Endobronchial Ultrasound Doppler Image Features Correlate with mRNA Expression of hif1-α and vegf-c in Patients with Non–Small-Cell Lung Cancer

IntroductionWe attempted to assess the correlation between the Doppler mode image patterns during endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration and the expression of angiogenesis-related molecules within lymph nodes in patients with non–small-cell lung cancer.MethodsThirty-eight archived EBUS- transbronchial needle aspiration samples of lymph nodes (27 metastatic and 11 nonmetastatic) in patients with non–small-cell lung cancer with Doppler mode ultrasound image were analyzed. The Doppler mode image of the vasculature of the targeted lymph node was categorized into the following groups: normal blood flow, low blood flow (LBF), and high blood flow (HBF). Vascular index ratio (vascular area/lymph node area) of each metastatic lymph node was calculated. Total RNA and protein was extracted and analyzed for expression of HIF-1α, VEGF-A, and VEGF-C by quantitative RT-PCR and enzyme-linked immunosorbent assay.ResultsWithin the 27 metastatic lymph nodes, eight were categorized into the LBF group and 19 into the HBF group. Vascular index ratio was significantly higher in HBF than LBF (p = 0.0003). mRNA expression of HIF-1α and VEGF-A was significantly higher in metastatic lymph nodes than in benign lymph nodes (p < 0.0001). Compared with LBF and HBF, HIF-1α mRNA expression was significantly higher in LBF (p = 0.01) and VEGF-C mRNA expression was significantly higher in HBF (p = 0.0315). There was no significant difference in protein expression by enzyme-linked immunosorbent assay analysis.ConclusionsThe vascularity of metastatic lymph nodes observed by EBUS correlates with the mRNA expression of HIF-1α and VEGF-C (not VEGF-A). This correlation is a clinical utility that needs to be evaluated further

Native defects and self-diffusion in GaSb

The native defects in GaSb have been studied with first-principles total-energy calculations. We report the structures and the formation energies of the stable defects and estimate the defect concentrations under different growth conditions. The most important native defect is the GaSb antisite, which acts as an acceptor. The other important defects are the acceptor-type Ga vacancy and the donor-type Ga interstitial. The Sb vacancies and interstitials are found to have much higher formation energies. A metastable state is observed for the SbGa antisite. The significantly larger concentrations of the Ga vacancies and interstitials compared to the corresponding Sb defects is in accordance with the asymmetric self-diffusion behavior in GaSb. The data supports the next-nearest-neighbor model for the self-diffusion, in which the migration occurs independently in the different sublattices. Self-diffusion is dominated by moving Ga atoms.Peer reviewe

Salivary Mucocele in a Laboratory Beagle

The histologic characteristics of a salivary mucocele in a beagle used in a toxicity study are described in this report. A pale yellowish cyst under the mandibular skin containing frothy mucus was observed at necropsy. Microscopically, numerous villous projections arose from the internal surface of the cyst and were lined by stratified epithelial-like macrophages, which were immunopositive for macrophage scavenger receptor A. A ruptured sublingual interlobar duct connected to the lumen was observed near the cyst. Luminal amorphous material showed a positive reaction with Alcian blue and periodic acid-Schiff staining as did mucin in the sublingual gland. Ultrastructurally, the epithelial-like macrophages had numerous vacuoles containing electron-lucent material, which was presumed to be lysosomal in origin, and had pseudopods on their cell surfaces interdigitating with those on the adjacent cells. This case report helps to understand the diversity of the background findings in beagles used in toxicity studies

Polygenic architecture informs potential vulnerability to drug-induced liver injury

Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market, and this is partially due to the inability to identify patients who are at risk1. Here, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS)2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin, and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over 10 different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy might potentially inform designs of safer, more efficient, and robust clinical trials

Paradoxical expression of cell cycle inhibitor p27 in endometrioid adenocarcinoma of the uterine corpus – correlation with proliferation and clinicopathological parameters

p27 is regarded as a cyclin-dependent kinase inhibitor of the G1-to-S cell cycle progression by suppressing the kinase activity of cyclin/cyclin-dependent kinase complex. This study aimed to investigate p27 expression in the normal endometrium and endometrioid adenocarcinoma of the uterine corpus and the correlation of its expression with cell proliferation and clinicopathological parameters. Tissue samples of 127 endometrioid adenocarcinomas and 15 normal endometria were used in the study. Immunohistochemical staining for detecting p27 and Ki-67 was performed by the labelled streptavidin-biotin method on formalin-fixed and paraffin-embedded tissue samples. The expression was given as the labelling index, which indicates the percentage of positive nuclei. p27 staining was observed in the nuclei of the glandular cells in the functional layer of the secretory phase endometrium, whereas it was negative in those of the proliferative phase. In endometrioid adenocarcinomas, the labelling index of p27 expression paradoxically increased more significantly in the higher histological grades and was correlated with that of Ki-67. The high level of p27 expression was associated with clinicopathological parameters such as FIGO stage, lymph node metastasis, lymphovascular space involvement and myometrial invasion. High p27 expression was linked to higher grades of endometrioid adenocarcinoma, cell proliferation and some clinical prognostic factors. These results indicate that p27 might be an indicator of poor prognosis

TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe

In Europe, high incidence rates of oesophageal squamous cell carcinoma (SCCE) are observed in western France (Normandy and Brittany) and in north-eastern Italy. Analysis of TP53 mutations in tumours from these regions has shown a high prevalence of mutations at A:T basepairs that may result from DNA damage caused by specific mutagens. However, the spectrum of TP53 mutations in regions of low incidence is unknown. We report here TP53 mutation analysis in 33 SCCE collected in Lyon, an area of low incidence. These tumours were also examined for MDM2 and P63 amplification, and for expression of p16INK4a/CDKN2a, cyclin E, p27Kipland Cox2. TP53 mutations were detected in 36% of the cases (12/33). In contrast with regions of high incidence, the mutation spectrum did not show a high prevalence of mutations at A:T base pairs. P63 was amplified in 5/32 cases tested (15.5%). No amplification of MDM2 was found. Expression studies revealed frequent loss of p16INK4a/CDKN2a(46%) and p27Kipl(25%) expression, and frequent overexpression of Cyclin E (70%) and Cox2 (42%). Overall, these results indicate that in Europe, SCCE from areas of high and low incidence present a similar pattern of molecular alterations but differ by the type of TP53 mutations. © 2001 Cancer Research Campaign http://www.bjcancer.co