tbuckley/cabot-search huggingface dataset:
Validation of an active surveillance threshold for the CCP score in conservatively managed men with localized prostate cancer.
Authors: Steven Stone, Jack M. Cuzick, Gabrielle Fisher, Zi Hua Yang, Bernard North, Daniel M. Berney, Luis Beltran, David Greenberg, Henrik Møller, Julia E. Reid, Alexander Gutin, Jerry S. Lanchbury, Michael K. Brawer, Peter T. Scardino
Journal: Journal of Clinical Oncology (2015)

54 Background: Active surveillance (AS) is an increasingly popular treatment modality for men with localized prostate cancer. However, better risk stratification is needed to appropriately select men for AS. The cell cycle progression (CCP) score has proven to be a robust predictor of prostate cancer outcomes in various clinical settings, including conservatively managed cohorts. Here, we present a validation of an AS threshold for a predefined score that combines CCP with CAPRA (combined clinical CCP risk (CCR) score) for predicting prostate cancer mortality (PCM) in conservatively managed patients. Methods: We determined the CCR score distribution in 505 men who were tested in our clinical laboratory and, based on their clinical characteristics, might typically be considered for AS. Specifically, the training cohort consisted of men who had Gleason score ≤ 3+4; PSA &lt; 10 ng/ml; &lt; 25% cores positive; and clinical stage ≤ T2a. A threshold CCR score of 0.80 was selected such that 90% of the men in the training cohort had scores below the threshold. The performance characteristics of the threshold were then evaluated in two independent cohorts of conservatively managed men (TAPG1 [N= 180] and TAPG2 [N=585]). Survival data were censored at 10 years. Results: The primary pre−planned analysis called for evaluating the CCR threshold on TAPG2. There were 60 men (of 585) below the threshold in the validation cohort and the threshold validated, dichotomizing the cohort into high and low risk groups (log rank P−value = 0.0008). There were no deaths in patients below the threshold and the Cox proportional hazard estimate of 10−year PCM associated with the CCR threshold was 3.3%. The 10−year risk of PCM associated with the threshold in the combined cohort (TAPG1 and TAPG2) was 3.2% and there were no observed prostate cancer deaths in patients below the threshold. Conclusions: For patients considering deferred treatment, the CCR score provides significant prognostic information at disease diagnosis. The threshold presented here was derived from the ‘typical’ risk of PSM for AS patients and can be used to guide patient selection for AS based on an integrated view of risk assessment.
Identifying Glucokinase Monogenic Diabetes in a Multiethnic Gestational Diabetes Mellitus Cohort: New Pregnancy Screening Criteria and Utility of HbA1c
Authors: Victoria L. Rudland, Marcus Hinchcliffe, Jason Pinner, Stuart Cole, Belinda Mercorella, Lynda Molyneaux, Maria Constantino, Dennis K. Yue, Glynis P. Ross, Jencia Wong
Journal: Diabetes Care (2015)

OBJECTIVE Glucokinase monogenic diabetes (GCK–maturity-onset diabetes of the young [MODY]) should be differentiated from gestational diabetes mellitus (GDM) because management differs. New pregnancy-specific screening criteria (NSC) have been proposed to identify women who warrant GCK genetic testing. We tested NSC and HbA1c in a multiethnic GDM cohort and examined projected referrals for GCK testing. RESEARCH DESIGN AND METHODS Using a GDM database, 63 of 776 women had a postpartum oral glucose tolerance test suggestive of GCK-MODY. Of these 63 women, 31 agreed to undergo GCK testing. NSC accuracy and HbA1c were examined. Projected referrals were calculated by applying the NSC to a larger GDM database (n = 4,415). RESULTS Four of 31 women were confirmed as having GCK-MODY (prevalence ∼0.5–1/100 with GDM). The NSC identified all Anglo-Celtic women but did not identify one Indian woman. The NSC will refer 6.1% of GDM cases for GCK testing, with more Asian/Indian women referred despite lower disease prevalence. Antepartum HbA1c was not higher in those with GCK-MODY. CONCLUSIONS The NSC performed well in Anglo-Celtic women. Ethnic-specific criteria should be explored.
The Histologic Analysis of Mammary Tumors of Mice. I. Scope of Investigations and General Principles of Analysis&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: L. Foulds
Journal: JNCI Journal of the National Cancer Institute (1956)

Journal Article The Histologic Analysis of Mammary Tumors of Mice. I. Scope of Investigations and General Principles of Analysis Get access L. Foulds L. Foulds Chester Beatty Research Institute, Institute of Cancer Research, Royal Cancer Hospital, London, England Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 17, Issue 6, December 1956, Pages 701–711, https://doi.org/10.1093/jnci/17.6.701 Published: 01 December 1956 Article history Received: 20 August 1956 Published: 01 December 1956
Clinical Activity of Sunitinib Rechallenge in Metastatic Renal Cell Carcinoma (Mrcc) – Results of the Resume Study
Authors: S. Oudard, M. Gross Goupil, L. Geoffrois, A. Guillot, C. Chevreau, J.L. Deville, S. Falkowski, H. Boyle, M. Baciuchka Palmaro, P. Gimel, B. Laguerre, M. Laramas, C. Pfister, D. Topard, F. Rolland, E. Legouffe, E. Amela, S. Abadie-Lacourtoisie, N. Mahi
Journal: Annals of Oncology (2014)
Abstract 17124: Myoscape Controls Cardiomyocyte Calcium Cycling and Contractile Function in vivo via Regulation of L-type Calcium Channel Surface Expression
Authors: Matthias Eden, Benjamin Meder, Mirko Voelkers, Rainer Will, Montatip Poomvanicha, Katrin Domes, Alexander Bernt, Christophe Heymes, Wolfgang Rottbauer, Hofmann Franz, Norbert Frey
Journal: Circulation (2014)

Alterations in cardiomyocyte calcium cycling have been shown to play a major role in the pathophysiology of contractile dysfunction, hypertrophy and the progression of heart failure. The L-type Ca2+channel controls calcium entry and subsequent calcium-induced calcium release. Here we report a novel muscle enriched protein termed Myoscape which directly interacts with the distal C-terminus of the L-type Ca2+channel (LTCC) and cardiac Alpha-Actinin 2. Knockdown of Myoscape in adult rat ventricular cardiomyocytes (ARVCMs) leads to a decrease in global calcium transients, with smaller Ca2+ amplitudes (n=4, p<0.001), lower diastolic Ca2+content and a prolonged time to peak. Consistently, analysis of single LTCC currents in ARVCM confirmed a significant reduction upon Myoscape ablation. Conversely, overexpression of Myoscape significantly increases global Ca2+transients and enhances LTCC currents. Moreover, overexpression of Myoscape almost completely restores decreased LTCC currents in failing ARVCMs. As a functional consequence, knockdown of Myoscape significantly reduced contractility of ARVCM, as assessed by fractional shortening measurements (n=3, p<0.001). Myoscape knockout mice develop reduced fractional shortening after 8 weeks which progresses to advanced cardiomyopathy after one year follow up (FS 51.7% ±4.2. vs. 33.3%±3.7, n=10). After 4 weeks of aortic constriction Myoscape null mice showed deteriorated contractile function with ventricular dilatation, enhanced fibrosis and increased pulmonary blood congestion as compared to wildtype mice. Myoscape KO’s showed increased heart weight to tibia length ratios and developed significantly exaggerated cardiomyocyte hypertrophy. Mechanistically, myoscape KO mice showed significantly reduced L-Type Ca2+currents, cell capacity and current densities (pA/pF 3.72±0.4 vs. 2.48±0.2) without affection of CDI and CDF. Instead, loss of Myoscape leads to reduced plasma membrane content of LTCC and its stabilizing agent Alpha Actinin 2 in vitro and in vivo, as assessed by surface membrane biotinylation assays and confocal immunofluorescence microscopy. Taken together, we have identified a novel modulator of cardiomyocyte L-type calcium channels and contractile function.
O006 : C-swift: grazoprevir/elbasvir + sofosbuvir in cirrhotic and noncirrhotic, treatment-naive patients with hepatitis C virus genotype 1 infection, for durations of 4, 6 or 8 weeks and genotype 3 infection for durations of 8 or 12 weeks
Authors: F. Poordad, E. Lawitz, J.A. Gutierrez, B. Evans, A. Howe, H.-P. Feng, J.J. Li, P. Hwang, M. Robertson, J. Wahl, E. Barr, B. Haber
Journal: Journal of Hepatology (2015)
Is the clinical course of HIV infection changing?
Authors: K. Porter, M. G Law, J. M Kaldor, A. C. Lepri, A. N Phillips, P. Pezzotti, G. Rezza, A Sinicco, R Fora, R Raiteri, M Sciandra, G Bechis, M M Calvo, P Gioannini
Journal: BMJ (1997)

The real ethics of rationing Purchasers, not surgeons, control waiting listsEditor-I applaud the BMJ's efforts to bring the important issue of rationing to the fore, but I cannot allow one aspect of Light's contribution to go without challenge. 1Under the heading "parasitic privatisation" he says, "to top it off, the surgeons control the waiting lists" (to encourage patients into the private sector).I despair that someone of his academic stature should show such a lack of understanding of the purchaser-provider split that we have had in the NHS for the past six years.In the vast majority of cases we as surgeons have a contract with purchasers that places an upper limit on the number of patients on whom we can operate.Thus surgeons have no control over the number of patients having surgery and therefore, by definition, over the waiting list.The role of the surgeon is to prioritise, on clinical grounds, within the contracted number.If surgeons are to operate on more patients then purchasers must contract for more operations.The onus to reduce waiting time, and therefore encourage patients not to use the private sector, lies solely with the purchasers.
The outcome of patients with advanced hepatocellular carcinoma (HCC) in pre- and post-sorafenib eras using the SEER database.
Authors: Jiahuai Tan, Minsig Choi, Philip Agop Philip, Gregory Dyson, Anthony Frank Shields, Richard D. Kim
Journal: Journal of Clinical Oncology (2013)

276 Background: HCC is the third most common cause of cancer-related death globally. Prognosis for advanced HCC is dismal due to lack of effective treatment options for the majority of patients who present with advanced disease. Sorafenib was the first agent reported to improve overall survival in patients with good liver function enrolled in phase III clinical trials. However, survival impact of sorafenib on the general population with advanced HCC has not been studied to date. Methods: Sorafenib was approved for patients with advanced HCC and Child-Pugh A liver disease in 2007. We analyzed 2005-2006 and 2008-2009 clinical outcome data from the SEER to compare the impact of this targeted therapy in the population based setting. The Kaplan-Meier method was used to estimate the median survival and 95% confidence intervals (CI). The log-rank test was used to test the difference in survival curves. Cox regression analyses were utilized for the estimation of hazard ratios. Results: We identified 2297 and 2808 stage III and IV HCC cases diagnosed in [2005, 2006] and [2008, 2009], respectively. Seventy-seven percent of the patients were male and the median age was 61 years old for males and 66 for females. The median survival estimates (95% CIs) are 3 (3, 4) months and 4 (4, 4) months for patients diagnosed in [2005, 2006] and [2008, 2009], respectively. The hazard ratio (95% CI) for overall survival comparing [2008, 2009] to [2005, 2006] was 0.92 (0.87, 0.98, p-value = 0.01). We performed multivariable Cox regression modeling and African American patients have a hazard ratio of death [1.14 (1.06, 1.23)] as compared to European American patients. Younger females have a decreased hazard of dying relative to younger men, while older females have an increase hazard of dying relative to older men. Conclusions: The approval of sorafenib treatment produced very modest median survival gain in advanced HCC patients based on SEER population study. However, the small benefit in hazard ratio may have been impacted by small number of patients with advanced HCC who are being treated or are able to be treated with sorafenib in this era.
Alveolar macrophages from smokers show strong intracellular fluorescence
Authors: CM Skold, A Eklund, J Hed
Journal: European Respiratory Journal (1990)

The paper of van Hengstum c.s. describes the inefficacy of oral high frequency oscillation (HF) combined with forced expiration manoeuvres on tracheobronchial clearance in patients with chronic bronchitis (1). In our experience with a slightly different technique, using an endotracheal catheter, oscillating frequency of 1.66-2.50 Hz and a stroke volume of 70-100 ml, a 3 to 5 fold increase in sputum production was found (2). The difference in results may be due to technical differences but also to a difference in patient characteristics. A major disadvantage of the technique of van Hengstum c.s. may be the oral administration of oscillating waves, because the force of these waves may be dampened by the flaccidity of the oropharyngeal cavity and the narrow laryngeal entrance. The weekly introduction of an endotracheal catheter with topical anaesthesia was well tolerated by our patient. Our patient with bronchiectasis had a normal specific compliance; the compliance of the 8 bronchitics of van Hengstum c.s. is not reported. In our experience (unpublished data) the results of HF in patients with a flaccid lung are disappointing. This is explained by the following theory. The efficacy of HF on the clearance of the bronchial tree depends on the capacity to mobilize sputum and on the capacity to produce a sufficient expelling gas flow. The cleansing model of an effective cough comprises two, main factors: 1. the preparation of the sputum for transportation by disrupting its adherence to the bronchial wall. Three mechanisms are involved: a. a tearing force due to the driving power of the gasflow; b. a whirling force due to the turbulence of the gas in the larger airways; c. a vibrating force due to the oscillations of the system causing standing oscillations of the gas which have a tearing effect and vibrations of the bronchial wall loosening adherent sputum. 2. the transport process in which
Bile salt export pump‐reactive antibodies form a polyclonal, multi‐inhibitory response in antibody‐induced bile salt export pump deficiency
Authors: Jan Stindt, Stefanie Kluge, Carola Dröge, Verena Keitel, Claudia Stross, Ulrich Baumann, Florian Brinkert, Anil Dhawan, Guido Engelmann, Rainer Ganschow, Patrick Gerner, Enke Grabhorn, A. S. Knisely, Khalid A. Noli, Ieva Pukite, Ross W. Shepherd, Takehisa Ueno, Lutz Schmitt, Constanze Wiek, Helmut Hanenberg, Dieter Häussinger, Ralf Kubitz
Journal: Hepatology (2015)

Progressive familial intrahepatic cholestasis type 2 (PFIC‐2) is caused by mutations in ABCB11 , encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC‐2 who developed PFIC‐like symptoms after orthotopic liver transplantation (OLT). BSEP‐reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody‐induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC‐2 patients who suffered from phenotypic disease recurrence post‐OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G‐class BSEP‐reactive antibodies in these patients. In all cases, the N‐terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C‐terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle‐based functional assay, transport inhibition by anti‐BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. Conclusions : PFIC‐2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post‐OLT. The antibody response is polyclonal, targeting both extra‐ and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis. (H epatology 2016;63:524–537)
Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway
Authors: Naoki Ohtsu, Yuka Nakatani, Daisuke Yamashita, Shiro Ohue, Takanori Ohnishi, Toru Kondo
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM)–initiating cells (GIC) are a tumorigenic subpopulation that are resistant to radio- and chemotherapies and are the source of disease recurrence. Therefore, the identification and characterization of GIC-specific factors is critical toward the generation of effective GBM therapeutics. In this study, we investigated the role of epithelial V-like antigen 1 (Eva1, also known as myelin protein zero-like 2) in stemness and GBM tumorigenesis. Eva1 was prominently expressed in GICs in vitro and in stem cell marker (Sox2, CD15, CD49f)-expressing cells derived from human GBM tissues. Eva1 knockdown in GICs reduced their self-renewal and tumor-forming capabilities, whereas Eva1 overexpression enhanced these properties. Eva1 deficiency was also associated with decreased expression of stemness-related genes, indicating a requirement for Eva1 in maintaining GIC pluripotency. We further demonstrate that Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-κB pathway by recruiting TRAF2 to the cytoplasmic tail. Taken together, our findings highlight Eva1 as a novel regulator of GIC function and also provide new mechanistic insight into the role of noncanonical NF-κB activation in GIC, thus offering multiple potential therapeutic targets for preclinical investigation in GBM. Cancer Res; 76(1); 171–81. ©2015 AACR.
XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with <i>Listeria monocytogenes</i> or certain viruses
Authors: Yannick O. Alexandre, Sonia Ghilas, Cindy Sanchez, Agnès Le Bon, Karine Crozat, Marc Dalod
Journal: The Journal of Experimental Medicine (2015)

Naive CD8+ T cell priming during tumor development or many primary infections requires cross-presentation by XCR1+ dendritic cells (DCs). Memory CD8+ T lymphocytes (mCTLs) harbor a lower activation threshold as compared with naive cells. However, whether their recall responses depend on XCR1+ DCs is unknown. By using a new mouse model allowing fluorescent tracking and conditional depletion of XCR1+ DCs, we demonstrate a differential requirement of these cells for mCTL recall during secondary infections by different pathogens. XCR1+ DCs were instrumental to promote this function upon secondary challenges with Listeria monocytogenes, vesicular stomatitis virus, or Vaccinia virus, but dispensable in the case of mouse cytomegalovirus. We deciphered how XCR1+ DCs promote mCTL recall upon secondary infections with Listeria. By visualizing for the first time the in vivo choreography of XCR1+ DCs, NK cells and mCTLs during secondary immune responses, and by neutralizing in vivo candidate molecules, we demonstrate that, very early after infection, mCTLs are activated, and attracted in a CXCR3-dependent manner, by NK cell–boosted, IL-12–, and CXCL9-producing XCR1+ DCs. Hence, depending on the infectious agent, strong recall of mCTLs during secondary challenges can require cytokine- and chemokine-dependent cross-talk with XCR1+ DCs and NK cells.
Why are Dutch GPs so much happier?:
Authors: Sophie Arie
Journal: BMJ (2015)

General practice is similar in the Netherlands and the UK yet it appeals far more to young Dutch doctors than to their British counterparts. In collaboration with the Dutch medical journal <i>Nederlands Tijdschrift voor Geneeskunde</i>, Roger Damoiseaux, professor of general practice, and Margaret McCartney, Glasgow GP and <i>The BMJ</i> columnist, met to try to work out why. <b>Sophie Arie</b> reports
A one-year survey of Microsporum audouinii infections in Belgium: epidemiological and genotypic characterization
Authors: R. Sacheli, C. Adjetey, R. Darfouf, S. Harag, P. Huynen, C. Meex, J. Descy, P. Melin, J. Arrese, M.-P. Hayette
Journal: Clinical Microbiology and Infection (2015)
Reduced-dose versus full-dose erlotinib for advanced EGFR-mutant non-small cell lung carcinoma (NSCLC): A retrospective analysis.
Authors: Benjamin L. Lampson, Abigail Santos, Pasi A. Janne, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2015)

8074 Background: Erlotinib is an EGFR tyrosine kinase inhibitor (TKI) which is FDA-approved at the maximum tolerated dose (MTD) of 150mg daily with dose limiting toxicities of diarrhea and rash. Preclinical data and small clinical series suggest that lower doses of erlotinib are biologically active against EGFR mutations. However, this has not been systematically studied. We aimed to study whether reduced-dose erlotinib is as effective as full-dose erlotinib for EGFR-mutant NSCLC. Methods: An institutional database was reviewed to identify patients (pts) who received erlotinib for advanced NSCLC carrying an EGFR exon 19 deletion or L858R mutation. Using a retrospective chart review, erlotinib dose was determined at treatment start and after 4 months of therapy. Progression free survival (PFS) was calculated from time of treatment start until date when the treating clinician documented clinical disease progression. Results: 206 eligible pts were identified: 118 exon 19 del, 88 L858R; 144 1st-line, 62 later-line. 34 pts (17%) initiated erlotinib at a reduced dose: 100mg (n = 29), 50 mg (n = 4), 25 mg (n = 1). Reduced-dose pts were older than full-dose pts (median age 70 vs. 64 yrs, p < 0.01), but otherwise clinically similar (Table). Reduced-dose pts had a median PFS of 8.8 months, not significantly different from those at full-dose (11.2 months, HR = 1.3, p= 0.14). Of 173 pts who had not progressed at 4 months, the 86 (50%) on reduced-dose erlotinib at that time had a significantly lower median PFS (11.7 vs. 14.0 months, HR = 1.5, p< 0.05). Conclusions: This is the largest series to date describing outcomes when initiating treatment for EGFR-mutant lung cancer with reduced-dose erlotinib. PFS was acceptable when treating at a reduced biologically active dose, though trends towards a lower PFS than with MTD dosing. A multivariate analysis controlling for baseline differences is underway. Full dose (n = 172) Reduced dose (n = 34) p Median age (years) 64 70 0.004 PS: 0-1, 2+ 113, 8 20, 3 0.383 Brain mets at start 57 (33%) 9 (26%) 0.548 Line: 1, 2+ 120, 52 24, 10 1.000 Median PFS 11.2 8.8 0.14 (HR 1.3)