TGFβ promotes YAP‐dependent AXL induction in mesenchymal‐type lung cancer cells

The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.

Abbreviations

AUC

area under the curve

AXL

AXL receptor tyrosine kinase

BCL2

B‐cell lymphoma 2

CTD2

cancer target discovery and development

CTGF

connective tissue growth factor

DEG

differentially expressed genes

DOXO

doxorubicin

EMT

epithelial–mesenchymal transition

Eto

etoposide

FDA

Food and Drug Administration

ITGB3

integrin beta‐3

MAPK

mitogen‐activated protein kinase

MMP2

matrix metalloproteinase‐2

MMP9

matrix metalloproteinase‐9

mRNA

messenger RNA

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

SBE

SMAD binding element

SERPINE1

serpin family E member 1

siRNA

small interfering RNA

ssGSEA

single‐sample gene set enrichment analysis

TCGA

The Cancer Genome Atlas

TGFβ

transforming growth factor beta

YAP

Yes‐associated protein

YAP8SA

mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP

ZEB1

zinc finger E‐box binding homeobox 1

ZEB2

zinc finger E‐box‐binding homeobox 2

     

Coronary Artery Lumen Segmentation Using Location–Adaptive Threshold in Coronary Computed Tomographic Angiography: A Proof-of-Concept

ObjectiveTo compare the lumen parameters measured by the location-adaptive threshold method (LATM), in which the inter- and intra-scan attenuation variabilities of coronary computed tomographic angiography (CCTA) were corrected, and the scan-adaptive threshold method (SATM), in which only the inter-scan variability was corrected, with the reference standard measurement by intravascular ultrasonography (IVUS).Materials and MethodsThe Hounsfield unit (HU) values of whole voxels and the centerline in each of the cross-sections of the 22 target coronary artery segments were obtained from 15 patients between March 2009 and June 2010, in addition to the corresponding voxel size. Lumen volume was calculated mathematically as the voxel volume multiplied by the number of voxels with HU within a given range, defined as the lumen for each method, and compared with the IVUS-derived reference standard. Subgroup analysis of the lumen area was performed to investigate the effect of lumen size on the studied methods. Bland-Altman plots were used to evaluate the agreement between the measurements.ResultsLumen volumes measured by SATM was significantly smaller than that measured by IVUS (mean difference, 14.6 mm³; 95% confidence interval [CI], 4.9–24.3 mm³); the lumen volumes measured by LATM and IVUS were not significantly different (mean difference, −0.7 mm³; 95% CI, −9.1–7.7 mm³). The lumen area measured by SATM was significantly smaller than that measured by LATM in the smaller lumen area group (mean of difference, 1.07 mm²; 95% CI, 0.89–1.25 mm²) but not in the larger lumen area group (mean of difference, −0.07 mm²; 95% CI, −0.22–0.08 mm²). In the smaller lumen group, the mean difference was lower in the Bland-Altman plot of IVUS and LATM (0.46 mm²; 95% CI, 0.27–0.65 mm²) than in that of IVUS and SATM (1.53 mm²; 95% CI, 1.27–1.79 mm²).ConclusionSATM underestimated the lumen parameters for computed lumen segmentation in CCTA, and this may be overcome by using LATM.     

Prosthetic management of a growing patient with Russell-Silver syndrome: a clinical report

Russell-Silver syndrome (RSS) is a congenital disease characterized by short stature due to growth hormone deficiency, physical asymmetry, inverted triangular face, micrognathia, prominent forehead, and hypodontia. This case report presents a prosthetic management of a 6-year-old patient with Russell-Silver syndrome treated with overdentures on the maxilla and the mandible using the remaining primary teeth. Subsequent and comprehensive dental management considering the growth and development of a young patient will be necessary.     

Design of an intravenous oxygenator

The aim of this study was to design a new intravenous blood–gas exchange device and to estimate the design characteristics of the device with a dimensionless function by using a substance that can be used instead of bovine blood. In addition, the characteristics of oxygen transfer were estimated using empirical formulas and the reliability of the equations was ascertained by comparing their output with an experiment performed using bovine blood. The dimensionless function was derived using distilled water and bovine blood to estimate the oxygen transfer rate. Using the derived equations, the calculated oxygen transfer rates for bovine blood and distilled water were similar for Reynolds numbers ranging from 0.7 to 7.0. Therefore, it is possible to estimate the oxygen transfer rate in bovine blood, which is a non-Newtonian fluid, using distilled water, which is a Newtonian fluid. Moreover, it was possible to verify the related equations because the oxygen transfer rate could be estimated using the derived equations, according to the diameters of the various device modules.     

Molecular cloning of agonistic and antagonistic monoclonal antibodies against human 4-1BB.

Previously, we prepared two different monoclonal antibodies (mAbs) against human 4-1BB (CD137): an agonistic mAb BBK-1 and an antagonistic mAb BBK-2. In this paper, we describe the molecular cloning of these two mAbs and present comparisons of their amino acid sequences. cDNAs encoding the heavy (H) and light (L) chains of the two mAbs were cloned by screening of cDNA libraries constructed from hybridomas secreting these mAbs. Comparisons of amino acid sequences of the two mAbs showed that, while the constant regions of the H and L chains were identical between the two mAbs, the variable region showed 45% identity in H chains and 48% identity in L chains. This suggests that these two mAbs recognize different epitopes of 4-1BB and may have different effects on the activity of 4-1BB.     

Effect of marginal zinc deficiency on the lymphatic absorption of [14C]cholesterol

The effect of zinc deficiency on intestinal absorption of cholesterol was investigated in adult male rats fed 3.6 ppm of dietary zinc (ZD) and compared with pair-fed (PF) and ad-libitum (CT) controls fed 30.6 ppm of zinc for 10 to 12 wk. The intestinal absorption of cholesterol was measured by collecting the mesenteric lymph at hourly intervals for 8 h after infusing a dose of [14C]cholesterol in a lipid emulsion through an indwelling duodenal catheter. Data on the hourly lymphatic output of [14C]cholesterol showed that the absorption of [14C]cholesterol plateaued at 4 h postdosing in all groups. The rate of the appearance of [14C]cholesterol in the mesenteric lymph significantly decreased in ZD rats at 5 h and thereafter. The cumulative absorption of [14C]cholesterol by ZD rats for the 8-h period was 4.4 +/- 1.0% of the dose, compared with 11.8 +/- 1.1% by PF and 10.7 +/- 1.4% by CT rats. There were no differences in percent distribution of esterified [14C]cholesterol among the three groups. Also, no significant change in mucosal cholesterol esterase activity was observed due to zinc deficiency. The present data and previous findings taken together suggest that the primary mechanism responsible for the impaired absorption of cholesterol may be associated with defective formation of chylomicrons in the intestinal mucosa.