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Find video protocols related to scientific articles indexed in Pubmed.
Making the Case for History in Medical Education.
J Hist Med Allied Sci
PUBLISHED: 11-15-2014
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Historians of medicine have struggled for centuries to make the case for history in medical education. They have developed many arguments about the value of historical perspective, but their efforts have faced persistent obstacles, from limited resources to curricular time constraints and skepticism about whether history actually is essential for physicians. Recent proposals have suggested that history should ally itself with the other medical humanities and make the case that together they can foster medical professionalism. We articulate a different approach and make the case for history as an essential component of medical knowledge, reasoning, and practice. History offers essential insights about the causes of disease (e.g., the non-reductionistic mechanisms needed to account for changes in the burden of disease over time), the nature of efficacy (e.g., why doctors think that their treatments work, and how have their assessments changed over time), and the contingency of medical knowledge and practice amid the social, economic, and political contexts of medicine. These are all things that physicians must know in order to be effective diagnosticians and caregivers, just as they must learn anatomy or pathophysiology. The specific arguments we make can be fit, as needed, into the prevailing language of competencies in medical education.
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Mechismo: predicting the mechanistic impact of mutations and modifications on molecular interactions.
Nucleic Acids Res.
PUBLISHED: 11-14-2014
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Systematic interrogation of mutation or protein modification data is important to identify sites with functional consequences and to deduce global consequences from large data sets. Mechismo (mechismo.russellab.org) enables simultaneous consideration of thousands of 3D structures and biomolecular interactions to predict rapidly mechanistic consequences for mutations and modifications. As useful functional information often only comes from homologous proteins, we benchmarked the accuracy of predictions as a function of protein/structure sequence similarity, which permits the use of relatively weak sequence similarities with an appropriate confidence measure. For protein-protein, protein-nucleic acid and a subset of protein-chemical interactions, we also developed and benchmarked a measure of whether modifications are likely to enhance or diminish the interactions, which can assist the detection of modifications with specific effects. Analysis of high-throughput sequencing data shows that the approach can identify interesting differences between cancers, and application to proteomics data finds potential mechanistic insights for how post-translational modifications can alter biomolecular interactions.
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DISOPRED3: Precise disordered region predictions with annotated protein binding activity.
Bioinformatics
PUBLISHED: 11-14-2014
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A sizeable fraction of eukaryotic proteins contain intrinsically disordered regions (IDRs), which act in unfolded states or by undergoing transitions between structured and unstructured conformations. Over time, sequence-based classifiers of IDRs have become fairly accurate and currently a major challenge is linking IDRs to their biological roles from the molecular to the systems level.
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Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles.
Brain Pathol.
PUBLISHED: 11-10-2014
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Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in-depth molecular characterization. 18 melanocytomas, 12 melanomas, 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (CNV). The methylome fingerprints assigned tumors to entity-specific groups. Methylation groups also showed a substantial overlap with histology-based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried GNAQ/11 mutations and presented with CNV involving chromosome 3 and 6. Melanomas were frequently mutated in the TERT promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosome 9, 10 and 6q as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.
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Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.
Sci Transl Med
PUBLISHED: 11-08-2014
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Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.
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Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-?B-Dependent Regulation of Twist1.
Mol. Cell. Biol.
PUBLISHED: 11-05-2014
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Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of BRMS1 contributes to epithelial-to-mesenchymal transition (EMT). Using an shRNA system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressing BRMS1 shRNAs (BRMS1(KD)) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed in BRMS1(KD) cells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor-kappa B (NF-?B). In addition, chromatin immunoprecipitation analysis demonstrates that loss of BRMS1 increases Twist1 promoter occupancy of RelA/p65 K310-a key histone modification associated with increased transcription. Knockdown of Twist1 results in reversal of BRMS1(KD)-mediated EMT phenotypic changes. Moreover, in our animal model, double-knockdown BRMS1(KD)/Twist1(KD) cells were less efficient in establishing lung tumors, compared with BRMS1(KD) cells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-?B-dependent regulation of Twist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.
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Genome3D: exploiting structure to help users understand their sequences.
Nucleic Acids Res.
PUBLISHED: 10-29-2014
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Genome3D (http://www.genome3d.eu) is a collaborative resource that provides predicted domain annotations and structural models for key sequences. Since introducing Genome3D in a previous NAR paper, we have substantially extended and improved the resource. We have annotated representatives from Pfam families to improve coverage of diverse sequences and added a fast sequence search to the website to allow users to find Genome3D-annotated sequences similar to their own. We have improved and extended the Genome3D data, enlarging the source data set from three model organisms to 10, and adding VIVACE, a resource new to Genome3D. We have analysed and updated Genome3D's SCOP/CATH mapping. Finally, we have improved the superposition tools, which now give users a more powerful interface for investigating similarities and differences between structural models.
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PAX8 expression is associated with SHH/WNT subtypes, desmoplastic histology and patient survival in human medulloblastomas.
Neuropathol. Appl. Neurobiol.
PUBLISHED: 09-25-2014
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The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. While its function is partly understood in vertebrate development, there is poor data concerning human CNS development and brain tumors.
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Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces.
Expert Opin Drug Deliv
PUBLISHED: 09-24-2014
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Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers. Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research. Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.
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Intraoperative near-infrared fluorescence imaging as an adjunct to robotic-assisted minimally invasive esophagectomy.
Innovations (Phila)
PUBLISHED: 09-20-2014
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During esophagectomy, identification and preservation of the right gastroepiploic vascular arcade are critical and may be challenging with minimally invasive approaches. We assessed the use of near-infrared fluorescence imaging fluorescence angiography (NIFI-FA) during robotic-assisted minimally invasive esophagectomy (RAMIE) as an aid to visualize the gastric vasculature with mobilization. After intravenous administration of 10 mg of indocyanine green, a robotic platform with near-infrared optical fluorescence capability was used to examine the gastric vasculature in patients undergoing RAMIE. Thirty (71%) of 42 patients undergoing RAMIE were assessed using NIFI-FA during mobilization of the greater gastric curve and fundus; 11 were excluded because the system was not available, and 1 was excluded because of documented allergy to iodinated contrast. The median time from indocyanine green administration to detectable fluorescence was 37.5 seconds (range, 20-105 seconds). Near-infrared fluorescence imaging FA identified or confirmed termination of the vascular arcade in all 30 cases. Subjectively, NIFI-FA often identified otherwise unvisualized small transverse vessels between the termination of the vascular arcade and the first short gastric artery, as well as between the short gastric arteries. Identification and/or confirmation of the vascular arcade position during mobilization of the greater curve/omentum were also aided by NIFI-FA. Although there are limitations to the current technology, NIFI-FA may be a useful adjunct to confirm and identify the position of gastroepiploic vessels, allow for safer and more confident dissections during gastric mobilization, as well as potentially decrease serious intraoperative vascular misadventures.
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Recent advances and clinical implications of the micropapillary histological subtype in lung adenocarcinomas.
Lung Cancer Manag
PUBLISHED: 09-10-2014
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Micropapillary (MIP) histologic subtype included in the classification of lung adenocarcinomas (ADCs) is associated with both size- and stage-independent poor prognoses. MIP pattern in lung ADCs, even at small, early stages, correlates with high lymphovascular invasion, visceral pleural invasion and lymph node metastases. Recently, we reported that patients with a MIP component are at a higher risk of locoregional recurrence after limited resection. Identification of a MIP pattern is only possible with permanent pathologic sections; preoperative imaging, cytology or intraoperative frozen section specimens remain unreliable. The intermixed, heterogenous morphology of lung ADC presents a technical challenge in investigating the molecular biology of cells with MIP morphology. A comprehensive understanding of the biology of MIP morphology is vital for therapeutic interventions.
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Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma.
Acta Neuropathol.
PUBLISHED: 08-21-2014
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Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in situ hybridization addressing surrogates for the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA, only alterations typical for oligodendroglioma were observed, while in 11/43 OA, only indicators for mutations typical for astrocytomas were detected. A single case exhibited a distinct pattern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contributing to the acquisition of this uncommon combination. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive, while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic. These data provide strong evidence against the existence of an independent OA entity.
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Predictors of early recurrence for node-negative t1 to t2b non-small cell lung cancer.
Ann. Thorac. Surg.
PUBLISHED: 08-16-2014
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Recurrence develops in nearly one-third of patients who undergo complete resection for non-small cell lung cancer (NSCLC). We sought to identify predictors of early recurrence (<2 years) in node-negative T1 to T2b NSCLC.
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Differences in Patterns of Recurrence in Early-Stage Versus Locally Advanced Non-Small Cell Lung Cancer.
Ann. Thorac. Surg.
PUBLISHED: 08-07-2014
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The benefits of screening for non-small cell lung cancer (NSCLC) have been established for high-risk individuals, and recent guidelines advocate continued surveillance after curative therapy. Yet the optimal posttreatment surveillance strategy remains to be determined. We compared patterns of recurrence and modes of detection in surgically treated patients with pathologic early-stage and locally advanced NSCLC.
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Ultrashort cationic naphthalene-derived self-assembled peptides as antimicrobial nanomaterials.
Biomacromolecules
PUBLISHED: 08-07-2014
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Self-assembling dipeptides conjugated to naphthalene show considerable promise as nanomaterial structures, biomaterials, and drug delivery devices. Biomaterial infections are responsible for high rates of patient mortality and morbidity. The presence of biofilm bacteria, which thrive on implant surfaces, are a huge burden on healthcare budgets, as they are highly resistant to current therapeutic strategies. Ultrashort cationic self-assembled peptides represent a highly innovative and cost-effective strategy to form antibacterial nanomaterials. Lysine conjugated variants display the greatest potency with 2% w/v NapFFKK hydrogels significantly reducing the viable Staphylococcus epidermidis biofilm by 94%. Reducing the size of the R-group methylene chain on cationic moieties resulted in reduction of antibiofilm activity. The primary amine of the protruding R-group tail may not be as readily available to interact with negatively charged bacterial membranes. Cryo-SEM, FTIR, CD spectroscopy, and oscillatory rheology provided evidence of supramolecular hydrogel formation at physiological pH (pH 7.4). Cytotoxicity assays against murine fibroblast (NCTC 929) cell lines confirmed the gels possessed reduced cytotoxicity relative to bacterial cells, with limited hemolysis upon exposure to equine erythrocytes. The results presented in this paper highlight the significant potential of ultrashort cationic naphthalene peptides as future biomaterials.
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Estimating smoking prevalence in general practice using data from the Quality and Outcomes Framework (QOF).
BMJ Open
PUBLISHED: 07-18-2014
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To determine to what extent underlying data published as part of Quality and Outcomes Framework (QOF) can be used to estimate smoking prevalence within practice populations and local areas and to explore the usefulness of these estimates.
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Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial.
Neuro-oncology
PUBLISHED: 07-15-2014
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Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay.
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Arhgap36-dependent activation of Gli transcription factors.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-14-2014
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Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.
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Pathophysiology of language, speech and emotions in neurodegenerative disease.
Parkinsonism Relat. Disord.
PUBLISHED: 07-12-2014
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Studying neurodegenerative diseases has greatly expanded our knowledge of language, speech and emotion as these diseases can affect areas not typically seen with stroke or tumor. Newer imaging techniques such as voxel based morphometry), fluorodeoxyglucose (F18) positron emission tomography and functional magnetic resonance imaging have allowed localization of these deficits and a greater understanding of the language network targeted by these progressive neurodegenerative illnesses. This review illustrates these important points by describing five syndromes, using clinical cases and then noting the anatomy, typical pathology, and proposed pathophysiology. The syndromes are Progressive Nonfluent Aphasia, Semantic Dementia, Logopenic Aphasia, Primary Progressive Apraxia of Speech and Dysprosody of Speech. Clinicians recognizing these syndromes using the associated clinico-anatomic patterns will lead to more accurate diagnosis and improved patient counseling and management. Further, patients may be included in appropriate clinical trials when their doctors are aware of the most likely pathology.
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A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007.
Breast Cancer Res. Treat.
PUBLISHED: 06-26-2014
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Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.
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Validation of the new IASLC/ATS/ERS lung adenocarcinoma classification: a surgeon's perspective.
J Thorac Dis
PUBLISHED: 05-12-2014
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The conclusions from the new IASLC/ATS/ERS lung adenocarcinoma classification portend important clinical consequences. The interpretation of the histological, biomolecular and radiological correlates of this classification not only allows for the definitive abandonment of the bronchoalveolar carcinoma definition but provides surgeons with significant clues to better understand the adenocarcinoma subsets and their surgical management. Indeed, the information will benefit surgeons who are fully involved in the lung cancer CT screening programs as well as in the diagnostic and therapeutic pathways of both early and locally advanced lung cancer. Moreover, intriguing perspectives are disclosing on the inclusion of the surgical modality among the ones used in the oligometastatic disease status. On the other hand, the new adenocarcinoma classification also emphasizes the need for surgeons working in a multidisciplinary environment to be thoroughly cognizant of the ever evolving lung cancer biomolecular knowledge and, in particular, of the potentially druggable somatic mutations in line with the modern professional profile of the so-called "surgeon scientist".
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Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas.
Neuro-oncology
PUBLISHED: 05-06-2014
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Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA.
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Connect four with glioblastoma stem cell factors.
Cell
PUBLISHED: 04-29-2014
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Hierarchical cell state models, wherein a few stem-like tumor-propagating cells repopulate the tumor after therapy, are often invoked in cancer. Suvà et al. demonstrate a plastic developmental hierarchy in glioma cell populations by characterizing the epigenetic states of phenotypically distinct cells and identifying four factors sufficient to reprogram differentiated cells into a tumorigenic stem-like state.
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Comprehensive long-term care of patients with lung cancer: development of a novel thoracic survivorship program.
Ann. Thorac. Surg.
PUBLISHED: 04-28-2014
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Recent advances have improved the likelihood of long-term survival for patients with lung cancer. However, little attention has been given to the growing need for dedicated survivorship care for these patients. To address this unmet need, we developed a unique follow-up care model.
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Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma.
Acta Neuropathol.
PUBLISHED: 04-18-2014
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The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.
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Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts.
Acta Neuropathol.
PUBLISHED: 04-08-2014
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Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)(Fl/+)Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.
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Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study.
Sci Rep
PUBLISHED: 04-07-2014
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In vitro studies have shown that hydrogen peroxide (H2O2) produced by high-concentration ascorbate and cell culture medium iron efficiently kills cancer cells. This provided the rationale for clinical trials of high-dose intravenous ascorbate-based treatment for cancer. A drawback in all the in vitro studies was their failure to take into account the in vivo concentration of iron to supplement cell culture media which are characterized by low iron content. Here we showed, using two prostate cancer cell lines (LNCaP and PC-3) and primary astrocytes, that the anticancer/cytotoxic effects of ascorbate are completely abolished by iron at physiological concentrations in cell culture medium and human plasma. A detailed examination of mechanisms showed that iron at physiological concentrations promotes both production and decomposition of H2O2. The latter is mediated by Fenton reaction and prevents H2O2 accumulation. The hydroxyl radical, which is produced in the Fenton reaction, is buffered by extracellular proteins, and could not affect intracellular targets like H2O2. These findings show that anticancer effects of ascorbate have been significantly overestimated in previous in vitro studies, and that common cell culture media might be unsuitable for redox research.
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Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort.
Acta Neuropathol.
PUBLISHED: 03-29-2014
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This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining "intermediate molecular risk" population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified, with speckled synaptophysin expression indicating worse outcome. Test and independent validation of the score confirmed significant discrimination of patients by risk profile. Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk stratification of medulloblastoma. A simple clinico-pathological risk score was identified, which was confirmed in a test set and by independent clinical validation.
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Coronary artery disease and the contours of pharmaceuticalization.
Soc Sci Med
PUBLISHED: 03-25-2014
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Coronary artery disease (CAD) has dominated mortality for most of the past century, not just in Europe and North America but worldwide. Treatments for CAD, both pharmaceutical and surgical, have become leading sectors of the healthcare economy. This paper focuses on the therapeutic landscape for CAD in the United States. We hope to add texture to the broader conversation of pharmaceuticalization explored in this issue by situating pharmaceutical therapies as just one element in the broader therapeutic terrain, alongside cardiac surgery and interventional cardiology. Patients with CAD must navigate a therapeutic landscape with three intersecting paths: lifestyle change, pharmaceuticals, and surgery. While pharmaceuticals are often seen as a quick fix, a way of avoiding more difficult lifestyle changes, it is surgery and angioplasty that promise patients the quickest fix of all. There also is another option, often overlooked by analysts but popular among physicians and patients: inaction. The U.S. context is often critiqued as a site of excessive treatment with respect to both drugs and procedures, and yet there is deep stratification within it - over-treatment in many populations and under-treatment in others. People who experience the serious risks of CAD do so in a racialized terrain of durable preoccupations with difference and unequal access to care. While the pharmaceuticalization literature disproportionately attends to lifestyle drugs, which some observers consider to be medically inappropriate or unnecessary, CAD does remain the leading cause of death. Thus, the stakes are high. Examination of the pharmaceuticalization of CAD in light of surgical treatments and racial disparities offers a window into the pervasiveness and persuasiveness of pharmaceuticals in an increasingly consumer-driven medicine, as well as the limits of their appeal and their reach.
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Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing.
Nature
PUBLISHED: 03-20-2014
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Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
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Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.
Nat. Genet.
PUBLISHED: 03-14-2014
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Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
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Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine.
Mol. Ther.
PUBLISHED: 03-07-2014
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Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.Molecular Therapy (2014); doi:10.1038/mt.2014.137.
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Probing the Effects of Experimental Conditions on the Character of Drug-Polymer Phase Diagrams Constructed Using Flory-Huggins Theory.
Pharm. Res.
PUBLISHED: 02-25-2014
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Amorphous drug-polymer solid dispersions have been found to result in improved drug dissolution rates when compared to their crystalline counterparts. However, when the drug exists in the amorphous form it will possess a higher Gibb's free energy than its associated crystalline state and can recrystallize. Drug-polymer phase diagrams constructed through the application of the Flory Huggins (F-H) theory contain a wealth of information regarding thermodynamic and kinetic stability of the amorphous drug-polymer system. This study was aimed to evaluate the effects of various experimental conditions on the solubility and miscibility detections of drug-polymer binary system.
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Statistical SPECT processing in MRI-negative epilepsy surgery.
Neurology
PUBLISHED: 02-14-2014
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To evaluate the benefit of statistical SPECT processing over traditional subtraction methods, we compared ictal-interictal SPECT analyzed by statistical parametric mapping (SPM) (ISAS), statistical ictal SPECT coregistered to MRI (STATISCOM), and subtraction ictal-interictal SPECT coregistered with MRI (SISCOM) in patients with MRI-negative focal temporal lobe epilepsy (nTLE) and extratemporal lobe epilepsy (nETLE).
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Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.
Cancer Cell
PUBLISHED: 02-13-2014
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Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
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Cytogenetic prognostication within medulloblastoma subgroups.
David J H Shih, Paul A Northcott, Marc Remke, Andrey Korshunov, Vijay Ramaswamy, Marcel Kool, Betty Luu, Yuan Yao, Xin Wang, Adrian M Dubuc, Livia Garzia, John Peacock, Stephen C Mack, Xiaochong Wu, Adi Rolider, A Sorana Morrissy, Florence M G Cavalli, David T W Jones, Karel Zitterbart, Claudia C Faria, Ulrich Schüller, Leos Kren, Toshihiro Kumabe, Teiji Tominaga, Young Shin Ra, Miklós Garami, Peter Hauser, Jennifer A Chan, Shenandoah Robinson, László Bognár, Almos Klekner, Ali G Saad, Linda M Liau, Steffen Albrecht, Adam Fontebasso, Giuseppe Cinalli, Pasqualino De Antonellis, Massimo Zollo, Michael K Cooper, Reid C Thompson, Simon Bailey, Janet C Lindsey, Concezio Di Rocco, Luca Massimi, Erna M C Michiels, Stephen W Scherer, Joanna J Phillips, Nalin Gupta, Xing Fan, Karin M Muraszko, Rajeev Vibhakar, Charles G Eberhart, Maryam Fouladi, Boleslaw Lach, Shin Jung, Robert J Wechsler-Reya, Michelle Fèvre-Montange, Anne Jouvet, Nada Jabado, Ian F Pollack, William A Weiss, Ji-Yeoun Lee, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Jeffrey R Leonard, Joshua B Rubin, Carmen de Torres, Cinzia Lavarino, Jaume Mora, Yoon-Jae Cho, Uri Tabori, James M Olson, Amar Gajjar, Roger J Packer, Stefan Rutkowski, Scott L Pomeroy, Pim J French, Nanne K Kloosterhof, Johan M Kros, Erwin G Van Meir, Steven C Clifford, Franck Bourdeaut, Olivier Delattre, François F Doz, Cynthia E Hawkins, David Malkin, Wieslawa A Grajkowska, Marta Perek-Polnik, Eric Bouffet, James T Rutka, Stefan M Pfister, Michael D Taylor.
J. Clin. Oncol.
PUBLISHED: 02-03-2014
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Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
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Implementing the new IASLC/ATS/ERS classification of lung adenocarcinomas: results from international and Chinese cohorts.
J Thorac Dis
PUBLISHED: 01-30-2014
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A new histologic classification of lung adenocarcinoma was proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) in 2011 to provide uniform terminology and diagnostic criteria for multidisciplinary strategic management. This classification proposed a comprehensive histologic subtyping (lepidic, acinar, papillary, micropapillary, and solid pattern) and a semi-quantitative assessment of histologic patterns (in 5% increments) in an effort to choose a single, predominant pattern in invasive adenocarcinomas. The prognostic value of this classification has been validated in large, independent cohorts from multiple countries. In patients who underwent curative-intent surgery, those with either an adenocarcinoma in situ (AIS) or a minimal invasive adenocarcinoma have nearly 100% disease-free survival and are designated "low grade tumors". For invasive adenocarcinomas, the acinar and papillary predominant histologic subtypes were usually designated as "intermediate grade" while the solid and micropapillary predominant histologic subtypes were designated "high grade" tumors; this was based on the statistic difference of overall survival. This classification, coupled with additional prognostic factors [nuclear grade, cribriform pattern, high Ki-67 labeling index, thyroid transcription factor-1 (TTF-1) immunohistochemistry, immune markers, and (18)F-fluorodeoxyglucose uptake on positron emission tomography (PET)] that we have published on, could further stratify patients into prognostic subgroups and may prove helpful for individual patient care. With regard to Chinese oncologists, the implementation of this new classification only requires hematoxylin and eosin (H&E) stained slides and basic pathologic training, both of which require no additional costs. More importantly, this new classification system could provide informative data for better selection and stratification of clinical trials and molecular studies.
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Thirty-Day Mortality Underestimates the Risk of Early Death After Major Resections for Thoracic Malignancies.
Ann. Thorac. Surg.
PUBLISHED: 01-29-2014
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Operative mortality rates are of great interest to surgeons, patients, policy makers, and payers as a metric for quality assessment. Thirty-day mortality and discharge mortality have been presumed to capture procedure-related deaths. However, many patients die after the 30-day mark or are transferred to other facilities or to home and die there, leading to the underreporting of surgically related deaths. We hypothesized that a longer period of observation would address these concerns and provide a more accurate measure of operative mortality.
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Second primary lung cancers: smokers versus nonsmokers after resection of stage I lung adenocarcinoma.
Ann. Thorac. Surg.
PUBLISHED: 01-29-2014
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Smokers have a higher risk of developing non-small cell lung cancer (NSCLC) than never-smokers, but the relative risk of developing second primary lung cancer (SPLC) is unclear. Determining the risk of SPLC in smokers versus never-smokers after treatment of an initial cancer may help guide recommendations for long-term surveillance.
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Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge.
Nat. Rev. Cancer
PUBLISHED: 01-25-2014
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We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.
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Language Networks Associated with Computerized Semantic Indices.
Neuroimage
PUBLISHED: 01-17-2014
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Tests of generative semantic verbal fluency are widely used to study organization and representation of concepts in the human brain. Previous studies demonstrated that clustering and switching behavior during verbal fluency tasks is supported by multiple brain mechanisms associated with semantic memory and executive control. Previous work relied on manual assessments of semantic relatedness between words and grouping of words into semantic clusters. We investigated a computational linguistic approach to measuring the strength of semantic relatedness between words based on latent semantic analysis of word co-occurrences in a subset of a large online encyclopedia. We computed semantic clustering indices and compared them to brain network connectivity measures obtained with task-free fMRI in a sample consisting of healthy participants and those differentially affected by cognitive impairment. We found that semantic clustering indices were associated with brain network connectivity in distinct areas including fronto-temporal, fronto-parietal and fusiform gyrus regions. This study shows that computerized semantic indices complement traditional assessments of verbal fluency to provide a more complete account of the relationship between brain and verbal behavior involved organization and retrieval of lexical information from memory.
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
Nature
PUBLISHED: 01-12-2014
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Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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Nuclear relocation of STAT6 reliably predicts NAB2-STAT6 fusion for the diagnosis of solitary fibrous tumour.
Histopathology
PUBLISHED: 01-10-2014
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Nuclear relocation of STAT6 has been shown in tumours with NAB2-STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT.
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Network meta-analysis of multiple outcome measures accounting for borrowing of information across outcomes.
BMC Med Res Methodol
PUBLISHED: 01-08-2014
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Network meta-analysis (NMA) enables simultaneous comparison of multiple treatments while preserving randomisation. When summarising evidence to inform an economic evaluation, it is important that the analysis accurately reflects the dependency structure within the data, as correlations between outcomes may have implication for estimating the net benefit associated with treatment. A multivariate NMA offers a framework for evaluating multiple treatments across multiple outcome measures while accounting for the correlation structure between outcomes.
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The neuroanatomy of pure apraxia of speech in stroke.
Brain Lang
PUBLISHED: 01-06-2014
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The left insula or Broca's area have been proposed as the neuroanatomical correlate for apraxia of speech (AOS) based on studies of patients with both AOS and aphasia due to stroke. Studies of neurodegenerative AOS suggest the premotor area and the supplementary motor areas as the anatomical correlates. The study objective was to determine the common infarction area in patients with pure AOS due to stroke. Patients with AOS and no or equivocal aphasia due to ischemic stroke were identified through a pre-existing database. Seven subjects were identified. Five had pure AOS, and two had equivocal aphasia. MRI lesion analysis revealed maximal overlap spanning the left premotor and motor cortices. While both neurodegenerative AOS and stroke induced pure AOS involve the premotor cortex, further studies are needed to establish whether stroke-induced AOS and neurodegenerative AOS share a common anatomic substrate.
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Photodynamic antimicrobial polymers for infection control.
PLoS ONE
PUBLISHED: 01-01-2014
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Hospital-acquired infections pose both a major risk to patient wellbeing and an economic burden on global healthcare systems, with the problem compounded by the emergence of multidrug resistant and biocide tolerant bacterial pathogens. Many inanimate surfaces can act as a reservoir for infection, and adequate disinfection is difficult to achieve and requires direct intervention. In this study we demonstrate the preparation and performance of materials with inherent photodynamic, surface-active, persistent antimicrobial properties through the incorporation of photosensitizers into high density poly(ethylene) (HDPE) using hot-melt extrusion, which require no external intervention except a source of visible light. Our aim is to prevent bacterial adherence to these surfaces and eliminate them as reservoirs of nosocomial pathogens, thus presenting a valuable advance in infection control. A two-layer system with one layer comprising photosensitizer-incorporated HDPE, and one layer comprising HDPE alone is also described to demonstrate the versatility of our approach. The photosensitizer-incorporated materials are capable of reducing the adherence of viable bacteria by up to 3.62 Log colony forming units (CFU) per square centimeter of material surface for methicillin resistant Staphylococcus aureus (MRSA), and by up to 1.51 Log CFU/cm(2) for Escherichia coli. Potential applications for the technology are in antimicrobial coatings for, or materials comprising objects, such as tubing, collection bags, handrails, finger-plates on hospital doors, or medical equipment found in the healthcare setting.
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De novo structure prediction of globular proteins aided by sequence variation-derived contacts.
PLoS ONE
PUBLISHED: 01-01-2014
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The advent of high accuracy residue-residue intra-protein contact prediction methods enabled a significant boost in the quality of de novo structure predictions. Here, we investigate the potential benefits of combining a well-established fragment-based folding algorithm--FRAGFOLD, with PSICOV, a contact prediction method which uses sparse inverse covariance estimation to identify co-varying sites in multiple sequence alignments. Using a comprehensive set of 150 diverse globular target proteins, up to 266 amino acids in length, we are able to address the effectiveness and some limitations of such approaches to globular proteins in practice. Overall we find that using fragment assembly with both statistical potentials and predicted contacts is significantly better than either statistical potentials or contacts alone. Results show up to nearly 80% of correct predictions (TM-score ?0.5) within analysed dataset and a mean TM-score of 0.54. Unsuccessful modelling cases emerged either from conformational sampling problems, or insufficient contact prediction accuracy. Nevertheless, a strong dependency of the quality of final models on the fraction of satisfied predicted long-range contacts was observed. This not only highlights the importance of these contacts on determining the protein fold, but also (combined with other ensemble-derived qualities) provides a powerful guide as to the choice of correct models and the global quality of the selected model. A proposed quality assessment scoring function achieves 0.93 precision and 0.77 recall for the discrimination of correct folds on our dataset of decoys. These findings suggest the approach is well-suited for blind predictions on a variety of globular proteins of unknown 3D structure, provided that enough homologous sequences are available to construct a large and accurate multiple sequence alignment for the initial contact prediction step.
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PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas.
Clin. Cancer Res.
PUBLISHED: 12-03-2013
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We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was first identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells.
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Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity.
Acta Neuropathol.
PUBLISHED: 10-31-2013
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Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.
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Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity.
Neurology
PUBLISHED: 10-16-2013
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To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.
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Solvent induced phase inversion-based in situ forming controlled release drug delivery implants.
J Control Release
PUBLISHED: 09-19-2013
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In situ forming (ISF) drug delivery implants have gained tremendous levels of interest over the last few decades. This is due to their wide range of biomedical applications such as in tissue engineering, cell encapsulation, microfluidics, bioengineering and drug delivery. Drug delivery implants forming upon injection has shown a range of advantages which include localized drug delivery, easy and less invasive application, sustained drug action, ability to tailor drug delivery, reduction in side effects associated with systemic delivery and also improved patient compliance and comfort. Different factors such as temperature, pH, ions, and exchange of solvents are involved in in situ implant formation. This review especially focuses on ISF implants that are formed through solvent induced phase inversion (SPI) technique. The article critically reviews and compares a wide range of polymers, solvents, and co-solvents that have been used in SPI implant preparation for control release of a range of drug molecules. Major drawback of SPI systems has been their high burst release. In this regard, the article exhaustively discusses factors that effect the burst release and different modification strategies that has been utilised to reduce the burst effect from these implants. Performance and controversial issues associated with the use of different biocompatible solvents in SPI systems is also discussed. Biodegradation, formulation stability, methods of characterisation and sterilisation techniques of SPI systems is comprehensively reviewed. Furthermore, the review also examines current SPI-based marketed products, their therapeutic application and associated clinical data. It also exemplifies the interest of multi-billion dollar pharma companies worldwide for further developments of SPI systems to a range of therapeutic applications. The authors believe that this will be the first review article that extensively investigate and discusses studies done to date on SPI systems. In so doing, this article will undoubtedly serve as an enlightening tool for the scientists working in the concerned area.
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Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.
Acta Neuropathol.
PUBLISHED: 09-10-2013
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Medulloblastoma is curable in approximately 70 % of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organizations classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Childrens Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.
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TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.
Acta Neuropathol.
PUBLISHED: 09-02-2013
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Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
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Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system.
Acta Neuropathol.
PUBLISHED: 09-02-2013
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Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.
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AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry.
Acta Neuropathol.
PUBLISHED: 08-30-2013
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The activating E17K mutation in the AKT1 gene has been detected in several tumor entities. Currently several clinical studies with specific AKT1 inhibitors are under way. To determine whether AKT1 mutations are involved in human tumors of the nervous system, we examined a series of 1,437 tumors including 391 primary intracranial brain tumors and 1,046 tumors of the coverings of the central and peripheral nervous system. AKT1E17K mutations were exclusively seen in meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance was seen in the variant of meningothelial meningioma WHO grade I of basal and spinal localization. In contrast, AKT1E17K mutations were rare in WHO grade II and absent in WHO grade III meningiomas. In order to more effectively detect this mutation, we tested for immunohistochemical markers associated with this alteration. We observed strong up-regulation of SFRP1 expression in all meningiomas with AKT1E17K mutation and in HEK293 cells after transfection with mutant AKT1E17K, but not in meningiomas and HEK293 cells lacking this mutation.
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A neurological complication of a uterine fibroid.
Neurocrit Care
PUBLISHED: 08-08-2013
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Uterine leiomyoma (or fibroid) can be associated with secondary polycythemia and venous thrombosis, but there has been no report of intracranial venous thrombosis associated with leiomyoma.
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Scalable web services for the PSIPRED Protein Analysis Workbench.
Nucleic Acids Res.
PUBLISHED: 06-08-2013
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Here, we present the new UCL Bioinformatics Groups PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/.
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Lecithin-based emulsions for potential use as saliva substitutes in patients with xerostomia--viscoelastic properties.
Int J Pharm
PUBLISHED: 05-29-2013
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The purpose of the present study was to investigate lecithin-rice bran oil rheological properties with the view to consider these as potential saliva substitutes in patients with severe xerostomia and salivary hypofunction. Pseudo-ternary phase diagrams of rice bran oil, lecithin and water mixtures were constructed and characterised using polarising light microscopy. Viscoelastic properties, which we hypothesise are important determinants in product performance, were analysed using both flow and oscillatory rheology. Rheological properties were influenced by composition, frequency and shear stress. Frequency-dependent viscoelasticity was observed in some formulations where viscosity dominated (tan?>1) at frequencies under 5 Hz and elasticity dominated (tan?<1) at higher frequencies. Threshold frequencies were determined for each formulation, where a peak in loss tangent was observed, coinciding with a reduction in the storage modulus and increase in loss modulus. The frequency-dependent behaviour of emulsions are of interest because these combinations exhibit viscous behaviour at low frequencies, which may improve lubrication of the oral cavity at rest, whereas increased elasticity at higher frequencies may improve retention during higher-shear tasks such as swallowing and speaking.
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Using Flory-Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions: a comparison between hot-melt extrusion and spray drying.
J. Pharm. Pharmacol.
PUBLISHED: 05-24-2013
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Amorphous drug forms provide a useful method of enhancing the dissolution performance of poorly water-soluble drugs; however, they are inherently unstable. In this article, we have used Flory-Huggins theory to predict drug solubility and miscibility in polymer candidates, and used this information to compare spray drying and melt extrusion as processes to manufacture solid dispersions.
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Microneedle-mediated intrascleral delivery of in situ forming thermoresponsive implants for sustained ocular drug delivery.
J. Pharm. Pharmacol.
PUBLISHED: 05-24-2013
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This paper describes use of minimally invasive hollow microneedle (HMN) to deliver in situ forming thermoresponsive poloxamer-based implants into the scleral tissue to provide sustained drug delivery.
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The decline and rise of coronary heart disease: understanding public health catastrophism.
Am J Public Health
PUBLISHED: 05-16-2013
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The decline of coronary heart disease mortality in the United States and Western Europe is one of the great accomplishments of modern public health and medicine. Cardiologists and cardiovascular epidemiologists have devoted significant effort to disease surveillance and epidemiological modeling to understand its causes. One unanticipated outcome of these efforts has been the detection of early warnings that the decline had slowed, plateaued, or even reversed. These subtle signs have been interpreted as evidence of an impending public health catastrophe. This article traces the history of research on coronary heart disease decline and resurgence and situates it in broader narratives of public health catastrophism. Juxtaposing the coronary heart disease literature alongside the narratives of emerging and reemerging infectious disease helps to identify patterns in how public health researchers create data and craft them into powerful narratives of progress or pessimism. These narratives, in turn, shape public health policy.
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Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 05-08-2013
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Current clinical trials are investigating the role of stereotactic body radiation therapy (SBRT) versus sublobar resection for patients with non-small cell lung carcinoma (NSCLC) and marginal pulmonary function tests (M-PFTs). We compared the outcomes of patients undergoing lobectomy with M-PFTs characterized by 2 accepted M-PFT criteria.
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On mind wandering, attention, brain networks, and meditation.
Explore (NY)
PUBLISHED: 05-07-2013
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Human attention selectively focuses on aspects of experience that are threatening, pleasant, or novel. The physical threats of the ancient times have largely been replaced by chronic psychological worries and hurts. The mind gets drawn to these worries and hurts, mostly in the domain of the past and future, leading to mind wandering. In the brain, a network of neurons called the default mode network has been associated with mind wandering. Abnormal activity in the default mode network may predispose to depression, anxiety, attention deficit, and posttraumatic stress disorder. Several studies show that meditation can reverse some of these abnormalities, producing salutary functional and structural changes in the brain. This narrative review presents a mechanistic understanding of meditation in the context of recent advances in neurosciences about mind wandering, attention, and the brain networks.
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Membrane protein orientation and refinement using a knowledge-based statistical potential.
BMC Bioinformatics
PUBLISHED: 05-03-2013
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Recent increases in the number of deposited membrane protein crystal structures necessitate the use of automated computational tools to position them within the lipid bilayer. Identifying the correct orientation allows us to study the complex relationship between sequence, structure and the lipid environment, which is otherwise challenging to investigate using experimental techniques due to the difficulty in crystallising membrane proteins embedded within intact membranes.
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Hypermutation of the inactive X chromosome is a frequent event in cancer.
Cell
PUBLISHED: 04-27-2013
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Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.
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Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study.
Lancet Oncol.
PUBLISHED: 04-16-2013
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Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours.
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Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.
Cancer Cell
PUBLISHED: 03-29-2013
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Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ?50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.