β-RUNX3 signaling by activated Shh is correlated with the development of TGF-β resistance in gastric cancer cells. [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 4962. doi:10.1158/1538-7445.AM2015-4962
Predictive role of Early Interim FDG-PET in Hodgkin Lymphoma.
Authors: Vittorio Stefoni, Alessandro Broccoli, Lapo Alinari, Valentina Ambrosini, Enrico Derenzini, Stefano Fanti, Mariapaola Fina, Letizia Gandolfi, Enrica Marchi, Cinzia Pellegrini, Federica Quirini, Pier Luigi Zinzani, Michele Baccarani
Journal: Blood (2009)
256. A Novel Rationally Designed AAV Capsid Yields a Potent Neurotropic Gene Therapy Vector
Authors: Els Henckaerts, Julie Tordo, Nuria Palomar, Jahedur Rahman, Patrick Aldrin-Kirk, Mark Basche, Antonette Bennett, Claire O'Leary, Robin Ali, Mavis Agbandje-McKenna, Brian Bigger, Ahad A. Rahim, Tomas Björklund, Simon Waddington, R. Michael Linden
Journal: Molecular Therapy (2016)

Recent clinical trials have demonstrated safety and efficacy of adeno-associated virus (AAV)-mediated gene therapy, and precipitated the approval of the first gene therapy product for commercial use. Although AAV is the most commonly used vector, there are limitations due to its restricted biological activity. This can be partially overcome by aligning capsid choice and target tissue. Tailoring of AAV capsids has traditionally been accomplished by simply selecting the most suitable available serotype or by further optimization of available serotypes by peptide insertion or capsid reshuffling and in vivo selection in mouse or humanised mouse models. A novel approach based on in silico reconstruction of ancestral viruses recently yielded a promising vector for gene therapy of diseases that affect liver, muscle or retina. Here we report an alternative evolutionary approach to AAV capsid design based on the introduction of amino acids that have been found at the other end of the evolutionary spectrum. Specifically, we have designed a novel AAV2 capsid by including amino acids that are conserved in natural AAV isolates found in human pediatric tissues. We have determined the structural and immunological characteristics of this novel AAV2-based capsid and performed biodistribution studies. When the bioactivity of the vector was evaluated in various in vivo contexts the data revealed extraordinary transduction characteristics in eye and brain tissues. Intracranial injections in mice and rats revealed a significantly increased spread and enhanced transduction of brain tissues as compared to AAV2, with evidence for retrograde transport. Additionally, intra-ocular injections in adult mice revealed a marked enhancement of transduction of photoreceptor cells by the novel vector when compared to AAV2. Peripheral injections also demonstrated strong affinity for the brain and showed little evidence for transduction of non-neuronal tissues. Importantly, we were able to demonstrate superior performance in a disease model that affects the central nervous system when compared to other serotypes that have a strong affinity for neuronal tissues. In summary, we have engineered a novel capsid to include key residues found in natural variants of AAV2, which yields a unique gene therapy vector for the treatment of diseases that affect the central nervous system.
529. Novel LTR-1 Lentiviral Vectors Are Fully Functional Following the Removal of HIV-1 Gag-RRE Sequences
Authors: John R. Counsell, Conrad A. Vink, Dany P.B. Perocheau, Rajvinder Karda, Joanne Ng, Suzanne M.K. Buckley, Michael Hubank, Tristan R. McKay, Juliette M.K.M. Delhove, Martijn H. Brugman, Simon N. Waddington, Steven J. Howe
Journal: Molecular Therapy (2015)

Standard lentiviral vectors (LVs) require sequences from the wild-type virus (most commonly HIV-1) for effective packaging of vector genomes into viral particles. These sequences are preserved in reverse-transcribed proviral DNA, maintaining the packaging signal, major splice sites, the REV-response element (RRE) and CpG islands which amount to approximately 19% of HIV-1 genome in 3rd generation vectors. For gene therapy applications, these regions have been shown to be problematic, or pose potential risks. Vector integrations in proximity to host-cell genes have produced aberrant transcripts through genome-vector splicing. Transcriptional silencing of delivered transgenes can occur through methylation of viral CpG islands and the presence of the packaging signal allows remobilisation of vector genomes in cells expressing LV proteins which could be detrimental in HIV-positive patients. In an attempt to reduce these risks and minimise HIV-1 sequence in the provirus, we have developed the novel LTR-1 vector in which the packaging sequences and RRE are located downstream of the 3' Long Terminal Repeat (LTR). This location means that the essential cis-elements are contained within the RNA genome for efficient processing and encapsidation, but eliminated from the delivered provirus following reverse transcription. This reduces the amount of HIV-1 genome in the integrated provirus to 4.9%. These vectors can be produced to high titre (>108 TU/ml by eGFP flow cytometry) and the proportion of eGFP positive cells is stable between 3 and 14 days post-transduction. Clonal analysis of plasmid rescue experiments confirm LTR-1 proviral sequences lack HIV packaging and RRE sequences following reverse transcription and sequencing confirms the expected structure. Unlike the 3rd generation vector, LTR-1 cannot be remobilised when transduced cells are transfected with HIV-1 packaging constructs. Investigations into safety improvements produced by the LTR-1 modifications are ongoing. Live bioimaging experiments and immunohistochemistry confirm that LTR-1 also functions effectively in vivo when measured for up to 5 weeks post-injection: intracranial or intravenous injections into neonatal mice result in comparable expression levels to standard 3rd generation vectors in the brain and liver respectively. We suggest that this LTR-1 configuration could have an improved safety profile for the next generation of retroviral gene therapy vectors.