tbuckley/cabot-search huggingface dataset:
505. Treatment of DMD 5’ Mutations Through Two Different exon2 Skipping Strategies: Intramuscular Delivery of rAAV9.snRNA Mediated Skipping and Antisense Morpholino Oligomers
Authors: Tabatha R. Simmons, Nicolas Wein, Adeline Vulin-Chaffiol, Kristin Heller, Andrea Rutherford, Louise Rodino-Klapac, Kevin M. Flanigan
Journal: Molecular Therapy (2015)

To date, exon-skipping therapies for Duchenne muscular dystrophy (DMD) patients have focused on patients with out-of-frame exon deletions, in whom treatment results in larger but in-frame internal deletions which lead to translation of an internally truncated but partially functional dystrophin protein. We are developing exon-skipping therapies for exon duplication mutations, accounting for around 6% of all mutations, with the intent to induce production of wild-type transcripts and protein. As a model of the most common single exon duplication, we have developed a new mouse with a duplication of exon 2 (the Dup2 mouse) that largely recapitulates the findings in the standard mdx mouse. Using this mouse, we are testing both virally (AAV) mediated skipping induced by a modified U7snRNA (rAAV9.U7.ACCA), and antisense oligomer-induced skipping. Intramuscular injections of the tibialias anterior (TA) (N=6 muscles each) were performed rAAV9.U7.ACCA at 6 doses between 1×1010 and 1×1012 total vector genomes. Intramuscular (TA) injections of an exon 2-directed antisense peptide-morpholino conjugate (PPMO) were performed at doses of either 10 or 20 ug total PPMO (N=3 each). For each study, mice were sacrificed 1 month post injection and muscle analysis of DMD mRNA and dystrophin protein expression. Treatment with either modality results in significant skipping of the duplicated exon 2, and expression of a functional dystrophin isoform at levels of up to 30% of normal with AAV-mediated skipping. Physiology has been assessed in the AAV-treated mice, in which correction of TA absolute force deficits in comparison to the background Bl6 strain are seen, along with a partial yet significant correction of eccentric contraction injury in comparison to untreated Dup2 mice. These data suggest that skipping of a duplicated exon 2 may be a feasible therapeutic approach, particularly because skipping of exon 2 may be associated with an apparently unlimited therapeutic window. Over-skipping – to the exclusion of exon 2 entirely – results in activation of an internal ribosome entry site (IRES) located in exon 5 of dystrophin that allows for cap-independent translation from an alternative initiation site within exon 6. This alternate dystrophin isoform is highly functional despite being N-truncated, consistent with the observation that patients expressing it have minimally symptomatic (or even asymptomatic) Becker muscular dystrophy (BMD), and suggesting a potential route to therapy for any of the approximately 5% of patients with mutations in the 5' end of the gene.
Abstract 879: Menopausal hormone therapy and risk of primary liver cancer in the UK Clinical Practice Research Datalink
Authors: Katherine A. McGlynn, Katrina Hagberg, Jie Chen, Susan Jick, Vikrant V. Sahasrabuddhe
Journal: Cancer Research (2015)

Abstract Background: The incidence of primary liver cancer (PLC) is three to four times higher among males than females in almost all countries. The discrepancy in rates is particularly notable prior to menopause, suggesting that estrogen exposure may be associated with lower risk. The relationship of menopausal hormone therapy (MHT) use to risk of PLC among women, however, has not been extensively examined. Methods: We conducted a nested case-control study among women in the U.K.'s Clinical Practice Research Datalink (CPRD). Women diagnosed with primary liver cancer (n = 339) between 1988 and 2011 were matched to controls at a 4:1 ratio on age, index year, general practice and length of history in the CPRD. Odds ratios (OR) and 95% confidence intervals (95%CI) for associations of MHT with PLC were estimated using conditional logistic regression. All models were conditioned on the matching factors and adjusted for body mass index, HBV, HCV, smoking, alcohol-related disorders, diabetes, rare metabolic disorders, history of a bilateral oophorectomy, and use of certain medications, including paracetamol, aspirin, anti-diabetes therapies, and statins. Results: Use of MHT for 6 months or longer was associated with a significantly lower risk of PLC (OR = 0.60, 95%CI = 0.39-0.92). Examination by length of MHT use found that use between 6-30 months was associated with significantly reduced risk (OR = 0.47, 95%CI = 0.24-0.91), while use greater than 30 months did not attain statistical significance (OR = 0.68, 95%CI = 0.41-1.13). When MHT was stratified by formulation (estrogen-only vs estrogen/progesterone), estrogen-only use was associated with significantly lower risk of PLC (OR = 0.51, 95%CI = 0.26-0.97) while estrogen/progesterone use did not attain statistical significance (OR = 0.65, 95%CI = 0.39-1.08). Conclusion: MHT use, in particular estrogen-only MHT use, may be associated with lower risk of PLC. These findings are consistent with rodent models which have reported suppression of both fatty liver and hepatocarcinogenesis with administration of estrogen. As the association in the current study was apparent among users of 6-30 months, even short-term use of estrogen-only MHT may reduce risk. Citation Format: Katherine A. McGlynn, Katrina Hagberg, Jie Chen, Susan Jick, Vikrant V. Sahasrabuddhe. Menopausal hormone therapy and risk of primary liver cancer in the UK Clinical Practice Research Datalink. [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 879. doi:10.1158/1538-7445.AM2015-879
Acyl-Protein Thioesterase 1 Functions in Palmitoylation/Depalmitoylation Cycles of G Proteins and Regulates Platelet Activation
Authors: Louisa M. Dowal, James R. Dilks, Nathalie A. Fadel, Omozuanvbo R. Aisiku, Glenn Merrill-Skoloff, Robert C. Flaumenhaft
Journal: Blood (2012)
Abstract A1-15: Systematic genomic characterization of uveal melanoma
Authors: Chelsea S. Place, Ivana K. Kim, Bita Esmaeli, Ali Amin-Mansour, Daniel J. Treacy, Scott L. Carter, Eran Hodis, Nikhil Wagle, Sara Seepo, Xiaoxing Yu, Francisca Vazquez, Elizabeth Nickerson, Kristian Cibulskis, Aaron McKenna, Stacey B. Gabriel, Gad Getz, Eliezer M. Van Allen, Levi A. Garraway, Scott E. Woodman
Journal: Cancer Research (2015)

Abstract Uveal melanoma (UM) is a rare type of melanoma that occurs in the iris, ciliary body, and choroid of the eye. Metastatic disease is typically found in the liver and has no effective therapeutic options. To improve our understanding of the genetic drivers of UM, we sequenced the exome of 61 primary tumors and 3 liver metastases, each with matched normal DNA. Consistent with prior studies, the majority of UM tumors harbored mutually exclusive mutations in GNAQ and GNA11. Co-occurring with GNAQ and GNA11 mutations were inactivating mutations throughout the BAP1 coding region as well as recurrent mutations in the splicing factor SF3B1 and the translation initiation factor EIF1AX. Somatic mutations found only in metastatic tumor samples were also identified. The function of mutant EIF1AX was probed using loss of function experiments. Reduction of EIF1AX expression impaired the growth of both wild type and mutant cells. To identify transcripts regulated by EIF1AX at the level of translation, RNA sequencing of polysome-associated mRNAs was performed. Knockdown of wild type, but not mutant EIF1AX reduced the efficiency of ribosomal protein translation. Cancer cells expressing mutant EIF1AX may harbor changes in protein translation, which may be important for tumorigenesis. Citation Format: Chelsea S. Place, Ivana K. Kim, Bita Esmaeli, Ali Amin-Mansour, Daniel J. Treacy, Scott L. Carter, Eran Hodis, Nikhil Wagle, Sara Seepo, Xiaoxing Yu, Francisca Vazquez, Elizabeth Nickerson, Kristian Cibulskis, Aaron McKenna, Stacey B. Gabriel, Gad Getz, Eliezer M. Van Allen, Levi A. Garraway, Scott E. Woodman. Systematic genomic characterization of uveal melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-15.
PWE-092 CT pneumocolon in a district general hospital – is this test being used appropriately?
Authors: P Sarai, G Sebepos-Rogers, S D Mann
Journal: Gut (2010)

<h3>Introduction</h3> CT pneumocolon (virtual colonoscopy, VC) is increasingly being used to investigate the colon in patients who would previously have had a barium enema or optical colonoscopy (OC). It is not associated with sedation complications and is rapid and relatively safe. Unlike OC, published guidelines for appropriate use and reporting standards for VC are scarce.1 We aimed to review the indications and the quality of VC reports in a single centre in the UK. <h3>Methods</h3> All patients investigated with VC at Barnet Hospital during a 12-month period from Jan to Dec 2008 were identified from the Radiology Department database. Demographic data, referral source, clinical indications, report details and findings were analysed. <h3>Results</h3> 355 patients had VC in 2008 (M=149; age range 29–96 years; mean 74.2 years). Out-patients represented 94% of requests (n=335). 75.8% were referred from GI surgeons, 11.8% from gastroenterologists and 8.4% from Elderly Care Medicine. 20 patients (6%) had VC as in-patients. The most common indications for VC were abdominal pain (23%), anaemia (17%) and weight loss (16%). Incomplete OC was the indication in 13% of requests and frailty in 1% of requests. Among in-patients, anaemia was the indication in 60% and frailty in 5%. The reports documented the procedure as suboptimal in 10% of requests even though poor prep was highlighted in 27% of cases (no faecal tagging used). Reference to the adequacy of distension and the use of anti-spasmodics were made in 61% and 30% of reports, respectively. The findings were similar for in-patients and out-patients, although more inpatients had poor prep (50%). There were no adverse events following VC. Normal or incidental benign observations (diverticular disease, gallstones, etc) were reported in 78.5% of out-patients. Polyps or cancer were found in 10% and another 4% had significant extra-colonic pathology. <h3>Conclusion</h3> The overwhelming majority of requests for VC are made by GI surgeons. The indications are varied and only 14% of out-patient procedures were for commonly accepted indications (frailty and incomplete OC). The quality of reporting detail varied with poor prep being identified in over one in four cases. Abdominal pain is associated with a poor yield from VC. Units that perform VC should establish guidelines for appropriate use. Like OC, we propose that VC is a specialist GI investigation which should be interpreted and reported by dedicated GI radiologists with a minimum recommended reporting standard.
Improvement in Weight and Total Cholesterol and Their Association with Survival in Ruxolitinib-Treated Patients with Myelofibrosis From COMFORT-I
Authors: Ruben A. Mesa, Srdan Verstovsek, Vikas Gupta, John Mascarenhas, Ehab Atallah, William Sun, Victor A. Sandor, Jason Gotlib
Journal: Blood (2012)
Abstract 2227: Effects of cathepsin S in differentiated and stem-like glioblastoma cells
Authors: Robyn A. Foster, Shahnaz T. Al Rashid, Roberta E. Burden, Christopher J. Scott, Kevin M. Prise, Thomas J. Flannery
Journal: Cancer Research (2015)

Abstract Background: Glioblastoma (GBM) is the most common and aggressive brain tumour subtype with a poor prognosis of ∼15 months. A GBM stem-like population within the tumour is hypothesised to promote resistance to current treatment and invasion through normal tissue. Cathepsin S (Cat S) is a lysosomal cysteine protease that remains catalytically active at neutral pH and has been shown to play a role in radiation resistance and invasion of cancer cells. It is also an independent predictor of GBM patient survival. Materials and methods: GBM cell lines (U87MG and LN229) with lentiviral shRNA knockdown of Cat S are grown in serum-free medium with growth factors that allow de-differentiation of the cells into a stem-like state. A transwell system is used for quantifying monolayer invasion. Under stem conditions, spheroid structures are formed and their invasion in 3D is analysed with GFP expression. Protein expression determined via Western blot. Radiation response determined via clonogenic survival assay. Proliferation measured using MTT assay. Cat S-like activity measured using fluorogenic peptide substrate cleavage. Results: Radiation induces Cat S protein expression and protease activity in both GBM cell lines at 24 hours. Knockdown of Cat S induces radiation sensitivity in both cell lines when differentiated. In stem-like conditions, this is observed for U87MG but not for LN229 cells. Similarly, Cat S knockdown has no effect on proliferation of cell lines, except LN229 stem-like cells where it is increased. Finally, Cat S knockdown reduces the invasive capacity of both differentiated cell lines and U87MG stem-like cells 3D invasion through both collagen and matrigel, but has no effect on LN229 stem-like cells. Cat S-like activity is reduced in all but stem LN229, despite complete knockdown. Further investigation into differential effects in stem-like cells will examine possible role of autophagy, which is linked to radiation resistance and Cat S inhibition. Conclusion Cat S is a potential drug target in GBM as it reduces invasion and radio-resistance of glioma cell lines. The differential effect seen in stem-like cells suggests that the genetic background of tumours may be an important factor in determining utility of Cat S therapy in targeting the stem-like GBM population thought to be responsible for recurrence. Citation Format: Robyn A. Foster, Shahnaz T. Al Rashid, Roberta E. Burden, Christopher J. Scott, Kevin M. Prise, Thomas J. Flannery. Effects of cathepsin S in differentiated and stem-like glioblastoma 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 2227. doi:10.1158/1538-7445.AM2015-2227
A Novel Prognostic Staging System for Light Chain Amyloidosis (AL) Incorporating Markers of Plasma Cell Burden and Organ Involvement.
Authors: Shaji Kumar, Angela Dispenzieri, Martha Q. Lacy, Suzzane Hayman, Francis Buadi, Steven R. Zeldenrust, Nelson Leung, Marina Ramirez-Alvarado, Robert A Kyle, S. Vincent Rajkumar, Morie A. Gertz
Journal: Blood (2009)
Abstract 4151: Interleukin 17 promotes tumor progression in oral squamous cell carcinoma
Authors: Avadhoot Avadhani, Trudy Milne, Gregory Seymour, Alison Rich
Journal: Cancer Research (2015)

Abstract Background: Interleukin 17 (IL17) is a proinflammatory cytokine with increased expression in some cancers. It has been demonstrated to exhibit both pro- and anti-tumor effects. Our group has previously demonstrated expression of IL17 from multiple cells in oral squamous cell carcinoma (OSCC) such that the aim of the current study was to examine the role of IL17 in OSCC progression. Methods: The cytoplasmic SEFIR sequence of the transmembrane IL17 receptor (IL17R) was detected in formalin Fixed Paraffin Embedded (FFPE) OSCC tissues (n = 14) using immunohistochemistry. Soluble IL17R was detected in the cell culture supernatants of three OSCC cell lines (SCC4, SCC15 and SCC25) using a sandwich ELISA. Human recombinant IL17 over a range of concentrations (0, 10, 50, 100 ng/mL) was used to stimulate the three OSCC cell lines.Proliferation at 0, 24, 48, 72 hours was then assayed by cell titer blue and invasion at 48 hours using a QCM ECMatrix cell invasion assay. The data were analyzed using unpaired Student's t test and ANOVA as appropriate using GraphPad Prism 6 software. Results:Cytoplasmic expression of transmembrane IL17R was detected in all FFPE OSCC tissues. Soluble IL17R was detected in the cell culture supernatants of all three OSCC cell lines and its concentration increased in a time dependent manner. SCC25 had significantly higher concentration of soluble IL17R at 72 hours than SCC4 and SCC15. The rate of proliferation of all three OSCC cell lines was not affected with the addition of recombinant IL17. However, IL17 promoted the in vitro invasion of SCC25 and SCC15 in a dose dependent manner. At the highest concentration of IL17 (100ng/mL), the SCC25 cells showed significant invasion compared to control cells (p&amp;lt;0.05), while the SCC15 cells exhibited significant invasion at both 50ng/mL and 100 ng/mL of IL17 (p&amp;lt;0.05). In contrast, IL17 failed to stimulate invasion in the SCC4 cell line. Conclusions: This study is the first to demonstrate in vitro association between IL17 and possible invasion of OSCC. The exact mechanism by which IL17 enhances invasion and thereby tumor progression in vivo remains to be elucidated and could involve a number of different mechanisms including cell adhesion and extracellular matrix proteins. Citation Format: Avadhoot Avadhani, Trudy Milne, Gregory Seymour, Alison Rich. Interleukin 17 promotes tumor progression in oral squamous cell 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 4151. doi:10.1158/1538-7445.AM2015-4151
Simple Risk Factors to Predict Urgent Endoscopy in Nonvariceal Upper Gastrointestinal Bleeding Pre-endoscopically
Authors: Jianzong Wang, Duanming Hu, Wen Tang, Chuanyin Hu, Qin Lu, Juan Li, Jianhong Zhu, Liming Xu, Zhenyu Sui, Mingjie Qian, Shaofeng Wang, Guojian Yin
Journal: Clinical Gastroenterology and Hepatology (2016)
No Evidence for t(14;18)-Positive Cells in Newborns and Young Children until the Age of 10 Followed by a Linear Increase of the Prevalence in Healthy Individuals until the Age of 50 Years.
Authors: Frank Schüler, Lars Dölken, Sandra Dölken, Carsten Hirt, Gerhard Fusch, Britta Bockholdt, Gerd Lorenz, Christoph Fusch, Gottfried Dolken
Journal: Blood (2006)
Abstract 1400: Evaluation of tumor-initiating cell populations in the KPC mouse model of pancreatic cancer
Authors: Joseph S. Dosch, Elizabeth K. Ziemke, Amrith Shettigar, Alnawaz Rehemtulla, Judith S. Sebolt-Leopold
Journal: Cancer Research (2015)

Abstract There continue to be many questions about the frequency and phenotype of tumor-initiating cells or cancer stem cells (CSCs) which may play an important role in cancer metastasis and drug resistance in several tumor types, including pancreatic cancer. The KrasG12D, Trp53R172H, and Pdx-1-Cre (KPC) induced model of pancreatic cancer has gained considerable attention for its ability to replicate the clinical features of the disease. Here, we report the generation of a novel syngeneic xenograft model of luciferase-tagged pancreatic tumor cells (KPCL) to facilitate the investigation of the tumorigenic capacity of this cancer model. Limiting dilution analysis of bulk KPCL tumor cells revealed that 1/87 cells were capable of forming new tumors, a number considerably higher than reported for human pancreatic adenocarcinomas. Cell surface markers CD44, CD24, CD133, c-Met, and functional ALDEFLUOR activity, previously shown to mark CSC populations in human and mouse pancreatic tumors, were heterogeneous across a large panel of spontaneous KPCL tumors. Additional testing of CD133 and ALDEFLUOR populations were unable to enrich for tumorigenic populations when transplanted into syngeneic mice. Additionally, spheroid cultures initiated from KPCL tumors did not enrich for cells with stem-like characteristics and were not significantly more tumorigenic than KPCL cells cultured as monolayers. These studies demonstrate that the tumor-forming potential of KPC cells is common, and may not fit the hierarchically organized CSC model that is reported for the human disease. Citation Format: Joseph S. Dosch, Elizabeth K. Ziemke, Amrith Shettigar, Alnawaz Rehemtulla, Judith S. Sebolt-Leopold. Evaluation of tumor-initiating cell populations in the KPC mouse model of pancreatic 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 1400. doi:10.1158/1538-7445.AM2015-1400
ASXL2 Is a Novel Mediator of RUNX1-ETO Transcriptional Function and Collaborates with RUNX1-ETO to Promote Leukemogenesis
Authors: Jean-Baptiste Micol, Nicolas Duployez, Alessandro Pastore, Robert Williams, Eunhee Kim, Stanley Lee, Benjamin Durham, Young Rock Chung, Hana Cho, Claude Preudhomme, Omar Abdel-Wahab
Journal: Blood (2015)
Platelet-Targeted Expression of Coagulation Factor VIII (FVIII) Shows Efficacy for Using the Dog as a Large Animal Model for Gene Therapy of Hemophilia a
Authors: David A. Wilcox, Lily M. Du, Sandra L. Haberichter, Paula M. Jacobi, Juan Fang, Eric S. Jensen, Qizhen Shi, Robert R. Montgomery
Journal: Blood (2008)
Abstract 1271: MDM2 small molecule inhibitors synergize with chemotherapeutics to attenuate senescence-driven inflammatory secretion
Authors: Nicholas Schaum, Fatouma Almirah, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos
Journal: Cancer Research (2015)

Abstract An attractive therapeutic approach for treatment of cancers with wild-type (wt) p53 is the emergent class of small molecule MDM2 inhibitors, including the imidazoline nutlin-3 and more potent spiro-oxindole MI-63. Both compounds rapidly increase intracellular wt p53 levels and induce apoptosis or a senescence growth arrest, depending on the target cell. A critical question in the clinical development of MDM2 inhibitors is their potential for normal tissue toxicity owing to their ability to cause p53-dependent apoptosis or cellular senescence. Recent work suggest senescent cells exhibit a senescence-associated secretory phenotype (SASP) that can stimulate cancer progression. We critically examined the effect of MDM2 small molecule inhibitors Nutlin-3a and MI-63 on non-senescent and senescent cells. Both compounds caused normal cells to undergo a transient growth arrest. Continuous incubation with MDM2 small molecule inhibitors caused normal cells to exhibit some hallmarks of senescence (arrested growth, SA-β-Gal expression and secretion of High Mobility Group Box 1 protein), but the cells resumed growth upon removal of the MDM2 inhibitors. Senescent cells cultured with MDM2 inhibitors failed to resume growth upon removal of the compounds, as expected. However, their SASP was markedly dampened, as determined by multiplex ELISA assays. Since NF-κB and IL-1α are major drivers of the SASP, we examined their status in senescent cells cultured with MDMD2 inhibitors. The small molecule MDM2 inhibitors significantly reduced NF-κB activity and IL-1α mRNA expression in senescent cells. Our data suggest using combinatorial therapy of chemotherapeutics or irradiation and MDMD2 small molecule inhibitors may provide a potent therapeutic strategy to promote apoptosis of p53 positive tumor cells after radio- or chemo-therapy and attenuate the potentially deleterious effects of the SASP. Citation Format: Nicholas Schaum, Fatouma Almirah, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos. MDM2 small molecule inhibitors synergize with chemotherapeutics to attenuate senescence-driven inflammatory secretion. [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 1271. doi:10.1158/1538-7445.AM2015-1271