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Nicola?Ronan Deirdre?M.?Bennett Kashif?A.?Khan Yvonne?McCarthy Darren?Dahly Louise?Bourke Adeline?Chelliah Alberto?Cavazza Kevin?O’Regan Fiachra?Moloney Barry?J.?Plant Michael?T.?HenryEmail authorView authors OrcID profile
return OK on get 《Lung》2018,196(5):543-552
Background
Pirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required.Objectives
The purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy.Methods
Thirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis.Results
All patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p?=?0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D.Conclusions
TBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.13.
Yangbo Feng HaJeung Park Luke Bauer Jae Cheon Ryu Sung OK Yoon 《ACS medicinal chemistry letters》2021,12(1):24
Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor 17 was a potent and isoform selective JNK3 inhibitor (IC50 = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome (t1/2 = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds 17 and 27 in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II. 相似文献
14.
The heterogeneity of individuals with blood pressure (BP) < 140/90 mmHg in terms of cardiovascular (CV) risk was reported as early as 1939 by Robinson and Brucer.1 BP in the range of 120–139/80–89 mmHg (labelled then as prehypertension) was observed to be associated with high risk of progression to hypertension (HT) and cardiovascular disease (CVD) later in life when compared with BP < 120/80 mm Hg.1The term prehypertension was adopted in May 2003 by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High blood Pressure (JNC-7) to describe BP range of 120–139/80–89 mmHg.2 The resuscitation of this terminology/concept in JNC-7 was a sequel to the documentation of a higher morbidity in individuals with prehypertension in landmark publications.3-5 Prehypertension (PHT) was defined in JNC-7 not only to emphasise the excess risk associated with BP in this range, but also to focus increased clinical and public health attention on prevention.2,6,7Prevalence rates of PHT among adults in the United States, Ghana and northern Nigeria have been reported to be 31, 40 and 58.7%, respectively.7-9 In most studies, including the ones above, PHT was more prevalent than hypertension.7-9 Though PHT is associated with increased risk of major CV events independently of other CV risk factors,10 most individuals (90%) with PHT have at least one cardiovascular risk factor such as dyslipidaemia, abdominal obesity, hyperinsulinaemia, impaired fasting glucose levels, insulin resistance, a prothrombotic state, tobacco use, endothelial dysfunction, and impaired vascular distensibility.6,7,9,10QT interval dispersion (QTd) (the difference between the longest and the shortest QT intervals on a surface ECG), when excessive, is associated with increased risk of cardiovascular morbidity and mortality in population studies, and many clinical conditions, including hypertension.11,12 This has been related to ventricular electrical instability, providing the necessary substrate for lethal ventricular arrhythmias.12,13 Greater QTd and left ventricular mass have been demonstrated in hypertensive individuals compared with normal individuals.11,13,14Considering the well-established, linear relationship between BP and the risk of cardiovascular events, the CV risk associated with PHT is intermediate between normotension and hypertension.2,03 Hence, electrocardiographic and echocardiographic indices of target-organ damage in PHT may also be intermediate between normotension and hypertension. The aims of this study were: (1) to compare the QTd and indices of left ventricular hypertrophy in adult black normal and prehypertensive subjects, and (2) to evaluate the relationship of QTd with electrocardiographic and echocardiographic indices in these subjects. 相似文献
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GAVRILOV LF 《Vestnik khirurgii imeni I. I. Grekova》1957,79(11):112-114
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NUR Bilge Gülsüm OK Evren Mustafa ALTUNSOY Osman Sami A?LARCI Mehmet ?OLAK Enes GüNG?R 《Journal of applied oral science : revista FOB》2014,22(6):502-508
Objective
This study aimed to assess the quality of root fillings, coronal restorations, complications of all root-filled teeth and their association with apical periodontitis (AP) detected by cone-beam computed tomography (CBCT) images from an adult Turkish subpopulation.Material and Methods
The sample for this study consisted of 242 patients (aging from 15 to 72 years) with 522 endodontically treated teeth that were assessed for technical quality of the root canal filling and periapical status of the teeth. Additionally, the apical status of each root-filled tooth was assessed according to the gender, dental arch, tooth type and age classification, undetected canals, instrument fracture, root fracture, apical resorption, apical lesion, furcation lesion and type and quality of the coronal structure. Statistical analysis was performed using percentages and chi-square test.Results
The success rate of the root canal treatment was of 54.4%. The success rates of adequate and inadequate root canal treatment were not significantly different (p>0.05). Apical periodontitis was found in 228 (45.6%) teeth treated for root canals. Higher prevalence of AP was found in patients aging from 20 to 29 years [64 (27%) teeth] and in anterior (canines and incisors) teeth [97 (41%) teeth].Conclusions
The technical quality of root canal filling performed by dental practitioners in a Turkish subpopulation was consistent with a high prevalence of AP. The probable reasons for this failure are multifactorial, and there may be a need for improved undergraduate education and postgraduate courses to improve the clinical skills of dental practitioners in endodontics. 相似文献20.