tbuckley/cabot-search huggingface dataset:
mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor
Authors: Heidi A. Lane, Jeanette M. Wood, Paul M.J. McSheehy, Peter R. Allegrini, Anne Boulay, Joseph Brueggen, Amanda Littlewood-Evans, Sauveur-Michel Maira, Georg Martiny-Baron, Christian R. Schnell, Patrizia Sini, Terence O'Reilly
Journal: Clinical Cancer Research (2009)

Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK).Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.RAD001 inhibited proliferation in vitro (IC50 values<1 nmol/L to >1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values>10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
Alu-SINE Exonization: En Route to Protein-Coding Function
Authors: Maren Krull, Jürgen Brosius, Jürgen Schmitz
Journal: Molecular Biology and Evolution (2005)

The majority of more than one million primate-specific Alu elements map to nonfunctional parts of introns or intergenic sequences. Once integrated, they have the potential to become exapted as functional modules, e.g., as protein-coding domains via alternative splicing. This particular process is also termed exonization and increases protein versatility. Here we investigate 153 human chromosomal loci where Alu elements were conceivably exonized. In four selected examples, we generated, with the aid of representatives of all primate infraorders, phylogenetic reconstructions of the evolutionary steps presumably leading to exonization of Alu elements. We observed a variety of possible scenarios in which Alu elements led to novel mRNA splice forms and which, like most evolutionary processes, took different courses in different lineages. Our data show that, once acquired, some exonizations were lost again in some lineages. In general, Alu exonization occurred at various time points over the evolutionary history of primate lineages, and protein-coding potential was acquired either relatively soon after integration or millions of years thereafter. The course of these paths can probably be generalized to the exonization of other elements as well.
Effect of Two Intensive Statin Regimens on Progression of Coronary Disease
Authors: Stephen J. Nicholls, Christie M. Ballantyne, Philip J. Barter, M. John Chapman, Raimund M. Erbel, Peter Libby, Joel S. Raichlen, Kiyoko Uno, Marilyn Borgman, Kathy Wolski, Steven E. Nissen
Journal: New England Journal of Medicine (2011)

Statins reduce adverse cardiovascular outcomes and slow the progression of coronary atherosclerosis in proportion to their ability to reduce low-density lipoprotein (LDL) cholesterol. However, few studies have either assessed the ability of intensive statin treatments to achieve disease regression or compared alternative approaches to maximal statin administration.We performed serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin, 40 mg daily, to compare the effect of these two intensive statin regimens on the progression of coronary atherosclerosis, as well as to assess their safety and side-effect profiles.After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P<0.001), and higher levels of high-density lipoprotein (HDL) cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P=0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], -1.19 to -0.63) with atorvastatin and by 1.22% (95% CI, -1.52 to -0.90) with rosuvastatin (P=0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: -6.39 mm(3) (95% CI, -7.52 to -5.12), as compared with -4.42 mm(3) (95% CI, -5.98 to -3.26) (P=0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P=0.07) and 64.7% and 71.3%, respectively, for TAV (P=0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events.Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups. (Funded by AstraZeneca Pharmaceuticals; ClinicalTrials.gov number, NCT000620542.).
Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein
Authors: Quy H. Phung, David B. Winter, Aaron Cranston, Robert E. Tarone, Vilhelm A. Bohr, Richard Fishel, Patricia J. Gearhart
Journal: The Journal of Experimental Medicine (1998)

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2−/− mice were immunized with oxazolone, and B cells were analyzed for mutation in their VκOx1 light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2+/+ mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G·C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.
Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial
Authors: J.P. Durand, G. Deplanque, V. Montheil, J.M. Gornet, F. Scotte, O. Mir, A. Cessot, R. Coriat, E. Raymond, E. Mitry, P. Herait, Y. Yataghene, F. Goldwasser
Journal: Annals of Oncology (2011)
Heat Shock Protein 90 Inhibition in Imatinib-Resistant Gastrointestinal Stromal Tumor
Authors: Sebastian Bauer, Lynn K. Yu, George D. Demetri, Jonathan A. Fletcher
Journal: Cancer Research (2006)

Abstract Inhibition of KIT oncoproteins by imatinib induces clinical responses in most gastrointestinal stromal tumor (GIST) patients. However, many patients develop imatinib resistance due to secondary KIT mutations. Heat shock protein 90 (HSP90) protects KIT oncoproteins from proteasome-mediated degradation, and we therefore did preclinical validations of the HSP90 inhibitor, 17-allylamino-18-demethoxy-geldanamycin (17-AAG), in an imatinib-sensitive GIST cell line (GIST882) and in novel imatinib-resistant GIST lines that are either dependent on (GIST430 and GIST48) or independent of (GIST62) KIT oncoproteins. 17AAG (&amp;gt;100 nmol/L) inhibited imatinib-sensitive and imatinib-resistant KIT oncoproteins, with substantially reduced phospho-KIT and total KIT expression after 30 minutes and 6 hours, respectively. KIT signaling intermediates, including AKT and mitogen-activated protein kinase, were inactivated by 17-AAG in the KIT-positive GIST lines, but not in the KIT-negative GIST62. Likewise, cell proliferation and survival were inhibited in the KIT-positive GISTs but not in GIST62. These findings suggest that 17-AAG biological effects in KIT-positive GISTs result mainly from KIT oncoprotein inhibition. The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients. (Cancer Res 2006; 66(18): 9153-61)
Expression of the p53 Target CDIP Correlates with Sensitivity to TNFα-Induced Apoptosis in Cancer Cells
Authors: Lauren Brown-Endres, David Schoenfeld, Fang Tian, Hyung-Gu Kim, Takushi Namba, César Muñoz-Fontela, Anna Mandinova, Stuart A. Aaronson, Sam W. Lee
Journal: Cancer Research (2012)

Abstract TNFα is a pleiotropic cytokine that signals for both survival and apoptotic cell fates. It is still unclear that the dual role of TNFα can be regulated in cancer cells. We previously described an apoptotic pathway involving p53→CDIP→TNFα that was activated in response to genotoxic stress. This pathway operated in the presence of JNK activation; therefore, we postulated that CDIP itself could sensitize cells to a TNFα apoptotic cell fate, survival, or death. We show that CDIP mediates sensitivity to TNFα-induced apoptosis and that cancer cells with endogenous CDIP expression are inherently sensitive to the growth-suppressive effects of TNFα in vitro and in vivo. Thus, CDIP expression correlates with sensitivity of cancer cells with TNFα, and CDIP seems to be a regulator of the p53-mediated death versus survival response of cells to TNFα. This CDIP-mediated sensitivity to TNFα-induced apoptosis favors pro- over antiapoptotic program in cancer cells, and CDIP may serve as a predictive biomarker for such sensitivity. Cancer Res; 72(9); 2373–82. ©2012 AACR.
Explanatory trials versus pragmatic trials
Authors: P. Sedgwick
Journal: BMJ (2014)

Researchers assessed the effectiveness of weekly delivery of low dose high frequency therapeutic ultrasound in conjunction with standard care for hard to heal venous leg ulcers. A multicentre pragmatic two arm randomised controlled trial study design was used. Ultrasound was delivered during weekly dressing changes, and the duration depended on the size of the ulcer. The control treatment was standard care alone, comprising low adherent dressings and four layer bandaging that was high compression, reduced compression, or no compression, depending on the patient’s tolerance. Treatment was delivered for a maximum of 12 weeks.1

Participants were 337 patients with at least one venous leg ulcer of more than six months’ duration or greater than 5 cm2 in area, and an ankle brachial pressure index of 0.8 or more. The primary outcome was time to healing of the largest eligible leg ulcer. Secondary outcomes included health related quality of life and adverse events. Participants were followed for a maximum of 12 months.

The researchers reported that low dose high frequency ultrasound given weekly for 12 weeks during dressing changes in addition to standard care did not significantly increase ulcer healing rates, affect quality of life, or reduce ulcer recurrence.

Which of the following statements, if any, are true?

Statements a and c are true, whereas b and d are false.

Clinical trials are described as explanatory or pragmatic. Explanatory trials generally measure efficacy—that is, the benefit of …
Fitness Inference from Short-Read Data: Within-Host Evolution of a Reassortant H5N1 Influenza Virus
Authors: Christopher J.R. Illingworth
Journal: Molecular Biology and Evolution (2015)

We present a method to infer the role of selection acting during the within-host evolution of the influenza virus from short-read genome sequence data. Linkage disequilibrium between loci is accounted for by treating short-read sequences as noisy multilocus emissions from an underlying model of haplotype evolution. A hierarchical model-selection procedure is used to infer the underlying fitness landscape of the virus insofar as that landscape is explored by the viral population. In a first application of our method, we analyze data from an evolutionary experiment describing the growth of a reassortant H5N1 virus in ferrets. Across two sets of replica experiments we infer multiple alleles to be under selection, including variants associated with receptor binding specificity, glycosylation, and with the increased transmissibility of the virus. We identify epistasis as an important component of the within-host fitness landscape, and show that adaptation can proceed through multiple genetic pathways.
Detection of weakly conserved ancestral mammalian regulatory sequences by primate comparisons
Authors: Qian-fei Wang, Shyam Prabhakar, Sumita Chanan, Jan-Fang Cheng, Edward M Rubin, Dario Boffelli
Journal: Genome biology (2007)

Abstract Background Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis -regulatory elements based on constrained sequence evolution. However, these methods fail to detect functional elements that are too weakly conserved among mammals to distinguish them from non-functional DNA. Results To evaluate a strategy for large scale genome annotation that is complementary to the commonly used distal species comparisons, we explored the potential of deep intra-primate sequence comparisons. We sequenced the orthologs of 558 kb of human genomic sequence, covering multiple loci involved in cholesterol homeostasis, in 6 non-human primates. Our analysis identified six non-coding DNA elements displaying significant conservation among primates but undetectable in more distant comparisons. In vitro and in vivo tests revealed that at least three of these six elements have regulatory function. Notably, the mouse orthologs of these three functional human sequences had regulatory activity despite their lack of significant sequence conservation, indicating that they are ancestral mammalian cis -regulatory elements. These regulatory elements could be detected even in a smaller set of three primate species including human, rhesus and marmoset. Conclusion We have demonstrated that intra-primate sequence comparisons can be used to identify functional modules in large genomic regions, including cis -regulatory elements that are not detectable through comparison with non-mammalian genomes. With the available human and rhesus genomes and that of marmoset, which is being actively sequenced, this strategy can be extended to the whole genome in the near future.
Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada
Authors: Philippe De Wals, Fassiatou Tairou, Margot I. Van Allen, Soo-Hong Uh, R. Brian Lowry, Barbara Sibbald, Jane A. Evans, Michiel C. Van den Hof, Pamela Zimmer, Marian Crowley, Bridget Fernandez, Nora S. Lee, Theophile Niyonsenga
Journal: New England Journal of Medicine (2007)

In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented.The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented.A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively).Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.
Splenic trauma during abdominal wall liposuction: a case report
Authors: Paul Harnett, Yashwant Koak, Daryl Baker
Journal: Journal of the Royal Society of Medicine (2008)

Summary A 35-year-old woman collapsed 18 hours after undergoing abdominal wall liposuction. Abdominal CT scan revealed a punctured spleen. She underwent an emergency splenectomy and made an uneventful recovery.
B Cell Maintenance of Subcapsular Sinus Macrophages Protects against a Fatal Viral Infection Independent of Adaptive Immunity
Authors: E. Ashley Moseman, Matteo Iannacone, Lidia Bosurgi, Elena Tonti, Nicolas Chevrier, Alexei Tumanov, Yang-Xin Fu, Nir Hacohen, Ulrich H. von Andrian
Journal: Immunity (2012)
Specificity of Panic Response to CO<sub>2</sub> Inhalation in Panic Disorder: A Comparison With Major Depression and Premenstrual Dysphoric Disorder
Authors: Justine M. Kent, Laszlo A. Papp, Jose M. Martinez, Susan T. Browne, Jeremy D. Coplan, Donald F. Klein, Jack M. Gorman
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The behavioral response to CO2 inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of CO2-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO2 inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO2, administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each CO2 inhalation. RESULTS: Panic disorder patients had a higher rate of CO2-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with CO2-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent CO2 was a more robust panicogen than 5%, and response to 7% CO2 better distinguished panic disorder patients from normal subjects than response to 5% CO2. CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO2-induced panic attacks, and depressed patients appear to be insensitive to CO2 inhalation. The symptoms of CO2-induced panic attacks have a similar intensity regardless of the subject's diagnosis.
Trust seeks legal advice to stop private firms selling GP practices
Authors: T. Foot
Journal: BMJ (2012)

NHS officials have admitted they were powerless to stop a US health giant from suddenly selling a Camden GP surgery to another private firm. The surgery closed less than a year later leaving 4700 patients looking for a new GP.1

Tony Hoolaghan, associate director of North Central London NHS Trust, described how the trust lost control of Camden Road Surgery and that he was seeking legal advice to stop a similar situation happening again. He was speaking on 31 May at an inquiry into the closure of the surgery held by Camden Council. 

Camden Road Surgery is one of three GP practices that were contracted out by the primary care trust to giant US healthcare company UnitedHealth in 2008. However, in April 2011 UnitedHealth sold its shares in the three practices, including the Camden Road surgery, to The Practice plc describing it as a “management transfer.”

The transfer shocked patients, who were not informed about the deal until after it was done. …
Molecular structure, packing and release of MUC2 with relevance to cystic fibrosis
Authors: Harriet Nilsson, Daniel Ambort, Gunnar Hansson, Hans Hebert
Journal: European Respiratory Journal (2011)

In Cystic Fibrosis extremely viscous fluid is built up likely connected to impaired release and expansion of mucins. MUC2 is mainly expressed in small and large intestine, but also in inflamed airways, and it is stored as a multimer in secretory granules of goblet cells at high [Ca 2+ ] and low pH. The extracellular milieu have to trigger the unpacking of MUC2 controled by its N-terminus, a not yet fully understood process. The aim is to elucidate organization and structure of MUC2 when it is packed and secreted.  The N-terminal part of MUC2 was expressed in CHO cells. The secreted trimerized recombinant mucin was purified from culture medium by anion exchange chromatography. Crosslinked samples were purified by density ultracentrifugation. Analysis was performed by transmission electron microscopy (TEM). The pH in the buffers was varied in the range from 5.2 to 8 to mimic conditions of secretory pathway and extracellular environment by adding HAc (pH 5.2), MES (pH 6.2) or Tris (pH 7.4 and pH 8) with or without calcium. Samples were adsorbed onto carbon coated EM grids and negative stained. Processing of micrographs was performed using EMAN1 software.  When pH was low and or calcium present, rings with an outer and inner diameter of 25-30 and 20-25 nm respectively were observed. Without calcium rings were assembled at pH 5.2 and 6.2, but vanished with increasing pH. 2D refinements of the projections showed rotational 5- or 6- folded symmetry. Assemblies of laterally concatenated rings were obtained in the high density fraction of MUC2 N-terminus. The formations of these rings are probably vital for proper packing and release of full length MUC2.  Harriet N. and Daniel A. have contributed equally