tbuckley/cabot-search huggingface dataset:
Human protease-activated receptor-1 and 4 (PAR-1 and PAR-4) expression in stage I non-small cell lung cancer (NSCLC)
Authors: G. Selvaggi, P. Ghio, S. Novello, S. Cappia, M. Papotti, P. Lausi, P. Borasio, G. V. Scagliotti
Journal: Journal of Clinical Oncology (2004)

7160 Background: PAR-1 and PAR-4 are reported to play a major role in extracellular matrix invasion by tumor cells and in the neoangiogenesis process (Even-Ram et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 1998; 4: 909–914). We investigated the expression of these receptors in 60 cases of radically resected stage IB (pT2N0) NSCLC [30 adenocarcinomas (AC) and 30 squamous cell carcinomas (SCC)] and their correlation with microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in tumor cells. Methods: Tumor samples were stained using an immunohistochemical technique with the following antibodies: anti-PAR-1 (clone WEDE 15), anti-PAR-4 (goat policlonal antibody), anti-VEGF (clone sc7269), and anti-CD34 (clone Qbend10), evaluating the percentage of positive cells. MVD was quantified according to CD34 staining. Results: All evaluated parameters were significantly higher in AC when compared to SCC. In particular, PAR-1 was expressed in 49% of tumor cells in AC and in 22% of cells in SCC (p<.001). PAR-4 was expressed in 29% of cells in AC and in 3% in SCC (p<.001). VEGF expression in AC was found in 15% of tumor cells vs. 5% in SCC (p<.001), while VEGF expression in endothelial AC cells was 22% vs. 13% in SCC (p<.002). MVD was 49.6 microvessel/m2 in AC, while it was 22.3 in SCC (p<.001). However, no correlation was found between PAR-1 and PAR-4 expression and VEGF and MVD levels, regardless of histology. Conclusions: PAR-1 and PAR-4 are significantly more expressed in AC than SCC. A longer follow up is needed to evaluate the prognostic implication of PAR-1 and PAR-4 in surgically resected patients. Potentially they can contribute to identify subgroups at higher risk of recurrence and candidates to more aggressive therapies. No significant financial relationships to disclose.
Association of Radiologic Indicators of Frailty With 1-Year Mortality in Older Trauma Patients
Authors: Stephen J. Kaplan, Tam N. Pham, Saman Arbabi, Joel A. Gross, Mamatha Damodarasamy, Itay Bentov, Lisa A. Taitsman, Steven H. Mitchell, May J. Reed
Journal: JAMA Surgery (2016)

Assessment of physical frailty in older trauma patients admitted to the intensive care unit is often not feasible using traditional frailty assessment instruments. The use of opportunistic computed tomography (CT) scans to assess sarcopenia and osteopenia as indicators of underlying frailty may provide complementary prognostic information on long-term outcomes.To determine whether sarcopenia and/or osteopenia are associated with 1-year mortality in an older trauma patient population.A retrospective cohort constructed from a state trauma registry was linked to the statewide death registry and Comprehensive Hospital Abstract Reporting System for readmission data analyses. Admission abdominopelvic CT scans from patients 65 years and older admitted to the intensive care unit of a single level I trauma center between January 2011 and May 2014 were analyzed to identify patients with sarcopenia and/or osteopenia. Patients with a head Injury Severity Score of 3 or greater, an out-of-state address, or inadequate CT imaging or who died within 24 hours of admission were excluded.Sarcopenia and/or osteopenia, assessed via total cross-sectional muscle area and bone density at the L3 vertebral level, compared with a group with no sarcopenia or osteopenia.One-year all-cause mortality. Secondary outcomes included 30-day all-cause mortality, 30-day readmission, hospital length of stay, hospital cost, and discharge disposition.Of the 450 patients included in the study, 269 (59.8%) were male and 394 (87.6%) were white. The cohort was split into 4 groups: 74 were retrospectively diagnosed with both sarcopenia and osteopenia, 167 with sarcopenia only, 48 with osteopenia only, and 161 with no radiologic indicators. Among the 408 who survived to discharge, sarcopenia and osteopenia were associated with higher risks of 1-year mortality alone and in combination. After adjustment, the hazard ratio was 9.4 (95% CI, 1.2-75.4; P = .03) for sarcopenia and osteopenia, 10.3 (95% CI, 1.3-78.8; P = .03) for sarcopenia, and 11.9 (95% CI, 1.3-107.4; P = .03) for osteopenia.More than half of older trauma patients in this study had sarcopenia, osteopenia, or both. Each factor was independently associated with increased 1-year mortality. Given the prevalent use of abdominopelvic CT in trauma centers, opportunistic screening for radiologic indicators of frailty provides an additional tool for early identification of older trauma patients at high risk for poor outcomes, with the potential for targeted interventions.
654. Recombinant Gene and Cell Therapy With Serine-Histogranin and Endomorphin-1 for the Experimental Treatment of Chronic Neuropathic Pain
Authors: Stana Jergova, Catherine E. Gordon, Shyam Gajavelli, Jacqueline Sagen
Journal: Molecular Therapy (2015)

The insufficient pain relief provided by current pharmacotherapy for chronic neuropathic pain represents a serious medical problem. The development of new treatment strategies is therefore of a high clinical interest. The mechanisms underlying development of chronic pain include decrease in spinal tonic inhibition due to the dysfunction of GABA signaling and increase in excitatory signaling through glutamate NMDA receptors. Previous studies showed beneficial effect of the intraspinal transplantation of GABAergic neuronal precursor cells (NPCs) and of the intraspinal delivery of serine histogranin (SHG), an NMDA receptor antagonist. Moreover, our studies showed that combined injection of SHG with another analgesic peptide, endomorphin-1 (EM-1), potentiated analgesic effect of SHG. Endomorphins are highly selective for μ-opioid receptors and have been shown to decrease neuropathic pain in previous studies. Cells and gene therapy provides suitable tools for targeted delivery of therapeutic peptides thus minimizing adverse effect of systemic delivery. Here we attempted to simultaneously target inhibitory and excitatory pathways in the spinal cord of injured animals by using either recombinant cells or recombinant AAV vectors. Recombinant plasmid encoding single- and multi-SHG and EM-1 was engineered and successful production of recombinant peptides by transduced HEK 293 cells was analyzed by immunocytochemistry and FLISA. AAV vectors were used as carriers of recombinant cDNA and used for either transduction of NPC or for direct spinal injection. Clip compression injury of the spinal cord was use as a model of central neuropathic pain. Animals showing clear sign of pain-related behavior were used for intraspinal injection of either recombinant NPCs or recombinant AAVs. Animals were tested weekly to evaluate analgesic effect of the treatment. Two week post injection animals treated with rAAVs showed significant attenuation of tactile sensitivity compared to controls and the antinociceptive effect sustained up to 6 weeks post injection. Enhanced analgesic effect was observed in the group with 6SHG-EM1 construct compared to 1SHG-EM1. Animals treated with rNPCs did not display significant pain relief compared to nonrecombinant NPCs group. However, these results may be masked by a low survival rate of the transplanted cells. Better strategies for rNPC engineering are currently examined. The presence of SHG and EM (above the levels of controls animals) was detected by FLISA methods and by immunohistochemistry in the spinal cord of treated animals suggesting successful production of recombinant peptides. This study demonstrates that the beneficial effect of combined therapy in the management of chronic pain may be enhanced by using gene engineering tools to deliver therapeutic substances into CNS in a single step and minimize the need for extensive surgical interventions.
The Expression of mRNA and Enzyme Activity of Deoxycytidine- and Deoxyguanosine Kinases in Cell from Patients with Untreated B-Cell Chronic Lymphocytic Leukemia.
Authors: Kourosh Lotfi, Karin Karlsson, Gunnar Juliusson, Curt Petersona, Staffan Eriksson, Freidoun Albertioni
Journal: Blood (2004)
Blockade of the Hedgehog Signaling Pathway by the Novel Agent NVP-LDE225 Induces Differentiation, Prevents De-Differentiation and Inhibits Proliferation of Multiple Myeloma Stem Cells in Vitro
Authors: Shihong Yang, Ross D Brown, Yen S Loh, Hayley Suen, James Favaloro, John Gibson, Phoebe Joy Ho, Douglas E Joshua
Journal: Blood (2012)
Inflammatory Cytokines and Acute Graft-Versus-Host Disease (aGVHD) after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT).
Authors: Mohamad Mohty, Beatrice Gaugler, Catherine Faucher, Norbert Vey, Reda Bouabdallah, Anne-Marie Stoppa, Frederic Viret, Gwenaelle Gravis, Daniel Olive, Didier Blaise
Journal: Blood (2005)
678. Neural Stem Cell-Based Gene Therapy for Malignant Brain Tumor by Doubl-Stranded Adeno-Associated Viral Vectors
Authors: Li-juan Wang, Hsin-I Ma
Journal: Molecular Therapy (2016)

Despite intensive efforts exploring gene therapeutic approaches for human cancers, the clinical results in treating of malignant brain tumors are still poor. We demonstrated that the combined therapeutic strategy by using an adenoviral vector carrying the thymidine kinase (suicidal) gene and an adeno-associated viral vector carrying the angiostatin gene achieved better therapeutic results. However, the malignant brain tumor could not be completely eradicated. Therefore, novel vectors and strategies are urgently needed. Neural stem cells (NSCs) may be used either for cell replacement or for gene delivery vehicles in neurodegenerative diseases. The expression of therapeutic proteins by NSCs can be enhanced by viral-mediated gene transfer, though the effects of several common recombinant viruses on primary progenitor cell populations have not been widely tested. The goal of this study is to identify and develop a safe and effective NSCs-based gene therapy protocol to treat malignant glioma. We examined what seral type of the novel double-stranded recombinant adeno-associated viral (AAV) vector can efficiently deliver anti-angiogenic genes and suicidal gene into the rat NSCs. Meanwhile, we investigated the gene product delivered by the genetically engineered NSCs in the adult normal brain. Then, we injected genetically engineered NSCs into different sites of the animal model of human malignant glioma. Flowcytometry data showed that AAV2 had higher transduction efficiency in neural stem cells. The NSCs were engineered to express Decorin and Angiostatin by AAV2, and then injected into the hemisphere contralateral to tumor cell implantation. We demonstrated that genetically-modified NSCs have the capacity to migrate into brain tumors. The therapeutic efficacy of genetically-modified NSCs is remaining explored.
Abstract 468: Delayed tumor growth in breast cancer is associated with reduced activity of the a2 isoform of vacuolar ATPase
Authors: Gajendra K. Katara, Arpita Kulshrestha, Alice Gilman-Sachs, Kenneth D. Beaman
Journal: Cancer Research (2015)

Abstract In cancer cells, vacuolar ATPase (V-ATPase), a multi-subunit enzyme, is expressed on the plasma as well as vesicular membranes and critically influences metastatic behavior. The soluble, cleaved N-terminal domain of a2 isoform of V-ATPase (a2NTD) is associated with in vitro induction of both tumor associated macrophages (TAMs) phenotype and activity in macrophages. This activity caused us to further investigate the role of a2NTD in cancer progression. We evaluated the effects of the knock down of a2 isoform (a2V) in tumor cells and the concomitant tumor microenvironment in the 4T-1 mouse breast cancer model. In vitro experiments showed that macrophages co-cultivated with a2V knocked down (sh-a2) tumor cells produced lower amounts of tumorigenic factors and have a reduced ability to suppress T cell activation and proliferation compared to control tumor cells. Furthermore, sh-a2 4T1 or control 4T-1 cells were inoculated into female Balb/c mice to generate mammary tumors. Data analysis showed that tumor growth in mice inoculated with sh-a2 4T-1 cells was delayed up to ten fold compared to control (mean±SD: 1.3 ± 1.15 vs 13.96 ± 4.06, P&amp;gt;0.01) at day 8 after inoculation. The expression of TAM associated molecules like mannose receptor-1 or CD206, IL-10, Arginase-1, matrix metalloproteinase and vascular endothelial growth factor were significantly down regulated in tumors from sh-a2 inoculated mice compared to control (P&amp;lt;0.01). Additionally, a significant reduction in the number of TAMs (F4/80+CD206+: mean = 6) and increase in macrophage with anti-tumor activity (F4/80+CD11c+: mean = 10.4) was also observed in these tumors which contributed towards delay in tumor growth. Further, we successfully deleted a2V gene in mice and its effect on tumor generation and microenvironment is evaluated. These findings demonstrated that in the absence of a2V in tumor cells, the resident TAM population in the tumor microenvironment is altered, which affected in vivo tumor growth. The data show that by involving the host innate immune system, tumor growth can be control through targeting of a2V and other related factors in tumor cells. Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Alice Gilman-Sachs, Kenneth D. Beaman. Delayed tumor growth in breast cancer is associated with reduced activity of the a2 isoform of vacuolar ATPase. [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 468. doi:10.1158/1538-7445.AM2015-468
Abstract B34: A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Cancer
Authors: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Pancreatic tumors with aberrant expression of macrophage migration inhibitory factor (MIF) are highly aggressive, and an increased MIF predicts poorer patient survival. We analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of PDAC patients to identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression. The identified key genes and pathways were linked to patients’ survival and were mechanistically, functionally and clinically characterized using cell lines, genetically engineered mouse model and PDAC patient cohorts. Here, we report mechanistic, functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor, nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2), leading to enhanced disease aggressiveness and poorer survival in PDAC. MIF upregulated miR-301b, which then targeted and suppressed NR3C2 expression. Tumors with high MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally, patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to chemotherapeutic drug gemcitabine. Furthermore, genetic deletion of MIF disrupted MIF-mir-301b-NR3C2 axis, which resulted in reduced metastasis and prolonged survival in genetically engineered mouse model of PDAC. These findings provide proof-of-principle that therapies targeting MIF-miR-301b-NR3C2 axis may improve disease outcome in PDAC Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain.{Authors}. A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B34.
Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome
Authors: Asger Sverrild, Pia Kiilerich, Asker Brejnrod, Rebecca Pedersen, Celeste Porsbjerg, Anders Bergqvist, Jonas S. Erjefält, Karsten Kristiansen, Vibeke Backer
Journal: Journal of Allergy and Clinical Immunology (2016)

BackgroundAsthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti-inflammatory treatment.ObjectiveWe sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects.MethodsBronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed.ResultsIn asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects.ConclusionThe level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.
Reply to Roberto Iacovelli, Walter Artibani, and Giampaolo Tortora's Letter to the Editor re: Ian D. Davis, Wanling Xie, Carmel Pezaro, et al. Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category. Eur Urol 2017;71:970–8
Authors: Ian D. Davis, Carmel Pezaro, Wanling Xie, Toni K. Choueiri, Daniel Y.C. Heng
Journal: European Urology (2016)
S68 Copd in the ed: eosinophils, treatment and outcomes, data from the pre-award study
Authors: REK Russell, T Doggett, I Pavord, R Pullinger, S Beer, M Bafadhel
Journal: Thorax (2016)

<h3>Rationale</h3> Acute exacerbations of COPD (AECOPD) are common. Peripheral blood eosinophil count (PBE) predicts outcomes in moderate and severe exacerbations, but little is known about PBE levels and outcomes of AECOPD in the emergency department (ED). <h3>Methods</h3> Data for all attendances to ED of a large teaching hospital throughout a 12-month period for patients attending with AECOPD were studied. Anonymised data was cleaned to remove diagnostic and data errors and analysed using GraphPadPrism6 with statistical methods suitable for the data collected. Data is presented as mean (SEM). Data collected included: demography, length of stay (LOS), vital status, initial treatment, full blood counts, renal function and CRP. <h3>Results</h3> There were 549 patients, with 768 AECOPD events. The mean (SD) age was 71 years and 192 episodes were associated with an eosinophil count &gt;2% (26.6%). There were 403 (56%) AECOPD episodes leading to admission; there was no difference in the eosinophil count between patients admitted or discharged from ED. Absolute and relative PBE levels were increased in patients re-attending ED (Absolute PBE mean difference 0.08, 95% CI: 0.02 to 0.13, p = 0.007; %PBE mean difference 0.6, 95% CI: 0.14 to 1.1, p = 0.001). Patients with a PBE &gt; 2% were readmitted more often (p = 0.002, RR 1.16, 95% CI: 1.05 to 1.26). For patients admitted, mean LOS was reduced if admission %PBE levels were &gt;2% (4.6 (0.5) vs. 5.8 (0.3) days, p = 0.012). In patients known to have received oral corticosteroids in ED, the reduction in LOS was greater still if the %PBE was &gt;2% compared to ≤2% (mean (SD) 4.1 (1.0) vs. 6.5 (0.9), p = 0.046). In-patient mortality occurred in 35 patients and occurred more frequently in patients with a %PBE ≤ 2% (RR 1.16, 95% CI: 1.04 to 1.68, p = 0.012). <h3>Conclusions</h3> This real-world data suggests that PBE levels may be a useful marker for predicting important clinical outcomes in AECOPD.
Gene-Modified CD8+ T Cells Undergo Functional Polarization to Effector and Central Memory Cells in Response to Antigen Exposure.
Authors: Paul Neeson, Amanda Shin, Tsin Tai, Karen Chen, Joanne Davis, Kellie Tainton, Phil Darcy, Michael H. Kershaw, Stefan Peinert, Preethi Guru, Simon Harrison, H. Miles Prince, D. Ritchie
Journal: Blood (2008)
Clinical Outcome of ALK -Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)
Authors: Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Martin Früh
Journal: Journal of Thoracic Oncology (2016)