tbuckley/cabot-search huggingface dataset:
NHS Direct may have to compete to provide call service within new NHS 111 scheme
Authors: A. O'Dowd
Journal: BMJ (2010)

The management of the nurse led 24 hour telephone advice service provided by NHS Direct in England is to be taken over by the new NHS 111 phone service, the government has confirmed.

Less than a week after a pilot of the NHS 111 service began, the Department of Health has confirmed it will take charge of the phone advice service provided by NHS Direct.

NHS Direct will have to compete with other organisations such as GP out of hours service providers and ambulance trusts to carry on providing the helpline service for 111, but will retain its other functions in providing health information.

NHS 111 is a new phone service designed to give patients access to non-emergency NHS health care. It has just begun piloting in County Durham and Darlington and, after other pilots later this year, will be rolled out nationally …
Geographical variability and environmental risk factors in inflammatory bowel disease
Authors: Siew C Ng, Charles N Bernstein, Morten H Vatn, Peter Laszlo Lakatos, Edward V Loftus, Curt Tysk, Colm O'Morain, Bjorn Moum, Jean-Frédéric Colombel
Journal: Gut (2013)

The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.
Oral Silibinin Inhibits Lung Tumor Growth in Athymic Nude Mice and Forms a Novel Chemocombination with Doxorubicin Targeting Nuclear Factor κB–Mediated Inducible Chemoresistance
Authors: Rana P. Singh, G. U. Mallikarjuna, Girish Sharma, Sivanandhan Dhanalakshmi, Anil K. Tyagi, Daniel C. F. Chan, Chapla Agarwal, Rajesh Agarwal
Journal: Clinical Cancer Research (2004)

The acute and cumulative dose-related toxicity and drug resistance, mediated via nuclear factor kappaB (NFkappaB), of anthracycline anticancer drugs pose a major problem in cancer chemotherapy. Here, we report that oral silibinin (a flavanone) suppresses human non-small-cell lung carcinoma A549 xenograft growth (P = 0.003) and enhances the therapeutic response (P < 0.05) of doxorubicin in athymic BALB/c nu/nu mice together with a strong prevention of doxorubicin-caused adverse health effects. Immunohistochemical analyses of tumors showed that silibinin and doxorubicin decrease (P < 0.001) proliferation index and vasculature and increase (P < 0.001) apoptosis; these effects were further enhanced (P < 0.001) in combination treatment. Pharmacologic dose of silibinin (60 mumol/L) achieved in animal study was biologically effective (P < 0.01 to 0.001, growth inhibition and apoptosis) in vitro in A549 cell culture together with an increased efficacy (P < 0.05 to 0.001) in doxorubicin (25 nmol/L) combination. Furthermore, doxorubicin increased NFkappaB DNA binding activity as one of the possible mechanisms for chemoresistance in A549 cells, which was inhibited by silibinin in combination treatment. Consistent with this, silibinin inhibited doxorubicin-caused increased translocation of p65 and p50 from cytosol to nucleus. Silibinin also inhibited cyclooxygenase-2, an NFkappaB target, in doxorubicin combination. These findings suggest that silibinin inhibits in vivo lung tumor growth and reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy most likely via an inhibition of doxorubicin-induced chemoresistance involving NFkappaB signaling.
A colorectal cancer classification system that associates cellular phenotype and responses to therapy
Authors: Anguraj Sadanandam, Costas A Lyssiotis, Krisztian Homicsko, Eric A Collisson, William J Gibb, Stephan Wullschleger, Liliane C Gonzalez Ostos, William A Lannon, Carsten Grotzinger, Maguy Del Rio, Benoit Lhermitte, Adam B Olshen, Bertram Wiedenmann, Lewis C Cantley, Joe W Gray, Douglas Hanahan
Journal: Nature Medicine (2013)
Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells
Authors: Dong-Ming Kuang, Chen Peng, Qiyi Zhao, Yan Wu, Min-Shan Chen, Limin Zheng
Journal: Hepatology (2009)

Although cancer patients exhibit a generalized immunosuppressive status, substantial evidence indicates that the inflammatory reaction at a tumor site can promote tumor growth and progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. We recently found that proinflammatory T helper (Th)17 cells are accumulated in HCC tissue, where they promote disease progression by fostering angiogenesis. Here we show that interleukin (IL)-17-producing cells were enriched predominantly in peritumoral stroma of HCC tissues, and their levels were well correlated with monocyte/macrophage density in the same area. Most peritumoral CD68(+) cells exhibited an activated phenotype. Accordingly, tumor-activated monocytes were significantly superior to the suppressive tumor macrophages in inducing expansion of Th17 cells from circulating memory T cells in vitro with phenotypic features similar to those isolated from HCCs. Moreover, we found that tumor-activated monocytes secreted a set of key proinflammatory cytokines that triggered proliferation of functional Th17 cells. Inhibition of monocytes/macrophages inflammation in liver markedly reduced the level of tumor-infiltrating Th17 cells and tumor growth in vivo.The proinflammatory Th17 cells are generated and regulated by a fine-tuned collaborative action between different types of immune cells in distinct HCC microenvironments, and allows the inflammatory response of activated monocytes to be rerouted in a tumor-promoting direction. Selectively modulating the "context" of inflammatory response in tumors might provide a novel strategy for anticancer therapy.
Perception of Complex Sounds: Abnormal Pattern of Cortical Activation in Autism
Authors: Nathalie Boddaert, Pascal Belin, Nadia Chabane, Jean-Baptiste Poline, Catherine Barthélémy, Marie-Christine Mouren-Simeoni, Francis Brunelle, Yves Samson, Mônica Zilbovicius
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Bilateral temporal hypoperfusion at rest was recently described in autism. In normal adults, these regions are activated by listening to speech-like sounds. To investigate auditory cortical processing in autism, the authors performed a positron emission tomography activation study. METHOD: Regional cerebral blood flow was measured in five autistic adults and eight comparison subjects during rest and while listening to speech-like sounds. RESULTS: Similar to the comparison subjects, autistic patients showed a bilateral activation of the superior temporal gyrus. However, an abnormal pattern of hemispheric activation was observed in the autistic group. The volume of activation was larger on the right side in the autistic patients, whereas the reverse pattern was found in the comparison group. The direct comparison between the two groups showed that the right middle frontal gyrus exhibited significantly greater activation in the autistic group. Conversely, the left temporal areas exhibited less activation in autistic patients. CONCLUSIONS: These findings suggest that abnormal auditory cortical processing is implicated in the language impairments and the inadequate response to sounds typically seen in autism.
The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer
Authors: Udai Banerji, D. Ross Camidge, Henk M.W. Verheul, Roshan Agarwal, Debashis Sarker, Stan B. Kaye, Ingrid M.E. Desar, Johanna N.H. Timmer-Bonte, S. Gail Eckhardt, Karl D. Lewis, Kathryn H. Brown, Mireille V. Cantarini, Clive Morris, Sarah M.A. George, Paul D. Smith, Carla M.L. van Herpen
Journal: Clinical Cancer Research (2010)

Abstract Purpose: In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation. Experimental Design: In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter. Results: The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve0-24, exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate–induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC50 of 352 ng/mL and maximum inhibition (Emax) of ∼91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy. Conclusions: The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials. Clin Cancer Res; 16(5); 1613–23
Spectrin Rouen (beta 220-218), a novel shortened beta-chain variant in a kindred with hereditary elliptocytosis. Characterization of the molecular defect as exon skipping due to a splice site mutation.
Authors: M Garbarz, W T Tse, P G Gallagher, C Picat, M C Lecomte, F Galibert, D Dhermy, B G Forget
Journal: Journal of Clinical Investigation (1991)

The molecular defect responsible for the shortened beta-spectrin chain variant, spectrin Rouen, was identified by analysis of cDNA and genomic DNA of affected individuals after amplification by the polymerase chain reaction. Peripheral blood reticulocyte RNA was transcribed into cDNA and amplified using primers corresponding to the 3' end of beta-spectrin cDNA. Agarose gel electrophoresis of cDNA amplification products from affected individuals revealed the expected band of 391 bp as well as a shortened band of 341 bp. Nucleotide sequencing of the shortened cDNA amplification product revealed that the sequences corresponding to the penultimate exon of the beta-spectrin gene (exon Y) were absent. This result was confirmed by hybridization of a Southern blot of amplification products with a labeled probe specific for exon Y. Nucleotide sequencing of the proband's amplified genomic DNA corresponding to this region of the beta-spectrin gene revealed a mutation in the 5' donor consensus splice site of the intron downstream of the Y exon, TGG/GTGAGT to TGG/GTTAGT, in one allele. We postulate that this mutation leads to the splicing out or skipping of exon Y, thus producing a shortened beta-spectrin chain. To our knowledge, this is the first documented example of exon skipping as the cause of a shortened beta-spectrin chain in a case of hereditary elliptocytosis. The exon skip results in the loss of the 17 amino acids of exon Y and creates a frameshift with the synthesis of 33 novel amino acids prior to premature chain termination 14 residues upstream of the normal carboxy terminus of the beta-spectrin chain, giving a mutant beta-spectrin chain that is 31 amino acids shorter than the normal chain.
Can We Predict Bevacizumab Responders in Patients With Glioblastoma?
Authors: Tina M. Mayer
Journal: Journal of Clinical Oncology (2015)

Glioblastoma is among the most devastating of oncologic diagnoses, with the disease being characterized by its aggressive recurrent nature and poor prognosis. Initial treatment with temozolomide in addition to radiation has been demonstrated to confer a modest survival benefit. 1 Since the US Food and Drug Administration approval of temozolomide in 2005, no other systemic therapies have been approved on the basis of demonstration of improvement in overall survival. Bevacizumab was approved by the US Food and Drug Administration in 2009 for monotherapy in patients with recurrent glioblastoma on the basis of two phase II trials that demonstrated durable objective response rates. 2,3 The hope was that the Radiation Therapy Oncology Group (RTOG) 0825 (Temozolomide and Radiation Therapy With or Without Bevacizumab in Treating Patients WithNewlyDiagnosedGlioblastoma)andAVAglio(AStudyofAvastin (Bevacizumab) in Combination With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Glioblastoma) studies would demonstrate an overall survival benefit with the use of bevacizumab. Both of these studies included patients with newly diagnosed glioblastoma who were undergoing standard of care treatment with concurrenttemozolomideandradiationandwererandomlyassigned to either bevacizumab or placebo. They demonstrated benefits in progression-free survival favoring the bevacizumab arm, but no such benefit was demonstrated in overall survival. 4,5 Looking at the subgroup analysis in the AVAglio study population, clinical prognostic factors such as extent of resection, performance status, recursive partitioning analysis class, baseline steroid use, and O 6 -methylguanineDNA-methyltransferase analysis of tumor tissue, did not seem to be predictiveofresponse. 4 Patientsinthisstudydidseemtobenefitfrom bevacizumabintermsofmaintenanceofqualityoflife. 4 However,the RTOG 0825 study had conflicting results, with higher rates of neurocognitive decline in patients on the bevacizumab arm. 5
Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis
Authors: Monika Schoels, Daniel Aletaha, Josef S Smolen, John B Wong
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Optimal treatment for rheumatoid arthritis (RA) after inadequate response (IR) to tumour necrosis factor α inhibitors (TNFi) remains uncertain. <h3>Objective</h3> To compare the efficacy and safety of biological agents after TNFi-IR. <h3>Methods</h3> A systematic literature search was carried out using Medline and Cochrane databases, as well as http://www.clinicaltrials.gov, and bibliographies of the retrieved literature were searched by hand. Randomised, placebo-controlled trials that enrolled patients with RA with TNFi-IR were included and American College of Rheumatology (ACR) response as primary efficacy outcome and adverse events (AEs), serious adverse events (SAEs) and serious infections (SIs) as safety measures were extracted. An indirect meta-analysis with pairwise comparisons of efficacy and safety data was then carried out using ORs or risk differences (RDs) in a random effects model. <h3>Results</h3> In four randomised controlled trials with 24 weeks9 follow-up, direct comparisons of abatacept, golimumab, rituximab and tocilizumab versus placebo showed statistically significant mean ORs of 3.3–8.9 for ACR20, 5.5–10.2 for ACR50 and 4.1–13.5 for ACR70. Risks of AEs, SAEs and SIs versus placebo were non-significant. Indirect pairwise comparisons of the four biological agents showed no significant differences in ACR50 and ACR70. Golimumab had a significantly lower OR (0.56–0.59) for ACR20 but significantly fewer AEs (RD 0.13–0.18). Efficacy after one versus multiple TNFi failures did not differ significantly between the different biological agents. <h3>Conclusion</h3> In patients refractory to one or more TNFi, new biological agents provide significant improvement with good safety. Lacking head-to-head trials, indirect meta-analysis enables a comparison of effectiveness and safety of biological agents with each other and shows that all biological agents have similar effects.
Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects
Authors: Lena M S Carlsson, Markku Peltonen, Sofie Ahlin, Åsa Anveden, Claude Bouchard, Björn Carlsson, Peter Jacobson, Hans Lönroth, Cristina Maglio, Ingmar Näslund, Carlo Pirazzi, Stefano Romeo, Kajsa Sjöholm, Elisabeth Sjöström, Hans Wedel, Per-Arne Svensson, Lars Sjöström
Journal: New England Journal of Medicine (2012)

Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.).
ErbB Receptors: Directing Key Signaling Networks Throughout Life
Authors: Thomas Holbro, Nancy E. Hynes
Journal: The Annual Review of Pharmacology and Toxicology (2004)

The epidermal growth factor (EGF)-related peptides bind the ErbB receptors, inducing the formation of different homo- and heterodimers. Receptor dimerization promotes activation of the intrinsic kinase, leading to phosphorylation of specific tyrosines located in the ErbB's cytoplasmic region. These phosphorylated residues serve as docking sites for a variety of signaling molecules whose recruitment stimulates intracellular signaling cascades, which ultimately control diverse genetic programs. Particular ligand-receptor complexes have essential roles in embryonic development as well as in the adult. Finally, ErbB receptors are being pursued as therapeutic targets because aberrant ErbB activity has been observed in many human cancers. In this review, we discuss these data in more detail, illustrating the importance of tightly regulated ErbB signaling throughout life.
L-Type Calcium Channel Blockers Exert an Antiinflammatory Effect by Suppressing Expression of Plasminogen Receptors on Macrophages
Authors: Riku Das, Tim Burke, David R. Van Wagoner, Edward F. Plow
Journal: Circulation Research (2009)

L-type Ca(2+) channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used antihypertensive drugs that also have antiinflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends on its interaction with Plg receptors (Plg-Rs). Plg-Rs include histone 2B, alpha-enolase, annexin 2, and p11, all proteins which lack signal sequences for cell surface export. When human or murine monocytoid cells were induced to differentiate into macrophages, their Plg binding and Plg-R expression increased by 4-fold. These changes were suppressed by pretreatment with verapamil and amlodipine. Expression of the Ca(v)1.2 LTCC pore subunit was induced in differentiated macrophages, and siRNA against this subunit suppressed the upregulation of Plg binding and Plg-Rs. In vivo, amlodipine and verapamil suppressed peritoneal macrophage recruitment in response to thioglycollate by >60% at doses that did not affect blood pressure. In drug-treated animals, macrophages migrated into but not through the peritoneal membrane tissue and showed reduced surface expression of Plg-Rs. These findings demonstrate that Plg-R expression on macrophages is dependent on Ca(v)1.2 LTCC subunit expression. Suppression of Plg-Rs may contribute to the antiinflammatory effects of the widely used LTCC blockers.