tbuckley/cabot-search huggingface dataset:
Efficacy of a special COPD consultation in reducing hospital admissions and emergency room visits
Authors: Antonia Fuster, Liliana Chacon, Joan Bauza, Silvia Torres, Isabel Mir
Journal: European Respiratory Journal (2013)

Introduction  The aim of this study was to evaluate the efficacy of a monographic consultation in patients with moderate- severe-very severe COPD with 2 or more exacerbations in the previous year that have required hospitalization to reduce the number of admissions and emergency room visits.  Methods  A retrospective study which analyzed data from 90 patients in the monographic COPD consultation between December 2009 and December 2011.The intervention consisted of monthly medical visits, health education and direct contact number in the case of exacerbations. The results were compared with data from the same cohort during the same period the year before inclusion in the consultation. Statistical Analysis: T-Student test.  Results  We included 90 patients, with a mean age of 70.0.± 0.9, 20% were current smokers. PB FEV1 (ml) medium was 1187 ± 43 (41 ± 2). The number of hospital admissions that the patients had had the year before inclusion in the special consultations was 2.4 ± 0.2 compared with the number of hospital admissions per year after inclusion in the consultations 1.1 ± 0.29, representing a decrease of 54% in hospital admissions and a decrease of 41% in emergency room visits. The inhalation technique improved from 1.33 ± 0.07 to 1.80 ± 0.05, which represents an improvement of 35% and improved treatment adherence 1.60 ± 0.07 to 1.84 ± 0.05, representing an improvement of 15%.  Conclusions  A special consultation for COPD patients with frequent exacerbations, leads to a significant reduction in the number of hospitalizations and emergency room visits, as well as improved treatment adherence.
G10 : Mitochondrial-targeted antioxidant mitoquinone reduces portal hypertension in CCL4-cirrhotic rats by decreasing intrahepatic resistance
Authors: M. Vilaseca Barceló, C. López-Sanjurjo, M.P. Murphy, J. Bosch, V. Hernández-Gea, J. Gracia-Sancho, J.C. García-Pagán
Journal: Journal of Hepatology (2015)
Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases.
Authors: R J Cote, P P Rosen, M L Lesser, L J Old, M P Osborne
Journal: Journal of Clinical Oncology (1991)

We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.
Optimal Planning Target Volume for Stage I Testicular Seminoma: A Medical Research Council Randomized Trial
Authors: S.D. Fosså, A. Horwich, J.M. Russell, J.T. Roberts, M.H. Cullen, N.J. Hodson, W.G. Jones, H. Yosef, G.M. Duchesne, J.R. Owen, E.J. Grosch, A.D. Chetiyawardana, N.S. Reed, B. Widmer, S.P. Stenning
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, −3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.
A logistic-regression model provides novel guidelines to maximize the anti-acute rejection properties of cyclosporine with a minimum of toxicity.
Authors: A Perna, E Gotti, E de Bernardis, N Perico, G Remuzzi
Journal: Journal of the American Society of Nephrology (1996)

Although cyclosporine has become the mainstay of immunosuppression in organ transplantation, there is still no consensus on the criteria to optimize its anti-rejection activity with minimum toxicity. A clear and objective definition of target cyclosporine trough levels at different times from renal transplantation is still lacking, primarily because of the lack of a model correlating cyclosporine levels with probability of rejection or toxicity. In this study, logistic-regression model was developed that was applied to data collected retrospectively from two postoperative periods, i.e., Days 0 to 9 and 10 to 30, in 135 consecutive cadaveric renal transplant recipients, for a total of 1851 determinations. Only minimum and maximum trough levels were considered for each period. Concentration-response curves were estimated for Days 0 to 9 (P = 0.0001 for efficacy and P = 0.028 for toxicity) and for Days 10 to 30 (P = 0.015 for efficacy and P = 0.037 for toxicity). Therapeutic intervals of 330 to 430 ng/mL (parent compound in whole blood) for Days 0 to 9 and 260 to 390 ng/mL for Days 10 to 30 predicted an incidence of acute rejection of 22% and 12%, respectively, with a reasonably low toxicity that primarily consisted of elevation of serum aminotransferases.
Imaging of De Novo Atherosclerotic Arterial Remodeling
Authors: Gerard Pasterkamp
Journal: Journal of the American College of Cardiology (2009)

Atherosclerotic lesion progression and the formation of luminal thrombosis superimposed on a ruptured or eroded vulnerable plaque is well recognized as the pathological cause of the majority of cardiovascular events, such as stroke and myocardial infarction. The artery is not a rigid tube because it
Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death
Authors: Eric I. Zimmerman, Alice A. Gibson, Shuiying Hu, Aksana Vasilyeva, Shelley J. Orwick, Guoqing Du, Gerard P. Mascara, Su Sien Ong, Taosheng Chen, Peter Vogel, Hiroto Inaba, Michael L. Maitland, Alex Sparreboom, Sharyn D. Baker
Journal: Cancer Research (2016)

The use of multikinase inhibitors (MKI) in oncology, such as sorafenib, is associated with a cutaneous adverse event called hand-foot skin reaction (HFSR), in which sites of pressure or friction become inflamed and painful, thus significantly impacting quality of life. The pathogenesis of MKI-induced HFSR is unknown, and the only available treatment options involve dose reduction or discontinuation of therapy, which have negative effects on primary disease management. To investigate the underlying mechanisms by which sorafenib promotes keratinocyte cytotoxicity and subsequent HFSR induction, we performed a transporter-directed RNAi screen in human epidermal keratinocytes and identified SLC22A20 (OAT6) as an uptake carrier of sorafenib. Further investigations into the intracellular mechanism of sorafenib activity through in situ kinome profiling identified the mitogen-activated protein kinase MAP3K7 (TAK1) as a target of sorafenib that induces cell death. Finally, we demonstrate that sorafenib induced keratinocyte injury in vivo and that this effect could be reversed by cotreatment with the OAT6 inhibitor probenecid. Collectively, our findings reveal a novel pathway that regulates the entry of some MKIs into keratinocytes and explains the basis underlying sorafenib-induced skin toxicity, with important implications for the therapeutic management of HFSR.
Non-invasive biomarkers applied in a case-control study
Authors: Karolien Bloemen, Rosette Van Den Heuvel, Gudrun Koppen, Vera Nelen, Erwin Witters, Kristine Desager, Greet Schoeters
Journal: European Respiratory Journal (2011)

Background:  Exhaled breath contains various potential noninvasive biomarkers for airway disease.   Aim:  This study aims to evaluate the performance of known exhaled markers and to search for potential new markers in exhaled breath.   Methods:  Asthmatic (N=72) and healthy (N=67) children (6-12 years) donated exhaled breath condensate (EBC; RTube) and exhaled gasses (Tedlar bag). Fractional exhaled nitric oxide (FeNO) was measured (NIOX MINO). EBC pH was measured directly after sampling without deaeration, EBC 8- isoprostane was measured by ELISA (Cayman). Patterns of exhaled proteins and gasses were analysed by LC/MS or GC/MS to obtain a fingerprint of molecules which are indicative for the airway status.   Results:  Increased FeNO values were observed in the asthma group compared to the healthy controls (Mann-Whitney U test; p=0.057), and in the allergic asthmatic patients compared to the non-allergic asthmatic patients (p=0.01). EBC pH was significantly lower in the asthma group compared to healthy controls (p=0.047). EBC 8-isoprostane was comparable between children with asthma and healthy controls, but was significantly increased in allergic asthma patients compared to non-allergic patients (p=0.032). Various proteins that might be relevant in respiratory health outcomes were for the first time identified in EBC, amongst which annexin A1 and A2, calgranulin A and B, catalase, galectin-7, and prolactin-induced protein. Prediction models of selected proteolytic peptides or gasses were build (Support Vector Machine analysis) based on the health outcome asthma.   Conclusion:  Exhaled molecules are influenced by asthma or allergy status. This study identified new exhaled molecules that might be relevant for respiratory health.
Abstract 3890: Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity
Authors: Hidewaki Nakagawa, Akihiro Fujimoto, Mayuko Furuta, Kunihito Gotoh, Toru Nakamura, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Tatsuhiko Tsunoda
Journal: Cancer Research (2015)

Abstract Primary liver cancer is the third leading cause of cancer death worldwide. Virus infection is the most common and strongest etiological factor for liver cancer development. Pathologically, primary liver cancer can be classified into ∼90% hepatocellular carcinoma (HCC), and 5∼10% intrahepatic cholangiocarcinoma (ICC), and the combined hepatocellular-cholangiocarcinoma (cHCC/CC) representing only a small portion. Clinically, ICC and cHCC/CC show much more aggressive behavior with poorer prognosis than HCC, and no standard treatment currently exists, other than surgical resection. ICC and cHCC/CC show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying a biliary phenotype (LCB). To gain insight into molecular alterations of LCBs, we performed whole genome sequencing analysis on 30 LCBs. Here we show the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, while those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs. Citation Format: Hidewaki Nakagawa, Akihiro Fujimoto, Mayuko Furuta, Kunihito Gotoh, Toru Nakamura, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Tatsuhiko Tsunoda. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3890. doi:10.1158/1538-7445.AM2015-3890
Abstract P054: Crosstalk Between Toll-like Receptor 4 and Lipid Metabolism Modulates Macrophage Survival
Authors: Joel Schilling, Heather Machkovech, Jean Schaffer
Journal: Circulation Research (2011)

Diabetes and obesity are well-established risk factors for cardiovascular disease, including atherosclerosis and adverse cardiac remodeling after myocardial infarction (MI). Abnormalities of lipid metabolism are a hallmark of diabetes and are strong predictors of the risk of future cardiac events. Macrophages are cells of the innate immune system that play a vital role in the host response to infection and tissue injury. In the cardiovascular system, macrophages are key participants in the pathogenesis of atherosclerosis and post-MI infarct remodeling. Toll-like receptor (TLR)-4 is highly active on macrophages and has been shown to contribute to the injury response in the heart and vasculature. Thus, understanding how lipids modulate TLR4-mediated macrophage responses is particularly relevant to diabetic cardiovascular disease. To investigate this question, we studied the effect of palmitate; an abundant dietary saturated fatty acid, on macrophage viability and inflammatory signaling after stimulation with the TLR4 ligand LPS. Interestingly, LPS or palmitate alone failed to trigger significant cell death; however, the combination of these stimuli markedly reduced macrophage viability. The synergistic death induced by LPS and palmitate required functional TLR4, yet occurred independently of ER stress, reactive oxygen species generation, ceramide production, caspase activation and autophagy. Instead, lysosomal integrity is compromised early and followed by the loss of mitochondrial membrane potential and ultimately cell death. Interestingly, inhibition of the lipid remodeling enzyme iPLA2 attenuates lysosomal instability and cell death following treatment with palmitate/LPS. Thus, we describe a novel cell death response in macrophages that occurs via a mechanism involving iPLA2 activation and lysosomal destabilization. These data provide evidence that the lipid environment modulates macrophage function following inflammatory stimuli. Given the critical role of macrophages in the response to tissue injury, these findings are highly relevant to understanding cardiac injury and repair in diabetics.
Abstract 13970: Precapillary Pulmonary Hypertension Prior to LVAD Implantation is Associated with Increased Mortality
Authors: Bryan C Lee, Sakima A Smith
Journal: Circulation (2014)

Introduction: Severe left ventricular (LV) dysfunction is often associated with pulmonary hypertension (PH). Data suggests that in PH patients worsening LV function can result in “out-of-proportion” PH (OOPPH), measured by the transpulmonary gradient (TPG) or diastolic pulmonary vascular pressure gradient (DPG), and portends a higher mortality. We hypothesized that patients with OOPPH who underwent left ventricular assist device (LVAD) placement would have worse outcomes, and we wanted to assess outcomes in pre and postcapillary PH patients.

Methods: We retrospectively identified all patients who underwent LVAD placement with RHC hemodynamic data available between Jan 1st 2007 and Dec 31st 2011. Demographic, clinical and procedural data were collated and analyzed. Multivariable analysis was used to assess for predictors of mortality.

Results: Within the patient cohort (n = 79), the mean age was 54 (range 20 - 78), 75% were male, and 78% were Caucasian. Precapillary PH was present in 10% of the patients and was an independent predictor for mortality (HR 4.71, 95% CI [1.53 - 14.5] p=0.007) after adjusting for race, gender, age and inotrope use. OOPPH was not associated with increased mortality.

Conclusion: In our institutional experience precapillary PH has shown to be an independent predictor for mortality in the setting of LVAD placement. These findings are intriguing and merit further investigation on a larger scale.

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A randomized second line trial in patients with gemcitabine refractory advanced pancreatic cancer - CONKO 003
Authors: H. Riess, U. Pelzer, J. Stieler, I. Schwaner, G. Heil, M. Görner, M. Mölle, A. Hilbig, B. Dörken, H. Oettle
Journal: Journal of Clinical Oncology (2007)

4517 Objective: For nearly ten years gemcitabine (G) was standard first line therapy for patients (pts) with advanced pancreatic cancer (APC). There is no consensus about second line therapy after disease progression while receiving G, but 5-FU-based regimens are considered. Results about randomized second line studies in APC are very rare. Our phase II study (ASCO 2002) showed activity of the OFF (oxaliplatin/folinic Acid (FA)/5-fluorouracil (FU) [24h] ) regimen in 23 pts. To examine the impact and the side effects of oxaliplatin we initiated a multicenter phase III study to compare OFF and FF in pts with G refractory APC. Methods: Pts with CT/ MRT confirmed failure with G in first line therapy, Karnofsky Performance Status (KPS) &gt;60%, controlled pain, adequate hematological, renal and liver functions were eligible. Pts were stratified according to duration of first line therapy, KPS and tumor stage. We randomized pts to outpatient treatment with FF (FU 2g/m 2 (24h)/ FA 200 mg/m 2 (30min) on d1, d8, d15 and d22) or OFF (FF+Oxaliplatin 85mg/m 2 , d8, d22). In both arms the next cycle started on day 43. Pts were followed with regular staging every 3 months or at any signs of disease progression. Results: Until now we randomized 161 of 165 (planned) pts between 02/2004 and 01/2007. So we expect to present first results (side effects, progression free survival, overall survival) at the meeting. No significant financial relationships to disclose.
P0061 : Treatment with new all-oral direct acting antivirals in HCV-recurrence in liver transplant-setting induces a reduction of immunosuppressive drug levels
Authors: J. Cabezas, M. Berenguer, J.M. Pascasio, M.-C. Londoño, J.M. Sousa Martín, C. Navascués, C. Vinaixa, I. Baños, J.L Calleja, M. Rodrìguez, X. Forns, J. Crespo
Journal: Journal of Hepatology (2015)
Abstract 18590: Oxidative Protein Modifications Mediate Mitochondrial Dysfunction in Metabolic Heart Disease: Correction ex vivo and in vivo
Authors: Aaron L Sverdlov, Aly Elezaby, Fuzhong Qin, Jessica B Behring, Markus M Bachschmid, Ivan Luptak, Timothy D Calamaras, Deborah A Siwik, Edward J Miller, Marc Liesa, Orian S Shirihai, David R Pimentel, Richard A Cohen, Wilson S Colucci
Journal: Circulation (2014)

Background: Diet-induced metabolic heart disease (MHD) characterized by LV hypertrophy (LVH), diastolic dysfunction and oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins suggests that mitochondrial reactive oxygen species (ROS) contribute to MHD. Hypothesis: We tested the hypotheses that in MHD mitochondrial dysfunction can be i) reversed by a reducing agent ex vivo, and ii) prevented by overexpression of mitochondria-targeted catalase (mCAT) in vivo. Methods and Results: mCAT or wildtype (WT) mice were fed a high-fat, high-sucrose (HFHS) or control diet (CD) for 4 months. Cardiac mitochondria from WT HFHS-fed mice (vs. CD) had a 3-fold greater rate of H2O2 production (p=0.001), a 30% decrease in complex II substrate-driven oxygen consumption (p=0.006), a 22% decrease in complex I and II substrate-driven ATP synthesis (p=0.01) and a 63% decrease in complex II activity (p=0.002). In WT HFHS-fed mice, complex II but not complex I substrate-driven ATP synthesis and activity ...
Use of olmesartan for ≥ 1 year was associated with hospitalization for intestinal malabsorption
Authors: Nicholas J. Talley
Journal: Annals of Internal Medicine (2015)

Source Citation Basson M, Mezzarobba M, Weill A, et al. Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. Gut. 2015 Aug 6. [Epub ahead of print] 26250345
Response to Letter Regarding Article, “Reduced Fetal Cerebral Oxygen Consumption Is Associated With Smaller Brain Size in Fetuses With Congenital Heart Disease”
Authors: Liqun Sun, Christopher K. Macgowan, John G. Sled, Shi-Joon Yoo, Cedric Manlhiot, Prashob Porayette, Lars Grosse-Wortmann, Edgar Jaeggi, Brian McCrindle, John Kingdom, Edward Hickey, Steven Miller, Mike Seed
Journal: Circulation (2015)
Safety and pharmacokinetics of two dose strengths of ciprofloxacin dry powder for inhalation (DPI) in patients with moderate to severe COPD
Authors: Heino Stass, Johannes Nagelschmitz, Henrik Watz, Anne Marie Kirsten
Journal: European Respiratory Journal (2012)

Introduction   Ciprofloxacin dry powder for inhalation (DPI), formulated using Novartis9 PulmoSphere™ technology for pulmonary delivery via a T-326 inhaler, is under investigation in various respiratory tract disorders.   Aim   To compare the safety and PK of two dose strengths of ciprofloxacin DPI in patients with COPD.   Methods   In a randomized, phase I, double-blind, crossover study, 12 (8m/4f) adults with GOLD stage II or III COPD received a single dose of 32.5 mg and 48.75 mg ciprofloxacin DPI (corresponding to 50 mg and 75 mg dry powder, respectively). The washout period was 7–14 days between doses.   Results   There were no severe or serious AEs nor clinically relevant differences in incidence or severity of AEs between the doses, most being mild. Drug-related AEs (bitter taste) occurred in 7 and 6 patients after 32.5 mg and 48.75 mg ciprofloxacin DPI, respectively. The PK (Table) was similar to previous studies, showing high and variable lung exposure at low systemic exposure.   Conclusions   Ciprofloxacin DPI was well tolerated in patients with moderate to severe COPD with no clinically relevant differences between the two dose strengths. Increased systemic exposure from the 48.75 mg dose was not matched by increased lung exposure. PK data indicate that the lower dose produced similar drug concentrations in the lung, with less powder inhaled.