tbuckley/cabot-search huggingface dataset:
Sequence-Modified Antibiotic Resistance Genes Provide Sustained Plasmid-Mediated Transgene Expression in Mammals
Authors: Jiamiao Lu, Feijie Zhang, Andrew Z. Fire, Mark A. Kay
Journal: Molecular Therapy (2017)

Conventional plasmid vectors are incapable of achieving sustained levels of transgene expression in vivo even in quiescent mammalian tissues because the transgene expression cassette is silenced. Transcriptional silencing results from the presence of the bacterial plasmid backbone or virtually any DNA sequence of >1 kb in length placed outside of the expression cassette. Here, we show that transcriptional silencing can be substantially forestalled by increasing the An/Tn sequence composition in the plasmid bacterial backbone. Increasing numbers of An/Tn sequences increased sustained transcription of both backbone sequences and adjacent expression cassettes. In order to recapitulate these expression profiles in compact and portable plasmid DNA backbones, we engineered the standard kanamycin or ampicillin antibiotic resistance genes, optimizing the number of An/Tn sequence without altering the encoded amino acids. The resulting vector backbones yield sustained transgene expression from mouse liver, providing generic DNA vectors capable of sustained transgene expression without additional genes or mammalian regulatory elements.
Abstract 4858: Cloud-based variant analysis solution using control-accessed sequencing data
Authors: Chunlin Xiao, Eugene Yaschenko, Stephen Sherry
Journal: Cancer Research (2015)

Abstract Variation analysis plays an important role in elucidating the causes of various human diseases. The drastically reduced costs of genome sequencing driven by next generation sequence technologies now make it possible to analyze genetic variations with hundreds or thousands of samples simultaneously, but currently with the cost of ever increasing local storage requirements. The tera- and peta-byte scale footprint for sequence data imposes significant technical challenges for data management and analysis, including the tasks of collection, storage, transfer, sharing, and privacy protection. Currently, each analysis group facing these analysis tasks must download all the relevant sequence data into a local file system before variation analysis is initiated. This heavy-weight transaction not only slows down the pace of the analysis, but also creates financial burdens for researchers due to the cost of hardware and time required to transfer the data over typical academic internet connections. To overcome such limitations and explore the feasibility of analyzing control-accessed sequencing data in cloud environment while maintaining data privacy and security, here we introduce a cloud-based analysis framework that facilitates variation analysis using direct access to the NCBI Sequence Read Archive through NCBI sratoolkit, which allows the users to programmatically access data housed within SRA with encryption and decryption capabilities and converts it from the SRA format to the desired format for data analysis. A customized machine image (swift) with preconfigured tools (including NCBI sratoolkit) and resources essential for variant analysis has been created for instantiating an EC2 instance or instance cluster on Amazon cloud. Performance of this framework has been evaluated and compared with that from traditional analysis pipeline, and security handling in cloud environment when dealing with control-accessed sequence data has been addressed. We demonstrate that it is cost effective to make variant calls using control-accessed SRA sequence data without first transferring the entire set of aligned sequence data into a local storage environment, thereby accelerating variation discovery using control-accessed sequencing data. Citation Format: Chunlin Xiao, Eugene Yaschenko, Stephen Sherry. Cloud-based variant analysis solution using control-accessed sequencing data. [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 4858. doi:10.1158/1538-7445.AM2015-4858
Survival after recurrence of medulloblastoma in the contemporary era.
Authors: C. Koschmann, K. L. Schmidt, J. R. Geyer, S. Leary
Journal: Journal of Clinical Oncology (2011)

2068 Background: Greater than 70% of patients diagnosed with medulloblastoma today are cured. However, salvage therapy after recurrence remains widely varied. Survival after recurrence of medulloblastoma has not been reported in an unselected cohort of patients in the contemporary era. Methods: With approval of the Institutional Review Board, medical records were reviewed for 55 patients diagnosed with medulloblastoma between 2000 and 2010, and treated at Seattle Children’s Hospital, the largest pediatric cancer center in the Pacific Northwest, with referrals from Washington, Alaska, Montana, Idaho and Wyoming. Forty-seven children over the age of three at initial diagnosis were considered for this analysis. The following variables were collected for patients diagnosed with recurrent or progressive disease: age at diagnosis, gender, stage, histology, time to relapse, site of relapse, treatment after relapse, and time to death or last contact. Survival was described according to the method of Kaplan and Meier and comparisons were made using the log rank test. Results: Fourteen of 47 patients (30%) experienced recurrent or progressive medulloblastoma. The median age at diagnosis was 9 years (range 5.8 to 15.9), and 71% (n=10) were male. Most patients had localized disease (M0, 78.6%), classic histology (78.6%) and gross total resection (92.9%) at initial diagnosis. The median time from diagnosis to recurrence was 18.0 months (range 3.6 – 62.6), and site of recurrence was metastatic in 86% (n=12). The median survival after relapse was 6.8 months (range 0.7 – 77.9); 3-year survival after relapse was 19%. There were trend associations between longer survival and having received additional chemotherapy (median survival 6.8 vs. 1.3 months, p = 0.06) and radiation therapy (15.4 vs. 4.4 months, p=0.13), but not research therapy (2.8 vs. 10.3 months, p =0.69.) Conclusions: Recurrence of medulloblastoma is much more likely to be metastatic than reported in previous eras. Within the limits of our small sample, our data suggest a potential survival benefit from re-treatment with cytotoxic chemotherapy and radiation even in heavily pre-treated patients. This report serves as a baseline against which to evaluate novel therapy combinations.
Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation
Authors: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, Edgardo Somigliana, Paola Viganò, Paolo Vercellini
Journal: European Urology (2016)
Abstract 360: Senescent hepatocytes secrete CCL2 to accelerate liver cancer growth via accumulation of immunosuppressive myeloid cells
Authors: Tobias Eggert, Juling Ji, Lars Zender, Xin Wei Wang, Tim F. Greten
Journal: Cancer Research (2015)

Abstract Aim: Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce the immune-mediated clearance of these senescent cells, preventing malignant transformation and tumor initiation; a process termed ‘senescence surveillance’. However, senescent hepatocytes can give rise to hepatocellular carcinomas (HCC), if additional oncogenic mutations, e.g. p53 mutation, abrogate the senescence program. We set out to investigate the effect of senescent cell secreted cytokines on growth of neighboring liver tumor cells. Experimental procedure: To induce senescence in mouse livers, we hydrodynamically injected a transposon system, which encodes for either oncogenic Nras (NrasG12V) or an effector loop mutant (NrasG12V/D38A) that is incapable of signaling to downstream pathways, into C57BL/6 or CCR2-/- mice. To achieve tumor development in senescent livers, hepatocellular carcinoma cells were intrasplenically injected into mice, which expressed either NrasG12V or NrasG12V/D38A in the liver. Hepatic immune cell infiltrates were analyzed using flow cytometry and immunohistochemistry. Immunosuppressive ability of CD11b+Gr1+ myeloid cells was analyzed in vitro after fluorescence-activated cell sorting. Furthermore, peritumor tissue of 226 HCC patients was hierarchical clustered based on the expression of 35 senescence-associated genes. Senescence-associated gene signature was then compared with CCL2 expression and survival. Results: Senescent hepatocytes promoted growth of hepatocellular carcinoma cells through accumulation of immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ cells inhibited T cell proliferation via an iNOS-dependent mechanism. Immunosuppressive myeloid cell accumulation as well as tumor growth promotion was abrogated, when senescence was induced in livers of CCR2 knockout mice, indicating a pivotal role for CCL2 in creating a tumor promoting immune environment. Finally, gene expression analysis in patients with hepatocellular carcinoma confirmed the association of senescence-induced CCL2 expression in peritumor tissue and poor prognosis. Conclusion: Senescent hepatocytes not only induce an inflammatory response that leads to their own clearance, preventing tumor initiation, but surprisingly also induce the accumulation of immunosuppressive myeloid cells that promote growth of neighboring hepatocellular carcinomas. Citation Format: Tobias Eggert, Juling Ji, Lars Zender, Xin Wei Wang, Tim F. Greten. Senescent hepatocytes secrete CCL2 to accelerate liver cancer growth via accumulation of immunosuppressive myeloid 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 360. doi:10.1158/1538-7445.AM2015-360
Targeting Cyclin D1 in the Treatment of Multiple Myeloma: Preclinical Validation of a Novel Specific Small Molecule Cyclin D1 Inhibitor, P276-00.
Authors: Noopur Raje, Teru Hideshima, Sonia Vallet, Shweta Chhetri, Constantine Mitsiades, Melissa Rooney, Hiroshi Yasui, Tanyel Kiziltepe, Klaus Podar, Yutaka Okawa, Hiroshi Ikeda, Dharminder Chauhan, Nikhil C. Munshi, Somesh Sharma, Himanshu Parikh, Bruce Chabner, Kenneth C. Anderson
Journal: Blood (2006)
Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide
Authors: W. J. Maples, J. Stevenson, S. V. Sumrall, M. Naughton, J. Kauh, J. Schwartz
Journal: Journal of Clinical Oncology (2004)

4082 Background: Advances in treatment of metastatic pancreatic cancer remain challenging with median survivals reported in the 4–6 month range following standard gemcitabine chemotherapy. Thalidomide, which has immunomodulatory and anti-angiogenesis properties has shown promising results in malignant and non-malignant conditions. K-ras mutations, which are present in 90% of patients with pancreatic adenocarcinoma can result in overexpression of VEGF, making Thalidomide an agent to explore. Methods: Phase II trial of gemcitabine 1000mg/m2day 1,8,15 every 28 days, with thalidomide dose escalation from 200mg daily to maximum tolerated dose by 12 weeks. Objectives: RR, TTP, overall survival, clinical benefit response (CBR), tolerability. Results: 27 patients (24 metastatic/3 locally advanced) were treated between 12/01 and 11/03, median age 60 (range 41–76), 17 males/10 females, all with a KPS of ≥ 70%; 6 received prior radiation therapy. Average Thalidomide dose 320 mg (range 50–700 mg). Grade 3–5 toxicities noted in 23 patients: sepsis 2, pneumonia 1, syncope 2, GI bleed 1, DVT 2, neutropenia 11, thrombocytopenia 1, peripheral neuropathy 1, stroke 1, and depressed level of consciousness 4. Constipation ≤ grade 2 was common. There were 4 deaths during treatment. Median number of cycles given 3, with average 4.6 (range 1–17). Response: Of 21 evaluable patients, PR: 3, stable: 13, progressive disease: 5. CBR: 35% scored positive based on pain scale, KPS, and weight gain. Median survival: 183 days with average 232 days (range 37–635+ days); 9 of 27 evaluable patients survived > 6+ months, and 4 > one+ year. Median TTP: 112 days with average 146 days (range 13–518 days). A >50% reduction in CA 19–9 occurred in 55% of patients. Conclusions: Gemcitabine with thalidomide appears to be a promising combination in the treatment of advanced pancreatic adenocarcinoma with suggestion of improvement in TTP and CBR compared to historical data from single agent Gemcitabine. Further studies with gemcitabine and newer immunomodulatory agents are warranted. No significant financial relationships to disclose.
540. Vectofusin-1 Significantly Enhances Transduction of Ex-Vivo Activated T Cells With RD114-TR-Pseudotyped Lentiviral Vectors Derived from the RD3-MolPack Stable Packaging Cells
Authors: Virna Marin, Stefano Corna, Erica Giuliani, Cinzia Scavullo, Sergio Bossi, Claudio Bordignon, Anne Galy, Gian Paolo Rizzardi, David Fenard, Chiara Bovolenta
Journal: Molecular Therapy (2015)

Cell therapy with T cells genetically modified with lentiviral vectors (LVs) carrying therapeutic genes is growing as a promising tool for tumor treatment. Noticeably, the clinical production of these cells relies on the availability of either LVs, whose production is cumbersome from a safety, cost and reproducibility standpoint, or transduction enhancers to get optimal transduction rates. Development of LV packaging cells represents therefore an obliged goal in LV-based gene therapy, allowing reduction of the manufacturing cost and increasing the overall quality of the vectors. Similarly, the identification of the optimal transduction conditions is crucial. We investigated the efficiency of the recently described transduction enhancer Vectofusin-1® in promoting transduction of human ex-vivo activated T cells with a RD114-TR-pseudotyped SIN-GFP LV derived from MolMed's proprietary RD3-MolPack-SIN-GFP producer cells. Vectofusin-1® is an histidine-rich cationic amphipathic peptide that has been recently shown to increase LV gene transfer in hematopoietic stem cells without inducing toxicity through improvement of adhesion and fusion of LVs with the cellular membrane. Vectofusin-1® is easily synthetized, purified, and can be added to the viral supernatant without a pre-coating step, thus requiring less overall manipulation. RD3-MolPack-SIN-GFP was generated exploiting our RD-MolPack technology which is based on the RD114-TR envelope glycoprotein that, in contrast to the most utilized VSV-G envelope, permits generation of constitutive packaging cells for the production of SIN-LV. We selected a producer clone growing continuously in disposable two-compartment bioreactor for longer than 3 months and releasing LV with a titer, on average, of 1-5 × 106 TU/ml. Here, we show that the addition of Vectofusin-1® significantly improved RD3-MolPack-SIN-GFP LV transduction rate, without spinoculation, of either CD3/CD28 or OKT-3 activated T cells (70% GFP+) compared to the absence of adjuvant (6% GFP+) at MOI 1. The analysis of the vector copy number (VCN) integration confirmed these results (VCN=4 in the presence of Vectofusin-1® vs VCN=0.09 in the absence of Vectofusin-1®, respectively). When Vectofusin-1® was compared with Retronectin® and polybrene a similar effect was registered. No major differences in the immune phenotype and expansion rate were observed between cells transduced with Vectofusin-1® and cells transduced without any adjuvant. In summary, we conclude that combination of SIN-LV produced by RD3-MolPack cells and Vectofusin-1® might be considered for clinical manufacturing of LV-transduced T cells.
Abstract 343: The homeobox gene DLX4 promotes inflammatory signaling and peritoneal metastasis of ovarian cancer
Authors: Dhwani Haria, Bon Q. Trinh, Song Yi Ko, Nicolas Barengo, Honami Naora
Journal: Cancer Research (2015)

Abstract The lethality of ovarian cancer stems from the propensity of the disease to involve the peritoneal cavity. However, the mechanisms that drive peritoneal metastasis of ovarian cancer are poorly understood. We previously identified that high expression of the homeobox gene DLX4 in ovarian cancer is strongly associated with advanced disease stage and reduced survival. In this study, we identified that DLX4 stimulates the attachment of ovarian cancer cells to mesothelial cells that line the peritoneal cavity. DLX4 induced expression of the cell adhesion molecule CD44 which interacts with hyaluronic acid, a glycosaminoglycan that is produced by peritoneal mesothelial cells. Neutralization of CD44 abrogated the ability of DLX4 to stimulate tumor-mesothelial cell interactions. The induction of CD44 expression by DLX4 was found to be largely due to the ability of DLX4 to transcriptionally activate the gene encoding the pro-inflammatory cytokine interleukin-1beta (IL-1beta) which in turn stimulated the nuclear factor kappa B (NF-kB) signaling pathway. Furthermore, inhibition of IL-1beta or of NF-kB activity abrogated the stimulatory effect of DLX4 on tumor-mesothelial cell interactions. This study provides insights into the mechanisms of inflammatory signaling and peritoneal metastasis of ovarian cancer, and raises the possibility that targeting inflammatory signaling might be a strategy for treatment of advanced-stage ovarian cancer. Citation Format: Dhwani Haria, Bon Q. Trinh, Song Yi Ko, Nicolas Barengo, Honami Naora. The homeobox gene DLX4 promotes inflammatory signaling and peritoneal metastasis of ovarian 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 343. doi:10.1158/1538-7445.AM2015-343
Moving Average Of Immature Platelet Fraction Predict Late Platelet Engraftment After Reduced-Intensity Cord Blood Transplantation: A Single-Institutional Study
Authors: Kanichi Iwama, Jun Aoki, Noriyuki Tadera, Daisuke Sinoda, Kouichi Kaziwara, Hideki Kodo, Yasuzi Kouzai
Journal: Blood (2013)
Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO).
Authors: Andrea Borghese Apolo, Bernard Bochner, Seth M. Steinberg, Dean F. Bajorin, William Kevin Kelly, David I. Quinn, Nicholas J. Vogelzang, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2012)

298 Background: Neoadjuvant chemotherapy (NC) for the treatment of MIBC remains underutilized in the United States despite evidence supporting its use. The aim of this project is to examine the current management of MIBC by MO to move towards standardization of practice. Methods: An electronic 26 question survey was emailed to 92 MO belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology, and posted on the US Oncology portal for 8 wks. The study was approved by the Office of Management and Budget (0925-0046). Percentages are based on the fraction that responded to a given question. Results: Of the 83 respondents: 48% were non-academic. 51% were general oncologists and 45% focused on GU malignancies. The majority of MIBC referrals came from urologists (79%). Initial CT staging with abd/pelvis was required by 88%, CT chest by only 72% and PET by 21%. NC is offered by 79% of MO to all MIBC pts and by 45% to all pts with high grade upper tract urothelial carcinoma. Adjuvant chemotherapy (AC) was offered by 46% to all MIBC pts and by 41% to pts with upper tract disease. NC was not offered if ECOG performance status (PS) was &gt;3 (49%), in T2 disease without lymphovascular invasion (29%), or with GFR of &lt;50 ml/min (35%). Chemotherapy regimens used for NC included gemcitabine/cisplatin (90%); methotrexate/vinblastine/adriamycin/cisplatin (MVAC) (30%), dose dense MVAC (20%); gemcitabine/carboplatin (36%); single-agent gemcitabine (10%), other regimens described include carboplatin/paclitaxel and ifosfamide/doxorubicin/gemcitabine. Response to NC was assessed by CT abd/pelvis (82%), CT chest (39%), cystoscopy (30%) and PET (12%). Pts with pathologic residual disease (&gt;pT2 or positive LN) after NC were generally observed (74%). Conclusions: The majority of MO do offer perioperative chemotherapy for MIBC pts with a trend towards increased use of NC over AC, which follows best evidence. The main reason for not offering perioperative chemotherapy was poor PS. The majority offer cisplatin-based combination therapy by preference. Increasing the rate of referrals of MIBC pts to MO, will result in more pts receiving perioperative cisplatin-based chemotherapy and may lead to better outcomes in this disease.
Improved Outcome with Androgens as Maintenance Treatment in Elderly Patients with Acute Myeloid Leukemia after ICL Regimen as Induction Therapy: Results of the GOELAMS SA-2002 Multicenter Phase III Randomized Open Trial
Authors: Arnaud Pigneux, Chantal Himberlin, Mathilde Hunault-Berger, Francis Witz, Christian Recher, Jean-Luc Harousseau, Olivier Tournilhac, Christian Berthou, Martine Escoffre-Barbe, Denis Guyotat, Nathalie Fegueux, Martine Delain, Bruno Lioure, Eric Jourdan, Didier Bouscary, Laurence Legros, Noel Milpied, Frederic Bauduer, Frederic Perry, Isabelle Luquet, Marie-Christine Bene, Norbert Ifrah, Jean-Jacques Sotto, Philippe Guardiola
Journal: Blood (2008)