tbuckley/cabot-search huggingface dataset:
<scp>CB</scp>2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma
Authors: M. E. Ferrini, S. Hong, A. Stierle, D. Stierle, N. Stella, K. Roberts, Z. Jaffar
Journal: Allergy (2016)

Allergic asthma is a chronic airway inflammatory disease involving the complementary actions of innate and adaptive immune responses. Endogenously generated cannabinoids acting via CB2 receptors play important roles in both homeostatic and inflammatory processes. However, the contribution of CB2-acting eicosanoids to the innate events preceding sensitization to the common house dust mite (HDM) allergen remains to be elucidated. We investigated the role of CB2 activation during allergen-induced pulmonary inflammation and natural killer (NK) cell effector function.Lung mucosal responses in CB2-deficient (CB2-/- ) mice were examined and compared with wild-type (WT) littermates following intranasal exposure to HDM allergen.Mice lacking CB2 receptors exhibited elevated numbers of pulmonary NK cells yet were resistant to the induction of allergic inflammation exemplified by diminished airway eosinophilia, type 2 cytokine production and mucus secretion after allergen inhalation. This phenomenon was corroborated when WT mice were treated with a CB2-specific antagonist that caused a pronounced inhibition of HDM-induced airway inflammation and goblet cell hyperplasia. Unexpectedly, the preponderance of NK cells in the lungs of CB2-/- mice correlated with reduced numbers of group 2 innate lymphoid cells (ILC2s). Depletion of NK cells restored the allergen responsiveness in the lungs and was associated with elevated ILC2 numbers.Collectively, these results reveal that CB2 activation is crucial in regulating pulmonary NK cell function, and suggest that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation.
Colon Cancer Clinical Practice Guidelines in Oncology
Authors: Paul F Engstrom, Al B Benson, Yi-Jen Chen, Michael A Choti, Raza A Dilawari, Charles A Enke, Marwan G Fakih, Charles Fuchs, Krystyna Kiel, James A Knol, Lucille A Leong, Kirk A Ludwig, Edward W Martin, Sujata Rao, M Wasif Saif, Leonard Saltz, John M Skibber, Alan P Venook, Timothy J Yeatman
Journal: Journal of the National Comprehensive Cancer Network (2005)

Colorectal cancer is the third most frequently diagnosed cancer in men and women in the United States, and in 2005, an estimated 104,950 new cases of colon cancer will occur. Despite these statistics, mortality from colon cancer has decreased over the past 30 years, possibly because of earlier diagnosis through screening and better treatment modalities. The NCCN guidelines summarize the management of colon cancer, from disease presentation through management of recurrent disease and patient surveillance. For the most recent version of the guidelines, please visit NCCN.org
Nonmyeloablative Allogeneic (Allo) BMT for B-Cell Lymphoma with Posttransplant Rituximab: Donor Selection by Prioritizing FCGR3A-158 Polymorphism Over HLA Matching.
Authors: Yvette L. Kasamon, Richard J. Jones, Christopher D. Gocke, Javier Bolaños-Meade, Lode J. Swinnen, Amanda Blackford, Douglas E. Gladstone, Ephraim J. Fuchs, Richard F. Ambinder
Journal: Blood (2012)
PTH-062 Interventional management of central venous thromboses associated with central venous catheters: our attempts are not in vein: Abstract PTH-062
Authors: A U Murugananthan, P Paskaran, M M Y Khoo, Y Naji, T Tran, J M D Nightingale, S M Gabe
Journal: Gut (2010)

<h3>Introduction</h3> Central venous thrombosis (CVT) associated with a central venous catheter (CVC) has an incidence of 0.027 episodes per catheter per year in parenteral nutrition use.1 Loss of venous access may occur, with loss of two or more central veins being an indication for intestinal transplantation. We describe a 4-year single centre experience of the interventional management of CVT associated with CVCs. <h3>Methods</h3> Patients who underwent interventional management of their CVTs were identified and clinical records assessed. Upper limb catheter position was recorded as described previously.2 <h3>Results</h3> Nine (eight females) patients underwent 10 interventions. Mean age: 48.8 years (range 22–67). Intestinal failure aetiology: functional (3), Crohn9s disease (3), mesenteric infarction (2) and FAP/desmoid disease.1 Six patients were smokers and two were on anti-coagulant therapy. Seven patients were on intravenous nutrition and 2 on parenteral fluids only. Mean duration of parenteral therapy was 4.4 years and the catheters were in situ for 19.2 months (mean, range 1 month–8 years). Interventions are summarised in Abstract 062. Four out of nine patients were noted to have a proximal catheter tip position at the time of thrombosis. Two patients developed complications of bleeding after thrombolysis (one at venepuncture site and the other developed occult GI bleeding) but required no therapy. 30-day mortality was 1 patient, unrelated to thrombosis. <h3>Conclusion</h3> We show that local thrombolysis, venoplasty and venous stenting are safe and when used in combination re-establish venous patency in 70%.
Erythrocyte Glutathione Depletion Is Associated with Severity of Anemia and Pulmonary Hypertension in Patients with Sickle Cell Disease.
Authors: Claudia R. Morris, Jung H. Suh, Sandra Larkin, D. Anton Bland, Adam Odhiambo, Martin H. Steinberg, Elliott P. Vichinsky, Mark Shigenaga, Bruce Ames, Frans A. Kuypers, Elizabeth S. Klings
Journal: Blood (2006)
PWE-050 United Kingdom Model for End-Stage Liver Disease and Model for End Stage Liver Disease scores predict outcome after oesophageal variceal haemorrhage
Authors: N Mangrolia, W Gelson, A Zissimopoulos, K Lee, M Allison
Journal: Gut (2010)

<h3>Introduction</h3> Variceal haemorrhage is a common, life-threatening complication of portal hypertension. In this study, we aim to assess mortality and predictors of outcome in a cohort of patients presenting acutely with a bleed. <h3>Methods</h3> We performed a retrospective review of consecutive cases of oesophageal variceal haemorrhage presenting acutely to our centre (a regional Hepatology Unit) in 2008. 30 cases were identified. Median age was 52 (range 29–79), 14 (46.7%) patients were male and underlying liver disease aetiology was alcohol-related in 15 (50%). The Mann–Whitney U test was used to compare United Kingdom Model for End-Stage Liver Disease and Model for End Stage Liver Disease (UKELD and MELD, respectively) scores at presentation by mortality. Receiver operating characteristic (ROC) curves were plotted when significant associations with UKELD and MELD scores were found. Binary logistic regression analyses were used to assess for associations with re-bleeding and death. <h3>Results</h3> 30-day mortality from admission to hospital was 13.3%, 90-day 30.0% and 180-day 40.0%. 7 (23.3%) patients had more than one bleed. Rescue TIPS shunt was required in 3 (10%). UKELD score at presentation was significantly higher in those who died within 30 days (mean 51.9 vs 60.6, p=0.02), but not thereafter. A similar finding for 30-day mortality was observed with MELD score (5.8 vs 20.5, p&lt;0.0001). In ROC analyses for death prediction at 30 days, the area under the curves were 0.89 for UKELD and 0.97 for MELD. Using a UKELD cut-off of 53.5 to predict death within 30 days, sensitivity was 75% and specificity 73%. With a MELD cut-off of 11.4, these were 75% and 89%, respectively. Univariate binary regression analyses identified positive associations of gender, creatinine and sodium with death, and ALD, bilirubin and creatinine with re-bleeding (p&lt;0.10). However, none of these variables achieved significance with multivariate analyses. <h3>Conclusion</h3> This study confirms a high mortality in patients presenting with variceal haemorrhage. UKELD and MELD scoring systems show promise at stratifying risk in this cohort.
Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia
Authors: Yana Pikman, Gabriela Alexe, Giovanni Roti, Amy Saur Conway, Andrew Furman, Emily S. Lee, Andrew E. Place, Sunkyu Kim, Chitra Saran, Rebecca Modiste, David M. Weinstock, Marian Harris, Andrew L. Kung, Lewis B. Silverman, Kimberly Stegmaier
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity. Results: We first determined that both NOTCH1-mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012–24. ©2016 AACR. See related commentary by Carroll et al., p. 873
A Randomized Trial of Heparin Plus Anti-Thrombin III (ATIII) vs. Heparin Alone To Prevent VOD after HSCT.
Authors: Chul W. Jung, Jeeyun Lee, Byeong Bae Park, Se H. Park, Jung Han Kim, Jung Mi Kwon, Sung Yong Oh, Hyun Jung Kim, Hyorak Lee, Kihyun Kim, Jin Seok Ahn, Won Seog Kim, Keunchil Park
Journal: Blood (2005)
594. PDGF-D Inhibition by Using Chitosan:siRNA Complexes in Breast Cancer Model of Rat
Authors: Julide Akbuga, Suna Ozbas-Turan, Levent Kabasakal, Emine Salva, Naziye Ozkan
Journal: Molecular Therapy (2015)

Cancers are characterized by the uncontrolled cell growth and angiogenesis. Expression of growth factors like platelet-derived growth factor (PDGF), an angiogenic molecule, increased in many types of human tumors incluiding breast cancer. PDGFs have been implicated in the pathogenesis and angiogenesis of different tumor types. PDGFs are growth factor family consist of 5 disulfide-linked dimers (PDGF-A to D). Among them PDGF-D has been recently found to be overexpressed in many tumor cells such as breast cancer and plays an important role in tumorgenesis. Overexpression of PDGF-D led to increased angiogenesis. Recently, RNAi offers a promising approach to develop a powerful class of inhibitors used to angiogenesis with siRNA as the therapeutic agent. However, siRNA has poor cellular uptake so, suitable delivery system is required. Among the different non-viral vectors, chitosan is an attractive gene delivery system. The aim of this project is to investigate anti-angiogenesis and tumor inhibition effects of PDGF-D targeting siRNA complexed with chitosan in breast cancer model of rat. siPDGF-D was complexed with chitosan at different N/P ratios (5/1 to 50/1) and the characterization of these complexes (size, surface charge and stability) was done. Chitosan/siPDGF-D complexes were injected intratumorally to rats bearing breast tumor. Tumor volumes were measured until 28 weeks. The PDGF-D mRNA expression level during the experiment were determined by RT-PCR. Apoptosis in tumor and treatment groups was studied by TUNEL method. To investigate the effect of complexes on the PDGF-D expression, PDGF-D was analyzed by western blotting. The size of complexes changed between 179.1- 342.0 nm depending on their different N/P ratios (5/1- 50/1). The surface charge of complexes was −0.20 mV to +23.79 mV. Tumor volume of rats decreased 95% after siRNA treatment. At untreated rat groups, tumor volume reaches to 593 mm3 after 28 days but in treated groups tumor volume (29 mm3) has not increased. The relative PDGF-D mRNA level in tumor tissue after injection of complexes was markedly reduced in comparison with the level of the control group. PDGF-D mRNA expression was reduced approximately 71% by chitosan complexes containing siPDGF-D. In TUNEL study, apoptotic index was high in treated group compared to tumor group. Western blot analysis showed decrease in PDGF-D protein level in complex group, compared with the tumor control group. Similar results were also obtained with RT-PCR. Free siRNA PDGF-D injections showed lower inhibition effect than complex forms. These results showed that the chitosan/siRNA complexes targeting to PDGF-D have a highest suppresive effect on protein and mRNA expressions and tumor volume in the breast cancer model of rats and chitosan is an effective vector for siRNA delivery. This study was supported by Marmara University Scientific Research Project Centre (BAPKO) with grant no: SAG-B-110412-0075.
The Cerebral Vasculopathy In Malian Sickle Cell Anemia Children: Lesson From Routine Transcranial Doppler Screening
Authors: Dapa Aly Diallo, Aldiouma Guindo, Alain Dorie, Boubacari Ali Touré, Baba Fané, Yaya Sarro, Gil Tchernia
Journal: Blood (2013)
Gene Expression Profiling Comparison between the Major Mature B-Cell Neoplasms and Their Normal Cellular and Anatomic Counterparts: Identification of Candidate Genes Potentially Involved in Lymphomagenesis.
Authors: Nicolas Blin, Celine Bossard, Jean-Luc Harousseau, Catherine Charbonnel, Wilfried Gouraud, Loic Campion, Florence Magrangeas, Stephane Minvielle, Herve Avet Loiseau
Journal: Blood (2006)
Bendamustin-Rituximab Induction Followed by Observation or Rituximab Maintenance for Newly Diagnosed Patients with Waldenström's Macroglobulinemia: Results From a Prospective, Randomized, Multicenter Study (StiL NHL 7–2008 –MAINTAIN-; ClinicalTrials.gov Identifier: NCT00877214).
Authors: Mathias J. Rummel, Christian Lerchenmüller, Richard Greil, Martin Görner, Manfred Hensel, Erik Engel, Ulrich Jaeger, Friedhelm Breuer, Bernd Hertenstein, Otto Prummer, Christian Buske, Juergen Barth, Alexander C. Burchardt, Wolfram Brugger
Journal: Blood (2012)
Endoscopic Sleeve Gastroplasty Significantly Reduces Body Mass Index and Metabolic Complications in Obese Patients
Authors: Reem Z. Sharaiha, Nikhil A. Kumta, Monica Saumoy, Amit P. Desai, Alex M. Sarkisian, Andrea Benevenuto, Amy Tyberg, Rekha Kumar, Leon Igel, Elizabeth C. Verna, Robert Schwartz, Christina Frissora, Alpana Shukla, Louis J. Aronne, Michel Kahaleh
Journal: Clinical Gastroenterology and Hepatology (2016)
Mutation Profile and Fluorescence In Situ Hybridization Analyses Increase Detection of Malignancies in Biliary Strictures
Authors: Tamas A. Gonda, Domenico Viterbo, Valerie Gausman, Claudine Kipp, Amrita Sethi, John M. Poneros, Frank Gress, Tina Park, Ali Khan, Sara A. Jackson, Megan Blauvelt, Nicole Toney, Sydney D. Finkelstein
Journal: Clinical Gastroenterology and Hepatology (2016)

Background & AimsIt is a challenge to detect malignancies in biliary strictures. Various sampling methods are available to increase diagnostic yield, but these require additional procedure time and expertise. We evaluated the combined accuracy of fluorescence in situ hybridization (FISH) and polymerase chain reaction–based DNA mutation profiling (MP) of specimens collected using standard brush techniques.MethodsWe performed a prospective study of 107 consecutive patients treated for biliary strictures by endoscopic retrograde cholangiopancreatography from June 2012 through June 2014. We performed routine cytology and FISH analyses on cells collected by standard brush techniques, and analyzed supernatants for point mutations in KRAS and loss-of-heterozygosity mutations in tumor-suppressor genes at 10 loci (MP analysis was performed at Interpace Diagnostics). Strictures were determined to be nonmalignant based on repeat image analysis or laboratory test results 12 months after the procedure. Malignant strictures were identified based on subsequent biopsy or cytology analyses, pathology analyses of samples collected during surgery, or death from biliary malignancy. We determined the sensitivity and specificity with which FISH and MP analyses detected malignancies using the exact binomial test.ResultsOur final analysis included 100 patients; 41% had biliary malignancies. Cytology analysis identified patients with malignancies with 32% sensitivity and 100% specificity. Addition of FISH or MP results to cytology results increased the sensitivity of detection to 51% (P < .01) without reducing specificity. The combination of cytology, MP, and FISH analyses detected malignancies with 73% sensitivity (P < .001). FISH identified an additional 9 of the 28 malignancies not detected by cytology analysis, and MP identified an additional 8 malignancies. FISH and MP together identified 17 of the 28 malignancies not detected by cytology analysis.ConclusionsAddition of FISH and mutation analyses to cytology analysis significantly increased the level of sensitivity with which we detected malignancy in biliary strictures, with 100% specificity. These techniques can be performed using standard brush samples collected during endoscopic retrograde cholangiopancreatography, with mutations detected in free DNA in supernatant fluid of samples. The tests are complementary and therefore should be used sequentially in the diagnostic evaluation of biliary strictures.
Abstract 4118: Near infrared photoimmunotherapy for lung metastases
Authors: Kazuhide Sato, Tadanobu Nagaya, Peter L. Choyke, Hisataka Kobayashi
Journal: Cancer Research (2015)

Abstract Introduction and Purpose Lung metastases are a leading cause of cancer related deaths. Current therapies include surgery, chemotherapy and radiotherapy but cause considerable side effects in the remaining normal lung, chest wall and heart. Therefore, a new-targeted therapy for lung metastases that results in minimal damage to adjacent structures, yet effectively treats lung metastases, is needed. Since one interesting property of the lung is that it transmits light better than other organs, light therapy is a viable alternative therapy. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experimental Design In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in a mouse model of lung metastases as well as a flank model, and assessed by tumor volume and/or bioluminescence (BLI). Results In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and BLI (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p &amp;lt; 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastases model (p &amp;lt; 0.0001). Conclusions NIR-PIT prolonged survival suggesting that NIR-PIT is a potential new therapy for the local control of lung metastases. Citation Format: Kazuhide Sato, Tadanobu Nagaya, Peter L. Choyke, Hisataka Kobayashi. Near infrared photoimmunotherapy for lung metastases. [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 4118. doi:10.1158/1538-7445.AM2015-4118
92. Detection and Characterization of Immune Response Against AAVrh10 Vector After Intrathecal Vector Delivery in Non-Human Primates
Authors: Gwladys Gernoux, Florie Borel, Guangping Gao, Robert Brown, Christian Mueller
Journal: Molecular Therapy (2015)

Immune responses against recombinant AAV (rAAV) capsid are a major concern in clinical trials. It was first described in hemophilic patients injected by intrahepatic delivery that AAV capsids elicited a cytotoxic lymphocyte response leading to clearance of transduced hepatocytes. On the other hand, intramuscular delivery of rAAV1 in humans induced a tolerogenic response against rAAV capsid mediated by regulatory T cells leading to stable expression in patients for more than 3 years. Several parameters could modulate this response and among them the mode of delivery. While transfer to the intact CNS has been shown to elicit a minimal T cell-mediated response without a salient plasma cell-mediated immune response in preclinical animal studies, these data are lacking in primate studies after intrathecal (IT) injection. In our study, African Green primates were injected intrathecally with a serotype 10 AAV vector (AAVrh10), described to transduce efficiently the central nervous system (CNS), expressing artificial miRNAs against superoxide dismutase 1 (SOD1) as a therapy for familial amyotrophic lateral sclerosis (ALS). This vector was administered at a dose of 6e12 viral genomes per kilogram modeled directly off the anticipated dose per patient in the clinical trial and based on IT rAAV delivery in primate studies showing robust cortical and spinal cord transduction. We are currently characterizing what type of immune response is elicited against the AAV capsid after IT delivery. A particular interest will be given to cytokine secretion mediated by restimulated T lymphocytes in vitro and to neutralizing antibodies directed against AAVrh10 and their potential cross-reactivity to other serotypes. In addition to the proof-of-concept of knockdown and spread of AAV vector after delivery to the CNS of primates, this study is important for the safety of IT delivery in large animal models before translation to human clinical trials.