tbuckley/cabot-search huggingface dataset:
Abstract 3083: Prior irradiation results in elevated programmed death 1 (PD-1) in T cells
Authors: Renxiang Chen, Deguan Li, Albert J. Fornace, Henghong Li
Journal: Cancer Research (2017)

Abstract It is well known that radiation has long-lasting effects on the immune system. In this study we address the question whether these radiation-induced adverse effects on T cell activation are associated with alterations of T cell inhibitory receptors. Expression levels of inhibitory receptors on T cells were analyzed at multiple post-radiation time points ranging from one to four weeks in mice receiving whole body irradiation. The level of the checkpoint receptor, PD-1, on different T cell subpopulations was determined. Our results showed that prior irradiation resulted in significant elevated expression of PD-1 in both CD4+ and CD8+ populations. T cells with elevated PD-1 mostly were either central memory or naïve cells. In addition, the feedback induction of PD-1 expression in activated T cells declined with time after radiation. Taken together, the elevated PD-1 level observed at weeks after radiation exposure is connected to T cell dysfunction. Similar changes were seen in samples from tumor patients receiving radiotherapy. Recent preclinical and clinical studies have shown that radiation alters the immune-modulatory microenvironment in tumor tissue, and implies that a combination of radiotherapy and T cell checkpoint blockade immunotherapy including targeting the PD-L1/PD-1 axis may potentiate the antitumor response. Therefore, understanding the dynamic changes in PD-1 levels in T cells after radiation should help in the development of a more effective therapeutic strategy. Citation Format: Renxiang Chen, Deguan Li, Albert J. Fornace, Henghong Li. Prior irradiation results in elevated programmed death 1 (PD-1) in T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2017-3083
Abstract 1882: Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion
Authors: Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya
Journal: Cancer Research (2017)

Abstract Tankyrase, a member of poly(ADP-ribose) polymerase (PARP) family, catalyzes addition of long PAR chains onto the acceptor proteins, such as TRF1, a telomere-binding protein, and Axin, a repressor of Wnt/β-catenin signaling. Tankyrase-mediated PARylation of TRF1 and Axin represses the biological functions of these proteins, leading to enhanced telomere elongation by telomerase and upregulation of Wnt/β-catenin signaling, respectively. Thus, tankyrase is a multifunctional protein that supports oncogenic properties of cancer cells. Given that tankyrase has a large protein-protein interaction platform called ANK repeat clusters, and is broadly distributed to various intracellular loci, including telomeres, nucleoplasm, nuclear pore complexes, cytoplasm, Golgi, and spindle poles, this protein seems to have a yet unidentified function. In the present study, we explored the function of a novel tankyrase-binding protein called TNKS1BP1 and elucidated its contribution to regulating cancer cell invasion. Since TNKS1BP1 co-localizes with the actin filaments, we first examined the effect of genetic manipulation of TNKS1BP1 expression on cell invasion. We found that TNKS1BP1 depletion by small interfering RNAs increased the invasive capacity of human fibrosarcoma cells, whereas its overexpression decreased the cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion and lamellipodia ruffling were increased with activation of the ROCK-LIMK-cofilin pathway, which promotes cell motility. Importantly, tankyrase overexpression reproduced the phenotype of TNKS1BP1-depleted cells and enhanced cell invasion in a PARP activity-dependent manner. Under approval by Institutional Review Board of Japanese Foundation for Cancer Research, we performed immunohistochemical analysis of clinical pancreatic cancer. We found that TNKS1BP1 protein expression is decreased in invasive regions of the tumors. Taken together, these observations suggest that the tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion and its aberration promotes cancer malignancy. Citation Format: Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya. Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2017-1882
Abstract 3771: Concurrent GVAX and anti-OX40 therapy in murine intracranial glioma model
Authors: Nusrat Jahan, Hammad Talat, William T. Curry
Journal: Cancer Research (2017)

Abstract Introduction: Malignant glioma is the most aggressive brain tumor with a median survival time of less than 1.5 years post diagnosis despite standard treatments. However, recent advancements in immunotherapy hold significant promise. Irradiated whole tumor cell vaccination stimulates antitumor immunity and prolongs survival in mice with intracranial glioma tumors. We have shown that vaccination and immune checkpoint blockade is synergistic and these efforts are underway in the clinic. In contrast to immune checkpoint blockade, agonist stimulation of OX40, a member of the TNFR/TNF superfamily that is expressed on activated CD4 and CD8 T lymphocytes increases T cell proliferation, clonal memory differentiation, and cytokine release. We hypothesized that subcutaneous vaccination with irradiated GM-CSF expressing glioma cells (GVAX) would, therefore, synergize with systemic delivery of stimulating anti-OX40 antibody and provide effective immunity against intracranial gliomas. Methods: Gl261 cells were implanted in the right frontal lobes of syngeneic c57/bl6 mice using a stereotactic implantation technique. Mice received concurrent subcutaneous injection of irradiated GM-CSF expressing glioma cells and intraperitoneal injection of OX40 antibody, either monotherapy, or control treatment on days 3, 6 and 9 following tumor implantation. Results: Combination immunotherapy with irradiated GM-CSF expressing glioma cells and intraperitoneal delivery of agonist monoclonal antibody against OX40 was more effective than either therapy alone and prolonged survival in mice with established intracranial GL261 tumors. Elispot analyses of peripheral lymphocytes revealed that combination immunotherapy reverses the Th2 cytokine skew that is induced by the presence of intracranial glioma. OX40 signaling alone and in combination with vaccination drove high levels of interferon gamma expression by splenocytes harvested from glioma-bearing animals, while IL-10 expression was little changed. In the tumor microenvironment, vaccination improves the CD8+ /FoxP3+ T lymphocyte ratio, while OX40 ligation overcomes tumor-driven lymphocyte exhaustion, demonstrated by reduced expression of PD1 and LAG3, measured by flow cytometery 2 weeks after initiation of treatment. Conclusions: Combination treatment with GVAX and OX-40 agonist antibody increased survival in mice bearing intracranial gliomas and are mechanistically complementary. Citation Format: Nusrat Jahan, Hammad Talat, William T. Curry. Concurrent GVAX and anti-OX40 therapy in murine intracranial glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2017-3771
Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma
Authors: Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M. Quinn, Fei Li, Ashley A. Merlino, Cyril Benes, Qingsong Liu, Nathanael S. Gray, Kwok-Kin Wong
Journal: Cancer Research (2017)

Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068-76. ©2017 AACR.
Abstract LB-327: Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization
Authors: Jason J. Kwon, Kayla Quirin, Arafat Aljoufi, Amira Nafiseh, Janaiah Kota
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) still remains to be one of the most highly malignant human diseases and is resistant to the majority of current therapeutic modalities. Oncogene MYC has been known to be upregulated in PDAC and plays a key role in carcinogenesis and tumor progression. In our previous work, we found the downregulation of miR-29 is a common phenomenon of PDAC, and its restored expression reduced cancer cell migration/invasive potential, anchorage independent growth, and sensitized them to gemcitabine. Furthermore, we showed that miR-29 blocks autophagy in cancer cells by targeting key autophagy related proteins. However, the mechanism associated with the loss of miR-29 in PDAC has yet to be elucidated. Here we demonstrate that MYC inhibits miR-29 expression in PDAC. MYC nuclear localization negatively correlates with miR-29 expression in various pancreatic cancer cell lines, and knockdown of MYC led to an increased expression of both primary miR-29a/b1 transcript and mature miR-29a. Furthermore, miR-29 overexpression in combination with gemcitabine led to decreased cancer cell viability and increased intracellular reactive oxygen species (ROS) and cell death. Our findings show for the first time that MYC represses miR-29 in PDAC, and miR-29 sensitizes pancreatic cancer cells to gemcitabine through increased intracellular ROS. Taken together our results, indicating the potential use of miR-29a as a novel therapeutic agent for PDAC. Citation Format: Jason J. Kwon, Kayla Quirin, Arafat Aljoufi, Amira Nafiseh, Janaiah Kota. Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-327. doi:10.1158/1538-7445.AM2017-LB-327
Abstract 2126: CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth <i>in vivo</i>
Authors: Eskouhie H. Tchaparian, Louis Lin
Journal: Cancer Research (2017)

Abstract Aberrant PI3K/Akt/mTOR signaling pathway is common in several human cancers, including CRC. The pathway regulates many major cellular processes and promotes tumorigenesis and inhibition of apoptosis. Targeting the PI3K/Akt/mTOR network could be important in resistance mechanisms in cancer. CA102N, is a conjugate of Hyaluronic Acid (HA) and H-Nim, a nimuselide (COX-2 inhibitor) derivative, currently under investigation for preclinical development in CRC. Studies have suggested that the anti-proliferative effects of COX-2 inhibitors could be attributed to modulation of the PI3K/AKT signaling pathway; therefore, in this study we aimed to examine the overall molecular mechanism of the antitumor activity of CA102N and evaluate its impact on the PI3K pathway proteins. Cell based studies indicated that in addition to cell cycle arrest; the antitumor activity of CA102N is also related to apoptosis. Administration of CA102N to nude mice bearing established HT29 subcutaneous tumor xenografts caused significant tumor growth inhibition with no signs of systemic toxicity. Immunohistochemical analyses of xenograft tumors demonstrated inhibition of VEGF and CD31, suggesting a role for CA102N in angiogenesis. Disruption of angiogenesis and apoptosis was correlated with a decrease in VEGF and the antiapoptotic protein BCL-2. Suppression of PI3K downstream signaling was a key observation in HT29 cells in vitro and in xenograft tumors treated with CA102N. As compared to untreated vehicle control, a significant decrease in phosphorylation of AKT, mTOR, p70S6K, PRAS40, 4EBP1 and FOXO1 was detected by Western blot analyses. The reduction observed may be caused by both specific protein dephosphorylation/deactivation and by ubiquitin-mediated proteasomal degradation of pathway proteins. These results suggest that the antitumor activity of CA102N may be at least partly related to the modulation of the PI3K/Akt pathway proteins. CA102N represents a promising anticancer agent with minimal toxicity, the insights provided into the mechanisms of its anticancer activity may be the basis for advancing this candidate into clinic. Citation Format: Eskouhie H. Tchaparian, Louis Lin. CA102N, a conjugate of hyaluronic acid (ha) and Nimuselide derivative (H-Nim) interferes with PI3K/Akt/mTOR signaling pathway in colorectal cancer (CRC) cells and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2017-2126
OP0030 Inequity in biologic dmard prescription for spa across the globe. results from the asas comospa study
Authors: E Nikiphorou, D van der Heijde, S Norton, R Landewé, A Moltό, M Dougados, F van den Bosch, S Ramiro
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The value of biologic DMARDs (bDMARDs) in SpA is well recognized but global access to these treatments can be limited due to high cost and other factors. <h3>Objectives</h3> This study explores variation in the use of bDMARDs in SpA across countries and to what extent socio-economic (SE) factors may explain variation. <h3>Methods</h3> Patients fulfilling the ASAS SpA criteria in the multi-national, cross-sectional ASAS COMOSPA study were studied. Multi-level logistic regression models with random intercept for country were constructed with current use of bDMARDs as the dependent variable. Contribution of socio-economic factors using country health expenditures and gross domestic product (GDP) (all low vs medium/high tertiles) as independent country-level factors, was explored in models adjusted for socio-demographic as well as clinical variables known to determine bDMARD-use in SpA. <h3>Results</h3> In total, 3370 patients from 22 countries were included (mean [SD] age 43 [14] years; 66% male; 88% axial disease). Across countries, 1275 (38%) were bDMARD users. Crude mean bDMARD-use varied between 5% (China) to 74% (Belgium). After adjustment for relevant socio-demographic and clinical variables, important variation in bDMARD-use across countries remained (Figure, p&lt;0.001). Country-level socio-economic factors, specifically higher health expenditures were related to higher bDMARD uptake (Table), though not meeting statistical significance (OR 1.91; 95% CI 0.93,3.92). Similar findings were found with country GDP (OR 1.72;95% CI 0.83,3.57). <h3>Conclusions</h3> There remains important residual variation across countries in bDMARD uptake of patients with SpA followed in specialized SpA centers. This is despite adjustment of well-known factors for bDMARD use such as clinical and country-level socio-economic factors. <h3>Disclosure of Interest</h3> None declared
Abstract 2945: Impact of intratumoral mature dendritic cells on prognosis of the patients with esophageal squamous cell carcinoma
Authors: Junya Nishimura, Hiroaki Tanaka, Yuichiro Miki, Tatsuro Tamura, Tatsunari Fukuoka, Go Ohira, Masatsune Shibutani, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Hisashi Nagahara, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2017)

Abstract [Background] Promising efficacy of the immunotherapy with anti-PD-1 antibody for esophageal squamous cell carcinoma (ESCC) is expected. Tumor-infiltrating lymphocytes (TILs)have been found to be associated with favorable outcome of patients in many cancers including ESCC. However, the contributing factor of TILs in the primary tumor remains unclear. Dendritic cells (DCs) are the most potent antigen-presenting cells to induce cytotoxic T lymphocytes. [Purpose] The aim of this study was to examine the correlation of mature dendritic cells with CD8+ cells in the tumor in order to clarify the impact of DCs on locally infiltrated lymphocytes in ESCC. [Object and Methods] Formalin-fixed, paraffin-embedded blocks of primary lesions were collected from 80 patients with ESCC who underwent surgical treatment at Osaka City University Hospital. Immunohistochemical analysis using anti-LAMP-3 antibody and CD8 antibody was used to evaluate intratumoral DCs and TILs. The number of LAMP-3+DCs and TILs were counted at ×400 magnification. We divided the 80 cases into two groups according to the median number of intratumoral DCs and TILs to examine the clinicopathological features. [Results] LAMP-3+DCs were predominantly observed in peritumoral area and sparsely found in intratumoral area, whereas CD8+T cells distributed between both peritumoral and intratumoral areas. The number of DCs was significantly associated with increasing TNM stage. For example, the median number of DCs was 59.9 in pathological T1, 34.2 in T2/3, 62.4 in pN1, 34.1 in pN1/2/3. In addition, many patients with high infiltaraion of DCs had positive lymphatic invasion (Ly). The number of intratumoral DCs was significantly correlated with the number of TILs which were observed in intratumoral regions. Patients in the high infiltration of DCs group showed a significant better prognosis than patients in the low infiltration group. Double staining showed that LAMP3+DC-CD8+T cell clusters were seen in peritumoral area. Citation Format: Junya Nishimura, Hiroaki Tanaka, Yuichiro Miki, Tatsuro Tamura, Tatsunari Fukuoka, Go Ohira, Masatsune Shibutani, Sadaaki Yamazoe, Kenjiro Kimura, Takahiro Toyokawa, Hisashi Nagahara, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Impact of intratumoral mature dendritic cells on prognosis of the patients with esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2945. doi:10.1158/1538-7445.AM2017-2945
EFFECTS OF TOBACCO SMOKING
Journal: JAMA (1929)

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Gestational diabetes mellitus and interpregnancy weight change: A population-based cohort study
Authors: L. M. Sorbye, R. Skjaerven, K. Klungsoyr, N. H. Morken
Journal: PLoS Medicine (2017)

Background Being overweight is an important risk factor for Gestational Diabetes Mellitus (GDM), but the underlying mechanisms are not understood. Weight change between pregnancies has been suggested to be an independent mechanism behind GDM. We assessed the risk for GDM in second pregnancy by change in Body Mass Index (BMI) from first to second pregnancy and whether BMI and gestational weight gain modified the risk. Methods and findings In this observational cohort, we included 24,198 mothers and their 2 first pregnancies in data from the Medical Birth Registry of Norway (2006–2014). Weight change, defined as prepregnant BMI in second pregnancy minus prepregnant BMI in first pregnancy, was divided into 6 categories by units BMI (kilo/square meter). Relative risk (RR) estimates were obtained by general linear models for the binary family and adjusted for maternal age at second delivery, country of birth, education, smoking in pregnancy, interpregnancy interval, and year of second birth. Analyses were stratified by BMI (first pregnancy) and gestational weight gain (second pregnancy). Compared to women with stable BMI (−1 to 1), women who gained weight between pregnancies had higher risk of GDM—gaining 1 to 2 units: adjusted RR 2.0 (95% CI 1.5 to 2.7), 2 to 4 units: RR 2.6 (2.0 to 3.5), and ≥4 units: RR 5.4 (4.0 to 7.4). Risk increased significantly both for women with BMI below and above 25 at first pregnancy, although it increased more for the former group. A limitation in our study was the limited data on BMI in 2 pregnancies. Conclusions The risk of GDM increased with increasing weight gain from first to second pregnancy, and more strongly among women with BMI < 25 in first pregnancy. Our results suggest weight change as a metabolic mechanism behind the increased risk of GDM, thus weight change should be acknowledged as an independent factor for screening GDM in clinical guidelines. Promoting healthy weight from preconception through the postpartum period should be a target.