tbuckley/cabot-search huggingface dataset:
Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer
Authors: R Jover
Journal: Gut (2005)

<b>Aim:</b> Some retrospective studies have shown a lack of benefit of 5-fluorouracil (5-FU) adjuvant chemotherapy in patients with mismatch repair (MMR) deficient colorectal cancer. Our aim was to assess if this molecular marker can predict benefit from 5-FU adjuvant chemotherapy. A second objective was to determine if MMR status influences short term survival. <b>Methods:</b> We included 754 patients with a median follow up of 728.5 days (range 1–1097). A total of 260 patients with stage II or III tumours received 5-FU adjuvant chemotherapy, according to standard clinical criteria and irrespective of their MMR status. A tumour was considered MMR deficient when either BAT-26 showed instability or there was loss of MLH1 or MSH2 protein expression. <b>Results:</b> At the end of the follow up period, 206 patients died and 120 presented with tumour recurrence. Sixty six (8.8%) patients had MMR deficient tumours. There were no significant differences in overall survival (MMR competent 72.1%; MMR deficient 78.8%; p = 0.3) or disease free survival (MMR competent 61.3%; MMR deficient 72.3%; p = 0.08). In patients with stage II and III tumours, benefit from 5-FU adjuvant chemotherapy was restricted to patients with MMR competent tumours (overall survival: chemotherapy 87.1%; non-chemotherapy 73.5%; log rank, p = 0.00001). Patients with MMR deficient tumours did not benefit from adjuvant chemotherapy (overall survival: chemotherapy 89.5%; non-chemotherapy 82.4%; log rank, p = 0.4). <b>Conclusions:</b> Benefit from 5-FU adjuvant chemotherapy depends on the MMR status of tumours in patients with colorectal cancer. 5-FU adjuvant chemotherapy improves survival in patients with MMR competent tumours but this benefit from chemotherapy cannot be extended to patients with MMR deficient tumours.
Infections and Airway Inflammation in Chronic Obstructive Pulmonary Disease Severe Exacerbations
Authors: Alberto Papi, Cinzia Maria Bellettato, Fausto Braccioni, Micaela Romagnoli, Paolo Casolari, Gaetano Caramori, Leonardo M. Fabbri, Sebastian L. Johnston
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial.We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation.We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection.Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% when stable, p = 0.08). Patients with infectious exacerbations (29.7% bacterial, 23.4% viral, 25% viral/bacterial coinfection) had longer hospitalizations (p < 0.02) and greater impairment of several measures of lung function (all p < 0.05) than those with noninfectious exacerbations. Patients with exacerbations with coinfection had more marked lung function impairment (p < 0.02) and longer hospitalizations (p = 0.001). Sputum neutrophils were increased in all exacerbations (p < 0.001) and were related to their severity (p < 0.001), independently of the association with viral or bacterial infections; sputum eosinophils were increased during (p < 0.001) virus-associated exacerbations.Respiratory infections are associated with the majority of COPD exacerbations and their severity, especially those with viral/bacterial coinfection. Airway neutrophilia is related to exacerbation severity regardless of viral and/or bacterial infections. Eosinophilia is a good predictor of viral exacerbations.
Extrapolation from incomplete data to total or lifetime risks at low doses.
Authors: M A Schneiderman
Journal: Environmental Health Perspectives (1981)

Both epidemiology and laboratory data can contribute to estimates of risks to humans of exposure to low doses of carcinogens. The sum of all these contributions does not permit us to make these estimates with certainty. In chronic disease epidemiology, in looking for possible excessive cancer risks, we sometimes fail to have an adequately long observation time or to observe a population sufficiently aged for cancers to appear in meaningful numbers. In studies of most human exposures, dose data are often lacking, beyond a vague "yes-no" or "lots, not much, hardly any." Thus, without a knowledge of what dose produced an observed result it becomes logically impossible to know what result some other (presumed) dose might yield. Animal data show some promise of being useful in extrapolating to low doses in man. However, several problems exist: (a) man is not a tailless, two-legged mouse, or featherless chicken--that is, we do not know if man is more or less sensitive than the laboratory animal; (b) the mathematical model used for extrapolation leads to large differences in estimates of response; (c) man is genetically heterogeneous and is usually exposed to many more hazards than is the laboratory animal. Thus, existing data, even from well-done studies, are inadequate if we want to make extrapolations in any detail or to apply to specific subgroups in the population. Any risk estimation we do may have to be stated in terms that point out the wide ranges of the estimates.
Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Heart Disease
Authors: Ann Marie Navar-Boggan, Eric D. Peterson, Ralph B. D’Agostino, Benjamin Neely, Allan D. Sniderman, Michael J. Pencina
Journal: Circulation (2015)

Background— Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk. Methods and Results— We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non–high-density lipoprotein cholesterol≥160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure ( P &lt;0.001); this association persisted after adjustment for other cardiac risk factors including non–high-density lipoprotein cholesterol at 55 years of age (hazard ratio, 1.39; 95% confidence interval, 1.05–1.85 per decade of hyperlipidemia). Overall, 85% of young adults with prolonged hyperlipidemia would not have been recommended for statin therapy at 40 years of age under current national guidelines. However, among those not considered statin therapy candidates at 55 years of age, there remained a significant association between cumulative exposure to hyperlipidemia in young adulthood and subsequent CHD risk (adjusted hazard ratio, 1.67; 95% confidence interval, 1.06–2.64). Conclusions— Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non–high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.
Antibodies to Merkel Cell Polyomavirus T Antigen Oncoproteins Reflect Tumor Burden in Merkel Cell Carcinoma Patients
Authors: Kelly G. Paulson, Joseph J. Carter, Lisa G. Johnson, Kevin W. Cahill, Jayasri G. Iyer, David Schrama, Juergen C. Becker, Margaret M. Madeleine, Paul Nghiem, Denise A. Galloway
Journal: Cancer Research (2010)

Merkel cell polyomavirus (MCPyV) is a common infectious agent that is likely involved in the etiology of most Merkel cell carcinomas (MCC). Serum antibodies recognizing the MCPyV capsid protein VP1 are detectable at high titer in nearly all MCC patients and remain stable over time. Although antibodies to the viral capsid indicate prior MCPyV infection, they provide limited clinical insight into MCC because they are also detected in more than half of the general population. We investigated whether antibodies recognizing MCPyV large and small tumor-associated antigens (T-Ag) would be more specifically associated with MCC. Among 530 population control subjects, these antibodies were present in only 0.9% and were of low titer. In contrast, among 205 MCC cases, 40.5% had serum IgG antibodies that recognize a portion of T-Ag shared between small and large T-Ags. Among cases, titers of T-Ag antibodies fell rapidly (∼8-fold per year) in patients whose cancer did not recur, whereas they rose rapidly in those with progressive disease. Importantly, in several patients who developed metastases, the rise in T-Ag titer preceded clinical detection of disease spread. These results suggest that antibodies recognizing T-Ag are relatively specifically associated with MCC, do not effectively protect against disease progression, and may serve as a clinically useful indicator of disease status.
The Inositol Polyphosphate 5-Phosphatase Ship Is a Crucial Negative Regulator of B Cell Antigen Receptor Signaling
Authors: Qiurong Liu, Antonio J. Oliveira-Dos-Santos, Sanjeev Mariathasan, Denis Bouchard, Jamie Jones, Renu Sarao, Ivona Kozieradzki, Pamela S. Ohashi, Josef M. Penninger, Daniel J. Dumont
Journal: The Journal of Experimental Medicine (1998)

Ship is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fcgamma receptor IIB (FcgammaRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-FcgammaRIIB coligation. The function of Ship in lymphocytes was investigated in Ship-/- recombination-activating gene (Rag)-/- chimeric mice generated from gene-targeted Ship-/- embryonic stem cells. Ship-/-Rag-/- chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship-/- splenic B cells displayed prolonged Ca2+ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-FcgammaRIIB coligation. These results demonstrate that Ship plays an essential role in FcgammaRIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca2+ flux and MAPK activation.
The Cost-Effectiveness of Treating All Patients with Type 2 Diabetes with Angiotensin-Converting Enzyme Inhibitors
Authors: Lubor Golan, John D. Birkmeyer, H. Gilbert Welch
Journal: Annals of Internal Medicine (1999)

Background: Although guidelines recommend angiotensin-converting enzyme inhibitors for diabetic patients with microalbuminuria, this strategy requires that providers adhere to screening recommendations. In addition, the benefit of angiotensin-converting enzyme inhibitors in normoalbuminuric patients was recently demonstrated. Objective: To evaluate the cost-effectiveness of treating all patients with type 2 diabetes. Design: Markov model simulating the progression of diabetic nephropathy. Data Sources: Randomized trials estimating the progression of diabetic nephropathy with and without angiotensin-converting enzyme inhibitors. Target Population: Patients 50 years of age with newly diagnosed type 2 diabetes (fasting plasma glucose level ≥ 7.8 mmol/L [140 mg/dL]). Time Horizon: Lifetime. Perspective: Societal. Interventions: Patients received angiotensin-converting enzyme inhibitors, screening for microalbuminuria, or screening for gross proteinuria. Outcome Measures: Lifetime cost, quality-adjusted life expectancy, and marginal cost-effectiveness. Results of Base-Case Analysis: Screening for gross proteinuria had the highest cost and the lowest benefit. Compared with screening for microalbuminuria, treating all patients was more expensive ($15 240 and $14 940 per patient) but was associated with increased quality-adjusted life expectancy (11.82 and 11.78 quality-adjusted life-years). The marginal cost-effectiveness ratio was $7500 per quality-adjusted life-year gained. Results of Sensitivity Analysis: Results were sensitive to the cost, effectiveness, and quality of life associated with angiotensin-converting enzyme inhibitor therapy, as well as age at diagnosis. The model was relatively insensitive to adherence with screening and costs of treating end-stage renal disease. Conclusions: Treating all middle-aged diabetic patients with angiotensin-converting enzyme inhibitors is a simple strategy that provides additional benefit at modest additional cost. The strategy assumes that patients meet the older diagnostic criteria for diabetes and makes sense only for those who are not bothered by treatment.
Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells <i>In Vitro</i> and <i>In Vivo</i> and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival
Authors: H. Artee Luchman, Owen D.M. Stechishin, Stephanie A. Nguyen, Xueqing Q. Lun, J. Gregory Cairncross, Samuel Weiss
Journal: Clinical Cancer Research (2014)

The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor-initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ) EXPERIMENTAL DESIGN: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan-Meier survival studies were performed with AZD8055 and in combination with TMZ.We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival.These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs.
Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy
Authors: Zully Pedrozo, Natalia Torrealba, Carolina Fernández, Damian Gatica, Barbra Toro, Clara Quiroga, Andrea E. Rodriguez, Gina Sanchez, Thomas G. Gillette, Joseph A. Hill, Paulina Donoso, Sergio Lavandero
Journal: Cardiovascular Research (2013)

Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ. These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy result in Danon disease characterized by hypertrophic cardiomyopathy. The ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte excitation-contraction and its dysfunction can lead to cardiac failure. Whether RyR2 is degraded by CMA is unknown.To induce CMA, cultured neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote protein degradation through this pathway. GA increased LAMP-2A levels together with its redistribution and colocalization with Hsc70 in the perinuclear region, changes indicative of CMA activation. The inhibition of lysosomes but not proteasomes prevented the loss of RyR2. The recovery of RyR2 content after incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ motifs which are required for the recognition Hsc70 and its degradation via CMA. Our data suggest that presenilins are involved in RyR2 degradation by CMA.These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.
M13 Outpatient ultrasound-guided fine-needle aspiration of supraclavicular lymph nodes, performed by chest physicians for diagnosis and staging of lung cancer
Authors: R Ahmed, MG Slade
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> Supraclavicular fossa (SCF) lymph node metastases are detectable in almost half of lung cancer patients where mediastinal lymphadenopathy is present (1). They represent N3 disease, not amenable to radical treatment. Ultrasound guided fine needle aspiration cytology (US-FNAC) is a sensitive test in this setting. We explored the accuracy of outpatient US-FNAC of SCF nodes performed by respiratory physicians. <h3>Methods</h3> Outpatients with suspected lung cancer were selected for US guided FNAC of SCF lymph nodes if they had one or more of: 1. Enlarged SCF lymph nodes on CT scanning 2. Palpable supraclavicular lymph nodes 3. Visible non-enlarged SCF lymph nodes on CT with associated mediastinal lymphadenopathy. After informed consent, the SCF was scanned with the patient semi-recumbent, using a Sonosite US with 13.6MHz linear probe, by MGS, or RA supervised by MGS, a level-2 non-radiologist US practitioner. Real-time US-FNAC was performed using a 21G or 19G needle and the capillary aspiration technique. Three passes were made and cores were put into a cytology fixative (Cytolyt). <h3>Results</h3> 14 patients (male = 8, median age 67.5 years) underwent US-FNAC. The median short-axis diameter of the target node was 11.5 mm (range 5–25 mm). A positive malignant diagnosis was obtained in 11/14 patients (78.6%), (adenocarcinoma n = 6, small cell lung cancer n = 4, non-small cell lung cancer n = 1), and all four sub-centimetre nodes gave positive results. There were two false-negatives (14.3%) on an intention-to-diagnose basis, in one of whom no specimen could be obtained. One sample was non-diagnostic. All patients found the procedure easy to tolerate and there were no complications. <h3>Discussion</h3> US-FNAC is well tolerated and can be safely performed opportunistically by respiratory physicians during outpatient visits. The diagnostic yield is high and comparable with previous published series. Its incorporation into the lung cancer pathway can facilitate prompt diagnosis and staging without more invasive investigations. <h3>Reference</h3> Fultz PJ, Feins RH, Strang JG <i>et al.</i> Detection and diagnosis of nonpalpable supraclavicular lymph nodes in lung cancer at CT and US. <i>Radiology </i>2002;<b>222</b>:245–51.
Characteristics and Short-Term Prognosis of Perioperative Myocardial Infarction in Patients Undergoing Noncardiac Surgery
Authors: P.J. Devereaux
Journal: Annals of Internal Medicine (2011)

Background: Each year, millions of patients worldwide have a perioperative myocardial infarction (MI) after noncardiac surgery. Objective: To examine the characteristics and short-term outcome of perioperative MI. Design: Cohort study. (ClinicalTrials.gov registration number: NCT00182039) Setting: 190 centers in 23 countries. Patients: 8351 patients included in the POISE (PeriOperative ISchemic Evaluation) trial. Measurements: Four cardiac biomarker or enzyme assays were measured within 3 days of surgery. The definition of perioperative MI included either autopsy findings of acute MI or an elevated level of a cardiac biomarker or enzyme and at least 1 of the following defining features: ischemic symptoms, development of pathologic Q waves, ischemic changes on electrocardiography, coronary artery intervention, or cardiac imaging evidence of MI. Results: Within 30 days of random assignment, 415 patients (5.0%) had a perioperative MI. Most MIs (74.1%) occurred within 48 hours of surgery; 65.3% of patients did not experience ischemic symptoms. The 30-day mortality rate was 11.6% (48 of 415 patients) among patients who had a perioperative MI and 2.2% (178 of 7936 patients) among those who did not (P < 0.001). Among patients with a perioperative MI, mortality rates were elevated and similar between those with (9.7%; adjusted odds ratio, 4.76 [95% CI, 2.68 to 8.43]) and without (12.5%; adjusted odds ratio, 4.00 [CI, 2.65 to 6.06]) ischemic symptoms. Limitation: Cardiac markers were measured only until day 3 after surgery, and additional asymptomatic MIs may have been missed. Conclusion: Most patients with a perioperative MI will not experience ischemic symptoms. Data suggest that routine monitoring of troponin levels in at-risk patients is needed after surgery to detect most MIs, which have an equally poor prognosis regardless of whether they are symptomatic or asymptomatic. Primary Funding Source: Canadian Institutes of Health Research.
Minimum skills required by children to complete health-related quality of life instruments for asthma: comparison of measurement properties
Authors: EF Juniper, GH Guyatt, DH Feeny, LE Griffith, PJ Ferrie
Journal: European Respiratory Journal (1997)

To gain a complete picture of a child's health-status, measurement of health-related quality of life (HRQL) is necessary. Since parents do not accurately perceive children's HRQL, information must be obtained from the children themselves. The aim of this study was to determine the minimum age and reading skills required by children to complete competently the Paediatric Asthma Quality of Life Questionnaire (PAQLQ), the Health Utilities Index (HUI), the Feeling Thermometer and the Standard Gamble, and to evaluate the validity of each for measuring HRQL in children with asthma. Fifty two children (age 7-17 yrs) with symptomatic asthma participated in a 9 week single cohort study with HRQL and clinical asthma control assessed every 4 weeks. All children provided very reliable data for the PAQLQ and the HUI but they needed &gt; or = grade 6 reading skills to complete the Standard Gamble and &gt; or = grade 2 skills for the Feeling Thermometer. In those children who were able to provide reliable data, the PAQLQ had the best discriminative and evaluative measurement properties, followed closely by the Feeling Thermometer. Measurement properties in the Standard Gamble were weaker and although the HUI was very reliable it was not actually measuring asthma-specific HRQL. The Paediatric Asthma Quality of Life Questionnaire may be used with confidence in clinical studies and practice to provide a profile of children's day-to-day experiences. In those children with adequate skills to complete the test reliably, the Feeling Thermometer provides a good estimate of the value that children place on their asthma health status.