tbuckley/cabot-search huggingface dataset:
Systematic Survey of Therapeutic Trials for Metastatic Colorectal Cancer: Room for Improvement in the Critical Pathway
Authors: Scott Kopetz, Michael Overman, David Z. Chang, Katrina Y. Glover, Imad Shureiqi, Robert A. Wolff, James L. Abbruzzese, Cathy Eng
Journal: Journal of Clinical Oncology (2008)

The current strategy of drug development has been criticized as being highly inefficient. In 2004, the US Food and Drug Administration (FDA) released recommendations to improve this process, including a push for increased use of enrichment trials. It is unclear to what extent aspects of this "Critical Path Initiative" have been adopted in trial designs in metastatic colorectal cancer.A systematic review was conducted of actively enrolling treatment trials in metastatic colorectal cancer. Trials were identified from the National Cancer Institute's clinicaltrials.gov and Investigative Drug Branch databases. Trials were categorized based on the number of prior treatments allowed, phase of the trial, agent mechanism of action, and FDA approval status of agents under investigation.One hundred two trials are enrolling, with a combined enrollment goal of more than 20,000 patients. Thirteen percent of trials investigated an agent not yet FDA-approved for any oncology indication. The most common study design was a phase II study limited to previously untreated patients; compared with the remaining trials, these phase II trials were more than 10 times more likely to only use agents FDA-approved for colorectal cancer. Three percent of patients were enrolled onto trials enriched for tumor characteristics that were hypothesized to improve clinical benefit.Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative.
EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies
Authors: M.-Y. Cai, Z.-T. Tong, F. Zheng, Y.-J. Liao, Y. Wang, H.-L. Rao, Y.-C. Chen, Q.-L. Wu, Y.-H. Liu, X.-Y. Guan, M. C. Lin, Y.-X. Zeng, H.-F. Kung, D. Xie
Journal: Gut (2011)

Background and aims A previous study of ours indicated that enhancer of zeste homologue 2 (EZH2) plays an important role in hepatocellular carcinoma (HCC) tumorigenesis. The aim of the present study was to investigate the potential diagnostic utility of EZH2 in HCC. Methods Immunohistochemistry was performed to examine the expression dynamics of EZH2 in two independent surgical cohorts of HCC and non-malignant liver tissues to develop a diagnostic yield of EZH2, HSP70 and GPC3 for HCC detection. The diagnostic performances of EZH2 and a three-marker panel in HCC were re-evaluated by using an additional biopsy cohort. Results Immunohistochemistry analysis demonstrated that the sensitivity and specificity of EZH2 for HCC detection was 95.8% and 97.8% in the testing cohort. Similar results were confirmed in the validation cohort. For diagnosis of well-differentiated HCCs, the sensitivity and specificity were 68.9% and 91.5% for EZH2, 62.5% and 98.5% for HSP70, 50.0% and 92.1% for GPC3, and 75.0% and 100% for a three-marker panel. In biopsies, positive cases for at least one marker increased from large regenerative nodule and hepatocellular adenoma (0/12) to focal nodular hyperplasia (2/20), dysplastic nodule (7/25), well-differentiated HCC (16/18) and moderately and poorly differentiated HCC (54/54). When at least two positive markers were considered, regardless of their identity, the positive cases were detected in 0/12 large regenerative nodules and hepatocellular adenomas, 0/20 focal nodular hyperplasias, 0/25 dysplastic nodules, 11/18 well-differentiated HCCs, 32/37 moderately differentiated HCCs and 15/17 poorly differentiated HCCs. Conclusion Our findings suggest that EZH2 protein, as examined by immunohistochemistry, may serve as a promising diagnostic biomarker of HCCs, and the use of a three-marker panel (EZH2, HSP70 and GPC3) can improve the rate of detection of HCCs in liver biopsy tissues.
Generalizability of Antidepressant Efficacy Trials: Differences Between Depressed Psychiatric Outpatients Who Would or Would Not Qualify for an Efficacy Trial
Authors: Mark Zimmerman, Iwona Chelminski, Michael A. Posternak
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: In recent years the generalizability of antidepressant efficacy trials has been questioned. Central to the question of generalizability is whether there are differences in clinical, demographic, and psychosocial characteristics between patients who would qualify for an antidepressant efficacy trial and those who would not qualify. METHOD: The authors compared three groups: 123 depressed patients who would qualify for an antidepressant efficacy trial, 289 whose symptom severity was too mild to qualify for an antidepressant efficacy trial, and 187 who would be excluded because they were suicidal or had a comorbid anxiety or substance use disorder. RESULTS: Compared with patients who would qualify for an antidepressant efficacy trial, patients who would be excluded because of comorbidity or suicidality were a more chronically ill group with more previous episodes, greater psychosocial impairment, and more personality pathology. CONCLUSIONS: These findings support further caution in generalizing the results from antidepressant efficacy trials to clinical populations.
Abstract P1-13-03: ER, PR, HER2, and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial
Authors: AS Knoop, A-V Lænkholm, M-B Jensen, KV Nielsen, J Andersen, D Nielsen, B Ejlertsen
Journal: Cancer Research (2013)

Abstract PURPOSE: The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30 years we report overall efficacy for the study and results according to subtypes subsequently assessed by immunohistochemistry and FISH. METHODS: Between 1977 and 1982, 1716 postmenopausal patients with tumors larger than 5 cm or positive axillary nodes were randomly assigned to no systemic therapy or tamoxifen 30 mg daily for one year. The main study is reported as an ITT analysis with the predefined DFS and BCM as endpoint. For multivariate analysis the Cox proportional hazards regression model was applied to assess the adjusted hazard ratio of treatment regimen, and to explore interactions. Formalin-fixed, paraffin-embedded primary breast tumor tissue blocks were available from 1548 (90%) of the 1716 participants enrolled and 1428 were assessable for ER, PR, HER2 and Ki67. The hormone receptor positive (ER and/or PR) cancers were defined as luminal A if Ki67 low and HER2-negative; as luminal B if Ki67 high or HER2-positive; and otherwise as HER2 positive or triple negative. RESULTS: In the intent-to-treat (ITT) population one year of tamoxifen improved the disease-free-survival (DFS) (Hazard ratio (HR) = 0.87; 95% CI 0.77-0.98), the recurrence-free-survival (RFS) (HR = 0.79; 0.69-0.90) and reduced the breast-cancer-specific-mortality (BCM) (HR = 0.83; 0.73-0.93). Recurrence-free survivals were improved significantly by tamoxifen in luminal A (HR = 0.66; 0.53-0.84) and luminal B/HER2- (HR = 0.54; 0.39-0.74) but not in the other subsets, and with similar results for BCM with 30 years follow-up. CONCLUSION: One year of treatment with tamoxifen significantly improves RFS and BCM in postmenopausal patients with ER positive breast cancers. The benefit from tamoxifen was not significantly different in luminal A and B subtypes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-03.
MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells
Authors: Llorenç Coll-Mulet, Daniel Iglesias-Serret, Antonio F. Santidrián, Ana M. Cosialls, Mercè de Frias, Esther Castaño, Clara Campàs, Montserrat Barragán, Alberto Fernández de Sevilla, Alicia Domingo, Lyubomir T. Vassilev, Gabriel Pons, Joan Gil
Journal: Blood (2006)
Distress in Older Patients With Cancer
Authors: Arti Hurria, Daneng Li, Kurt Hansen, Sujata Patil, Ravi Gupta, Christian Nelson, Stuart M. Lichtman, William P. Tew, Paul Hamlin, Enid Zuckerman, Jonathan Gardes, Sewanti Limaye, Mark Lachs, Eva Kelly
Journal: Journal of Clinical Oncology (2009)

Purpose To determine the predictors of distress in older patients with cancer. Patients and Methods Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined. Results The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score. Conclusion Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.
Protection against murine osteoarthritis by inhibition of the 26S proteasome and lysine-48 linked ubiquitination
Authors: Marta Radwan, David J Wilkinson, Wang Hui, Auriane P M Destrument, Sarah H Charlton, Matt J Barter, Beth Gibson, Josée Coulombe, Douglas A Gray, Andrew D Rowan, David A Young
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA). <h3>Methods</h3> Bovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin–proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA. Subsequently, DMM was induced in Lys-to-Arg (K48R and K63R) mutant ubiquitin (Ub) transgenic mice. Cytokine signalling in SW1353s was monitored by immunoblotting and novel ubiquitinated substrates identified using Tandem Ubiquitin Binding Entities purification followed by mass spectrometry. The ubiquitination of TRAFD1 was assessed via immunoprecipitation and immunoblotting and its role in cytokine signal-transduction determined using RNA interference and real-time RT-PCR for MMP13 and interleukin-6 (IL6). <h3>Results</h3> Supplementation with the proteasome inhibitor MG132 protected cartilage from cytokine-mediated resorption and degradation in vivo in mice following DMM-induced OA. Using transgenic animals only K48R-mutated Ub partially protected against OA compared to wild-type or wild-type Ub transgenic mice, and this was only evident on the medial femoral condyle. After confirming ubiquitination was vital for NF-κB signalling and MMP13 expression, a screen for novel ubiquitinated substrates involved in cytokine-signalling identified TRAFD1; the depletion of which reduced inflammatory mediator-induced MMP13 and IL6 expression. <h3>Conclusions</h3> Our data for the first time identifies a role for ubiquitination and the proteasome in the induction of OA via regulation of inflammatory mediator-induced MMP13 expression. These data open avenues of research to determine whether the proteasome, or K48-linked ubiquitination, are potential therapeutic targets in OA.
Extinction debt: a challenge for biodiversity conservation
Authors: Mikko Kuussaari, Riccardo Bommarco, Risto K. Heikkinen, Aveliina Helm, Jochen Krauss, Regina Lindborg, Erik Öckinger, Meelis Pärtel, Joan Pino, Ferran Rodà, Constantí Stefanescu, Tiit Teder, Martin Zobel, Ingolf Steffan-Dewenter
Journal: Trends in Ecology & Evolution (2009)
Clinical Value of a New Reflex in Chorea
Authors: G. A. Stephens
Journal: BMJ (1931)

A boy, aged 9, was sent home from a boarding school because his behaviour was peculiar, and his teachers were tunable to manage him.He was brought to me by his mother, who was more concerned about his mentality than about his general health.The school medical officer had noted that his heart was not normal, and for this reason had suggested I should be consulted.On examination I found his mental cond8ition sound, but sluggish.His heart beat was heaving, and the sounds were abnormal, having a relative
<i>In vivo</i>Targeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab
Authors: Paolo Macor, Claudio Tripodo, Sonia Zorzet, Erich Piovan, Fleur Bossi, Roberto Marzari, Alberto Amadori, Francesco Tedesco
Journal: Cancer Research (2007)

Abstract An in vivo model of human CD20+ B-lymphoma was established in severe combined immunodeficiency mice to test the ability of human neutralizing miniantibodies to CD55 and CD59 (MB55 and MB59) to enhance the therapeutic effect of rituximab. The miniantibodies contained single-chain fragment variables and the hinge-CH2-CH3 domains of human IgG1. LCL2 cells were selected for the in vivo study among six B-lymphoma cell lines for their high susceptibility to rituximab-dependent complement-mediated killing enhanced by MB55 and MB59. The cells injected i.p. primarily colonized the liver and spleen, leading to the death of the animals within 30 to 40 days. Thirty percent of mice receiving biotin-labeled rituximab (25 μg) i.p. on days 4 and 11 after cell injection survived to 120 days. Administration of biotin-labeled rituximab, followed by avidin (40 μg) and biotin-labeled MB55–MB59 (100 μg) at 4-h intervals after each injection resulted in the survival of 70% of mice. Surprisingly, 40% of mice survived after the sole injection of avidin and biotin-labeled MB55–MB59, an observation consistent with the in vitro data showing that the miniantibodies induced killing of ∼25% cells through antibody-dependent cell cytotoxicity. In conclusion, MB55 and MB59 targeted to tumor cells represent a valuable tool to enhance the therapeutic effect of rituximab and other complement-fixing antitumor antibodies. [Cancer Res 2007;67(21):10556–63]
Tax evading retired surgeon is struck off for "prolonged dishonesty"
Authors: C. Dyer
Journal: BMJ (2015)

A former NHS consultant surgeon who made £1.4m writing expert reports for court cases has been struck off the medical register after admitting to evading nearly £459 000 in taxes.

Francis D’Arcy, 73, was semiretired as an NHS consultant ear, nose, and throat surgeon in Belfast when he began writing reports for police employees and soldiers who were bringing deafness claims against the UK government. He reported on hundreds of cases from 2008 to 2012, receiving an average of £250 a case, but he did not declare this income.

Last April he …
Integration of new or experimental treatment options and new approaches to clinical trials
Authors: M. Quinn, J. Pfisterer, E. Avall-Lundqvist, M. Bookman, D. Bowtell, A. Casado, A. Cervantes, S. Grenman, P. Harper, A. Oza, S. Pecorelli, E. Pujade-Lauraine, E. Trimble, P. Vasey, U. Wagner
Journal: Annals of Oncology (2005)
Maximizing the Natriuretic Peptide System in Experimental Heart Failure
Authors: Horng H. Chen, John G. Lainchbury, Gail J. Harty, John C. Burnett
Journal: Circulation (2002)

A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF.We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 micromol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 microg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 microg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone.This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.
Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of Tumor Necrosis Factor α in the Development of Pulmonary Fibrosis
Authors: Ila A. Davis, Stephen J. Kennel
Journal: Clinical Cancer Research (1999)

A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to cyclohexyl diethylenetriaminepentaacetic acid, successfully delivers chelated  213 Bi, an α-particle emitter, ( 213 Bi-201B) rapidly to lung vascular endothelium. When injected at doses of 1 MBq/mouse,  213 Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors, and others had extended life spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4–6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3–4 months later, these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor α (TNF-α), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events that culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (rhuTNFR:Fc) as inhibitors of TNF-α, were unsuccessful. Additionally, mice genetically deficient for TNF-α production developed pulmonary fibrosis following  213 Bi-201B treatment. Interestingly, non-tumor-bearing BALB/c mice receiving rhuTNFR:Fc or mice genetically deficient in TNF-α production and treated with  213 Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or  213 Bi-201B alone. We speculate that in normal mice, although TNF-α may induce an inflammatory response following α-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.
Factors Associated With Short- and Long-Term Outcomes of Therapy for Crohn’s Disease
Authors: Walter Reinisch, Jean-Frederic Colombel, William J. Sandborn, Gerassimos J. Mantzaris, Asher Kornbluth, Omoniyi J. Adedokun, Michael Miller, Kezhen L. Tang, Paul Rutgeerts, Freddy Cornillie
Journal: Clinical Gastroenterology and Hepatology (2014)

Our post hoc analysis assessed the association of early (at weeks 26-30) clinical, endoscopic, biologic, and pharmacokinetic outcomes with corticosteroid-free remission at week 50 (CSFR50); CSFR50 was observed in 55.2% and 65.4% of patients treated with infliximab, alone or in combination with azathioprine, respectively.We analyzed data from 203 patients: 96 received infliximab monotherapy and 107 received combination therapy. Receiver operating characteristic analysis was used to set cut-off points for the week 30 trough serum infliximab concentration (SIC30) and percentage change, from baseline, in the C-reactive protein (CRP) level at week 26, to predict CSFR50. Univariate and multivariate procedures analyzed predictive parameters of CSFR50 (odds ratio [OR] and 95% confidence interval [CI]). Mucosal healing (MH, zero ulcers) and CRP normalization (<8.0 mg/L) also were assessed.Trough SIC30 was higher in patients with than without CSFR50. Patients given combination therapy had higher trough SIC30s than those given monotherapy. Median trough SIC30 was significantly higher in patients with than without CSFR50 among those on infliximab monotherapy (2.14 vs 0.80 μg/mL; P = .006), but not for those on combination therapy (3.56 vs 3.54 μg/mL; P=.31). In patients with increased baseline levels of CRP (n = 120), corticosteroid-free remission at week 26 (CSFR26) (OR, 4.09; 95% CI, 1.65-10.11), and trough SIC30s of 3.0 μg/mL or greater (OR, 3.20; 95% CI, 1.38-7.42) were associated significantly with CSFR50. In patients evaluable for MH (n = 123), trough SIC30s of 3.0 μg/mL or greater (OR, 3.34; 95% CI, 1.53-7.28) and CRP normalization (OR, 2.69; 95% CI, 1.10-6.54) were associated significantly with MH at week 26 (MH26). Furthermore, CSFR26 (OR, 4.43; 95% CI, 1.81-10.82) and MH26 (OR, 3.01; 95% CI, 1.33-6.81) were associated significantly with CSFR50.Trough SIC30 is associated positively with MH26; CSFR26 and MH26 are independent predictors of CSFR50. Trough SIC30 of 3.0 μg/mL or greater early during maintenance treatment is an important determinant of clinical and endoscopic Crohn's disease outcomes. ClinicalTrials.gov number, NCT00094458.