tbuckley/cabot-search huggingface dataset:
Abstract 4957: Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer
Authors: Maria Schwaederle, Gregory A. Daniels, David E. Piccioni, Paul T. Fanta, Richard B. Schwab, Kelly A. Shimabukuro, Barbara A. Parker, Razelle Kurzrock
Journal: Cancer Research (2015)

Abstract Next generation sequencing is advancing at a breathtaking pace, and is transforming patient care by allowing physicians to customize and match treatment to their patients’ tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We retrospectively reviewed the clinicopathologic and clinical outcomes of 392 patients for whom molecular testing had been performed. Potential associations between clinical characteristics and outcome parameters (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) were examined. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P&amp;lt;0.0001), PTEN (P&amp;lt;0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer. Citation Format: Maria Schwaederle, Gregory A. Daniels, David E. Piccioni, Paul T. Fanta, Richard B. Schwab, Kelly A. Shimabukuro, Barbara A. Parker, Razelle Kurzrock. Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with 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 4957. doi:10.1158/1538-7445.AM2015-4957
140. Non-SELEX Bead-Based X-Aptamer Selection
Authors: Curtis H. Lam, Nancy E. Ward, Johnnie Englehardt
Journal: Molecular Therapy (2015)

Aptamers are typically found using an in vitro selection technique known as systematic evolution of ligands by exponential enrichment (SELEX). This process involves multiple repetitive rounds of partitioning and enzymatic amplification. Due to the limited chemical diversity of nucleic acids, especially when compared to proteins, numerous SELEX experiments have been performed with modified nucleotides in an effort to enhance aptamer-target interactions. These experiments have been successful; however, the use of nucleic acid modifications during SELEX is rather limited. Each modified nucleotide that is used in SELEX must be a compatible substrate for polymerases and will completely replace its unmodified equivalent. Herein, a one-round, bead-based aptamer selection process will be described that eliminates enzymatic amplification of candidate oligonucleotides. Due to the solid phase synthesis of the libraries, this selection process is extraordinarily flexible in terms of what modifications can be used and how many of each modification is used. For example, one single bead-based library can include all of the R-groups of the twenty most common amino acids! The bead-based selection is accomplished using a simple and rapid two-stage process that can be completed within one week without the use of any specialized equipment. The first stage involves the magnetic pull-down of library beads with labeled target, and the second involves magnetic pull-down of the modified oligonucleotides released into solution from the selected beads. This two-stage selection can be carried out against several targets simultaneously. PCR is used to create unmodified DNA replicates (i.e., bar codes) of the selected modified sequences and next generation sequencing and bioinformatics analysis are performed to identify X-Aptamer candidates for resynthesis. In this manner, X-Aptamers routinely exhibiting nanomolar affinity have been successfully developed against a long list of targets that include P. falciparum LDH, HIV p24, osteoprotegerin, HSA, myotoxin as well as his-tag. The simplicity of X-Aptamer development has allowed the process to be packaged into a kit. This selection kit enables virtually any laboratory scientist to rapidly develop his or her own X-Aptamers. The kit contains a bead-based library and multiple bar-coded primers that allow for the use of up to three targets. The customer performs the two-stage selection and then PCR amplifies the selected material using unmodified nucleotides. The PCR product, which is comprised of unmodified DNA, is then sent to AM Biotech for sequencing. AM Biotech identifies the candidate X-Aptamers from the sequencing data, resynthesizes them with the appropriate modifications and sends the X-Aptamers to the customer for affinity validation. To date, β-tests of the selection kit have been very successful.
The potential of the human CD38-specific antibody daratumumab to improve the antimyeloma effect of novel multidrug therapies including patients refractory to lenalidomide or bortezomib.
Authors: T. Mutis, M. de Weers, M. S. van der Veer, B. v. Kessel, J. M. Bakker, S. Wittebol, P. Parren, H. M. Lokhorst
Journal: Journal of Clinical Oncology (2011)

e18571 Background: Multiple myeloma (MM) represents an incurable malignancy of antibody-producing clonal plasma cells. Over the past decade significant progress has been made in MM treatment using novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). Daratumumab (DARA) is a first-in-class human therapeutic CD38-specific antibody with a broad mechanism of action. DARA mediates MM cell death primarily via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. We are currently exploring the possibility to further improve MM therapy by combining novel MM therapeutics with DARA. Our initial in vitro work already showed significantly improved MM cell killing by combining DARA with LEN treatment. Methods: In ex vivo assays, which allow us to address killing of MM cells in bone marrow aspirates isolated from MM patients, we now investigated whether the addition of DARA to the LEN+BORT combination significantly exceeds the effectiveness of LEN+BORT treatment alone. DARA was also combined with two recently introduced triple combination therapies: LEN, BORT, dexamethasone (RVD) and melphalan, prednisone, BORT (MPV). Results: we demonstrate that the addition of DARA to the LEN+BORT combination significantly exceeds the effectiveness of LEN+BORT treatment alone (P<0.001). Strikingly, killing was most improved in treatment of patient samples which showed poor responses to the LEN-BORT combination. Notably, 5 of these samples were derived from patients who were refractory to BORT and/or LEN. In these samples DARA increased MM cell killing up to 50%. Furthemore, when DARA was combined with novel triple agent regimens RVD and MPV, it almost doubled MM cell killing especially in the low-dose range of these novel cocktails. Conclusions: Our results illustrate that treatment of MM with DARA in combination with novel multidrug therapies bears great promise.
Salvage Allogeneic Hematopoietic Cell Transplantation with Fludarabine and Total Body Irradiation (3 or 4 Gy) after Failure of First Allografts.
Authors: Boglarka Gyurkocza, Thai M. Cao, Rainer F. Storb, Thoralf Lange, Wendy Leisenring, Georg Franke, Mohamed L. Sorror, David G. Maloney, Judith Shizuru, Brenda M. Sandmaier
Journal: Blood (2008)
Anti-Leukemic Effect of Tetra-Arsenic Oxide in Acute Promyelocytic Leukemia Cells in Vitro and In Vivo
Authors: So Young Chong, Moon Ju Jang, Sun Ju Lee, Ji Young Huh, Jeehyeon Bae, Kwang-Hoe Chung, Doyeon Oh, Hau C. Kwaan
Journal: Blood (2011)
Merkel-Cell Polyomavirus Is Rarely Associated to B-Chronic Lymphocytic Leukemia and Occurs Late in the Natural History of the Disease
Authors: Manola Comar, Antonio Cuneo, Rosa Rinaldi, Iva Maestri, Elisabetta Melloni, Olga Soffritti, Paola Secchiero, Mitja Nabergoj, Giorgio Zauli, Gabriele Pozzato
Journal: Blood (2012)
Nanoparticle-based ultra-sensitive assay for discovery and evaluation of cancer markers.
Authors: Y. P. Bao, R. Beal, R. Khan, W. Gibbons
Journal: Journal of Clinical Oncology (2011)

e21169 Background: Our aim was to develop ultra-sensitive nanoparticle based assay for discovery of new cancer markers and evaluation of diagnostic applications. Methods: The nanoparticle probe based assay format uses a multi-step deterministic robotic process, which relies on non-isotropically oriented antibodies on functionalized glass as multiplexed microarrays to capture protein or DNA markers from biological samples. Functionalized, 130 angstrom diameter gold-probes also bind to the markers through a molecular-scale complex containing antibodies or DNA hybridization. The marker-bound molecular complex is then quantified through silver enhancement of the functionalized gold. Results: We have demonstrated the feasibility for the detection of cancer markers including NQO1, uteroglobin, CLC-5, uroplakin, RSOR, p53, CA125, AFP, HE4, CA15-3, CA19-9, beta-hCG, CEA, and PSA. The high sensitivity (e.g., PSA LOD <0.1pg/mL, uteroglobin LOD <10pg/mL) and broad dynamic range were demonstrated by target titrations in both buffer and serum samples. The clinical application has been explored by testing 288 bladder cancer serum samples, 144 kidney cancer samples, and over 500 PSA serum samples. Conclusions: The ultra-sensitive gold nano-particle probe-based tumor marker assay could provide a powerful tool for evaluating novel tumor markers, validation and clinical applications, including early diagnosis.
2-Methoxyestradiol Sensitizes B-NHL Cells to TRAIL-Mediated Apoptosis Via Inhibition of HIF-1α, NF-κ B, YY1 and Induction of DR5 Expression.
Authors: Sara Huerta-Yepez, Mario I. Vega, Stavroula Baritaki, Eriko Suzuki, Theresa La Vallee, Benjamin Bonavida
Journal: Blood (2006)
586. Development of Anti-Angiogenic miRNA Therapeutics for Corneal Neovascularization
Authors: Yi Lu, Shaoyong Li, Jianzhong Ai, Dominic J. Gessler, Xun Xu, Guangping Gao
Journal: Molecular Therapy (2015)

GG and XX are co-corresponding authors Corneal diseases are the second major cause of blindness worldwide. Corneal neovascularization (CNV) is one of the most common pathological processes in corneal diseases, leading to vision loss or even blindness in patients. However, even though different treatments for CNV are available in clinic, a safe and effective therapy remains to be an unmet medical challenge. MicroRNAs (miRNAs) play roles in regulating more than half of all protein-coding genes in mammals including those involved with angiogenesis. Therefore, modulating expression of angiogenesis-related miRNAs might be an effective approach for treating this blindness-causing corneal lesion. To this end, we first tested four angiogenesis-related miRNAs (i. e. miR-126, miR-10, miR-17a and miR-92) for their role in angiogenesis in vitro by assessing cell proliferation and tube formation of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) transfected with the plasmid constructs overexpressing the pri-miRNAs or Tough Decoy (Tud) RNAs inhibitory to the corresponding target miRNAs. We found that TuD-miR-10b, pri-miR-17a and pri-miR-92 were significantly inhibitory for the cell proliferation and tube formation of HUVECs, while TuD-miR-126-5p could impede HUVEC tube formation but not proliferation. Our data reveal that miR-126 and miR-10 are pro-angiogenic regulators, whereas miR-17a and miR-92 are negative regulators of angiogenesis, suggesting the feasibility of using miRNA as therapeutic targets to modulate angiogenesis in CNV. We next set out to identify more target miRNAs that play roles in CNV. To date, there has been no report on miRNA expression profile of CNV. Using Nanostring technologies and the classic alkali-burn induced CNV mouse model, we profiled small RNAs prepared from the corneal tissues harvested from the study mice before and days 5, 10 and 15 after alkali injury for expression levels of 618 mouse miRNAs. We found 35 up-regulated and 3 down-regulated miRNAs in the mouse neovascularized corneas. Currently, we are in the process of confirming expression profiles of those candidate target miRNAs by qRT-PCR. For proof-of-concept, we proposed to use rAAV vector for efficient delivery of those pri-miRNAs or their corresponding Tud RNAs to the corneas of alkali-burn induced CNV mice and evaluate their potency in preventing or treating CNV. To this end, we first assessed several serotypes of rAAV EGFP for gene transfer efficiency in mouse corneas after delivery by ectopic eye drops, or intrastromal or subconjunctival injections to identify the most efficient AAV serotype and method of delivery for miRNA therapeutics. The results of those experiments will be presented. In sum, our study has great clinical relevance; miRNA-targeted novel therapeutics that can be delivered as either rAAV or synthetic nucleic acid drugs (i. e. miRNA mimics and antagomir) might offer an additional clinical option for treating CNV.
Predictors and Prognostic Implications of Incident Heart Failure in Patients With Prevalent Atrial Fibrillation
Authors: Ambarish Pandey, Sunghee Kim, Curtiss Moore, Laine Thomas, Bernard Gersh, Larry A. Allen, Peter R. Kowey, Kenneth W. Mahaffey, Elaine Hylek, Eric D. Peterson, Jonathan P. Piccini, Gregg C. Fonarow
Journal: JACC Heart Failure (2016)
PTH-068 Development of nurse led paracentesis service
Authors: K J Caddick, A D Dhanda, P L Collins, F H Gordon, A C McCune, A J Portal
Journal: Gut (2010)

<h3>Introduction</h3> Patients (Pts) with chronic liver disease who have refractory or diuretic resistant ascites require regular paracentesis. Previously this resulted in urgent admission via the medical take leading to inconvenience for the patient and additional work for the admitting team. Pts admitted for paracentesis had an average length of stay of 6.4 days. The Hepatology Nurse Specialist (HCNS)-lead outpatient (OP) paracentesis service was initiated in November 2007 which intended to reduce the frequency of hospital admissions for ascites drainage and the length of stay as an inpatient. The service aims to improve the Pts9 quality of life and to reduce healthcare associated infection. We report the outcome of the first 2 years of the service. <h3>Methods</h3> Pts are referred to the HCNS from the Hepatology ward, or consultant clinics. The HCNS initiates regular Pt contact to monitor blood tests and weight. On admission HCNS reviews the Pt and their blood results. The amount of ascites drained is recorded ensuring frequency of drainage is optimised. It is possible for two-three Pts to access OP paracentesis service each week, which is planned to fit around Pts9 commitments. Following drainage HCNS remains in contact with Pts to establishing a pattern of drainage planned 2–3 months in advance giving Pts control over admissions, preventing adhoc admissions via A&amp;E. <h3>Results</h3> 18 Patients on the hepatology OP paracentesis database; 16 analysed (2 unavailable) 95 paracentesis admissions over 18 mths since service initiation; 73.6% Pts used the outpatient paracentesis service and remained an inpatient for 8 h; 26.3% were admitted as inpatients due to decompensation. The mean time interval between drains was 22 days. Average 8500 mls drained per episode. Disease progression required some hospital admissions, as Pts became more unwell requiring interventions or palliation not offered by the OP paracentesis service or community care. Adhoc emergency admissions required longer admission and caused distress. Planned paracentesis allowed Pts to have control of their admissions. Pts are at lower risk of hospital-acquired infection. Pts and families felt supported by the service, being rapidly able to access assessment and assistance from HCNS. 70 admissions were avoided by having a daycase procedure. Admissions to the ward increased with disease progression. <h3>Conclusion</h3> Our nurse-led OP paracentesis service avoided 70 hospital admissions over a 2-year period and reduced Pts stay in hospital from an average of 6.4 days to 8 h. Regular large volume paracentesis was successful. Planned admissions are more acceptable for both Pts and staff. Service flexibility gives the Pts more control of their admissions and improves their quality of life.
Abstract 151: Transcriptome-wide expression profiling of long noncoding and small nucleolar RNAs in head and neck squamous cell carcinomas identifies novel transcripts associated with survival
Authors: Thomas K. Honda, Angela Zou, Vicky Yu, Hao Zheng, Selena Kuo, Maarouf Saad, Yinan Xuan, Pranav Singh, Jessica Wang-Rodriguez, Weg M. Ongkeko
Journal: Cancer Research (2015)

Abstract Head and neck squamous cell carcinoma (HNSCC) persists as one of the most common and deadly malignancies, with early detection and effective treatment still posing formidable challenges. To expand our currently sparse knowledge of the epigenetic alterations involved in this disease and identify potential biomarkers and therapeutic targets, we globally profiled the dysregulation of small nucleolar (snoRNA) and long non-coding RNAs (lncRNA) in head and neck tumors. Using next-generation RNA-sequencing data from 40 pairs of tumor and matched normal tissues, we profiled lncRNA expression by mapping each RNA-seq library to a reference annotation containing 32,108 lncRNAs. Using edgeR, we found 19,681 lncRNA transcripts significantly differentially expressed by a fold change magnitude ≥ 4 with a false discovery rate &amp;lt;10-4. We selected the 10 most dysregulated lncRNAs and further confirmed the dysregulation of these lncRNAs in-vitro by performing quantitative reverse transcriptase PCR (RT-qPCR) on two normal oral epithelial cell lines and five HNSCC cell lines. Using Kaplan-Meier analysis, we demonstrated a correlation between high expression of several lncRNAs, including JPH1-7, upregulated by 40-fold in HNSCC, with overall poor survival in a cohort of over 400 HNSCC patients (HR = 1.62, p &amp;lt; 0.01). Meanwhile, RNA-sequencing analysis of 31 tumor-normal pairs yielded 33 significantly dysregulated snoRNA. We identified one snoRNA, SNORD116-20, downregulated by 4-fold in HNSCC, whose expression levels correlated significantly with overall patient survival (HR = 1.64, p &amp;lt; 0.05), suggesting its functional significance and clinical relevance in head and neck cancer pathogenesis. Similarly, in in-vitro experiments, we found reduced expression of this snoRNA in HNSCC cell lines compared to normal oral epithelial cell lines. The precise molecular roles of these transcripts identified warrants further characterization, but our data suggest that they are likely to play substantial roles in head and neck cancer pathogenesis and are significantly associated with patient survival. Note: This abstract was not presented at the meeting. Citation Format: Thomas K. Honda, Angela Zou, Vicky Yu, Hao Zheng, Selena Kuo, Maarouf Saad, Yinan Xuan, Pranav Singh, Jessica Wang-Rodriguez, Weg M. Ongkeko. Transcriptome-wide expression profiling of long noncoding and small nucleolar RNAs in head and neck squamous cell carcinomas identifies novel transcripts associated with survival. [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 151. doi:10.1158/1538-7445.AM2015-151
Abstract 4036: Palmitoylated Ras-driven MAPK signaling, transformation and tumorigenesis, but not tumor progression, are spatially regulated by plasma membrane microdomains
Authors: James Michael, Jeremy G.T. Wurtzel, Lawrence E. Goldfinger
Journal: Cancer Research (2015)

Abstract In this study, we assessed the contributions of plasma membrane (PM) microdomain targeting to the functions of H-Ras and paralogue R-Ras. Activated H-Ras is a mitogen which can drive tumorigenesis through Raf activation, while R-Ras is weakly mitogenic and does not induce the MAPK pathway in cells, despite binding Raf in vitro. These paralogues have identical effector-binding regions, but variant C-terminal targeting domains (tDs). Ras tDs are responsible for lateral distribution within PM microdomains as a result of distinct lipid modifications: activated H-Ras targets to lipid ordered/disordered (Lo/Ld) domain borders, whereas active R-Ras is sequestered in Lo domains (rafts). We hypothesize that PM segregation regulates effector interactions and downstream signaling. We used tD swap mutants, and assessed effects on MAPK pathway activation, cell proliferation, transformation, and tumorigenesis. Activated R-Ras harboring the H-Ras tD (R-Ras-tH), stably expressed in NIH3T3 fibroblasts, interacted with Raf and induced MEK and ERK phosphorylation. Furthermore, R-Ras-tH stimulated cell growth, and supported anchorage-independent growth in soft agar, indicating induction of a transformed phenotype in vitro. Conversely, stable transfectants of H-Ras harboring the R-Ras tD (H-Ras-tR) had reduced MEK and ERK phosphorylation, cell growth, and colony formation in soft agar compared with H-Ras cells. Thus, Ras access to Raf at the PM is a critical step for Ras mitogenic signaling. However, tumor progression driven by these cells in xenografts in mice did not match in vitro phenotypes. R-Ras-expressing cells produced few solid tumors, while R-Ras-tH cells produced relatively larger, but size-limited, avascular tumors with a higher frequency per xenograft. Surprisingly, both H-Ras and H-Ras-tR xenografts produced large and heavily vascularized tumors, implicating an important role of Ras in modulating tumor angiogenesis in this model. Indeed, the conditioned media (secretome) of R-Ras-expressing cells did not support endothelial cell cord formation in growth factor-reduced Matrigel, while the secretome from H-Ras cells robustly induced cord formation; these effects were independent of Ras microdomain localization. Thus, targeting Ras to the Lo/Ld border is sufficient to initiate tumor formation, however, a tD-independent angiogenic effect is required for progression of Ras-induced tumors. Citation Format: James Michael, Jeremy G.T. Wurtzel, Lawrence E. Goldfinger. Palmitoylated Ras-driven MAPK signaling, transformation and tumorigenesis, but not tumor progression, are spatially regulated by plasma membrane microdomains. [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 4036. doi:10.1158/1538-7445.AM2015-4036