tbuckley/cabot-search huggingface dataset:
Abstract 4022: Fibroblast-derived PEDF inhibits tumor growth and angiogenesis and is suppressed by TGF-β and PDGF
Authors: Nkechiyere G. Nwani
Journal: Cancer Research (2015)

Abstract Rationale and Objective: PEDF (pigment epithelium-derived factor) is an endogenous angiogenesis inhibitor and a type II tumor suppressor whose expression is often reduced/ lost in a variety of tumors, including malignant melanoma. To date, the mechanisms and consequences of PEDF loss on tumor progression have been investigated in neoplastic cells but not in the tumor-associated non-neoplastic cells. Fibroblasts are extremely abundant in the tumor microenvironment and can switch to the tumor-promoting phenotype in response to the tumor-associated factors. Here, we investigated how the loss of fibroblast-derived PEDF in the tumor microenvironment alters melanoma progression and the mechanisms, by which melanoma cells attenuate PEDF expression in fibroblasts. Methods: We used lentiviral vectors for PEDF knockdown (shPEDF and control). Tumor growth was evaluated in immunodeficient mice (flank injections). Angiogenesis and proliferation in the tumor were measured by immunohistochemistry (IHC) for CD31 and Ki-67, respectively. Gene expression was evaluated by q-PCR and protein levels were detected by western blot/ IHC. The contribution of growth factors tested using specific pathway inhibitors. Results: We have measured tumorigenesis of highly aggressive melanoma cell line C8161-HA co-mixed with shPEDF or control fibroblasts. PEDF loss in fibroblasts promoted tumor growth/ angiogenesis in xenografted human melanoma. Seeking mechanisms by which tumors attenuate PEDF expression in fibroblasts we found that it is mildly attenuated by hypoxia and potently down-regulated by the soluble factors produced by melanoma cells. Using recombinant growth factors and tumor conditioned media in combination with receptor and pathway-specific inhibitors we have identified TGF-β and PDGF as the main antagonists of PEDF expression. We have also discovered that PDGF directly blocks PEDF expression while regulation by TGF-β is indirect, whereby it elevates PDGFR expression by fibroblasts and thus increases their sensitivity to both paracrine and autocrine PDGF. Conclusions: Together, our data demonstrate the key role of PEDF loss in non-neoplastic cells in the tumor microenvironment and the mechanisms by which tumors overcome its anti-cancer effects. Our data also indicate potential utility of PDGF inhibitors to restore PEDF in the tumor microenvironment. Citation Format: Nkechiyere G. Nwani. Fibroblast-derived PEDF inhibits tumor growth and angiogenesis and is suppressed by TGF-β and PDGF. [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 4022. doi:10.1158/1538-7445.AM2015-4022
Bias in medical literature on health outcomes: bias in commentary?
Authors: David Barlow
Journal: BMJ (2016)

Parmar and colleagues ask an important question about research on the health impact of the 2008 financial crisis in Europe and in answering have devised a new assessment tool for observational studies.1 They spend time on seven aspects of bias: among the 41 studies included (from an original 5670), risk of bias was deemed high in 30, moderate in nine, and low in two. These values do not reflect well on …
Preliminary Results From A Phase I Dose Escalation Study to Determine the Maximum Tolerated Dose of Plerixafor In Combination with Rituximab In Patients with Relapsed Chronic Lymphocytic Leukemia
Authors: Leslie Andritsos, John C. Byrd, Jeffrey A. Jones, Becker Hewes, Thomas J. Kipps, Frank J Hsu, Jan A. Burger
Journal: Blood (2010)
Dendritic Cell-Based Immunotherapeutic Strategies in Adult Acute Lymphoid Leukemia Patients Treated with Conventional Therapy or with Imatinib.
Authors: Anna Guarini, Roberta Maggio, Maria Stefania De Propris, Nadia Peragine, Monica Messina, Elisabetta Calabrese, Cristina Ariola, Giovanna Meloni, Antonella Vitale, Robert Foà
Journal: Blood (2005)
Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis
Authors: Kyle S. McCommis, Wesley T. Hodges, Elizabeth M. Brunt, Ilke Nalbantoglu, William G. McDonald, Christopher Holley, Hideji Fujiwara, Jean E. Schaffer, Jerry R. Colca, Brian N. Finck
Journal: Hepatology (2016)

Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin‐sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose‐limiting side effects thought to be due to activation of the peroxisome proliferator–activated receptor γ. We sought to determine whether a next‐generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator–activated receptor γ (MSDC‐0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC‐0602. We found that MSDC‐0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans‐fatty acids, fructose, and cholesterol. Moreover, mice with liver‐specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC‐0602 directly reduced hepatic stellate cell activation in vitro , and MSDC‐0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion : Collectively, these data demonstrate the effectiveness of MSDC‐0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (H epatology 2017;65:1543‐1556).
Dental outcomes of osteonecrosis of the jaw (ONJ).
Authors: T. L. O'Connor, N. Ngamphaiboon, M. Sullivan, E. B. Kossoff, A. Elefante, J. L. Frustino
Journal: Journal of Clinical Oncology (2011)

e19675 Background: The optimal treatment and expected dental outcome of osteonecrosis of the jaw (ONJ) is not well understood. Dental management is recommended and administered as per a standard guideline at our institution, which has not changed over time. However, baseline dental screening and the increased awareness of ONJ may contribute to earlier diagnosis and improved dental outcomes. Methods: We performed a retrospective analysis of ONJ patients diagnosed at our institution between 6/2001- 6/2010. Patient characteristics, manifestations of ONJ, stage at presentation, dental treatments, and dental response were stratified by year of diagnosis. Results: We identified 56 ONJ patients with a median age of 58.5 years (40-82) who were diagnosed with breast cancer (63%), myeloma (30%), and 4 other cancers (7%). All patients received IV bisphosphonate (BP), zolendronate (78%), pamidronate (13%), or both (9%). Additional patient characteristics will be reported. ONJ characteristics, sites, and stage at presentation are recorded in the table. Median duration and dose of BP before ONJ diagnosis were 27.9 months (2.9-100.4), and 29.5 doses (4-100). Dental treatment and outcome are recorded in the table. Conclusions: Although the treatment for ONJ and the stage of presentation has not changed over time, the CR rate has improved at Roswell Park Cancer Institute. ONJ presentation, treatments, and response. Results (%) All ≤2006 2007-2010 n = 56 n = 28 n = 28 Necrotic bone 50 (89) 24 (86) 26 (93) Purulence 26 (46) 11 (39) 15 (54) Swelling 20 (36) 9 (32) 11 (39) Pain 33 (59) 14 (50) 19 (68) Paresthesia 9 (16) 5 (18) 4 (14) Tooth mobility 13 (23) 4 (14) 9 (32) Edentulous 6 (11) 3 (11) 3 (11) Sites of ONJ Maxilla only 14 (25) 9 (32) 5 (18) Mandible only 32 (57) 13 (46) 19 (68) Both 10 (18) 6 (22) 4 (14) Stages 0 5 (9) 3 (11) 2 (7) 1 19 (34) 10 (36) 9 (32) 2 30 (54) 14 (50) 16 (57) 3 2 (4) 1 (4) 1 (4) Treatments Antibiotics 46 (82) 23 (82) 23 (82) Alveoplasty/debridement 37 (66) 17 (61) 20 (71) Chlorhexidine scrub 49 (88) 23 (82) 26 (93) Alvogyl/dressing 7 (13) 3 (11) 4 (14) Denture adjustment 6 (11) 5 (18) 1 (4) Dental response Complete resolution 18 (38) 7 (30) 11 (42) Partial resolution 11 (22) 7 (30) 4 (15) Stable disease 13 (26) 5 (22) 8 (31) Progressive disease 7 (14) 4 (18) 3 (12) Missing 7 5 2
332. ZFN-Mediated Minigene or Dinucleotide Gene Correction of p47phox Deficient Autosomal Recessive Chronic Granulomatous Disease iPSC to Generate Oxidase Functional Neutrophils
Authors: Randall K. Merling, Suk See De Ravin, Colin L. Sweeney, Douglas B. Kuhns, Giovanni Di Pasquale, John A. Chiorini, Harry L. Malech
Journal: Molecular Therapy (2015)

Chronic granulomatous disease is an immune deficiency caused by defective phagocyte NADPH oxidase resulting in severe infections and autoimmune complications. NCF1 gene mutations resulting in p47phox deficiency are the most common cause of autosomal-recessive chronic granulomatous disease (AR-CGD), and notably, >80% of patients have homozygous GT-deletions in exon 2, resulting in a frame shift, premature termination, and absence of p47phox expression. Here we show two nucleofection strategies for NCF1 gene correction using zinc-finger nuclease (ZFN) targeting the NCF1 locus in patient EBV-immortalized B cells and in induced pluripotent stem cells (iPSC) derived from p47phox-deficient patients. With the first strategy, ZFN-mediated cut at start of exon 2 allows insertion of a minigene (NCF1 cDNA with deleted exon 1) to allow continuous transcription from the endogenous NCF1 exon 1 to the donor minigene exon 2 until the end of the cDNA and beta-globin polyadenylation signal. The second strategy takes advantage of the most prevalent GT-deletion by providing a dinucleotide corrective donor plasmid for gene editing using the same ZFNs. The two donors contain ~750 bp to 1000 bp flanking homology arms and also encode a selectable marker: a puromycin resistance gene flanked by loxP sites to allow for excision after selection. In patient EBV-immortalized B cells, minigene and dinucleotide targeted gene correction of constitutively active NCF1 was 8-20% after puromycin-selection from obtained clones. The rates of correction in iPSC were generally lower, less than 2%. Use of AAV2 vector to deliver dinucleotide corrective donor to iPSC increased insertion efficiency to >80% after puromycin selection. Gene corrected B cells for both correction strategies restored ROS function, shown by chemiluminescence assay. Neutrophils differentiated from gene corrected iPSCs demonstrated correction of oxidase activity by chemiluminescence or dihydrorhodamine flow cytometry assay. With both methods, p47phox protein expression is seen in neutrophils differentiated from iPSC but not in undifferentiated iPSC, demonstrating cell type-specific regulation of expression at the corrected locus. In summary, we show that iPSC generated from CGD patient cells can be gene corrected through a targeted dinucleotide correction method for greater than 80% of alleles and minigene correction for mutations other than the GT-deletions.
Impact of CPAP therapy on health-related quality of life in elderly patients with apnoea–hypopnea syndrome: a systematic review of randomised clinical trials
Authors: Jesús Serrano Merino, Luis A. Pérula de Torres, Rafaela Muñoz Gómez, Ana Roldán Villalobos, M. Nuria Feu Collado, Roger Ruiz-Moral, Bernabe Jurado-Gámez
Journal: European Respiratory Journal (2016)

Obstructive sleep apnoea (OSA) is a chronic pathology characterised by the presence of repetitive upper airway obstruction during the sleep, the prevalence of which increases with the age [1], and for which continuous positive airway pressure (CPAP) is the treatment of choice [2–4]. However, there have been few studies on diagnosis and management of OSA in elderly people. A qualitative systematic review of randomised clinical trials (RCTs) was conducted to evaluate the impact of CPAP therapy on health-related quality of life (HRQL) in OSA patients (aged >65 years), diagnosed by polysomnography or polygraphy and treated with CPAP for at least 3 months (>4 h·day−1). Studies whose primary outcome did not assess HRQL were excluded. Interventions were categorised according to whether or not they included CPAP treatment. The primary outcome was HRQL based on validated generic or specific questionnaires. CPAP therapy could have a positive impact on health-related quality of life of elderly patients with OSA <http://ow.ly/Qxtf305VNa2> We thank Raisa Serrano Muñoz (Universidad de Córdoba, Córdoba, Spain) for the translation of this manuscript.
High Correlation Clinical Responses to 1st Line Acute Myeloid Leukemia Treatment with an Ex Vivo Native Environment Precision Medicine Test
Authors: Pau Montesinos, Joan Ballesteros, David Martínez-Cuadrón, Joaquín Martínez-López, Josefina Serrano, Jaime Perez de Oteyza, Pascual Fernández, Gabriela Rodriguez-Macías, Mª Belén Vidriales, Pilar Herrera, Mar Tormo, Juan Bergua, Raimundo García, Susana Vives, Mª Ángeles Fernández, Esperanza Lavilla, Santiago Jimenez, Jose Antonio Pérez-Simón, Adriana Simiele, Ataulfo González, Bernardo J. González, Carmen Burgaleta, Juan Antonio López, Concepción Bethancourt, Guiomar Bautista, Arancha Alonso, Mercedes Colorado, Jordi Sierra, Begoña Navas, José Angel Hernández-Rivas, Juan Antonio Vera, Mª Lourdes Amador, Raúl Cordoba, Adolfo de la Fuente, Fernando Ramos, Carlos Javier Cerveró, Consolación Rayón, Olga Salamero, Edelmira Martí, Aurelio López, Teresa Olavé, Marta Gaspar, Julian Gorrochategui, José Luis Rojas, Cristina Gomez, Pilar Hernández, Alicia Robles, Ignacio Ortega, Jesús Villoria, Federico Moscardó, Iñaki Troconiz, Miguel A. Sanz
Journal: Blood (2015)
Defining the Leukemia Epigenome: Distinct Genome Wide Histone H3 Modification Patterns Exist in AML, ALL and Healthy Hematopoietic Progenitor Cells.
Authors: Carsten Muller-Tidow, Claudia Homme, Hans-Ulrich Klein, Antje Hascher, Steffen Koschmieder, Anke Becker, Yipeng Wang, Michael McClelland, Udo zur Stadt, Florian Battke, Kay Nieselt, Christian Thiede, Gerhard Ehninger, Wolfgang E. Berdel, Martin Dugas, Hubert Serve
Journal: Blood (2007)
Effect of Time to Dasatinib Initiation On Outcome of Imatinib-Intolerant Patients with Chronic-Phase Chronic Myelogenous Leukemia (CP-CML): Results From a European Observational Study (FORTE; CA180–211)
Authors: David Marin, Enrica Morra, Mauricette Michallet, Andrzej Hellmann, Dietger Niederwieser, Ernst Schloegl, Mats Björeman, Kajetana Foryciarz, Aloysius Y Ho, Kazimierz Kuliczkowski, Gert Ossenkoppele, Antonella Gozzini, M. Lurdes Guerra, Gregor Verhoef, Ave Mori, Miranda Pans, Marc van Baardewijk, Juan Luis Steegmann
Journal: Blood (2011)
PWE-043 Nurse-led abdominal paracentesis service
Authors: S D Bissmire
Journal: Gut (2010)

<h3>Introduction</h3> Increasing number of decompensated liver disease of varying aetiology with diuretic resistant, refractory ascites requiring paracentesis for symptomatic management. Increasing demand upon inpatient medical beds, therefore unable to accommodate patients for paracentesis as and when necessary within acute medical take. Delay is clinical risk – potential for development of spontaneous bacterial peritonitis±variceal bleed. Semi elective admissions for total paracentesis. Due to bed constraints admission was usually late in the day (&gt;13.00 h), therefore overnight stays were needed in the interest of patient safety (clinical governance issue). <h3>Methods</h3> Development of a direct access nurse led, abdominal paracentesis service, in an environment which would facilitate procedure and management of such individuals without inpatient stay. Training – initially observed practice by consultant gastroenterologist. Competence achieved. Total &gt;100 procedures. Completion of the independent prescribing module has enabled the activity to be managed and led by gastroenterology nurse practitioner without need for medical cover. Programme investigation unit (PIU) approached as highly skilled experienced medical nurses, with facility to offer a safe clinical environment for up to 8 h per day. Patients attend PIU at 9 am with drain being inserted, paracentesis to dryness with cover prior to discharge home. <h3>Results</h3> Service has been able to accommodate 33 patients since November 2008. All of the patients drained have been discharged home without the need for overnight stay, therefore at least 66 bed days have been saved. <h3>Conclusion</h3> Development of the advanced therapeutic role of the nurse practitioner has enabled practice to be developed with few post procedure complications. Pressures of being admitted as part of the emergency medical intake have been removed. Development of insertion criteria documentation, including standardised device throughout trust. It is believed that there is no other nurse led and managed paracentesis service in Wales
Neurosarcoidosis on FET and FDG PET/CT
Authors: Mico Chan, Edward Hsiao
Journal: Clinical Nuclear Medicine (2016)

O-(2-fluoroethyl)-L-tyrosine (FET) PET/CT is a promising imaging modality for brain tumor imaging because of its reported high sensitivity for biologically active tumor tissue. We present a case of biopsy-proven neurosarcoidosis showing FET uptake. It is an important cause of false-positive uptake on FET PET/CT.
Abstract 272: Checkpoint inhibitor combinations in a human mixed leukocyte reaction
Authors: Erin Sult, Carl Hay, Qihui Huang, Stacy Fuhrmann, Robert Hollingsworth, Kris F. Sachsenmeier
Journal: Cancer Research (2015)

Abstract In an effort to identify effective target combinations, molecules specific for several immuno-oncology targets were combined in vitro using a mixed leukocyte reaction (MLR) assay. Briefly, 20 different healthy human peripheral blood mononuclear cell donor pairs were tested for proliferation and cytokine release in the presence of each molecule alone and in combination. The collection of agents targeted CTLA-4, PD-1, PD-L1, and CD73. Examples of significant (p&amp;lt;0.05) synergy as well as antagonism and additivity were observed. In addition the phenotype and genotype of the MLR donor PBMCs were characterized. The results from this study are significant for at least two reasons: 1) In contrast to murine syngeneic models they represent aspects of multiple different human donor “immune responses” and 2) In contrast to purified T-cell assays they represent an assay system in which both the lymphoid and myeloid/innate immune compartments play a crucial role, and so better recapitulate a physiological T-cell response. Furthermore, these results provide information at the human population level, offering a glimpse of “responder” and “non-responder” population profiles. This information is impossible to obtain from the currently available collection of syngeneic mouse models. Citation Format: Erin Sult, Carl Hay, Qihui Huang, Stacy Fuhrmann, Robert Hollingsworth, Kris F. Sachsenmeier. Checkpoint inhibitor combinations in a human mixed leukocyte reaction. [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 272. doi:10.1158/1538-7445.AM2015-272
Abstract POSTER-THER-1411: MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth <i>in vitro</i>
Authors: Michael Curley, Akos Czibere, Alexey Lugovskoy
Journal: Clinical Cancer Research (2015)

Abstract PURPOSE OF STUDY: Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, IGF-1R inhibitors have had limited efficacy in clinical trials to date. ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate AKT survival signaling through binding of its ligand heregulin (HRG) in a majority of IGF-1 sensitive human cancer cell lines. ErbB3 and pAKT expression are upregulated following IGF-1R blockade and thus activated ErbB3 signaling may represent a potential escape route in the development of resistance to therapy. MM-141, an IGF-1R and ErbB3 directed bispecific antibody, blocks and degrades IGF-1R and ErbB3 containing receptor complexes leading to inhibition of downstream tumor pro-survival signaling to a greater extent as compared to anti-IGF-1R and ErbB3 antibodies. Here we explore the activity of MM-141 in ovarian cancer cell lines in vitro. EXPERIMENTAL PROCEDURES: Growth inhibitory activity of MM-141 was tested on a panel of established ovarian cancer cell lines in vitro. The ability of MM-141 to inhibit basal and IGF-1- and HRG-induced signaling was explored by ELISA and western blotting analyses. DATA SUMMARY: Inhibition of cell proliferation mediated by MM-141 varied among the ovarian cancer cell lines profiled in vitro. Furthermore, MM-141 treatment inhibited basal and ligand-activated IGF-1R, ErbB3 and downstream signaling in a selection of these ovarian cell lines. CONCLUSIONS: Our findings suggest that co-inhibition of IGF-1R and ErbB3 signaling with MM-141 has the potential to be an effective therapy for ovarian cancer patients by blocking redundant survival pathway activation. Citation Format: Michael Curley, Akos Czibere, Alexey Lugovskoy. MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1411.