tbuckley/cabot-search huggingface dataset:
Abstract 311: Early Evaluation Biomarkers-Based of Neurological Prognosis in Hypothermic Post--Cardiac Arrest Patients
Authors: Luisa Cacciavillani, Nicola Gasparetto, Daniele Scarpa, Monica Mion, Luca Brugnaro, Armando Marzari, Martina Zaninotto, Chiara Salotti, Mario Plebani, Sabino Iliceto
Journal: Circulation (2012)

Early prognosis of neurological outcome in patients resuscitated from cardiac arrest (CA) is a major medical challenge. High serum levels of both serum neuron-specific enolase (NSE) and S-100B protein are related with brain damage, but the relationship with neurological outcome at hospital discharge, in hypothermic post CA patients, is uncertain. The aim of this study was to evaluate the prognostic value and cut-off values of NSE and S-100B protein in predicting neurological outcome in comatose patients after CA treated with therapeutic hypothermia (TH). Methods: We enrolled consecutive patients, between November 2010 and May 2012. NSE and S-100B values were sampled at admission and every 24 hours since discharge from intensive care unit. According to Cerebral Performance Category (CPC) scale, neurological outcome was dichotomized into good (CPC 1-2) or poor (CPC 3-5). Results: thirty-one patients (25 males; mean age 60±15years). Twenty patients had a favourable outcome. Median values of serum NSE peak and S-100B peak were 25 ug/L (interquartile range, 20.8 to 43.3 ug/L) and 0.3 ug/L (range, 0.15 to 0.7 ug/L) respectively. High peak values of NSE and S-100B were significantly associated with poor neurological outcome (p=0.015 and p=0.007 respectively). Using a regression tree model we found worst neurological recovery for NSE peak value above 64.7 ug/L or S-100B above 0.65 ug/L (p=0.01 and p=0.007 respectively). Good neurological outcome was associated with NSE peak value less than 40.5 ug/L (p=0.012) especially if S-100B was less than 0.23 ug/L (p=0.031) (figure). Conclusion: Serum peak concentrations of NSE and S-100B result to be highly predictive of neurological outcome, especially when combined. Moreover, our data demonstrate that a good neurological outcome is associated with NSE peak value minor than 40.5 ug/L especially with S-100B minor than 0.23 ug/L. On this basis, determination of NSE and S-100B peak values may be useful in the early evaluation of prognostic neurological outcome to guide clinical decision making, in hypothermic post CA patients.
Systematic review of trials comparing antibiotic with placebo for acute cough in adults
Authors: C J Cates, T. P Shakespeare, R. C Bourke, J. Harris, T. Fahey, N. Stocks
Journal: BMJ (1998)

Further studies of heroin treatment are neededEditor-On the basis of a trial in Switzerland, 1 Farrell and Hall conclude that medically prescribed heroin is likely to have only a limited role in the future. 2 It is hard to know how any judgment can be made about this approach after only one randomised control trial, 3 one case-control study, 4 and the large but uncontrolled study that the authors commented on. 1 Farrell and Hall are right to emphasise the difficulty of disentangling the contribution of comprehensive social and psychological inventions in the impressive results obtained in this population. 1After more than three decades of research evaluating the effectiveness of methadone maintenance treatment it is safe to conclude that such interventions improve outcomes but difficult to be much more precise than this.Social and psychological interventions probably improve results of virtually all interactions between patients and the healthcare system.The authors say that the proposal to conduct a heroin trial in Australia damaged support for harm reduction.This is arguable.The mood in Australia has generally been more conservative over the past two years.The controversy over the heroin trial in Australia probably contributed to major improvements in a local methadone programme and certainly led directly to a commitment and funding for research on an expanded range of pharmacological treatments for heroin dependence.The authors question whether Australia is in the middle of a national heroin crisis.If a sixfold increase in mortality from drug overdose during the past 16 years 5 is not a crisis it is hard to know what would be.The Swiss heroin trial may have been more expensive than routine prescription methadone.But trials of new treatment are invariably more costly than providing well established treatments as a routine.Heroin
OC-007 Oxidative Stress Rather than Triglyceride Accumulation Perturbs Glutathione Metabolism in an in Vitro Model of Cellular Steatosis
Authors: K A Lockman, L J Nelson, J R Manning, K E Burgess, S F Martin, T Le Bihan, D R Dunbar, S D Morley, P C Hayes, J N Plevris
Journal: Gut (2013)

<h3>Introduction</h3> Oxidative stress is the central to molecular events leading to the progression of simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that an <i>in vitro</i> cellular steatosis model using C3A cells treated with energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N), recapitulates the sequence of events in dietary-induced NAFLD; namely enhanced acute respiration and reactive oxygen species (ROS) formation leading to mitochondrial impairment. In contrast, treatment with oleate results in similar triglyceride accumulation but with relatively low ROS. Using a combined microarray, proteomic and metabolomic approach, we aimed to explore how triglyceride accumulation and enhanced ROS affect glutathione metabolism in our <i>in vitro</i> cell model. <h3>Methods</h3> C3A cells were treated with either LPON or oleate for 72 hours. Microarray RNA expression was measured using Illumina® Whole Human Genome BeadChip H12 Microarray. For proteomics, peptides were analysed by liquid chromatography (LC) coupled mass spectrometry (MS) (Agilent HPLC/OrbitrapXL). Data were quantified label-free using Progenesis LC-MS and MASCOT. For metabolomics, LC separation was performed using hydrophilic interaction chromatography with a ZIC–HILIC. MS was performed using Orbitrap Exactive with HESI 2 probe. Raw LC/MS data were processed with XCMS Centwave and mzMatch. <h3>Results</h3> LPON led to 2-fold downregulation of GCLC (encodes glutamate-cysteine ligase catalytic subunit, the rate limiting enzyme for glutathione synthesis) and upregulation of GPX1 and TXNDC12. Expression of GCLC and TXNDC12 was unchanged with oleate. Metabolomics confirmed that oxidised glutathione, glutathione disulfide, was higher in LPON- than oleate-treated cells. Among glutathione <i>S</i>-transferase genes, GSTA1 was unchanged with oleate but was upregulated by LPON (2.4-fold). Similarly, GSTT1, GSTK1 and GSTO1 were significantly increased by LPON. In contrast, MGST2 expression was higher in oleate than LPON-treated cells. Finally, proteomics showed that microsomal glutathione <i>S</i>-transferase 2 was downregulated by 2.5-fold by LPON. <h3>Conclusion</h3> Our data show that increased ROS formation rather than triglyceride accumulation alters glutathione metabolism. Such alterations may influence susceptibility to further insults, particularly those accelerating glutathione depletion, for example, paracetamol overdose. <h3>Disclosure of Interest</h3> None Declared
Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152
Authors: J. H. Schellens, D. Boss, P. O. Witteveen, A. Zandvliet, J. H. Beijnen, M. Voogel-Fuchs, C. Morris, D. Wilson, E. E. Voest
Journal: Journal of Clinical Oncology (2006)

3008 Background: AZD1152 is a specific aurora kinase inhibitor, selective for Aurora B, currently undergoing Phase I evaluation in patients with advanced solid malignancies. AZD1152 induces p53 independent cellular multinucleation and polyploidy, resulting in apoptosis. It is rapidly converted to the active moiety (AZD1152-HQPA) in plasma. This is the first human study, aimed at determining the maximum tolerated dose, dose limiting toxicities (DLT), pharmacokinetic profile (PK), and to recommend a dose and schedule for further clinical evaluation. Methods: AZD1152 is being administered as a 2-hour IV infusion given weekly in a dose-escalating manner, utilizing an accelerated titration design in patients for whom no other therapy of proven benefit exists. Patients with WHO-PS of 0-2 and adequate bone marrow, liver and renal function were eligible. Results: To date, a total of 13 patients have been recruited: 10M/3F, median age 58 yrs (range 52–71). Patients had colon cancer (n = 3), melanoma (n = 2), or various other solid tumors. Doses were escalated from 100 mg to 200, 300 and 450 mg. DLT was CTC grade 4 neutropenia in 3 patients at 450 mg, signifying a non-tolerated dose on this schedule. Bone marrow recovery was generally noted by 2 wks post-dose. Problematic non-hematological toxicities have not been reported to date. Five patients have remained on therapy for &gt;12 wks (2 × 12+ wks, 16+ wks, 20+ wks and 28+ wks, respectively). AZD1152 is rapidly converted to AZD1152-HQPA with an apparent dose proportional increase in the systemic exposures of both. Population PK analysis of AZD1152-HQPA in the first eight patients revealed a linear three compartment model with clearance 22.4 ± 1.03 L/h. Interoccasion variability was low (CV 5.7%). Conclusions: To date, AZD1152 has been well tolerated when administered IV over 2 hours on a weekly schedule at doses up to 300 mg, however further patients are being enrolled to confirm. Neutropenia is the DLT at 450 mg and no other clinically significant toxicities have been reported. Both AZD1152 and AZD1152-HQPA appeared to have linear kinetics. Significant disease stabilization observed in this rapidly progressive disease setting supports continued clinical development. [Table: see text]
Abstract 19362: Bridging the Gap Between Functional and Biological Phenotypes in Pediatric Pulmonary Hypertension
Authors: Vitaly O Kheyfets, Jamie Dunning, Ivy Dunbar, Kendall Hunter, Uyen Troung, Robin Shandas
Journal: Circulation (2014)

Introduction: Pediatric Pulmonary Hypertension (PH) is a degenerative disease that ultimately leads to Right Ventricular (RV) dysfunction. RV functional and biological (e.g. N-Terminal proB-type Natriuretic Peptide, NT-proBNP) phenotypes can provide insight into performance and ventricular distress, respectively. Nevertheless, they are normally considered independently, and should be associated to paint a more comprehensive picture of the cardio-pulmonary system. The most utilized prognostic metric of RV performance is Cardiac Output (CO), as it gives a direct measure of the ventricle’s “pumping” ability. CO is only indicative of the immediate functional state and lacks any predictive or stratification value. RV-Pulmonary Artery (PA) axis decoupling (VVC = RV end-systolic elastance/arterial elastance) represents a decrease in the RV functional reserve, and therefore an inability to accommodate an increase in afterload. Therefore, it is more comprehensive of the entire cardio-pulmonary system than CO. Hypothesis: RV-PA coupling is better associated with NT-proBNP than Cardiac Index (CI = CO/Body Surface Area). Methods: 26 pediatric PH patients underwent Right Heart Catheterization (RHC), an echocardiograph, and blood composition diagnostics. A 0-D model (Fig. 1a) of the comprehensive cardio-pulmonary system, incorporating extensive patient specificity, was developed to estimate RV pressure-volume curves under baseline and challenged conditions, and approximate the VVC ratio. Results: CI was not found to be statistically associated with NT-proBNP (Fig. 1b). Nevertheless, VVC was found to be non-linearly related to NT-proBNP expression (Fig. 1c), thus rejecting the null hypothesis . Conclusion: NT-proBNP is a biomarker of RV-PA functional decoupling. Considering the inter-compartmental interaction of the entire cardio-pulmonary system offers a better picture of PH disease progression then assessing RV “pump” performance.
Single, low dose treatment of lymphoma and renal cancer xenografts with human anti-CD70 antibody-toxin conjugates, results in long term cures
Authors: Jonathan Terrett, Sanjeev Gangwar, Chetana Rao-Naik, Chin Pan, Vincent Guerlavais, Mary Huber, Colin Chong, Lynae Green, Pina Cardarelli, David King, Shrikant Deshpande, Vangipuram Rangan, Marco Coccia, Lisheng Lu, David Passmore, Diann Blansett, Rory Dai, Bilal Sufi, Qian Zhang, Liang Chen, Carol Soderberg, Eilene Kwok, Killian Horgan, Orville Cortez, Peter Sattari
Journal: Cancer Research (2007)

4112   CD70 is highly expressed in multiple tumor types including many lymphomas and clear cell renal carcinomas. The expression in lymphomas is not surprising given the role of CD70 in B and T cell activation. However, expression of CD70 at high levels and very high prevalence in renal cancer was initially unexpected. The tightly controlled and limited expression in normal tissues, together with this high level tumor expression makes CD70 an extremely attractive target for antibody-directed therapy. In order to exploit this specificity we have isolated and characterized a human anti-CD70 antibody of high affinity and specificity from transgenic mice. This antibody has been conjugated to highly potent DNA alkylating agents via hydrazone and amino acid based linkers. The resulting CD70 targeted antibody-drug conjugates show potent and curative anti-tumor activity at low doses; highly specific antigen targeting activity (as shown by comparing CD70 antibody conjugates with isotype control conjugates  in vivo ), and an extremely wide therapeutic window in both lymphoma and renal cancer models. Furthermore, these CD70 antibody drug conjugates are demonstrating favorable toxicity profiles in larger animals at levels far in excess of the xenograft model determined efficacious doses.
Endoscopic Sleeve Gastroplasty Alters Gastric Physiology and Induces Loss of Body Weight in Obese Individuals
Authors: Barham K. Abu Dayyeh, Andres Acosta, Michael Camilleri, Manpreet S. Mundi, Elizabeth Rajan, Mark D. Topazian, Christopher J. Gostout
Journal: Clinical Gastroenterology and Hepatology (2015)
Prognostic significance of the number of tumor (+) N2 nodes in N2 stage IIIA non-small cell lung cancer after curative resection.
Authors: C. Yoo, S. Yoon, D. Lee, C. Suh, J. Lee, S. Park, D. Kim, Y. Kim, W. Kim, S. Kim
Journal: Journal of Clinical Oncology (2010)

7023 Background: N2 stage IIIA non-small cell lung cancer (NSCLC) has heterogeneous prognosis. Further prognostic stratification may help to improve the management of patients in this category. We investigated the prognostic value of the number of positive N2 lymph nodes in patients who were registered as pathologic N2-stage IIIA NSCLC in our institution. Methods: From January 1997 to December 2004, 250 patients were classified as pathologic N2 stage IIIA after curative resection with mediastinal lymph node dissection. With exclusion of 44 patients with previous induction chemotherapy, incomplete resection, and post-surgical mortality, 206 patients were included. Patients were grouped by the number of positive N2 lymph nodes (1 vs 2-5 vs ≥6) and analyzed for survival outcomes. Results: The median age was 59 years old and 145 (70.4%) patients were male. Pneumonectomy was undergone in 43 (21%) patients, and lobectomy or bilobectomy was in 163 (79%) patients. Of 178 (86%) patients who were given adjuvant therapy, 59 (33%) patients received only radiotherapy and 119 (67%) patients had both chemotherapy and radiotherapy. With a median follow-up of 41.3 months, 5-year disease-free survival (DFS) was 27.2% (95% CI, 21.6-33.7) and 5-year overall survival (OS) was 37.7% (31.5-44.7). Seventy-nine (38%) patients had 1 (N2a) positive N2 lymph node, and 95 (46%) and 32 (16%) had 2-5 (N2b) and 6 or more (N2c), respectively. The number of positive N2 lymph nodes was associated with DFS (p=0.005) and OS (p=0.024). The 5-year DFS were 37%, 22%, and 9% and 5-year OS were 47%, 35%, and 25% in N2a, N2b, and N2c, respectively. A multivariate analysis including age, sex, weight loss, pathologic T stage, and adjuvant therapy identified the number of positive N2 lymph nodes was an independent prognostic factor. Hazard ratios (95% CI) of N2b and N2c with respect to N2a were 1.52 (1.07-2.17) and 2.32 (1.44-3.74) for DFS, and 1.77 (1.22-2.58) and 1.91 (1.17-3.14) for OS, respectively. Conclusions: The number of positive N2 lymph nodes was an independent prognostic factor in patients with completely resected N2-stage IIIA NSCLC. It might be considered in the future staging system. No significant financial relationships to disclose.
Utilization and clinical practice impact of an interactive tool for guiding choice of systemic adjuvant treatment (adj TX) for patients with early breast cancer (EBC).
Authors: P. Ravdin, S. Martino, M. D. Pegram, N. J. Robert, S. M. Swain, D. Janssen, A. Bowser, J. A. Mortimer, R. W. Carlson
Journal: Journal of Clinical Oncology (2011)

6063 Background: Guidelines list more than 20 regimens as options for adjuvant breast cancer treatment. Adjuvant!Online provides risk assessment based on patient characteristics and expected risk reduction, but lacks guidance on specific treatment choice. An online tool was developed to provide expert guidance in choice of adj TX for EBC. Methods: Six experts made first and second treatment recommendations for 864 patient case variations based on age, menopausal status, nodes, tumor grade/size, and receptor status (HR, HER2). Their choices were incorporated into an interactive decision support tool. Users of the tool entered specific patient characteristics and their own choice of therapy; then, expert recommendations were displayed for a patient case variation matching the user’s case, and users were asked if those recommendations impacted their treatment decision. Expert and participant responses were analyzed. Results: In cases needing adj TX, experts all chose tamoxifen for premenopausal HR+, AI for postmenopausal HR+ cases, and a trastuzumab-containing regimen for HER2+ cases. Experts varied in their choice of chemotx in HER2- (AC-P wkly, 37%; DCx4, 30%; DAC, 21%; AC-P dd, 8%; and CMF, 4%) and HER2+ cases (DCbH, 64%; AC-PH, 34%; and other-H, 3%). More than 2000 users accessed the tool, including 1043 physicians. When prompted, “Did the tool impact your adjuvant treatment decision?” 65% of physicians (n = 669) said “yes” for at least one case. Cases entered by users appear to reflect incidence of patient types in the general population. Participants’ initial treatment choices included some regimens never selected by experts with a different frequency for chemotx in HER2- (AC-P q3wk, 20%; DC, 17%; AC, 16%; AC-P wkly, 12%; FEC, 8%; CMF, 7%; FEC-D, 6%; AC-P dd, 5%; DAC, 3%; AC-D, 3%) and trastuzumab+chemo in HER2+ (AC-PH, 38%; DCbH, 27%; other-H, 17%; AC-DH, 14%; and DH-FEC, 3%). Detailed analysis by specific characteristics will be presented. Conclusions: Tools that provide expert guidance on adjuvant treatment of breast cancer may impact clinicians’ treatment decisions and improve patient care. Supported by education grants from Genentech and Pfizer.
Looking to possible predictive factors of primary resistance to abiraterone acetate (AA) and enzalutamide (ENZ) in pretreated patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Orazio Caffo, Antonello Veccia, Francesca Maines, Alberto Bonetta, Gilbert Spizzo, Enzo Galligioni
Journal: Journal of Clinical Oncology (2014)

248 Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are new generation hormonal agents (NHA) which demonstrated a survival gain in patients (pts) with castration-resistant prostate cancer (CRPC) pre-treated with docetaxel. Although all patients eventually became resistant to these NHAs, some of them show primary resistance, defined as an early progression within the first 3 months, which leads to an early treatment interruption. In the present analysis we have tried to identify which factor, if any, may predict primary resistance to AA and ENZ. Methods: We evaluated a consecutive series of 57 pts, treated in our hospital in two successive named patient programs conducted in our hospital to allow pre-treated CRPC patients to receive NHAs before their approval in Italy: 26 received AA (1,000 mg po + prednisone 10 mg po daily) and 31 ENZ (160 mg po daily). For each pt we have recorded the pre- and post-NHA clinical history, the treatment details and outcomes. We have also assessed the ability of a series of 24 selected clinical factors to predict NHAs resistance, through a logistic regression analysis. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: Among the 24 factors, the presence of pain at baseline, high baseline lactate dehydrogenase levels and prostate-specific antigen (PSA) levels after one month of treatment were predictive of primary NHA resistance at the univariate analysis. However, only PSA levels were confirmed at the multivariate analysis [exp(beta) 0.115; p = 0.007], as patients failing to achieve a 50% or more reduction in baseline PSA levels, were more likely to show primary NHA resistance (48% vs. 15%). Conclusions: Our results suggest that PSA trend may represent a simple and rapid method of identifying patients with primary resistance to NHAs, so patients failing to achieve a 50% or more reduction within the first month of treatment should undergo intensive investigations, to verify whether they have primary resistance to NHAs. These data should be confirmed in a larger patient population.
Enhancement of Experimental Pancreatic Cancer in Syrian Golden Hamsters by Dietary Fat&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: D F Birt, S Salmasi, P M Pour
Journal: JNCI Journal of the National Cancer Institute (1981)

The effects of dietary fat on the induction and development of pancreatic ductular adenocarcinoma were studied in randombred Syrian golden hamsters. Diets containing low-fat (LF) or high-fat (HF) levels of corn oil [4.5 or 18.0 g/385 kilocalorie (kcal)], contributing 10 or 41% of the calories, respectively, were fed either before or after a single injection of N-nitrosobis(2-oxopropyl)amine (BOP) (10 mg/kg body wt). Control hamsters were fed corn oil at a medium-fat (MD) level (9 g/385 kcal) for life. The incidence of ductular adenocarcinomas increased in both males and females (LF diet, 16%; HF diet, 34%) when the HF diet was fed after BOP treatment. The average number of carcinomas per carcinoma-bearing animal also increased (LF diet, 1.3; HF diet, 3.0), but the carcinoma incidence was not influenced by these diets being fed before carcinogen treatment. The incidence of ductular adenomas was high with all treatments and was not influenced by diet. However, the number of adenomas was increased in animals fed HF diets. In addition, the incidence of acinar cell nodules was elevated in animals fed the MF and HF diets after BOP administration. These results showed that dietary fat modified the development of experimental ductular adenocarcinoma of the pancreas.