tbuckley/cabot-search huggingface dataset:
ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis
Authors: Abdo Mahli, Michael Saugspier, Andreas Koch, Judith Sommer, Peter Dietrich, Seren Lee, Reinhard Thasler, Jan Schulze-Luehrmann, Anja Luehrmann, Wolfgang Erwin Thasler, Martina Müller, Anja Bosserhoff, Claus Hellerbrand
Journal: Gut (2017)

<h3>Objective</h3> Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown. <h3>Design</h3> Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients. <h3>Results</h3> Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers. <h3>Conclusions</h3> Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.
P3.02c-083 Treatment Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center
Authors: Aaron Lisberg, D. Andrew Tucker, Jonathan W. Goldman, Brian Wolf, James Carroll, Ariana Hardy, Karolyn Morris, Paulina Linares, Carlos Adame, Marshall Spiegel, Courtney Wells, Jordan Mckenzie, Blanca Ledezma, Melody Mendenhall, Phillip Abarca, Krikor Bornazyan, Jamie Hunt, Sina Famenini, Jennifer Strunck
Journal: Journal of Thoracic Oncology (2017)
A High Number of Losses in 13q14 Chromosome Is Associated with a Worse Outcome and Biological Differences in Patients with B Chronic Lymphoid Leukemia.
Authors: José-Ángel Hernández, Ana-Eugenia Rodríguez, Marcos González, Rocío Benito, Celia Fontanillo, Virgilio Sandoval, Mercedes Romero, Guillermo Martín-Núñez, Alfonso García de Coca, Rosa Fisac, Josefina Galende, Isabel Recio, Francisco Ortuño, Juan-Luis García, Javier de las Rivas, Norma-Carmen Gutiérrez, Jesús-Maria Hernández, J.F. San Miguel
Journal: Blood (2008)
Reconstitution of Regulatory T Cells after Selective Depletion of CD25+ Host-Reactive Donor Lymphocytes from Allografts and Association with Acute Graft-Versus-Host-Disease.
Authors: Stephan Mielke, Katayoun Rezvani, Scott R. Solomon, Yasemin Kilical, Bipin N. Savani, Laura Wish, Charles S. Carter, John Schindler, Nancy Hensel, Roger Kurlander, Elizabeth J. Read, Ellen S. Vitetta, A. John Barrett
Journal: Blood (2005)
P290 Drug product performance after simulated patient handling of an inhalation powder using a lama/laba combination in a dry powder inhaler
Authors: J Plugge, U Basaldella, B Fyrnys, T Pieper
Journal: Thorax (2016)

<h3>Introduction</h3> Three studies simulating various patient handling effects were performed with aclidinium bromide 400 μg/formoterol fumarate dihydrate 12 μg inhalation powder in the Genuair™* inhaler. <h3>Methods</h3> Developmental batches representative for commercial production were used. Samples were tested before and after cleaning of the mouthpiece with a dry tissue, after dosing at various orientations (+45°/−45°) to the horizontal axis of the inhaler, or before and after dropping the inhaler in different orientations from a 1 m height. Test parameters included delivered dose uniformity (DDU) and fine particle dose (FPD). <h3>Results</h3> All results for the LAMA (aclidinium bromide) and LABA (formoterol fumarate dihydrate) active ingredients were within the expected ranges and well inside the acceptance criteria applied during development (Figure 1). For aclidinium bromide, DDU mean values between 388 and 424 µg (specification range 320–480 µg), and single values between 343 and 464 µg (not specified) were observed. Mean FPD was tested within 156 and 175 µg (specification range 120–200 µg), and FPD single values between 136 and 198 µg (not specified). Results for the LABA active ingredient, formoterol fumarate dihydrate, were between 11.7 and 12.8 µg for DDU mean values (specification range 9.6–14.4 µg) and between 9.6 and 13.8 µg for DDU single values (not specified). Mean FPD was observed within 3.1 and 3.5 µg (specification range 2.2–4.5 µg), and FPD single values between 2.6 and 4.0 µg (not specified). <h3>Conclusions</h3> The studies show that stable pharmaceutical quality can be guaranteed even if the device is used in different positions to the one explained in the patient information leaflet, after cleaning the mouthpiece, or after dropping the device in different orientations. *Registered trademark of AstraZeneca group of companies; for use within the USA as Pressair® and Genuair™ within all other licensed territories.
P3.02c-016 Efficacy of Bevacizumab Combined with Chemotherapy in Lung Adenocarcinoma-Induced Malignant Pleural Effusion
Authors: Hong Tao, Qiyi Meng, Zhe Liu, Mingzhi Li, Liang Shi, Junfang Tang, Liyan Xu
Journal: Journal of Thoracic Oncology (2017)
P1.08-032 Impact of the Oncogenic Status on the Mode of Recurrence in Resected Non-Small Cell Lung Cancer
Authors: Tetsuya Mizuno, Yasushi Yatabe, Shozo Sakata, Katsutoshi Seto, Hitoshi Dejima, Hiroaki Kuroda, Noriaki Sakakura, Yukinori Sakao
Journal: Journal of Thoracic Oncology (2017)
P261 Development of an extended specificity multiplex immunoassay using human monoclonal antibodies for detection of streptococcus pneumoniae serotype-specific antigen in urine
Authors: S Eletu, C Sheppard, E Thomas, K Smith, D Litt, N Fry
Journal: Thorax (2016)

<i>Streptococcus pneumoniae</i> (pneumococcus) is a major cause of morbidity and mortality worldwide. To date 93 capsular serotypes of pneumococcus have been described, but many of these are rarely found in disease. Currently vaccines are targeted at between 7 and 23 of the most common circulating serotypes. However, with the uptake of any pneumococcal serotype based vaccine the risk of serotype-replacement and an increase in disease caused by non-vaccine serotypes remains. This highlights the importance of determination of the serotype responsible for the infection. The diagnosis and subsequent serotype surveillance of pneumococcal infection relies heavily on culture techniques which are known to be insensitive, particularly in cases of non-invasive disease. There are, therefore, potentially many pneumococcal disease cases where an isolate for serotyping is never obtained. Urine antigen detection using methods such as BinaxNOW (Alere) can be used to confirm pneumococcal infection in the absence of an isolate, but does not give serotype information. Previously described serotype-specific urine assays covering mainly conjugate vaccine serotypes, give no/very little information about circulating non-vaccine serotypes and are currently only available in one or two specialist laboratories. Our laboratory has just completed initial development of an extended range antigen capture Luminex based assay to detect <i>S. pneumoniae</i> serotype specific antigen in urine samples using fully human human, full length monoclonal antibodies. The assay covers 24 different serotypes/groups plus C-polysaccharide, including all the currently available conjugate vaccine and 23-valent polysaccharide vaccine types plus some cross-reactive serotypes. We have validated the assay for sensitivity, specificity and reproducibility using spiked urine samples and a panel of BinaxNOW tested clinical urine specimens, some of which were from patients from whom a pneumococcal isolate was also cultured. The results for the validation will be presented. This assay can be extended to testing other clinical samples such as cerebrospinal and pleural fluids and with development has the potential to greatly improve serotype-specific surveillance in the many cases of pneumococcal disease from which a culture is never obtained.
P182 Current characteristics, coping strategies and outcomes of young people with cystic fibrosis transitioning to adulthood
Authors: R Miller, K Askew, J Bamford, N Hudson, J Moratelli, A Anderson, S Doe, SJ Bourke
Journal: Thorax (2016)

<h3>Introduction</h3> Transition is a process that addresses the medical, psychosocial and vocational needs of young adults, and it is a crucial stage for patients with CF. <h3>Methods</h3> Patients who transferred to the adult service via a transition clinic within the last 5 years underwent an interview with a psychologist using a questionnaire of demographic data, their experience of transition, their concerns and the effect of CF on their lifestyle. They completed the Hospital Anxiety Depression Scale (HADS) and the Ways of Coping Scale. Clinical data, complications and outcomes were noted at transfer and one year later. <h3>Results</h3> 45 patients (27 men) participated; mean age at transfer was 17 (range 15–21) years and at interview was 20.7 (17–24) years; 25 (53%) had chronic Pseudomonas infection, 7 (15.5%) were receiving gastrostomy feeding, 9 had diabetes, one had had liver transplantation and one had undergone termination of pregnancy. At the transition clinic 94% attended with a parent but after transfer 33% attended alone and 18% with a partner; 87% felt that the timing of transition was correct and 80% found the transition clinic helpful. Self-reported adherence to treatment declined in 18% and improved in 24%. Life satisfaction was high with 74% reporting that CF had no effect on their social lives, but 52% felt it impacted on work or studies, although 76% were in employment or education. Mean FEV1 remained stable at 76.6 (26.4–119.6)% at transfer and 75.4 (19–111)% one year later, but varied with 15 patients (33%) having a deterioration of &gt;5% and 8 (18%) improving by &gt;5%. Mean BMI changed from 20.8 (16.5–29.7) to 21.2 (17.3–29.2); 11 patients (24%) improved by &gt;1 kg/m<sup>2</sup>, 4 (9%) deteriorated by &gt;1 kg/m<sup>2</sup>. Psychological distress was low with 7 (15.6%) having anxiety and 3 (6.7%) depression; 84.4% used ‘optimistic acceptance’ as their main way of coping, 8.8% used ‘avoidance’ 2.2% ‘distraction’, and 2.2% ‘hopefulness’. <h3>Conclusion</h3> Young people with CF still face daunting problems but are functioning well. There is a need for close monitoring during transition to provide treatment and support to those showing clinical deterioration. <h3>Reference</h3> Abott J. <i>Disability Rehabilitation</i> 2001;<b>23</b>:315.
Comparative Antithrombotic and Antihemostatic Effects of the Direct Factor Xa Inhibitors, Apixaban and Rivaroxaban, and the Direct Thrombin Inhibitors, Dabigatran and Lepirudin, in Rabbit Models of Venous Thrombosis and Bleeding Time
Authors: Pancras C. Wong, Earl Crain, Carol Watson
Journal: Blood (2008)
P35 A retrospective observational study designed to characterise individuals with pulmonary Arteriovenous Malformations (PAVMS) and cerebral abscesses at a single institution
Authors: EJ Boother, S Brownlow, JE Jackson, CL Shovlin
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Individuals with pulmonary arteriovenous malformations (PAVMs), who often concurrently have hereditary haemorrhagic telangiectasia (HHT), are at increased risk of cerebral abscess, frequently resulting in life-changing deficits. Current aetiological consensus supports paradoxical emboli of periodontal origin, with preventative dental recommendations published in 2008.<sup>1</sup> Limited knowledge is available to identify specifically at-risk individuals. This study aimed to characterise a cohort from 2005–2016; recognise potential precipitants; and compare results to an earlier published series. <h3>Methods</h3> With ethical approval, notes of patients newly presenting at a single institution between 2005–2016 were reviewed to collect cohort characteristics. GraphPad Prism was used to calculate descriptive statistics, and to perform Mann-Whitney and Chi-squared statistical tests for comparison between the two cohorts. <h3>Results</h3> Of 488 new patients with PAVMs, 33 (6.8%) had cerebral abscesses. 21 were female (63.6%), 12 male. The rate corrected for ascertainment bias was 3.8%. The median age at abscess was 46 years (range 13–69). The median oxygen saturation (SaO<sub>2</sub>) was 90.75% (range 70–97.5%), with 9 individuals having respiratory symptoms. There were 29 confirmed HHT diagnoses (87.9%). The median largest feeding artery diameter was 5mm, and for 5 individuals, all feeding arteries had diameter ≤3 mm. In total, 19 (57.6%) had residual PAVMs too small for embolization. Organisms identified (Table 1) suggest periodontal origin; 16 individuals (48.5%) had poor dental hygiene and 9 (27.3%) had dental events as abscess precipitants. Interestingly, 4 individuals had abscesses whilst on holiday abroad. 5 individuals reported worsening migraines and 2 individuals had increased seizure frequency ≤ 3 months pre-abscess. Within the non-overlapping 1999–2005 cohort, there were 28/219 abscesses (12.8%, 9.05% adjusting for ascertainment bias). Compared to the later series, similar proportions of abscesses occurred prior to PAVM diagnosis (18/28 (64.3%) vs. 24/33 (72.3%)). Proportionally more males were affected (57.1%). No other significant differences were found for age, SaO<sub>2</sub>, feeding artery diameter, presence of respiratory symptoms, or HHT (all p values &gt;0.12). <h3>Conclusion</h3> The PAVM cohort remains at high risk of cerebral abscess. Scrupulous dental hygiene appears to remain paramount to reduce risk. The worsening migraines and abscess occurrence whilst abroad are unexpected findings recommended for further investigation. <h3>Reference</h3> Shovlin C, <i>et al</i>. Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. <i>Br Dent J</i> 2008;<b>205</b>(10):531–3.
Concurrent Fludarabine and Cyclophosphamide As a Reduced Intensity Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation Ablates Host T-Cells and Results in Rapid Full Donor Chimerism
Authors: Rachel B. Salit, Michael R. Bishop, Steven Z. Pavletic, Frances T. Hakim, Seth M. Steinberg, Jeanne Odom, Kelly Bryant, Jennifer Wilder, Daniele N. Avila, Bazetta Blacklock-Schuver, Ronald E. Gress, Daniel H. Fowler
Journal: Blood (2011)
Living near major roads and the incidence of dementia, Parkinson's disease, and multiple sclerosis: a population-based cohort study
Authors: Hong Chen, Jeffrey C Kwong, Ray Copes, Karen Tu, Paul J Villeneuve, Aaron van Donkelaar, Perry Hystad, Randall V Martin, Brian J Murray, Barry Jessiman, Andrew S Wilton, Alexander Kopp, Richard T Burnett
Journal: The Lancet (2017)
High Numbers of CD34+ Cells/kg and CD3+ Cells/kg Have No Negative Impact on the Incidence of Severe GvHD and Survival in a Large Series of Children Undergoing Unmanipulated Allogeneic HCT from Matched or Mismatched Unrelated Donors.
Authors: Krzysztof Kalwak, Joanna Owoc-Lempach, Ewa Gorczynska, Marek Ussowicz, Dominik Turkiewicz, Dorota Wojcik, Agnieszka Dyla, Alicja Chybicka
Journal: Blood (2006)
Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs
Authors: Anastasia Khvorova
Journal: New England Journal of Medicine (2017)

Another drug class may soon be added to cholesterol-lowering strategies: a chemically modified, small interfering RNA conjugated to the trivalent N-acetylgalactosamine. The siRNAs are oligonucleotide therapeutics, which destroy RNA before a protein is synthesized.
P3.04-044 Surgical Management of Arteriovenous Malformations: Our Experience
Authors: Fadil Gradica, Lutfi Lisha, Dhimitraq Argjiri, Flora Gradica, Valbona Rexha, Alma Cani, Fahri Kokici, Saudin Maliqi, Shqiptar Demaci, Agron Poniku, Safet Beqiri
Journal: Journal of Thoracic Oncology (2017)
A Novel Approach to a Retrospective Longitudinal Analysis of Dose Change or Discontinuation of Imatinib Therapy in Chronic Phase–Chronic Myeloid Leukemia
Authors: Serena Merante, Cristiana Pascutto, Chiara Elena, Barbara Rocca, Rita Zappatore, Paola Maria Cavigliano, Mario Cazzola, Ester Orlandi
Journal: Blood (2014)
P3.04-046 Cases of Surgical Resection of Post-Operative Lymph Node Recurrences from Primary Lung Cancer
Authors: Ema Mitsui, Masafumi Kataoka, Daisuke Okutani, Haruyuki Kawai, Kazuhiko Watanabe, Toshinori Ohara
Journal: Journal of Thoracic Oncology (2017)
P2.03a-053 Immuno-Inflammatory Markers in Advanced NSCLC Patients Undergone Fractioned Cisplatin, Oral Etoposide and Bevacizumab
Authors: Pierpaolo Pastina, Valerio Nardone, Battaglia Giuseppe, Cirino Botta, Paolo Tini, Cristiana Bellan, Veronica Ricci, Marcella Barbarino, Stefania Croci, Michele Caraglia, Antonio Giordano, Maria Grazia Cusi, Luigi Pirtoli, Pierpaolo Correale
Journal: Journal of Thoracic Oncology (2017)
A phase Ib study to evaluate the PI3-kinase inhibitor GDC-0941 with paclitaxel (P) and carboplatin (C), with and without bevacizumab (BEV), in patients with advanced non-small cell lung cancer (NSCLC).
Authors: B. Besse, J. Soria, C. Gomez-Roca, J. A. Ware, A. A. Adjei, G. K. Dy, G. Shankar, R. K. Brachmann, H. J. Groen
Journal: Journal of Clinical Oncology (2011)

3044 Background: Genetic alterations affecting the PI3K pathway are frequently observed in NSCLC (eg. PTEN loss, PIK3CA gene amplification). In preclinical tumor models GDC-0941 is synergistic with chemotherapy and increases the efficacy of anti-VEGF when dosed concurrently. This study sought to determine whether GDC-0941 can be safely combined with P + C +/- BEV. Methods: In Arm A, BEV-ineligible patients (pts) with advanced NSCLC and 0 or 1 prior chemotherapy regimen received increasing GDC-0941 doses (3 + 3 design) with P (200 mg/m2) and C (AUC 6 mg/mL·min) every 3 weeks. BEV-eligible pts in Arm B received BEV (15 mg/kg) in addition to P and C. In both arms, GDC-0941 was given once daily on Days 1-14 of a 21-day cycle. P and C were given up to 6 cycles, while GDC-0941 (with or without BEV) was given to progression or toxicity. Study objectives were to evaluate safety and pharmacokinetics (PK), and to determine the maximum tolerated dose (MTD) of GDC-0941 in both arms. Results: As of 9 January 2011, 18 pts were enrolled in GDC-0941 cohorts of 60, 100, and 165 mg (Arm A) and GDC-0941 cohorts of 100, 165 and 250 mg (Arm B). Eleven of 18 pts were active. Treatment-related adverse events (AEs) in ≥20% of pts were alopecia, asthenia, nausea, stomatitis, neutropenia, decreased appetite, paresthesia, epistaxis, arthralgia, peripheral neuropathy and rash. All treatment-related AEs were Grade 1 and 2 except for neutropenia. Grade 3 (16%) and 4 (11%) neutropenia events were not dose-limiting. PK characteristics of GDC-0941, P, 6-OH-P and C were similar to historical single-agent profiles. Based on preclinical efficacy, target exposures were achieved in the 250 mg cohort. Dose escalation will continue to a maximum of 400 mg. Confirmed partial responses (PR) were seen in 8 of 18 (44%) patients, including 1 squamous NSCLC pt with a pathologic complete response upon resection of the primary lung lesion (Arm A, 165 mg GDC-0941). Median follow up at the time of data cut-off was 5.4 months (range 0.6-10.3 m). Conclusions: The combination of GDC-0941, P and C (+/- BEV) was well tolerated. The combination MTD has not yet been reached. Antitumor activity was observed.
Left ventricular responses to supine bicycle exercise assessed by radionuclide angiocardiography and a Swan-Ganz catheter.
Authors: Akira Yoshida, Kazunori Kadota, Hirofumi Kambara, Shunichi Tamaki, Yukisono Suzuki, Chuichi Kawai, Nagara Tamaki, Kanji Torizuka
Journal: Circulation (1985)

Left ventricular responses to supine bicycle ergometer exercise were studied by gated radionuclide angiocardiography (RNA), in 12 normal subjects (group A), 11 coronary patients without effort angina (group B) and 17 coronary patients with effort angina (group C). In the serial measurement of global ejection fraction (EF) there was a significant increase during peak exercise (PEx) in group A and B. In group C, global EF during mild exercise (MEx) did not increase, but decreased significantly during PEx. These results suggest the necessity of achieving adequate exercise loading in the diagnosis of exercise-induced ischemia, and also, that the serial measurement of global EF during exercise appears to be highly valuable. In the assessment of regional wall motion on the basis of regional EF, abnormal responses to exercise were highly inducible in the anteroseptal region in coronary patients with left anterior descending artery involvement. Abnormal wall motion in the other regions was less indicative for right coronary or left circumflex artery dysfunction. We examined hemodynamic responses to exercise by a Swan-Ganz catheter during RNA study in 5 patients of group A, 5 of group B, and 9 of group C. There was a large increase in left ventricular stroke work index (LVSWI) with a small rise in pulmonary capillary wedge pressure (PCWP) in group A. In group B LVSWI increased with a moderate rise in PCWP during PEx. In group C there was a negligible increase of LVSWI despite a marked rise in PCWP. A similar relationship was present between the LVSWI and the end-diastolic count (EDC) in the left ventricular region of interest. In MEx, however, the rise in PCWP in group C was more prominent than the increase in EDC. Thus, the present data indicate that the left ventricle in group C operates on a steeper portion of the diastolic pressure-volume curve than that in group A or B.