tbuckley/cabot-search huggingface dataset:
Mechanisms of sunitinib malate (SU) resistance in gastrointestinal stromal tumors (GISTs)
Authors: M. C. Heinrich, C. L. Corless, B. Liegl, C. D. Fletcher, C. P. Raut, R. Donsky, M. M. Bertagnolli, A. Harlow, G. D. Demetri, J. A. Fletcher
Journal: Journal of Clinical Oncology (2007)

10006 Background: SU, an oral, multitargeted inhibitor of KIT, PDGFRs, VEGFRs, FLT3, and RET receptor tyrosine kinases, is now the standard therapy for treatment of imatinib mesylate (IM)-resistant GIST tumors or IM-intolerant GIST patients. However, it is unclear if the clinical efficacy of SU in this setting is due to inhibition of KIT and/or PDGFRA in tumor cells, inhibition of VEGFRs and PDGFRs in endothelial cells and pericytes, respectively, or a combination of antitumor and antiangiogenic effects. In order to address this question, we studied the molecular mechanisms of SU resistance in vitro and in patient-derived tumors. Methods: We studied the in-vitro effects of IM or SU on cells with KIT exon 11 mutations, either alone or in combination with known IM-resistant secondary mutations. In addition, we analyzed tumor samples obtained from patients undergoing salvage surgery after SU treatment failure. Tumor specimens were genotyped for primary and secondary mutations. Results: SU was approximately 2–5-fold more potent than IM against typical GIST-associated KIT exon 11 mutations. In addition, the presence of secondary mutations involving the ATP/drug binding pocket (V654A or T670I) did not substantially alter SU potency. In contrast, these ATP/drug-binding-pocket mutations conferred high-level resistance to IM. However, SU had no significant inhibitory effect on the kinase activity of secondary IM-resistant mutations involving the KIT activation loop (exon 17, codons 816, 820, 822, and 823). Surgical resection was performed on two GIST patients who had clinical progression on SU. Among nine progressing lesions, substitutions were detected in codons 816, 820, and 822; a novel mutation, L783V, was also identified. In contrast, two non-progressing tumors both contained a V654A secondary mutation. Conclusions: Consistent with in-vitro studies, acquired IM-resistant mutations of the KIT activation loop in GIST are associated with clinical resistance to SU and IM. In addition, novel kinase mutations not previously associated with IM resistance may contribute to clinical SU resistance. These findings suggest that the antiangiogenic effects of SU may be insufficient to inhibit GIST progression when the targeted oncogenic kinase remains active. [Table: see text]
What Practices Will Most Improve Safety?
Authors: Lucian L Leape, Donald M Berwick, David W Bates
Journal: JAMA (2002)

convertedanissueofgrowingprofessionalaware-ness to one of substantial public concern in a mannerandpaceunprecedentedinmodernexperiencewithmattersof health care quality. The epidemiologic finding that morethan 1 million injuries and nearly 100000 deaths occur inthe United States annually as a result of mistakes in medicalcare came from studies nearly a decade old, but it was newinformationforthepublic,anditresonatedstrongly.Inshortorder, the US Congress initiated hearings and the presidentordered a government-wide feasibility study, which led to asubsequent directive to governmental agencies to imple-menttherecommendationsoftheIOMreport.TheIOMcalledonallpartiestomakeimprovingpatientsafetyanationalpri-ority. In response, physicians, hospitals, and health care or-ganizations have been searching for safe practices and ask-ing what they should do to make health care safer.Anticipating this need, the IOM report also recom-mendedthattheAgencyforHealthcareResearchandQual-ity (AHRQ) determine which safety practices are effectiveand disseminate a list of “best practices” to all clinicians.Responding to this appeal, AHRQ requested the NationalQuality Forum to use a consensus process of experts to de-fine a list of best practices. To inform this process, it alsocommissioned the Evidence-Based Practice Center (EPC),University of California, San Francisco–Stanford Univer-sity, to evaluate the evidence supporting a long list of pro-posedsafetypractices.Givena6-monthtimeframe,theEPCenlistednumerousexpertsnationwidetoconducttheanaly-ses. The resulting report by Shojania and colleagues
EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells
Authors: J H W Distler, Y Allanore, J Avouac, R Giacomelli, S Guiducci, F Moritz, A Akhmetshina, U A Walker, A Gabrielli, U Müller-Ladner, A Tyndall, M Matucci-Cerinic, O Distler
Journal: Annals of the Rheumatic Diseases (2008)

Systemic sclerosis (SSc) is characterised by a progressive microangiopathy that contributes significantly to the morbidity of patients with SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers of endothelial precursor cells (EPCs) might also contribute to the vascular pathogenesis of SSc. However, different protocols for isolation, enrichment, culture and quantification of EPCs are currently used, which complicate comparison and interpretation of the results from different studies. The aim of the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group expert panel was to provide recommendations for standardisation of future research on EPCs. Consensus statements and recommendations were developed in a face to face meeting by an expert panel of the basic science working group of EUSTAR. The findings were: cardiovascular risk factors and medications such as statins should be described in detail. A detailed description of methods considering isolation, culture, enrichment and detection of EPCs should be given. For in vitro culture of EPCs, no protocol has been shown to be superior to another, but coating with laminin and type IV collagen would resemble most closely the situation in vivo. The endothelial phenotype should be confirmed in all in vitro cultures at the end of the culture period. We recommend using CD133, vascular endothelial growth factor type 2 receptor (VEGFR2) and CD34 in combination with a viability marker for quantification of EPCs in the blood. Finally, exact standard operating procedures for fluorescence-activated cell sorting (FACS) analysis are given that should be strictly followed. In summary, the EUSTAR recommendations will help to unify EPC research and allow better comparison between the results of different studies.
EGFR Blockade Enriches for Lung Cancer Stem–like Cells through Notch3-Dependent Signaling
Authors: Rajeswara Rao Arasada, Joseph M. Amann, Mohammad A. Rahman, Stacey S. Huppert, David P. Carbone
Journal: Cancer Research (2014)

Mutations in the epidermal growth factor receptor (EGFR) are the most common actionable genetic abnormalities yet discovered in lung cancer. However, targeting these mutations with kinase inhibitors is not curative in advanced disease and has yet to demonstrate an impact on potentially curable, early-stage disease, with some data suggesting adverse outcomes. Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH(+) stem-like cells through EGFR-dependent activation of Notch3. In addition, we demonstrate that erlotinib treatment increases the clonogenicity of lung cancer cells in a sphere-forming assay, suggesting increased stem-like cell potential. We demonstrate that inhibition of EGFR kinase activity leads to activation of Notch transcriptional targets in a γ secretase inhibitor-sensitive manner and causes Notch activation, leading to an increase in ALDH high(+) cells. We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3. This could explain the worsened survival observed in some studies of erlotinib treatment at early-stage disease, and suggests that specific dual targeting might overcome this adverse effect.
Dietary Protein, Weight Loss, and Weight Maintenance
Authors: M.S. Westerterp-Plantenga, A. Nieuwenhuizen, D. Tomé, S. Soenen, K.R. Westerterp
Journal: Annual Review of Nutrition (2009)

The role of dietary protein in weight loss and weight maintenance encompasses influences on crucial targets for body weight regulation, namely satiety, thermogenesis, energy efficiency, and body composition. Protein-induced satiety may be mainly due to oxidation of amino acids fed in excess, especially in diets with "incomplete" proteins. Protein-induced energy expenditure may be due to protein and urea synthesis and to gluconeogenesis; "complete" proteins having all essential amino acids show larger increases in energy expenditure than do lower-quality proteins. With respect to adverse effects, no protein-induced effects are observed on net bone balance or on calcium balance in young adults and elderly persons. Dietary protein even increases bone mineral mass and reduces incidence of osteoporotic fracture. During weight loss, nitrogen intake positively affects calcium balance and consequent preservation of bone mineral content. Sulphur-containing amino acids cause a blood pressure-raising effect by loss of nephron mass. Subjects with obesity, metabolic syndrome, and type 2 diabetes are particularly susceptible groups. This review provides an overview of how sustaining absolute protein intake affects metabolic targets for weight loss and weight maintenance during negative energy balance, i.e., sustaining satiety and energy expenditure and sparing fat-free mass, resulting in energy inefficiency. However, the long-term relationship between net protein synthesis and sparing fat-free mass remains to be elucidated.
Effect of caudal epidural steroid or saline injection in chronic lumbar radiculopathy: multicentre, blinded, randomised controlled trial
Authors: T. Iversen, T. K. Solberg, B. Romner, T. Wilsgaard, J. Twisk, A. Anke, O. Nygaard, T. Hasvold, T. Ingebrigtsen
Journal: BMJ (2011)

<b>Objective</b> To assess the efficacy of caudal epidural steroid or saline injection in chronic lumbar radiculopathy in the short (6 weeks), intermediate (12 weeks), and long term (52 weeks). <b>Design</b> Multicentre, blinded, randomised controlled trial. <b>Setting</b> Outpatient multidisciplinary back clinics of five Norwegian hospitals. <b>Participants</b> Between October 2005 and February 2009, 461 patients assessed for inclusion (presenting with lumbar radiculopathy &gt;12 weeks). 328 patients excluded for cauda equina syndrome, severe paresis, severe pain, previous spinal injection or surgery, deformity, pregnancy, ongoing breast feeding, warfarin therapy, ongoing treatment with non-steroidal anti-inflammatory drugs, body mass index &gt;30, poorly controlled psychiatric conditions with possible secondary gain, and severe comorbidity. <b>Interventions</b> Subcutaneous sham injections of 2 mL 0.9% saline, caudal epidural injections of 30 mL 0.9% saline, and caudal epidural injections of 40 mg triamcinolone acetonide in 29 mL 0.9% saline. Participants received two injections with a two week interval. <b>Main outcome measures</b> Primary: Oswestry disability index scores. Secondary: European quality of life measure, visual analogue scale scores for low back pain and for leg pain. <b>Results</b> Power calculations required the inclusion of 41 patients per group. We did not allocate 17 of 133 eligible patients because their symptoms improved before randomisation. All groups improved after the interventions, but we found no statistical or clinical differences between the groups over time. For the sham group (n=40), estimated change in the Oswestry disability index from the adjusted baseline value was −4.7 (95% confidence intervals −0.6 to −8.8) at 6 weeks, −11.4 (−6.3 to −14.5) at 12 weeks, and −14.3 (−10.0 to −18.7) at 52 weeks. For the epidural saline intervention group (n=39) compared with the sham group, differences in primary outcome were −0.5 (−6.3 to 5.4) at 6 weeks, 1.4 (−4.5 to 7.2) at 12 weeks, and −1.9 (−8.0 to 4.3) at 52 weeks; for the epidural steroid group (n=37), corresponding differences were −2.9 (−8.7 to 3.0), 4.0 (−1.9 to 9.9), and 1.9 (−4.2 to 8.0). Analysis adjusted for duration of leg pain, back pain, and sick leave did not change this trend. <b>Conclusions</b> Caudal epidural steroid or saline injections are not recommended for chronic lumbar radiculopathy. <b>Trial registration</b> Current Controlled Trials ISRCTN No 12574253.
Mutation in the ARH Gene and a Chromosome 13q Locus Influence Cholesterol Levels in a New Form of Digenic-Recessive Familial Hypercholesterolemia
Authors: Hussam Al-Kateb, Sylvia Bähring, Katrin Hoffmann, Konstantin Strauch, Andreas Busjahn, Gudrun Nürnberg, Muhidien Jouma, Eckehard K.F. Bautz, Hans A. Dresel, Friedrich C. Luft
Journal: Circulation Research (2002)

We studied a Syrian family with 3 children who had low-density lipoprotein cholesterol (LDL) concentrations of 13.3, 12.2, and 8.6 mmol/L, respectively. Three other siblings and the parents all had LDL values &lt;4.52 mmol/L, suggesting an autosomal-recessive mode of inheritance. The extended pedigree had 66 additional persons with normal LDL values. A genome-wide scan in the core family with 427 markers showed support for linkage on both chromosomes 1 and 13. Markers on chromosome 1 revealed a 3.07 multipoint LOD score between 1p36.1-p35, an 18-cM interval. Surprisingly, we also found linkage to 13q22-q32, a 14-cM interval, with a 3.08 LOD score. We had identified this locus earlier as containing a gene strongly influencing LDL in another Arab family with autosomal-dominant familial hypercholesterolemia and in normal dizygotic twins. We found evidence for an interaction between these loci. We next genotyped our twin panel and confirmed linkage of the 1p36.1-p35 locus to LDL ( P &lt;0.002) in this normal population. Elucidation of ARH, the LDL receptor adaptor protein at chromosome 1p35, caused us to sequence that gene. We first identified the genomic structure of ARH gene and then sequenced the gene in our family. We found an intron 1 acceptor splice-site mutation. This mutation was not found in any other family members, in 31 nonrelated Syrian persons, or in 30 Germans. Our results underscore the importance of ARH on chromosome 1 and the chromosome 13q locus to LDL, not only in families with unusual illnesses, but also to the general population.
Insulin Signaling and Its Regulation of System A Amino Acid Uptake in Cultured Rat Vascular Smooth Muscle Cells
Authors: Toshiyuki Obata, Atsunori Kashiwagi, Hiroshi Maegawa, Yoshihiko Nishio, Satoshi Ugi, Hideki Hidaka, Ryuichi Kikkawa
Journal: Circulation Research (1996)

Hyperinsulinemia has been recognized as an independent risk factor for atherosclerosis. However, its exact mechanisms are still unclear. In our previous work, we showed that 10 nmol/L insulin stimulated neither mitogen-activated protein kinase (MAP kinase) activity nor [ 3 H]thymidine incorporation but did stimulate S6 kinase through the specific insulin receptors in cultured rat vascular smooth muscle cells (VSMCs). In this study, we observed that ≥1 nmol/L insulin stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and activated IRS-1–dependent phosphatidylinositol 3′-kinase (PI 3′-kinase) and p70 S6 kinase (p70 S6K ) but not MAP kinase (extracellular signal-regulated kinase 2) and p90 S6 kinase (p90 RSK ). However, 10 nmol/L insulin-like growth factor I stimulated all these pathways. Finally, 10 nmol/L insulin stimulated α-aminoisobutyric acid (AIB) uptake, and wortmannin (100 nmol/L) completely inhibited insulin-stimulated AIB uptake, whereas rapamycin (20 nmol/L) had no such effect. Furthermore, cycloheximide (10 μg/mL) completely inhibited insulin-stimulated AIB uptake, but actinomycin D (5 μg/mL) failed to inhibit this. Thus, we reached the following conclusions: (1) Insulin (1 nmol/L) induced phosphorylation of IRS-1 and activated the PI 3′-kinase and p70 S6K pathways in VSMCs, even though 10 nmol/L insulin did not significantly stimulate MAP kinase or p90 RSK . (2) Stimulation of AIB uptake by insulin was regulated at the translational level via wortmannin-sensitive pathways but not p70 S6K pathways.
Oxysterols: Old Tale, New Twists
Authors: Winnie Luu, Laura J. Sharpe, Isabelle Capell-Hattam, Ingrid C. Gelissen, Andrew J. Brown
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Oxysterols have long been known for their important role in cholesterol homeostasis, where they are involved in both transcriptional and posttranscriptional mechanisms for controlling cholesterol levels. However, they are increasingly associated with a wide variety of other, sometimes surprising cell functions. They are activators of the Hedgehog pathway (important in embryogenesis), and they act as ligands for a growing list of receptors, including some that are of importance to the immune system. Oxysterols have also been implicated in several diseases such as neurodegenerative diseases and atherosclerosis. Here, we explore the latest research into the roles oxy-sterols play in different areas, and we evaluate the current evidence for these roles. In addition, we outline critical concepts to consider when investigating the roles of oxysterols in various situations, which includes ensuring that the concentration and form of the oxysterol are relevant in that context—a caveat with which many studies have struggled.
Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project
Authors: Jan Delabie, Harald Holte, Julie M. Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage, Joseph M. Connors, Lisa Rimsza, Nancy L. Harris, Konrad Müller-Hermelink, Thomas Rüdiger, Bertrand Coiffier, Randy D. Gascoyne, Françoise Berger, Kensei Tobinai, Wing Y. Au, Raymond Liang, Emili Montserrat, Ephraim P. Hochberg, Stefano Pileri, Massimo Federico, Bharat Nathwani, James O. Armitage, Dennis D. Weisenburger
Journal: Blood (2011)
Journal Prestige, Publication Bias, and Other Characteristics Associated With Citation of Published Studies in Peer-Reviewed Journals
Authors: Michael Callaham, Robert L Wears, Ellen Weber
Journal: JAMA (2002)

Citation by other authors is important in the dissemination of published science, but factors predicting it are little studied.To identify characteristics of published research predicting citation in other journals, we searched the Science Citations Index database for a standardized 3.5 years for all citations of published articles originally submitted to a 1991 emergency medicine specialty meeting. Analysis was conducted by classification and regression trees, a nonparametric modeling technique of regression trees, to determine the impact of previously determined characteristics of the full articles on the outcome measures. We calculated the the number of times an article was cited each year and calculated the mean impact factor (citations per manuscript per year) in other citing journals.Of the 493 submitted manuscripts, 204 published articles met entry criteria. The mean citations per year was 2.04 (95% confidence interval, 1.6-2.4; range, 0-20.9) in 440 different journals. Nineteen articles (9.3%) were never cited. The ability to predict the citations per year was weak (pseudo R(2) = 0.14.). The strongest predictor of citations per year was the impact factor of the original publishing journal. The presence of a control group, the subjective newsworthiness score, and sample size predicted citation frequency (24.3%, 26.0%, and 26.5% as strongly, respectively). The ability to predict mean impact factor of the citing journals was even weaker (pseudo R(2) = 0.09). The impact factor of the publishing journal was the strongest predictor, followed by the newsworthiness score (89.9% as strongly) and a subjective quality score (61.5%). Positive outcome bias was not evident for either outcome measure.In this cohort of published research, commonly used measures of study methodology and design did not predict the frequency of citations or the importance of citing journals. Positive outcome bias was not evident. The impact factor of the original publishing journal was more important than any other variable, suggesting that the journal in which a study is published may be as important as traditional measures of study quality in ensuring dissemination.
Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo
Authors: Andelko Hrzenjak, Farid Moinfar, Marie-Luise Kremser, Bettina Strohmeier, Edgar Petru, Kurt Zatloukal, Helmut Denk
Journal: Molecular Cancer (2010)

Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo. Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 μM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21WAF1 expression and apoptosis. Nude mice injected with 5 × 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice. Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.
Tracheobronchial transplantation with a bioartifical nanocomposite
Authors: K Sritharan
Journal: Thorax (2012)

Tracheobronchial transplantation with a bioartifical nanocompositeThis proof-of-concept study describes the transplantation of a tracheobronchial airway with a stem-cell-seeded bioartifical nanocomposite in a 36-year-old man presenting with symptoms consistent of a recurrent primary mucoepidermoid cancer.He had previously been treated with debulking surgery and postoperative radiation.The tumour extension was deemed unresectable, thus, transplant with artificial biomaterial was offered.The distal trachea and proximal bronchi were resected for complete tumour removal.The airway was replaced with a synthetic bioartificial nanocomposite, tailor-made in the shape of the patient's airway.The graft was seeded with autologous bone-marrow cells and cultured in a bioreactor for 36 h prior to transplantation.An extracellular like matrix and proliferating cells were noted within the graft following incubation.To augment the regeneration process, the patient received granulocyte colony-stimulating factor and epoetin b subcutaneous injections for 2 weeks postoperatively.No major complications were encountered and the patient remained asymptomatic and tumour-free 5 months later.Postoperative investigations suggested integration and remodelling of the transplanted material.Biopsies demonstrated vessel formation and epithelialisation.In addition, up-regulation of miR-34/449 micro-RNA, epoetin-receptor expression and anti-apoptotic genes and an increase in the number of plasma components contributing to regeneration were seen.This study demonstrates the feasibility of tailor-made bioengineered synthetic transplants in patients.However, further long-term studies are needed to ensure transplant effectiveness, efficacy and safety.