tbuckley/cabot-search huggingface dataset:
Adoption of Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Population-Based Outcomes Study
Authors: Christopher M. Booth, Frances A. Shepherd, Yingwei Peng, Gail E. Darling, Gavin Li, Weidong Kong, William J. Mackillop
Journal: Journal of Clinical Oncology (2010)

Since 2004, several clinical trials have demonstrated that adjuvant chemotherapy (ACT) improves survival in patients with early-stage non-small-cell lung cancer (NSCLC). Here, we evaluate the uptake of ACT and its impact on outcomes in the general population of Ontario, Canada.All patients diagnosed with NSCLC in Ontario from 2001 to 2006 who underwent surgical resection (n = 6,304) were identified using the Ontario Cancer Registry. We linked electronic records of treatment to the registry. We described uptake of ACT and compared survival of all patients with surgically resected NSCLC diagnosed from 2001 to 2003 with patients diagnosed from 2004 to 2006. As a proxy measure of ACT-related toxicity, we evaluated hospitalizations within 6 months of surgery.Demographic, disease, and treatment-related characteristics did not differ between the 2001 to 2003 and 2004 to 2006 study cohorts. Over the study period, the proportion of patients receiving ACT increased from 7% (192 of 2,950 patients) to 31% (1,032 of 3,354 patients; P < .001). The proportion of patients admitted to hospital within 6 months of surgery remained stable and (36% in the 2001 to 2003 cohort and 37% in the 2004 to 2006 cohort). However, within 2 years of surgery, there was a 33% reduction in the proportion of patients admitted to hospital with metastatic disease (P < .001). During the study period, there was a substantial improvement in 4-year survival among surgically resected patients, from 52.5% (2001 to 2003) to 56.1% (2004 to 2006; P = .001).There has been a rapid uptake of ACT for NSCLC, which was not associated with an increased rate of hospitalization. The adoption of ACT was associated with a substantial improvement in overall survival, suggesting that the benefits seen in clinical trials are generalizable to the general population.
Stumbling Blocks on the Path to Personalized Medicine in Breast Cancer: The Case of PARP Inhibitors for <i>BRCA1/2</i>-Associated Cancers
Authors: Judith Balmaña, Susan M. Domchek, Andrew Tutt, Judy E. Garber
Journal: Cancer Discovery (2011)

The popular vision for the future of oncology includes the rational design of therapies inhibiting specific targets, for which development would be less expensive and the chance of success greater because the agent, the target, and a population predicted to benefit maximally would be known from the outset. In the breast cancer arena, successful targeted therapies have entered clinical practice. Recently, patients with BRCA-associated cancers have been identified as eligible for novel investigational therapies targeting their genetic deficiency. Preclinical data, phase I results, and 2 phase II proof-of-concept studies support the continued development of PARP inhibitors, either as single agents or in combination with specific cytotoxic drugs in this setting. In this article, we provide a brief review of current developments concerning PARP inhibitors in BRCA-associated cancers and express concerns about challenges to further development.PARP inhibitors may represent a new and promising targeted therapy for patients with BRCA1/2 -associated cancer. In this review we summarize the main challenges in the clinical development of these agents.
Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme
Authors: Chris A. Learn, Tristan L. Hartzell, Carol J. Wikstrand, Gary E. Archer, Jeremy N. Rich, Allan H. Friedman, Henry S. Friedman, Darell D. Bigner, John H. Sampson
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We have reported previously that tumors expressing wild-type epidermal growth factor receptor (EGFR) in a murine model are sensitive to the EGFR tyrosine kinase inhibitor gefitinib, whereas tumors expressing mutant EGFR variant III (EGFRvIII) are resistant. Determination of how this differential inhibition occurs may be important to patient selection and treatment criteria, as well as the design of future therapeutics for glioblastoma multiforme. Experimental Design: We have determined and quantified how treatment with gefitinib at commonly used, noncytotoxic doses affects neoplastic functions ascribed to EGFRvIII, including downstream signaling by Akt, DNA synthesis, and cellular invasion. In doing so, we have tested and compared a series of wild-type and mutant EGFRvIII-expressing fibroblast and glioblastoma cell lines in vitro after treatment with gefitinib. Results: The results of these experiments demonstrate that short-term treatment with gefitinib (∼24 h) does not reduce phosphorylation of EGFRvIII, whereas EGFR phosphorylation is inhibited in a dose-dependent manner. However, after daily treatment with gefitinib, phosphorylation declines for EGFRvIII by day 3 and later. Nevertheless, after 7 days of daily treatment, cells that express and are dependent on EGFRvIII for tumorigenic growth are not effectively growth inhibited. This may be due in part to phosphorylation of Akt, which is inhibited in EGFR-expressing cells after treatment with gefitinib, but is unaffected in cells expressing EGFRvIII. Cell cycle analysis shows that nascent DNA synthesis in EGFR-expressing cells is inhibited in a dose-dependent manner by gefitinib, yet is unaffected in EGFRvIII-expressing cells with increasing dosage. Furthermore, cells expressing EGFRvIII demonstrate greater invasive capability with increasing gefitinib concentration when compared with cells expressing EGFR after treatment. Conclusions: We conclude that the neoplastic phenotype of EGFRvIII is relatively resistant to gefitinib and requires higher doses, repeated dosing, and longer exposure to decrease receptor phosphorylation. However, this decrease does not effectively inhibit the biologically relevant processes of DNA synthesis, cellular growth, and invasion in cells expressing EGFRvIII.
Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence
Authors: T. Islam, C. Breton, M. T. Salam, R. McConnell, M. Wenten, W. J. Gauderman, D. Conti, D. Van Den Berg, J. M. Peters, F. D. Gilliland
Journal: Thorax (2009)

<h3>Background</h3> Inducible nitric oxide (NO) synthase (iNOS, encoded by <i>NOS2A</i>) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory health, it was hypothesised that variants in <i>NOS2A</i> are associated with asthma incidence and lung function growth during adolescence. <h3>Methods</h3> In this prospective study, spirometric testing was performed at school and a presence or absence of asthma was ascertained annually by questionnaire among children participating in the Southern California Children9s Health Study. 24 single nucleotide polymorphisms (SNPs) of the <i>NOS2A</i> region (with seven promoter SNPs in one haplotype block), spanning 20 kb upstream and 10 kb downstream were genotyped. Association between the <i>NOS2A</i> region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (n=1596) and lung function growth (n=2108). <h3>Result</h3> A pair of “yin–yang” haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The “yin” haplotype (h0111101) was associated with 44% increased asthma risk (p=0.003) and reduced forced expiratory volume in 1 s (FEV<sub>1</sub>) growth from 10 to 18 years of age (−29.46 ml, p=0.07), whereas the “yang”(h1000010) haplotype was associated with 23% reduced asthma risk (p=0.13) and better FEV<sub>1</sub> growth (43.84 ml, p=0.01). Furthermore, the increased asthma risk associated with h0111101 was restricted to children with the <i>GSTM1</i> “null” genotype (interaction p=0.002, HR 1.89, 95% CI 1.34 to 2.60). <h3>Conclusion</h3> Common haplotypes in the <i>NOS2A</i> promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the <i>GSTM1</i> “null” genotype.
Invasion and Persistent Intracellular Colonization of Erythrocytes
Authors: Ralf Schülein, Anja Seubert, Christian Gille, Christa Lanz, Yves Hansmann, Yves Piémont, Christoph Dehio
Journal: The Journal of Experimental Medicine (2001)

The expanding genus Bartonella includes zoonotic and human-specific pathogens that can cause a wide range of clinical manifestations. A productive infection allowing bacterial transmission by blood-sucking arthropods is marked by an intraerythrocytic bacteremia that occurs exclusively in specific human or animal reservoir hosts. Incidental human infection by animal-adapted bartonellae can cause disease without evidence for erythrocyte parasitism. A better understanding of the intraerythrocytic lifestyle of bartonellae may permit the design of strategies to control the reservoir and transmittable stages of these emerging pathogens. We have dissected the process of Bartonella erythrocyte parasitism in experimentally infected animals using a novel approach for tracking blood infections based on flow cytometric quantification of green fluorescent protein–expressing bacteria during their interaction with in vivo–biotinylated erythrocytes. Bacteremia onset occurs several days after inoculation by a synchronous wave of bacterial invasion into mature erythrocytes. Intracellular bacteria replicate until reaching a stagnant number, which is sustained for the remaining life span of the infected erythrocyte. The initial wave of erythrocyte infection is followed by reinfection waves occurring at intervals of several days. Our findings unravel a unique bacterial persistence strategy adapted to a nonhemolytic intracellular colonization of erythrocytes that preserves the pathogen for efficient transmission by blood-sucking arthropods.
Novel Single-Chain Antibody-Targeted Microbubbles for Molecular Ultrasound Imaging of Thrombosis
Authors: Xiaowei Wang, Christoph E. Hagemeyer, Jan David Hohmann, Ephraem Leitner, Paul C. Armstrong, Fu Jia, Manfred Olschewski, Andrew Needles, Karlheinz Peter, Ingo Ahrens
Journal: Circulation (2012)

Molecular imaging is a fast emerging technology allowing noninvasive detection of vascular pathologies. However, imaging modalities offering high resolution currently do not allow real-time imaging. We hypothesized that contrast-enhanced ultrasound with microbubbles (MBs) selectively targeted to activated platelets would offer high-resolution, real-time molecular imaging of evolving and dissolving arterial thrombi.Lipid-shell based gas-filled MBs were conjugated to either a single-chain antibody specific for activated glycoprotein IIb/IIIa via binding to a Ligand-Induced Binding Site (LIBS-MBs) or a nonspecific single-chain antibody (control MBs). Successful conjugation was assessed in flow cytometry and immunofluorescence double staining. LIBS-MBs but not control MBs strongly adhered to both immobilized activated platelets and microthrombi under flow. Thrombi induced in carotid arteries of C57Bl6 mice in vivo by ferric chloride injury were then assessed with ultrasound before and 20 minutes after MB injection through the use of gray-scale area intensity measurement. Gray-scale units converted to decibels demonstrated a significant increase after LIBS-MB but not after control MB injection (9.55±1.7 versus 1.46±1.3 dB; P<0.01). Furthermore, after thrombolysis with urokinase, LIBS-MB ultrasound imaging allows monitoring of the reduction of thrombus size (P<0.001).We demonstrate that glycoprotein IIb/IIIa-targeted MBs specifically bind to activated platelets in vitro and allow real-time molecular imaging of acute arterial thrombosis and monitoring of the success or failure of pharmacological thrombolysis in vivo.
Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24-week phase III double-blind randomised placebo-controlled study of certolizumab pegol
Authors: D van der Heijde, R Fleischmann, J Wollenhaupt, A Deodhar, D Kielar, F Woltering, C Stach, B Hoepken, T Arledge, P J Mease
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. <h3>Methods</h3> The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated. <h3>Results</h3> 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. <h3>Conclusions</h3> Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.
The Methamphetamine Problem in the United States
Authors: Rachel Gonzales, Larissa Mooney, Richard A. Rawson
Journal: Annual Review of Public Health (2010)

Significant public health problems associated with methamphetamine (MA) production and use in the United States have emerged over the past 25 years; however, there has been considerable controversy about the size of the problem. Epidemiological indicators have provided a mixed picture. National surveys of the adult U.S. population and school-based populations have consistently been used to support the position that MA use is a relatively minor concern. However, many other data sources, including law-enforcement groups, welfare agencies, substance abuse treatment program admissions, criminal justice agencies, and state/county executives indicate that MA is a very significant public health problem for many communities throughout much of the country. In this article, we describe (a) the historical underpinnings of the MA problem, (b) epidemiological trends in MA use, (c) key subgroups at risk for MA problems, (d) the health and social factors associated with MA use, (e) interventions available for addressing the MA problem, and (f) lessons learned from past efforts addressing the MA problem.
Increased Vascularization Predicts Favorable Outcome in Follicular Lymphoma
Authors: Ad Koster, Joannes H.J.M. van Krieken, Marius A. MacKenzie, Margit Schraders, George F. Borm, Jeroen A.W.M. van der Laak, William Leenders, Konnie Hebeda, John M.M. Raemaekers
Journal: Clinical Cancer Research (2005)

Abstract Purpose: In malignant lymphoma, angiogenesis has been associated with adverse outcome or more aggressive clinical behavior. This correlation has been established in groups of patients with a large heterogeneity regarding lymphoma subtypes and treatment regimens. The aim of this study is to investigate the significance of vascularization in patients with follicular lymphoma receiving uniform first-line treatment. Experimental Design: We assessed microvessel density (MVD) in pretreatment lymph node biopsies of 46 previously untreated patients with follicular lymphoma using anti-CD34 immunohistochemical staining and interactive quantification. In a selection of cases, vascular endothelial growth factor (VEGF)-RNA in situ hybridization was done. Patients were treated with cyclophosphamide-vincristine-prednisone induction chemotherapy combined with IFN-α2b. Thirty-six patients responded and received IFN-α as maintenance therapy. Results: MVD ranged from 10 to 70 per measurement field of 0.19 mm2 (median, 38). Median progression-free survival was 47 months in patients with MVD in the highest tertile and only 13 months in patients with lower MVD. Overall survival in patients with low vessel density was 59 months. In patients with high vessel density, median overall survival was not reached. Multivariate analysis indicated that MVD was independently associated with overall survival. There was a lack of correlation between VEGF-RNA expression and vessel density. Conclusion: This study shows that in follicular lymphoma increased vascularization is associated with improved clinical outcome. Furthermore, VEGF-A expression seems not to be involved in follicular lymphoma angiogenesis.
Anti-Phospholipase A2 Receptor Antibody in Membranous Nephropathy
Authors: Weisong Qin, Laurence H. Beck, Caihong Zeng, Zhaohong Chen, Shijun Li, Ke Zuo, David J. Salant, Zhihong Liu
Journal: Journal of the American Society of Nephrology (2011)

The M-type phospholipase A2 receptor (PLA2R) is a target autoantigen in adult idiopathic membranous nephropathy (MN), but the prevalence of autoantibodies against PLA2R is unknown among Chinese patients with MN. Here, we measured anti-PLA2R antibody in the serum of 60 patients with idiopathic MN, 20 with lupus-associated MN, 16 with hepatitis B (HBV)-associated MN, and 10 with tumor-associated MN. Among patients with idiopathic MN, 49 (82%) had detectable anti-PLA2R autoantibodies using a Western blot assay; an assay with greater sensitivity detected very low titers of anti-PLA2R in 10 of the remaining 11 patients. Using the standard assay, we detected anti-PLA2R antibody in only 1 patient with lupus, 1 with HBV, and 3 with cancer, producing an overall specificity of 89% in this cohort limited to patients with secondary MN. The enhanced assay detected low titers of anti-PLA2R in only 2 additional samples of HBV-associated MN. In summary, these results suggest that PLA2R is a major target antigen in Chinese idiopathic MN and that detection of anti-PLA2R is a sensitive test for idiopathic MN.
Endoscopic Deployment of Multiple JOSTENT SelfX Is Effective and Safe in Treatment of Malignant Hilar Biliary Strictures
Authors: Hirofumi Kawamoto, Koichiro Tsutsumi, Ryo Harada, Masakuni Fujii, Hironari Kato, Ken Hirao, Naoko Kurihara, Takashi Nakanishi, Osamu Mizuno, Etsuji Ishida, Tsuneyoshi Ogawa, Hirotoshi Fukatsu, Kohsaku Sakaguchi
Journal: Clinical Gastroenterology and Hepatology (2008)
Inactivation of the Lysyl Oxidase Gene <i>Lox</i> Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice
Authors: Joni M. Mäki, Juha Räsänen, Hilkka Tikkanen, Raija Sormunen, Kaarin Mäkikallio, Kari I. Kivirikko, Raija Soininen
Journal: Circulation (2002)

The lysyl oxidases are extracellular copper enzymes that initiate the crosslinking of collagens and elastin, 5 human isoenzymes having been characterized so far. The crosslinks formed provide the tensile strength and elastic properties for various extracellular matrices, including vascular walls. We studied the role of the first described isoenzyme Lox by inactivating its gene in mice.Murine Lox gene was disrupted by routine methods. Lox(-/-) mice died at the end of gestation or as neonates, necropsy of the live-born pups revealing large aortic aneurysms. In light microscopy, hazy and unruffled elastic lamellae in the Lox(-/-) aortas were observed, and electron microscopy of the aortic walls of the Lox(-/-) fetuses showed highly fragmented elastic fibers and discontinuity in the smooth muscle cell layers in Lox(-/-) fetuses. The wall of the aorta in the Lox(-/-) fetuses was significantly thicker, and the diameter of the aortic lumen was significantly smaller than that in the Lox(+/+) aortas. In Lox(-/-) fetuses, Doppler ultrasonography revealed increased impedance in the umbilical artery, descending aorta, and intracranial artery blood velocity waveforms, decreased mean velocities across cardiac inflow and outflow regions, and increased pulsatility in ductus venosus blood velocity waveforms.Lox has an essential role in the development and function of the cardiovascular system. Inactivation of the Lox gene causes structural alterations in the arterial walls, leading to abnormalities in the cardiovascular functions. Alterations in LOX activity may also play a critical role in certain human cardiovascular diseases.
Plasma exchange in systemic lupus erythematosus.
Authors: H F Parry, C J Moran, M L Snaith, J D Richards, A H Goldstone, L J Nineham, F C Hay, W J Morrow, I M Roitt
Journal: Annals of the Rheumatic Diseases (1981)

Eight out of 10 patients studied longitudinally received benefit from plasmapheresis. The patients were used as their own controls, being treated in a steady state as far as was possible. Levels of circulating complexes did not bear a close relationship with clinical results. On the evidence plasma exchange alone does not appear to represent an important part of the long-term management of patients with systemic lupus erythematosus but may well be of value in combination with other therapy.
THE HYDROGEN ION CONCENTRATION OF JOINT EXUDATES IN RHEUMATIC FEVER AND OTHER FORMS OF ARTHRITIS
Authors: Ralph H. Boots, Glenn E. Cullen
Journal: The Journal of Experimental Medicine (1922)

1. The hydrogen ion concentration of joint exudates aspirated from patients ill with acute rheumatic fever, arthritis of undetermined origin, and bacterial arthritis was determined. The hydrogen ion concentrations of the joint exudates from patients with acute rheumatic fever approximated the normal reaction of blood, varying from pH 7.27 to 7.42. Exudates from patients with arthritis of undetermined origin varied in pH from 7.33 to 7.47. The pH of a joint effusion occurring in a patient with myocardial insufficiency was 7.34. Bacteriologically, all of these fluids were sterile by ordinary means of cultivation. An exudate aspirated from a knee infected with Staphylococcus aureus had a pH of 6.69, while that from a patient having an arthritis due to Streptococcus hoemolyticus was also acid, having a pH of 6.19. 2. Since a definitely acid medium is necessary for the liberation of free salicylic acid and since all of the joint fluids from patients with acute rheumatic fever were slightly alkaline, no free salicylic acid could possibly exist in such joint fluids following the administration of salicylates.
Lymphangitis after tuberculin tests.
Authors: J B Morrison
Journal: BMJ (1984)

Lymphangitis after tuberculin testsLymphangitis after tuberculin testing has rarely been reported.I report 12 such reactions seen during 1979-83, five after Mantoux and seven after Heaf tests.I had not seen any in the previous 39 years. CommentHigham and Jayson showed that 79°" of patients with rheumatoid arthritis or back pain used self prescribed analgesics.2Although there is