Optical Coherence Tomography of Pulmonary Arterial Walls in Humans and Pigs (Sus scrofa domesticus)

Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by progressive elevation of the pulmonary pressures that, in the absence of therapy, results in chronic right-heart failure and premature death. The vascular pathology of PAH is characterized by progressive loss of small (diameter, less than 50 μm) peripheral pulmonary arteries along with abnormal medial thickening, neointimal formation, and intraluminal narrowing of the remaining pulmonary arteries. Vascular pathology correlates with disease severity, given that hemodynamic effects and disease outcomes are worse in patients with advanced compared with lower-grade lesions. Novel imaging tools are urgently needed that demonstrate the extent of vascular remodeling in PAH patients during diagnosis and treatment monitoring. Optical coherence tomography (OCT) is a catheter-based intravascular imaging technique used to obtain high-resolution 2D and 3D cross-sectional images of coronary arteries, thus revealing the extent of vascular wall pathology due to diseases such as atherosclerosis and in-stent restenosis; its utility as a diagnostic tool in the assessment of the pulmonary circulation is unknown. Here we show that OCT provides high-definition images that capture the morphology of pulmonary arterial walls in explanted human lungs and during pulmonary arterial catheterization of an adult pig. We conclude that OCT may facilitate the evaluation of patients with PAH by disclosing the degree of wall remodeling present in pulmonary vessels. Future studies are warranted to determine whether this information complements the hemodynamic and functional assessments routinely performed in PAH patients, facilitates treatment selection, and improves estimates of prognosis and outcome.Abbreviations: OCT, optical coherence tomography; PAC, pulmonary artery catheter; PAH, pulmonary arterial hypertensionPulmonary arterial hypertension (PAH) is a devastating disorder characterized by progressive elevation of pulmonary pressures that, when untreated, can lead to chronic right heart failure and death.¹⁴ The vascular pathology of PAH is characterized by neointimal formation, medial thickening, intravascular thrombi and, in severe cases, intravascular clusters of disorganized endothelial cells that give rise to tortuous endovascular channels.⁸ Most of the early vascular lesions are found in small (diameter, less than 50 μm) pulmonary arteries. However, as the disease advances, pulmonary arteries (diameter, 50 μm or larger) proximal to these lesions also display evidence of luminal narrowing and medial thickening.^7,8,15 Most patients with PAH are younger than those with chronic systemic vascular disorders (that is, coronary artery disease, peripheral vascular disease, systemic hypertension), whose vascular pathology involves mostly large to medium-sized arteries. However, both patient populations demonstrate various pathologic features, including vascular smooth-cell accumulation, neointimal formation, inflammation, luminal narrowing, and alterations in the composition of the extracellular matrix.^6,17The only definite way to diagnose PAH is through right heart catheterization to directly measure the pressure in the pulmonary circulation. Although pulmonary angiography during right heart catheterization cannot be used to diagnose PAH, it provides supportive evidence of PAH by demonstrating significant peripheral small vessel loss and luminal narrowing in the remaining central vessels. Angiography can help clinicians visualize pulmonary vessels in real time, but this diagnostic technique has important limitations. The use of ionized contrast can cause allergic reactions and may trigger acute renal failure due to contrast-induced nephropathy.²⁶ In addition, pulmonary angiography provides information regarding gross vessel appearance and small vessel perfusion but not about the state of vascular wall remodeling or the extent of luminal narrowing associated with PAH at any stage.^5,16 Therefore, imaging techniques are urgently needed that complement the hemodynamic information obtained via right heart catheterization with a safe and reproducible method to assess vascular wall pathology, thereby allowing clinicians to correlate the clinical evolution of PAH with the progression of vascular pathology.The last decade has seen tremendous progress in the development of intravascular imaging modalities that can identify patients at risk for developing complications related to systemic vascular disease and therefore prevent disease-related morbidity and mortality.⁴ One such modality is optical coherence tomography (OCT), an imaging technique that uses a thin (diameter, 1.0 mm) wire and near-infrared light to capture micrometer-resolution, 3D images from within optical scattering media (for example, biologic tissue).¹ Superior to other intravascular imaging techniques, OCT is frequently used in patients with coronary artery disease, where it provides high-resolution images of the coronary arterial wall that correlate highly with pathology seen in explanted vessels.^10,11,21 To date, several small studies have demonstrated the application of OCT to the evaluation of vascular remodeling in both idiopathic PAH and chronic thromboembolic PAH.^7,21 However, despite OCT''s obvious advantages in the characterization of vascular remodeling in discrete segments of the pulmonary circulation, whether OCT provides anatomic information across the length of the pulmonary artery has not been tested.Here, we report the capacity of OCT to obtain both longitudinal and cross-sectional images that provide accurate anatomic information on healthy pulmonary arteries in explanted human lungs and during the pulmonary arterial catheterization of a live adult pig (Sus scrofa domesticus).     

Prognostic Value of Cancer Stem Cell Marker Aldehyde Dehydrogenase in Ovarian Cancer: A Meta-Analysis

Objective

Aldehyde dehydrogenase (ALDH) has recently been reported as a marker of cancer stem-like cells in ovarian cancer. However, the prognostic role of ALDH in ovarian cancer still remains controversial. In this study, we aimed to evaluate the association between the expression of ALDH and the outcome of ovarian cancer patients by performing a meta-analysis.

Methods

We systematically searched for studies investigating the relationships between ALDH expression and outcome of ovarian cancer patients. Only articles in which ALDH expression was detected by immunohistochemical staining were included. A meta-analysis was performed to generate combined hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS).

Results

A total of 1,258 patients from 7 studies (6 articles) were included in the analysis. Our results showed that high ALDH expression in patients with ovarian cancer was associated with poor prognosis in terms of Os (HR, 1.25; 95% CI, 1.07-1.47; P = 0.005) and DFS (HR, 1.58; 95% CI, 1.00-2.49; P = 0.052), though the difference for DFS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg’s and Egger’s tests (Begg’s test, P = 0.707; Egger’s test, P = 0.355).

Conclusion

The present meta-analysis indicated that elevated ALDH expression was associated with poor prognosis in patients with ovarian cancer.     

无噪声Hodgkin-Huxley神经元对正弦信号的响应

研究了无噪声影响下的Hcdgkin-Huxley神经元在正弦信号刺激下的动力学行为,并利用“魔梯”图和峰峰间期分布图来分别描述。数值模拟结果表明,当信号振幅一定时,神经元的发放情况随频率而改变;当信号的频率一定时,峰峰间期分布随振幅而改变,相应地,峰峰间期序列也具有不同的特点。     

New thiazole carboxamides as potent inhibitors of Akt kinases

A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit N-(1-amino-3-phenylpropan-2-yl)-2-phenylthiazole-5-carboxamide (1). One of the most potent compounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC(50) values of 25, 196 and 24nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2 and GSK3β proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhibitors might serve as lead compounds for further development of novel effective anticancer agents.     

出芽酵母Saccharomyces cerevisiae转录抑制因子Rdr1负调控细胞胁迫应答

Rdr1是出芽酵母Saccharomyces cerevisiae的一个转录抑制因子,参与控制细胞的多重药物耐受性,并可能与细胞胁迫应答相关．利用PCR方法扩增RDR1基因片段,将其克隆至高拷贝表达载体pYES2/NTA上并诱导Rdr1蛋白在酵母细胞中过表达．为了揭示转录抑制因子Rdr1在胁迫应答中的作用,比较了RDR1过表达细胞、RDR1缺失突变体细胞和野生型细胞在过氧化氢处理、热胁迫和高盐处理条件下的生长状态,结果显示,RDR1过表达导致细胞对上述3种胁迫作用更敏感,而RDR1缺失则使细胞对这些胁迫作用的耐受性不受影响或有一定增强．为了揭示上述不同细胞在胁迫条件下生长状态的差异与细胞内抗氧化酶活性之间的关系,测定并比较了RDR1过表达细胞、RDR1缺失突变体细胞和野生型细胞中超氧化物岐化酶(superoxide dismutase SOD)、过氧化氢酶、葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase G6PDH)、谷胱甘肽还原酶(glutathione reductase GR)的活性．结果表明,RDR1缺失突变体细胞具高活性的SOD、过氧化氢酶、G6PDH和GR,而Rdr1过表达细胞中SOD、过氧化氢酶、G6PDH和GR的活性较低．RDR1对SOD和过氧化氢酶活性的影响要大于G6PDH和GR．细胞抗氧化酶活性的变化初步揭示,RDR1过表达细胞对胁迫的敏感和RDR1缺失突变体细胞对胁迫耐受性增加的原因．为转录抑制因子Rdr1在胁迫应答中的负调控作用及其机理提供了初步的遗传学和生物化学证据．     

BitPhylogeny: a probabilistic framework for reconstructing intra-tumor phylogenies

Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, we present BitPhylogeny, a probabilistic framework to reconstruct intra-tumor evolutionary pathways. Using a full Bayesian approach, we jointly estimate the number and composition of clones in the sample as well as the most likely tree connecting them. We validate our approach in the controlled setting of a simulation study and compare it against several competing methods. In two case studies, we demonstrate how BitPhylogeny reconstructs tumor phylogenies from methylation patterns in colon cancer and from single-cell exomes in myeloproliferative neoplasm.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0592-6) contains supplementary material, which is available to authorized users.