tbuckley/cabot-search huggingface dataset:
Refining medulloblastoma subgroups
Authors: Björn-Ole Juhnke, Martin Mynarek, Stefan Rutkowski
Journal: The Lancet Oncology (2017)

Medulloblastoma is currently deemed to be composed of four molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4). 1 Taylor MD Northcott PA Korshunov A et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012; 123: 465-472 Crossref PubMed Scopus (1244) Google Scholar Reports from retrospective data collection have shown distinct clinical and biological characteristics and outcomes for the four subgroups, with the MBWNT subgroup having an excellent prognosis and patients in the MBGrp3 subgroup having very poor prognosis across several studies. 2 Kool M Korshunov A Remke M et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012; 123: 473-484 Crossref PubMed Scopus (718) Google Scholar , 3 Remke M Hielscher T Korshunov A et al. FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. J Clin Oncol. 2011; 29: 3852-3861 Crossref PubMed Scopus (134) Google Scholar , 4 Remke M Hielscher T Northcott PA et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol. 2011; 29: 2717-2723 Crossref PubMed Scopus (189) Google Scholar , 5 Northcott PA Korshunov A Witt H et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011; 29: 1408-1414 Crossref PubMed Scopus (975) Google Scholar However, substantial heterogeneity in clinical and molecular features still exists in these subgroups. On the basis of preclinical data, further stratification of medulloblastoma into distinct molecular subgroups beyond the four that are generally accepted have been attempted. 5 Northcott PA Korshunov A Witt H et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011; 29: 1408-1414 Crossref PubMed Scopus (975) Google Scholar , 6 Kool M Koster J Bunt J et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One. 2008; 3: e3088 Crossref PubMed Scopus (567) Google Scholar , 7 Pomeroy SL Tamayo P Gaasenbeek M et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002; 415: 436-442 Crossref PubMed Scopus (1983) Google Scholar However, most of the molecular subgrouping of medulloblastoma has been generated from large cohorts without taking clinical and therapeutic information of the treated patients into account. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort studyThe discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. Full-Text PDF Open Access
New Insights into Lymphoma Pathogenesis
Authors: Kojo S.J. Elenitoba-Johnson, Megan S. Lim
Journal: Annual Review of Pathology Mechanisms of Disease (2017)

Lymphomas represent clonal proliferations of lymphocytes that are broadly classified based upon their maturity (peripheral or mature versus precursor) and lineage (B cell, T cell, and natural killer cell). Insights into the pathogenetic mechanisms involved in lymphoma impact the classification of lymphoma and have significant implications for the diagnosis and clinical management of patients. Serial scientific and technologic advances over the last 30 years in immunology, cytogenetics, molecular biology, gene expression profiling, mass spectrometry-based proteomics, and, more recently, next-generation sequencing have contributed to greatly enhance our understanding of the pathogenetic mechanisms in lymphoma. Novel and emerging concepts that challenge our previously accepted paradigms about lymphoma biology and how these impact diagnosis, molecular testing, disease monitoring, drug development, and personalized and precision medicine for lymphoma are discussed.
Cortical Pyramidal Neurons Show a Selective Loss of New Synapses in Chronic Schizophrenia
Authors: Joseph T. Coyle
Journal: American Journal of Psychiatry (2017)

that schizophrenia "was the graveyard of neuropathology" (1).This pessimistic view reflected the inability of investigators to identify consistent pathology in the brains of individuals with schizophrenia.This failure "to see pathology" in schizophrenia largely stemmed from limitations of tissue stains, which were successfully employed in neuropathology to reveal neuronal loss, astrocytosis, senile plaques, and Lewy bodies in neurodegenerative diseases.However, these stains cannot reveal synaptic structures, the microscopic wiring of the nervous system that is situated in the space between neurons and that is known as "neuropil."Nevertheless, CT studies (2) at the time and subsequent MRI studies (3) in schizophrenia revealed consistent, significantly reduced cortical volume and increased ventricular size.Concerted efforts were made to identify the missing neurons that could account for this cortical atrophy in schizophrenia.However, no neuronal loss commensurate with the degree of cortical atrophy could be found in the brains of individuals with schizophrenia with rigorous stereology.However, using standard cell stains, Selemon et al. (4) reported that the reduced size of the neuronal cell bodies and increased neuronal "packing" density resulting from loss of neuropil accounted for the cortical atrophy in schizophrenia.The millennium heralded two major advances that dramatically improved our ability to decipher the neuropathology of schizophrenia.First, a powerful confocal microscopic imaging method was developed that used laser illumination to visualize the localization of fluorescent-labeled immune markers with high resolution.Thus, it became possible to study the components of synaptic structures that were, up to that time, inaccessible with standard light microscopy (5).Second, advances in molecular genetics permitted the identification of risk genes that provide both targets as well as context for interpreting synaptic pathology.Thus, a recent genome-wide association study (GWAS) sufficiently powered (.100,000 subjects) to achieve a rigorous statistical threshold of 5310 28 to compensate for the multiple comparisons inherent in a GWAS found 108 sites on the genome associated with significant risk for schizophrenia (6).These sites do not involve highly penetrant dominant or recessivemutations but rather subtlegeneticvariants, often located in noncoding regions of the genes, such as promoters.The present study from MacDonald et al. ( 7) involved a reanalysis of a cohort of postmortem brain samples from
MEDU-29. A NOVEL MOUSE MODEL OF PI3 KINASE PATHWAY IN METASTATIC SHH MEDULLOBLASTOMA
Authors: Xiaochong Wu, Michael Taylor
Journal: Neuro-Oncology (2017)

Sleeping Beauty transposon mutagenesis in Shh medulloblastomas enabled us to identify that Pten was a common insertion site in both primary tumor and matched spinal metastases, suggesting PI3 kinase pathway is important for the progression of Shh medulloblastoma, in particular, for its metastasis. And PI3K-addiction could be one of mechanisms for the resistance to SHH signaling inhibitors seen in SHH medulloblastoma patients. To dissect the role of PI3 kinase pathway during the development of metastatic Shh medulloblastoma, and to establish an in vivo model for pre-clinical trials for PI3K pathway inhibitors on metastatic SHH medulloblastoma, we recently generate a novel targeted mutant mouse model Rosa-Tetoff-lsl-Pik3CAH1047R –t2a-Fluc. In this mouse model, a Dox-off and Cre-LoxP dual system mediates the spatial-temporal specific expression of Pik3CAH1047R, and the tumor cells could be visualized by bioluminescent imaging (BLI). We have crossed Rosa-Tetoff-lsl-Pik3CAH1047R –t2a-Fluc mouse with Math1Cre and Ptc heterozygous deletion mice to generate Pik3CAH1047R/Math1Cre/Ptc triple mice. Preliminary results showed that in the absence of Doxycycline the triple mice developed massive metastases at the frontal brain and spinal cord. More mice are generated and aged for detail experiments. In summary, we established a novel mouse model to express Pik3CAH1047R in a spatial-temporal specific manner, and the mutant Pik3CA greatly promoted Shh medulloblastoma metastasis to the spinal cord and frontal brain.
DIPG-22. IDENTIFICATION OF THERAPEUTIC TARGETS IN DIPGS USING LARGE-SCALE RNAI SCREENING
Authors: Kathrin Schramm, Murat Iskar, Daniela Sohn, Norman Mack, Lotte Hiddingh, Michelle Monje, Angel Montero Carcaboso, Marc Zapatka, Jan Gronych, David Jones, Peter Lichter
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive pediatric brain tumors that are characterized by a recurrent mutation (K27M) within the histone H3 encoding genes H3F3A or HIST1H3A/B/C. These mutations have been shown to induce a global reduction in the repressive histone modification H3K27me3. Together with global changes in DNA methylation patterns this results in a broad diversity of downstream effects which hampers the identification of single therapeutic targets based on a molecular rationale. Therefore, our aim is to identify critical nodes of tumor development and maintenance using a DECIPHER pooled shRNA screening approach in combination with next-generation sequencing. The shRNA library targets more than 5,000 genes, with multiple shRNAs per target as well as internal controls. Currently, four patient-derived H3.3K27M mutated DIPG vs. two H3.3WT control high-grade glioma cell lines are being screened for shRNAs inducing cell death. Preliminary hits unexpectedly included the H3.3-specific histone chaperone complex components ATRX (alpha thalassemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein) - targets which are sometimes mutated in DIPG. This suggests a more complex role of H3.3-dependent heterochromatin formation in DIPGs than is currently appreciated. These and other promising hits will be validated in an expanded cell line panel using a custom CRISPR/Cas9 library, with top candidates further taken forward to in vivo pre-clinical testing for identification of drug targets.
Defining sepsis: inspiring proposals meet practical realities
Authors: Melinda Munang, Saleem Chaudhri, Methini Himayakanthan, Steven Laird, Amy Moltu, Natasha Naworynsky, Christopher Pollard, Tahir Saeed, Paul Scott, Cathleen Chan, Maya Sussman, Shaun Thein, George Trafford, Ariyur Balaji, Neil Jenkins, Ed Moran
Journal: The Lancet Infectious Diseases (2017)
Integrative analyses reveal biological pathways and key genes in psoriasis
Authors: J. Dou, L. Zhang, X. Xie, L. Ye, C. Yang, L. Wen, C. Shen, C. Zhu, S. Zhao, Z. Zhu, B. Liang, Z. Wang, H. Li, X. Fan, S. Liu, X. Yin, X. Zheng, L. Sun, S. Yang, Y. Cui, F. Zhou, X. Zhang
Journal: British Journal of Dermatology (2017)

Psoriasis is a complex disease influenced by both genetic and environmental factors with abnormal gene expression in lesional skin. However, no studies are available on genome‐scale gene expression of psoriatic lesions in the Chinese population. In addition, systematic studies on the biological pathways, pathogenicity and interaction networks of psoriasis‐related genes with abnormal expression profiles require further investigation. To further explore the associated pathways in psoriasis by functional analysis and to identify the key genes by gene pathogenicity analysis. We performed RNA sequencing on 60 skin biopsy samples from patients with psoriasis and healthy controls to identify the primary differentially expressed genes in psoriatic lesional skin. We retrieved all reported psoriasis‐associated genes and performed integrative analyses covering gene expression profiling, pathway analysis, gene pathogenicities and protein–protein interaction networks. We found that internal and external stimuli may activate immunoinflammatory responses to promote the development of psoriasis. Pathways associated with infectious diseases and cancers were identified by functional and pathway analyses. The gene pathogenicity analysis revealed five key genes in psoriasis: PPARD, GATA3, TIMP3, WNT5A and PTTG1. Our analyses showed that genes contributed to the pathogenesis of psoriasis by activating risk pathways with components abnormality in expression. We identified five potentially pathogenic genes for psoriasis that may serve as important biomarkers for the diagnosis and treatment.
Predicting recurrent pulmonary embolism and chronic thromboembolic pulmonary hypertension: one more way to skin the cat
Authors: Frederikus A. Klok, Marius M. Hoeper
Journal: European Respiratory Journal (2017)

In this issue of the European Respiratory Journal , Pesavento et al . [1] present the results of the Study on the Clinical Course Of Pulmonary Embolism (SCOPE). In this huge effort, 647 consecutive patients with a symptomatic, confirmed first episode of acute pulmonary embolism (PE) were recruited and subjected to lung scanning after an initial treatment period of 6 months to assess the presence of residual pulmonary obstruction. Patients were followed for an additional 3-year period to monitor the occurrence of recurrent venous thromboembolism (VTE) and/or chronic thromboembolic pulmonary hypertension (CTEPH). The primary aim of the SCOPE study was to evaluate the predictive value of persistent perfusion defects for recurrent PE and CTEPH. Notably, 50% of patients were found to have some degree of persistent perfusion defects, with 56 (8.7%) patients having a persistent perfusion obstruction of >25% and none >72%. Both higher age (OR 1.03, 95% CI 1.02–1.04, per year) and unprovoked PE (OR 1.40, 95% CI 1.01–1.95) were predictive of persistent perfusion defects, whereas among others reperfusion therapy at baseline was not. During the 3-year follow-up period, 40 patients were diagnosed with recurrent VTE (6.2%; 95% CI 4.5–8.3) and 11 with CTEPH (1.7%; 95% CI 0.9–3.0). In multivariate COX regression analysis, persistent perfusion defects predicted the combined endpoint of recurrent VTE and/or CTEPH for an adjusted hazard ratio of 2.26 (95% CI 1.23–4.16). From these results, the authors conclude that a single assessment of persistent perfusion defects at 6 months may guide treatment decisions regarding duration of anticoagulation therapy. Persistent perfusion defects predict recurrent pulmonary embolism and CTEPH <http://ow.ly/xMHm30aD7aB>
Abstract 64: Meis1 Is a Key Regulator of Postnatal Cardiomyocyte Cell Cycle Arrest
Authors: Fatih Kocabas, Ahmed I Mahmoud, Shalini Muralidhar, Enzo Porrello, Eric Olson, Hesham A Sadek
Journal: Circulation Research (2012)

Heart failure is a costly and deadly disease affecting over 5 million Americans. The inability of the adult mammalian heart to regenerate following injury lies at core of the pathophysiology of heart failure. We recently showed that the neonatal mammalian heart is capable of complete regeneration following resection of the entire ventricular apex. Moreover, our preliminary data indicate that the neonatal mouse heart is also capable of complete regeneration following ischemic myocardial infarction. In both these types of injury, the regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. Genetic fate mapping studies demonstrated that the majority of newly formed cardiomyocytes originated from pre-existing cardiomyocytes. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal timepoints. This enabled us to identify Meis1 as a potential regulator of neonatal cardiomyocyte proliferation. Meis1, which belongs to the TALE family of homeodomain transcription factors, is required for normal hematopoiesis and cardiac development. While Meis1 has been extensively studied in the hematopoietic system, little is known about its role in the heart. Our results indicate that Meis1 expression and nuclear localization in the post-natal cardiomyocytes coincides with cell cycle arrest. To further explore this pattern, we generated a cardiomyocyte-specific Meis1 knockout mouse, and showed that loss of Meis1 results in robust cardiomyocyte proliferation in the adult heart. Moreover, we identified p16 and p21; two synergistic cyclin dependent kinase inhibitors that induce arrest at all three cell cycle checkpoints, as potential targets for transcriptional activation by Meis1. These results identify Meis1 as a key regulator of post-natal cardiomyocyte cell cycle arrest, and a potential therapeutic target for cardiac regeneration.
Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy
Authors: Natalie Cureton, Iana Korotkova, Bernadette Baker, Susan Greenwood, Mark Wareing, Venkata R Kotamraju, Tambet Teesalu, Francesco Cellesi, Nicola Tirelli, Erkki Ruoslahti, John D Aplin, Lynda K Harris
Journal: Theranostics (2017)

Fetal growth restriction (FGR) in pregnancy is commonly caused by impaired uteroplacental blood flow.Vasodilators enhance uteroplacental perfusion and fetal growth in humans and animal models; however, detrimental maternal and fetal side effects have been reported.We hypothesised that targeted uteroplacental delivery of a vasodilator would enhance drug efficacy and reduce the risks associated with drug administration in pregnancy.Phage screening identified novel peptides that selectively accumulated in the uteroplacental vasculature of pregnant mice.Following intravenous injection, the synthetic peptide CNKGLRNK selectively bound to the endothelium of the uterine spiral arteries and placental labyrinth in vivo; CNKGLRNK-decorated liposomes also selectively bound to these regions.The nitric oxide donor 2-[[4-[(nitrooxy)methyl]benzoyl]thio]-benzoic acid methyl ester (SE175) induced significant relaxation of mouse uterine arteries and human placental arteries in vitro; thus, SE175 was encapsulated into these targeted liposomes and administered to healthy pregnant C57BL/6J mice or endothelial nitric oxide synthase knockout (eNOS -/-) mice, which exhibit impaired uteroplacental blood flow and FGR.Liposomes containing SE175 (0.44mg/kg) or PBS were administered on embryonic (E) days 11.5, 13.5, 15.5 and 17.5; fetal and placental weights were recorded at term and compared to mice injected with free PBS or SE175.Targeted uteroplacental delivery of SE175 had no effect on fetal weight in C57BL/6J mice, but significantly increased fetal weight and mean spiral artery diameter, and decreased placental weight, indicative of improved placental efficiency, in eNOS -/-mice; free SE175 had no effect on fetal weight or spiral artery diameter.Targeted, but not free SE175 also significantly reduced placental expression of 4-hydroxynonenal, cyclooxygenase-1 and cyclooxygenase-2, indicating a reduction in placental oxidative stress.These data suggest that exploiting vascular targeting peptides to selectively deliver SE175 to the uteroplacental vasculature may represent a novel treatment for FGR resulting from impaired uteroplacental perfusion.
Abstract 28: Extracellular Matrix Coating Enhances Nanoparticle Uptake by Lung Epithelial Cells
Authors: Primana Punnakitikashem, Priya Ravikumar, Jinglei Wu, Kytai Nguyen, Connie Hsia, Yi Hong
Journal: Circulation Research (2015)

Introduction: Rapid uptake of drug-loaded nanoparticles (NPs) by lung cells is critical for effective pulmonary delivery of therapeutic agents because of the rapid pulmonary clearance mechanisms. We tested the possibility that coating NPs with extracellular matrix (ECM) derived from lung tissue enhances nanoparticles uptake by lung cells. Methods and Results: Fresh adult porcine lung tissue obtained from a local slaughterhouse was decellularized using detergent (sodium dodecyl sulfate) and then enzymatically digested into a soluble solution. The double emulsion method was utilized to fabricate core-shell poly(lactic-co-glycolic) (PLGA) nanoparticles loaded with bovine serum albumin (BSA) for protein release studies, 6-coumarin for cellular uptake studies, or human erythropoietin receptor (hEPOR) cDNA co-expressing green fluorescent protein (GFP) for in vivo gene expression studies. The ECM was coated onto the nanoparticle surface by physical adsorption using the ECM solution (100 μg/ml). There is no significant difference in the diameter, blood compatibility or cell toxicity between coated and uncoated NPs. ECM-coated NPs showed slower protein release rate than uncoated NPs as the ECM coating hindered protein diffusion into the solution. ECM-coated NPs showed significantly higher cellular uptake by human lung epithelial cells than collagen-coated or uncoated NPs. In addition, ECM-coated and uncoated NPs loaded with hEPOR-GFP cDNA were aerosolized and delivered by inhalation into rat lung. Following single inhalation using uncoated NPs, GFP expression in lung tissue progressively increased for up to 21 days. Using the ECM-coated NPs EPOR expression peaked at 14 days, then declined thereafter. Conclusions: Coating NPs with lung-derived ECM markedly enhances NP uptake by lung cells, delays the release of encapsulated protein or DNA, and shortens the duration of peak tissue gene expression compared to uncoated NPs. This NP formulation may be useful where more precise timing of delayed payload release is desired.
“I am not dead yet!” – The Item responds to Hulleman &amp; Olivers
Authors: Jeremy M Wolfe
Journal: Behavioral and Brain Sciences (2017)

Abstract The item can only be dispensed within artificial tasks that, although useful in the lab, do not reflect the real world. There, the attended item is the goal of search. Hulleman &amp; Olivers' (H&amp;O's) model can ignore the item only by reducing search to the question of whether a patch of 0s (distractors) contains a 1 (target).