tbuckley/cabot-search huggingface dataset:
PDCT-08. DOES THE INTERVAL FROM TUMOUR SURGERY TO RADIOTHERAPY INFLUENCE SURVIVAL IN PAEDIATRIC HIGH GRADE GLIOMA?
Authors: Amedeo A. Azizi, Simon Paur, Alexandra Kaider, Karin Dieckmann, Andreas Peyrl, Monika Chocholous, Thomas Czech, Irene Slavc
Journal: Neuro-Oncology (2016)

Children > 3 years with high grade glioma (HGG) receive radiotherapy as standard of care. A short interval between tumour surgery and start of radiotherapy is intended empirically to prevent early relapse. In adults the influence of delayed radiotherapy on survival is disputed in glioblastoma patients, some studies suggesting early irradiation even as a negative factor. This study investigates the interval of tumour surgery to radiotherapy (ISRT) and its influence on survival in paediatric HGG patients. Retrospective analysis including patients aged 3-19 years with histologically confirmed HGG (excluding brainstem) treated at the Dept. of Pediatrics, Medical University of Vienna, Austria. thirty-eight patients were included (f:m 19:19) with a mean age of 11.0 years (3.4-17.7). Twenty-one patients had grade 3, 17 grade 4 glioma. Gross total resection was achieved in 26.3%, partial resection in 36.8%, 36.8% underwent biopsy. Eight patients received upfront window chemotherapy and were analysed separately. Of the remaining 30 patients all received concomitant and adjuvant chemotherapy. 50% (n=15) started irradiation ≤14 days (median interval 11 days [range 5-14]), 50% thereafter (median 23 days [range 15-78]). No significant difference in OS or PFS was seen between the two groups or for ISRT as continuous variable. In accordance with previous studies OS was significantly influenced by the extent of resection (EOR) and showed a trend for tumour grade. Results may be influenced by the fact that more patients with biopsy only and with grade 4 tumours were treated shortly after surgery and only four patients had a delay of >28 days. EOR but not ISRT (within a range of four weeks) influenced survival in paediatric HGG patients. In view of upcoming targeted treatment options in paediatric HGG the present data suggest that it is safely feasible to perform molecular analyses before starting radiotherapy.
Tuberculosis treatment outcomes of notified cases: trends and determinants of potential unfavourable outcome, France, 2008 to 2014
Authors: Jean-Paul Guthmann, Lucie Léon, Delphine Antoine, Daniel Lévy-Bruhl
Journal: Eurosurveillance (2020)

Background Surveillance of tuberculosis (TB) treatment outcome, for which reporting has been mandatory in France since 2007, is a key component of TB control. Aim We aimed to present surveillance data for non-multidrug-resistant (MDR) cases reported between 2008 and 2014, and identify factors associated with potentially unfavourable treatment outcome. Methods Patients were classified according to their treatment outcome 12 months after beginning treatment. Poisson regression with a robust error variance was used to investigate factors associated with potentially unfavourable treatment outcome. Missing data were handled using multiple imputation. Results A total of 22,526 cases were analysed for treatment outcome. Information available on treatment outcome increased between 2008 (60%) and 2014 (71%) (p &lt; 0.001). During this period, 74.1% of cases completed treatment, increasing from 73.0% in 2008 to 76.9% in 2014 (p &lt; 0.001). This proportion was 74.0% in culture-positive pulmonary cases. Overall, 19.8% of cases had a potentially unfavourable outcome, including lost-to-follow-up, transferred out, still on treatment, death related to TB and interrupted treatment. Potentially unfavourable outcome was significantly associated with TB severity, residing in congregate settings, homelessness, being a smear-positive pulmonary case, being born abroad and residing in France for &lt; 2 years, history of previous anti-TB treatment and age &gt; 85 years. Conclusion Monitoring of treatment outcome is improving over time. The increase in treatment completion over time suggests improved case management. However, treatment outcome monitoring needs to be strengthened in cases belonging to population groups where the percentage of unfavourable outcome is the highest and in cases where surveillance data shows poorer documented follow-up.
Immunogenicity and Safety of the Prame Cancer Immunotherapeutic in Non-Small Cell Lung Cancer (NSCLC): Phase I Dose Escalation Study
Authors: J. Pujol, T. De Pas, A. Rittmeyer, B. Kubisa, E. Vallieres, E. Levchenko, B. Salaun, N. Vanhoutte, M. Debois, V. Brichard
Journal: Annals of Oncology (2012)
The thrombin cleavage domain of osteopontin is important for mediating growth and adhesive properties of human breast cancer cells
Authors: Erika B. Schulze, Ann F. Chambers, Alan B. Tuck, Alison L. Allan
Journal: Cancer Research (2006)

3432  Osteopontin (OPN) is a secreted phosphoprotein that has been associated with malignancy of breast and other cancers. OPN contains several conserved structural domains, including two integrin-binding sites and a thrombin cleavage site located in close proximity to each other. Recent evidence indicates that thrombin, commonly known for its proteolytic role in coagulation, may also play an important role in tumor growth and metastasis. The presence of a thrombin cleavage site in the OPN backbone suggests that the function of OPN may rely, at least in part, on its interaction with thrombin. The purpose of this study was to determine if OPN-mediated malignancy depends on conservation of the thrombin cleavage site within OPN. MDA-MB-468 human breast cancer cells were stably transfected to overexpress wildtype OPN (468-OPN), mutant OPN containing a deleted thrombin cleavage site (468-ΔTC), or a control vector (468-CON). Pooled populations of 468-OPN, 468-ΔTC, and 468-CON cells were compared for functional differences in malignant behavior in vitro, including cell proliferation, plating efficiency (colony formation), and cell adhesion. Proliferation assays demonstrated that there was no significant difference in doubling time between the three cell lines. However, an extended lag phase in the growth of 468-ΔTC cells was observed relative to 468-OPN and 468-CON cells. In plating efficiency assays, overexpression of either wildtype OPN or thrombin-uncleavable OPN resulted in the formation of a significantly greater number of colonies relative to control, but the mean diameter of the colonies formed by 468-ΔTC cells was significantly less than colonies formed by 468-OPN cells. Overexpression of wildtype OPN also resulted in significantly increased cell adhesion to vitronectin, and this adhesion was dependant on conservation of the thrombin cleavage site. Differences in cell growth and adhesion were specific to the interaction between OPN and thrombin, since treatment with the thrombin-specific inhibitor Argatroban caused 468-OPN cells to develop an extended lag phase of growth similar to that shown by 468-ΔTC cells, as well as significantly reducing their adhesion to vitronectin. In contrast, treatment with Argatroban had little effect on the growth or adhesion of 468-ΔTC and 468-CON cells. These novel findings indicate that the thrombin cleavage site in OPN is important for mediating growth and adhesive properties of MDA-MB-468 breast cancer cells in vitro, potentially by increasing accessibility to adjacent integrin-binding sites. Ongoing studies are aimed at determining the involvement of integrins, as well as investigating the role of thrombin in OPN-mediated malignancy in vivo. These studies complement clinical findings in our laboratory that have identified OPN as an important prognostic indicator and potential therapeutic target in breast cancer patients.
Immune correlates of tuberculosis disease and risk translate across species
Authors: Mushtaq Ahmed, Shyamala Thirunavukkarasu, Bruce A. Rosa, Kimberly A. Thomas, Shibali Das, Javier Rangel-Moreno, Lan Lu, Smriti Mehra, Stanley Kimbung Mbandi, Larissa B. Thackray, Michael S. Diamond, Kenneth M. Murphy, Terry Means, John Martin, Deepak Kaushal, Thomas J. Scriba, Makedonka Mitreva, Shabaana A. Khader
Journal: Science Translational Medicine (2020)

Comparison of human TB gene signature to mouse and macaque models reveals common immune correlates of TB disease and risk.
<sup>68</sup>Ga-PSMA-HBED-CC PET/CT imaging for adenoid cystic carcinoma and salivary duct carcinoma: a phase 2 imaging study
Authors: Wim van Boxtel, Susanne Lütje, Ilse C.H. van Engen-van Grunsven, Gerald W. Verhaegh, Jack A. Schalken, Marianne A. Jonker, James Nagarajah, Martin Gotthardt, Carla M.L. van Herpen
Journal: Theranostics (2020)

Rationale: Treatment options for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC) and salivary duct carcinoma (SDC), major subtypes of salivary gland cancer, are limited.Both tumors often show overexpression of prostate-specific membrane antigen (PSMA).In prostate cancer, PSMA-ligands labeled with 68 Ga or 177 Lu are used for imaging and therapy, respectively.Primary aim of this study in R/M ACC and SDC patients was to systematically investigate 68 Ga-PSMA-uptake by PET/CT imaging to determine if PSMA radionuclide therapy could be a treatment option.Methods: In a prospective phase II study, PET/CT imaging was performed 1 h post injection of 68 Ga-PSMA-HBED-CC in 15 ACC patients and 10 SDC patients.Maximum standardized uptake values (SUV) were determined in tumor lesions.Immunohistochemical PSMA expression was scored in primary tumors and metastatic tissue.Standard imaging (MRI or CT) was performed for comparison.Results: In ACC patients, SUVmax ranged from 1.1 to 30.2 with a tumor/liver-ratio >1 in 13 out of 14 evaluable patients (93%).In SDC patients, SUVmax ranged from 0.3 to 25.9 with a tumor/liver-ratio >1 in 4 out of 10 patients (40%).We found a large intra-patient inter-metastatic variation in uptake of 68 Ga-PSMA, and immunohistochemistry did not predict ligand uptake in ACC and SDC.Finally, PSMA-PET detected additional bone metastases compared to CT in 2 ACC patients with unexplained pain. Conclusion:In 93% of ACC patients and 40% of SDC patients we detected relevant PSMA-ligand uptake, which warrants to study PSMA radionuclide therapy in these patients.Additionally, our data provide arguments for patient selection and treatment timing.Finally, PSMA-PET imaging has added diagnostic value compared to CT in selected patients.
Development of a high affinity Anticalin<sup>®</sup> directed against human CD98hc for theranostic applications
Authors: Friedrich-Christian Deuschle, Volker Morath, André Schiefner, Corinna Brandt, Simone Ballke, Sybille Reder, Katja Steiger, Markus Schwaiger, Wolfgang Weber, Arne Skerra
Journal: Theranostics (2020)

Enhanced amino acid supply and dysregulated integrin signaling constitute two hallmarks of cancer and are pivotal for metastatic transformation of cells.In line with its function at the crossroads of both processes, overexpression of CD98hc is clinically observed in various cancer malignancies, thus rendering it a promising tumor target.Methods: We describe the development of Anticalin proteins based on the lipocalin 2 (Lcn2) scaffold against the human CD98hc ectodomain (hCD98hcED) using directed evolution and protein design.X-ray structural analysis was performed to identify the epitope recognized by the lead Anticalin candidate.The Anticalin -with a tuned plasma half-life using PASylation ® technology -was labeled with 89 Zr and investigated by positron emission tomography (PET) of CD98-positive tumor xenograft mice. Results:The Anticalin P3D11 binds CD98hc with picomolar affinity and recognizes a protruding loop structure surrounded by several glycosylation sites within the solvent exposed membrane-distal part of the hCD98hcED.In vitro studies revealed specific binding activity of the Anticalin towards various CD98hc-expressing human tumor cell lines, suggesting broader applicability in cancer research.PET/CT imaging of mice bearing human prostate carcinoma xenografts using the optimized and 89 Zr-labeled Anticalin demonstrated strong and specific tracer accumulation (8.6 ± 1.1 %ID/g) as well as a favorable tumor-to-blood ratio of 11.8. Conclusion:Our findings provide a first proof of concept to exploit CD98hc for non-invasive biomedical imaging.The novel Anticalin-based αhCD98hc radiopharmaceutical constitutes a promising tool for preclinical and, potentially, clinical applications in oncology.
RING finger-mediated instability of Cbl-c
Authors: Ashley O. Coats, Yaffa R. Rubinstein, Nina Sivadasan, Mauricio Cuello, Marion M. Nau, Stan Lipkowitz
Journal: Cancer Research (2004)

877  The Cbl family of proteins, first identified by homology to the viral oncogene v-cbl, is highly conserved in metazoans from C. elegans to humans. All Cbl proteins share homology in their amino-terminal regions, including a phosphotyrosine-binding domain and a C3HC4 RING finger. There are three mammalian Cbl proteins: Cbl, Cbl-b and Cbl-c. Cbl-c lacks the extensive carboxy-terminal proline-rich region and UBA domain shared by Cbl and Cbl-b. Because of the differences between Cbl-c and its two mammalian homologs, we sought to characterize further this newest addition to the Cbl family. Expression of Cbl-c is lower than both Cbl and Cbl-b when transfected into 293T or HeLa cells. This difference in protein expression results from the shorter half-life of Cbl-c compared to Cbl and Cbl-b and not from differences in transcription levels or translation rates. We mapped the region of Cbl-c responsible for its instability to the RING finger domain. Deletion or mutation of the RING finger of Cbl-c increased its stability. Cbl-c, like other Cbl proteins, acts as an ubiquitin protein ligase (E3) in an in vitro E3 assay and its E3 activity depends upon an intact RING finger. Additionally, we constructed two chimeric proteins in which the RING fingers of Cbl-b and Cbl-c were swapped. Replacing the RING finger of Cbl-b with the RING finger of Cbl-c destabilizes Cbl-b. Conversely, replacing the RING finger of Cbl-c with that of Cbl-b stabilizes the protein. Consistent with the requirement for an intact RING finger of Cbl-c to destabilize the protein, wild type Cbl-c, but not Cbl-c with a RING finger mutation or RING finger deletion, is ubiquitinated. To determine the mechanism of Cbl-c degradation, we used a variety of inhibitors which block either the proteasome or lysosome. Only proteasome inhibitors prevented Cbl-c degradation. Together, these data indicate that the instability of Cbl-c is mediated by its own RING finger and requires E3 ligase activity, suggesting that its instability is due to auto-ubiquitination and degradation by the proteasome. These data further suggest that the E3 activity of Cbl-c is regulated in a fundamentally different fashion than either Cbl or Cbl-b.
Following the evidence, from coronavirus to terrorism response
Authors: Tom Moberly
Journal: BMJ (2020)

The emergence of a novel coronavirus has led China to impose travel restrictions around Wuhan and other cities (doi:10.1136/bmj.m349). Yet, as G James Rubin and Simon Wessely point out (doi:10.1136/bmj.m313), we don’t not know whether the potential benefits of mandatory mass quarantine outweigh the psychological costs of such an intervention to the people affected. Elisabeth Mahase summarises what we know so far about the virus and its effects (doi:10.1136/bmj.m308); clearly there is much we are yet to understand.

Researchers studying this novel infection and its epidemiology …
The Role of the Epicardium During Heart Development and Repair
Authors: Pearl Quijada, Michael A. Trembley, Eric M. Small
Journal: Circulation Research (2020)

The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.
急性気管支炎を契機に発症した咳嗽失神の1例 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: 村嶋英達, 藤井拓朗, 高塚久史, 梶原秀俊, 古賀純, 栗須崇, 妹尾篤史, 芝田貴裕, 谷口正幸, 吉村道博
Journal: Circulation (2008)
Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon- inhibition
Authors: Yishan Ye, Laure Ricard, Lama Siblany, Nicolas Stocker, Frédéric De Vassoigne, Eolia Brissot, Baptiste Lamarthée, Arsène Mekinian, Mohamad Mohty, Béatrice Gaugler, Florent Malard
Journal: Acta Pharmaceutica Sinica B (2020)

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As2O3 preferentially inhibited IFN-α secretion as compared to other cytokines such as TNF-α, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As2O3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition, and regulatory phenotype induced by As2O3. Collectively, our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.
Functional isolation of pancreatic cancer tumor suppressor activity at 12q21-23
Authors: Young Mi Park, Ryan D. George, Julie A. Mackey, Katherine L. Pogue-Geile
Journal: Cancer Research (2004)

2705  Purpose: The purpose of this work is to isolate novel, functional pancreatic cancer-tumor suppressor (TS) gene(s) located at 12q21-23. This region represents one of the most frequently deleted genomic regions in pancreatic cancer for which no known TS gene has been identified. This region has been finely mapped to two minimal regions of deletion at 12q21.31-.32 and at 12q23.3 (Kimura et al. Cancer Research 58:2456-60, 1998). Methods: To achieve this goal we have preformed genetic complementation studies, using yeast artificial chromosomes (YACs). YACs contain large regions of human DNA (up to 2 Mb) which eliminates the need for subcloning because all of the signals required for gene expression are likely to be included in a single clone. This allows for the genes to be expressed at physiological levels and may provide a better understanding of gene function, than genes introduced with artificial control signals. To carry out this study: 1) A positive control for TS activity (Y807E4-containing the p16 gene) and YACs that map to the two minimal regions of LOH at 12q (Fig 1) were retrofitted with a neomycin resistance gene (NeoR), a mammalian cell selectable marker. 2) Panc-1 and A9 cells were fused to yeast cells containing YACs. 3) NeoR resistant colonies were selected. 4) To help in the identification of potential TS genes we made a custom cDNA composed of 28 genes localized to this region. Results: Evidence for TS activity at 12q21.31-32 include 1) The observation that fusions of Panc-1 cells with YAC 790F8 yielded Panc-1 colony that later failed to grow and no NeoR colonies were observed when 790F8 was fused with A9 cells and 2) Three A9 NeoR colonies were isolated with 909H1 but all three showed selective loss of human DNA based on microsatellite analysis. Evidence for TS activity in region 12q23.3 is two NeoR colonies were isolated with fusions with a YAC which contains only a portion of 12q23.3 (721G9), but not with 948E9, which contains all of region 12q23.3. In parallel we analyzed gene expression pattern of 28 genes that had been localized to this region of the genome. We found that stabilin-2, which is localized to 23q23.3 showed significant down regulation in pancreatic cancer. Electronic mapping places stabilin-2 in the YAC with tumor suppressor activity (Y909H1) but not in the YAC with no tumor suppressor activity (Y721G9). This provides additional support for proposal that stabilin-2 is a tumor suppressor. Conclusions: Functional evidence for tumor suppressor activity at 12q21.31-.32 and at 12q23.3 was detected. Stabilin-2 is a potential candidate for tumor suppressor activity at 12q23.3 and additional evidence for this possibility is currently being tested.
Proteoglycan 4 predicts tribological properties of repaired cartilage tissue
Authors: Zhiguang Qiao, Mei Xin, Ling Wang, Huiwu Li, Chengtao Wang, Liao Wang, Tingting Tang, Bangshang Zhu, Gang Huang, You Wang, Minghao Zheng, Kerong Dai
Journal: Theranostics (2020)

Purpose: One of the essential requirements in maintaining the normal joint motor function is the perfect tribological property of the articular cartilage. Many cartilage regeneration strategies have been developed for treatment in early stages of osteoarthritis, but there is little information on how repaired articular cartilage regains durability. The identification of biomarkers that can predict wear resistant property is critical to advancing the success of cartilage regeneration therapies. Proteoglycan 4 (PRG4) is a macromolecule distributing on the chondrocyte surface that contributes to lubrication. In this study, we investigate if PRG4 expression is associated with tribological properties of regenerated cartilage, and is able to predict its wear resistant status. Methods: Two different strategies including bone marrow enrichment plus microfracture (B/BME-MFX) and microfracture alone (B-MFX) of cartilage repair in sheep were used. PRG4 expression and a series of tribological parameters on regenerated cartilage were rigorously examined and compared. Results: Highly and continuously expression of PRG4 in regenerated cartilage surface was negatively correlated with each tribological parameter (P<0.0001, respectively). Multivariate analysis showed that PRG4 expression was the key predictor that contributed to the promotion of cartilage wear resistance. Conclusion: Higher PRG4 expression in regenerated cartilage is significantly associated with wear resistance improvement. PRG4 may be useful for predicting the wear resistant status of regenerated cartilage and determining the optimal cartilage repair strategy.