tbuckley/cabot-search huggingface dataset:
A phase III randomised trial assessing the activity of first-line ifosfamide-gemcitabine (IG), a non-platinum chemotherapy (CT), in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Thierry Berghmans, Jean-Jacques Lafitte, Marianne Paesmans, Anne-Pascale Meert, Arnaud Scherpereel, Nathalie Leclercq, Jean-Paul Sculier
Journal: European Respiratory Journal (2011)

Rationale:  Few data showed similar survival for platinum-free and platinum-based CT regimens. Our primary endpoint was to determine if cisplatin-based chemotherapy, GIP or DP, will improve survival in comparison to the IG combination in patients with advanced NSCLC.   Methods:  After central randomisation, patients received either GIP (gemcitabine 1g/m 2  D1-8, ifosfamide 3g/m 2 , cisplatin 50 mg/m 2 ), IG (gemcitabine 1g/m 2  D1-8, ifosfamide 3g/m 2 ) or DP (docetaxel 75 mg/m 2 , cisplatin 50 mg/m 2 ). According to the ELCWP experience, an increase of the 1 year survival rate from 35% in the IG arm to 50% in the two cisplatin arms will require to observe 360 deaths.   Results:  From 12/2003 to 03/2009, 693 eligible patients were randomised. Main characteristics were: median age 58 years, male/female 523/170, squamous/adenocarcinoma/other 152/386/155, Karnofsky PS 60-70/80-100 157/536, stage IIB-III/IV 129/564. The main results are:  GIP was associated with (p    Conclusion:  In this large phase III trial, a non-platinum CT regimen (ifosfamide-gemcitabine) had similar activity to cisplatin-based CT in terms of survival, PFS and response rates with a favourable toxicity profile.
Cigarette smoke enhances -defensin 2 expression in rat airways via nuclear factor- B activation
Authors: L. Chen, B-B. Sun, T. Wang, X. Wang, J-Q. Li, H-X. Wang, S-F. Zhang, D-S. Liu, L. Liu, D. Xu, X-M. Ou, Y-J. Chen, T. Yang, H. Zhou, F-Q. Wen
Journal: European Respiratory Journal (2010)

β-defensin 2 (BD-2), an antimicrobial peptide, participates in airway defence. Cigarette smoke (CS) is a major risk factor for the development of chronic obstructive pulmonary disease. This study mainly aims to investigate the effect of CS on rat BD-2 (rBD-2) expression in rat airways. Rats were exposed to CS and treated with caffeic acid phenethyl ester (CAPE), a nuclear factor (NF)-κB inhibitor, or astragaloside IV (AS-IV), an active ingredient of Astragalus mongholicus . Besides the analysis of bronchoalveolar lavage fluid (BALF) and histological changes after CS exposure, rBD-2 expression was investigated with immunohistochemistry, reverse transcription PCR and ELISA. Total glutathione and nitric oxide (NO) levels in rat lungs were also detected. CS exposure markedly increased rBD-2 immunoreactivity, as well as rBD-2 mRNA and protein levels in rat airways, which were inhibited by CAPE treatment. Moreover, associated airway inflammation induced by CS was demonstrated by histological changes, increased cell counts and pro-inflammatory cytokines in BALF, and NF-κB activation and high levels of total glutathione and NO, which were all reversed by AS-IV in a dose-dependent fashion. In conclusion, CS exposure induces rBD-2 expression in rat airways via a NF-κB-dependent pathway, and AS-IV attenuates CS-induced airway inflammation due to its anti-inflammatory and antioxidant properties, at least partly through NF-κB inactivation.
The renal mitochondrial toxicity of beta-lactam antibiotics
Authors: B M Tune, C Y Hsu
Journal: Journal of the American Society of Nephrology (1990)

The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.
Inhaled budesonide in chronic bronchitis. Effects on respiratory impedance
Authors: GJ Wesseling, M Quaedvlieg, EF Wouters
Journal: European Respiratory Journal (1991)

In a placebo controlled study the effects of 6 weeks' treatment with inhaled budesonide (1.6 mg daily) on the impedance of the respiratory system, spirometry and symptom scores were evaluated in 35 patients with chronic bronchitis with forced expiratory volume in one second (FEV1) greater than or equal to 70% predicted. Thirty patients completed the study. No statistically significant differences in the changes in morning peak expiratory flow rate (PEFR), symptom scores, use of terbutaline rescue medication and FEV1 were found between the placebo and the active treatment group. Budesonide treatment was found to result in a small decrease in resonant frequency and a less negative frequency dependence of resistance compared with the placebo group.
Maximal root mean square (RMS) of surface electromyography (sEMG) signal in different respiratory muscles
Authors: Ingrid Azevedo, Kardec Aguiar, Morgana Evangelista, Dayane Montemezzo, Vanessa Lima, Ana Paula Miranda, Danielle Pereira, Armele De Andrade, Veronica Parreira, Marcelo Velloso, Raquel Brito, Andrea Aliverti, Guilherme Fregonezi
Journal: European Respiratory Journal (2014)

The most common method of normalizing sEMG signals from a given muscle is to refer it to the signal recorded from the same muscle during a maximal voluntary isometric contraction (MVIC). It is still not fully clear, however, what test should be used to produce maximum neural activation in a given muscle, particularly for sEMG analysis of respiratory muscles. The aim of this study was to evaluate and compare RMS values of sEMG of the sternocleidomastoid (SCM), scalene (SCA), diaphragm (eighth intercostal space, EIS) and rectus abdominal (RA), while performing different maneuvers. 24 healthy subjects underwent the protocol (9M, 15F, age 27,8±7,1 years, BMI 23,7±3,4 kg/m², FVC% 92,20 ± 12,63; FEV 1 /FVC% 86,56 ± 4,94). After skin preparation , sEMG signals were acquired by wireless sEMG sensors positioned accordingly to previously published protocols (Falla, 2002; De Andrade, 2005; Maarsingh, 2000), during sniff test, MIP, MEP and MVIC of RA, SCM and SCA. Electromyographic values of the maneuvers and respective signal muscle groups are presented on table 1.  In conclusion, MVIC specific for the muscles provides the maximal RMS for SCM, SC and RA muscles, while for the EIS the maneuver providing maximal RMS is MVIC of RA.
Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53
Authors: Shengliang Zhang, Lanlan Zhou, Bo Hong, A. Pieter J. van den Heuvel, Varun V. Prabhu, Noel A. Warfel, Christina Leah B. Kline, David T. Dicker, Levy Kopelovich, Wafik S. El-Deiry
Journal: Cancer Research (2015)

Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling. Cancer Res; 75(18); 3842–52. ©2015 AACR.
Follow up of lung transplant recipients using electronic nose
Authors: Dorottya Kovacs, Andras Bikov, Judit Pako, Zsuzsanna Kovats, Zoltan Sutto, Veronika Muller, Gabriella Murakozy, Gyorgy Losonczy, Ildiko Horvath
Journal: European Respiratory Journal (2011)

Background: The close follow up of lung transplant patients is essential in the recognition of both early and late complications, however today these can be confirmed only by invasive techniques. Analysis of exhaled breath might be promising, as various studies showed relationship between breath components and the development of BOS in lung transplant recipients. Electronic nose is able to analyse the molecular pattern of breath (breathprint), and it discriminated different lung diseases successfully, however lung transplant patients were not studied yet.

Aim: To investigate the relationship between breathprint and various clinical parameters in lung transplant recipients.

Methods: Sixteen patients following lung transplantation participated in our study (mean age 39±14). The study had a model (N=25 samples) and a validation part (N=35 samples). Hence, in average 3.7±2.5 samples per patient were analysed. During their scheduled follow up at the outpatient clinic exhaled breath collection for E-nose measurement (Cyranose 320) as well as blood test and lung function was performed. Breathprints were analysed using principal component analysis and the relationship between breathprint and clinical parameters was assessed by linear regression.

Results: A significant relationship was detected between the breathprint and MEF50 as well as between breath pattern and tacrolimus plasma levels (p<0.05) which was confirmed by the validation set.

Conclusions: The analysis of exhaled breath can be useful in the follow-up of lower airway obstruction in lung transplant recipients. The relation with the drug level draws attention to the interfering effect of treatment and to the possibility of monitoring drug level by exhaled breath testing.
Platelets decline during <scp>V</scp>aso‐occlusive crisis as a predictor of acute chest syndrome in sickle cell disease
Authors: Chaher H. Alhandalous, Jin Han, Lewis Hsu, Michel Gowhari, Johara Hassan, Robert Molokie, Taimur A. Abbasi, Victor R. Gordeuk
Journal: American Journal of Hematology (2015)

interesting, because it defines the 8p11 myeloproliferative syndrome, known also as Stem Cell Leukemia/Lymphoma, an extremely rare stem cell disorder characterized by very poor prognosis and association of myeloproliferative neoplasm with T/B-cell lymphoma.Notably, this fusion causes constitutive activation of the FGFR1 kinase and, therefore, it is potentially targetable using drugs such as ponatinib [6].Indeed, in vitro treatment of patient's cells with nanomolar concentration of ponatinib caused a potent and specific growth inhibition (Supporting Information Fig. 2).A total of three NPM1 insertions were reported by both standard techniques and RNA-Seq; FLT3-ITD was detected in six samples by RNA-Seq and in four by standard PCR-based techniques (not tested in the remaining two).Although the numbers are too limited to drive definitive conclusions, this suggests comparable sensitivity of standard techniques and RNA-Seq in detecting these variants (Table I).A total of 23 SNV were also identified by RNA-Seq with a median of one variant per patient (range 0-4).Globally, 22/23 SNV have been confirmed by Sanger sequencing, suggesting that the accuracy of our pipeline for SNV detection is 96%.Of the 22 confirmed SNV, 10 were new and 12 were known variants (Table I).Taken globally, these data suggest that a single RNA-Seq analysis performed at diagnosis in AML patients, even in absence of a matched control sample, allows to quickly detect a large number of abnormalities that are not detected using standard clinical tests.This analysis will allow to achieve a better prognostic assessment and to identify potentially new treatment options, such as ponatinib for the patient carrying the ZMYM2-FGFR1 translocation.This is of paramount importance, as the list of clinically available selective inhibitors keeps growing at very fast pace and the discovery of new driver variants may lead to the development of novel targeted therapies (Supporting Information Table I).
Skin Cancer Risk in Hematopoietic Stem-Cell Transplant Recipients Compared With Background Population and Renal Transplant Recipients
Authors: Silje Haukali Omland, Robert Gniadecki, Merete Hædersdal, Jannik Helweg-Larsen, Lars Haukali Omland
Journal: JAMA Dermatology (2015)

While a high risk of nonmelanoma skin cancer is well recognized in solid-organ transplant recipients, the risk of skin cancer in hematopoietic stem-cell transplant (HSCT) recipients has not been extensively studied.To determine the risk of cutaneous cancer in HSCT recipients and compare it with the risk in renal transplant recipients (RTRs) and individuals who have not received any transplant.A nationwide population-based cohort study from the Danish National Hospital Register including 3302 patients who underwent HSCT (1007 allogeneic, 2295 autologous) from 1999 through 2014, 4789 RTRs from 1976 through 2014, and 10 age- and sex-matched nontransplanted individuals for each of the groups from the background population. Person-years at risk were calculated from the time of study inclusion until first cutaneous cancer. To compare the risk of skin cancer between transplant recipients and background population, we used a stratified proportional hazard regression model for hazard ratio (HR) estimations. By use of the cumulative incidence, we estimated 5- and 10-year risks of skin cancers. All RTR and HSCT recipients were treated and followed up in specialized hospital departments in Denmark (total population 5.7 million).Primary outcomes were time to first appearance of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or malignant melanoma (MM) and comparative risk estimates of cutaneous cancers in HSCT recipients and RTRs. The hypothesis was tested during data collection.Allogeneic HSCT recipients had an increased risk of BCC, SCC, and MM, with respective HRs of 3.1 (95% CI, 1.9-5.2), 18.3 (95% CI, 4.1-81.8), and 5.5 (95% CI, 1.7-17.7) compared with the background population. Compared with RTRs, allogeneic HSCT recipients had a 3-fold higher risk of MM. The risk of BCC after allogeneic HSCT was seen only in patients conditioned with total-body irradiation (HR, 3.9 [95% CI, 2.6-6.8]). The risk of BCC was similar for allogeneic HSCT recipients and RTRs, while the risk of SCC was highest for RTRs. Autologous HSCT recipients had no increased risk of skin cancer.Allogeneic HSCT recipients have an increased risk of BCC, SCC, and MM. Total-body irradiation was a major determinant for BCC. Our findings indicate the relevance of dermatologic follow-up in HSCT recipients.
Enterococcal endocarditis in the beginning of the 21st century: analysis from the International Collaboration on Endocarditis-Prospective Cohort Study
Authors: C. Chirouze, E. Athan, F. Alla, V.H. Chu, G. Ralph Corey, C. Selton-Suty, M.-L. Erpelding, J.M. Miro, L. Olaison, B. Hoen
Journal: Clinical Microbiology and Infection (2013)
Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism
Authors: Tatsuhiro Shibata, Shoji Kawakami, Teruo Noguchi, Tomotaka Tanaka, Yasuhide Asaumi, Tomoaki Kanaya, Toshiyuki Nagai, Kazuhiro Nakao, Masashi Fujino, Kazuyuki Nagatsuka, Hatsue Ishibashi-Ueda, Kunihiro Nishimura, Yoshihiro Miyamoto, Kengo Kusano, Toshihisa Anzai, Yoichi Goto, Hisao Ogawa, Satoshi Yasuda
Journal: Circulation (2015)

Coronary artery embolism (CE) is recognized as an important nonatherosclerotic cause of acute myocardial infarction. Its prevalence, clinical features, and prognosis remain insufficiently characterized.We screened 1776 consecutive patients who presented with de novo acute myocardial infarction between 2001 and 2013. CE was diagnosed based on criteria encompassing histological, angiographic, and other diagnostic imaging findings. The prevalence, clinical characteristics, treatment strategies, in-hospital outcomes, and long-term risk of CE recurrence or major adverse cardiac and cerebrovascular events (cardiac death, fatal arrhythmia, or recurrent thromboembolism) were evaluated. The prevalence of CE was 2.9% (n=52), including 8 (15%) patients with multivessel CE. Atrial fibrillation was the most common cause (n=38, 73%). Only 39% of patients with CE were treated with vitamin K antagonists, and the median international normalized ratio was 1.42 (range, 0.95-1.80). Eighteen of the 30 CE patients with nonvalvular atrial fibrillation had a CHADS2 score of 0 or 1. When those patients were reevaluated using CHA2DS2-VASc, 61% were reassigned to a higher risk category. During a median follow-up of 49 months, CE and thromboembolism recurred in 5 atrial fibrillation patients. The 5-year rate of major adverse cardiac and cerebrovascular events was 27.1%. In the propensity score-matched cohorts (n=45 each), Kaplan-Meier analysis showed a significantly higher incidence of cardiac death in the CE group than in the non-CE group (hazard ratio, 9.29; 95% confidence interval, 1.13-76.5; P<0.001).Atrial fibrillation is the most frequent cause of CE. Patients with CE represent a high-risk subgroup of patients with acute myocardial infarction and require close follow-up.
What is significant sleep disordered breathing in patients with interstitial lung disease
Authors: Lauren Troy, Keith Wong, Brendon Yee, Nicole Taylor, Ron Grunstein, Peter Corte, Paul Torzillo, Tamera Corte
Journal: European Respiratory Journal (2013)

Sleep disordered breathing (SDB) is common in interstitial lung disease (ILD) and may be associated with increased mortality and development of pulmonary hypertension (PH). However, there is no consensus on the optimal assessment of SDB in ILD.

Aim: To investigate 1) The relationship of SDB with markers of ILD disease severity; and 2) The utility of pre-specified variables in assessing SDB.

Methods: All polysomnograms (PSG) in ILD patients were reviewed (Mar 2009-Mar 2013). Significant nocturnal oxygen desaturation (NOD) was defined as >10% sleep time with SpO2<90%. The relationship of these variables with parameters of ILD severity and pulmonary haemodynamics was explored.

Results: 44 ILD patients underwent PSG and lung function testing (27 males; mean age 67.5±7.6years; BMI 31.4±5.5; FVC 78.4±19.9%; DLCO 51.0±15.7%). SDB variables included: median AHI 8 (2-98), ODI 11.3 (1.7-90.5), % night with SpO2<90% 5.8 (0-100%). Mild and mod-severe OSA was seen in 18(41%) and 16(36%) subjects respectively.

No SDB parameter was associated with ILD severity (FVC, DLCO), or presence of PH (systolic pulmonary artery pressure>40mmHg) on echocardiogram (n=25). Patients with significant NOD had lower awake resting Spo2 (p<0.01) but no difference in nadir Spo2 on 6minute walk testing (n=31; p=0.08).

Significant NOD occurred in 20 (45%) patients. Compared to those without significant NOD, AHI was not significantly different (p=0.23). ODI was higher (p<0.01) and nadir sleep Spo2 lower (p<0.01).

Conclusions: NOD and OSA are common in ILD but not synonymous, and cannot be predicted from usual markers of disease severity. Further studies to identify the SDB markers that affect longer term outcomes are needed.
Female pulmonary arterial hypertension is associated with decreased microRNA96 expression
Authors: Emma Wallace, Kirsty Mair, Lu Long, Xu D. Yang, Nick Morrell, Andrew H. Baker, Margaret R. MacLean
Journal: European Respiratory Journal (2014)

Introduction  Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene underlie heritable PAH. PAH occurs more frequently in women. MicroRNAs (miRs) are gene regulators involved in vascular processes including proliferation.   Aims  We investigated miR expression in mice with a BMPR2 R899X mutation.   Methods  miRNA and mRNA expression by qRTPCR and protein by westerns were determined in human pulmonary arterial smooth muscle cells (hPASMCs). Proliferation was assessed by cell counts. In vivo levels of oestrogen were depleted in female mice using the aromatase inhibitor anastrozole (3mg/kg/day for 2 weeks). All data, n>6.   Results  Expression of miR96 was decreased from 1±0.09 to 0.09±0.002 (p 1B  protein elevated by ∼61% in PASMCs from female PAH patients (not males) vs. Controls and associated with increased serotonin-induced proliferation. Pre-miR-96 transfected in human PASMCs decreased 5HT 1B  protein expression by 40%. Depletion of oestrogen caused a ∼77% increased expression of miR96 and an ∼84% decrease in 5HT 1B  expression in whole lung. In hPASMCs, 1nM oestrogen decreased miR96 expression by ∼80% and increased 5HT 1B  expression 2-fold.   Conclusions  Oestrogen-induced decreased miR96 expression, leading to derepressed 5HT 1B  expression may predispose female PASMCs to proliferation, contributing to the development of PAH.