tbuckley/cabot-search huggingface dataset:
142. Evolution of Cell-Specific RNA Aptamers Against Glioblastoma Cancer Stem Cells Via Live Cell-Based SELEX
Authors: Jiehua Zhou, Qi Cui, Yanhong Shi, John J. Rossi
Journal: Molecular Therapy (2015)

Glioblastoma (GBM) is the most prevalent and lethal primary brain tumour and ranks among the most lethal of all cancers. The median survival time is only 12 to 15 months despite surgical resection followed by radio- and chemotherapy. Cancer stem cells (CSCs), also called self-renewing tumour-initiating cells (TICs), represent a malignant subpopulation of cells in hierarchically organized tumours. GBM CSCs are thought to be portion of glioblastoma cells that are responsible for both cellular invasion and therapeutics resistance, indicating the need for therapies that kill these cells and for imaging reagents that can identify them in vivo. Although several surface CSCs markers have shown their promise in glioblastoma to prospectively enrich or deplete CSCs, their uses were limited by a shared antigen with normal stem cells. Novel biomarkers that specifically recognize CSCs are highly desired. Therefore, developing a cell-type specific aptamers that prospectively identify GBM CSCs may not only serve as a platform for the development of novel targeted therapies and imaging reagents, but also permit the discovery of novel biomarkers for GBM CSCs. Additionally, we reasoned that a combinatorial use of various nucleic acids such as small interfering RNAs (siRNAs) and aptamers could be more efficacious in suppressing tumour growth through specifically targeting to GBM CSCs. In the present study, by combining the "Live Cell-based SELEX" strategy with high throughput sequencing (HTS) technology and bioinformatics analysis, we successfully identified several 2'-Fluoropyrimidine modified RNA aptamers targeted to Glioblastoma cancer stem cells. One of the best candidates (S-2 aptamer) specifically bound and was efficiently internalized into Glioblastoma cancer stem cells. Our efforts demonstrate that the cell-specific, internalizing RNA aptamers offer great promise for cell-type- or tissue-specific delivery and imaging reagents for targeted treatment of glioblastoma. We are presently investigating the ligand recognized by the aptamer.
Experiences and perspectives on the journey of the patient with gastrointestinal stromal tumors (GIST).
Authors: L. A. Sirulnik, C. M. Bender, N. J. Macdonald, M. Paolantonio, A. Shapiro, J. Coombs
Journal: Journal of Clinical Oncology (2011)

e19619 Background: The tyrosine kinase inhibitor (TKI) imatinib (IM) has improved outcomes for adult pts with KIT+ unresectable and/or metastatic GIST, and for adult pts receiving adjuvant therapy following resection of GIST. This qualitative study explored the experiences and emotions of pts through GIST diagnosis, treatment initiation, disease control, loss of response, and therapy switch. Methods: Ethnographic investigations were conducted, including semi-structured qualitative interviews of pts with resected or advanced GIST, and their caregivers, from Canada (n=15); US (n=10); and Brazil, Spain, and Russia (n=5 for each). Week-long photojournals were also kept by interviewees. Captured data were qualitatively analyzed to assess the perceptions and attitudes of pts about their disease and therapy (adjuvant or primary), and to identify gaps where communication about disease, treatments, and adherence would be most effective. Results: Patients shared common emotions and experiences for each stage of disease management, which we define as crisis, hope, adaptation, new normal, and uncertainty. Pts felt a sense of crisis during diagnosis, followed by hope associated with the start of TKI therapy. Over time, they came to adapt to their new lives (new normal) with a chronic cancer. With each follow-up imaging scan, pts confronted the uncertainty of becoming TKI resistant and the possible need to switch therapy. During uncertainty many GIST pts increased their interest, and sought current information regarding GIST. Disease progression and subsequent drug switching caused pts to revert back to crisis and restart the journey. Pts with either resected or advanced GIST shared similar journeys, especially with regard to uncertainty, although differences in the scope and timing of phases were observed. Strategies patients used to adhere to therapy included family member support, setting alarm clocks, taking medicine at routine times, and storing medicine in prominent places. Conclusions: Along the GIST pt journey, physicians can manage pt expectations, encourage adherence, and optimize outcomes. Pt education about current GIST developments and adherence may be especially beneficial during uncertainty.
Molecular and clinicopathologic characteristics of HER2-mutant lung adenocarcinoma (ADC).
Authors: M. E. Arcila, J. E. Chaft, K. Nafa, M. G. Kris, M. F. Zakowski, M. Ladanyi
Journal: Journal of Clinical Oncology (2011)

10596 Background: Activating mutations within the tyrosine kinase domain of HER2 have been reported in a small subset of lung ADCs. HER2 mutations are mutually exclusive with EGFR and KRAS mutations and are associated with increased sensitivity to specific kinase inhibitors in preclinical models. To date, the frequency, molecular, and clinicopathologic characteristics of HER2 mutant lung ADC in the US have not been well defined. Methods: Consecutive clinical cases of lung ADC (n=419) known to be negative for mutations in EGFR (exons 19-21) and KRAS (codons 12-13) were selected based on DNA availability. HER2 mutation analysis was done by fragment analysis for small indels in exon 20 and a Sequenom assay panel for the most common point mutations. A subset of tumors (n=245) was tested for ALK fusions by FISH. Results: HER2 mutations were present in 4.8% (20/419) of lung ADCs. Nineteen (95%) were exon 20 insertions and 1 (5%) was a point mutation (L755S). None of the 16 HER2-mutants tested by FISH harbored an ALK fusion. The incidence of HER2 mutations in the “triple negative” (EGFR/KRAS/ALK) group was 6.5% (16/245). Morphologically, 75% (15/20) were moderately (9) or poorly differentiated (6) ADCs of mixed phenotype. Two (10%) were well differentiated and 3 could not be graded due to small sampling. Eight tumors had a bronchoalveolar component and 2 had a mucinous component. The patients (65% female) had a median age of 56 at diagnosis (range 43-87); 8 patients presented with advanced disease; 12 patients were never smokers. The prevalence of HER2 mutations was significantly higher (p=0.0005) in never smokers (13.5%) than in current/former smokers (2.6%) but there was no significant difference between females (5.8%) and males (4.9%). Conclusions: HER2 mutations in lung ADCs are mutually exclusive with EGFR and KRAS mutations and ALK fusions. The clinical and pathologic features of HER2 mutant patients show similarities to EGFR mutant cases. While the overall prevalence of these mutations is low, estimated at 2.2% of all lung ADCs, testing of “triple negative” patients identifies HER2 mutations in 6.5%, thereby more efficiently screening for this subset of patients who could potentially benefit from alternate targeted therapies.
Candidemia-Induced Emergency Granulopoiesis Consists of Successive Dual Waves Triggered by the Shift From C/EBPalpha to C/EBPbeta Dependency.
Authors: Sakiko Satake, Hideyo Hirai, Nobuaki Shime, Rina Nagao, Ruriko Tanaka, Hisayuki Yao, Yoshihiro Hayashi, Eishi Ashihara, Tohru Inaba, Naohisa Fujita, Jiro Imanishi, Taira Maekawa
Journal: Blood (2010)
87. Towards Renal-Targeted Gene Delivery: Identification of Clades A, B, E and F Adeno-Associated Virus Sequences from Human Urine Samples
Authors: Claire Schreiber, Lemuel Hackshaw, Yasuhiro Ikeda
Journal: Molecular Therapy (2015)

Adeno-associated virus (AAV) vectors have been successful in gene therapy for a range of inherited and acquired diseases. However, the development of efficient AAV-based gene delivery systems to treat renal diseases is lagging behind, mainly due to the unavailability of highly kidney-tropic AAV serotypes. To identify novel AAV capsid mutants with a natural renal tropism, we tested human urine samples for the presence of AAV sequences. We treated a combination of 293T, HeLa and Vero cells with 93 individual clinical urine samples, followed by one day of infection with high titer adenovirus 5 for AAV expansion. The majority of samples, 69%, were positive for AAV DNA by capsid specific, N-terminus nested PCR. Out of these samples 63% were AAV2-like (Clade B), 27% AAV8-like (Clade E), 1.6% AAV1-like (Clade A) and 8.7% had chimeric cap sequences (Clades B-E, B-F, F-B-E, F-E and E-B hybrids). In characterizing the AAV rep-cap junction region from DNA samples that were not uniquely AAV2 cap positive, the sequences were most closely related to the following: AAV1 rep-AAV1 cap, AAV2 rep-AAV2cap, AAV9 rep-AAV9 cap and AAV2 rep-AAV8 cap. Analysis of full length capsid sequences from overlapping PCRs revealed AAV8-like sequences, AAV2-like sequences and chimeric sequences of AAV8, AAV9 and rhesus isolates. We have cloned these AAV variants into the pXR plasmid and are currently testing their tissue tropisms in vivo. This study is the first to report frequent detection of AAV sequences in human urine. AAV vectors with novel AAV capsid variants may accelerate renal-targeted AAV gene therapy applications.
Human Monoclonal Cryocrystalglobulinemia: First Complete Heavy and Light Chain Variable Region Nucleotide Sequences.
Authors: Vittorio Perfetti, Valentina Navazza, Sofia Giorgietti, Loredana Marchese, Giovanni Palladini, Roberto Caporali, Claudio Montecucco, Giampaolo Merlini
Journal: Blood (2004)
Two urologists conducted research without consent or ethics approval
Authors: Clare Dyer
Journal: BMJ (2016)

Two senior consultant urologists at St Bartholomew’s Hospital in London conducted research without obtaining patients’ permission or ethics committee approval, a medical practitioners tribunal has found.

Niels Buchholz and Junaid Masood should each have known that their work on percutaneous nephrolithotomy comparing outcomes in randomised patients constituted clinical research that required full consent, the tribunal concluded.

“When the randomisation process began through coin flipping, study 1 developed from being an audit into being research,” the tribunal’s chair, Sandra Sturdy, told Buchholz, imposing six months of conditions on his registration. “At this point you should have recognised the need to obtain ethics and research and development approval and patient consent.”

A PowerPoint presentation to the Royal Society of …
Evidence for a bacterial dysbiosis in pouchitis after restorative proctocolectomy using 16 S rRNA sequencing: Preliminary report of an ongoing study
Authors: S D McLaughlin, L Petrovska, A Walker, S K Clark, M W Johnson, P P Tekkis, J Parkhill, G Dougan, Paul Ciclitira, R Nicholls
Journal: Gut (2008)
Abstract B12: CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K
Authors: Michael James
Journal: Cancer Research (2016)

Abstract Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. Tumor cells must endure ER stress caused by microenvironmental, oxidative, energetic, and therapeutic stresses to survive. However, the role of ER stress survival signaling in pancreatic tumorigenesis has not been elucidated. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related target in pancreatic cancer. We recently demonstrated that CRR9/CLPTM1L is overexpressed in 90% of pancreatic ductal adenocarcinomas and associated with poor outcome, while it is not expressed in normal pancreatic ductal epithelium. Furthermore, we have shown that CLPTM1L can confer resistance to chemotherapeutic killing, apoptosis, and anoikis, and is critical for KRas transformation and tumorigenesis. Here, we demonstrate that CLPTM1L interacts with phosphoinositol-3-kinase (PI3K) and the ER stress protein Glucose Related Protein 78 (GRP78) at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt survival signaling. Surface accumulation of both CLPTM1L and GRP78 are induced by ER stress and by chemotherapy in vitro. Subsequent to our recent discovery of the presence of CLPTM1L at the cell surface, we have developed antibody inhibitors of CLPTM1L, which deplete chemotherapy-inducible surface accumulation of CLPTM1L and GRP78, as well as downstream survival signaling through the Akt pathway and Bcl-xL expression. These agents have shown striking anti-tumorigenic efficacy in preclinical models of pancreatic cancer and present a promising therapeutic and chemosensitization approach. Citation Format: Michael James.{Authors}. CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B12.
Allogeneic Hematopoietic Stem Cell Transplantation (Allo-SCT) Versus Conventional Postremission Therapy (PRT) for AML in First Complete Remission (CR1): A Matched Pairs Analysis Based on Data of the AML Cooperative Group (AMLCG) 1999 Trial.
Authors: Joachim Kienast, D.W. Beelen, H.J. Kolb, R. Schwerdtfeger, R. Arnold, A. Reichle, E. Holler, P. Staib, M.C. Sauerland, B. Berning, C. Schmid, M. Stelljes, W.E. Berdel, W. Hiddemann, T. Buchner
Journal: Blood (2007)
462. Serum Free Clinical Grade Large Scale Lentiviral Production System for Gene Therapy Application
Authors: Xin Yu, Mu Li, Xavier de Mollerat du Jeu
Journal: Molecular Therapy (2016)

Recently, lentiviral vectors have become the center of attention for its use as gene transfer vectors in gene therapy. Current new generation of therapies CAR - T requires the lentiviral vectors as efficient gene transfer tool to express engineered Chimeric Antigen Receptors (CAR) on the surface of the T-cells to recognize and kill the cancer cells. One problem of developing CAR T cell therapies is the high cost associated with lentiviral viral production. Therefore preclinical and clinical researchers have demanded their lentiviral production on a much larger scale, high-titer and in animal serum free medium. Current lentiviral production system use mainly adherent cells which need fetal bovine serum to support cell growth in flasks or cell factories, the system is suitable for research purpose at small scale, but not at large scale which requires large incubators and large cell culture vessels. Such system is hard to operator and requires more effort to produce large amount of LVVs, and increase the cost. We have developed a new lentiviral system to produce vectors in a serum free suspension platform and at very high titers. This technology employs a newly developed propriety set of GMP reagents comprising of a new media, new cells, new Transfection reagent and enhancers. With this new system we are able to deliver >5×10^8 (TU/ml) of unconcentrated lentiviral vectors, which is at least 10 folds higher than any other published method of lentiviral production. In this report, we will describe the methods and DOE experiments that we used to identify this new suite of reagent and their application in the immune cell therapy field.
Abstract 4669: Druggable oncogene fusions in lung invasive mucinous adenocarcinoma
Authors: Takashi Nakaoku, Koji Tsuta, Hitoshi Ichikawa, Kouya Shiraishi, Hiromi Sakamoto, Masato Enari, Koh Furuta, Yoko Shimada, Hideaki Ogiwara, Shun-ichi Watanabe, Hiroshi Nokihara, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Young Hak Kim, Michiaki Mishima, Jun Yokota, Teruhiko Yoshida, Takashi Kohno
Journal: Cancer Research (2015)

Abstract Invasive mucinous adenocarcinoma (IMA) of lung, a subtype of lung adenocarcinoma, is known to be strongly associated with KRAS mutation. Genetic aberration is unknown in IMA without KRAS mutation. From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations, we conducted whole-transcriptome sequencing on 32 IMAs, including 27 cases without KRAS mutation. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1 (NRG1 fusions: 6/90), EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. The CD74-NRG1 and SLC3A2-NRG1 fusion proteins contained the transmembrane domain of CD74 and SLC3A2 and retained the EGF-like domain of the NRG1 protein (NRG1 III-β3 form). Membrane-tethered EGF-like domain might activate juxtacrine signaling through HER2:HER3 receptors. To reveal the mechanism of the oncogenicity, exposing EFM-19 cells which express HER2 and HER3 to conditioned media from H1299 cells expressing exogenous CD74-NRG1 fusion protein resulted in phosphorylation of HER2 and HER3, and downstream mitogen-activated kinase and AKT. The phosphorylation was suppressed by lapatinib and afatinib. When EZR-ERBB4 or TRIM24-BRAF cDNA was exogenously expressed in NIH3T3 cells, ERBB4 or downstream mediator of BRAF was phosphorylated under serum-free condition. The expression of fusion genes induced anchorage-independent growth. The phosphorylation and growth were suppressed by the kinase inhibitors targeting fusion-induced signaling. These results show that the NRG1, ERBB4 and BRAF fusions are novel driver mutations and potential targets. About 15% (13/90; 14.4%) of IMAs harbor druggable aberrations, taken together a small fraction of known driver aberrations. Citation Format: Takashi Nakaoku, Koji Tsuta, Hitoshi Ichikawa, Kouya Shiraishi, Hiromi Sakamoto, Masato Enari, Koh Furuta, Yoko Shimada, Hideaki Ogiwara, Shun-ichi Watanabe, Hiroshi Nokihara, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Young Hak Kim, Michiaki Mishima, Jun Yokota, Teruhiko Yoshida, Takashi Kohno. Druggable oncogene fusions in lung invasive mucinous adenocarcinoma. [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 4669. doi:10.1158/1538-7445.AM2015-4669
The Effect of Rapamycin, 17-AAG and the Combination on the Bone Marrow Microenvironment in Multiple Myeloma (MM).
Authors: Lanie Francis, Judy Anderson, Michael Timm, Noriyoshi Kurihara, Ujjal Singha, Yazan Alsayed, Alissa Huston, Suzanne Lentzsch, G. David Roodman, Irene M. Ghobrial
Journal: Blood (2005)
Clinical and Outcomes Findings for Thrombotic Thrombocytopenic Purpura among 467 Persons with Severely Versus Not Severely Deficient ADAMTS-13 Levels.
Authors: Charles L. Bennett, Thanh Ha Luu, Anaadriana Zakarija, Hau C. Kwaan, Nicholas Bandarenko, Dilip K. Pandey, John F. Cursio, June M. McKoy, Charlie Buffie, Jeffrey L. Winters, Thomas L. Ortel, Ravindra Sarode, X. Long Zheng, Thomas J. Raife, Masanori Matsumoto, Yoshihiro Fujimura, Gail A. Rock
Journal: Blood (2007)
Validation of International Classification of Disease Ninth Revision codes for atopic dermatitis
Authors: D. Y. Hsu, P. Dalal, K. A. Sable, N. Voruganti, B. Nardone, D. P. West, J. I. Silverberg
Journal: Allergy (2016)

Evaluation of large-scale data sets is needed to better understand the epidemiology, cost, and burden of atopic dermatitis (AD). We sought to validate the use of ICD-9-CM codes for identifying AD.Patients from a large metropolitan quaternary care medical center with a diagnostic code of either 691.8 (AD) or 692.9 (eczema and contact dermatitis) were queried. Medical records were reviewed for demographics, Hanifin & Rajka (H&R) and United Kingdom Working Party (UKWP) criteria. Sensitivity, specificity, and positive predictive values (PPV) of the codes were calculated.Of 43 278 patients identified with associated ICD-9 codes of 691.8 or 692.9, 519 and 253 with 691.8 and 692.9 were randomly selected for chart review. There was extensive overlap: 34.3% had ≥1 occurrences of 691.8 and 692.9 and 25.6% had multiple occurrences of both codes. Among patients with ≥1 occurrence of 691.8, 29.9% and 30.8% met the H&R and UKWP criteria, respectively. Similarly, among patients with ≥1 occurrence of 692.9, 33.7% and 32.2% met the H&R and UKWP criteria. Increased PPV was associated with concomitant diagnoses of asthma, hay fever, and food allergy and increased disease severity.In the outpatient setting, the ICD-9-CM codes 691.8 and 692.9 alone have poor PPV. Incorporation of diagnoses of asthma, hay fever, and food allergy improves PPV and specificity. In the inpatient setting, a primary discharge diagnosis of 691.8 had excellent PPV. Although ICD-10 has been adopted in Europe and more recently in the USA, the same systematic errors would likely occur unless providers standardize their coding.
Intraocular Hemorrhages and Retinopathy of Prematurity in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study
Authors: Ebenezer Daniel, Gui-shuang Ying, R. Michael Siatkowski, Wei Pan, Eli Smith, Graham E. Quinn
Journal: Ophthalmology (2016)
Abstract 3367: BMP-6 regulates expression of androgen receptor via NF-κB signaling pathway and activated macrophages
Authors: Emma Wilcox, Seok Joo Kwon, Geun Taek Lee, Isaac Yi Kim
Journal: Cancer Research (2015)

Abstract Prostate cancer (CaP) is the most common non-cutaneous cancer among men in the United States (US). Recent report estimated that around 233,000 new CaP cases will be occurred in 2014 and about 29,480 men will be death because of CaP in the US. Despite recent progress in CaP treatment, metastatic CaP patients still have a poor prognosis due to the inevitable emergence of castration resistant prostate cancer (CRPC). It has been reported that androgen hypersensitivity and tumor microenvironment were critical factors for developing CRPC. In the present study, we investigate the role of BMP-6 on androgen hypersensitivity in the context of macrophages. Initially, we co-cultured androgen responsive murine CaP cell lines TRAMP-C1 and PTEN-CaP8 with RAW 264.7 murine macrophage cell lines and treated with BMP-6. We found that androgen receptor (AR) expression was increased in both cell lines by treatment of BMP-6 and BAY 11-7082 NF-κB inhibitor neutralized this augmentation. The result indicates that NF-κB signaling pathway is involved in up-regulation of AR in CaP cells. To find which NF-κB is activated, we analyzed NF-κB signaling pathway with immunoblot and found that canonical NF-κB pathway was activated in CaP cells. Cytokines such as IL-6 and TNF-α are potential inducer of NF-κB signaling pathway and these cytokines were up-regulated in RAW cells in our co-culture system. Based on these observations, we suggest that BMP-6 potentially regulates expression of AR in CaP cells via activated macrophages and canonical NF-κB pathway. Citation Format: Emma Wilcox, Seok Joo Kwon, Geun Taek Lee, Isaac Yi Kim. BMP-6 regulates expression of androgen receptor via NF-κB signaling pathway and activated macrophages. [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 3367. doi:10.1158/1538-7445.AM2015-3367