tbuckley/cabot-search huggingface dataset:
Mutations of the Growth Hormone Receptor in Children with Idiopathic Short Stature
Authors: Audrey D. Goddard, Robin Covello, Shiuh-Ming Luoh, Tim Clackson, Kenneth M. Attie, Neil Gesundheit, Amy Chen Rundle, James A. Wells, Lena M.S. Carlsson
Journal: New England Journal of Medicine (1995)

Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein.
P55 Syngenic bone marrow transfer stimulates hepatic progenitor cell expansion via TWEAK/Fn14 Signalling: implications for human autologous cell therapy
Authors: T Bird, B Knight, L Boulter, S Gordon-Keylock, D Wjotacha, J Thomas, O Sansom, J Iredale, S Forbes
Journal: Gut (2010)

Introduction  Autologous bone marrow cell (BMC) therapy for liver disease has shown increased liver regeneration in animal studies and in phase 1 clinical studies. As yet no clear mechanism accounts for these observations. BMCs do not directly form into hepatocytes but can improve liver regeneration and function. In chronic liver disease hepatic progenitor cells (HPCs) are a potential source of parenchymal regeneration. Whilst the transplantation of human HPCs is not currently a practical therapeutic option, manipulating endogenous HPCs in vivo represents a potential approach. HPCs exist in a specialised niche of leukocytes and mesenchymal cells, which secrete cytokines that are capable of regulating HPC behaviour. We therefore hypothesised that infusion of BMC into the liver may induce HPC expansion via paracrine signalling.  Aim  To investigate the effect of autologous BMC infusion upon regeneration by hepatic progenitor cells.  Method  107 syngenic BMCs were infused into healthy mice by tail vein, we examined intrahepatic donor cell engraftment, cytokine expression, liver function tests, and HPC activation. Cell tracking utilised either GFP+ or male cells delivered into female wild type mice. Whole liver and specific cell fractions were analysed by immunocytochemistry, in-situ hybridisation, FACS, and qRT-PCR.  Results  Following BMC transfer, a progressive and sustained expansion of HPCs was observed (mean±SEM 41.9±2.1 cells per field vs PBS control 23.5±4.1 at 21 days post infusion, p=0.003) with associated increase in liver/body weight ratio (BMC 0.0513±0.001 vs PBS control 0.0470±0.001, p=0.022). BMCs engrafted the liver adjacent to HPCs for up to 3 weeks and were mostly F4/80+ macrophages (81%). Transfer of F4/80+ macrophages alone into healthy mice recapitulated the HPC expansion. Cytokine gene expression analysis revealed one soluble signal in particular, TWEAK, increased in the recipient9s liver following donor BMC engraftment (5.20-fold induction vs control at Day 3). Extracted donor derived BMCs expressed TWEAK, as do macrophages. TWEAK is known to be a direct mitogen to HPCs via the Fn14 receptor. When Fn14-/- mice were used as recipients to wild type BMC infusions the expansion of HPCs was entirely lost (mean±SEM 27.2±1.4 vs negative PBS control 30.6±2.4, p=0.128 vs positive wild-type control 42.7±2.3, p=0.0002), demonstrating that the HPC expansion is dependent on TWEAK-Fn14 paracrine signalling between BMCs and HPCs.  Conclusion  These data describe a hitherto unknown mechanism by which infused autologous macrophages signal in a paracrine manner to HPCs via TWEAK. These observations suggest potential for the development of novel therapies to promote human liver regeneration.
Dynamic Evolution of Nitric Oxide Detoxifying Flavohemoglobins, a Family of Single-Protein Metabolic Modules in Bacteria and Eukaryotes
Authors: Jennifer H. Wisecaver, William G. Alexander, Sean B. King, Chris Todd Hittinger, Antonis Rokas
Journal: Molecular Biology and Evolution (2016)

Due to their functional independence, proteins that comprise standalone metabolic units, which we name single-protein metabolic modules, may be particularly prone to gene duplication (GD) and horizontal gene transfer (HGT). Flavohemoglobins (flavoHbs) are prime examples of single-protein metabolic modules, detoxifying nitric oxide (NO), a ubiquitous toxin whose antimicrobial properties many life forms exploit, to nitrate, a common source of nitrogen for organisms. FlavoHbs appear widespread in bacteria and have been identified in a handful of microbial eukaryotes, but how the distribution of this ecologically and biomedically important protein family evolved remains unknown. Reconstruction of the evolutionary history of 3,318 flavoHb protein sequences covering the family's known diversity showed evidence of recurrent HGT at multiple evolutionary scales including intrabacterial HGT, as well as HGT from bacteria to eukaryotes. One of the most striking examples of HGT is the acquisition of a flavoHb by the dandruff- and eczema-causing fungus Malassezia from Corynebacterium Actinobacteria, a transfer that growth experiments show is capable of mediating NO resistance in fungi. Other flavoHbs arose via GD; for example, many filamentous fungi possess two flavoHbs that are differentially targeted to the cytosol and mitochondria, likely conferring protection against external and internal sources of NO, respectively. Because single-protein metabolic modules such as flavoHb function independently, readily undergo GD and HGT, and are frequently involved in organismal defense and competition, we suggest that they represent "plug-and-play" proteins for ecological arms races.
Phenylpropanolamine and the Risk of Hemorrhagic Stroke
Authors: Walter N. Kernan, Catherine M. Viscoli, Lawrence M. Brass, Joseph P. Broderick, Thomas Brott, Edward Feldmann, Lewis B. Morgenstern, Janet Lee Wilterdink, Ralph I. Horwitz
Journal: New England Journal of Medicine (2000)

Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case–control study.
Book: Governing Medicine: Theory and Practice
Authors: Conor Brophy
Journal: BMJ (2004)

I've a fantastic idea for a reality TV show. But it's one with a twist: the future of the NHS will be decided on the outcome. The show takes place in a hospital, and the contestants will be doctors and managers. The audience will be the patients, who vote on how to run the hospital. But they won't be told that the options are unworkable. The contestants know, given the equipment and information supplied to them, that the options are impossible. But they're out of the show (it's in their contracts) if they say anything to try to influence the voting. There'll be plenty of crisis and angst. The contrast will be provided by the nurses: they'll exude calm while the protagonists argue. But peace won't break out; it's not good for ratings.​ratings.




Figure 1



Eds Andrew Gray, Stephen Harrison

Open University Press, £22.99, pp 224 ISBN 0 335 21435 5 www.openup.co.uk

Rating: ★★★




The game rules are that the doctors must do what they are trained to do: treat the sick to the best of their ability. But they also must prove it to the satisfaction of the managers, who aren't trained to know. Meanwhile the managers have to get the doctors to see certain patients when and how we tell them. And we'll change that from episode to episode ostensibly on the basis of audience voting. We all know that making doctors do anything against their will is like herding cats. So the managers can't make it work either. Brilliant, isn't it?

Governing Medicine shows the extent to which the NHS has become a cynical political game. Gray and Harrison have brought together an impressive list of observers of the health service who have produced a highly readable social commentary on clinical governance. I found the introduction and the first section to be riveting. The thesis is that clinical governance is really a means of controlling doctors, while the publicly acceptable rationale is to drive up standards. The authors of the first six chapters provide ample evidence and cogent reasons for the likely failure of that rationale. The second section reveals practical faults in the bedrock of clinical governance: the use of randomised controlled trials to predict best practice, guidelines that don't allow for human nature, information systems that are judged in different ways by policy makers and practitioners, and circumscribed user involvement.

However, I was disappointed by the third and final section. The authors seem to have learnt nothing from the analyses of the earlier sections and revert to the rhetoric of clinical governance and NHS politics. The premise seems to be that if only everyone would behave as they're supposed to then clinical governance would work, and doctors, nurses, managers, and patients would between them create the ideal health service. Unfortunately the anthropological critique in the first two sections shows that people don't always follow the script.
Characteristics of the Inferior-Cava Venogram in Retroperitoneal Cancer
Authors: Robert M. Filler, Stuart H. Harris, Edward A. Edwards
Journal: New England Journal of Medicine (1962)

REPORTS from diverse clinics1 2 3 have indicated the usefulness of the venographic study of the iliac and inferior-vena-cava system in venous occlusive disease and extrinsic disease in the retroperitoneum. For the latter purpose, caval venography is one of several technics available. Others include simple roentgenography, pyelography, visualization after air injection and indirect visualization by barium studies of the gastrointestinal tract.Venography can be most useful if the configuration of the normal pattern and its modification by disease are well appreciated. It is the purpose of this paper to demonstrate and emphasize the characteristics of the venogram that we have found significant. . . .
Complications of Smallpox Vaccination, 1968
Authors: J. Michael Lane, Frederick L. Ruben, John M. Neff, J. D. Millar
Journal: New England Journal of Medicine (1969)

In 1968, 572 persons in the United States had confirmed vaccination complications. Of these, 82.5 per cent had received Vaccinia Immune Globulin. Sixty-eight per cent of the patients were primary vaccinees, 7 per cent were revaccinees, 20 per cent acquired vaccinia not by vaccination but by contact, and 5 per cent had unknown histories of vaccination. There were nine deaths: four caused by postvaccinial encephalitis, four associated with vaccinia necrosum, and one caused by eczema vaccinatum. There were 74 complications and one death per 1,000,000 primary vaccinations. Morbidity and mortality rates were highest for infants, with 112 complications and five deaths per 1,000,000 primary vaccinations. Eczema vaccinatum was more severe for contacts than for vaccinees. Although the risk with revaccination is less than a tenth that with primary vaccination, vaccinia necrosum develops in patients with immunologic disorders whether or not they have been previously vaccinated. These estimates, based on surveillance, must be considered minimal.
The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging–Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging–Assisted TURBT in Primary Non–Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results
Authors: Seiji Naito, Ferran Algaba, Marko Babjuk, Richard T. Bryan, Ying-Hao Sun, Luc Valiquette, Jean de la Rosette
Journal: European Urology (2016)
A benchmark for RNA-seq quantification pipelines
Authors: Mingxiang Teng, Michael I. Love, Carrie A. Davis, Sarah Djebali, Alexander Dobin, Brenton R. Graveley, Sheng Li, Christopher E. Mason, Sara Olson, Dmitri Pervouchine, Cricket A. Sloan, Xintao Wei, Lijun Zhan, Rafael A. Irizarry
Journal: Genome biology (2016)

Obtaining RNA-seq measurements involves a complex data analytical process with a large number of competing algorithms as options. There is much debate about which of these methods provides the best approach. Unfortunately, it is currently difficult to evaluate their performance due in part to a lack of sensitive assessment metrics. We present a series of statistical summaries and plots to evaluate the performance in terms of specificity and sensitivity, available as a R/Bioconductor package ( http://bioconductor.org/packages/rnaseqcomp ). Using two independent datasets, we assessed seven competing pipelines. Performance was generally poor, with two methods clearly underperforming and RSEM slightly outperforming the rest.
CBM-01CHARACTERIZATION OF microRNAome IN GLIOBLASTOMA STEM CELLS AND THEIR EXTRACELLULAR VESICLES
Authors: Agnieszka Bronisz, Marco Mineo, Ruben Ferrer-Luna, E. Antonio Chiocca, Jakub Godlewski
Journal: Neuro-Oncology (2015)

Glioblastoma multiforme (GBM) is highly malignant and lethal brain tumor, which displays cellular hierarchies with a sub-population of self-renewing and highly tumorigenic GBM stem cells (GSCs). To shape the tumor stroma to their own advantage, GSCs interact with other cells in the tumor microenvironment, however key signaling molecules that mediate such interactions remain to be fully characterized. Extracellular vesicles (EVs) have recently emerged as important mediators of inter-cellular communication which act by facilitating the horizontal transfer of bioactive molecules (including microRNAs), highlighting them as potential novel targets for therapeutic intervention. Discovery of microRNAs significantly expanded the knowledge and availability of strategies for GBM therapy. Their molecular signatures are associated with GBM/GSC subtypes and, in contrast to other components of EV cargo, can predict survival of GBM patients. Using well characterized panel of patient-derived GSCs we confirmed that GSC heterogeneity is reflected by disparate microRNA expression. Unbiased analysis of GSC heterogeneity revealed coherent microRNA-dependent molecular modules when analyzed along with mRNA expression profiling. Analysis of GSC EV microRNAome revealed only partial overlap with cellular expression profiles. To test the hypothesis that EV secretion of microRNAs reflects both their cellular status (e.g. miR-31) and EV-specific loading (e.g. miR-4443), we validated the secretion of microRNAs by analyzing their precursor and mature form in cells and EVs. The transfer and uptake of EVs and EV-microRNAs were monitored using fluorescence-labeled EVs and microRNAs. The functional transfer of EV microRNAs was monitored by analysis of direct mRNA targets in the recipient cells from the brain microenvironment (GSC, endothelial cells and astrocytes). We demonstrated that the EV transfer of active microRNAs between the cells with different molecular background results in direct and indirect targeting of recipient cell-specific effectors (e.g. ID2, p21). Our results shed a light on an additional layer of the complexity in heterogeneity of GBM.
Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
Authors: Emanuel Fryk, Jeanna Perman Sundelin, Lena Strindberg, Maria J. Pereira, Massimo Federici, Nikolaus Marx, Fredrik H. Nyström, Martin Schmelz, Per-Arne Svensson, Jan W. Eriksson, Jan Borén, Per-Anders Jansson
Journal: Metabolism (2016)
ATPS-06BRAIN-PENETRANT ALKYLINDOLE COMPOUNDS PROMOTE APOPTOSIS IN GLIOMA CELLS THROUGH MICROTUBULE DESTABILIZATION
Authors: Allison Cherry, Brian Haas, Alipi Naydenov, Susan Fung, Cong Xu, Katie Swinney, Michael Wagenbach, Jennifer Freeling, David Canton, Jonathan Coy, Eric Horne, Barry Rickman, John Scott, Rodney Ho, Denny Liggitt, Linda Wordeman, Nephi Stella
Journal: Neuro-Oncology (2015)

Glioblastoma multiforme (GBM) is the most common and aggressive brain neoplasm. Treatment options for this cancer are limited, and the five-year survival rate is less than 5%. Cannabinoid compounds have the ability to cross the blood brain barrier (BBB) and selectively kill tumor cells while maintaining a favorable safety profile, making them attractive candidates as novel GBM therapeutics. For example, the cannabinoid agonists WIN55212-2 (WIN-2) and Δ9-tetrahydrocannabinol (THC) induce GBM cell death both in vitro and reduce tumor growth in vivo, while sparing healthy cells. While cannabinoid compounds typically act through two G protein-coupled receptors (GPCR), CB1, and CB2, evidence suggests that WIN-2, an alkylindole (AI) cannabinoid, kills tumor cells through a separate, unknown mechanism. To explore this unknown mechanism, our lab developed a novel series of AI compounds that exhibit reduced affinity to CB1 and CB2 receptors. The model AI compound, ST-11, was found to destabilize microtubules (MTs) and promote both cell cycle arrest in prometaphase and caspase-dependent apoptosis. Recent studies have shown that GBMs are particularly sensitive to mitotic disruption; however, the use of MT-targeting agents is limited by toxic side effects and a general inability to cross the BBB. ST-11 was found to exhibit a promising safety profile in mice and did not induce overt toxicity in any major organs up to its maximal administrable dose of 240 mg/kg. Additionally, ST-11 readily crossed the BBB within 60 min of intraperitoneal injection and dose-dependently induced caspase activation and reduced tumor size in an orthotopic syngeneic glioma mouse model. Our findings suggest that AI compounds such as ST-11 belong to a new class of brain-penetrant MT-targeting agents that preferentially kill tumor cells.
Relation of Cervical Cancer to Early Marriage and Childbearing
Authors: William M. Christofherson, James E. Parker
Journal: New England Journal of Medicine (1965)

RESOURCES are not always available for unlimited cytologic examinations of women in a given population once a year for carcinoma of the cervix. It is extremely important, therefore, to identify the high-risk patient so that a logical priority can be allotted for population screening. It is important to know the relative risk of the disease according not only to age but also to a multitude of factors that may influence the risk. It is difficult, if not impossible, to get accurate data on the sexual activity of a large group of women. It is possible, however, to get accurate data . . .
Abstract 107: Mitochondrial Dysfunction Mediated Myocardial Stunning Following Resuscitation From Cardiac Arrest
Authors: Willard W Sharp, Lin Piao, Yong Fang, David G Beiser, James K Liao, Stephen L Archer
Journal: Circulation Research (2015)

Rationale: Severe myocardial contractile dysfunction following resuscitation from cardiac arrest (CA) is a major contributor to CA mortality. The pathophysiology and etiology of this dysfunction is not known and there are no pharmacological therapies known to improve outcomes. Previously, we demonstrated that Dynamin related protein 1 (Drp1) is activated and recruited to the mitochondria during CA and that the Drp1 inhibitor Mdivi-1 improves post CA survival. Objective: To determine the effects of CA length on myocardial and mitochondrial function. We also sought to determine the effects of Mdivi-1 on post CA outcomes. Methods and Results: Asystolic cardiac arrest (CA) was induced in mice by IV injection of 0.08 mg/g KCL. CPR begun at 4, 8, 12, and 16 minutes post-cardiac arrest had rates of return of spontaneous circulation (ROSC) of 100%(12/12), 93%(14/15), 71%(10/14), and 44% (4/9) and 2-hour survival of 100%(12/12), 67%(10/15), 50%(7/14), and 11%(1/9). Transthoracic echocardiography 15 min post-resuscitation demonstrated percent fractional shortening of 36±4% (Sham,n=6), 30±4% (4 minCA,n=11), 24±5% (8minCA,n=10), 15±2% (12minCA,n=12). In surviving animals, myocardial dysfunction persisted for 2 hours post-resuscitation, but slowly recovered to baseline by 72 hours. No evidence of myocardial necrosis, inflammation, or apoptosis was noted following resuscitation. Progressive increases in mitochondrial derived reactive oxygen species (ROS) during CA was observed by MitoSOX red myocardial tissue staining. Mitochondria isolated from 12 min CA hearts demonstrated decreased substrate coupled and uncoupled respiration. Mdivi-1, a mitochondrial inhibitor of division (fission), improved survival and neurological scores in mice following an 8 min cardiac arrest compared to controls. Conclusions: Severe, time dependent myocardial stunning (contractile dysfunction in the absence of irreversible injury) was observed following asystolic cardiac arrest. This myocardial stunning was associated with mitochondrial injury and improved by an inhibitor of Drp1. Strategies targeting ischemia/reperfusion-induced changes in mitochondrial dynamics hold promise for improving myocardial function and survival following cardiac arrest.
Involvement of the Steroid and Xenobiotic Receptor SXR in Irinotecan resistance
Authors: Agnès Basseville, Laurence Gamelin, Michèle Boisdron-Celle, Olivier Coqueret, Erick Gamelin, Alain Morel
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1264 

Induction of detoxification proteins is an underlying mechanism of drug resistance in cancer chemotherapy. SXR (Steroid and Xenobiotic Receptor) is one of the main xenobiotic sensors whose activation induces transporter and drug-metabolizing enzyme gene transcription. Unlike the vast majority of nuclear receptors, SXR responds to a wide variety of chemically distinct xenobiotics and endobiotics, regulating the expression of genes involved in both inactivation and clearance of these compounds. Preliminary studies have shown that induction of this receptor by Taxol or rifampicin induces overexpression of some genes involved in Irinotecan metabolism and excretion. Irinotecan (CPT-11) is a drug usually employed in metastatic colon cancer which is among the four most common cancers in the world. CPT-11 is frequently submitted to de novo or acquired clinical resistance. Then a better understanding of molecular mechanisms of resistance could lead to an improvement of its therapeutic capacities. We studied here the hypothetical implication of SXR in Irinotecan resistance in LS180, a colorectal cell line. We wondered whether SXR could be an Irinotecan target and whether SXR activated by Irinotecan, could be able to induce its metabolism and excretion genes. First, by immunofluorescence and cellular fractionment, we observed that SXR was translocated in nucleus after 4h-exposure to 500 ng/ml of CPT-11 or 7.5 ng/ml of SN-38, its active metabolite. Then, chromatin immunoprecipitation showed in the same conditions that CPT-11 and SN-38 induced SXR recruitment on cytochrome p450 3A4 and p21waf1 promoters. SXR binding to both promoters was followed by mRNA (x10 and x15 with SN-38, respectively) and protein overexpression, detected by quantitative RT-PCR and western blot after 24h stimulation. Thus the nuclear receptor SXR, when activated by CPT-11 or SN-38, induced CYP3A4, partially responsible for CPT-11 inactivation, and p21waf1, a cell cycle regulatory gene. Cell cycle arrest, coupled to detoxification, would allow the cells to repair DNA damages induced by chemotherapy, confirming SXR role in Irinotecan resistance. We currently try to inhibit SXR by siRNA during CPT-11/SN-38 treatment to observe the impact upon drug cytotoxicity, visualised by the number of cells blocked in S phase (by FACS). Given that SXR can be activated by other cytotoxic drugs, such as Taxol or cisplatin, and that SXR can regulate a broad range of detoxification genes, the nuclear receptor is an ideal molecular target for the manipulation of this detoxification network.