tbuckley/cabot-search huggingface dataset:
Protein kinase C θ (PKCθ) expression as a potential diagnostic marker for KIT-negative GIST
Authors: D. A. Braggio, S. Romano, I. A. Small, F. A. Soares, C. G. Ferreira, D. P. Guimarães
Journal: Journal of Clinical Oncology (2009)

10561 Background: Currently, GIST is differentiated from other mesenchymal tumors based on morphologic characteristics and immunohistochemical detection of KIT. Nevertheless, 5% of tumors with clinicopathologic features of GIST lack KIT expression (KIT-negative GIST). A precise diagnosis of GIST is crucial due to the therapeutic efficacy of tyrosine kinase inhibitors. Our goal was to characterize mutational status of tyrosine kinase receptors (KIT and PDGFRA) and to evaluate the value of PKCθ as a diagnostic marker in KIT-negative GISTs. Methods: KIT-negative GISTs (n=22) were analyzed in a retrospective manner. As controls, we included KIT-positive GISTs (n=46), mesenchymal non-GIST tumors (n=28) and KIT-positive non-GIST tumors (n=32). PKCθ and diagnostic markers including CD34, S-100 and desmin were analyzed by immunohistochemistry using a tissue microarray. The χ 2 test was used to compare the presence of PKCθ among the tumors included. Further, PDGFRA gene (exons 12, 14, 18) and KIT gene (exons 9, 11) were examined in KIT-negative GISTs (n=14) by sequencing. Results: PKCθ expression was detected in 63.6% (14/22) of KIT-negative GISTs and this was significantly higher than the frequency of non-GIST tumors (23.3%; 14/60) (p=0.001). PKCθ was detected in 83.7% of KIT-positive GISTs. We found no significant difference between expression rates for PKCθ in KIT-negative and KIT positive GISTs (p=0.069). However, expression rates for PKCθ was higher among all GISTs, regardless KIT expression, when compared to non-GISTs tumors (p&lt;0.001). In addition, among KIT-negative GISTs, CD34 was detected in 59.1% and desmin in 13.6%. None expressed S-100. PDGFRA mutations were found in 5/14 (35.7%) (exon 18, 33.3%; exon 12, 33.3%; exon 14, 16.7%). KIT mutation was found in 1/14 (16.7%; exon 9) tumors analyzed. Conclusions: In contrast to previous reports, there was no predominance of PDGFRA exon 18 mutations in our KIT-negative GISTs. Further, mutation frequency was lower in these tumors than those reported for KIT-positive GISTs. The diagnostic and pathogenic relevance of both PDGFRA and KIT mutations should be better explored. In this study, PKCθ could differentiate GIST, regardless KIT expression, from non-GIST tumors and emerged as a potential diagnostic biomarker for KIT-negative GISTs. No significant financial relationships to disclose.
Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity
Authors: Shasha Chen, Chenxu Cai, Zehua Li, Guangao Liu, Yuande Wang, Marzenna Blonska, Dan Li, Juan Du, Xin Lin, Meixiang Yang, Zhongjun Dong
Journal: The Journal of Experimental Medicine (2017)

Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (TFH) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in TFH cell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient TFH cells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP.
Prognostic Import of French-American-British (FAB) System As Embedded in 2008 Revision of World Health Organization Classification of AML: Review of SWOG Data
Authors: Laura F Newell, Megan Othus, Roland B. Walter, Stephen H. Petersdorf, Thomas Chauncey, Jeanne E. Anderson, John E. Godwin, Kenneth J. Kopecky, Frederick R. Appelbaum, Elihu H. Estey
Journal: Blood (2011)
Abstract 1516: YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like cells
Authors: Namrata Bora Singhal, Jonathan Nguyen, Courtney Schaal, Deepak Perumal, Sandeep Singh, Domenico Coppola, Srikumar Chellappan
Journal: Cancer Research (2015)

Abstract Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that cancer stem-like cells (CSCs) contribute to the genesis and progression of NSCLC. These cells have been shown to form differentiated tumor cells upon receiving appropriate microenvironmental cues and can give rise to multiple components of the tumor, including the vasculature. Earlier work from our laboratory had shown that Hoechst 33342 dye excluding side-population (SP) cells are enriched in cells having stem-like properties. SP cells displayed high self-renewal capacity, were highly drug resistant, and could form metastatic tumors in immunocompromised mice. The present study shows that the transcriptional co-activator YAP1, which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules in matrigel. Inhibition of YAP1 by a small molecule inhibitor Visudyne or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor Sox2. YAP1 could associate with the Sox2 promoter and could transcriptionally induce Sox2 as seen by qRT-PCRs, ChIP assays and promoter luciferase assays; this induction was through a physical interaction of YAP1 with Oct4 protein. The binding of Oct4 to YAP1 could be detected in cell lines as well as NSCLC tumor tissues as seen by immunofluorescence, proximity ligation assays (PLA), immunoprecipitation-western blot experiments and GST binding assays. Interestingly, the interaction was elevated in NSCLC samples compared to normal tissue as seen by PLA. A peptide that could disrupt the interaction between YAP1 and Oct4 abrogated Sox2 expression, self-renewal and vascular mimicry. Depleting YAP1 reduced the expression of EMT genes and prevented the growth and metastasis of tumor xenografts in mice, while overexpression of Sox2 in YAP1 depleted cells could rescue self-renewal of stem-like cells. In conclusion, our results demonstrate that YAP1 can modulate the stem-like functions of cancer stem cells by regulating Sox2, and this regulatory pathway can potentially be targeted for combating NSCLC. Citation Format: Namrata Bora Singhal, Jonathan Nguyen, Courtney Schaal, Deepak Perumal, Sandeep Singh, Domenico Coppola, Srikumar Chellappan. YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like 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 1516. doi:10.1158/1538-7445.AM2015-1516
Spread of yellow fever virus outbreak in Angola and the Democratic Republic of the Congo 2015–16: a modelling study
Authors: Moritz U G Kraemer, Nuno R Faria, Robert C Reiner, Nick Golding, Birgit Nikolay, Stephanie Stasse, Michael A Johansson, Henrik Salje, Ousmane Faye, G R William Wint, Matthias Niedrig, Freya M Shearer, Sarah C Hill, Robin N Thompson, Donal Bisanzio, Nuno Taveira, Heinrich H Nax, Bary S R Pradelski, Elaine O Nsoesie, Nicholas R Murphy, Isaac I Bogoch, Kamran Khan, John S Brownstein, Andrew J Tatem, Tulio de Oliveira, David L Smith, Amadou A Sall, Oliver G Pybus, Simon I Hay, Simon Cauchemez
Journal: The Lancet Infectious Diseases (2016)

BackgroundSince late 2015, an epidemic of yellow fever has caused more than 7334 suspected cases in Angola and the Democratic Republic of the Congo, including 393 deaths. We sought to understand the spatial spread of this outbreak to optimise the use of the limited available vaccine stock.MethodsWe jointly analysed datasets describing the epidemic of yellow fever, vector suitability, human demography, and mobility in central Africa to understand and predict the spread of yellow fever virus. We used a standard logistic model to infer the district-specific yellow fever virus infection risk during the course of the epidemic in the region.FindingsThe early spread of yellow fever virus was characterised by fast exponential growth (doubling time of 5–7 days) and fast spatial expansion (49 districts reported cases after only 3 months) from Luanda, the capital of Angola. Early invasion was positively correlated with high population density (Pearson's r 0·52, 95% CI 0·34–0·66). The further away locations were from Luanda, the later the date of invasion (Pearson's r 0·60, 95% CI 0·52–0·66). In a Cox model, we noted that districts with higher population densities also had higher risks of sustained transmission (the hazard ratio for cases ceasing was 0·74, 95% CI 0·13–0·92 per log-unit increase in the population size of a district). A model that captured human mobility and vector suitability successfully discriminated districts with high risk of invasion from others with a lower risk (area under the curve 0·94, 95% CI 0·92–0·97). If at the start of the epidemic, sufficient vaccines had been available to target 50 out of 313 districts in the area, our model would have correctly identified 27 (84%) of the 32 districts that were eventually affected.InterpretationOur findings show the contributions of ecological and demographic factors to the ongoing spread of the yellow fever outbreak and provide estimates of the areas that could be prioritised for vaccination, although other constraints such as vaccine supply and delivery need to be accounted for before such insights can be translated into policy.FundingWellcome Trust.
Abstract 5054: Discerning the PARP-dependent AR cistrome/transcriptome in prostate cancer
Authors: Matthew J. Schiewer, Sumin Han, Joseph Evans, Michael A. Augello, Lisa Berman-Booty, Theodore Parsons, Ruth Birbe, Adam P. Dicker, William Kevin Kelly, Leonard G. Gomella, Felix Feng, Karen E. Knudsen
Journal: Cancer Research (2015)

Abstract Poly (ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly (ADP-ribose)-ylation. Although PARP-1 has a number of well-described roles in the response to and repair of DNA damage (especially as associated with base excision repair), significant studies have demonstrated that PARP-1 functions in transcriptional regulation in multiple contexts. In the context of prostatic adenocarcinoma (PCa), our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function, and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression, and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. Accordingly, to gain further mechanistic insight in to the PARP-1-dependent AR cistrome/transcriptome, unbiased genome-wide analyses were undertaken in both hormone therapy-sensitive PCa and CRPC model systems. Data to be discussed provide essential insight into the mechanisms by which PARP-1 modulates gene regulation and AR function, but also identifies new and unexpected functions of PARP-1 in human malignancies. Citation Format: Matthew J. Schiewer, Sumin Han, Joseph Evans, Michael A. Augello, Lisa Berman-Booty, Theodore Parsons, Ruth Birbe, Adam P. Dicker, William Kevin Kelly, Leonard G. Gomella, Felix Feng, Karen E. Knudsen. Discerning the PARP-dependent AR cistrome/transcriptome in 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 5054. doi:10.1158/1538-7445.AM2015-5054
Abstract 2737: Dynamics of Epstein-Barr virus loss in the live epithelial cells
Authors: Yuan Zhou, George Tsao
Journal: Cancer Research (2015)

Abstract Epstein-Barr virus (EBV) infection is highly associated with not only lymphoma but also some solid tumour such as nasopharyngeal carcinoma (NPC) and gastric adenocarcinoma. Previous study found that EBV genomes were present in all of NPC cells in vivo, however they lost rapidly during in vitro cell culture. Previously, because it was difficult to label the EBV DNA with fluorescence protein in the nuclear, the mechanism for EBV loss has not been well studied. In present study, we confirmed in the immortalized nasopharyngeal epithelial cells that the percentage of EBV positive cells decreased rapidly after infection. In addition, we infected epithelial cells with recombinant EBV particles that could be visualized as fluorescent signals after entering host nuclear. We further monitored the dynamics of EBV in host nucleus at single cell level by live cell imaging. We found that inefficient replication and uneven partition may contribute to the EBV loss in epithelial cells. In conclusion, our data provides quantitative information about the dynamics of EBV plasmids in epithelial cells at single cell level. This information will shed light to uncover the mechanism for EBV loss after infection in epithelial cells. This work is supported in part by grants from GRF, HKU 779713M and HKU779312M. Citation Format: Yuan Zhou, George Tsao. Dynamics of Epstein-Barr virus loss in the live epithelial 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 2737. doi:10.1158/1538-7445.AM2015-2737
Previous Intravitreal Therapy Is Associated with Increased Risk of Posterior Capsule Rupture during Cataract Surgery
Authors: Aaron Y. Lee, Alexander C. Day, Catherine Egan, Clare Bailey, Robert L. Johnston, Marie D. Tsaloumas, Alastair K. Denniston, Adnan Tufail, Toks Akerele, Saher Al-Husainy, Christopher Brand, Usha Chakravarthy, Louise Downey, Alan Fitt, Rehna Khan, Vineeth Kumar, Aires Lobo, Sajjad Mahmood, Kaveri Mandal, Martin McKibbin, Geeta Menon, Salim Natha, Jong Min Ong, Atul Varma, Elizabeth Wilkinson
Journal: Ophthalmology (2016)
Emergence of drug resistance in patients with tuberculosis cared for by the Indian health-care system: a dynamic modelling study
Authors: Stephanie Law, Amy S Piatek, Cheri Vincent, Olivia Oxlade, Dick Menzies
Journal: The Lancet Public Health (2016)

India has the highest number of patients with tuberculosis and multidrug-resistant tuberculosis in the world. We used a transmission model to project the emergence of drug resistance in India due to incorrect tuberculosis management practices in multiple sectors, including public and private providers, chemists, and non-allopathic practitioners.We constructed a dynamic Markov model to represent India's tuberculosis epidemic, including a probabilistic framework reflecting complex treatment-seeking pathways. Underlying drug resistance and the acquisition of drug resistance during treatment were included. India-specific epidemiological data, including tuberculosis management practices, were obtained from published literature. Outcomes, which included annual risk of infection, incidence of new disease, prevalence of untreated tuberculosis, and tuberculosis-related mortality, were stratified by underlying drug resistance, as well as by health sector to understand how each sector contributes to the emergence of drug resistance.If tuberculosis management practices across sectors in India remain unchanged over the next 20 years, we estimated a 47% increase in the incidence of isoniazid resistance, a 152% increase in multidrug-resistant tuberculosis incidence, a 242% increase in prevalent untreated multidrug-resistant tuberculosis, and a 275% increase in the risk of multidrug-resistant tuberculosis infection. By 2032, an estimated 85% of multidrug-resistant tuberculosis will be primary multidrug-resistant tuberculosis compared with only 15% in 2012. The public sector contributed 87% of acquired multidrug-resistant tuberculosis, related to irregular adherence; the remainder came from the private sector, related to treatment non-completion. Chemists and non-allopathic practitioners do not treat with rifampicin, but because of the high rates of inappropriate isoniazid-containing regimens, and treatment non-adherence, this would generate isoniazid resistance.We predict a gradual transformation from the current epidemic of drug-susceptible tuberculosis to a drug-resistant epidemic. Evidence-based strategies to improve provider practices and patient adherence across health sectors are urgently needed to prevent this.United States Agency for International Development and the Canadian Institutes for Health Research.
711. Development of a Clinically-Acceptable Lentiviral Vector for Cystic Fibrosis Airway Gene Therapy
Authors: Alexandra McCarron, Chantelle McIntyre, Martin Donnelley, Patricia Cmielewski, David Parsons
Journal: Molecular Therapy (2016)

Background: Lentiviral (LV) vectors are a promising gene delivery vehicle for cystic fibrosis airway gene therapy. However, the development of a clinically-acceptable method suited to large-scale lentivirus production remains a barrier to the translation of gene therapy to the clinic. Current virus production methods have limited-scalability and often result in contamination of the vector preparation with potentially immunogenic components such as bacterially-derived plasmid DNA, and animal sera products. Accordingly, a scalable process for the production of clinical-grade vector is required. Methods: LV vector preparations were treated with Deoxyribonuclease I (DNase I) to remove residual plasmid DNA, with the effectiveness measured by PCR using primers to detect the presence of the cytomegalovirus promoter sequence. The potential for scalable LV vector production in serum-free conditions was investigated by performing transient transfection of HEK 293FT cells adapted to grow in serum-free, suspension culture. To determine the efficiency of the virus production system RNA titering was performed using a commercial qPCR kit, and reporter gene expression of GFP and Luciferase were quantified using FACS and IVIS bioluminescence imaging. Results: Plasmid DNA was detected in the vector preparations following DNase treatment, indicating that DNase I was ineffective at eliminating the residual plasmid DNA. Lentivirus was successfully produced using transient transfection of serum-free, suspension growing HEK 293FT cells, and was scaled-up to a one-litre culture capacity in shake flasks. Titres of up to 108 TU/mL were achieved in the suspension cell culture system, which is comparable to the yields obtained in the standard adherent culture system. Conclusions: The protocol developed in this study for serum-free suspension culture virus production resulted in high vector titres that were comparable to those routinely achieved using adherent cells. Furthermore, relative to traditional virus production methods, this protocol is easily scalable, less labour intensive, and has less potential for contamination of the final vector preparation. DNase I treatment was ineffective at removing residual plasmid DNA from the vector preparation, indicating that enzymatic removal of plasmid DNA may not be a feasible approach. Funding: The University of Adelaide; Cure4CF Foundation.
Myeloablative Chemotherapy for T-Cell Lymphoma: a Case for Autologous Stem Cell Transplantatin (Auto) in First Remission.
Authors: Issa F Khouri, Adriana Lopez, Grace-Julia Okoroji, Martin Korbling, Gloria McCormick, Yvonne Hsu, Leandro de Padua, Amin M. Alousi, Chitra M. Hosing, Partow Kebriaei, Gabriela Rondon, Sergio A Giralt, Marcos J. de Lima, Paolo Anderlini, Uday R Popat, Muzaffar H. Qazilbash, Richard E. Champlin, Barbara Pro
Journal: Blood (2008)
Abstract 20211: Contrast Improvement of Biodegradable Stents for X-ray Computed Tomography Visualization
Authors: James Winters, James Bennett, Manfred Guelcher, Anthony Mathur, John Martin, Tarek Fahmy, Albert Sinusas
Journal: Circulation (2014)

Introduction: Biodegradable stents present challenges during percutaneous coronary intervention (PCI) because they are typically radiolucent. For the same reason they cannot be visualized in vivo with clinical CT. By impregnating a contrast agent in the stents’ polymer coating, the stents can be seen during PCI and their degradation can be tracked in vivo using serial CT imaging. We evaluated the degradation of a polymer coated magnesium (Mg) stent in a bioreactor using dual energy microCT. Methods: Bare Mg stents with 125 μm strut thickness were coated with either a mixture of poly(lactic-co-glycolic acid) (PLGA) and triiodobenzoic acid (TIBA) or PLGA and iodinated dendrimer (ID), deployed in latex tubing, and imaged using high resolution microCT (eXplore CT120, GE) at both 80kVp and 120kVp. Stents were exposed to physiological flow in a bioreactor for 5 days, removed and dual energy microCT was repeated using same protocol. Dual energy images were processed using a custom Matlab algorithm, and the iodinated polymer was digitally segmented from the Mg struts. Results: Images of stents at baseline coated with both PLGA-ID and PLGA-TIBA showed a marked increase in CT attenuation. Images of degraded stents coated with PLGA-TIBA showed a loss of attenuation in the polymer coating but little degradation, which suggests the small TIBA molecules was not retained in the polymer. Using dual energy CT enabled segmentation of the struts and polymers. Conclusions: We have demonstrated that the radio-opacity of polymer-coated biodegradable stents can be improved with the addition of an X-ray contrast agent during the process of polymer coating with microCT. The results suggest that the degradation of biodegradable stents could be tracked in vivo. This approach could help with stent deployment and determine when the standard dual anti-platelet therapy can be stopped based on degradation as assessed with dual energy CT.