tbuckley/cabot-search huggingface dataset:
Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages – a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape
Authors: Itsaso Montalbán del Barrio, Cornelia Penski, Laura Schlahsa, Roland G. Stein, Joachim Diessner, Achim Wöckel, Johannes Dietl, Manfred B. Lutz, Michel Mittelbronn, Jörg Wischhusen, Sebastian F. M. Häusler
Journal: Journal for ImmunoTherapy of Cancer (2016)

<h3>Background</h3> Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo. <h3>Methods</h3> Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized “TAM-like” macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4<sup>+</sup> T cells and specific inhibitors. <h3>Results</h3> When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4<sup>+</sup> T cell proliferation which could be rescued via blockade of CD39 or CD73. <h3>Conclusion</h3> Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.
Abstract 2973: CD269 - A promising target for amanitin based ADCs
Authors: Aniko Palfi, Torsten Hechler, Christoph Mueller, Andreas Pahl, Michael Kulke
Journal: Cancer Research (2016)

Abstract Antitumor activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval of Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising to strengthen the therapeutic capabilities for cancer treatment in the next decade. Surprisingly most ADCs are based on one of few toxic compounds only and on an even smaller number of toxicity mechanisms: Most antibodies are coupled to the microtubuli-targeting auristatins and maytansines. Toxins that operate through such a mechanism could suffer from limited activity in different cancer indications and in cells expressing resistance mechanisms. Accordingly the use of new drugs that function via alternative toxicity mechanisms could enhance the therapeutic potential of ADCs. Heidelberg Pharma focuses on Amanitin, the most well-known toxin of the amatoxin family. Amanitin binds to the eukaryotic RNA pol II and thereby inhibits the cellular transcription at very low concentrations. In the current study, in vitro and in vivo Data of Amanitin-ADCs targeting CD269 (B cell maturation antigen) are presented. CD269 is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. It is not expressed on naïve B cells, germinal center B cells and memory B-cells (Darce et al. (2007) J Immunol 179:7276-7286). CD269 is highly expressed on malignant plasma cells like multiple myeloma, a B cell non Hodgkin lymphoma of the bone marrow (Novak et al. (2004) Blood 103:689-94). Since multiple myeloma is a usually incurable malignancy of plasma cells, new therapies are urgently needed. Using ADCs in the cure of multiple myeloma could be a promising approach, especially by using a toxin whose mode of action was not applied before, like amanitin based ADCs. In vitro data of anti-CD269-amanitin ADC showed cytotoxicity on CD269 positive cell lines in picomolar range, while up to micromolar concentrations, no cytotoxic activity on CD269 negative cells was observed. In mouse xenograft models, anti-CD269-amanitin showed clear anti-tumorigenic potential. A comprehensive data package will be presented. Citation Format: Aniko Palfi, Torsten Hechler, Christoph Mueller, Andreas Pahl, Michael Kulke. CD269 - A promising target for amanitin based ADCs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2973.
Abstract 342: BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition
Authors: Ye Liu, Xi Yuan, Zhiyu Tang, Lai Wang, Lusong Luo, Min Wei
Journal: Cancer Research (2016)

Abstract Dysregulations of the mitogen-activated protein kinase (MAPK) signaling through abnormal expression or activating mutations of key signaling molecules, including RAS and RAF, have been identified in a wide range of cancers. Targeting these signaling molecules in the pathway represents a promising strategy to target dysregulated MAPK signaling. BGB-283 is a novel pan-RAF inhibitor and currently under clinical development to treat BRAF and KRAS/NRAS mutated tumors. In this study, we show that BGB-283 inhibits WT B-RAF dimer much more potently than vemurafenib at millimolar ATP concentration that is representative of the cellular ATP level, although BGB-283 and vemurafenib display similar inhibitory activity at the Km ATP concentration. BGB-283 has very slow off-rate and the dissociation half-life (t1/2) on WT B-RAF enzyme is well above 24 hrs. In comparison, vemurafenib has much faster off rates with t1/2 in the range of minutes. The crystal structure of BGB-283/B-RAF protein complex shows the benzimidazole and trifluoro group of BGB-283 binds significantly deeper into pocket formed by α-C helix and activation loop than vemurafenib. BGB-283 exhibits time-dependent inhibition both in biochemical assay and in B-RAF or K-RAS mutated cells. BGB-283 potently inhibits the p-ERK signaling in splicing isoform p61B-RAF(V600E) cells which were reported to be resistant to vemurafenib through a dimer mechanism. In vivo, BGB-283 significantly suppressed the tumor growth in A375-p61B-RAF(V600E) melanoma xenograft model. In addition, BGB-283 inhibits vemurafenib induced p-ERK activation and selumetinib induced p-MEK feedback activation in K-RAS mutated cancer cells. In both cases, activation is reported to be mediated by RAF dimers. Taken together, we propose that BGB-283 is a novel, slow-off RAF dimer inhibitor that targets the MAPK signaling differently from the first generation BRAF inhibitor vemurafenib. This feature of BGB-283 may help to address the drug resistance issues in BRAF mutated tumors and further expand its utility as mono- or combination therapy into RAS mutated patient populations. Citation Format: Ye Liu, Xi Yuan, Zhiyu Tang, Lai Wang, Lusong Luo, Min Wei. BGB-283, a slow-off inhibitor of RAF dimers, differentiates from vemurafenib in MAPK signaling inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 342.
Case 50-1969
Authors: Alfred Kranes, Austin L. Vickery
Journal: New England Journal of Medicine (1969)

PRESENTATION OF CASEAn eighty-two-year-old man was admitted to the hospital because of anorexia and a cough of three weeks' duration.The patient, who was unreliable, stated that he had lost 8 pounds in weight and had had a hacking, nonproductive cough. He denied fever, chills, night sweats, pain in the chest and dyspnea.He had worked as a railroad laborer. There was no known exposure to tuberculosis. A sterile abscess of the left lower leg had been drained one year previously. He smoked heavily and imbibed large quantities of alcohol.He was a thin man in mild respiratory distress. . . .
Abstract 2304: Attenuated oncolytic virus HSV1716 increases <i>in vivo</i> expansion of GD2- targeting CAR T cells in murine solid tumor models
Authors: Samuel T. Haile, Joe Conner, Crystal Mackall
Journal: Cancer Research (2016)

Abstract Neuroblastoma, osteosarcoma, and rhabdomyosarcoma are among the most prevalent childhood solid tumors. Each of these tumor types as well as melanomas exhibit increased levels of the tumor associated carbohydrate, GD2 on their cell surface making them ideal targets for chimeric antigen receptor (CAR) T cell-directed therapies. Despite the ability of GD2 CAR T cells to target tumor cells in vitro, there is great interest in improving tumor clearance in vivo, especially for solid tumors where current outcomes remain poor. We hypothesize that the immunosuppressive milieu present within the solid tumor microenvironment serves as a major factor limiting the effectiveness of GD2 CAR T cells. Additionally, we propose that administration of oncolytic viruses could induce inflammation within the tumor microenvironment that may enhance, rather than inhibit, the effectiveness of immune based therapies. GD2 CAR T cells composed of the 14G2a single chain variable fragment linked to the cytoplasmic signaling domains of CD28 and CD3 zeta (GD2-28z) were expressed in murine lymphocytes and evaluated for the ability to target and lyse GD2-expressing tumor cells. Additionally GD2-28z T cells were evaluated for their ability to secrete the proinflammatory cytokines IFNγ and IL-2. In order to determine the oncolytic ability of attenuated HSV1716, tumor cells were cultured in the presence or absence of HSV1716 and relative cell survival was measured. We observed specific lysis of GD2-expressing tumor cells when co-cultured with GD2-28z, but not mock T cells. Furthermore, GD2-28z T cells secrete IFNγ and IL-2 following co-culture with GD2-expressing tumor cells. Interestingly, melanoma cell lines were not susceptible to oncolytic lysis while rhabdomycosarcoma (RMS) cell lines were susceptible. The combination of GD2-28z and HSV1716 enhanced CAR expansion in both melanoma and RMS models. Given that the melanoma cells in our model are not susceptible to oncolytic lysis yet we observe an increased T cell expansion when used in combination with HSV1716, this supports our hypothesis that HSV1716 is inducing inflammation, which may then triggering T cell expansion. Citation Format: Samuel T. Haile, Joe Conner, Crystal Mackall. Attenuated oncolytic virus HSV1716 increases in vivo expansion of GD2- targeting CAR T cells in murine solid tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2304.
Association of Ambient Air Pollution with Depressive and Anxiety Symptoms in Older Adults: Results from the NSHAP Study
Authors: Vivian C. Pun, Justin Manjourides, Helen Suh
Journal: Environmental Health Perspectives (2016)

Ambient fine particulate matter (PM2.5) is among the most prevalent sources of environmentally induced inflammation and oxidative stress, both of which are implicated in the pathogenesis of most mental disorders. Evidence, however, concerning the impact of PM2.5 on mental health is just emerging.We examined the association between PM2.5 and current level of depressive and anxiety symptoms using a nationally representative probability sample (n = 4,008) of older, community-dwelling individuals living across the United States (the National Social Life, Health and Aging project).Mental health was evaluated using validated, standardized questionnaires and clinically relevant cases were identified using well-established cutoffs; daily PM2.5 estimates were obtained using spatiotemporal models. We used generalized linear mixed models, adjusting for potential confounders, and explored effect modification.An increase in PM2.5 was significantly associated with anxiety symptoms, with the largest increase for 180-days moving average (OR = 1.61; 95% CI: 1.35, 1.92) after adjusting for socioeconomic measures (SES); PM2.5 was positively associated with depressive symptoms, and significantly for 30-day moving average (OR = 1.16; 95% CI: 1.05, 1.29) upon SES adjustment. The observed associations were enhanced among individuals who had low SES and history of comorbidity. When considering mental health as chronic conditions, PM2.5 was significantly associated with incident depressive symptoms for all exposure windows examined, but with incident anxiety symptoms only for shorter exposure windows, which may be due to a drop in power resulting from the decreased between-subject variability in chronic PM2.5 exposure.PM2.5 was associated with depressive and anxiety symptoms, with associations the strongest among individuals with lower SES or among those with certain health-related characteristics. Citation: Pun VC, Manjourides J, Suh H. 2017. Association of ambient air pollution with depressive and anxiety symptoms in older adults: results from the NSHAP study. Environ Health Perspect 125:342-348; http://dx.doi.org/10.1289/EHP494.
Treatment of Higher-Risk Patients With an Indication for Revascularization
Authors: Ajay J. Kirtane, Darshan Doshi, Martin B. Leon, John M. Lasala, E. Magnus Ohman, William W. O’Neill, Adhir Shroff, Mauricio G. Cohen, Igor F. Palacios, Nirat Beohar, Nir Uriel, Navin K. Kapur, Dimitri Karmpaliotis, William Lombardi, George D. Dangas, Manish A. Parikh, Gregg W. Stone, Jeffrey W. Moses
Journal: Circulation (2016)

Patients with severe coronary artery disease with a clinical indication for revascularization but who are at high procedural risk because of patient comorbidities, complexity of coronary anatomy, and/or poor hemodynamics represent an understudied and potentially underserved patient population. Through advances in percutaneous interventional techniques and technologies and improvements in patient selection, current percutaneous coronary intervention may allow appropriate patients to benefit safely from revascularization procedures that might not have been offered in the past. The burgeoning interest in these procedures in some respects reflects an evolutionary step within the field of percutaneous coronary intervention. However, because of the clinical complexity of many of these patients and procedures, it is critical to develop dedicated specialists within interventional cardiology who are trained with the cognitive and technical skills to select these patients appropriately and to perform these procedures safely. Preprocedural issues such as multidisciplinary risk and treatment assessments are highly relevant to the successful treatment of these patients, and knowledge gaps and future directions to improve outcomes in this emerging area are discussed. Ultimately, an evolution of contemporary interventional cardiology is necessary to treat the increasingly higher-risk patients with whom we are confronted.
Investigation of TCR-Vβ CDR3 Spectrotypes in CD4 and CD8 Lymphocytes from Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients.
Authors: Akiko Nakamura, Tsutomu Shichishima, Hideyoshi Noji, Kazuhiko Ikeda, Yukio Maruyama
Journal: Blood (2004)
Abstract SY16-02: The discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design
Authors: Stephen W. Fesik
Journal: Cancer Research (2016)

Abstract Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins that is overexpressed and amplified in a wide variety of cancers and causes resistance to many chemotherapies. Although a very promising cancer target, it exerts its activity through protein-protein interactions and is very challenging to drug with small molecules. Indeed, there are no Mcl-1 inhibitors that have entered clinical trials. In this presentation, I will describe the discovery of picomolar Mcl-1 inhibitors using fragment-based methods and structure-based design that show promise as therapeutic agents for the treatment of heme malignancies and solid tumors. Citation Format: Stephen W. Fesik. The discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY16-02.
Abstract 3945: Antigen-specific immunity and regulation as predictive biomarkers for anti-tumor vaccination
Authors: Laura E. Johnson, Brian M. Olson, Douglas G. McNeel
Journal: Cancer Research (2016)

Abstract We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, PAP-specific proliferating and IFNγ-producing T cells developed in some patients, and persistent Th1-type immunity was associated with an increase in PSA doubling time. In the current study, we sought to determine if one or more measures of antigen-specific or antigen non-specific immunity present prior to treatment was associated with subsequent immune response as a possible predictive biomarker. Specifically, patients who had developed PAP-specific, IFNγ-secreting immune responses, detectable at least twice over one year after immunization, were defined as immune “responders”. The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells did not differ between the immune responder and non-responder groups. PAP-specific immune responses, detected as cytokine secretion following antigen stimulation of peripheral blood mononuclear cells in vitro, were detected in many patients pre-immunization. PAP-specific expression of granzyme B, IFNγ, and IL-6 was not significantly different between immune responding (n = 7) and non-responding patients (n = 23), however non-responder patients tended to have higher PAP-specific IL-10 production (p = 0.09). Using a trans vivo delayed-type hypersensitivity (DTH) assay to assess for antigen-specific immune regulation, responder patients tended to have preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen, a response previously demonstrated to be IL-35-mediated (p = 0.049). While the number of patients analyzed was low, these results suggest that different measures of antigen-specific regulation might help predict outcome from vaccination. These will be prospectively evaluated in an ongoing randomized, placebo-controlled, phase II trial evaluating this vaccine (NCT01341652). Citation Format: Laura E. Johnson, Brian M. Olson, Douglas G. McNeel. Antigen-specific immunity and regulation as predictive biomarkers for anti-tumor vaccination. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3945.
P1193 : Necroptosis contributes to the pathogenesis of cholestatic liver injury
Authors: M.B. Afonso, P.M. Rodrigues, A.L. Simão, H. Cortez-Pinto, D. Ofengeim, J. Amaral, R.E. Castro, J. Yuan, C.M.P. Rodrigues
Journal: Journal of Hepatology (2015)
3T Magnetic Resonance Imaging Identifies Unstable Carotid Atherosclerotic Plaque in the Very Early Phase of Acute Stroke
Authors: A C Lindsay, I Kylintireas, J M Lee, B J Maclntosh, W Kuker, A Handa, P Jezzard, Robson, S Neubauer, J Kennedy, R P Choudhury
Journal: Circulation (2008)
Missing HLA C Group 1 Ligand In Patients With AML and MDS Is Associated With Reduced Risk Of Relapse After Allogeneic Stem Cell Transplantation With Fludarabine and Treosulfan Reduced Toxicity Conditioning
Authors: Avichai Shimoni, Massimo Bernardi, Ronit Yerushalmi, Jacopo Peccatori, Noga Shem-Tov, Alessandro Lo Russo, Yulia Volchek, Luca Vago, Chiara Bonini, Maria Teresa Lupo Stanghellini, Arnon Nagler, Fabio Ciceri
Journal: Blood (2013)
Detection of intracellular interleukin-1 beta (IL-1 beta) in mononuclear cells of children with acute non lymphoblastic leukemia (ANLL) at diagnosis.
Authors: Esjm deBont, AE Niemarkt, Ryj Tamminga, Jll Kimpen, E vanWering, Lhmf deLeij, WA Kamps
Journal: Blood (1996)
Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.
Authors: Sebastian Stintzing, Andreas Jung, Lisa Rossius, Dominik Paul Modest, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Salah-Eddin Al-Batran, Ursula Vehling-Kaiser, Tobias Heintges, Markus Moehler, Werner Scheithauer, Thomas Kirchner, Volker Heinemann
Journal: Journal of Clinical Oncology (2014)

445 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.