tbuckley/cabot-search huggingface dataset:
Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation
Authors: Jose Marino, Mohamed H. Babiker-Mohamed, Patrick Crosby-Bertorini, Joshua T. Paster, Christian LeGuern, Sharon Germana, Reza Abdi, Mayuko Uehara, James I. Kim, James F. Markmann, Georges Tocco, Gilles Benichou
Journal: Science Immunology (2016)

Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation.
Abstract 2725: Probing mitotic functions of BUB1 kinase using the small molecule inhibitors BAY-320 and BAY-524
Authors: Anna P. Baron, Conrad von Schubert, Fabien Cubizolles, Gerhard Siemeister, Marion Hitchcock, Anne Mengel, Jens Schröder, Amaury Fernández-Montalván, Martin Lange, Franz von Nussbaum, Dominik Mumberg, Erich Nigg
Journal: Cancer Research (2016)

Abstract The maintenance of correct chromosome number (euploidy) during cell division is ensured by a highly conserved surveillance mechanism termed ‘spindle assembly checkpoint’ which safeguards correct chromosome segregation by delaying anaphase onset until all chromosomes are properly bi-oriented on the spindle apparatus. The mitotic kinase BUB1 (budding uninhibited by benzimidazoles 1) was reported to contribute to both chromosome congression and checkpoint function, yet the role of BUB1 catalytic activity in these processes remains a matter of debate. To differentiate between catalytic and non-catalytic functions of BUB1 we compared phenotypes provoked by BUB1 protein depletion with specific BUB1 kinase inhibition using two novel small molecule inhibitors of BUB1, termed BAY-320 and BAY-524. BAY-320 and BAY-524 were highly potent and selective ATP-competitive inhibitors of BUB1 kinase activity with IC50 values in the single digit nanomolar range (at 10 micromolar ATP concentration). By monitoring phosphorylation of Thr120 in histone H2A, we showed that both compounds acted as potent BUB1 kinase inhibitors both biochemically and in human cells. We found that BUB1 inhibition substantially altered the chromosomal association of Shugoshin and the chromosomal passenger complex without major effects on global Aurora B function. Consequently, inhibition of BUB1 kinase clearly impaired chromosome arm resolution but, in stark contrast to depletion of BUB1 protein, only had a minor effect on cell cycle and SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of paclitaxel, synergistically affecting chromosome segregation and cell proliferation. These findings are highly relevant to both our understanding of BUB1 kinase function during mitosis and the prospects of BUB1 as a target of anti-cancer therapies. In this regard, BAY-320 and BAY-524 are first-in-class inhibitors of BUB1 kinase and their potential utility as anti-cancer agents is being explored. Citation Format: Anna P. Baron, Conrad von Schubert, Fabien Cubizolles, Gerhard Siemeister, Marion Hitchcock, Anne Mengel, Jens Schröder, Amaury Fernández-Montalván, Martin Lange, Franz von Nussbaum, Dominik Mumberg, Erich Nigg. Probing mitotic functions of BUB1 kinase using the small molecule inhibitors BAY-320 and BAY-524. [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 2725.
Analyses of Results From Cardiovascular Safety Trials With DPP-4 Inhibitors: Cardiovascular Outcomes, Predefined Safety Outcomes, and Pooled Analysis and Meta-analysis
Authors: Edoardo Mannucci, Ofri Mosenzon, Angelo Avogaro
Journal: Diabetes Care (2016)

The U.S. Food and Drug Administration requires that the cardiovascular (CV) safety of all new drugs for diabetes be demonstrated through pooled analyses of phase III studies or specifically designed trials. This requirement prompted several placebo-controlled, noninferiority CV safety trials in high-risk patients; to date, all completed trials showed that dipeptidyl peptidase (DPP)-4 inhibitors do not increase or reduce the risk of major CV events. These results apparently contrast with those of pooled analyses and meta-analyses of previous, smaller trials with metabolic end points, which had suggested a reduction of risk. However, the design of CV trials, which were required to demonstrate safety, is not adequate (for duration, management of concurrent therapies, etc.) for the assessment of potential therapeutic benefits. In addition, CV safety trials enroll patients at high risk of CV events, who are different from those included in earlier trials with metabolic end points. Differences in characteristics of patients enrolled probably account for most of the discrepancy in CV outcomes between CV safety studies and earlier trials. The availability of several large-scale trials with longer duration provides the unique opportunity for assessment of the safety of DPP-4 inhibitors not only with respect to major CV events but also with reference to other safety issues. For example, CV safety trials can be a source of information for pancreatitis, cancer, or hypoglycemia.
RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis
Authors: Hao Zhang, Zheng Xing, Saravana Kumar Kailasam Mani, Brigitte Bancel, David Durantel, Fabien Zoulim, Elizabeth J. Tran, Philippe Merle, Ourania Andrisani
Journal: Hepatology (2016)

Chronic hepatitis B virus (HBV) infection is a major factor in hepatocellular carcinoma (HCC) pathogenesis by a mechanism not yet understood. Elucidating mechanisms of HBV-mediated hepatocarcinogenesis is needed to gain insights into classification and treatment of HCC. In HBV replicating cells, including virus-associated HCCs, suppressor of zeste 12 homolog (SUZ12), a core subunit of Polycomb repressive complex2 (PRC2), undergoes proteasomal degradation. This process requires the long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR). Intriguingly, HOTAIR interacts with PRC2 and also binds RNA-binding E3 ligases, serving as a ubiquitination scaffold. Herein, we identified the RNA helicase, DEAD box protein 5 (DDX5), as a regulator of SUZ12 stability and PRC2-mediated gene repression, acting by regulating RNA-protein complexes formed with HOTAIR. Specifically, knockdown of DDX5 and/or HOTAIR enabled reexpression of PRC2-repressed genes epithelial cell adhesion molecule (EpCAM) and pluripotency genes. Also, knockdown of DDX5 enhanced transcription from the HBV minichromosome. The helicase activity of DDX5 stabilized SUZ12- and PRC2-mediated gene silencing, by displacing the RNA-binding E3 ligase, Mex-3 RNA-binding family member B (Mex3b), from HOTAIR. Conversely, ectopic expression of Mex3b ubiquitinated SUZ12, displaced DDX5 from HOTAIR, and induced SUZ12 down-regulation. In G2 phase of cells expressing the HBV X protein (HBx), SUZ12 preferentially associated with Mex3b, but not DDX5, resulting in de-repression of PRC2 targets, including EpCAM and pluripotency genes. Significantly, liver tumors from HBx/c-myc bitransgenic mice and chronically HBV-infected patients exhibited a strong negative correlation between DDX5 messenger RNA levels, pluripotency gene expression, and liver tumor differentiation. Notably, chronically infected HBV patients with HCC expressing reduced DDX5 exhibited poor prognosis after tumor resection, identifying DDX5 as an important player in poor prognosis HCC.The RNA helicase DDX5, and E3 ligase Mex3b, are important cellular targets for the design of novel, epigenetic therapies to combat HBV infection and poor prognosis HBV-associated liver cancer. (Hepatology 2016;64:1033-1048).
Impact of precise quantitative assessment of visceral obesity on outcomes of patients with metastatic renal cell carcinoma treated with systemic therapy.
Authors: Ryuichi Mizuno, Akira Miyajima, Nozomi Hayakawa, Eiji Kikuchi, Shuji Mikami, Masahiro Jinzaki, Mototsugu Oya
Journal: Journal of Clinical Oncology (2016)

597 Background: With its excellent resolution of adipose tissue, CT presents precise quantitative assessment of visceral obesity. We assessed the impact of visceral obesity on progression free and overall survival in patients treated with systemic therapy for metastatic renal cell carcinoma. Methods: This retrospective cohort study included 114 patients treated with systemic therapy for metastatic renal cell carcinoma between 2007 and 2015 at Keio university hospital in Japan. The visceral fat area was measured at the level of umbilicus using CT. A visceral fat area ≥100cm2 was used as the definition of visceral obesity. Progression free and overall survival was compared according to visceral obesity. Results: In the whole cohort, the median progression free survival in first line treatment was 12.0 month. The median overall survival was 42.5 month. According to Memorial Sloan-Kettering Cancer Center classification, 31 patients were favorable risk, 61 were intermediate risk, and 22 were poor risk; median overall survival for these groups were 76.9, 40.8, and 23.7 months, respectively (P&lt;0.0001). Visceral obesity correlated with improved progression free (P=0.0095) and overall survival (P=0.0002). On multivariate analysis, visceral obesity (HR 0.64, P=0.0393) and Memorial Sloan-Kettering Cancer Center classification (P=0.0037) were independent indices to predict progression free survival in first line treatment. In addition, visceral obesity (HR 0.42, P=0.0016) and Memorial Sloan-Kettering Cancer Center classification (P=0.0006) independently predicted overall survival. Conclusions: The precision of CT imaging for measuring visceral fat tissue provides useful clinical venue to predict prognosis for metastatic renal cell carcinoma. Visceral obesity may be a useful and independent indicator for a better prognosis in patients treated with systemic therapy for metastatic renal cell carcinoma.
Abstract 5061: Evaluating the role of durotactic migration in the tumor microenvironment
Authors: Brian J. DuChez, Kenneth M. Yamada
Journal: Cancer Research (2016)

Abstract Durotaxis is a mechanism of directional migration in which cells respond to a stiffness gradient in their local microenvironment. While durotaxis has been characterized primarily in cells of mesenchymal origin, its role in cancer biology has not been clearly defined. At a cellular and molecular level, evidence suggests cancer cells sense and respond to the stiffening tumor microenvironment in a manner that promotes malignant and invasive characteristics. Given the gradual stiffening of tumors, it is interesting to speculate how durotaxis might contribute to cell flux to and from primary tumors and metastatic sites. We hypothesize that a durotactic mechanism may, in part, contribute to the dissemination of cancer cells into the stiffened microenvironment associated with primary tumors and also possibly with pre-metastatic sites. To directly characterize the impact of local stiffness on directional migration, cancer cells were cultured on a hydrogel possessing a stiffness gradient, then imaged by time-lapse microscopy and tracked using custom automated tracking software. Automated cell tracking allows for unbiased, accurate, and high-speed generation of large migratory datasets not feasible with conventional manual tracking and enables more robust analysis of cell populations. Preliminary data reveal that multiple cancer cell lines respond to a stiffness gradient with directed migration towards the stiffer part of the gel. The strength of the directional migratory response to stiffness gradients was found to depend on the magnitude of stiffness a cell encounters. By manipulating stiffness gradients to accurately reflect stiffness encountered by cancer subtypes, we will better understand if a durotactic mechanism has a global or cancer-specific impact on disease progression. Citation Format: Brian J. DuChez, Kenneth M. Yamada. Evaluating the role of durotactic migration in the tumor microenvironment. [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 5061.
Abstract 1559: CCR5-CCRL2 regulates CCL5-induced organ specific metastasis: thein vitroandin vivostudies
Authors: Chia-Ling Hsieh, Che-Ming Liu, Shian-Ying Sung
Journal: Cancer Research (2016)

Abstract Previous studies of soluble factors in the tumor associated stromal cells demonstrated the elevation of CCL5 expression in prostate cancer patient sera that correlated wit malignant cancer progression. To evaluate the expression level of chemokine receptors in response to chemokines released by reactive stroma, quantitative PCR to evaluate the mRNA level of chemokine receptors was performed. We noticed the significant increased of CCRL2 (86-fold) and CXCR4 (45-fold) in androgen independent prostate cancer (AIPC) cells. This increased of CCRL2 expression also confirmed in malignant lung, breast and rental cells. Knockdown of CCRL2 declined 75% of migration activities induced by CCL5, suggests CCRL2 involve in CCL5 induce cancer migratory activities (t-test, p&amp;lt;0.001). IHC analysis of CCRL2 in paired prostate cancer patients was performed and revealed increasing of CCRL2 expression in malignant prostate cancer locus, whereas no CCRL2 can be detected in the benign region of same patient. Proximity ligation assays (PLAs) of benign, high grade tumor and tissues collected from patients less than 5-year survive demonstrated the PLA signals only in the lethal progression on patients. In vivo xenograft mice model studies demonstrated the organ specific cancer metastasis can be enhanced after overexpressed CCRL2 in cancer cells. Molecular analysis of CCRL2 demonstrated that CCRL2 regulated EZH2 expression in prostate cancer cells. In summary, out studies indicated the increased expression of CCRL2 play a central role in cancer cell migration induced by chemokine CCL5. The released of CCL5, secreted by bone stromal cells after interaction with dormancy cancer cell, may induce directional migration and invasion of circulating cancer cells. Clinical analyses demonstrated increased of CCRL2 in malignant prostate cancer. Inhibition of these homing mechanisms might significantly decreased cancer cell metastatic activities of AIPC patients. Citation Format: Chia-Ling Hsieh, Che-Ming Liu, Shian-Ying Sung. CCR5-CCRL2 regulates CCL5-induced organ specific metastasis: the in vitro and in vivo studies. [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 1559.
ATPS-89LOCAL DELIVERY OF A SMALL-MOLECULE INHIBITOR OF HYPOXIA INDUCIBLE FACTOR-1: A NEW CANDIDATE DRUG FOR BRAIN TUMOR THERAPY
Authors: Antonella Mangraviti, Tula Raghavan, Francesco Volpin, Nicolas Skuli, Jinyuan Zhou, Charles Eberhart, Fausto Rodriguez, Eric Sankey, David Gullotti, Ann Liu, Yuan Wang, Destiny Schriefer, Henry Brem, Alessandro Olivi, Betty Tyler
Journal: Neuro-Oncology (2015)

This work investigated the efficacy of intracranial delivery of acriflavine (ACF), a small-molecule hypoxia-inducible factor 1α (HIF-1α) therapeutic inhibitor, for the treatment of primary brain malignancies. ACF, a mixture of two closely related acridine molecules, has only recently been recognized as a potent hypoxia-inducible factor 1α (HIF-1α) inhibitor, but has already demonstrated highly effective anti-tumor activity against a wide spectrum of cancers. Thus far, no study has reported its efficacy in either glioma cell lines or brain tumor models. In our in vitro study on rodent and human glioma cell lines, we showed that ACF suppressed cell viability and increased cell death in a dose-dependent manner. Our in vivo study examined the safety and efficacy of locally delivered ACF in monotherapy. To overcome ACF's poor systemic bioavailability and limited BBB penetration, we delivered ACF directly to the site of the tumor via biodegradable polymer wafers. Throughout three separate experiments, enrolling a total of 60 F334 Fisher rats, we showed that animals receiving local implantation of ACF wafers achieved an extraordinary 100% survival rate of up to 300 days (p <0.0001 vs. controls and 0.0002 vs. a Temozolomide-treated positive control), whereas the systemic administration of ACF provided no survival benefit compared to the control. Neuropathological examination at 120 days, as well as neuroimaging follow-up using MRI, confirmed tumor growth arrest in animals treated with ACF wafers, as opposed to progressive tumor growth in both untreated animals and animals treated with empty wafers. This is the first study to describe the extraordinary potential of ACF for the treatment of brain tumors as well as the effectiveness of interstitial local therapy via biodegradable polymer wafers for the use of ACF for brain tumor therapy.
Abstract 3105A: Titanium(IV) regulation by serum transferrin and citrate sheds new insight into the use of chemical transferrin mimetics for Ti(IV) anticancer drug development
Authors: Arthur D. Tinoco, Sergio A. Loza-Rosas, Alexandra Vazquez, Kennett I. Rivero, Lenny M. Negron, Manoj Saxena, Shweta Sharma, Yamixa Delgado, Annelis Sanchez, Nicole Zambrana, Timothy B. Parks
Journal: Cancer Research (2016)

Abstract A recently resolved structure of Ti(IV) bound human serum transferrin (sTf) and cell viability studies reveal that the small molecule citrate and the iron(III) transport protein sTf work together to maintain Ti(IV) in a nontoxic speciation in the body. Identification of this biomolecular interaction elucidates important factors that must be considered when developing Ti(IV)-based anticancer agents. Chemical transferrin mimetic (cTfm) ligands are being employed in a Ti(IV) anticancer drug design strategy to take advantage of the structural features of the sTf metal binding site favorable for Ti(IV) coordination to facilitate Ti(IV) cytotoxicity. The very strong Fe(III) binding property of these ligands are exploited to create stable Ti(IV) complexes that are able to deliver Ti(IV) into cells but exhibit lability in the presence of Fe(III). These complexes are intended to operate by the dual function of iron depletion and Ti(IV) attack at intracellular sites. Work with the cTfm ligands N,N’-di(o-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) and deferasirox reveal the structural features of the cTfm ligands that maximize the stability of the Ti(IV) complex outside the cell but enable sufficient lability to trigger cytotoxicity within the cell. The features are those that minimize induced dissociation due to the presence of citrate and sTf. Preliminary results suggest that while Fe(III) depletion may play an important role in the activity of the Ti(IV) cTfm complexes, the two lead complexes may operate via different mechanisms of action. Citation Format: Arthur D. Tinoco, Sergio A. Loza-Rosas, Alexandra Vazquez, Kennett I. Rivero, Lenny M. Negron, Manoj Saxena, Shweta Sharma, Yamixa Delgado, Annelis Sanchez, Nicole Zambrana, Timothy B. Parks. Titanium(IV) regulation by serum transferrin and citrate sheds new insight into the use of chemical transferrin mimetics for Ti(IV) anticancer drug development. [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 3105A.
Chimeric Antigen Receptor T Cells Directed Against CD19 Induce Durable Responses and Transient Cytokine Release Syndrome in Relapsed, Refractory CLL and ALL
Authors: David L Porter, Stephan A. Grupp, Michael Kalos, Alison W. Loren, Lester Lledo, Joan Gilmore, Michael C Milone, Anne Chew, Bruce L. Levine, Carl H. June
Journal: Blood (2012)
The intraductal injection of 5-fluorouracil for breast cancer: Preventive effect and immune response.
Authors: Tsuyoshi Mori, Satoshi Wada, Kelly Olino, Barish H Edil, Drew M. Pardoll, Richard D. Schulick, Saraswati Sukumar, Kiyoshi Yoshimura
Journal: Journal of Clinical Oncology (2012)

e13559 Background: Chemotherapy has been shown to act as an immune response modifier. Many groups are using chemotherapy to induce immune responses such as by using low doses of cyclophosphamide. Building up on our previous work (Murata et al., 2006, Stearns et al., 2011), we demonstrate that intraductal (i.duc), but not the intravenous (IV) route of injection of chemotherapy to HER2/neu transgenic mouse mammary glands (MMG) alters the tumor environment to effectively induce immune effector cells. Methods: 1.Tumor-free survival: 5-fluorouracil (5FU) was administered intraductally to the MMGs on the left side of mice; the MMG on right side were untreated. 2. FACS analysis: 20w mice were administered 5FU 2 times in a 4 week interval i.duc only to the left side, IV, or no treatment (NT). At week 5, the mice were sacrificed and the regional lymph nodes (RLN) and spleen were removed. Lymphocytes from RLN and spleen were analyzed. 3. Tumor re-challenge: GT8 cancer cells were injected into the one side of 4th mammary gland fat pad of 12 week mice. The mice were then injected i.duc with 5-FU to all teats in the tumor implanted side, or IV or given NT. The surviving mice were re-challenged with GT8 cancer cells into the ipsilateral 3rd mammary gland fat pad, 4 weeks after the first inoculation. Results: 1. The tumor incidence in the 5FU treated side after 16 weeks was significantly lower (13% of 70 glands) compared to mice that received NT (34% of 150, p=0.001), and IV (28% of 70, p=0.03). The tumor incidence in the untreated side of 5FU-treated mice was also significantly lower (18% of 70) compared to the NT (p=0.01). 2. The number of CD8 T cell showed no change among the groups in the RLN but was significantly lower (p=0.01) in the spleen of the i.duc. The number of CD62L LOW+ T cell in treated side of RLN was significantly higher compared to the IV (p=0.02) and NT (p=0.02). The number of CD62L LOW+ was low in the spleen. 3. The survivors in the group previously treated with i.duc 5-FU were able to achieve a lasting rejection of the tumor re-challenge when compared to mice who previously received 5-FU IV. Conclusions: I.duc administration of 5FU into MMG effectively induced immune effector cells and prevented mammary tumor growth in HER2/neu transgenic mice.