tbuckley/cabot-search huggingface dataset:
Analysis of genomic ancestry in a sample of high-risk patients with hereditary breast cancer from Bahia, Brazil.
Authors: I. L. O. Nascimento, T. M. B. Machado, B. Toralles, L. A. Ferreira, M. Romeo, C. A. Sandes, L. Meyer, B. Garicochea, R. Meyer, S. Freire, K. Abe-Sandes
Journal: Journal of Clinical Oncology (2011)

1515 Background: Many diseases, including cancer, have prevalence related to race and/or to ethnics or geographics aspects. Admixture mapping has been done in several populations including Brazilian people. Muniz et al (2008) observed an ancestry of 62% European, 26% African and 12% Natives in Brazilian afrodescendents. According to IBGE (Brazilian Institut of Geography and Statistic) data the people from Bahia is predominantely made by afrodescendent (77,5%) but this information is based on pheonotype analysis. There is no information about the association between this admixture and hereditary breast/ovary cancer (HBOC) in patients from Bahia- Brazil. The primary objective of this work is to study the genomic ancestry of HBOC high risk patients from Bahia’s (Brazil) ethnically diverse population. Methods: Charts of 109 patients referred to the Oncogenetics Service were reviewed and the blood samples were collected and submitted to molecular studies for the following ancestry informative markers (AIMs): AT3-I / D, PDB SB19.3, PV92, FY-null, LPL, CKMM, GC1S and GC-1F. Admixture mapping was analyzed using the program ADMIX. Results: Ancestry as reported by the patients: 49% referred “Brazilian” (they do not know to specify); 38% referred European and only 5.5% reported African ancestries. Genomic ancestry analysis showed the following contribuition: 66% of European and 34% of African. South American natives contribuition it was not detected in this sample. Conclusions: The genomic ancestry analysis shows a high European contribuition which agrees with the literature that reports a higher prevalence of breast cancer among Caucasian women. So, although the Bahia’s population has a well known large African ancestry, the sample of HBOC high risk patients studied has a larger European than African ancestry contribuition.
JAK2 (V617F) Mutation and Cerebral Venous Thrombosis,
Authors: Ida Martinelli, Serena Maria Passamonti, Eugenia Biguzzi, Franca Franchi, Francesca Gianniello, Paolo Bucciarelli, Daniela Pietra, Pier Mannuccio Mannucci, Mario Cazzola
Journal: Blood (2011)
Association of Polymorphisms of the Transforming Growth Factor-β/Bone Morphogenetic Protein (TGF-β/BMP) Pathway with Sickle Cell Bacteremia.
Authors: Adeboye H. Adewoye, Vikki G. Nolan, Clinton T. Baldwin, Diego F. Wyszynski, Qian-Li Ma, John J. Farrell, Alice Bisbee, Erica Homan, Paola Sebastiani, Lindsay A. Farrer, Martin H. Steinberg
Journal: Blood (2005)
Abstract 2218: Qualitative and quantitative analysis of IDH1 mutation in progressive gliomas by allele-specific quantitative RT-PCR and Western blot analysis
Authors: Marco Timmer, Moritz Perrech, Gabriele Röhn, Lena Dreher, Roland Goldbrunner
Journal: Cancer Research (2015)

Abstract Diagnostic of the IDH1 mutation (IDH1mut) is so far based on DNA sequencing and immunohistochemistry (IHC), methods limited in terms of sensitivity and ease of use. Recently, measuring the IDH1mut level by real time PCR was introduced as alternative method. Therefore, we aimed to (i) validate this new technique in a larger patient cohort, compare it to control tissue, and (ii) investigate if the expression of both, IDH1mut and IDH1 wildtype (IDH1wt) correlates with the course of disease and different treatment regimens. A total of 113 tumor samples were obtained intraoperatively from 84 glioma patients with diagnosis of diffuse glioma (WHO°II), anaplastic glioma (WHO°III), secondary glioblastoma +/- chemotherapy (CTx), primary glioblastoma +/- CTx (WHO°IV). Tumor samples were snap frozen and processed for sectioning, RNA and protein isolation. The quantitative expression of IDH1 mRNA was assessed using real-time PCR with specific primers for IDH1mut and -wt; protein expression was verified by Western Blot analysis and IHC. Additionally, 19 samples of LGG and their consecutive HGG were analyzed at different time points of disease. Allele-specific quantitative RT-PCR does work in larger patient cohorts and seems to be an easy and ∼10 times more sensitive method for quantitative IDH1mut evaluation compared to the ones used so far. Our results with this new method confirmed previous data showing that most astrocytomas and secondary GBM bear the mutation (conc. 0.13 to 0.2) whereas most primary GBM do not (conc. ∼0.025). Quantitative analysis revealed that IDH1mut expression is upregulated in sGBM (mean±SEM: 3.52±0.55) compared to lower grade glioma (II° = 1.54±0.22; III° = 1.67±0.23). By contrast, IDH1wt expression is upregulated in all glioma grades (con. &amp;gt;0.1) compared to control brain tissue (0.007± 0.0016). Western Blot analysis showed a high concordance to both, sequencing and RT-PCR results in qualitative analysis of IDH1mut status (specificity 100% and sensitivity 100%). Moreover, semiquantitative protein expression analysis also showed higher expression levels of mutated IDH1 in sGBM. Taken together, recurrent disease and radiochemotherapy do not alter the general IDH1 status. Moreover, we found an increase of IDH1mut gene expression in sec. GBM compared to lower grade glioma indicating a pivotal role of IDH1mut not only in gliomagenesis but also in glioma progression. Citation Format: Marco Timmer, Moritz Perrech, Gabriele Röhn, Lena Dreher, Roland Goldbrunner. Qualitative and quantitative analysis of IDH1 mutation in progressive gliomas by allele-specific quantitative RT-PCR and Western blot analysis. [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 2218. doi:10.1158/1538-7445.AM2015-2218
PTH-098 A study of HLA status and thyroid peroxidise antibodies in adult patients with coeliac disease
Authors: A J Ball, J S Leeds, R C Bunn, N R Lewis, A Allahabadia, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> We have previously shown that thyroid peroxidase antibodies (TPO) are more commonly found in patients with coeliac disease (CD) compared to controls and raised titres are associated with an increased risk of thyroid disease. Some studies have suggested that compliance reduces the risk of other autoimmune disease including thyroid dysfunction. The relationship between dietary adherence and TPO titre is not known. We sought to assess the changes in TPO before and after a gluten free diet (GFD). Furthermore, we also investigated whether HLA type has any influence on the prevalence of thyroid disease and TPO in these patients. <h3>Methods</h3> Patients were recruited from the specialist coeliac clinic. Demographic details, current thyroid status (including TPO level), HLA status, duration of both CD and thyroid disease were recorded. Tissue-transglutaminase antibodies (tTG) were measured at baseline along with TPO. At follow-up both antibody titres were measured and compared to baseline values. <h3>Results</h3> 36/120 patients were excluded from analysis due to incomplete tTG and TPO testing. 84 patients with CD had sequential TTG and TPO analysis (mean age 48, 25 males, and median duration of follow-up 3 years). At baseline 19/84 (22.6%) had positive TPO (normal &lt;50 iu/ml) compared to 18/84 (21.4%) at follow-up. On analysis of tTG with unpaired t test, individuals with positive TPO had a trend towards higher tTG antibodies at baseline (229 vs 174, p=0.08) and a significantly higher tTG at follow-up (96 vs 44, p=0.03). We did not find any significant difference between TPO titres at diagnosis and follow-up (Mean TPO titre; at diagnosis=340, at follow-up=274, p=0.68). HLA status was tested on 88/120 patients (21/88 HLA DQ2 homozygotes, 61/88 HLA DQ2 heterozygotes and 6/88 were HLA DQ 8) Patients who were heterozygous for HLA DQ2 were significantly more likely than patients who were homozygous for HLA DQ8 to have raised TPO titres (21/61 heterozygotes were TPO positive compared to 2/21 homozygotes, OR 5.0, CI 1.1 to 23.5, p=0.046. <h3>Conclusion</h3> TPO positivity is common in patients with coeliac disease. This study uniquely shows that TPO positivity is predictive of higher tTG at follow-up. In addition we have also shown that CD patients with HLA DQ2 homozygosity have a reduced TPO titre.
OC-032 Persisting histological inflammation in autoimmune hepatitis despite biochemical remission: assessment of factors influencing outcome
Authors: B S R Hoeroldt, C Salmon, A Dube, E MacFarlane, D Gleeson
Journal: Gut (2010)

<h3>Introduction</h3> We have previously1 reported presence of persisting necro-inflammation (Ishak score (NIS) &gt;3), despite biochemical remission, in 38% of AIH patients; this was independently associated with mortality. <h3>Aim</h3> We aimed here to assess outcome further in these patients and to identify demographic, disease and treatment-related factors associated with death or for liver transplantation (OLT). <h3>Patients and Methods</h3> 50 patients with AIH by IAIHG criteria (16 probable, 34 definite, 39 women, median age 52 years), who had achieved biochemical remission (ALT&lt;2× upper normal limit, median (range) 29 U/l (9–84)) for 1 (0.5–5.5) years on immunosupression (IS) treatment, but had NIS &gt;3 on remission biopsy (performed 2.1 (1–14) years, following diagnostic biopsy. After remission biopsy, 30 patients were given routine IS (Prednisolone withdrawal plus increased Azathioprine to 2 mg/kg BW/day) and 20 received altered/enhanced IS (increased Azathioprine with continuation of Prednisolone (n=11) or change to another IS drug n=9). <h3>Results</h3> 16 patients died, six due to liver disease (2 HCC, 3 liver failure, 1 portal vein thrombosis). 2/6 died post OLT. 10- and 20-year mortality was 11+6% and 65+11% (all cause death/OLT) and 5+4% and 32+12 (liver related death/OLT). 11 patients had cirrhosis at diagnosis; in the remainder, de-novo cirrhosis development rate was 37+12% after 10 years. In Cox regression analysis, all-cause death/OLT was associated with older age (p=0.029) but with no other parameter, including NIS or fibrosis on follow-up biopsy, whether subsequently given routine or altered/enhanced IS, or whether or not Prednisolone was continued. Likewise, no parameters were associated with liver-related death/OLT. 18 patients underwent further remission biopsy 2.3 (1–5.5) years later. NIS fell slightly, compared to first remission biopsy (median 5 to 4 p=0.011) and fell to &lt;3 in eight patients, all of whom survived. Fibrosis stage was unchanged (median 3 to 3). <h3>Conclusion</h3> Persistent necroinflammation in AIH is associated with substantial mortality. However (apart from age) we could not identify predictors of mortality and specifically, could not relate outcome to alterations in IS. More intensive IS strategies may be required for these patients.
Free Versus Neutrophil-Bound Antibodies in 100 Consecutive Italian Children with Chronic Neutropenia.
Authors: Laura Porretti, Raffaella Lopa, Alessandra Cattaneo, Paola Portararo, Roberta Ghilardi, Piero Farruggia, Baldassarre Martire, Alessandra Corti, Paolo Rebulla
Journal: Blood (2006)
Diversification of Cell Lineages in Ureter Development
Authors: Tobias Bohnenpoll, Sarah Feraric, Marvin Nattkemper, Anna-Carina Weiss, Carsten Rudat, Max Meuser, Mark-Oliver Trowe, Andreas Kispert
Journal: Journal of the American Society of Nephrology (2016)

The mammalian ureter consists of a mesenchymal wall composed of smooth muscle cells and surrounding fibrocytes of the tunica adventitia and the lamina propria and an inner epithelial lining composed of layers of basal, intermediate, and superficial cells. How these cell types arise from multipotent progenitors is poorly understood. Here, we performed marker analysis, cell proliferation assays, and genetic lineage tracing to define the lineage relations and restrictions of the mesenchymal and epithelial cell types in the developing and mature mouse ureter. At embryonic day (E) 12.5, the mesenchymal precursor pool began to subdivide into an inner and outer compartment that began to express markers of smooth muscle precursors and adventitial fibrocytes, respectively, by E13.5. Smooth muscle precursors further diversified into lamina propria cells directly adjacent to the ureteric epithelium and differentiated smooth muscle cells from E16.5 onwards. Uncommitted epithelial progenitors of the ureter differentiated into intermediate cells at E14.5. After stratification into two layers at E15.5 and three cell layers at E18.5, intermediate cells differentiated into basal cells and superficial cells. In homeostasis, proliferation of all epithelial and mesenchymal cell types remained low but intermediate cells still gave rise to basal cells, whereas basal cells divided only into basal cells. These studies provide a framework to further determine the molecular mechanisms of cell differentiation in the tissues of the developing ureter.
Human Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease and Maintain Graft-Versus-Leukemia in Murine Allogeneic Bone Marrow Transplantation
Authors: Jeffery J Auletta, Saada Eid, Matthew Keller, Leland Metheny, Rocio Guardia-Wolff, Zhenghong Lee, Luis A Solchaga, Kenneth R. Cooke
Journal: Blood (2011)
121. T Cell Receptor Modification by Highly Specific TALEN and CRISPR/Cas9
Authors: Friederike Knipping, Karl Petri, Eliana Ruggiero, Mark Osborn, Jakub Tolar, Manfred Schmidt, Christof von Kalle, Richard Gabriel
Journal: Molecular Therapy (2016)

Adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach, however it comprises certain challenges. Endogenous and transferred TCR chains compete for surface expression and may pair inappropriately, potentially leading to autoimmunity. This can be prevented by designer nucleases such as transcription activator-like effector nucleases (TALEN) and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) system. Their ability to introduce specific DNA double strand breaks (DSB) at their target sites can be harnessed for targeted genome editing. DSB repair through non-homologous end joining (NHEJ) can result in permanent gene knockout due to frame shift mutations. Alternatively, if a homology-containing donor template is provided, transgenes can be integrated into the specific target locus by homology directed repair (HDR). In order to disrupt endogenous TCR expression, we assembled nine TALEN and two CRISPR/Cas9 guide RNA (gRNA) targeting the constant region of the TCR α-chain (TRAC) and four TALEN and three CRISPR/Cas9 gRNA targeting both constant regions of the TCR β-chain (TRBC1/TRBC2). Here we show specific DSB induction by TALEN and CRISPR/Cas9 in K562 and primary T cells using T7 endonuclease I targeting efficiency assay and deep sequencing. Electroporation of primary T cells with TRAC-TALEN or TRBC-TALEN mRNA led to successful elimination of surface TCR expression in about 76% of the cells. To analyze nuclease specificity, K562 cells were transduced with an integrase-defective lentiviral vector (IDLV) prior to nucleofection with TALEN- or CRISPR/Cas9-expressing plasmids. IDLV can be integrated into DSB during DNA repair, thereby serving as stable markers for transient DSB. IDLV-marked DSB were subsequently localized using LAM-PCR and deep sequencing. Clustered integration sites (CLIS) were detected around all nuclease target sites, confirming on-target activity. Although up to 3268 IDLV integration sites were analyzed for each TALEN and CRISPR/Cas9 gRNA, only one CLIS for one gRNA was mapped at an off-target position, indicating a very high level of specificity. To establish HDR-mediated targeted integration, we assembled donor templates containing a GFP expression cassette flanked by 800bp TRAC- or TRBC1-homologous sequences. We verified targeted gene addition in 10% of K562 cells treated with TALEN and the respective donor template. Delivery of the TRAC-donor packaged into IDLV resulted in targeted integration of the GFP expression cassette in 5% of primary T cells. To sum up, here we present highly efficient and specific TALEN and CRISPR/Cas9 and their utility for T cell engineering.
229. PGE2 Increases Lentiviral Vector Transduction Efficiency of Human HSC
Authors: Garrett Heffner, Melissa Bonner, Dakota Campbell, Lauryn Christiansen, F. John Pierciey, Wen Zhang, Gretchen Lewis, Yegor Smurnyy, Amanda Hamel, Seema Shah, Holly Horton, Byoung Ryu, Kendrick Goss, Olivier Negre, Gabor Veres, Christopher Horvath, Mitchell Finer, Philip Gregory
Journal: Molecular Therapy (2016)

Gene therapy for congenital hematopoietic disorders frequently relies on ex vivo lentiviral transduction of isolated CD34+ hematopoietic progenitor cells. Through a high-throughput small molecule screen, we identified PGE2 as a positive mediator of lentiviral transduction of hematopoietic stem and progenitor cells enriched from mobilized peripheral blood (PB CD34+ cells). CD34+ cells transduced with a VSVG-pseudotyped lentiviral vector in the presence of cytokines and 10 uM PGE2 yielded a vector copy number per cell (VCN) approximately 2-fold higher than CD34+ cells transduced in the absence of PGE2. This effect was seen consistently in 16 of 16 tested normal human donors in vitro, as well as primary CD34+ cells from both thalassemia and sickle cell disease patients. Importantly, PGE2 was observed to improve transduction of prospectively-isolated CD34+CD38- hematopoietic stem cells - a sub-population thought to be enriched for the long term repopulating stem cell. Transduction improvements were not associated with increased viral entry, but were associated with elevated expression of cAMP genes, supporting a post-entry mechanism of action that involves cAMP signaling downstream of prostaglandin receptors. Lastly, in a mouse xenotransplantation model of hematopoietic stem cell transplant, transduction of PB CD34+ cells in the presence of PGE2 improved VCN levels in engrafted human CD45+ cells 4-5 months post-transplant by ~2-fold without adversely affecting overall human cell engraftment. These data suggest that PGE2-mediated improvements in lentiviral transduction of human CD34+ cells could result in higher transduction efficiency and provide potential benefit in clinical gene therapy applications.
Suppression of Cyclin D 1 (CD1) by on 01910.Na Is Associated with Decreased Survival or Trisomy 8 Myelodysplastic Bone Marrow: A Potential Targetted Therapy for Trisomy 8 MDS.
Authors: Aarthi Shenoy, Loretta Pfannes, Francois Wilhelm, Manoj Maniar, Neal Young, Elaine M Sloand
Journal: Blood (2008)
Abstract SY42-03: One carbon metabolism and cancer
Authors: Oliver Maddocks, Christiaan Labuschagne, Karen H. Vousden
Journal: Cancer Research (2015)

Abstract Cancer cells adapt their metabolism to allow for growth and proliferation, while maintaining survival under conditions of fluctuating nutrient availability. Recent studies have shown that cancer cells are highly dependent on the non-essential amino acid serine. We have found a key requirement for serine is to maintain the one carbon cycle needed for nucleotide synthesis. Serine depletion impedes nucleotide synthesis and inhibits proliferation, a response that can be rescued by providing glycine and one-carbon units in the form of formate. More recently, we have been examining the fate of serine and the effect of serine depletion on other pathways that require one-carbon metabolism, such as NADPH production and the methionine cycle. We found that the adaptation to serine starvation involves diversion of glycolytic intermediates into the de novo SSP, resulting in a greater dependence on OXPHOS to provide energy. Interestingly, the serine produced during this period of adaptation is channeled into antioxidant defense through generation of both glutathione and NADPH, to help buffer the ROS produced from this increase in OXPHOS. Defects in the ability to make this adaptation and limit ROS, as seen in cells lacking p53, impedes the ability of cells to cope with a loss of exogenous serine. Serine is also required to support the S-adenosyl methionine (SAM) cycle, although surprisingly we have found that this reflected a requirement for ATP rather than one-carbon units. As a consequence, serine depletion caused a decrease in the conversion of methionine to SAM and a rapid remodeling of DNA methylation. We are currently examining the consequences on gene specific methylation and expression. Funded by CR-UK and ERC Citation Format: Oliver Maddocks, Christiaan Labuschagne, Karen H. Vousden. One carbon metabolism and 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 SY42-03. doi:10.1158/1538-7445.AM2015-SY42-03
Statins Reduce Disease Activity (SLAM-R) and Organ Damage Accrual (SLICC Damage Index, SDI) Scores in SLE Patients From A Multi-Center, Multi-Ethnic, US Cohort.
Authors: Silvia S Pierangeli, Alan SEif, Renan Aguilar-Valenzuela, Laura Aline Martinez-Martinez, Ellis Doan, Neha Dang, Elizabeth Papalardo, John D. Reveille, Graciela S. Alarcon
Journal: Blood (2009)
NK Cell Subsets Isolated From Human Thymus Differ From Peripheral Blood NK Cells in Their Cytotoxic and Cytokine Secreting Capability
Authors: Stephanie Krieg, Wolfgang Koehler, Gordon Heidkamp, Julia Schneider, Franziska Ganss, Ariawan Purbojo, Andreas Mackensen, Robert Cesnjevar, Diana Dudziak, Evelyn Ullrich
Journal: Blood (2012)
Transgene Deletions in Long-Term Circulating Donor Gene-Modified T Lymphocytes Infused at Time of Hematopoietic Transplantation.
Authors: Patricia Mercier, Marina Deschamps, Christophe Ferrand, Eric Robinet, Jean-Marie Certoux, Delphine Sauce, Bruno Lioure, Eric Deconinck, Pierre Tiberghien
Journal: Blood (2005)