tbuckley/cabot-search huggingface dataset:
Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli
Authors: Satish Singh, Aiilyan Houng, Guy L. Reed
Journal: Circulation (2016)

In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of α2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and α2-antiplasmin inactivation on experimental thrombus dissolution and bleeding.Pulmonary embolism was induced by jugular vein infusion of 125I-fibrin or fluorescein isothiocyanate-fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and α2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism.The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal α2-antiplasmin levels treated with an α2-antiplasmin-inactivating antibody (P<0.0001). Dissolution of pulmonary emboli by α2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with α2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (P<0.001) or α2-antiplasmin inactivation alone (P<0.001). Despite greater thrombus dissolution, α2-antiplasmin inactivation alone, or in combination with low-dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA (P<0.001).Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by α2-antiplasmin. Inactivation of α2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, α2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like α2-antiplasmin, may have unique therapeutic value in pulmonary embolism.
653. Systemic High Mobility Group Box 1 Administration Suppresses Skin Inflammation By Inducing Accumulation of PDGFRα+ Mesenchymal Cells from Bone Marrow
Authors: Eriko Aikawa, Ryo Fujita, Yasufumi Kaneda, Katsuto Tamai
Journal: Molecular Therapy (2015)

High-mobility group box 1 (HMGB1), which is released by necrotic tissue, mobilises platelet-derived growth factor receptor alpha-positive (PDGFRα+) mesenchymal cells from bone marrow (BM) into circulation as a rescue signal. However, whether circulating HMGB1-induced endogenous PDGFRα+ mesenchymal cells stimulate skin regeneration has been unclear. Here we investigated the functions of the HMGB1/BM-PDGFRα+ mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFRα+ mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFRα+ mesenchymal cells showed massive inflammation of skin grafts compared to mice that had normal levels of PDGFRα+ mesenchymal cells. This was true even when HMGB1 was administered, suggesting that endogenous PDGFRα+ mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM-PDGFRα+ mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on BM-PDGFRα+ mesenchymal cells. We additionally investigated the therapeutic activity of the HMGB1/PDGFRα+ mesenchymal cell axis in inflammatory skin diseases using an allergic contact dermatitis model. The results illustrated the pivotal role of the HMGB1/BM-PDGFRα+ mesenchymal cells axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases.
Abstract 3967: miRNA reference samples for interlaboratory study
Authors: P. Scott Pine, Lynn R. Sorbara, Sudhir Srivastava, Marc Salit
Journal: Cancer Research (2015)

Abstract The biomarkers of interest in this study are microRNA (miRNA), small non-coding RNAs involved in the regulation of gene expression. Currently, over 1000 human miRNAs have been identified. Several laboratories within the Early Detection Research Network are currently profiling miRNA as potential biomarkers. The reference sample paradigm presented and evaluated here is designed to provide measurement assurance in the earliest phases of a cancer biomarker development pipeline. Three commercially available samples of human total RNA (brain, liver, and placenta) were selected for detectable differences in miRNA expression based upon previously reported miRNA microarray experiments. For each round of this study, replicate samples of each tissue were aliquoted, blinded, and distributed to participating laboratories. The samples were then profiled using the standard workflows of each laboratory. This was repeated over multiple rounds of measurement. Raw data were processed in pair-wise comparisons between tissue types. Log2 transformed ratios were calculated for each detectable miRNA. For each of these miRNA ratios, the results among laboratories were compared to the consensus value to provide a measure of concordance and help identify laboratories that might need to make adjustments to their process. Results demonstrated repeatability within labs and reproducibility among labs with respect to direction and magnitude of differential miRNA expression between tissues for a set of miRNAs of interest (MOI). For the first round, 79% of reported results for all log2 ratio combinations and MOI were in agreement with the consensus values. Subsequent rounds demonstrated increased concordance, with 91 and 100% agreement, respectively. The data from the nine “neat” tissue total RNA samples were also used for in silico modeling to predict the values for two complex mixtures based on three components. The two mixture designs provide a pair of reference samples with designed-in reciprocal ratios of 2:1 for brain and placenta, as well as a shared 1:1 liver component. For two brain-selective and two placenta-selective MOI, 91% of reported values were in close agreement with the target values. Overall, measurement results were harmonious for a set of miRNAs of interest measured by all participants, both within rounds and between rounds. The laboratories were also able to demonstrate the ability to resolve the 2-fold differences created with complex mixtures. These results suggest that endogenous miRNAs present within total RNA may be suitable as QA/QC process controls. Citation Format: P. Scott Pine, Lynn R. Sorbara, Sudhir Srivastava, Marc Salit. miRNA reference samples for interlaboratory study. [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 3967. doi:10.1158/1538-7445.AM2015-3967
Facing the dilemma of patient-centred psoriasis care: a qualitative study identifying patient needs in dermatological outpatient clinics
Authors: L.R. Khoury, L. Skov, T. Møller
Journal: British Journal of Dermatology (2016)

Caregivers must be aware of patients' current needs by providing care responsive to patients' values and preferences and by identifying what approach improves and encourages patients to participate in their treatment and disease management. Patients with psoriasis healthcare needs perhaps change as medical knowledge improves, new drugs emerge and the healthcare system improves its efficiency as a result of constant structural development. To explore the unmet needs and health perceptions of people with psoriasis, regarding interaction with clinicians and the structure inherent to consultations in a hospital outpatient dermatological clinic. A qualitative investigation with data generated from semi‐structured interviews. Transcriptions were subsequently analysed using the template analysis method. Sixteen patients with psoriasis were interviewed. Challenges and dilemmas of patient‐centred psoriasis care were identified. Patients have a strong need to be met as individuals as the burden of living with psoriasis goes beyond the skin. Patients strive for efficient treatment and ultimately dream of being cured of psoriasis. They prefer individualized health education in order to adjust their knowledge and self‐management skills. These central issues are as yet rarely addressed in clinical consultations. Consultations with a standardized structure do not match the individual challenges and healthcare needs of patients with psoriasis. In order to achieve a more patient‐centred approach, health professionals should implement minor structural changes to dermatological services to meet patients' current needs and invite dialogue about the patients' emotional well‐being and concerns that go beyond biomedical factors, as well as offer individualized health education.
A Phase II Trial of IPH2101 (anti-KIR mAb) in Smoldering Multiple Myeloma
Authors: Neha Korde, Jane Trepel, Mattias Carlsten, Adriana Zingone, Rene Costello, Mary Ann Yancey, Marcia Mulquin, Irina Maric, Katherine Calvo, Prashant Ramesh Tembhare, Constance Yuan, Maryalice Stetler-Stevenson, Min-Jung Lee, Sylvia Alarcon, George Carter, Richard Childs, Ola Landgren
Journal: Blood (2011)
The Affordable Care Act's Impacts on Access to Insurance and Health Care for Low-Income Populations
Authors: Gerald F. Kominski, Narissa J. Nonzee, Andrea Sorensen
Journal: Annual Review of Public Health (2016)

The Patient Protection and Affordable Care Act (ACA) expands access to health insurance in the United States, and, to date, an estimated 20 million previously uninsured individuals have gained coverage. Understanding the law's impact on coverage, access, utilization, and health outcomes, especially among low-income populations, is critical to informing ongoing debates about its effectiveness and implementation. Early findings indicate that there have been significant reductions in the rate of uninsurance among the poor and among those who live in Medicaid expansion states. In addition, the law has been associated with increased health care access, affordability, and use of preventive and outpatient services among low-income populations, though impacts on inpatient utilization and health outcomes have been less conclusive. Although these early findings are generally consistent with past coverage expansions, continued monitoring of these domains is essential to understand the long-term impact of the law for underserved populations.
Prognostic significance of absolute lymphocyte count in patients with early-stage diffuse large B-cell lymphoma treated with RCHOP.
Authors: Y. S. Chae, Y. J. Lee, B. W. Kang, J. H. Moon, J. G. Kim, S. K. Sohn, D. H. Yang, J. Lee, T. I. Park
Journal: Journal of Clinical Oncology (2011)

8057 Background: Although novel molecular markers have been introduced as independent predictors of outcome in lymphomas, their applicability in routine practice is still limited due to technical and financial demands. As lymphocytes play active role in tumor control as well as targets for immuno-chemotherapy in DLBCL patients treated with RCHOP, we analyzed the prognostic significance of absolute lymphocyte count (ALC) and its change after RCHOP in patients with early-stage DLBCL. Methods: From 2003 until 2009, 230 consecutive stage I and II DLBCL patients treated with RCHOP were included in this study. ALC was measured just before and D+21 after RCHOP. Results: During the median follow-up of 31.8 (range, 1.8-70.0) months, 200 patients (89.7%) achieved CR and 20 PR (9.0%) among 233 evaluable patients, leading to an overall response rate of 98.7%. Although ALC before RCHOP was not associated with survival, ALC ≥ 1.34 x 109/l at D+21 predicted a longer disease-free and overall survival (P = 0.010 and 0.001, respectively). Moreover, multivariate analysis revealed that high ALC at D+21had better PFS (HR = 0.423; P = 0.031) and OS (HR = 0.351; P = 0.005), independent of revised international prognostic index (rIPI). Conclusions: ALC after RCHOP can be regarded as a prognostic marker in early-stage DLBCL patients.
Abstract 415: Differential expression of therapeutic targets across tumor micro-environments and at infiltrative margins in glioblastoma
Authors: Myles R. McCrary, David Gutman, William Dunn, Milota Kaluzova, Alexandros Bouros, Merete Williams, Xialong Zhang, Lee AD Cooper, Constantinos G. Hadjipanayis, Daniel J. Brat
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM; WHO grade IV) is the most common primary brain tumor and is associated with a poor prognosis. The Cancer Genome Atlas (TCGA) project has revealed discrete molecular classes of GBM, raising the possibility of targeted therapies. Molecular heterogeneity across tumor microenvironments presents a challenge to targeted therapy, since effective therapies will be directed at targets near resection margins rather than those expressed in bulk resected tumor. To this end, we initiated studies to delineate spatial and temporal variations of potential druggable targets in GBM, focusing on potential protein targets at the tumor margin. By utilizing 5-ALA (5-aminolevulinic acid, an oral compound that accumulates in malignant glioma cells and is metabolized to the fluorescent agent, protoporphyrin IX) fluorescence-guided surgery of primary and recurrent GBMs in a Phase II clinical trial, we were able to precisely define perinecrotic, bulk, and marginal regions within the glioma intraoperatively in order to sample tissues for further molecular characterization. Tissues harvested from these 3 tumor regions from 5 patients were analyzed using reverse phase protein array (RPPA) analysis with 218 antibodies (Array-Pro). Relative protein levels were determined and a heatmap was generated as a hierarchical cluster using Pearson Correlation and a center metric. Forty proteins had statistically significant altered expression at the tumor margin compared with bulk and perinecrotic tumor. Among these, STAT1, STAT2, STAT3, PDGFRA, PDGFRB, EGFR, JAK2, MET, PIK3R1, and ERBB2 were upregulated at the margins and are potential druggable targets worthy of further investigation. Also upregulated at the tumor margins were NFKBIA, JUN, ZAP70, GAPDH, and CD28, whereas STAT5A, EFNB2, NTRK1, KDR, FGFR1, PTPRA, IFNGR1, and EFNB1 were downregulated at margins. Our data demonstrate significant variation of druggable targets and signaling networks across tumor microenvironments in GBM. Marginal tumor differs from bulk and perinecrotic tumor by the relative overexpression of STAT proteins, growth factor receptors, and receptor kinases. Directing therapy at networks and targets present at the tumor margin of GBM may be an effective strategy. Citation Format: Myles R. McCrary, David Gutman, William Dunn, Milota Kaluzova, Alexandros Bouros, Merete Williams, Xialong Zhang, Lee AD Cooper, Constantinos G. Hadjipanayis, Daniel J. Brat. Differential expression of therapeutic targets across tumor micro-environments and at infiltrative margins in glioblastoma. [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 415. doi:10.1158/1538-7445.AM2015-415
Abstract 3920: Identification of LASEP1 as a new serological and prognostic biomarker and a therapeutic target for lung cancer
Authors: Atsushi Takano, Yusuke Nakamura, Yataro Daigo
Journal: Cancer Research (2015)

Abstract Lung cancer is the leading cause of cancer deaths in the world and the overall prognosis remains poor. The poor prognosis of lung cancer patients is largely a result of the occult metastatic dissemination. Thus, the development of early cancer detection biomarker and new treatment is required. This study aims to identify novel biomarkers or therapeutic targets for lung cancers. We used cDNA microarrays for screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers. As a result of this process, we identified a secreted protein, LASEP1 (lung cancer-associated serum protein 1) as a candidate. Immunohistochemical staining of LASEP1 showed that LASEP1 expression was observed in 210 (56.1%) of 374 NSCLC (non-small cell lung cancer) that had undergone curative surgery. High level of LASEP1 expression was associated with poor prognosis for NSCLC patients (P&amp;lt;0.0001 by log-rank test). Serum LASEP1 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 NSCLCs, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, reduction of LASEP1 by siRNA significantly induced the apoptosis of lung cancer cells. Furthermore, the growth activity of the LASEP1-positive cells was neutralized by addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media, and the systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth without any adverse events. By gene expression analysis using microarray and mRNAs from lung cancer cells transfected with siRNA for LASEP1, we identified WHSC1 gene that encodes an oncogenic histone methyltransferase as one of LASEP1-target genes. These data suggest that LASEP1 is a possible diagnostic and prognostic biomarker and therapeutic target for lung cancer. Citation Format: Atsushi Takano, Yusuke Nakamura, Yataro Daigo. Identification of LASEP1 as a new serological and prognostic biomarker and a therapeutic target for lung 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 3920. doi:10.1158/1538-7445.AM2015-3920
675. Exploring the Effects of Stroma-Derived PPARB Signaling in Colorectal Tumorigenesis
Authors: Eddie H.P. Tan, Walter Arthur Wahli, Nguan Soon Tan
Journal: Molecular Therapy (2016)

Peroxisome Proliferator Activated Receptors (PPARs) are members of the superfamily of nuclear receptor transcription factor. While the roles of isotypes PPARα and PPARγ in colorectal cancer have been well studied, the role of PPARβ/Δ still remains controversial. The reason for the discrepancies remains unclear and several explanations have been put forth. One explanation for the contrary view is the heterogeneous tumor microenvironment. A tumor is made up of the cancerous epithelia, as well as stromal elements such as cancer-associated fibroblasts (CAFs). The role of PPARβ/Δ in CAFs is not well understood, and concomitantly on tumor progression is not easily determined. We first examined mRNA expression of PPARβ/Δ in murine intestinal tumor stroma. Laser-capture microdissected tumor stroma showed a statistical significant change in stromal PPARB expression upon tumor formation. Mouse carrying a stromal-specific deletion of PPARβ/Δ showed that these mutant mice demonstrated increased cancer survivability, with reduced tumor size and numbers compared to their wild-type littermates, confirming the importance of stromal-derived PPARβ/Δ in colorectal tumorigenesis. Preliminary observations also suggest that stromal PPARβ/Δ may be a potential target for adjunctive anti-tumor treatment.
Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study
Authors: Robert E Marcus, Andrew J Davies, Kiyoshi Ando, Wolfram Klapper, Stephen Opat, Carolyn J Owen, Elizabeth H Phillips, Randeep Sangha, Rudolf Schlag, John F Seymour, William Townsend, Marek Trněný, Michael K Wenger, Günter Fingerle-Rowson, Kaspar Rufibach, Tom Moore, Michael Herold, Wolfgang Hiddemann
Journal: Blood (2016)
346. AAV9 Delivery into Cerebrospinal Fluid Corrects CNS Disease in a Murine Model of Mucopolysaccharidosis Type II
Authors: Christian Hinderer, Nathan Katz, Jean-Pierre Louboutin, Peter Bell, Hongwei Yu, Mohamad Naval, Karen Kozarsky, Timothy O'Brien, Tamara Goode, James M. Wilson
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder typically manifesting in early childhood with bone and joint deformities, cardiac and respiratory disease, and developmental delay. Systemic delivery of the deficient enzyme, iduronate-2-sulfatase (IDS), improves many symptoms of MPS II, but because the enzyme does not cross the blood-brain barrier, there is currently no effective method to prevent the progression of central nervous system (CNS) disease. Using a mouse model of MPS II, we evaluated AAV serotype 9 vector-mediated delivery of the IDS gene as a means of achieving continuous IDS expression in the CNS. IDS knockout mice received a single injection into the lateral ventricle of one of three vector doses (3 × 108, 3 × 109 or 3 × 1010 genome copies) and were sacrificed either three weeks after vector administration for assessment of vector biodistribution and IDS expression (n = 7-8 mice per group), or 3 months after vector administration to evaluate the impact of gene transfer on disease progression (n = 7-8 mice per group). IDS activity was detectable in cerebrospinal fluid, reaching 15% of wild-type levels in the low-dose cohort and 268% of normal at the highest dose. Brain enzyme activity ranged from 2.7% of normal in the low-dose cohort to 32% in the high-dose cohort. Quantification of brain storage lesions by staining for the ganglioside GM3 indicated dose-dependent correction, with 35%, 46%, and 86% reductions in the low-, mid-, and high-dose cohorts, respectively. Treated mice also demonstrated improved cognitive function in a novel object recognition test. These findings indicate that intrathecal AAV-mediated gene transfer could serve as a platform for sustained enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II.
OS2.7 An open-labelled, randomized phase II study in patients with recurrent Glioblastoma Multiforme comparing progression free survival of ALECSAT (Autologous lymphoid effector cells specific against tumour-cells) versus Bevacizumab/Irinotecan
Authors: C. Haslund, A. Muhic, S. Lukacova, B. Lund, Y. Lassen-Ramshad, M. Meyer, M. Roland, H. Skovgaard Poulsen
Journal: Neuro-Oncology (2016)
The Two Phases of Heparin-Induced Thrombocytopenia (HIT): Early Monocyte/Tissue Factor (TF) Phase and Late Platelet Phase
Authors: Lubica Rauova, Valerie Tutwiler, Hyun Sook Ahn, Vincent M. Hayes, Richard H. Aster, Douglas B. Cines, Mortimer Poncz
Journal: Blood (2012)
A RANDOMIZED, PHASE 2 STUDY OF PACLITAXEL (P) AND CARBOPLATIN (C) +/- CONATUMUMAB (CON) FOR FIRST-LINE TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC)
Authors: L. Paz-Ares, B. Balint, J. P. van Meerbeeck, R. Wierzbicki, P. L. Desouza, F. Galimi, V. Haddad, Y. Hei, R. Ramlau, Rudolf de Boer
Journal: Annals of Oncology (2010)