tbuckley/cabot-search huggingface dataset:
Abstract 288: TG3003, an immunomodulatory anti-CD115 mAb targeting M2-macrophage polarization in the tumor microenvironment
Authors: Hélène Haegel, Christelle Ziller-Remy, Luc Barraud, Jean-Yves Bonnefoy, Sandrine Cochin, Vanessa Duong, Michel Geist, Benoit Grellier, Rémy Hallet, Jean-Baptiste Marchand, Thierry Menguy, Ronald Rooke, Christine Thioudellet, Carine Reymann, Xavier Préville
Journal: Cancer Research (2015)

Abstract Cancer progression has been associated with the presence of tumor-associated M2-type macrophages (M2-TAMs) able to inhibit anti-tumor immune responses, stimulate neo-angiogenesis and facilitate metastasis. Colony-stimulating factor-1 (CSF-1, M-CSF) is a cytokine required for the survival and differentiation of myeloid cell lineages, and CSF-1 signaling is known to polarize macrophages towards the M2-type. M2-TAMs can represent the most abundant immunosuppressive cell population in the tumor microenvironment, notably recruited by CSF-1 and MCP-1/CCL2. Transgene has developed a monoclonal antibody (mAb), TG3003, directed against the CSF-1 cell-surface receptor, CD115 (CSF-1R, M-CSFR). This mAb does not block the binding of CSF-1 to its receptor, but down-modulates CD115 signaling. In contrast to other anti-CD115 mAbs currently in development, whose modes of action rely on the blockade of ligand binding, TG3003 is not cytotoxic to normal myeloid cells that require CD115-mediated signaling for their survival. In vitro, TG3003 skews monocyte differentiation from M2-type macrophages towards dendritic cells, most potent antigen-presenting cells capable of stimulating efficacious T cell responses. It inhibits the secretion of MCP-1/CCL2 by differentiating macrophages and decreases their IL-6 production. Through this inhibition of M2-TAMs, TG3003 may potentiate immune responses in patients and impact on tumor progression. Moreover, due to its unique non-competitive mode of action, TG3003 does not block the physiological pathway for CSF-1 clearing from the circulation, thus avoiding the issue of toxic or rebound effects in treated patients. To investigate the properties of TG3003 in vivo, we have generated a transgenic mouse strain where the mAb epitope has been inserted into murine CD115 without affecting murine CSF-1 binding nor signaling. We will present the results of preclinical proof-of-concept experiments validating the mechanism of action and the immunomodulatory properties of mAb TG3003. Citation Format: Hélène Haegel, Christelle Ziller-Remy, Luc Barraud, Jean-Yves Bonnefoy, Sandrine Cochin, Vanessa Duong, Michel Geist, Benoit Grellier, Rémy Hallet, Jean-Baptiste Marchand, Thierry Menguy, Ronald Rooke, Christine Thioudellet, Carine Reymann, Xavier Préville. TG3003, an immunomodulatory anti-CD115 mAb targeting M2-macrophage polarization in the tumor microenvironment. [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 288. doi:10.1158/1538-7445.AM2015-288
Howell–Jolly bodies in acute hemolytic anemia
Authors: Barbara J. Bain
Journal: American Journal of Hematology (2016)

Howell–Jolly bodies are not infrequently observed is acute hemolytic anemia when the hemolysis is largely extravascular. The upper images show the blood film of a 62-year-old woman with acute warm autoimmune hemolytic anemia. Her hemoglobin concentration (Hb) was 68 g/l, mean cell volume (MCV) 110 g/l and mean cell hemoglobin concentration (MCHC) 306 g/L. Her blood film showed spherocytes, polychromatic macrocytes, and quite frequent Howell–Jolly bodies. A direct antiglobulin test showed immunoglobulin +++++ and C3d +++. The autoantibody showed no specificity. The raised MCV and reduced MCHC are the result of marked reticulocytosis; reticulocytes are not only much larger than mature red cells but also have a considerably lower hemoglobin concentration. The lower images show the blood film of a 7-year-old boy with acute hemolysis in glucose-6-phosphate dehydrogenase deficiency and an Hb of 58 g/l. His film showed irregularly contracted cells, keratocytes, polychromatic macrocytes, nucleated red blood cells, Pappenheimer bodies, and quite frequent Howell–Jolly bodies. It is postulated that the presence of significant numbers of Howell–Jolly bodies in patients with acute hemolytic anemia is indicative of splenic macrophages that are overloaded with phagocytosed red cells and cellular debris are thus unable to carry out their normal “pitting” function. The Pappenheimer bodies are likely to result from the same mechanism. none
410. Oncolytic Adenoviruses Armed with TNFa and IL-2 Induce Antitumor Immune Responses and Protection from Tumor Rechallenge
Authors: Riikka Havunen, Mikko Siurala, Suvi Parviainen, Michael Behr, Dirk Nettelbeck, Anja Ehrhardt, Akseli Hemminki
Journal: Molecular Therapy (2016)

During the past few years, immune system-stimulating factors have emerged as promising means to treat malignant tumors. We aim to use cytokine-bearing oncolytic adenoviruses to improve and to extend the usage of adoptive T cell therapy, a treatment known to benefit a portion of melanoma and leukemia patients. Administered systemically or intratumorally the virus induces immune responses against the tumor by revealing tumor antigens, but immunostimulatory cytokines augment the effect further. We have shown that the most promising cytokines in this regard are interleukin (IL) -2 and Tumor Necrosis Factor alpha (TNFa). IL-2 is a common treatment for malignant melanoma and renal cell carcinoma, but systemic administration may lead to severe side effects. While IL-2 has a key role in recruiting and activating T cells, TNFa has prominent anti-immunosuppressive actions. Further, it directly promotes tumor cell death by apoptosis and necrosis. Armed oncolytic viruses accomplish local, long-lasting, high-level cytokine expression while systemic level remains low. Moreover, we have proven that adenoviruses enhance adoptive T cell therapy. In this study, we treated Syrian hamsters (Mesocricetus auratus) with Ad5/3-E2F-d24 virus bearing human IL-2, TNFa, or both in its E3 region. Hamster cell lines are semipermissive for 5/3-chimeric adenoviruses and produce active transgenes from these viruses. In addition, human IL-2 and TNFa are evidently active in hamsters. Hamster pancreatic cancer (HapT1) was implanted subcutaneously and treated once with TILs extracted from syngenic tumors, and with five viral injections. We saw synergy between unarmed virus and TILs, while the armed viruses turned out to be even more effective. When the cured animals were rechallenged with the same cancer cells, previous treatment with cytokine-armed viruses protected the animals against new tumors. Also, splenocytes derived from animals treated with cytokine-bearing viruses proliferated more actively ex vivo than the controls. To conclude, our data demonstrates the immunological benefit gained with viruses bearing IL-2 and TNFa, and further supports combining oncolytic viruses with adoptive cell transfer.
A Varicella Outbreak in Diffuse Large B-Cell Lymphoma Patients Receiving Rituximab-Containing Chemotherapy
Authors: Akinao Okamoto, Akihiro Abe, Masataka Okamoto, Yoko Inaguma, Tokuda Masutaka, Satoko Morishima, Masamitsu Yanada, Tadaharu Kanie, Yukiya Yamamoto, Shuichi Mizuta, Yoshiki Akatsuka, Tetsushi Yoshikawa, Nobuhiko Emi
Journal: Blood (2014)
Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines
Authors: Sebastian Salas-Vega, Othon Iliopoulos, Elias Mossialos
Journal: JAMA Oncology (2016)

There is a dearth of evidence examining the impact of newly licensed cancer medicines on therapy. This information could otherwise support clinical practice, and promote value-based decision-making in the cancer drug market.To evaluate the comparative therapeutic value of all new cancer medicines approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) between 2003 and 2013.We used a narrative synthesis approach to systematically synthesize and analyze English, French, and Australian health technology assessments (HTAs) of all new cancer medicines licensed in the United States and Europe between 2003 and 2013.Sixty-two new molecular entities with a primary oncology indication.Overall survival (OS), quality of life (QoL), and safety.Of the 62 new active cancer molecules approved by the FDA and EMA between 2003 and 2013, 53 were appraised by English, French, or Australian HTA agencies through May 2015. Of these 53 drugs, 23 (43%) increased OS by 3 months or longer, 6 (11%) by less than 3 months, and 8 (15%) by an unknown magnitude; there was no evidence to suggest that the remaining 16 (30%) increased OS over best alternative treatments. Where overall survival gains could be quantified, all new cancer drugs were associated with a mean (SE) total increase in OS of 3.43 (0.63) months over the treatments that were available in 2003. Drug-related improvements in OS were, however, widely distributed across therapeutic targets-ranging between 0 (thyroid, ascites) and 8.48 months (breast cancers)-and were sometimes based on modeled data, indirect or nonactive comparisons, or nonvalidated evidence. Although 22 (42%) of 53 new medicines were associated with an increase in QoL, 24 (45%) were also associated with reduced patient safety. Of the 53 new cancer drugs, 42 (79%) were associated with at least some improvement in OS, QoL, or safety.Although innovation in the oncology drug market has contributed to improvements in therapy, the magnitude and dimension of clinical benefits vary widely, and there may be reasons to doubt that claims of efficacy reflect real-world effectiveness exactly. These findings raise important questions for clinical decision-making and value-based policy.
38. CCR5 Gene Edited Hematopoietic Stem Cells Engraft in Diverse Anatomical Locales and Undergo SHIV-Dependent Positive Selection in Nonhuman Primates
Authors: Christopher W. Peterson, Jianbin Wang, Patricia Polacino, Shiu-Lok Hu, Michael C. Holmes, Hans-Peter Kiem
Journal: Molecular Therapy (2016)

Background: Gene editing in hematopoietic stem/progenitor cells (HSPCs) has rapidly emerged as a promising therapy for a number of diseases, including human immunodeficiency virus (HIV) infection. We have previously demonstrated the feasibility of this approach in nonhuman primates. Here, we leverage our expertise with gene editing in large animal models to interrogate the clonal persistence, trafficking, and antiviral efficacy of CCR5-edited cells in the pigtailed macaque, M. nemestrina. Our objectives were to map the tissue distribution of HSPC-derived, gene edited progeny, understand how individual gene edited HSPCs persist following autologous transplantation, and develop strategies to select for these cells in vivo. Methods: Zinc Finger Nucleases (ZFNs) are used to target the CCR5 locus in macaque HSPCs. Engraftment and persistence of these autologous stem cells, and stem cell-derived lymphoid and myeloid cells, are measured ex vivo and in vivo. Animals are challenged with simian/human immunodeficiency virus (SHIV). Gene edited HSPCs are transplanted either prior to SHIV infection, or in SHIV-infected animals that are treated with combination antiretroviral therapy (cART) in order to approximate a well-suppressed HIV+ patient. Edited cells are measured longitudinally in peripheral blood, bone marrow, gastrointestinal (GI) tract, and lymph nodes, and at necropsy in a panel of 25 tissues, using methods including deep sequencing. Results: We observe up to 14-fold enrichment of CCR5-gene edited memory CD4+ T-cells in SHIV-infected animals, consistent with virus-dependent selection against CCR5 wt memory CD4+ T-cells. Gene edited cells are found in a broad array of anatomical sites, including GI tract and lymph nodes. Spatial and temporal tracking of CCR5 mutations suggests that gene edited cells persist in an analogous fashion to control lentivirus gene-marked cells. Homology directed repair (HDR) pathways can be exploited in macaque CD34+ HSPCs, facilitating knock-in of selectable markers at the disrupted CCR5 locus. Conclusions: Our results in SHIV-infected animals reinforce that this gene editing strategy results in stable engraftment of CCR5-mutated and SHIV-resistant HSPCs and their progeny. Additionally. gene edited CD4+ T-cells undergo positive selection during active infection, further supporting the validity of this approach in the clinic. Moreover, our preliminary ex vivo HDR data suggest that these gene edited cells could be engineered to undergo virus-independent selection.
C-KIT with D816Y/V Mutations Cooperate with CBFB-MYH11 to Accelerate Leukemogenesis in Mice.
Authors: Ling Zhao, J. Joseph Melenhorst, Lemlem Alemu, Martha Kirby, Stacie M Anderson, Shelley Hoogstraten-Miller, Yasuhiko Kamikubo, D. Gary Gilliland, Pu Paul Liu
Journal: Blood (2009)
Abstract 5366: Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells
Authors: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. TROY expression increases with glial tumor grade and inversely correlates with patient survival. TROY stimulates GBM cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. Conversely, knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. In this study, we demonstrated that PPF decreases TROY protein expression in glioma cells, and subsequently suppress activation downstream signaling effectors including AKT, NF-κB, and Rac1. PPF treatment of glioma cells also suppressed glioma cell migration and invasion, demonstrated by transwell migration assay and reduced membrane ruffling. Finally, PPF treatment increased vulnerability of glioma cells to Temozolomide (TMZ) and radiation. In summary, this study demonstrates that PPF provides a pharmacologic approach to target TROY to inhibit glioma cell invasion and reduce therapeutic resistance to TMZ and radiation. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran. Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma 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 5366. doi:10.1158/1538-7445.AM2015-5366
Abstract 796: Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression
Authors: Sergei Tjulandin, Mikhail Byakhov, Evgenia Stepanova, Dmitry Khochenkov, Daniel Harrison, Ilya Tsimafeyeu
Journal: Cancer Research (2015)

Abstract Alofanib (formerly known as RPT835) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing triple-negative breast cancer [Tjulandin S, et al. San Antonio Breast Cancer Symposium 2014]. Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity [Cole C, et al. Cancer Biol Ther. 2010]. We investigated antitumor activity of alofanib in ovarian cancer in vitro and in vivo. To assess the efficacy of alofanib on FGF-mediated cell proliferation, ovarian cancer (SKOV-3) FGFR2-expressing cells were incubated in a 96-well microculture plate and were treated with serially diluted RPT835. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of FGFR2 high-expressing ovarian cancer cells (SCOV-3). Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 30 days after tumor inoculation. Basic FGF significantly increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib treatment resulted in growth inhibition of SKOV-3 cell line in vitro. Treatment of alofanib in combination with paclitaxel/carboplatin demonstrated significant tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Alofanib exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated dramatic effect (inhibiting growth by 80% and by 53% in comparison with vehicle and chemotherapy group alone, respectively (P&amp;lt;0.001). Alofanib decreased number of vessels in tumor on 49% compared with chemotherapy alone (P&amp;lt;0.05). There were tumor necrosis and cell degeneration in alofanib group. These results provide strong rationale for evaluation of alofanib in combination with paclitaxel and carboplatin in patients with ovarian cancer. Citation Format: Sergei Tjulandin, Mikhail Byakhov, Evgenia Stepanova, Dmitry Khochenkov, Daniel Harrison, Ilya Tsimafeyeu. Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression. [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 796. doi:10.1158/1538-7445.AM2015-796
Influence of Cardiopulmonary Bypass Temperature on Circulatory Pathophysiology and Clinical Outcomes
Authors: Kazuhiro Hashimoto, Tatsuumi Sasaki, Takashi Hachiya, Katsuhisa Onoguchi, Hiromitsu Takakura, Motohiro Oshiumi, Sigeyuki Takeuchi
Journal: Circulation (2000)

This study was designed to investigate the effects of cardiopulmonary bypass (CPB) perfusion temperature. Forty-four patients who had undergone elective coronary bypass surgery were randomly divided into 2 groups (22 patients each) according to their perfusion temperature (N group=36 degrees C; L group=30 degrees C). The concentrations of endogenous catecholamines, complements, elastase, serotonin, arachidonic acid metabolites and endothelin underwent various changes throughout the CPB but did not exhibit any statistical differences in either group. None of the substances measured correlated with systemic vascular resistance at any time. The temperature of the perfusion appears to be a major determinant of vascular tone. The postoperative PO2 was better, and postoperative pulmonary vascular resistance lower in the N group (p<0.05), most likely because of a much larger water balance during hypothermic CPB (p<0.01). The postoperative blood loss was statistically less in the N group (p<0.05). Although apparent brain damage, evidenced by the leakage of creatine kinase-BB, was not seen, the jugular bulb venous hemoglobin saturation levels (<50% in 27% of the N group, p<0.05) and higher lactate levels suggested that normothermic perfusion was relatively disadvantageous. It is concluded that normothermic CPB was relatively safe and advantageous with regard to hemostasis and pulmonary function.
OC-081 Can a “risk of coeliac disease” scoring system reduce the number of patients referred for duodenal biopsy?
Authors: J S Leeds, N Libzo, R Sidhu, K E Evans, M Kurien, E J Hall, V S Jandu, A D Hopper, P Basumani, K L Dear, M E McAlindon, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Coeliac disease (CD) affects 1% of the population. Despite this prevalence, the majority of individuals are undetected and patients present with atypical/subtle symptoms contributing to under diagnosis. The aim of this study was to determine the importance of different presenting characteristics and risk factors to provide a biopsy reducing strategy. <h3>Methods</h3> Patients referred to the SYLGRG were investigated for CD using antiendomyseal and anti-tissue transglutaminase antibodies plus total IgA level. Demographics, reason for referral and comorbidities were noted. Patients with positive antibodies or IgA deficiency were offered a duodenal biopsy. Duodenal biopsies were graded using the modified Marsh criteria with grade 3 (villous atrophy) taken as diagnostic of CD. Multivariate analysis was performed to identify independent risk factors. Using these factors a coeliac risk score was constructed and tested on a second cohort (n=609). <h3>Results</h3> 4089 patients were assessed (mean age 55.8, 2392 females). 386 patients had positive profiles (9.5%, 8.6–10.4%) of which 128 had CD (3.1%, 2.6–3.7%). Univariate analysis showed CD was associated with age &lt;55 years (OR 2.2), IBS symptoms (OR 2.8), anaemia (OR 4.8), diarrhoea (OR 3.6), positive antibodies/need for duodenal biopsy (OR 28.7). Analysis of comorbidities revealed CD was associated with osteoporosis (OR 4.4), autoimmune disease (OR 2.3) and a family history (FHx) of CD (OR 9.0). Linear regression showed that age&lt;55, FHx CD, Anaemia and Osteoporosis were independent risk factors for CD and these factors were then modelled and attributed scores. Age &lt;55 = 1, anaemia=1 and EMA positive=2 giving compositae scores from 0 to 4. Scores of 0–2 corresponded to a very low risk of CD (0.84%, 0.6–1.2) and scores of 3+ corresponded to a risk of 13%–80%. Receiver operating curve analysis for the score gave an area under the curve of 0.79 (0.75–0.85, p&lt;0.001). When applied to the validation cohort, scores of 0–2 corresponded to 0% risk of CD (0.0–0.7) and scores of 3+ corresponded to a risk of 4%–50%. <h3>Conclusion</h3> CD accounted for one in 30 referrals. CD was associated with younger age, anaemia, positive family history and osteoporosis. Modelling of these risk factors lead to a potentially valuable scoring system that could be used to determine pre-biopsy risk of CD and in many patients avoid unnecessary biopsy. This score needs to be validated in other cohorts.
Translating Findings of Proteasome Inhibitors Effects from the in VivoDrosophila Experimental Model to Humans: The Paradigm of the Molecular-Cellular Responses to Bortezomib and Carfilzomib
Authors: Ioannis P. Trougakos, Eleni-Dimitra Papanagnou, Tina Bagratuni, Efstathios Kastritis, Issidora S. Papassideri, Evangelos Terpos, Meletios A. Dimopoulos
Journal: Blood (2014)
A NEW DEVELOPMENT of Triterpene Acids-CONTAINING Extracts FROM Viscum Album L. Displays Synergistic INDUCTION of Apoptosis In Childhood LEUKEMIA
Authors: Catharina I. Delebinski, Kristin Kemnitz-Hassanin, Sebastian Jaeger, Holger N. Lode, Karl-Heinz Seeger, Guenter Henze, Georg Seifert
Journal: Blood (2011)