tbuckley/cabot-search huggingface dataset:
P11.17 Splicing dysregulation drives glioblastoma malignancy: SRSF3 as a potential therapeutic target to impair glioblastoma progression
Authors: A C Fuentes-Fayos, M C Vázquez-Borrego, J M Jiménez-Vacas, L Bejarano, C Blanco-Acevedo, R Sánchez-Sánchez, J Solivera, M A Blasco, J P Castaño, R M Luque
Journal: Neuro-Oncology (2019)

Abstract Glioblastomas (GBMs) remain the deadliest human brain tumors, with poor prognosis despite years of research. Currently, standard therapeutic strategies to treat GBM are not efficient and common survival from diagnosis is ~12–16 months. Thus, identification of new diagnostic/prognostic/therapeutic tools to tackle GBMs is crucial. Emerging evidence indicates that the cellular machinery controlling alternative splicing is altered in tumor pathologies, leading to oncogenic splicing events linked to tumor progression. Accordingly, we aimed to determine the expression pattern of the spliceosome components (SCs) and splicing factors (SFs) in high-grade astrocytomas (HGAs), mostly GBMs, and to ascertain the potential consequences of its dysregulation on GBM development. To this end, expression levels of SCs core and selected SFs were measured using a customized-microfluidic qPCR array in a well-characterized cohort of HGAs (n=33). Our results unveiled a profound alteration in the expression of multiple SCs and SFs in HGAs compared to healthy brain control-samples, wherein levels of particular elements (SRSF3/RBM22/PTBP1/RBM3) enabled perfect discrimination between non-pathological vs. tumor human-tissues, and between proneural and mesenchymal-like GBMs vs. control samples in mouse-models. Results were confirmed in an independent validation-cohort (n=49) and available Microarray dataset (Murat), which revealed that the expression of these splicing elements was correlated with relevant tumor markers and with survival. Remarkably, SRSF3/RBM22/PTBP1/RBM3 silencing (using specific siRNAs) decreased several aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere formation, VEGFA secretion, etc.) and induced apoptosis, being SRSF3 the most relevant element affecting these parameters. Hence, a preclinical mouse model (U87MG-xenografts) with SRSF3 silencing drastically decreased in vivo tumor development/progression (i.e. tumor size, %MKI67, mitosis number, etc.) likely through a molecular/cellular mechanism involving the regulation of PDGFRB expression and its associated oncogenic signaling pathways. Overall, our results demonstrate that there is a profound dysregulation of the splicing machinery (spliceosome core and SFs) in HGAs/GBMs, which is directly associated to the development/progression of GBMs. Furthermore, this study reveals that SRSF3 can be a novel biomarker of malignancy and a potential therapeutic target to impair GBMs progression.
Middle-aged Man With Exertional Dyspnea and Neck Fullness
Authors: Joshua C. Vogt, Rick A. Nishimura, D. Brian Newman
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
P08.01 Impact of cannabis use on quality of life in patients with central nervous system tumors
Authors: J E Rodriguez Almaraz, N A Butowski, S M Chang, N A E Oberheim-Bush, J R Clarke, J W Taylor, R A Buerki, M S Berger
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year in the United States: 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy and potential benefits and risks. MATERIAL AND METHODS We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer(EORTC): QLQ-C30 and its complementary module BN-20 as well as the EuroQol group’s instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion. RESULTS To date, 45 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 13.5) years, 31 were male, 25 were considered active cannabis users (624% males and 36% females). At baseline, the mean Global Health score in the QLQ-C30 instrument was 68.6 (SD: 20.6) among cannabis users and 82 (SD: 18.05) among non-users. The mean difference in Global Health QOL scores between users and non-users was 13.35 (95%CI: 1.34, 25.35; p=0.03). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (0.77 vs 0.91; p=0.002). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p&gt;0.001). CONCLUSION In our analysis, patients who use cannabis have, on average, lower QOL scores signaling that sicker patients resort to cannabis to improve their symptoms and ultimately their quality of life. Patients’ perception is one of improvement in the overall quality of life when using cannabis. Our findings provide background support to perform prospective studies in the impact of cannabis in quality of life of patients with central nervous system tumors.
Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma
Authors: Robert P. Jones, Eftychia-Eirini Psarelli, Richard Jackson, Paula Ghaneh, Christopher M. Halloran, Daniel H. Palmer, Fiona Campbell, Juan W. Valle, Olusola Faluyi, Derek A. O’Reilly, David Cunningham, Jonathan Wadsley, Suzanne Darby, Tim Meyer, Roopinder Gillmore, Alan Anthoney, Pehr Lind, Bengt Glimelius, Stephen Falk, Jakob R. Izbicki, Gary William Middleton, Sebastian Cummins, Paul J. Ross, Harpreet Wasan, Alec McDonald, Tom Crosby, Yuk Ting, Kinnari Patel, David Sherriff, Rubin Soomal, David Borg, Sharmila Sothi, Pascal Hammel, Markus M. Lerch, Julia Mayerle, Christine Tjaden, Oliver Strobel, Thilo Hackert, Markus W. Büchler, John P. Neoptolemos
Journal: JAMA Surgery (2019)

The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.
P04.04 Different stages of astrocytoma in young adult patient
Authors: E Susanti, R Kamarlis, N Suci Rahayu
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND astrocytoma is a type of cancer that involve brain parenchym or spinal cord. It arises from glial cells, called astrocytes-star shaped cells which function as supportive tissue of the brain. About 50% of primary brain tumors are astrocytomas. It’s more common in men than women and most often occur at the age of after 45. There are several types of astrocytoma and some of them grow faster than other. We found a rare case where different stages of astrocytoma occur in different areas of the brain and where the latter seemed to show up just within 8 months after the first. MATERIAL AND METHODS a 43 year old male patient admitted to neurology ward after a convulsion and hemiparesis on the left extremities. Patient was known to have suffered from astrocytoma in the frontal lobe in October 2017, and had undergone craniectomy evacuation and subsequent radiotherapy which was completed in March 2018. A few months while during recovery at home, patient complained about headache which increased in intensity over a period of 3 months before admission. The first and only convulsion occurred just 12 hours before admission, while left side weakness occurred 7 days prior. Patient underwent a series of radiologic examination after the radiotherapy and also while admitted into hospital. We found a new and large mass in the right temporoparietal lobe from the latest head ct scan. This large mass was not found from the last MRI and head ct scan which was done 8 months prior. pathology anatomy examination was done to the first and second mass found. RESULTS Pathology anatomy examination depicted different stages from the two masses, the first one was pleomorphic xanthoastrocytoma (WHO grade II) and the second one was pilocytic astrocytoma (WHO grade I) CONCLUSION pleomorphic xanthoastrocytoma (WHO grade II) and pilocytic astrocytoma (WHO grade I) both are considered low grade glioma. neverthless treatment for this devastating disease still far from favorable result or outcome
OS3.3 Development of an EORTC questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumours: phase I-III
Authors: Q Oort, L Dirven, F Boele, R Grant, H Sato, A Talacchi, T Young, J C Reijneveld, M J B Taphoorn
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND In brain tumour patients, impairments in every day functioning can impact quality of life, and are therefore an important outcome in both clinical trials and practice. One way to measure every day functioning is with an activities of daily living (ADL) questionnaire. Instrumental ADL (IADL) are the cognitively more complex activities, that are essential to function autonomously within society. Cognitive decline may therefore negatively impact IADL, making these activities particularly relevant to brain tumour patients. The aim of this study is to develop a reliable and valid questionnaire to measure IADL in primary malignant and metastatic brain tumour patients. MATERIAL AND METHODS The questionnaire development study followed the standard European Organisation for Research and Treatment of Cancer (EORTC) four phase methodology: (I) generation of activities list, (II) construction of item list, (III) pre-testing, and (IV) field testing. This report covers phases I-III. To ensure cross-cultural validity, participants were recruited from different countries (The Netherlands, United Kingdom, Italy, Austria and Japan). In phase I, potential activities were identified based on a literature review and in-depth interviews with patients, proxies and healthcare professionals. In phase II, activities were turned into items, and translated into all required languages by the EORTC Translation Unit. In phase III, the item list was pre-tested in patient-proxy dyads. In accordance with predetermined decision rules to reduce items, final items were selected, and preliminary psychometric properties (i.e. factor structure, validity, reliability) were assessed. RESULTS Phase I (N=44 dyads) resulted in 59 IADL activities which were converted into 59 items in phase II. In phase III, N=85 dyads completed and reviewed this item list. The item list was subsequently reduced to 32 items. An exploratory factor analysis indicated several items measuring similar underlying constructs (e.g. domestic life and using computer/smartphone) showing acceptable to good (α≥0.7) internal consistency (range α=0.69–0.89). Seven items were less related to these underlying constructs (e.g. work or managing your own medication), and therefore single items. Construct validity, measured with known-group comparisons analyses between cognitively impaired and unimpaired patients, showed significant differences in scores between the two groups on some scales and several single items. CONCLUSION The currently developed EORTC IADL-BN32 questionnaire can be a valuable asset in assessing IADL functioning in brain tumour patients, but further validation in phase IV is required and is planned.
OS12.1 Editing of IDH1 R132H mutation in human induced pluripotent stem cells to investigate tumor genesis in glioma
Authors: A Köpp, M Preussler, S Richter, M Heide, L Marrone, J Sterneckert, A Schöler, D Capper, E Schröck, B Klink
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Low grade gliomas and secondary glioblastomas are characterised by a hot-spot mutation in the Isocitrate dehydrogenase 1 (IDH1). The mutation causes a new catalytic function of the enzyme resulting in the production of 2-Hydroxyglutarat (2-HG), which is known as an oncometabolite. To this day, the pathomechanism by which IDH1 mutation promotes tumorigenesis is not completely understood and the tumour cell of origin for glioma is not known. Moreover, reliable cell models reflecting the patient ́s situation are not available. Thus, we aim at creating human induced pluripotent stem cells (hiPSC) carrying the IDH1 R132H mutation. We will utilize this cell model to investigate how the mutation influences stem cell properties and cell differentiation in neuronal progenitor cells. MATERIAL AND METHODS For designing the cell model, we applied the novel CRISPR/Cas9 based genome editing tool Base Editor 3 and 4. We transiently transfected the cells with two plasmids containing the Cas9 enzyme and sgRNA respectively. To determine editing efficiency, cells were investigated using the T7 Endonuclease 1 assay and Next Generation Sequencing. Single cell clones were picked to analyse allele status using allele-specific PCR with subsequent Sanger Sequencing. RESULTS Using fluorescence-activated cell sorting we measured a transfection efficiency in iPSCs for one plasmid of 33.8% ± 5.92%. Out of 96 picked clones one clone showed the IDH1 mutation. Thus, the overall editing efficiency was about 1%. We confirmed expression of mutated IDH1 R132H by Western Blot. Measurement of the tricarboxylic acid cycle metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) showed a forty times increased concentration of 2-HG in IDH-mutated compared to the wildtype iPSCs, proving that the mutated enzyme is functional. To investigate effects of the IDH1 R132H on cell differentiation, we generated cerebral organoids from our iPSC-models. The IDH1 R132H mutation did not inhibit the cell differentiation in maturation of cerebral organoids. However, we observed differences in the growth between mutated and wildtype brain organoids. We additionally characterized our cell models using genome wide methylation arrays and RNA-Seq; these results will also be presented. CONCLUSION We successfully established a heterozygous IDH1 R132H mutated hiPSC cell line, which represents a promising cell model for future studies of early glioma genesis.
Conceptual deficits without features: A view from atomism
Authors: Roberto G. de Almeida
Journal: Behavioral and Brain Sciences (2001)

Humphreys and Forde fail to account for the ontology of the “features” that they claim are constitutive of concepts. This failure is common to decompositional theories of conceptual representation. Category-specific deficits can be better explained by a theory that takes inferential relations among atomic concepts to be the key characteristic of conceptual representation and processing.
Overexpression of human Cripto-1 in transgenic mice impairs mammary gland development and differentiation and induces mammary tumorigenesis.
Authors: Youping Sun, Christian Wechselberger, Caterina Bianco, Morihisa Hirota, Luigi Strizzi, Nadia I. Khan, Brenda Jones, Nicholas Kenney, David Salomon
Journal: Cancer Research (2004)

3517  Cripto-1 is a member of the EGF-CFC gene family that performs an important role in vertebrate development. Overexpression of Cripto-1 is reported in several types of cancer in mice and humans, including human breast cancer. In order to investigate the role of human Cripto-1 in mammary gland development and carcinogenesis, we have developed transgenic mice expressing of the human Cripto-1 gene under the regulation of the WAP promoter in FVB/N mice. We found that Cripto-1 transgene expression was high at mid-pregnancy and early lactation, and highest at late lactation. In virgin mice, mammary gland development was unimpaired Beta-casein expression was suppressed in the pregnant mammary glands of WAPCripto-1 transgenic mice compared to FVB/N mice. During early lactation alveolar structures in WAP-Cripto-1 expressing mice were less differentiated and delayed compared to FVB/N mice. As a result, WAP-Cripto-1 homozygous females had impaired lactation as compared to FVB/N mice. Involution is enhanced in the mammary glands of WAP-Cripto-1 mice compared to FVB/N mice. These results indicate that Cripto-1 inhibits mammary gland development and differentiation and enhances apoptosis. Seven out of 9 of multiparous heterozygous WAP-Cripto-1 female mice showed hyperplastic changes in mammary gland, and 4 out of 9 mice developed mammary tumors .These results indicate that Cripto-1 plays a role in mammary tumorigenesis.
Immunopharmacology of cancer vaccines: Restoration of NKG2D levels and functions in metastatic melanoma treated with exosomes
Authors: N. Chaput, F. Andre, C. Menard, B. Escudier, C. Robert, C. Lhomme, L. Zitvogel, T. Tursz
Journal: Journal of Clinical Oncology (2006)

2554 Background: The C-type lectin-like stimulatory immune receptor Natural Killer group 2 receptor (NKG2D) is expressed by NK and CD8+ T cells. NKG2D engagement is a natural mediator of immunosurveillance which can be compromised by locally sustained ligand expression. In cancer patients with NKG2D ligand- expressing tumors, NK and CD8+ T cells often express low levels of NKG2D and are functionally compromised. Dentritic cell-derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection in mice. Two Dex Phase I trials highlighted the and the safety of exosome administration. The observation of clinical regressions in the absence of detectable T cell responses prompted the search for alternate effector mechanisms. We study NKG2D expression and NK cells function in peripheral lymphocytes before and after Dex therapy. Methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients were enrolled and received exosome vaccinations. NK cells functions prior or following exosome vaccines were tested in standard Na 2 51CrO4 chromium release assays. NKG2D and NKG2D ligand expression were studied using flow cytometry and/or western blot experiments. Results: In sharp contrast with DC, Dex bear functional NKG2D ligands leading to a selective downregulation of NKG2D activating receptors on autologous NK cells in vitro. Long term administration of Dex could enhance NKG2D expression levels on NK and CD8+ T cells in 50% of patients, restoring killing of NKG2D ligand expressing K562 and autologous tumour. In contrast to NKG2D ligands shed by tumors mediating immunosuppressive activity, exosomal NKG2D ligands promote NKG2D-dependent effector functions in vivo, that might account for the non MHC restricted-antitumor effects observed in the trial. Conclusions: NK cell activation represent a new pharmacodynamic for Dex leading to tumor recognition and regression in vivo. The Phase II trial using Dex shall include the monitoring of NKG2D ligands on Dex preparation and follow up NKG2D levels, functions and polymorphism in patients. No significant financial relationships to disclose.
Immunological and mutational characterization of non-uterine leiomyosarcoma: A pilot study.
Authors: Katarzyna Seliga, Pawel Teterycz, Anna Szumera-Cieckiewicz, Andrzej Tysarowski, Michal Wagrodzki, Hanna Melania Kosela, Katarzyna Kozak, Tomasz Goryn, Janusz A Siedlecki, Piotr Rutkowski
Journal: Journal of Clinical Oncology (2019)

e22529 Background: Data from many studies in cancer studies suggest that factors such as expression of PD-L1, tumor infiltrating lymphocytes (TILs) and high mutational burden (TMB) in the tumor cells are connected with better response to immune check-point blockage and may have prognostic value. Little is known about those factors in other neoplasms. Methods: In this retrospective study, we have included 31 patients with leiomyosarcoma (LMS) localized on extremity (21) or in retroperitoneal space (10) treated in our center between 2002-2018 with available biopsy specimens obtained before treatment. Mean age was 58 year (SD: 17). Male:Female ratio was 0.82. 14(45%) lesions were deemed high-grade sarcomas. 3 patients had metastases at the time of diagnosis. Immunohistological assays for TILs, tumor associated macrophages (TAMs), PD-1 and PD-L1. TMB was assessed in Tumor Mutational Burden Panel in the formalin-fixed paraffin-embedded samples. 7 cases were excluded from TMB analysis due to poor specimens quality. Fisher exact test was used to compare discrete variables while Kaplan-Meier estimate and stratified log-rank test were used to examine impact of explored factors on survival. Results: The median overall survival in this cohort was 33.4 months (95% confidence intervals, CI: 32-NA). TMB &gt; = 10 mutations/Mb was present in 33% high-grade (HG) and in 25% cases of low-grade (LG) LMS (p = 0.067). PD-L1 expression was present in 54% of HG lesions and in 31% of LG LMS (p = 0.43). TILs and TAMs were highly correlated and present in 40% and 50% of HG LMS and LG LMS respectively (p = 0.722). Among explored factors only TILs and TAMs had significant influence on survival as deemed by log-rank test stratified by tumor grade (p = 0.004) with 3-year survival rate of 100% in groups without TILs/TAMs regardless of grade and 0% in HG TILs/TAMs(+) group and 60% (95% CI: 31-100%) in LG TILs/TAMs(-) group. Conclusions: Significant percentage of LMS exhibit immunohistological and molecular traits which potentially are connected with good response to check-point blockage agents. The immunological infiltration of primary LMS may be strong negative prognostic factor, what is interesting in sarcoma. Future expansion of this study cohort is warranted.
Abstract 12464: Incidence and Impact of Heparin Induced Thrombocytopenia in Patients Undergoing Percutaneous Coronary Intervention: A Propensity Matched Analysis From a National Database
Authors: Hossam Abubakar, Oluwole Adegbala, Ahmed Subahi, Ahmed Yassin, Emmanuel Akintoye, Abdelrahman Ahmed, Ahmed Elhag, Radowan Elnair, Mohamed Shokr
Journal: Circulation (2018)

Introduction: Heparin-Induced thrombocytopenia (HIT) is a known mortality predictor amongst patients undergoing cardiac surgery. Little is known about the impact of HIT on in-hospital outcomes of p...