tbuckley/cabot-search huggingface dataset:
TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS
Authors: Sebastian Brabetz, Christin Schmidt, Susanne N. Groebner, Norman Mack, Huriye Seker-Cin, David T.W. Jones, Lukas Chavez, Till Milde, Olaf Witt, Sarah E. Leary, Xiao-Nan Li, Robert J. Wechsler-Reya, James M. Olson, Stefan M. Pfister, Marcel Kool
Journal: Neuro-Oncology (2017)

Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies for children with malignant brain tumors.
Cannabis based drug shows promise in children with resistant epilepsy
Authors: Nigel Hawkes
Journal: BMJ (2017)

A cannabis based drug has shown encouraging results in treating a form of epilepsy unresponsive to existing drugs.1

Children with Dravet syndrome, a rare and catastrophic form of epilepsy, may experience many seizures a day. The condition, caused in most cases by a known genetic mutation affecting sodium channels in the brain, occurs in one child in 40 000 and leads to developmental damage and long term learning difficulties. Children affected require lifelong care.

Anecdotal evidence has suggested that cannabis helps some children, but the new research is the first randomised controlled trial to test the idea. It randomly assigned 120 children aged 2-18 in Europe and the US either to cannabidiol—a purified form of cannabis with very low levels …
Finding Joy in Practice
Authors: Kathryn B. Kirkland
Journal: JAMA (2017)

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LATE RADIATION EFFECTS IN ROENTGEN THERAPY FOR HYPERTHYROIDISM
Authors: Edith H. Quimby
Journal: JAMA (1949)

Their Possible Bearing on the Use of Radioactive Iodine  To the Editor:—  Radioactive iodine, especially the isotope of 8 day half-life, I131, has been employed in the treatment of hyperthyroidism in several clinics during recent years, a total of several hundred patients probably having received the material. The question of the possibility of late radiation changes leading to malignant degeneration has been raised and cannot be disregarded. Serious sequelae to radiation therapy usually appear several years after the treatment; hence such damage from radioiodine would not be expected for some time. If it is to be feared that this will be a serious hazard, the use of the material ought to be very sharply restricted until sufficient time has elapsed to ascertain the late results in persons already treated. On the other hand, if any pertinent evidence can be obtained from the already large experience with roentgen rays, it
Autoantibodies against C-Reactive Protein Influence Complement Activation and Clinical Course in Lupus Nephritis
Authors: Qiu-yu Li, Hai-yun Li, Ge Fu, Feng Yu, Yi Wu, Ming-hui Zhao
Journal: Journal of the American Society of Nephrology (2017)

Autoantibodies against the major acute-phase reactant C-reactive protein (CRP) are frequently found in patients with lupus nephritis. Further defining the autoimmune epitopes on CRP may not only improve patient stratification but also, hint at mechanisms of CRP action. Herein, we show that amino acids 35–47 constitute the major epitope recognized by anti-CRP autoantibodies in patients with lupus nephritis. Notably, the presence of autoantibodies against amino acids 35–47 associated with more severe renal damage and predicted worse outcome. This epitope is exposed on CRP only after irreversible structure changes, yielding a conformationally altered form termed modified or monomeric CRP (mCRP). ELISA and surface plasmon resonance assays showed that amino acids 35–47 mediate the interaction of mCRP with complement factor H, an inhibitor of alternative pathway activation, and this interaction greatly enhanced the in vitro cofactor activity of complement factor H. In contrast, autoantibodies against amino acids 35–47 inhibited these actions of mCRP. Our results thus provide evidence for the in vivo generation of mCRP in a human disease and suggest that mCRP actively controls the pathogenesis of lupus nephritis by regulating complement activation. Therefore, amino acids 35–47 constitute a functional autoimmune epitope on CRP that can be targeted therapeutically and diagnostically.
Prognostic significance of stromal versus intratumoral infiltrating CD8+ lymphocytes in resected non-small cell lung cancer.
Authors: Malaka Ameratunga, Khashayar Asadi, Marzena Walkiewicz, Carmel Murone, Paul Mitchell, Tom John
Journal: Journal of Clinical Oncology (2015)

11051 Background: The prognostic significance of tumor infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC) remains unclear. Immunotherapies in NSCLC have recently shown therapeutic promise. Assays predicting response to PD1/PDL-1 inhibitors have utilized expression of its ligand PDL-1 on tumor cells or the surrounding immune infiltrate. In other tumor types, stromal CD8+- TILs have been reported to be prognostic. We sought to characterize the immune infiltrate in a large series of resected NSCLC to determine their prognostic significance, focusing on intra-tumoral and stromal TILs. Methods: A tissue microarray (TMA) was constructed with triplicate cores of primary tumor from 507 NSCLC lobectomy or pneumonectomy cases. Immunohistochemistry was performed for CD8, CD4 and FoxP3. PDL1 was performed using a proprietary assay from BMS. CD8+ TILs were manually counted and assigned global tumoral and stromal scores based on TIL density, with the scorer blinded to clinical outcomes. Cases were categorized: stromal (S), tumoral (T) or other (equal proportions of tumoral:stromal CD8+-TILs). Disease-specific survival (DSS) was correlated with TIL characteristics. Results: Most patients were male (69%). Histologically, 50% were adenocarcinoma (AC) and 42% squamous (SQ). Comparisons were stratified by nodal stage: node negative (N0, n = 354) and node positive (N+, n = 153). In N0 there were 24(7%) T, 40(11%) S and 290(82%) other, compared to 16(11%), 11(7%) and 126(82%) respectively in N+ (p = 0.16). There were no differences in CD8+ TILs based on histology (p = 0.73). In the N0 population, there was no significant difference in DSS, based on TIL characteristics. In the N+ population, the presence of an S infiltrate was associated with significantly increased DSS compared to a T infiltrate (HR 0.36, 95% CI 0.14-0.96; p = 0.05) or other (HR 0.36, 95% CI 0.26-0.92; p = 0.03). Conclusions: In this large patient cohort, the presence of stromal CD8+ TIL infiltrates was not prognostic in N0 NSCLC but was associated with significantly improved survival in node positive NSCLC. Correlation of PDL-1, FOXP3 and CD4+ stains may further define the TILs and will be reported.
The HIV Protease Inhibitor Nelfinavir in Combination with Bortezomib and Dexamethasone (NVd) Has Excellent Activity in Patients with Advanced, Proteasome Inhibitor-Refractory Multiple Myeloma: A Multicenter Phase II Trial (SAKK 39/13)
Authors: Christoph Driessen, Rouven Müller, Urban Novak, Nathan Cantoni, Daniel Betticher, Nicolas Mach, Michael Gregor, Panagiotis Samaras, Catherine Berset, Stephanie Rondeau, Hanne Hawle, Felicitas Hitz, Thomas Pabst, Thilo Zander
Journal: Blood (2016)
Aberrantly Expressed APOBEC3B Induces Mutations in Multiple Myeloma
Authors: Hiroyuki Yamazaki, Kotaro Shirakawa, Tadahiko Matsumoto, Hiroyuki Matsui, Wataru Maruyama, Masayuki Kobayashi, Keisuke Shindo, Anamaria Daniela Sarca, Masaki Ri, Shinsuke Iida, Akifumi Takaori-Kondo
Journal: Blood (2016)
Effects of cytochrome P450 inducer and inhibitor coadministration on the pharmacokinetics of trabectedin in patients with advanced or metastatic solid tumors.
Authors: Jean-Pascal Machiels, Arthur P. Staddon, Catherine Herremans, Chi Keung, Apexa Bernard, Charles Phelps, Ana L. Aymes, Nushmia Z. Khokhar, Roland Elmar Knoblauch, Trilok V. Parekh, Luc Dirix, Sunil Sharma
Journal: Journal of Clinical Oncology (2014)

e13520 Background: Trabectedin (T) is extensively metabolized via the cytochrome P450 (CYP) 3A4 enzyme. Drug-drug interaction studies of T coadministered with rifampin (CYP3A4 inducer) and ketoconazole (CYP3A4 inhibitor) were performed in adult patients with advanced solid tumors. Methods: We conducted two phase 1/2a, open-label, single-dose, 2-way crossover studies. In the rifampin study, 12 patients were randomized (1:1) to the treatment order, which included a single cycle of T (1.3 mg/m2, 3 h, i.v.) and rifampin (600 mg/day, 6 doses) coadministration, and a single cycle of T monotherapy (1.3 mg/m2, 3 h, i.v.). In the ketoconazole study, 8 patients were randomized (1:1) to the treatment order, which included a single cycle of T (0.58 mg/m2, 3 h, i.v.) and ketoconazole (200 mg, twice daily, 15 doses) coadministration, and a single cycle of T monotherapy (1.3 mg/m2, 3 h, i.v.). Pharmacokinetics and safety of T were evaluated alone and with coadministration. Results: The systemic exposure of T decreased when coadministered with rifampin (Cmax: 22% [geometric mean ratio, GMR (90% CI): 78.5% (70.7% – 87.2%)]; AUClast: 31% [GMR: 68.5% (60.6% – 77.5%)]), and increased when coadministered with ketoconazole (Cmax: 22% [GMR: 121.5% (96.0% – 153.7%)]; AUClast: 66% [GMR: 165.9% (122.7% – 224.2%)]). During coadministration, the clearance of T increased (39.6 to 59.8 L/h) with rifampin and decreased (20.3 to 12.0 L/h) with ketoconazole. Consistent with earlier studies, the most common (≥40%) treatment-emergent adverse events in both studies were nausea, vomiting, diarrhea, hepatic function abnormal, anemia, neutropenia, thrombocytopenia, and leukopenia. Conclusions: Coadministration of rifampin or ketoconazole altered the metabolic clearance of T in patients with advanced or metastatic solid tumors, but no new safety signals were observed. Coadministration of T with potent CYP3A4 inhibitors or inducers should be avoided if possible. If coadministration of T with a strong CYP3A4 inhibitor is required, close monitoring for toxicities is recommended, so that appropriate dose reductions can be instituted as warranted. Clinical trial information: NCT01273480; NCT01267084.
Abstract P221: Retinoblastoma Protein--Associated Proteins 48 and 46 Are Novel p300/GATA4-Binding Partners Involved in Hypertrophic Responses in Cardiomyocytes
Authors: Yoichi Sunagawa, Yasufumi Katanasaka, Taishi Terada, Yuichi Watanabe, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation Research (2011)

Background: A zinc finger protein GATA4 is one of hypertrophy-responsive transcription factors, and increases its DNA-binding and transcriptional activities in response to hypertrophic stimuli in cardiomyocytes. Activation of GATA4 during this process is mediated, in part, through acetylation by intrinsic histone acetyltransferases such as a transcriptional coactivator p300. Here, we show that retinoblastoma protein (Rb)-associated protein 48 and 46 (RbAp48, RbAp46), components of NuRD (nucleosome remodeling and deacetylase) complex that has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation, are novel components of p300/GATA4 complex. However, the precise functional relationships among p300, GATA4, RbAp48, and RbAp46 remain unknown. Methods and Results: A series of GST pull-down assays revealed that the C-terminal domain of RbAp48/46 bound to the N-terminal transcriptional activation domain of GATA4 and C/H-3 domain of p300, respectively. Immunoprecipitation followed by western blotting demonstrated that RbAp48/46 repressed p300-induced acetylation of GATA4 and histones. While overexpressions of RbAp48/46 inhibited p300/GATA4-induced atrial natriuretic factors (ANF) and endotheline-1 (ET-1) promoter activities, knockdown of neither RbAp48 nor RbAp46 by RNAi enhanced these promoter activities in HEK293 cells. Stimulation of cardiomyocytes with phenylephrine (PE) decreased the binding of GATA4/p300 with RbAp48/46. RbAp48/46 repressed PE-induced hypertrophic responses such as myofibrillar organization, increase in cell size and promoter activation of the ANF and ET-1 in cardiomyocytes. Conclusion: These findings demonstrate that RbAp48 and RbAp46 form a functional protein complex with GATA4/p300 and regulated hypertrophic responses in cardiomyocytes.
Proposed appraisal system and political correctness
Authors: A. Whitehouse, K G M M Alberti, J. R Bennett
Journal: BMJ (1999)

Children born after intracytoplasmic sperm injection What do authors mean by control infants?Editor-Sutcliffe et al compare babies born through intracytoplasmic sperm injection with control babies (matched for social class, maternal education, region, and sex) born after unassisted conception. 1 In their table they give means, standard deviations, and 95% confidence intervals for the two groups separately.These confidence intervals tell us about the estimation of the mean in the population of which the babies are a random sample, which they are not.They tell us nothing about the comparison between the cases and controls.These controls have been chosen to be similar to the study babies in many ways; they are not a representative sample of babies.It is the difference between the study babies and the control babies that is of interest, and the confidence interval we should have is that for this difference in mean.We cannot work this out from the data given, because this is a paired study and we have unpaired standard deviations.All we have for the comparison is the implication, not actually stated, that the differences are not significant.What we should be given are confidence intervals that tell us how different the cases and controls are.
Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas‐Induced Apoptosis–Transgenic Mice
Authors: Chia‐Lung Wu, Jenna McNeill, Kelsey Goon, Dianne Little, Kelly Kimmerling, Janet Huebner, Virginia Kraus, Farshid Guilak
Journal: Arthritis & Rheumatology (2017)

Objective To investigate whether short‐term, systemic depletion of macrophages can mitigate osteoarthritis (OA) following injury in the setting of obesity. Methods CSF‐1R–GFP+ macrophage Fas‐induced apoptosis (MaFIA)–transgenic mice that allow conditional depletion of macrophages were placed on a high‐fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effects of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and micro–computed tomography. Immunohistochemical analysis was performed to identify various immune cells. The levels of serum and synovial fluid cytokines were also measured. Results Macrophage‐depleted mice had significantly fewer M1 and M2 macrophages in the surgically operated joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate the severity of OA in obese mice; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage‐depleted mice also demonstrated a markedly increased number of proinflammatory cytokines including granulocyte colony‐stimulating factor, interleukin‐1β (IL‐1β), IL‐6, IL‐8, and tumor necrosis factor in both serum and joint synovial fluid, although the mice showed a trend toward decreased levels of insulin and leptin in serum after macrophage depletion. Conclusion Our findings indicate that macrophages are vital for modulating homeostasis of immune cells in the setting of obesity and suggest that more targeted approaches of depleting specific macrophage subtypes may be necessary to mitigate inflammation and OA in the setting of obesity.
Long-Lasting Increased Risk of Human Papillomavirus–Related Carcinomas and Premalignancies After Cervical Intraepithelial Neoplasia Grade 3: A Population-Based Cohort Study
Authors: Renée M.F. Ebisch, Dominiek W.E. Rutten, Joanna IntHout, Willem J.G. Melchers, Leon F.A.G. Massuger, Johan Bulten, Ruud L.M. Bekkers, Albert G. Siebers
Journal: Journal of Clinical Oncology (2017)

Purpose The aim of this study was to determine the risk of human papillomavirus (HPV)–related carcinomas and premalignancies in women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3). Knowledge of this risk is important to preventing the development and progression of other HPV-related premalignancies and carcinomas, by considering prophylactic HPV vaccination and/or by paying increased attention to other HPV-related carcinomas and premalignancies when CIN3 is identified. Methods Women diagnosed with a CIN3 between 1990 and 2010 were identified from the Dutch nationwide registry of histopathology and cytopathology (PALGA) and matched with a control group of women without CIN3. Subsequently, all cases of high-risk (hr) HPV–associated high-grade lesions and carcinomas in the anogenital region and oropharynx between 1990 and 2015 were extracted. Incidence rate ratios were estimated for carcinomas and premalignancies of the vulva, vagina, anus, and oropharynx. Results A total of 178,036 women were identified: 89,018 with a previous diagnosis of CIN3 and 89,018 matched control subjects without a history of CIN3. Women with a history of CIN3 showed increased risk of HPV-related carcinomas and premalignancies, with incidence rate ratios of 3.85 (95% CI, 2.32 to 6.37) for anal cancer, 6.68 (95% CI, 3.64 to 12.25) for anal intraepithelial neoplasia grade 3, 4.97 (95% CI, 3.26 to 7.57) for vulvar cancer, 13.66 (93% CI, 9.69 to 19.25) for vulvar intraepithelial neoplasia grade 3, 86.08 (95% CI, 11.98 to 618.08) for vaginal cancer, 25.65 (95% CI, 10.50 to 62.69) for vaginal intraepithelial neoplasia grade 3, and 5.51 (95% CI, 1.22 to 24.84) for oropharyngeal cancer. This risk remained significantly increased, even after long-term follow-up of up to 20 years. Conclusion This population-based study shows a long-lasting increased risk for HPV-related carcinomas and premalignancies of the anogenital and oropharyngeal region after a CIN3 diagnosis. Studies that investigate methods to prevent this increased risk in this group of patients, such as intensified screening or vaccination, are warranted.
Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism
Authors: Raffaele Pesavento, Lucia Filippi, Antonio Palla, Adriana Visonà, Carlo Bova, Marco Marzolo, Fernando Porro, Sabina Villalta, Maurizio Ciammaichella, Eugenio Bucherini, Giovanni Nante, Sandra Battistelli, Maria Lorenza Muiesan, Giampietro Beltramello, Domenico Prisco, Franco Casazza, Walter Ageno, Gualtiero Palareti, Roberto Quintavalla, Simonetta Monti, Nicola Mumoli, Nello Zanatta, Roberto Cappelli, Marco Cattaneo, Valentino Moretti, Francesco Corà, Mario Bazzan, Angelo Ghirarduzzi, Anna Chiara Frigo, Massimo Miniati, Paolo Prandoni
Journal: European Respiratory Journal (2017)

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.