tbuckley/cabot-search huggingface dataset:
Prevalence of Diagnosed Primary Immunodeficiencies Diseases in France: Results From the French National Registry and the CEREDIH Network.
Authors: Nizar Mahlaoui, Julien Beauté, Yasmine Dudoit, Sophie Hilpert, Nathalie de Vergnes, Gaelle Obenga, Loic Le Mignot, Romain Micol, Paul Landais, Capucine Picard, Felipe Suarez, Olivier Hermine, Marc Lecuit, Olivier Lortholary, Jean Donadieu, Eric Oksenhendler, Alain Fischer
Journal: Blood (2009)
Craniectomy for Traumatic Intracranial Hypertension
Authors: Jimmy W Huh, Shih-Shan Lang, Todd J Kilbaugh
Journal: New England Journal of Medicine (2016)

To the Editor: In the Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) trial reported by Hutchinson and others (Sept.22 issue), 1 mortality among patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension who underwent decompressive craniectomy was lower than that among patients who received medical care.However, at 6 months, patients in the surgical group were more likely to have severe disability (as assessed with the use of the Extended Glasgow Outcome Scale [GOS-E] 2 ) than patients in the medical group.At 12 months, a higher percentage of patients in the surgical group than in the medical group had a favorable outcome.Although most patients in the surgical group underwent a bifrontal decompressive craniectomy (63%), an analysis according to the type of surgery (i.e., bifrontal or unilateral craniectomy) was not performed.This analysis would be helpful given that in the United States, unilateral decompressive craniectomy is a more common surgical decompression procedure than bifrontal decompressive craniectomy.This trial included children as young as 10 years of age.Since among patients with severe TBI, school-aged children generally tend to have better outcomes than adults, 3,4 these patients perhaps should be assessed with a pediatric version of the GOS-E in a separate subgroup analysis. 5
Onset of Autoimmunity In ALPS as a Consequence of Genetic Defects Accumulation
Authors: Aude Magerus-Chatinet, Benedicte Neven, Marie-Claude Stolzenberg, Cecile Daussy, Peter Arkwright, Marina Cavazzana-Calvo, Capucine Picard, Alain Fischer, Frederic Rieux-Laucat
Journal: Blood (2010)
PTH-085 Routine duodenal biopsy for coeliac disease is not cost effective
Authors: G Chakrabarty, H Dambha, R Lawrence, S Zar, A Mahmood
Journal: Gut (2010)

<h3>Introduction</h3> The prevalence of coeliac disease in UK is about 1.5%. Serology provides a relatively cheap and non-invasive means for diagnosis. IgA endomysial (EMA) and IgA anti-tissue transglutaminase (tTG) antibodies are routinely used as a screening tool and carry high sensitivity and specificity. However duodenal biopsy is the accepted gold standard for diagnosis of coeliac disease. Adult coeliac disease generally presents with anaemia and/or non-specific GI symptoms. Both BSG and NICE guidelines recommend that patients with unexplained anaemia should be screened for coeliac disease. If coeliac serology is negative then small bowel biopsies are generally not necessary. Despite this many patients have duodenal biopsy during upper GI endoscopy. Random duodenal biopsies result in increased cost and workload. <h3>Aim</h3> To evaluate the diagnostic yield of a routine duodenal biopsy. <h3>Methods</h3> Retrospective analysis of all duodenal biopsies undertaken between April-July 2009 was done. Endoscopy records, serology and histology records were reviewed. <h3>Results</h3> Total of 103 cases (45M, 58F, mean age 62.6±19.4 years) were examined during the 4-month period. Most common indication was anaemia (57.7%), followed by GI symptoms (17.3%), and weight loss (14.4%). 98 cases were taken for final analysis (5 excluded – 3 biopsies taken to exclude malignancy and 2 for coeliac disease follow-up). Only 1 biopsy out of 98 was diagnostic of coeliac disease, another biopsy showed mild inflammatory changes of uncertain significance and 96 (97.9%) were normal. 18 cases had serology prior to biopsy, out of them 4 had positive tTG, however only one of them was positive for both tTG and EMA and was confirmed coeliac disease on biopsy as well. 80 out of 98 (81.6%) cases had no serology done. All of these had normal histology. Only 10 out of 60 (16.6%) anaemia cases had serology recorded prior to duodenal biopsy. <h3>Conclusion</h3> This study demonstrates that coeliac serology as a screening tool is greatly underutilised and duodenal biopsy is being used as the first choice test for diagnosis of coeliac disease. Despite BSG and NICE guidelines, only 16% of patients with anaemia had serology prior to duodenal biopsy. This may be due to the fact that these patients would have needed endoscopy, so it may have been considered convenient to perform duodenal biopsy at the same time. The cost of serology and histology is about £10 and £35, respectively. Therefore appropriate use of diagnostic tools can result in substantial cost saving. We need more stringent implementation of local protocols to facilitate greater adherence to national guidelines. The prevalence of coeliac disease in our population (1.02%) is in keeping with UK population.
106. Novel Subventricular Zone Early Progenitor Cell Specific Adenovirus for In Situ Brain Stem Cell Bioengineering Unveils Cellular Heterogeneity
Authors: Julia Reetz, Steve Hildebrandt, Anke Schmidt, Claudia Meier, Ottmar Herchenröder, Anne Gläser, Martin Witt, Andreas Wree, Brigitte M. Pützer
Journal: Molecular Therapy (2015)

Neural stem/progenitor cells (NSPC) have the potential to self-renew and to generate all neural lineages as well as to repopulate damaged areas in the brain. Our recent endeavors in the generation of Ad vectors that specifically target SPC in situ have focused on linking selective peptides to viral particles that direct the vector to yet unknown receptors on the surface of stem cells. Using an Ad-PEGylation approach, we demonstrated that a short artificial peptide, which specifically binds neural precursor cells established from the hippocampal area of adult mice or rats, was highly effective in targeting NSPC after vector administration into the brain. These studies also revealed that long-term transgene expression was restricted to precursor cells located in dentate gyrus, and was not detected in other brain regions such as the SVZ and the ependyma of the lateral ventricle. This new indirect evidence for precursor cell heterogeneity in different brain regions that warrants the development of NSPC-specific delivery vehicles was further investigated. Here, we demonstrate a target-specific adenoviral vector system for in vivo manipulation of stem cells in the subventricular zone of the adult mouse brain. For this purpose, we identified a series of peptide ligands via phage display. The peptide with the highest affinity was expressed in conjunction with a bispecific adaptor molecule. In order to verify the targeting potential of the specific peptide, green fluorescent protein-expressing Ad vectors were coupled with the adaptor molecule and injected into the subventricular region of adult mice by stereotaxic surgery. An efficient and selective transduction of NSPC in the SVZ was achieved, whereas hippocampal NSPC were negative. Our results offer an expeditious and simple tool to produce target-specific viral vectors for selective and direct bioengineering of stem cells in situ. This powerful technique provides an excellent opportunity to gain new insight into the fundamental mechanisms that control stem cell fate and to develop innovative strategies for a successfull treatment of brain disorders. This work was supported by the German Research Foundation (DFG) grant PU 188/8-1, WR 20/2-1 and Research funding provided by the Medical Faculty of Rostock University (FORUN program).
In-Vitro Treatment with the AKT-Inhibitor GSK 690693 Induces Cell Death in Lymphoma Cell Lines and in Primary CLL Cells and Is Followed by Caspase-3 Activation and Cytochrome C Release.
Authors: Dirk Winkler, Thorsten Zenz, Daniel Mertens, Annett Habermann, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2008)
Frequent methylation of the calcium channel-related gene, CACNA2D3, in gastric cancers
Authors: Yoshimitsu Akiyama, Aira Wanajo, Akane Sasaki, Yasuhito Yuasa
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Loss of heterozygosity on chromosome 3p21 region frequently occurs in several types of cancers including gastric cancers, and some tumor-related genes, such as Rassf1 and hMLH1, have been identified in this region. We also searched for tumor-related genes locating on the 3p21 region by computer analysis and found the voltage-activated calcium channel alpha-2 delta-3 subunit (CACNA2D3) gene, which contains dense CpG island in the 5’ region of its exon 1. It was recently reported that another calcium channel-related genes, CALCA1I and CACNA1G, were frequently methylated in gastro-intestinal cancers. However, it remains unknown whether or not CACNA2D3 is related to carcinogenesis. To clarify the role of CACNA2D3, we examined expression and methylation status of it in gastric cancers. Normal stomach tissues abundantly expressed CACNA2D3 mRNA, while two of the four cultured gastric cancer cell lines and one colon cancer cell line did not. These three CACNA2D3-negative cell lines restored its expression after 5-aza-2’-deoxycytidine treatment. Aberrant methylation of CACNA2D3 was detected in CACNA2D3-negative cells but not in positive cells and normal stomach by using methylation-specific PCR (MSP) and bisulfite sequencing. As for the primary gastric cancers, 23 of the 79 cases (29.1%) demonstrated CACNA2D3 methylation by MSP. CACNA2D3 methylation was frequently found in the diffuse type (15/37, 40.5%) than in the intestinal type (8/42, 19.0%) gastric cancers (p=0.04). Over-expression of CACNA2D3 in 293T cells induced the growth inhibition by WST-1 cell proliferation assay. Our data suggest that loss of CACNA2D3 expression through aberrant methylation may contribute to gastric carcinogenesis.
Abstract 3946: Secretory ANXA3 endows liver cancer cells with tumorigenic and self-renewal abilities and promotes HCC development
Authors: Man Tong, Stephanie Ma
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of mortality in Southeast Asia and in Hong Kong. Despite advances in treatment, the prognosis of advanced HCC patients remains dismal. Contemporary challenge in treating HCC has been the common chemotherapy resistance and recurrence after therapy.Therefore, the identification of valid targets and the development of new therapies are urgently needed for more effective clinical management of this deadly disease. We found secretory annexin A3 (ANXA3) to be up-regulated in HCC cell lines, compared with immortalized normal liver cell line MIHA. Clinically, secretory ANXA3 levels in the serum were found to be progressively elevated from non-HCC individuals to early and advanced HCC patients, with up-regulation of serum ANXA3 to be tightly associated with gender, number of tumor nodules, tumor sizes and tumor stages. More importantly, the diagnostic value of secretory ANXA3, as evident by ROC analysis, was found to be more superior to the commonly used biomarker alpha-fetoprotein (AFP). Subsequent functional studies found secretory ANXA3 to promote cancer and stem cell-like properties of HCC cells. Co-culture of conditioned medium from ANXA3-overexpressing cells with ANXA3-absent HCC cells potentiated the abilities of HCC cells to migrate, invade, self-renew, induce tube formation in endothelial cells, and resist apoptosis induced by staurosporine and chemotherapy. The in vivo tumor-initiating capacity was also significantly enhanced in HCC cells when co-cultured with ANXA3-containing conditioned medium compared with conditioned medium from cells transfected with empty vector control. Similar functional properties were also observed when MIHA cells were treated with recombinant ANXA3 proteins. In an effort to characterize the molecular mechanism by which ANXA3 drives cancer and stem cell-like properties in HCC, cDNA microarray profiling was performed to compare the gene expression between ANXA3-depleted and control cells. Pathway enrichment analysis found many of the deregulated genes to be closely associated with the JNK/AP-1 signaling cascade. Activation of JNK pathway was detected when cells were treated with recombinant ANXA3 proteins or ANXA3-containing conditioned medium. Collectively, our findings suggest that secretory ANXA3 plays pivotal roles in promoting tumor initiation, growth and chemoresistance through the activation of JNK signaling pathway in HCC. Citation Format: Man Tong, Stephanie Ma. Secretory ANXA3 endows liver cancer cells with tumorigenic and self-renewal abilities and promotes HCC development. [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 3946. doi:10.1158/1538-7445.AM2015-3946
Efficacy and Safety of Biosimilar G-CSF and Originator G-CSF for Haematopoietic Stem Cell Mobilisation: A Randomised Comparison
Authors: Anna Dmoszynska, Joanna Manko, Adam Walter Croneck, Norbert Grzasko, Piotr Klimek, Aleksandra Nowaczynska, Magdalena Gorska-Kosicka
Journal: Blood (2011)
Abstract 184: Pressure Overload Activates Left Ventricular (LV) Intramyocardial Vascular Endothelial Cells and induces T Cell Infiltration into the LV
Authors: Pilar Alcaide, Anna Grodecki-Pena, Andrew Knapp, Tanya Kershaw, Mark Aronovitz, Navin Kapur, Robert Blanton, Richard H Karas
Journal: Circulation Research (2013)

Left ventricular dysfunction and Heart Failure (HF) are associated with systemic inflammation with clinical data showing that HF patients have higher levels of circulating pro-inflammatory cytokines. Recruitment of circulating T cells to tissues across the vascular endothelium is a key event in the inflammatory response, but whether it plays a role in the heart in HF is unknown. We hypothesized that pressure overload induced HF activates cardiac endothelial cells resulting in T cell recruitment into the left ventricle (LV). Using transverse aortic constriction (TAC), quantitative flow cytometry, immunohistochemistry, qPCR and real time live cell videomicroscopy, we examined mRNA and protein expression levels of endothelial cell adhesion molecules and the presence of T cell infiltrates in the LV in vivo , and also studied the T cell interactions with primary mouse heart endothelial cells (MHEC) under flow conditions in vitro , comparing Sham and TAC operated mice (6-10/group) during the course of HF. 48h after TAC, in the pre-hypertrophic state, no differences were observed in the recruitment of T cells in the LV. Interestingly, two and four weeks after TAC, when mice developed LVH and LV dysfunction (Fractional Shortening 25±13%), E-Selectin, VCAM-1 and ICAM-1 mRNA levels were significantly upregulated in the LV as compared to Sham mice (2.3, 2.8 and 4 fold, respectively), with notable enhancement of endothelial ICAM-1 protein levels in the LV intramyocardial vessels, and T cells infiltrated in the LV in response to TAC (P≤0.05 TAC vs Sham). Furthermore, T cells isolated from mice 2 and 4 weeks after TAC adhered to MHEC under flow conditions in significantly higher numbers than T cells from Sham mice (P≤0.01 TAC vs Sham). Systemically, the frequency of three different T cell subsets in the peripheral lymphoid organs was increased in TAC vs Sham mice, indicating activation of the adaptive immune response to pressure overload. Taken together, our studies indicate that activation of the heart vascular endothelium occurs in response to pressure overload resulting in T cell recruitment into the LV. Further studies will be needed to determine in the extent to which T cell recruitment into the heart contributes to the pathogenesis of HF.
Autoinflammatory Disease Damage Index (ADDI): a possible newborn also in hidradenitis suppurativa daily practice
Authors: Giovanni Damiani, Valentina della Valle, Michela Iannone, Valentina Dini, Angelo Valerio Marzano
Journal: Annals of the Rheumatic Diseases (2016)

To the Editor:

Ter Haar et al 1 report a new tool, Autoinflammatory Disease Damage Index (ADDI), to measure damage caused by autoinflammatory diseases. Although this preliminary instrument was for patients with familial Mediterranean fever, cryopyrin associated periodic syndrome, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency, we found a great utility also in another …
Abstract 2643: Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53
Authors: Liz J. Hernandez Borrero, Shengliang Zhao, David T. Dicker, Wafik El-Deiry
Journal: Cancer Research (2015)

Abstract One of the most explored cancer targets has been the tumor suppressor p53. p53 is mutated in more than half of all human tumors and therefore provides an attractive way to selectively target cancer cells that harbor the mutant protein. Mutant p53 protein can acquire a gain-of-function activity, losing its normal tumor suppressor properties and gaining oncogenic characteristics. Various approaches have been taken to restore the p53 pathway in mutant p53 expressing cells including the modulation of mutant p53 conformation to wild-type, and through the upregulation of p53 family members i.e. p73. Unlike p53, p73 is not commonly mutated in cancer cells and thus confers restoration of the p53 pathway through pharmacological stimulation. We characterized a small molecule that restores the p53 pathway through p73. A high-throughput cell-based screen identified small molecule CB002 as a potential candidate for the restoration of the p53 pathway in mutant p53 containing human colorectal cancer cells. Two colorectal cancer cell lines: SW480, DLD-1, and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 for various time points. SW480 cells treated with CB002 for 8 hrs showed a decrease in p53 followed by an increase in DR5 expression at 16 hrs. DLD-1 cells treated with CB002 showed a decrease in p53 expression at 8 hrs. Although no change was observed in proteins involved in cell cycle arrest or cell death that were tested, colony formation was suppressed as compared to control. RXF393 cells treated with CB002 for 48 hrs showed decreased expression of p53 levels and increased levels of p21. These data suggest that CB002 is able to decrease mutant p53 protein expression, increase p53 target genes and promote expression of proteins involved in apoptosis, such as p21 and DR5, respectively. It appears that the CB002 mechanism is different depending on the cell line tested. We hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p73 in colorectal cancer cells. Current undergoing experiments are focused on unraveling the p73 dependence through p73 knockdown and the mechanism of action involved in each cell line. The following project will aid in the understanding of the role of p73 in pharmacological restoration of the p53 pathway in cancer therapy. Citation Format: Liz J. Hernandez Borrero, Shengliang Zhao, David T. Dicker, Wafik El-Deiry. Small molecule identification for the restoration of p53 pathway through p73 and by degradation of mutant p53. [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 2643. doi:10.1158/1538-7445.AM2015-2643
279. Efficient and Safe Lentiviral Vector-Mediated Hematopoietic Stem Cell Gene Therapy in MNGIE Mice
Authors: Rana Yadak, Javier T. Torronteras, Raquel C. Pérez, Elly Bogaerts, George de Ruijter, Jordi Barquinero, Ramon Marti, Bert J. Smeets, Marshall W. Huston, Niek P. van Til, Gerard Wagemaker, René F.M. de Coo
Journal: Molecular Therapy (2015)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients are deficient in thymidine phosphorylase(TP) resulting in systemic thymidine(Thd) and deoxyuridine(dUrd) accumulation affecting mtDNA replication and causing mitochondrial dysfunction. Common symptoms are gastrointestinal dysmotility, progressive ophthalmoplegia and leukoencephalopathy. Allogenic hematopoietic stem cell (HSC) transplantation has been shown to reduce disease symptoms, but is not well tolerated due to the inherent toxicity of the procedure. Therefore, syngeneic ex vivo lentiviral vector HSC gene therapy overexpressing the native cDNA or the codon optimized (TPco) sequence driven by the phosphoglycerate kinase (PGK) or spleen focus forming virus (SFFV) promoters in Tp−/-Upp−/- double knockout mice, a model for MNGIE disease, was investigated. At 1 month post transplantation after sublethal total body irradiation, very low TP activity was detected in blood of control wild type mice (0.07±0.03nmoles/h/mg), but enzyme activities in PGK treated mice were at least 90-fold higher (PGK-TP = 150±4 and PGK-TPco = 96±4 nmoles/h/mg), and in SFFV recipient mice 400-fold higher (450±5 nmoles/h/mg). Consequently, a significant reduction of plasma and urine Thd and dUrd levels was observed. Long-term follow up (14 months) showed on average 1.2-fold wild type TP activity levels increase in LV-PGK-TP and LV-PGK-TPco and 36-fold in SFFV-TPco treated mice. This was sufficient for sustained reduction of plasma and urine nucleoside levels, which was achieved at 76.5±8.2% donor chimerism levels with low LV vector copy numbers (1.0±1.1VCN/donor cell). The LV integration profile in bone marrow cells of primary recipients was analyzed; LVs displayed the expected tendency to integrate within highly expressed genes and the integration pattern did not differ from that of other SIN-LV vectors in other disease models (primary immune deficiencies and lysosomal enzyme storage disorders). Overall, stem cell gene therapy provided stable TP expression and long-term biochemical correction in MNGIE mice without genotoxicity or apparent phenotoxicity, which will be further evaluated for somatic and neurological phenotype correction and optimized to develop a clinical protocol to treat MNGIE patients.
Impact of Prior Treatment on Patients with Relapsed Multiple Myeloma Treated with Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in a Subgroup Analysis of the Phase 3 Endeavor Study (NCT01568866)
Authors: Philippe Moreau, Douglas Joshua, Wee-Joo Chng, Antonio Palumbo, Hartmut Goldschmidt, Roman Hájek, Thierry Facon, Heinz Ludwig, Ludek Pour, Ruben Niesvizky, Albert Oriol, Laura Rosiñol, Aleksandr Suvorov, Gianluca Gaidano, Tomas Pika, Katja Weisel, Vesselina Goranova-Marinova, Heidi H. Gillenwater, Nehal Mohamed, Shibao Feng, Meletios Dimopoulos
Journal: Blood (2015)