tbuckley/cabot-search huggingface dataset:
539. Screening for Recombinant Adeno-Associated Viral Vectors That Selectively Transduce Hepatitis B Virus Infected Cells
Authors: Gustavo de Alencastro, Katja Pekrun, Mark Kay
Journal: Molecular Therapy (2016)

Hepatitis B is a disease caused by infection with the hepatitis B virus (HBV), a small enveloped DNA virus which belongs to the Hepadnaviridae family. Even though a safe and effective vaccine is available, HBV represents the ninth most common cause of death worldwide with an estimated 350 million chronically infected individuals. HBV infection can cause cirrhosis and hepatocellular carcinoma and currently there are 7 approved drugs for the treatment of HBV infection in the USA. These drugs decrease the risk of liver damage from HBV by slowing but not eliminating viral replication in most patients, possibly related to the persistence of integrated HBV genomes. Gene therapy using recombinant adeno-associated viral (rAAV) vectors constitute a promising tool to combat HBV infection as rAAV vectors have the ability to transduce and establish long-term and stable transgene expression in liver cells. Preclinical studies have successfully utilized rAAV vectors to combat viral infections after delivering short-hairpin RNA (shRNA) expression cassettes for knocking down viral coding or host genes required for viral replication and spread. Because promiscuous targeting of host cellular genes in the majority of non-infected cells may be detrimental, specific targeting of HBV-infected cells adds a new layer of potential therapeutic targets and safety. Thus we set out to identify new AAV capsids that selectively transduce HBV-infected cells. To do this, we created new AAV shuffled capsid libraries and used these for multiple rounds of infection in HBV-infected hepatoma cells. Each library is co-infected with wild-type Adenovirus-5 (helper virus) allowing the rAAV genomes to replicate in the HBV-infected cells. Isolation of replicating rAAV over successive passages in cultured cells allows for a more stringent selection as all steps in AAV transduction must occur. We have varied the screens using various multiplicity of infections (MOIs) of the library and/or utilized a pre-clearing step using a HBV negative hepatoma cell line. Several selected capsids derived from multiple parental capsids were vectorized. One capsid (AAV-GK4) was found to transduce the infected cells approximately 6 times more robustly than uninfected cells (using an MOI of 100 and 1,000). Interestingly, the same result was observed with AAV-DJ, a variant previously selected on human hepatoma cells. Additional screens and candidates are pending further evaluation. The possibility of finding new rAAV capsids with an increased transduction efficiency and selective tropism for HBV-infected cells will provide a reagent or therapeutic that can deliver a transgene that will allow one to selectively modify or potentially kill infected but not the uninfected cells contained within the liver.
PWE-095 CT colonography: incidental findings and their impact on further investigations in an urban UK teaching hospital: Abstract PWE-095
Authors: T Huda, A Mcpartlin, L Chan, J Iqbal, R P Willert
Journal: Gut (2010)

<h3>Introduction</h3> CT Colonography (CTC) availability is increasing and is being utilised more frequently for patients with lower gastrointestinal symptoms as an alternative to colonoscopy. Increased use of CTC at our hospital led us to determine the frequency and potential impact of the incidental findings (IF) found at CTC. <h3>Methods</h3> We performed a retrospective analysis of consecutive patients undergoing CTC over 12 months between Jan and Dec 2008 using the radiological database. All IF were extracted and then medical records were reviewed to see if patients received further intervention based on these incidental findings. <h3>Results</h3> Of 531 analysed CTC procedures 276 patients (52.3%) had one or more IF documented on the CTC report. 173 patients (63%) were over the age of 70. Total IF were 508, with non-colonic malignancy (new diagnosis) found in 59 patients (11%), most frequently in the form of liver metastases. Documented follow-up (further imaging and multidisciplinary team involvement) occurred in all but two cases. The most common non-malignant IF were renal or liver cysts, gallstones or hiatus hernias accounting for 248 (49%) of the documented IF. Surgical intervention was required in 41 patients (7.7%) in cases that included appendicitis, strangulated hernia, abdominal aortic aneurysm, renal calculi and cholecystitis. 149 IF (29%) required follow-up in the form of clinic review, further imaging or blood tests which was 117 of the 531 patients (22%) who underwent CTC (Abstract 095). <h3>Conclusion</h3> Incidental findings were surprisingly common compared to the published literature. While many of the documented IF had little clinical relevance the incidence of new malignancy requiring follow-up investigations is very high in our urban city cohort compared to the published literature.1 This may reflect the indication for the CTC as over 12% had weight loss as a part of the referring indication (see abstract J Iqbal). Many of the benign IF required further investigation before confirming a diagnosis which results in increased cost and patient worry for limited clinical benefit in the majority. Therefore, all doctors requesting CTC should make sure this is the most appropriate test and that the patient is aware of the potential for increased investigations required following CTC.
29. Novel Surgical Method for Intravitreal AAV Administration Overcomes Transduction Barriers in Non-Human Primates
Authors: Jason Comander, Livia Carvalho, Sarah Wassmer, Ru Xiao, Eva Plovie, Aliete Langsdorf, Lawrence Lim, Brian Hafler, David M. Wu, Dean Eliott, Leo A. Kim, Luk H. Vandenberghe
Journal: Molecular Therapy (2016)

Introduction For gene therapy applications in the primate retina, intravitreal injections (IVT) of adeno-associated virus (AAV) have been shown to target the retina inefficiently, mainly in retinal ganglion cells within a small perifoveal region. The internal limiting membrane (ILM) has been previously hypothesized to be a barrier to broader transduction. We further hypothesized that the local concentration and residence time of AAV at the vitreo-retinal interface was insufficient for efficient retinal transduction. Here, we investigate gene delivery to the retina in rhesus macaque with regular IVT injection as compared to a novel surgical technique "Peel and Puddle" aimed at overcoming these potential barriers. Methods Three eyes of rhesus macaques were injected with AAV-CMV-GFP via a traditional IVT at a concentration of 1E+11 particles (2/2 or Anc80 capsid). Another two eyes from different rhesus macaques had the ILM surgically removed followed by the concentrated application of AAV2 onto the peeled area, known as "Peel and Puddle" (PP), also at 1E+11 particles. The PP procedure consisted of a vitrectomy, posterior hyaloid separation, ILM staining and subsequent ILM peel over the majority of the macula. This was followed by fluid-air exchange, and deposition of the virus on the peeled area with 30 minutes of supine positioning generating a "puddle" onto the retina aimed at maximizing the AAV residence time at an undiluted concentration. Results GFP expression in the PP condition was dramatically greater than with a regular intravitreal injection, both in intensity and the region of transduction. In the PP eyes, fluorescence was noted in an area that matched the extent of the ILM peel and puddle, as shown by imaging and histology whereas traditional IVT demonstrated the expected parafoveal dim pattern of transduction. All eyes, irrespective of the type of IVT injection, presented clinically significant signs of inflammation, which was managed effectively by intravitreal steroid injections. Histological sections show increase microglia infiltration in both groups compared to un-injected controls. Conclusions The vitreous, ILM, and/or physical parameters of the vector delivery significantly limit gene transfer to the retina. Surgical minimization of these barriers demonstrated highly increased levels and distribution of transduction. Inflammation following intravitreal injection with a non-self transgene is of concern and requires further study.
575. Complete Removal of E-Cadherin from 4T-1 Murine Breast Cancer Cells Has No Effect on Metastasis
Authors: Jeffrey M. Spencer, Armando Rivera, Xiaoliu Zhang
Journal: Molecular Therapy (2015)

Currently accepted models for metastatic progression involve several steps. The first of these, local invasion of the primary tumor, requires detachment from the tumor mass and increased mobility. Epithelial to Mesenchymal Transition (EMT) is believed to play an important role in this increased mobility and consequent local invasion. Following local invasion, the tumor cells must intravasate and survive in the bloodstream prior to extravasation. Once the metastatic tumor cells have completed these steps, it is believed that the invading cells must undergo Mesenchymal to Epithelial Transition (MET), returning to their epithelial phenotype, in order to effectively establish metastasis. Importantly, E-cadherin expression positively correlates with the epithelial status of the cell. As part of the EMT mechanism, the change from E-cadherin to N-cadherin is driven by the ZEB and SNAIL family transcription factors. Loss of E-cadherin contributes to the increased cell motility associated with EMT by reducing the number of cell-cell contacts, allowing the cell to emerge from its local tissue environment. On the contrary, during MET, the re-expression of E-cadherin reestablishes cell connections. In order to test the requirement of MET during the final stages of metastasis, we used Cas9 to knock-out E-cadherin in the murine breast cancer cell line 4T1. As a result, the cells converted to a mesenchymal-like morphology. We hypothesized that the permanent disruption of the E-cadherin gene would prevent the cancer cells from undergoing MET thereby suppressing their ability to form metastasis. Surprisingly, upon implantation of the modified 4T1 cells, there was no difference in the appearance of metastasis as compared to the control. Both parental and E-cadherin knock-out 4T1 cells were able to form metastasis in the lung. These results demonstrate that E-cadherin is not necessary for the metastatic process in 4T1 cells. Further, the study suggests that MET may not be crucial during the final stages of metastasis. More detailed understanding of when MET is required, if at all, during metastatic progression will help to shape treatment strategies and continued research of metastatic disease.
Safety of Low Dose Enoxaparin in Thrombocytopenic Hematopoeitic Stem Cell Recepients: A Single Institution’a Case Series.
Authors: Rami B. Ibrahim, Nikki Milan, Edward Peres, Muneer H. Abidi, Roger Dansey, Esteban M. Abella, Lance K. Heilbrun, Jared Klein
Journal: Blood (2004)
Is ventilatory breakaway in heavy exercise really due to metabolic acidaemia
Authors: S C Morrison
Journal: Thorax (1996)

Background: The disproportionate increase in ventilation found during high intensity exercise (ventilatory breakaway, VB) is traditionally attributed to accumulation of lactic acid resulting from  metabolism, and has been termed the anaerobic threshold; VB has however been observed when lactate formation is impeded or prevented. This study was undertaken to determine whether VB is abolished when acidaemia in heavy exercise is prevented by infusion of alkali. Methods: Eight healthy males underwent incremental cycle ergometry to exhaustion. Ventilation, mixed expired O and CO, blood lactate (La) and pH were measured each min. On a separate day, 4.2% NaHCO solution was infused during exercise to keep blood pH close to pre-exercise level. Results: Mean exercise duration was 17.9 ± 2.0 (SD) min and peak VO 4.00 ± 0.30 l/min. On the control day blood pH at rest was 7.41 ± 0.01, falling to 7.27 ± 0.07 at peak exercise, and to 7.22 ± 0.07 in early recovery. Infusion of alkali commenced 6.6 ± 1.9 min prior to exercise cessation, and 307 ± 77 mmol was required to maintain blood pH near pre-exercise level (7.39 ± 0.03 at peak exercise, 7.35 ± 0.03 in early recovery). Although ventilation at peak exercise was lower after the infusion than in the control study (132.5 vs 147.4 l/min respectively, p = 0.03), ventilatory pattern was not altered by the infusion; VB was evident in 7 of the 8 subjects in the control study, and remained so during the infusion study. VCO values at peak exercise were insignificantly different in infusion and control studies, but peak La was significantly higher in the infusion study than in the control (16.6 vs 13.6 mmol/l respectively, p = 0.004). Conclusion: Persistence of VB in the absence of metabolic acidaemia indicates that factors additional to acid-base disturbance in the blood contribute to the commonly found ventilatory pattern during heavy exercise. Higher blood La following alkali infusion may be due to facilitated transport of La from muscle, or to an increased rate of glycolysis, or both.
Antitumor activity of endostar in combination with radiation in human nasopharyngeal carcinoma xenograft models.
Authors: Z. Juying
Journal: Journal of Clinical Oncology (2011)

e21015 Background: Radiation treatment for nasopharyngeal carcinoma (NPC) is common and effective. However, local recurrence was frequently occurred. Endostar, a novel recombinant human endostatin, is an antiangiogenic drug with potent antitumor effect. The objective of this study was to observe and explore the radiosensitization effects of Endostar on nasopharyngeal carcinoma (NPC) and its underlying mechanism. Methods: NPC subcutaneous transplantation tumor animal model was established to evaluate the antitumor activity of Endostar combined with radiation (Endostar+radiation) treatment compared with monotherapy (Endostar or radiation). Tumor growth and tumor weight were measured to evaluate the antitumor effect. The level of vascular endothelial growth factor (VEGF) and microvessel density (MVD) were measured by immunohistochemical stain of tumor tissues. Results: Significant antitumor activity was found in Endostar+ radiation group. Tumor inhibition rate of Endostar, radiation and Endostar+ radiation were 27.12%, 60.45% and 86.11% respectively. Level of VEGF in tumor tissue of Endostar+radiation group was lower than that of radiation or control. And MVD in tumor tissues of Endostar+radiation group was 12.2±2.5, much lower than Endostar (29.3±3.4), radiation (23.5±3.6) and control (44.7±5.1) group. Conclusions: These results suggested that Endostar could increase the sensitivity of NPC transplantation tumors in nude mice to radiation by lowering the expression of VEGF. In this study, NPC animal model was established which reflected the efficacy of clinical combination therapies, combination of Endostar and radiation. We will further investigate the mechanisms of the combination therapies using this model.
Use of a New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Excellent Specimens Quickly and Efficiently.
Authors: Ronan T. Swords, Kevin R. Kelly, Devalingam Mahalingam, Stephen C. Cohen, Larry J. Miller, Thomas E. Philbeck, Sander O. Hacker, Cathy J. Spadaccini, Andrew Brenner, Francis J. Giles
Journal: Blood (2009)
Abstract A1-43: Targeted amplicon-based next-generation sequencing of routine solid tumor specimens to detect clinically relevant somatic alterations
Authors: Daniel H. Hovelson, Andrew S. McDaniel, Bryan Johnson, Andi K. Cani, Kate Rhodes, Paul D. Williams, Chia-Jen Liu, Santhoshi Bandla, Catherine S. Grasso, Michael J. Quist, Seth Sadis, Daniel R. Rhodes, Scott A. Tomlins
Journal: Cancer Research (2015)

Abstract Background: Although precision medicine approaches have revolutionized oncology, widespread adoption requires robust, inexpensive approaches enabling the targeted assessment of all relevant alteration classes from routine tissue samples. Methods: Here we interrogated &amp;gt;7,000 cancer exomes and transcriptomes, along with &amp;gt;30,000 array based cancer genomes to identify recurrent somatic alterations (mutations, copy number alterations [CNAs] and gene fusions) across solid tumors. From this analysis, we developed and validated an integrated multiplexed PCR based Ion Torrent next generation sequencing panel (Oncomine Cancer Research Panel [OCP]) targeting the actionable somatic cancer genome optimized for 20ng of formalin-fixed, paraffin-embedded (FFPE) tissue isolated DNA/RNA. Results: We validated the OCP using FFPE cell line mixtures, as well as a prospective cohort of 104 FFPE tumor specimens sent for concurrent clinical molecular testing, with &amp;gt;97% sensitivity and specificity for the presence/absence of KRAS, EGFR, BRAF and ALK point mutations, indels or gene fusions in this molecular testing cohort. We also applied the OCP to 100 lung cancers, identifying known and novel alterations, including ALK and ROS1 gene fusions. Lastly, applying the OCP to 116 prostate cancers, including 50 previously treated samples, we recapitulated known molecular subtypes, observed distinct profiles according to previous treatment and obtained 100% concordance for isoform specific TMPRSS2:ERG gene fusion detection compared to qPCR. Additionally, OCP profiling supports a novel molecular subtype of prostate cancer defined by IDH1 R132 hotspot mutations and informed on resistance mechanisms in a pre- and post-treatment sample pair. Importantly, 44%, 35% and 9% of patients in the molecular testing, lung and prostate cancer cohorts, respectively, harbored additional alterations (beyond routine molecular testing) associated with FDA approved or NCCN guideline referenced therapies. Conclusions: Through analysis of both DNA and RNA to assess the actionable somatic cancer genome, the validated OCP panel may have utility in both clinical and research settings. Citation Format: Daniel H. Hovelson, Andrew S. McDaniel, Bryan Johnson, Andi K. Cani, Kate Rhodes, Paul D. Williams, Chia-Jen Liu, Santhoshi Bandla, Catherine S. Grasso, Michael J. Quist, Seth Sadis, Daniel R. Rhodes, Scott A. Tomlins. Targeted amplicon-based next-generation sequencing of routine solid tumor specimens to detect clinically relevant somatic alterations. [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 A1-43.
A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma
Authors: E. Jonasch, E. Hasanov, P.G. Corn, T. Moss, K.R. Shaw, S. Stovall, V. Marcott, B. Gan, S. Bird, X. Wang, K.A. Do, P.F. Altamirano, A.J. Zurita, L.A. Doyle, P.N. Lara, N.M. Tannir
Journal: Annals of Oncology (2016)
PTH-099 Vitamin D levels in coeliac disease: do they warrant monitoring?: Abstract PTH-099
Authors: N M Joshi, M R Aljabiri, L Fuller, C Butcher, M Ifijen, E Good, D Ramdass, N van Someren, K Besherdas
Journal: Gut (2010)

<h3>Introduction</h3> Coeliac disease is a lifelong inflammatory condition affecting the small bowel. Treatment involves a strict gluten free diet that should be supervised by a dietician. Follow-up is important because of potential long-term complications. The British Society of Gastroenterology (BSG) coeliac guidelines say that with a satisfactory response to diet, specialist outpatient follow-up should be at 6–12-month intervals to assess symptomatic improvement, nutritional state, dietary compliance and to check routine blood tests. Coeliacs are predisposed to metabolic bone disease and current guidelines recommend measuring bone mineral densitometry in all coeliacs. Vitamin D deficiency can also lead to metabolic bone disease and as coeliacs are predisposed to fat malabsorption they are also at risk of being vitamin D deficient and hence at further risk of developing bone de-mineralisation. Checking vitamin D levels is not mentioned in the BSG guidance on management of coeliacs and hence, it is not routinely measured. If vitamin D deficiency is noticed, simple replacement would further minimise the chance of developing osteopaenia/osteoporosis. <h3>Methods</h3> A single centre retrospective analysis of coeliac disease patients under follow-up was performed. Vitamin D levels were measured as part of routine blood test monitoring at follow-up in coeliac clinic. As some of these patients were also on combined calcium and vitamin D replacement, this was also taken into account. The resulting data were then analysed. Our laboratory vitamin D reference range is 47–144 ng/ml. <h3>Results</h3> 56 patients (12 male) attended follow-up in the study period with an average age of 62.7 years (22–90 years). The average vitamin D level was 73.2 ng/ml (15–153 ng/ml). 9 (16.7%) patients, all female, were vitD deficient with an average vitD level of 27.5 ng/ml (15–46 ng/ml). Further results of the nine patients with VitD deficiency are summarised in Abstract 099. <h3>Conclusion</h3> 16.7% of coeliac patients in this study have vitamin D deficiency. Monitoring vitamin D levels is easy and we advocate measuring vitamin D levels in all coeliac patients in view of enhanced risk of developing osteoporosis. Monitoring of vitamin D should be included in any national guideline on management of coeliac disease. We further promote dieticians to council patients on increasing the vitamin D in their diets when discussing gluten free diets. One osteoporotic patient was not on combined calcium-vitD supplementation as she could not tolerate the large size of tablets. No patients were on vitamin D only supplementation.
A Pilot Study for Haploidentical Transplant Using a Chemotherapy only Preparative Regimen eith T-Cell Depleted Haploidentical Transplant and Intensive Antibiotic Prophylaxis To Treat Advanced Leukemia Patients (pts).
Authors: James L. Gajewski, Rima Saliba, John D. McMannis, Elizabeth J. Shpall, Cindy Ippoliti, Sergio A. Giralt, Roy B. Jones, Issa F. Khouri, Chitra M. Hosing, Martin J. Korbling, Michele L. Donato, Richard E. Champlin
Journal: Blood (2004)
In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia
Authors: Stephen Starko Francis, Amelia D. Wallace, George A. Wendt, Linlin Li, Fenyong Liu, Lee W. Riley, Scott Kogan, Kyle M. Walsh, Adam J. de Smith, Gary V. Dahl, Xiaomei Ma, Eric Delwart, Catherine Metayer, Joseph L. Wiemels
Journal: Blood (2016)
Mutations of the Genes for Ribosomal Proteins L5 and L11 Are a Common Cause of Diamond-Blackfan Anemia.
Authors: Hanna T. Gazda, Mee Rie Sheen, Natasha Darras, Hal Shneider, Colin A. Sieff, Sarah E. Ball, Edyta Niewiadomska, Peter E. Newburger, Eva Atsidaftos, Adrianna Vlachos, Jeffrey M. Lipton, Alan H. Beggs
Journal: Blood (2007)
Clinical Characterization and Proteomic Consequences of Mutated Ras in Acute Myeloid Leukemia.
Authors: Tapan Kadia, Steven M. Kornblau, Hagop Kantarjian, Stefan Faderl, Dan Jones, Guillermo Garcia-Manero, Gautam Borthakur, Charles Koller, Srdan Verstovsek, Sherry Pierce, Jorge Cortes, Farhad Ravandi
Journal: Blood (2009)