tbuckley/cabot-search huggingface dataset:
219. Investigation of the Role of Decorin Gene (DCN) in Glioblastoma and Cancer Stem Cells (CSCs)
Authors: Jun-Ming Han, Hsin-I Ma
Journal: Molecular Therapy (2016)

Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors.
New Insights Into Autoimmune Hemolytic Anemia of children : A French National Observational study of 268 Children.
Authors: Nathalie Aladjidi, Thierry Leblanc, Guy Leverger, Marie Quitterie Picat, Gerard Michel, Brigitte Bader-Meunier, Yves Bertrand, Alain Fischer, Genevieve Chene, Yves Perel
Journal: Blood (2009)
Stem Cell Transplantation: Impact of High Efficiency Particulate Air (HEPA) vs. Non-HEPA BMT Unit on Transplant Outcome: A Single Centre Experience from India.
Authors: Velu Nair, Ajay Sharma, Deepak K. Mishra, Gurvinder S. Chopra, J. Kotwal, Mohan B. Agarwal, N. K. Bhandari, Ramji Rai
Journal: Blood (2005)
Abstract 2394: Cancer-associated fibroblasts in invasive lobular breast carcinoma
Authors: Mirjam C. Boelens, Ellen Wientjens, Eva Schut, Sjoerd Klarenbeek, Karin E. de Visser, Jos Jonkers
Journal: Cancer Research (2015)

Abstract Cancer-associated fibroblasts (CAFs) can promote breast cancer progression and therapy response through paracrine and juxtacrine signaling pathways. CAFs are abundantly observed in especially the invasive lobular carcinoma (ILC) subtype of breast cancer. Surprisingly, there is nothing known about the function of these CAFs in ILC. Given the fact that human ILC is generally resistant to standard chemotherapy, we believe that the cause of this therapy resistance lies into the active crosstalk between CAFs and tumor cells leading to a more progressive and resistant phenotype. Therefore, we aim to discover the exact function of CAFs in ILC as well as their drugable targets. In order to reliably study the role of CAFs in ILC, we generated a genetically engineered mouse model for ILC based on the tissue-specific loss of E-cadherin and PI3K signaling pathway activation, two hallmarks of human ILC. This clinically relevant mouse model spontaneously developed tumors that grow as typically invasive ‘indian files’ into a rigid extracellular matrix (ECM) that is very rich of CAFs. Uniquely, these tumors closely resemble human classical ILC, including its growth rate. Based on a mammary gland transplantation setting using fluorescent labeled hosts, we have shown that fibroblasts are recruited by ILC, both in vivo and in vitro, suggesting ILC-secreted mediators. Interestingly, in vitro inhibition of PDGFRβ (expressed by fibroblasts) can at least in part inhibit this recruitment. We are currently investigating whether inhibition of PDGFRβ in vivo can prevent the recruitment of fibroblasts and subsequently tumor development or progression. In parallel, we have isolated fibroblasts and epithelial cells from primary mouse ILCs and wild-type mammary glands to screen for other important players in the tumor-stroma crosstalk using RNA-seq and secretome proteomics. We will subsequently assess their functional significance during ILC development, progression and therapy response. Citation Format: Mirjam C. Boelens, Ellen Wientjens, Eva Schut, Sjoerd Klarenbeek, Karin E. de Visser, Jos Jonkers. Cancer-associated fibroblasts in invasive lobular breast carcinoma. [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 2394. doi:10.1158/1538-7445.AM2015-2394
Abstract 365: Mobilizing prostate cancer cells from the endosteal niche by targeting the SDF-1/CXCR4 axis
Authors: Kenneth C. Valkenburg, Kenneth J. Pienta
Journal: Cancer Research (2015)

Abstract Metastatic prostate cancer cells preferentially home to bone, and skeletal metastases are present in approximately 90% of patients upon autopsy. Our lab was the first to show that prostate cancer cells compete with hematopoietic stem cells (HSCs) for space within the endosteal niche. The HSC niche is located on the surface of endosteal osteoblasts, where HSCs are kept in a slow-cycling, protective state. The niche also provides prostate cancer cells with a chemoprotective environment in which they can remain dormant for an extended period of time, even decades. C-X-C chemokine receptor 4 (CXCR4) is required for HSC recruitment to the HSC niche. Osteoblasts secrete stromal cell derived factor 1 (SDF-1, also known as CXCL12), the ligand for CXCR4, which attracts HSCs to the niche via a chemotactic gradient. CXCR4 is also expressed by disseminated prostate cancer cells and is required for prostate cancer cells homing to bone. HSCs can be mobilized from the niche into the bloodstream physiologically via infection or stress and pharmacologically via proteins like granulocyte-colony stimulating factor (G-CSF) or small molecule inhibitors like AMD3100 (plerixafor). AMD3100, which antagonizes CXCR4, is capable of mobilizing both HSCs and prostate cancer cells from the niche. When combined with AMD3100, docetaxel (the standard of care for prostate cancer) is more effective at killing tumor cells than when given as a single agent. This indicates that mobilization of disseminated tumor cells (DTCs) from the endosteal niche by targeting the SDF-1/CXCR4 axis might cause these cells to be more sensitive to chemotherapy in patients. This strategy would theoretically kill DTCs, which, when they become metastatic lesions, lead to most of the morbidity and mortality that affects prostate cancer patients. We are engaged in a Phase 0 clinical trial in metastatic prostate cancer patients to test this strategy in human patients. To complement the human trial, we are testing several CXCR4 inhibitors combined with G-CSF and docetaxel. We are able to detect CTCs in human patients, as well as CTCs and DTCs in mice via several techniques, and will use this technology as a readout for the clinical trial, as well as the preclinical studies. Citation Format: Kenneth C. Valkenburg, Kenneth J. Pienta. Mobilizing prostate cancer cells from the endosteal niche by targeting the SDF-1/CXCR4 axis. [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 365. doi:10.1158/1538-7445.AM2015-365
Abstract 726: Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer
Authors: Hirotaka Kanzaki, Nishit Makhopadhya, Xiaojiang Cui, Krishnan V. Ramanujan, Tatsuaki Takeda, Yoshihisa Kitamura, Toshiaki Sendo, Ramachandran Murali
Journal: Cancer Research (2015)

Abstract [Purpose] Luminal B breast cancer patients are significantly at the risk of relapse with in 5 years. Acquired resistance to the receptor tyrosine kinase HER2 targeting antibody trastuzumab is a major clinical problem in the treatment of recurrent HER2-positive breast cancer. The molecular mechanisms leading to trastuzumab resistance (TZR) remain unclear in luminal B breast cancer. Here, we investigated the mechanism of TZR in HER2-positive luminal B breast cancer cells with acquired resistance. [Methods and Results] We generated trastuzumab resistant breast cancer cell line (BT-474-R) by treating BT-474 cells with trastuzumab for over long-term. Initial validation showed that HER2 overexpression in the BT-474-R cells remained unaltered suggesting that probably HER2 independent signaling pathway is involved in the development of TZR. We demonstrated that NF-κB is constitutively activated in the BT-474-R cells by quantitative realtime RT-PCR, western blotting and immunofluorescent microscopy. Expression of pro-inflammatory cytokines were also demonstrated. Pharmacologic inhibition of NF-κB improved sensitivity to trastuzumab in BT-474-R cells. We identified both IKK-α and IKK-β as the major determinants of the activation of the NF-κB signaling in the resistant cells. [Conclusion] Our study suggests by activating NF-κB pathway, luminal B cells may facilitate acquiring basal-like, Her2+ phenotype a notion consistent with “progression through grade” hypothesis. Finally, our study suggests that blocking NF-κB will provide a new treatment option to limit relapse in HER2 positive breast cancer patients treated with trastuzumab. Citation Format: Hirotaka Kanzaki, Nishit Makhopadhya, Xiaojiang Cui, Krishnan V. Ramanujan, Tatsuaki Takeda, Yoshihisa Kitamura, Toshiaki Sendo, Ramachandran Murali. Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer. [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 726. doi:10.1158/1538-7445.AM2015-726
Dendritic cell vaccination in melanoma patients: Update and subgroup analysis of clinical response to post-vaccine treatment
Authors: L. Ridolfi, L. Fiammenghi, M. Petrini, A. M. Granato, V. Ancarani, E. Pancisi, L. Valmorri, A. Riccobon, R. Ridolfi
Journal: Journal of Clinical Oncology (2009)

9042 Background: Dendritic cells (DCs) play a crucial role in the interplay between innate and adaptive immune response towards cancer. The combination of immunotherapies with standard treatments for cancer could represent a further chance for advanced melanoma patients. In the literature, higher response rates than those normally obtained have been reported after second-line chemotherapy in patients with non small cell lung cancer pre-treated with vaccines and in patients with follicular B-cell lymphoma vaccinated with an anti-idiotype vaccine whilst in remission. On the basis of this data, we reviewed and updated the clinical results of our dendritic cell based vaccine clinical trial in stage IV melanoma patients. Methods: From December 2002 to 2007, 24 pre-treated metastatic melanoma patients were vaccinated with mature DCs (mDCs) pulsed with autologous tumor lysate (ATL) and keyhole limpet hemocyanin (KLH) followed by a 5-day treatment with low-dose subcutaneous Interleukin-2. Results: We observed 2 complete response (CR), 2 mixed response (MR), 5 partial response (PR), 4 stable disease (SD) and 11 progressive disease (PD) (overall response (OS) 37.5%; clinical benefit 54.1%). All 13 responders had delayed-type hypersensitivity (DTH) positivity to KLH, of whom 10 also showed positivity to the lysate. Eleven (45.8%) of the 24 patients underwent further lines of treatment (5 chemotherapy [CT], 3 surgery [S], 4 biotherapy, 2 radiotherapy [RT] and 4 biochemotherapy [BioCT]) after stopping vaccination (8 due to progression and 3, in SD, because all of their lysate had been used). Of these 11 patients, 2 obtained CR (1 RT, 1 S), 5 PR (3 BioCT, 2 S) for an OR of 63.6%, 1 SD (BioCT) and 3 showed PD as the best response to subsequent therapies, with a median OS of 30 months (range 16–52). Of the 3 SD patients who were forced to stop vaccine treatment, 1 had CR following RT and 2 progressed. Conclusions: Metastatic melanoma responds poorly to standard therapy, in particular after first-line treatment. Vaccination could enhance clinical response to subsequent third- or fourth-line therapies, thus prolonging overall survival. No significant financial relationships to disclose.
677. Evaluation of Tumor Specific Promoters for Use in Conditionally Replicating Adenovirus Mediated Virotherapy of Canine Lymphoma
Authors: Abdul Mohin Sajib, Samantha Morici, Maninder Sandey, Payal Agarwal, Bruce Smith
Journal: Molecular Therapy (2016)

Conditionally Replicating Adenoviruses (CRAds) are genetically modified therapeutic viruses that incorporates transcriptional targeting of replication to promote selective killing of tumor cells. Transcriptional targeting utilizes tissue/tumor-specific promoters driving the expression of genes in a tissue- or tumor-specific manner to allow replication of the virus in tumor cells while sparing normal cells. Selection of appropriate intermediate animal models is a basic-requirement for successful cancer virotherapy. The dog is an outstanding animal model of cancer and other complex human diseases. The outbred nature of the dog, the heterogeneity of their tumors, their genomic similarity to humans and similar disease causation, progression and pathology support the use of this animal model. Previous studies have shown high levels of expression of several promoters, including human telomerase reverse transcriptase (hTERT), survivin, chemokine receptor 4 (CXCR4) and progression elevated gene 3 (PEG3) in a variety of human cancers and murine models. The exogenous promoter PEG3 from rats has not only shown tumor-specificity in the human model, but has also shown pan-tumor properties with active transcription occurring in almost all tumor cells. None of these promoters have been tested for their potential as a transcriptional targeting tool for canine cancers. Non-Hodgkin lymphoma accounts for 83% of all hematopoietic cancer and 6 % of all malignancies in the dog. Resistance to current treatments has emerged as a critical challenge for lymphoma treatment due to the presence of genetic diversity among tumor cells. These studies explore tumor-specific activity of these promoters with the goal of identifying a suitable canine lymphoma specific promoter to generate transcriptionally targeted CRAds facilitating viral replication in canine lymphoma, but not in normal cells. In this regard, a GFP reporter gene driven by the rat PEG3 promoter was evaluated for activity after transfection into canine lymphoma cells as well as normal canine cells. The activity of the endogenous canine promoters CXCR4, cTERT, and cSurvivin were examined using quantitative reverse transcriptase PCR. Results showed negligible expression differences between normal and lymphoma cells for cTERT and PEG3 whereas cSurvivin and cCXCR4 showed markedly higher expression in tumor cells when compared with most normal cells and tissues. However, cCXCR4 also showed a high level of expression in normal peripheral blood mononuclear cells (PBMC) cells. In contrast, cSurvivin showed increased expression in canine lymphoma cells, along with other canine tumors, with reduced expression in normal canine cells/tissues and canine PBMCs. These findings will be used to generate a canine lymphoma specific CRAd.
Reducing Bias in Academic Search Committees
Authors: Michael T. Railey, Kenyon M. Railey, Paul J. Hauptman
Journal: JAMA (2016)

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Cyclophosphamide and Fludarabine Conditioning Chemotherapy Induces a Key Homeostatic Cytokine Profile in Patients Prior to CAR T Cell Therapy
Authors: Adrian Bot, John M. Rossi, Yizhou Jiang, Lynn Navale, Yueh-wei Shen, Marika Sherman, Armen Mardiros, Sean C. Yoder, William Y. Go, Steven A. Rosenberg, Jeff Wiezorek, David D. Chang, James N. Kochenderfer, Margo R. Roberts
Journal: Blood (2015)
Abstract 5509: A drug-screening model to identify compounds active in cells under metabolic stress
Authors: Paola Pellegrini, Martin Haraldsson, Annika Jenmalm Jensen, Thomas Lundbäck, Angelo De Milito
Journal: Cancer Research (2015)

Abstract Background and aim: Promising anticancer compounds often fail in vivo due to lack of efficacy. Drug screenings to identify anticancer agents are usually performed in culture conditions that very poorly represent the complex metabolic tumor environment. Tumor tissues are characterised by low oxygen (hypoxia) and acidic extracellular pH (acidosis). A screen of a drug-library for compounds able to induce cell death in acidic/hypoxic conditions may lead to discover effective drugs targeting quiescent/hypoxic cells, normally considered responsible for tumor relapses after therapy. Methods: The colon carcinoma cell line HCT-116 has been adapted to grow in low pH conditions (pH 6.8). The Prestwick compound library (1200 FDA-approved compounds) was used to validate the assay. Cell viability was measured using the acid phosphatase assay after 48 hours exposure to test compounds. The assay was validated in HCT-116 cells cultured in normoxic and hypoxic conditions. Multicellular spheroids (MCS) were used to evaluate the sensitivity to hit compounds confirmed at least three times in 2D culture conditions. Results: The assay was optimized to perform the screening at pH 6.8 in normoxic and hypoxic conditions. Experiments have demonstrated the ability of cells to survive and grow in hypoxic conditions (1% oxygen) for at least 4 days. The test was optimized in terms of number of plated cells and serum concentration. Hit compounds were identified based on the mean values for quality control plus 3 standard deviations of untreated samples. The screen led to identify 20 hits for both conditions and 11 hits were further confirmed for hypoxic/acidic conditions. Auranofin and Verteporfin showed to better induce cell death in cells adapted or acutely exposed to low pH compared to parental cells and immortalized epithelial cells (RPE1). Both drugs showed cytotoxic effects on cells grown as MCS, suggesting a potential good efficacy of the therapeutic agent in vivo. In addition, the screening of about 10000 compounds of the LCBKI library is ongoing and about 100 hits have been identified. Conclusions: The screening validation on the Prestwick library will hopefully lead to identify potential “off-label” effects of already approved drugs. The screening of larger drug-libraries will hopefully lead to find and characterize more compounds able to target slow proliferating and therapy resistant cells. Citation Format: Paola Pellegrini, Martin Haraldsson, Annika Jenmalm Jensen, Thomas Lundbäck, Angelo De Milito. A drug-screening model to identify compounds active in cells under metabolic stress. [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 5509. doi:10.1158/1538-7445.AM2015-5509
Post-Transplant Platelet Recovery Kinetics and Its Association with Overall Survival in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
Authors: Jie Li, Jillian Alyse Deppa, Zahir Ali, Michael Graiser, Amelia Langston, Charise Gleason, Jessica Thomas, Edmund K Waller
Journal: Blood (2011)
Abstract 11017: Renin Inhibition Reduces Atherosclerotic Plaque Neovessel Formation and Regresses Advanced Atherosclerotic Plaques
Authors: Hongxian WU, Xian Wu Cheng, Lina Hu, Chang-Ning Hao, Mutsuharu Hayashi, Kyosuke Takeshita, Mohammad Shoaib Hamrah, Guo-Ping Shi, Masafumi Kuzuya, Toyoaki Murohara
Journal: Circulation (2014)

Background: The interaction between the renin-angiotensin system and toll-like receptors (TLRs) in the pathogenesis of advanced atherosclerotic plaques is not well understood. We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient (ApoE –/– ) mice with a special focus on plaque neovessel formation. Methods and Results: Four-wk-old ApoE –/– mice were fed a high-fat diet for 8 wks, and the mice were randomly assigned to one of three groups and administered a vehicle, hydralazine, or aliskiren for an additional 12 wks. Aliskiren reduced the atherosclerotic plaque area and plaque neovessel density. It increased the plaque collagen and elastin contents, and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S (CatS) protein. Aliskiren also decreased the levels of AT1R, gp91phox, TLR2, monocyte chemotactic protein-1, and CatS mRNAs in the aortic roots. Hydralazine had no beneficial vascular effects, although its administration resulted in the same degree of blood pressure reduction as aliskiren. CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE –/– mice, but aliskiren showed no further benefits in ApoE –/– CatS –/– mice. In vitro , CatS mRNA expressions were induced by angiotensin II, and TLR2 silencing reduced CatS mRNA expression. Moreover, the genetic inhibition of CatS impaired the endothelial cell angiogenic action in vitro and ex vivo . Conclusion: Renin inhibition appears to inhibit advanced plaque neovessel formation in ApoE –/– mice and to decrease the vascular inflammatory action and extracellular matrix degradation, partly by reducing AT1R/TLR2-mediated CatS activation and activity, thus regressing advanced atherosclerotic plaques.
Report of a Phase1/2 Study of 5-Azacitidine and Cytarabine in Patients with Relapsed, Refractory Acute Myelogenous Leukemia.
Authors: Gautam Borthakur, Hagop Kantarjian, Susan O’Brien, Farhad Ravandi, Charles Koller, Zeev Estrov, Ritva Torma, Jean-Pierre Issa
Journal: Blood (2007)