tbuckley/cabot-search huggingface dataset:
OC-054 Initial experience of St Mark's Bowel Cancer Screening Centre
Authors: S Gupta, C Fraser, N Suzuki, M E Vance, B P Saunders, S Thomas-Gibson
Journal: Gut (2010)

<h3>Introduction</h3> St Mark9s Bowel Cancer Screening Centre (BCSC) was one ofthe first English screening centres rolled out between Oct 2006-Nov 2007. We report the preliminary experience of St Mark9s BCSC over the first 35 months of screening. <h3>Methods</h3> To review the outcomes of 1488 screening participants referred following positive FOBT. Those unfit for colonoscopy were offered alternatives such as CT Virtual Colonoscopy (VC). Data regarding gender, age, colonoscopy findings and screening outcomes were analysed. <h3>Results</h3> 98 815 FOBT kits were sent out and 42 523 returned (43% uptake).1488 positive FOBT participants were referred to the nurse clinic. 1339 (90%) attended. 57% were men. 1138 (85%) were suitable for colonoscopy, 122 (9%) for VC and 17 (1%) for flexible sigmoidoscopy. 62 (5%) were not referred further on medical grounds. 1057 (79%) screenees underwent first procedure colonoscopy, 115 had a VC and eight had a flexible sigmoidoscopy. 514 (44%) procedures were “normal”, 583 (50%) patients had polyps (155 (26%) high risk, 170 (29%) intermediate risk and 258 (45%) low risk polyps). In 583 patients with polyps, 1625 polyps were found (average 2.8 polyps per patient). 96% were adenomas. Median polyp size was 5 mm (1–80). 74 patients (6%) had colorectal cancer. Three patients had non-colonic incidental cancers. Overall, 1200 colonoscopies were performed by five screeners until September 2009 (1057 first procedure colonoscopies, 82 repeat colonoscopies, 61 surveillance procedures), with a 96% completion rate. There was one 30-day post surgical mortality. <h3>Conclusion</h3> Over the period reviewed, &gt;1200 colonoscopies were performed with excellent (96%) completion rates. Significant pathology (cancers and polyps) was found in 45% of patients with a positive FOBT. Despite the polyp/adenoma detection rates being higher than those expected, cancer rates were lower than national figures. This was possibly due to a previous flexible sigmoidoscopy trial in the centre in 1999.
358. Non-Viral/Minicircle Vector Transduction of Hepatocytes in Small Pigs By Hydrodynamic Intraportal Injection
Authors: Hiu Man Viecelli, Fabienne Stoller, Andrea Schlegel, Veronique Rüfenacht, Nikola Cesarovic, Claudio Viecelli, Sereina Deplazes, Xaver Sidler, Philipp Kron, Philipp Dutkowski, Rolf Graf, Beat Thöny, Johannes Häberle
Journal: Molecular Therapy (2015)

Non-viral and non-plasmid-based vectors that express a therapeutic protein from an episomal element have the potential of robust and sustained transgene expression and at the same time bear a very low risk of insertional mutagenesis. While hydrodynamic injection into the tail vein of mice to target the liver is an efficient but experimental approach, delivery of naked DNA/minicircle vectors into large animals and humans remains a challenge. Here we show successful hepatocyte transfection in domestic small pigs treated immediately after weaning with portal vein catheterization and hydrodynamic injection of naked DNA/minicircle vectors expressing the luciferase gene from a liver-specific promoter. We established a surgical method allowing hydrodynamic portal vein pressurization up to 90 mmHg and infusion of naked DNA in pigs with long-term survival. No acute adverse effects such as changes in liver transaminases or signs of liver cell damage were observed. Stable hepatocyte transfections at 10 and 28 days in single experiments were found in up to 60% of samples (45/75 were PCR-positive for minicircle-DNA) and 13% of the positive specimens (6/45) showed low but stable luciferase expression with up to two vector copies per diploid hepatocyte genome. While further optimization to enhance transfection efficiency and transgene expression is required, we conclude that hydrodynamic gene delivery using minicircle vectors in small pigs is a safe procedure for stable transfection of liver cells as a prerequisite to potentially treat infants with genetic liver diseases.
Improved Prognosis of Chronic Lymphocytic Leukemia (CLL) Patients with Increased IgVH Mutations May Reflect Greater Alteration of the B-Cell Receptor (BCR) Binding Site
Authors: Matthew Kaufman, Xiao Yan, Rajendra Damle, Nina Kohn, Martin Lesser, Nancy Driscoll, Christina Johnson, Jahan Aghalar, Yehuda Lebowicz, Kanti Rai, Nicholas Chiorazzi
Journal: Blood (2008)
Abstract 3994: Herpes virus microRNA expression and significance in serous ovarian cancer
Authors: Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini
Journal: Cancer Research (2015)

Abstract Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality. Citation Format: Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini. Herpes virus microRNA expression and significance in serous 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 3994. doi:10.1158/1538-7445.AM2015-3994
Abstract 4117: Syk is a candidate kinase target for the treatment of advanced prostate cancer
Authors: Erik Danen
Journal: Cancer Research (2015)

Abstract Improved targeted therapies are needed to combat metastatic prostate cancer. Here we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. While SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacological inhibitors of SYK kinase currently in Phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer. Citation Format: Erik Danen. Syk is a candidate kinase target for the treatment of advanced prostate 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 4117. doi:10.1158/1538-7445.AM2015-4117
238. Cell Therapeutic Approach Using Dental Pulp Stromal Cells for Duchenne Muscular Dystrophy
Authors: Yuko N. Kasahara, Mutsuki Kuraoka, Hiromi H. Kinoh, Chiaki Masuda, Kiwamu Imagawa, Katsuhiko Tachibana, Shin'ichi Takeda, Takashi Okada
Journal: Molecular Therapy (2016)

Background: Duchenne muscular dystrophy (DMD) is an incurable genetic disease with early mortality that exhibits skeletal muscle weakness with chronic inflammation. Dental pulp stromal cells (DPCs) could be potential therapeutics because of their immunosuppressive properties and multipotency. In the present study, we examined the strategies for effective cell transplantation to develop a novel approach for functional recovery of the skeletal as well as cardiac muscles using a dog model of Duchenne muscular dystrophy. Methods: DPCs were intravenously injected into two littermates of canine X-linked muscular dystrophy in Japan (CXMDJ) at weekly interval for 8 weeks without immunosuppression. Clinical phenotypes in the transplanted dogs were analyzed by using blood exams, physical capacity, magnetic resonance imaging (MRI) analysis compared with non-injected littermates as controls. Results: The downregulation of inflammation in the lower legs of DPCs-treated CXMDJ was confirmed by MRI analysis. Serum levels of pro-inflammatory cytokine IL-6 were well regulated in the treated CXMDJ during experiments, unlike non-injected dogs. Although CXMDJ showed progressive muscle atrophy in the all four limbs, exercise intolerance and abnormal locomotion, we observed improved phenotypes in the DPCs-treated CXMDJ along with the improved pace of walking and running. Conclusion: We suggested that the systemic injection of DPCs ameliorated the progressive phenotype in CXMDJ. The therapeutic effects might be associated with the production of paracrine or endocrine factors that regulate inflammation, and might also stimulate the proliferation of endogenous stem cells at the injured muscle tissue. This strategy of DPCs treatment would be promising for the future DMD cell therapy.
362. Utilization of Magnetic Field To Redirect Oncolytic Adenovirus Complexed With Iron Oxide for Augmented Therapeutic Efficacy
Authors: Joung-Woo Choi, Ji Won Park, You Jin Na, Soo-Jung Jung, Dayananda Kasala, June Kyu Hwang, Chae-Ok Yun
Journal: Molecular Therapy (2015)

Adenovirus (Ad) is a widely used vector for cancer gene therapy but its therapeutic efficacy is limited on the lacked expression of the coxsackievirus and adenovirus receptor (CAR) in tumor tissues as well as specificity of targeted infection. Ad infectivity and specificity can be markedly improved by creating Ad-magnetic nanoparticles cluster complexes and subjecting them to an external magnetic field. First, we characterized the PEGylated and cross-linked iron oxide nanoparticles (PCION) through NMR, transmission electron microscope, and cytotoxicity assay. Then, we electrostatically complexed GFP-expressing replication-incompetent Ad (dE1/GFP, or dAd) with PCION, generating dAd/PCION complex. dAd/PCION showed increased transduction efficiency, independent of CAR in the absence or presence of an external magnetic field (MGF). The size distribution and zeta potential of the polyelectrolyte complex (dAd/PCION) were shown 182.3 and 24.6, respectively, compared with naked Ad (74.6 and -22.6). Due to the magnetic properties of the clustered magnetic nanoparticles, we attributed the markedly enhanced transduction efficiency to be primarily mediated by the MGF. Cancer cell killing effect was significantly increased Hmt/PCION+MGF system compared to that of HmT or HmT/PCION, independent of CAR expression. Importantly, in MCF7 tumor xenograft models, the magnetofection-mediated HmT/PCION complex displayed significantly enhanced anti-tumor efficacy in the presence of an external magnetic field by 2.74- and 2.10- fold than cancer cell killing effects in the absence of an MGF and Ad alone, respectively. These results demonstrate that magnetofection-mediated oncolytic Ad infection is able to overcome CAR-dependent infectivity while producing higher antitumor efficacy.
Further Characterization of T-Cellular Precursors Generated From CD34+ Progenitors by Exposure to Immobilized Notch Ligand Delta-Like 4 In Vitro.
Authors: Christian Reimann, Andrea Schiavo, Julien Rouiller, Elodie Vidal, Kheira Beldjord, Liliane Dal-Cortivo, Marina Cavazzana-Calvo, Isabelle Andre-Schmutz
Journal: Blood (2010)
Risk of osteoporosis/osteopenia events in patients newly diagnosed with neuroendocrine tumors.
Authors: J. W. Hill, C. Chen, G. P. Hess, Z. Liu, J. C. Yao, A. T. Phan
Journal: Journal of Clinical Oncology (2011)

e16602 Background: Neuroendocrine tumors (NET) derive from peptides- and hormones-producing cells scattered throughout the body. In excess, these can lead to many clinical manifestations. This study evaluated patient’s risk of experiencing osteoporosis/osteopenia in the first three years post diagnosis, comparing NET to general non-cancer patients. Methods: This is a retrospective matched-control cohort study utilizing SDI’s claims databases. NET patients consisted of adults newly diagnosed with one of the following specific NET ICD9-CM codes: 157.4, 209.xx, 258.01, 259.2 from 2001 to 2007. Non-cancer controls were matched 2 to 1 with NET patients on age, gender, region, and hospital data availability. Risk of osteoporosis/osteopenia related diagnosis or procedures were captured during the 3-year post index period, and were analyzed using Cox proportional hazards and logistic regressions adjusting for baseline comorbidity index, age, gender, region, payer, and physician specialty/academic affiliation. Results: The study sample consisted of 1,762 newly diagnosed NET (median age=61 years, 59.3% female, 70.4% commercially insured and 28.8% Medicare patients) and 3,524 matched control patients. During the 3-year follow-up, 9.1% of NET and 8.9% of control patients experienced osteoporosis/osteopenia events (p=0.838). Osteoporosis/osteopenia event rates were markedly higher in NET patients (5.0%) than controls (1.7%, p=0.002) in the patients aged less than 50 years (n=1,077, 359 NET and 718 control patients). In this younger patient group, NET patients were more than three times likely to have osteoporosis/osteopenia events than controls (hazard ratio=3.38, 95% CI: 1.44-7.91, p=0.005; odds ratio=3.24, 95% CI: 1.36-7.73, p=0.008). Conclusions: Osteoporosis/osteopenia events were much more prevalent in NET patients post diagnosis than in non-cancer controls aged 50 years or less. The results of this study suggest a higher incremental risk of osteoporosis in NET patients, and warrant additional investigation in future studies, as well as greater clinical awareness.
Use of HER2 amplification in the primary tumor to predict presence of circulating tumor cells in inflammatory breast cancer.
Authors: A. Bhattacharyya, S. Krishnamurthy, A. Lodhi, C. Hall, A. Anderson, H. M. Kuerer, I. Bedrosian, R. H. Alvarez, N. T. Ueno, S. Jackson, B. Singh, A. Lucci
Journal: Journal of Clinical Oncology (2011)

e11133 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 3-6% of all cases. IBC patients have higher rates of distant recurrence. We hypothesized that circulating tumor cells (CTCs) can be identified in patients with IBCs and may correlate with primary tumor characteristics. Methods: All patients had blood samples taken at the time of primary surgery. CTCs (per 7.5 ml blood) were detected using the Cell Search system (Veridex) and were defined as nucleated cells lacking CD45 but expressing cytokeratins (CK) 8, 18, or 19. The presence of ≥ 1 epithelial cells meeting morphologic criteria for malignancy was considered a positive result. Statistical analyses used Chi square and Fisher's exact tests. Results: We prospectively evaluated 38 IBC patients enrolled in an IRB approved protocol undergoing surgery for stage I-III breast cancer. Median follow-up was 27 months and mean age was 51 years. Eleven patients (29%) were ER +ve, 10 (26%) were PR +ve and 18 (47%) were HER2 positive. Thirty four patients (94%) had positive lymph nodes (LNs) at presentation, 29 (78%) had high-grade tumors and 19 (54%) had lymphovascular invasion. IBCs were more likely to be high grade (P<0.0001), ER –ve (P<0.0001), PR –ve (P<0.0001), HER2 +ve (P<0.0001), High Ki-67 (P= 0.005) and have a BMI > 25kg/m2 (P=0.04). Ten (30%) patients were CTC positive. CTCs were more likely be found in HER2 +ve (8/16; 50%) vs. HER2 –ve primary tumors (2/17; 12%) [OR= 7.5; 95% C.I. = 1.05-83.4; P= 0.026]. No statistically significant correlations were observed between primary tumor characteristics (ER, PR, LNs, high grade) and presence of CTCs. Conclusions: Approximately, one-third of IBC patients had CTCs at the time of primary surgery. HER2 overexpression predicted the presence of CTCs in these patients. Further study with longer follow up is needed to determine if CTCs predicted relapse in this cohort.
408. CD19-Targeted CAR T Cells “Armored” To Secrete IL-12 Demonstrate Superior Efficacy Against B Cell Acute Lymphoblastic Leukemia and Resist Treg Immunosuppression
Authors: Peter S. Chang, James C. Lee, Mythili Koneru, Renier J. Brentjens
Journal: Molecular Therapy (2015)

For an adoptive T cell immunotherapy to successfully treat cancer, T cells must be able to recognize the tumor antigen, expand and persist in the tumor microenvironment, and deliver its effective function. Treatment of B cell acute lymphoblastic leukemia (B-ALL) using human T cells modified to express a "second generation" CD19-targeted chimeric antigen receptor (CAR), which includes the CD28 co-stimulatory signaling domain (19-28z) along with the CD3 zeta chain signaling domain, has been successfully demonstrated in both the pre-clinical and clinical setting. However, application of CAR therapy for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and solid tumors remains a challenge. Here, we present preclinical studies demonstrating that further modifying 19-28z T cells to additionally secrete a recombinant fusion protein of the proinflammatory interleukin 12 (IL-12) (19-28z/IL-12 T cells) enhances the potency of adoptive T cell immunotherapy. We demonstrate that these 19-28z/IL-12 "armored" CAR T cells display increased proliferation, enhanced persistence, up-regulation of perforin and granzyme B, as well as a central memory-like phenotype when compared to T cells transduced to express the 19-28z CAR alone. In vivo, treatment of systemic NALM-6 B-ALL tumor-bearing SCID-Beige mice with 19-28z/IL-12 CAR T cells significantly improved survival when compared to mice treated with T cells modified to express the 19-28z CAR alone. Furthermore, in contrast to T cells modified to express the 19-28z CAR alone, 19-28z/IL-12 T cells resist CD4+CD25hiFOXP3+ Treg-mediated immunosuppression in vitro and successfully eradicate Raji Burkitt's lymphoma tumor in SCID-Beige tumor-bearing mice previously infused with CD19-targeted CAR modified Tregs. These findings have important implications for future clinical trials with CAR T cells designed to enhance the clinical outcomes of relapsed B-CLL as well as solid tumor malignancies.
Lipid and copper metabolism in humans with wilson disease: Enigmatic relationship
Authors: Palittiya Sintusek, Anil Dhawan
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. To the Editor: We read with interest the article by Hamilton et al. published in hepatology, an experimental study highlighting the role of nuclear receptors in a mouse model of Wilson disease (WD).1 Their previous study demonstrated that lipid metabolism was inhibited in response to hepatic copper accumulation in the WD mouse model,2 and this expanded study showed that up‐regulation of the nuclear receptor by liver X receptor agonist administration can increase serum lipid values to normal despite significant hepatic copper overload. These findings seem very convincing and throw light on WD pathogenesis. The only human study describing attenuation in lipid metabolism in WD suggests low cholesterol levels, but the study does not provide correlation of lipids with hepatic copper.3 We had opportunity to retrospectively study serum lipid profiles, liver function tests, and hepatic copper in our WD children (n = 26) seen at King's College Hospital from 2005 to 2015. WD diagnosis was established with ATP7B mutations in all. Serum total cholesterol (TC) and triglyceride (TG) data before starting treatment were collected. Hepatic copper was measured in four explant livers of WD/acute liver failure children and 22 core liver biopsy tissues from WD/non–acute liver failure children. The median age at diagnosis was 10.86 (1.64‐17.26) years, and 62% were female. The median hepatic copper was high (513 [7‐4225] μg/g dry weight liver). Interestingly, the median TC and TG in our study were normal, with values of 4.45 (1.7‐6.3) and 1.3 (0.5‐3.2) mmol/L. Indeed, the median body mass index that might affect the lipid profile level was also normal (19.8 [13.7‐40.7] kg/m2). We further assessed the correlation between serum lipid profiles with hepatic copper and liver function tests. There was no correlation between lipid profiles (TC and TG) and hepatic copper (Fig. 1). TG has no correlation with other parameters, while TC significantly correlates with total bilirubin (r = –0.621, P = 0.001) and alanine aminotransferase (r = 0.422, P = 0.028).Figure 1: The correlation between lipid profiles and hepatic copper content.Our data suggest that low cholesterol in hepatic WD patients might relate to severity of liver disease. Our data on correlation of hepatic copper with cholesterol in children with liver disease are not in keeping with the observation in the animal model. However, we were not able to perform nuclear receptor studies in our patient population, but our finding may be of relevance before applying the data from animal studies to humans.