tbuckley/cabot-search huggingface dataset:
Molecular classification of the invasive front in colorectal cancer.
Authors: Darragh McArt, Philip Dunne, Elaine Kay, Anthony O'Grady, Helen Barrett, Ken Arthur, Daniel Longley, Peter W Hamilton, David J. Waugh, Mark Lawler, Patrick G. Johnston, Manuel Salto-Tellez, Sandra Van Schaeybroeck
Journal: Journal of Clinical Oncology (2015)

3573 Background: Despite the use of 5-FU-based adjuvant therapies, a large proportion of stage III (locally advanced) colorectal cancer (CRC) patients will relapse and die of metastatic disease. Recent data from phase III trials using the anti-VEGF or the anti-EGFR mAbs have shown that, in contrast to the metastatic setting, these agents do not prolong survival in stage III CRC. Therefore, novel drugs are needed that result in further increases in overall survival in stage III CRC patients. The aim of this study was to investigate the invasive front of stage III CRC at the molecular level and correlate with clinical and pathological variables. Methods: mRNA was extracted from macrodissected FFPE CRC, central tumour and invasive front from 25 patients. Transcriptional analysis was performed using the CRC DSA microarray. Samples were analysed using limma for lists of differential expressed genes and using a supervised learning approach, pamr, to extract succinct gene lists between contrasts and visualised with bootstrap clustering and heatmaps. Expression of E-cadherin was measured using IHC. Results: IHC staining showed loss of E-cadherin expression in tumour cells at the invasive front, in keeping with an epithelial-to mesenchymal transition (EMT). Limma and pamr analysis depicted strong overlap of probes to differentiate central tumour from the invasive front. Prominent classifiers evidenced included genes with a role in inflammation and immune signalling (eg. CXCL5, C7, IL8), EMT (eg. SFRP2, WNT5A) and growth factor receptor signalling (eg. IGF1). Comparison of this expression list with the recent published gene lists, characterizing the poorest prognostic EMT/stem-cell like subgroup, showed that there is a high degree of overlap between these two signatures. Conclusions: Taken together, our study is the first to indicate that, in order to disseminate and metastasize, tumour cells at the invasive front develop an EMT phenotype with a molecular signature, similar to the poor prognostic stem-like molecular CRC subgroup. This data could aid in the identification of novel treatment strategies to prevent tumour recurrence/metastasis in stage III CRC.
Global Measles and Rubella Laboratory Network Support for Elimination Goals, 2010–2015
Authors: Mick N. Mulders, Paul A. Rota, Joseph P. Icenogle, Kevin E. Brown, Makoto Takeda, Gloria J. Rey, Myriam C. Ben Mamou, Annick R.G.A. Dosseh, Charles R. Byabamazima, Hinda J. Ahmed, Sirima Pattamadilok, Yan Zhang, Marta Gacic-Dobo, Peter M. Strebel, James L. Goodson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan (GVAP)* with the objective to eliminate measles and rubella in five World Health Organization (WHO) regions by 2020. In September 2013, countries in all six WHO regions had established measles elimination goals, and additional goals for elimination of rubella and congenital rubella syndrome were established in three regions (1). Capacity for surveillance, including laboratory confirmation, is fundamental to monitoring and verifying elimination. The 2012-2020 Global Measles and Rubella Strategic Plan of the Measles and Rubella Initiative(†) calls for effective case-based surveillance with laboratory testing for case confirmation (2). In 2000, the WHO Global Measles and Rubella Laboratory Network (GMRLN) was established to provide high quality laboratory support for surveillance (3). The GMRLN is the largest globally coordinated laboratory network, with 703 laboratories supporting surveillance in 191 countries. During 2010-2015, 742,187 serum specimens were tested, and 27,832 viral sequences were reported globally. Expansion of the capacity of the GMRLN will support measles and rubella elimination efforts as well as surveillance for other vaccine-preventable diseases (VPDs), including rotavirus, and for emerging pathogens of public health concern.
ATNT-04NOVOTTF™-100A SYSTEM (TUMOR TREATING FIELDS) TRANSDUCER ARRAY LAYOUT PLANNING FOR RECURRENT GLIOBLASTOMA: RESULTS OF A NOVOTAL™ YSTEM USER STUDY
Authors: Aafia Chaudhry, Laura Benson, Michael Varshaver, Ori Farber, Uri Weinberg, Eilon Kirson, Yoram Palti
Journal: Neuro-Oncology (2015)
Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis–like disease
Authors: Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Peter M. Andersen, Stefan L. Marklund, Thomas Brännström
Journal: Journal of Clinical Investigation (2016)

Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.
PTU-066 Characteristics and outcomes of patients undergoing second intestinal resection for crohn’s disease in a tertiary referral centre
Authors: A O’Connor, J Taylor, M Pinder, G Dowson, N Scott, PJ Hamlin, AC Ford
Journal: Gut (2015)

Introduction Up to 70% of patients with Crohn’s disease (CD) may require surgery at some point in their lives and 39% may require several surgeries. Repeated resections put patients at risk of greater morbidity including short gut syndrome and intestinal failure. Method We aimed to examine the demographic and clinical characteristics and outcomes of patients requiring repeated resections for CD. We performed a retrospective analysis by interrogating the pathology database over a five year period from 2009 to 2013 to identify cases and data was extracted by chart review. Results Of 152 cases in the time frame, 54 were having repeat intestinal resections undertaken. Median age was 43 years (range 20 to 75). 59.3% were female. The median duration between resections in this group was 9 years (range 1 to 49). 29.6% were emergency procedures. 41 patients had 1 previous resection, 9 had 2 previous surgeries with 4 having had 3 or more prior resections. The most common procedures were re-do right hemicolectomy accounting for 38.9% of procedures. 13.0% of patients had repeat small bowel resections. 14.8% had right hemicolectomy after previous small bowel resection. 14.8% had small bowel resection after previous partial or total colectomy. 11.1% patients had completion colectomy. 25.9% of patients had no prophylactic therapy against CD since the previous resection. Median duration to repeat resection in this group was 15 years. 35 patients had received azathioprine with a median duration to resection of 8 years, 20 patients had been on anti-tnf with median duration to resection of 8.5 years and 11 had methotrexate with median duration to resection of 7 years. Median duration of follow-up was 30 months (range 3 to 69). At end of follow up 66.6% of patients remained steroid and repeat resection free. 11.1% had required corticosteroids, 7.4% had gone on to have a further resection within the period of follow up and 5.6% of patients had died. In the same follow up period only 1 death was noted in the group who had their first resection (1%). 4 were lost to follow up (mean duration 17.5 months). Conclusion Repeat resections are common undertakings in patients with postoperative CD. The proportion of these cases being done as emergencies is similar to those in the surgery naïve cohort. The most common procedure is redo right hemicolectomy and resection of anastomosis. Duration to repeat resection is considerably longer in those who don’t receive medical prophylaxis against CD, indicating a prolonged silent, indolent disease course in a particular subgroup. Among patients who receive prophylaxis, patients with anti-TNF have a longer median duration to repeat resection compared to those on immunomodulators. Disclosure of interest None Declared.
EBUS-guided mediastinal lung cancer staging: monitoring of quality standards improves performance: Table 1
Authors: Matthew Evison, Philip Crosbie, Julie Martin, Rajesh Shah, Helen Doran, Zoe Borrill, Jennifer Hoyle, Durgesh Rana, Simon Bailey, Richard Booton
Journal: Thorax (2016)

This audit examined key performance indices related to endobronchial ultrasound (EBUS)-guided mediastinal lung cancer staging before and after the introduction of defined quality standards, at four independent EBUS centres in one cancer network. Data from 642 procedures were prospectively collected and analysed. The introduction of standards was associated with a significant increase (p&lt;0.001) in sampling of key mediastinal lymph node stations (4R, 4L and 7) and a reduction in the variability of staging sensitivity between centres. These data reinforce the requirement for an appropriate regulatory framework for EBUS-transbronchial needle aspiration provision that includes quality assurance and performance monitoring.
Linking primary and secondary care data shows undertreated CVD in patients with severe mental illness
Authors: Susan Mayor
Journal: BMJ (2016)

Linking primary and secondary care data can successfully identify patients with severe mental illness whose cardiovascular disease (CVD) is undertreated, a UK study has shown,1 confirming that many of these patients are currently not receiving treatment for their heart disease.

Researchers studied primary and secondary care records of patients aged 16 and over with severe mental illness in one London borough and looked at their prevalence of CVD and the measurement and treatment of CVD risk factors.

The team extracted pseudonymised …
The European Medicines Agency is still too close to industry:
Authors: Silvio Garattini
Journal: BMJ (2016)

Two decades after its inception, the agency still fails to put patients’ interests first

Fifteen years ago I raised criticisms about the policy and attribution of the then young European Medicines Agency (EMA) and its Committee for Medicinal Products for Human Use (CHMP).1

With the same aim of encouraging this institution to put the interests of patients and public health services first, I now offer an updated picture (see table).

The current supervising directorate general of the European Commission is certainly more appropriate than before: first it was DG Enterprise, which also represents drug companies—a considerable conflict of interest. Today it is DG Sanco, which is responsible for health and consumers.

Withdrawal by a company of an application for marketing authorisation no longer precludes the publication of a negative opinion by the CHMP with its reasons. And now, when the CHMP does not unanimously …
Vital Signs: National and State-Specific Patterns of Attention Deficit/Hyperactivity Disorder Treatment Among Insured Children Aged 2–5 Years — United States, 2008–2014
Authors: Susanna N. Visser, Melissa L. Danielson, Mark L. Wolraich, Michael H. Fox, Scott D. Grosse, Linda A. Valle, Joseph R. Holbrook, Angelika H. Claussen, Georgina Peacock
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Background: Attention deficit/hyperactivity disorder (ADHD) is associated with adverse outcomes and elevated societal costs.The American Academy of Pediatrics (AAP) 2011 guidelines recommend "behavior therapy" over medication as first-line treatment for children aged 4-5 years with ADHD; these recommendations are consistent with current guidelines from the American Academy of Child and Adolescent Psychiatry for younger children.CDC analyzed claims data to assess national and state-level ADHD treatment patterns among young children.Methods: CDC compared Medicaid and employer-sponsored insurance (ESI) claims for "psychological services" (the procedure code category that includes behavior therapy) and ADHD medication among children aged 2-5 years receiving clinical care for ADHD, using the MarketScan commercial database (2008)(2009)(2010)(2011)(2012)(2013)(2014) and Medicaid (2008Medicaid ( -2011) ) data.Among children with ESI, ADHD indicators were compared during periods preceding and following the 2011 AAP guidelines. Results:In both Medicaid and ESI populations, the percentage of children aged 2-5 years receiving clinical care for ADHD increased over time; however, during 2008-2011, the percentage of Medicaid beneficiaries receiving clinical care was double that of ESI beneficiaries.Although state percentages varied, overall nationally no more than 55% of children with ADHD received psychological services annually, regardless of insurance type, whereas approximately three fourths received medication.Among children with ESI, the percentage receiving psychological services following release of the guidelines decreased significantly by 5%, from 44% in 2011 to 42% in 2014; the change in medication treatment rates (77% in 2011 compared with 76% in 2014) was not significant.Conclusions and Comments: Among insured children aged 2-5 years receiving clinical care for ADHD, medication treatment was more common than receipt of recommended first-line treatment with psychological services.Among children with ADHD who had ESI, receipt of psychological services did not increase after release of the 2011 guidelines.Scaling up evidence-based behavior therapy might lead to increased delivery of effective ADHD management without the side effects of ADHD medications.
Abstract 17127: RVX-208 a Selective Bromodomain and Extra-terminal BET Protein Inhibitor Acts on Several Pathways to Benefit Cardiovascular Risks
Authors: Norman C Wong, Ewelina Kulikowski, Sylwia Wasiak, Dean Gilham, Christopher Halliday, Kenneth Lebioda, Mike Sweeney, Jan O Johansson
Journal: Circulation (2015)

The epigenetic modifying compound RVX-208 selectively inhibits the second ligand binding domain in BET proteins to increase ApoA-I/HDL production. In recent trials of CVD patients given standard of care and RVX-208 (200mg/d) there was a 55% relative risk reduction of MACE vs. placebo. This reduction is greater than expected from modest increases in ApoA-I/HDL, thus suggesting benefits of RVX-208 beyond lipid effects. Whether added benefits exist was explored by microarray survey of differential gene expression in primary human hepatocytes (PHH) and whole blood (WB). In PHH, RVX-208 downregulated genes within the complement, fibrin clotting, cholesterol biosynthesis, fatty acid biosynthesis, diabetes and acute phase response (APR) pathways. These data guided more focused analyses on the known HDL proteome encoded by 89 genes of which 30 were affected by RVX-208 and many of these were members of the APR or complement pathways. In support of the microarray data, we used RT-PCR and found RVX-208 lowered mRNA encoding complement 3, 4a/4b and 5 by &gt;50% in Huh-7 and HepG2 cells exposed to RVX-208. Consistent with the mRNA data, secretion of these complement proteins were less from the treated cells. Next the cells were exposed to cytokines in order to mimic an inflammatory state thus inducing complement expression. Treatment with RVX-208 blocked this effect by &gt;50%. Furthermore, in Huh-7 cells, RVX-208 repressed both fibrin clotting factors II (prothrombin) and XI (thromboplastin antecedent) consistent with the PHH microarray data thus suggesting an anti-thrombotic effect for RVX-208. To further extend findings in vitro from hepatoma cells, plasma from patients in our clinical trials who received RVX-208 were assayed and found to have decreased levels of both APR and complement proteins. Lastly, microarray studies of WB from healthy donors treated ex-vivo with RVX-208 uncovered differential regulation of anti- and pro-atherogenic gene sets that were activated and suppressed, respectively by RVX-208. In summary, RVX-208, a selective BET inhibitor, affects several pathways involved in CVD including; reverse cholesterol transport, atherogenesis, complement, thrombosis and vascular inflammation that cumulatively may reduce MACE in high risk CVD patients.
Pediatric Emergency Visits and Short-Term Changes in PM <sub>2.5</sub> Concentrations in the U.S. State of Georgia
Authors: Matthew J. Strickland, Hua Hao, Xuefei Hu, Howard H. Chang, Lyndsey A. Darrow, Yang Liu
Journal: Environmental Health Perspectives (2015)

Associations between pediatric emergency department (ED) visits and ambient concentrations of particulate matter ≤ 2.5 μm in diameter (PM2.5) have been reported in previous studies, although few were performed in nonmetropolitan areas.
The Emergence of a Circuit Model for Addiction
Authors: Christian Lüscher
Journal: Annual Review of Neuroscience (2016)

Addiction is a disease of altered behavior. Addicts use drugs compulsively and will continue to do so despite negative consequences. Even after prolonged periods of abstinence, addicts are at risk of relapse, particularly when cues evoke memories that are associated with drug use. Rodent models mimic many of the core components of addiction, from the initial drug reinforcement to cue-associated relapse and continued drug intake despite negative consequences. Rodent models have also enabled unprecedented mechanistic insight into addiction, revealing plasticity of glutamatergic synaptic transmission evoked by the strong activation of mesolimbic dopamine—a defining feature of all addictive drugs—as a neural substrate for these drug-adaptive behaviors. Cell type–specific optogenetic manipulations have allowed both identification of the relevant circuits and design of protocols to reverse drug-evoked plasticity and to establish links of causality with drug-adaptive behaviors. The emergence of a circuit model for addiction will open the door for novel therapies, such as deep brain stimulation.
Margaret McCartney: Welfare is not a dirty word
Authors: Margaret McCartney
Journal: BMJ (2016)

The UK chancellor's budget originally proposed to cut personal independence payments (PIPs) by £1.3bn (€1.67bn; $1.9bn).An outcry, and a new secretary of state for welfare and pensions, reversed this proposal.PIPs are not means tested and should allow people with disabilities to take part in life and work with equal opportunity.These payments should proudly promote equality.PIPs were overhauled from the old disability living allowance, supposedly to make savings.Because people may have been assessed only once, so the theory went, they may subsequently recover.This resulted in people with clearly lifelong, worsening, or terminal conditions being subjected to the stress of uncertain outcomes
Development of a novel electrospun nanofibrous delivery system for poorly water-soluble β-sitosterol
Authors: Urve Paaver, Ivo Laidmäe, Hélder A. Santos, Jouko Yliruusi, Jaan Aruväli, Karin Kogermann, Jyrki Heinämäki
Journal: Asian Journal of Pharmaceutical Sciences (2016)

Electrospinning was used as a novel technique for fabricating polymeric nanofibers of a serum cholesterol lowering and poorly water-soluble plant sterol, β-sitosterol. Chitosan was used as a stabilizer/carrier polymer. The mean diameters of nanofibers ranged from 150 nm to 218 nm. β-sitosterol was in an amorphous form and homogeneously dispersed in the nanofibers. The β-sitosterol-loaded nanofibers were freely water-soluble and exhibited very short lag-time in releasing the plant sterol. The dissolution was associated with an immediate recrystallization of β-sitosterol in submicron level. In conclusion, electrospinning is a promising future technology for the formulation of poorly water-soluble plant sterols.
CBIO-23THE TEAD4-DRIVEN TRANSPORTOME MEDIATES ACTIVATION OF THE OSMOTIC ENGINE TO POTENTIATE GLIOBLASTOMA INVASION
Authors: Juan Carlos Martinez-Gutierrez, Sagar R. Shah, Alejandro Ruiz-Valls, Bin S. Wong, Nathaniel D. Tippens, Konstantinos Konstantopoulos, Alfredo Quinones-Hinojosa
Journal: Neuro-Oncology (2015)

Cancer cell migration is a critical process that underlies invasion, treatment evasion, and tumor recurrence. In the complex 3D-confined microenvironments of the body, a diverse molecular machinery drives migratory behavior. In particular, the recently discovered osmotic engine plays a pivotal role in promoting cell dispersal through directed water permeation. This osmotic engine machinery is driven by solute transporters and aquaporins, collectively named the transportome. Hence, it is imperative to determine the role of this transportome and its implications for invasive gliomas. Using novel in vitro microfluidic technology, we demonstrate for the first time that human glioblastoma (GBM) cells rely on the osmotic engine to migrate in confined microenvironments. In particular, using microchannel microfluidic devices, we characterize the migratory capacity of GBM cells in 3D-confined microenvironments using real-time imaging and assess their migratory behavior upon osmotic shock treatment. Our results show that GBM cells readily migrate in high degrees of confinement (3uM). In addition, when exposed to either a hypotonic shock at the leading edge or hypertonic shock at the lagging edge, these primary GBM cells reverse their directional migration, signifying the role of the osmotic engine model in brain cancer (p < 0.05). Furthermore, we uncover the transcription factor TEAD4 as a master regulator of the transportome gene signature and the osmotic engine collectively. Genetic inhibition of TEAD4 results in reduced migratory potential through confined microchannels as well as decreased speed within these confined spaces in vitro (p < 0.05). Using TCGA (n = 528) and REMBRANDT (n = 228) GBM patient datasets, we found that the TEAD4-controlled transportome machinery is overrepresented in glioblastomas and correlates with its poor prognosis. Taken together, our results show that the osmotic engine is a crucial mechanism for GBM cell migration driven by the TEAD4-dependent transportome machinery. Targeting this TEAD4-driven osmotic engine may hold a promising alternative for management of invasive gliomas.
Endothelium-derived relaxing factor, nitric oxide
Authors: L Raij, P J Shultz
Journal: Journal of the American Society of Nephrology (1993)

The endothelium-derived relaxing factor nitric oxide (EDRF/NO) is a labile, endogenous vasodilator that is important in the control of systemic vascular tone. This review focuses on the effects of EDRF/NO on glomerular mesangial cells in vitro and on the role of EDRF/NO in mesangial and glomerular physiology and pathophysiology in vivo. It was concluded that EDRF/NO can stimulate increases in cGMP, inhibit mesangial cell contraction, and inhibit growth factor-induced proliferation of mesangial cells in culture. Furthermore, incubation with endotoxin or cytokines stimulates mesangial cells to produce EDRF/NO, via an inducible NO synthase enzyme. Therefore, it is likely that NO could play a role in the inflammatory response within the glomerulus. Finally, recent studies providing evidence that EDRF/NO is functional within the glomerulus in vivo, especially during endotoxemia and inflammation are also reviewed.