tbuckley/cabot-search huggingface dataset:
Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium over Time
Authors: Grace E. Lidgerwood, Anne Senabouth, Casey J.A. Smith-Anttila, Vikkitharan Gnanasambandapillai, Dominik C. Kaczorowski, Daniela Amann-Zalcenstein, Erica L. Fletcher, Shalin H. Naik, Alex W. Hewitt, Joseph E. Powell, Alice Pébay
Journal: Genomics Proteomics & Bioinformatics (2020)

Human pluripotent stem cell (hPSC)-derived progenies are immature versions of cells, presenting a potential limitation to the accurate modelling of diseases associated with maturity or age. Hence, it is important to characterise how closely cells used in culture resemble their native counterparts. In order to select appropriate time points of retinal pigment epithelium (RPE) cultures that reflect native counterparts, we characterised the transcriptomic profiles of the hPSC-derived RPE cells from 1- and 12-month cultures. We differentiated the human embryonic stem cell line H9 into RPE cells, performed single-cell RNA-sequencing of a total of 16,576 cells to assess the molecular changes of the RPE cells across these two culture time points. Our results indicate the stability of the RPE transcriptomic signature, with no evidence of an epithelial-mesenchymal transition, and with the maturing populations of the RPE observed with time in culture. Assessment of Gene Ontology pathways revealed that as the cultures age, RPE cells upregulate expression of genes involved in metal binding and antioxidant functions. This might reflect an increased ability to handle oxidative stress as cells mature. Comparison with native human RPE data confirms a maturing transcriptional profile of RPE cells in culture. These results suggest that long-term in vitro culture of RPE cells allows the modelling of specific phenotypes observed in native mature tissues. Our work highlights the transcriptional landscape of hPSC-derived RPE cells as they age in culture, which provides a reference for native and patient samples to be benchmarked against.
LGG-46. MOLECULAR CHARACTERIZATION OF HEMISPHERIC LOW-GRADE GLIOMAS IN CHILDREN
Authors: Adéla Mišove, Lenka Krsková, David Sumerauer, Josef Zámečník, Kateřina Váňová, Jan Starý, Ivana Perníková, Aleš Vícha, Petr Libý, Michal Tichý, Jakub Táborský, Martin Kynčl, Michal Zápotocký
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Heterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options. METHODS Demographic data was collected and targeted genomic approach was employed in the single institutional study. RT-PCR was used to screen for KIAA1549-BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD). Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1 ex12 and ex14). Samples with no detected alteration were subjected to panel RNA-sequencing (FusionPlex Archer Diagnostics). RESULTS Within 2000–2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range 0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG were characterized by BRAF alterations with over 2/3 of those cases harboring BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF fusions were uncommon and detected only in six patients (two KIAA-BRAF fusion, two minor oncogenic BRAF variants, two non-KIAA BRAF fusion). 25 % of alterations were found in genes for receptor tyrosine kinases, consisting of seven patients with FGFR1-ITD, three FGFR2/3 fusions, two FGFR1 mutations, two ALK fusions, and one ROS fusion. Out of MAP kinase pathway, the most frequent alteration was IDH1 mutations (n=9). Two angiocentric gliomas were characterized by MYB-QKI fusion. CONCLUSION Targeted sequencing combined with RNA-sequencing is feasible to establish molecular diagnosis in majority of cases and reveal new and rare alterations. Significant prevalence of non-BRAF alterations explains heterogeneity among hemLGG.
MRI in interstitial lung disease (M-ILD): a momentum to innovate lung diagnostic
Authors: Pierluigi Ciet
Journal: Thorax (2020)

The prevalence of interstitial lung disease (ILD) is high and progressively increasing.1 Mortality and morbidity vary according to ILD subtype, but overall median survival is poor, ranging from 5 to 14 years.2 Irrespective of classification and cause of lung fibrosis, several patients present with progressive-fibrosing ILD (PF-ILD), characterised by a rapid decline in lung function.3 

A recent landmark study demonstrated a reduction in PF-ILD disease progression using costly antifibrotic drugs.4 However, half of patients with ILD do not benefit from these expensive antifibrotic drugs but could be better treated with anti-inflammatory or combined treatment. Hence, there is an unmet need for a monitoring tool to phenotype patients with ILD by assessing the amount of pulmonary fibrosis and inflammation to guide treatment choices and monitor response.3 

Current monitoring, namely, high-resolution CT (HRCT) and pulmonary function …
ETMR-15. USE OF HIGH-DOSE CHEMOTHERAPY FOR TWO CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Shimpei Kusano, Junya Fujimura, Megumi Fujiwara, Akinori Yaguchi, Takeshi Ishibashi, Osamu Tomita, Hiroyuki Tamaichi, Akihide Kondo, Toshiaki Shimizu
Journal: Neuro-Oncology (2020)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is new entity defined in the 4th revised edition of the WHO classification of tumors of the central nervous system. Although radical resection, radiotherapy, and multiagent chemotherapy are considered to be necessary for ETMR, the efficacy of chemotherapy for ETMR in Japan has not been established. Here, we report different clinical courses for two children with localized ETMR treated with the St. Jude medulloblastoma-96 (SJMB96) regimen, which consists of four cycles of high-dose chemotherapy with autologous peripheral blood stem cell transplantation. For both children, the diagnosis of ETMR, C19MC-altered was confirmed after gross total tumor resection. Multiagent chemotherapy was administered following cranio-spinal irradiation with local boost. One month after completion of the treatment, one patient experienced local recurrence but has been in remission for over 2 years after tumor resection and stereotactic irradiation with a CyberKnife and treatment every three weeks with bevacizumab. The other patient also experienced local recurrence after the third cycle of chemotherapy and several times thereafter. Although she again underwent tumor resection and local irradiation, her tumor grew larger and invaded. Because her prognosis was very poor, her parents choose only palliative care. Based on our experience, we believe that continuous chemotherapy at conventional doses is preferred over intensive-dose chemotherapy such as SJMB96. However, the number of reports on chemotherapy for ETMR is still small, and a prospective multicenter trial is needed to establish effective chemotherapy for ETMR.
Multidisciplinary consensus on sputum induction biosafety during the COVID‐19 pandemic
Authors: Astrid Crespo‐Lessmann, Vicente Plaza
Journal: Allergy (2020)

Abstract Sputum induction (SI) is the gold standard approach to the non‐invasive study of airway inflammation. The differential count of inflammatory cells for SI allows patients with asthma to be classified according to inflammatory phenotypes and predicted therapeutic responses. Since SI involves the generation of aerosols, there is a need to establish a protocol to ensure biosafety in clinical practice during the current COVID‐19 pandemic. The multidisciplinary consensus on SI described in this article was developed by 22 experts in SI from different Spanish hospitals who drew on available scientific evidence in achieving consensuated opinions, compiled by means of an electronic survey. We hope that these unified criteria and recommendations will guide health professionals in implementing SI sampling and processing procedures as safely as possible during the COVID‐19 pandemic.
Cost-effectiveness of Statin Use Guidelines
Authors: Conrad B. Blum, Neil J. Stone
Journal: JAMA Cardiology (2020)

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
The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial
Authors: Christine R. Jenkins, Fu-Qiang Wen, Allison Martin, Peter J. Barnes, Bartolome Celli, Nan-Shan Zhong, Jin-Ping Zheng, Anish Scaria, Gian-Luca Di Tanna, Thomas Bradbury, Norbert Berend
Journal: European Respiratory Journal (2020)

Background The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment. Methods In this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks. The primary end-point was annualised exacerbation rate. Results 1670 subjects were randomised and 1242 completed the study (1142 with acceptable data at week 48). Subjects (75.7% male) had a mean age of 64.4 years, with mean± sd baseline post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 1.1±0.4 L (42.2% predicted) and St George's Respiratory Questionnaire (SGRQ) score 45.8±20.1. There were negligible differences between annualised exacerbation rates across the three treatments: 0.89 (95% CI 0.78–1.02) on theophylline plus prednisone, 0.86 (95% CI 0.75–0.99) on theophylline plus placebo and 1.00 (95% CI 0.87–1.14) on placebo. The rate ratio for theophylline plus prednisone versus pooled theophylline plus placebo and placebo was 0.96 (95% CI 0.83–1.12), for theophylline plus placebo versus placebo was 0.87 (95% CI 0.73–1.03; p=0.101) and for theophylline plus prednisone versus placebo was 0.90 (95% CI 0.76–1.06; p=0.201). Secondary outcomes of hospitalisations, FEV 1 , SGRQ and COPD Assessment Test score showed no statistically significant difference between treatment arms. Serious adverse events other than exacerbations were &lt;2% and did not differ between treatment arms. Conclusions Low-dose theophylline alone or in combination with prednisone did not reduce exacerbation rates or clinically important secondary end-points compared with placebo.
QOL-17. BIOLOGICAL CORRELATES OF QUALITY OF SURVIVAL AND NEUROCOGNITIVE OUTCOMES IN MEDULLOBLASTOMA; A META-ANALYSIS OF THE SIOP-UKCCSG-PNET3 AND HIT-SIOP-PNET4 TRIALS
Authors: Mathilde Chevignard, Kim Bull, James Holt, Marie-Amelie Heng, Colin Kennedy, Francois Doz, Birgitta Lannering, Stefan Rutkowski, Maura Massimino, Steven Clifford, Debbie Hicks
Journal: Neuro-Oncology (2020)

Abstract Relationships between biological factors (genetic, tumour molecular subgroup) and neurocognitive/Quality of Survival (QoS) outcomes in medulloblastoma survivors are emerging, based on studies of limited retrospective cohorts. Integrated investigations of the medulloblastoma late-effects pathway (considering biological, clinical and treatment factors), using larger clinically-controlled cohorts, are now essential to determine their independent significance and potential for clinical application. In a combined cohort of SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 patients (n=150), molecular subgroup (MBWNT, MBSHH, MBGrp3, MBGrp4) was assessed against QoS measures [health status: HUI3; emotional and behavioural difficulties: SDQ; Health-related Quality of Life (HrQoL): PedsQL]. Additionally, in DNA remaining from HIT-SIOP-PNET4 (n=74), 39 candidate SNPs (involved in metabolism, DNA maintenance/repair, neural growth/repair and oxidative stress/inflammation) were genotyped by multiplexed MALDI-TOF MassArray and assessed against Wechsler Intelligence Scale (WISC) scores. Molecular subgroup was significantly associated with HrQoL and health status in univariate analyses; MBGrp4 predicted significantly worse outcomes than MBSHH and MBGrp3 (p&amp;lt;0.05), but not in multivariate analyses taking into consideration other significant and reported QoS predictors (e.g. treatment, gender, age). In contrast, 6 SNPs were significantly associated with ≥1 WISC domain; 4/6 showed associations across domains. 3 SNPs were independently prognostic in multivariate analyses, and further significant associations were apparent at the gene (BDNF, APOE) and pathway (folate) level. This cross-discipline, international study encompassing two medulloblastoma trials has identified relationships between molecular subgroup, genotype and survivorship outcomes. These findings now require assessment in larger series, to inform our understanding of medulloblastoma survivorship outcomes and impact future disease management strategies.
YAP in pancreatic cancer: oncogenic role and therapeutic strategy
Authors: Wenhao Mao, Jia Mai, Hui Peng, Junhu Wan, Ting Sun
Journal: Theranostics (2020)

Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments.The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis.The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC.Considering its importance in cancer, YAP is emerging as a promising therapeutic target.In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.
John Thomas Anderson
Authors: Rachael Martin
Journal: BMJ (2020)

At the age of 15 15, John Thomas Anderson was laid on his back in a hospital for almost a year with Scheuermann’s disease. This motivated him to pursue a career in medicine. The son of a steelworker on Teesside, he had never left his hometown of Middlesbrough but decided he was going to study at University College London. After finishing his studies he returned to Teesside …
A general Fc engineering platform for the next generation of antibody therapeutics
Authors: Da Chen, Yingjie Zhao, Mingyu Li, Hang Shang, Na Li, Fan Li, Wei Wang, Yuan Wang, Ruina Jin, Shiyu Liu, Xun Li, Shan Gao, Yujie Tian, Ruonan Li, Huanhuan Li, Yongyan Zhang, Mingjuan Du, Youjia Cao, Yan Zhang, Xin Li, Yi Huang, Liaoyuan A. Hu, Fubin Li, Hongkai Zhang
Journal: Theranostics (2020)

Fc engineering has become the focus of antibody drug development. The current mutagenesis and
Echocardiography for the “Superior Doctor”: A Call to Action in the Management of Heart Failure⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Walter P. Abhayaratna
Journal: JACC. Cardiovascular imaging (2012)
β-blockers in advanced cirrhosis: More friend than enemy
Authors: Ki Tae Yoon, Hongqun Liu, Samuel S. Lee
Journal: Clinical and Molecular Hepatology (2020)

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.
BIOM-14. METHODS FOR SCREENING AND MONITORING BY GBM MASTER REGULATORY GENE MARKERS IN LIQUID BIOPSY
Authors: Tianyi Liu, Son Le, David Tran
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Current liquid-based cancer screening relies on massive deep NGS to detect rare cancer cell-derived genetic materials - a costly method fraught with high false-negative and false-positive rates. We aim to develop a non-NGS-centered, AI-directed liquid-based detection of GBM stem-like cells (GSC). METHODS Utilized a robust AI suite, NETZEN, we defined a common master regulatory gene network (MRGN) in GSC. Since master regulators (MR) in MRGN are developmentally restricted, their chromosomal loci are accessible in GSC but not in normal cells. Downstream factors in MRGN are massively overexpressed in GSC compared to normal cells. Thus, we measured 1) accessibility of MR genes using transposase/transposons carrying unique barcodes that can be detected after insertion into the MR’s predetermined accessible locations, and 2) expression of downstream factors using nested qRT-PCR, in PBMC from healthy controls spiked with known quantities of GSC or patients with GBM. RESULTS We characterized 10 MR genes in GSC with ≥1 GC-rich promoter region that is hypomethylated and accessible (ATACseq) in GBM/GSC per GSE70175/92460/52271 (19 samples) and GSE67633/96088 (14 samples), and hypermethylated and inaccessible in lymphocytes/PBMC per GSE98837 (6) and GSE74912 (13), respectively. Using barcoded transposons, we specifically disrupted 4 MR’s accessible regions only in GSC, not in PBMC. We also characterized 50 upregulated downstream factors with the top 20 having 3 to 5-orders-of-magnitude higher mean expression in GSC compared to PBMC (GSE79362/86884, 451 samples). Currently our method has a detection limit of 0.2–1 GSC in 106 PBMC. Using the first iteration, we detected GSC’s MRGN in blood samples of 14/14 GBM patients before resection, compared to in none of 15 healthy donors. CONCLUSIONS Chromosomal accessibility of MR and signal amplification in MRGN of GSC provide powerful substrates for a non-NGS, low-cost, liquid-based GBM detection system with potentially high sensitivity and specificity. Further testing and optimization are ongoing.
37P First-line BRAF/MEK-inhibitors versus anti-PD-1 monotherapy in BRAFV600-mutant advanced melanoma patients: A propensity-matched survival analysis
Authors: J.V. Breeschoten, M. Wouters, D. Hilarius, J.B.A.G. Haanen, C.U. Blank, M. Aarts, F. Van den Berkmortel, J.W. de Groot, G.A. Hospers, E. Kapiteijn, D. Piersma, R. Van Rijn, K. Suijkerbuijk, W.A.M. Blokx, A. Ten Tije, A.A.M. Van der Veldt, G. Vreugdenhil, M. Boers-Sonderen, A.J.M. van den Eertwegh
Journal: Annals of Oncology (2020)
CTNI-02. TBCRC049: A PHASE II STUDY TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF TUCATINIB, TRASTUZUMAB AND CAPECITABINE FOR THE TREATMENT OF LEPTOMENINGEAL METASTASIS IN HER2 POSITIVE BR1AST CANCER
Authors: Rashmi Murthy, Barbara O’Brien, Donald Berry, Nicholas Navin, Jason Johnson, Maria Gule-Monroe, Jose Leone, Jennifer Specht, Michelle Melisko, Aki Morikawa, Anna Storniolo, Adam Brufsky, Paula Pohlmann, Deric Park, Ben Park, Ian Krop, Nancy Lin, Mothaffar Rimawi, Antonio Wolff, Andres Forero-Torres, Erica Stringer-Reasor
Journal: Neuro-Oncology (2020)

Abstract Treatment options for patients with leptomeningeal metastasis (LM) from HER2-positive breast cancer (HER2+ BC) are limited and prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and combinatory anti-tumor activity, including partial responses in heavily treated patients and those with brain metastases (BM). This is a phase 2 single-arm study to evaluate the efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly-diagnosed LM. CNS disease will be evaluated at screening and every 6 weeks by neuroaxis MRI, CSF cytology, and neurological assessments per RANO-LMD (adapted) and RANO-BM criteria. Extra-CNS disease will be evaluated at screening and every 12 weeks by CT scan per RECIST criteria. All patients will be followed for survival. Symptom burden and quality of life assessments, as well as correlative blood and CSF samples, will be collected. Eligible patients include adults with HER2+ BC, KPS &amp;gt; 50, and newly-diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM are allowed. Patients treated with capecitabine within the last 12 months are excluded. This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, success is defined as CNS PFS for 12 weeks. Enrollment will end if fewer than two successes are observed in the first 15 patients. Secondary endpoints include safety, CNS PFS at 12 weeks, RR in CNS and extra-CNS, and symptom burden/quality of life. The regimen will be considered worthy of future study if the median OS is &amp;gt; 4.4 months. Fourteen of 30 patients have accrued thus far. The study is active at multiple Translational Breast Cancer Research Consortium sites around the country.