Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer.

Colon cancer is the third leading cause of death from cancer worldwide with less than 10% survival rate at the late stage. Although mutations of certain genes have been implicated in familial colon cancer development, the etiology of the majority of colon cancer remains unknown. Herein, we identified TYRO3 as a potential oncogene. Immunohistochemical staining results demonstrated that levels of TYRO3 were markedly elevated in polyps and colon cancer cells and were negatively correlated with prognosis. Overexpression of TYRO3 enhanced cell motility, invasion, anchorage-independent growth and metastatic ability, while knockdown of TYRO3 impaired all these processes. Results from meta-analysis showed that TYRO3 was associated with epithelial-mesenchymal transition (EMT) signatures. Gain-of-function and loss-of-function experiments demonstrated that expression of SNAI1, the master regulator of EMT, was regulated by TYRO3 and played a major role in mediating TYRO3-induced EMT processes. The murine model also demonstrated that Tyro3 and Snai1 were upregulated in the early stage of colon cancer development. To provide a proof-of-concept that TYRO3 is a druggable target in colon cancer therapy, we raised anti-TYRO3 human antibodies and showed that treatment with the human antibody abolished TYRO3-induced EMT process. More importantly, administration of this anti-TYRO3 antibody increased drug sensitivity in primary cultured colon cancer cells and xenografted mouse tumors. These findings demonstrate that TYRO3 is a novel oncogene and a druggable target in colon cancer.

Metabolic and ventilatory responses to hypoxia in two altitudinal populations of the toad, Bufo bankorensis.

Effects of hypoxia on resting oxygen consumption (MO2), lung ventilation, and heart rate at different ambient PO2 were compared between lowland and high altitude populations of the toad, Bufo bankorensis. Resting MO2 decreased significantly in mild hypoxia (PO2 = 120 mm Hg) at 10 degrees C and in moderate hypoxia (PO2 = 80 mm Hg) at 25 degrees C in both altitudinal populations; however, resting MO2 did not differ significantly between the two populations. Numbers of lung ventilation periods (VP) and total inspired volume (VL) did not change with PO2 at 10 degrees C, but did increase at moderate and severe hypoxia (40 mm Hg), respectively, at 25 degrees C. Resting heart rates did not change during hypoxia and did not differ between altitude populations. The results suggest (1) the effect of PO2 change on MO2 should be considered in future studies involving transfer of anurans to a different altitude; and (2) the metabolic and ventilatory physiology in B. bankorensis does not compensate for the low temperature and PO2 at high altitude.

The accuracy of bioimpedance cardiography in the measurement of cardiac output in comparison with thermodilution method.

BACKGROUND: Continuous noninvasive measurement of cardiac output (CO) is clinically desirable. Thoracic electrical bioimpedance (TEB) offers such a continuous noninvasive technique for the measurement of CO on a beat-by-beat basis. The purpose of this study was to compare the correlation of TEB with the thermodilution (TD) method of measuring CO during surgery. METHODS: Eighteen patients (age 39-64 yr), with coronary artery disease undergoing coronary artery bypass graft surgery were studied. Patients were excluded if severe arrhythmias or aortic insufficiency was present before operation. Simultaneous measurements of CO were performed in each patient with the use of a 7F Swan-Ganz catheter and TEB. 128 matched pair values were obtained and compared using regression analysis. Bias (mean difference between measurements) and limits of agreement with 95% confidence limits were also calculated. RESULTS: A good correlation (correlation coefficient, r = 0.86; TEB = 0.55 + 0.82TD, p < 0.001) between the two methods of measuring CO was observed, and the standard error was small (SE = 0.218). The mean difference between CO measurements (TEB-TD) was -0.66 L/min and had a 95% confidence interval of 0.12 to 0.98 L/min. The standard deviation of the difference was 0.915 L/min and the limits of agreement were from -2.49 to 1.17 L/min. There appeared to be a good agreement between TEB and TD CO measurement in this study. CONCLUSIONS: Technological advances in TEB have resulted in more accurate CO measurements. Such device offers a noninvasive alternative to the TD technique for the determination of CO, and may potentially be very useful as a powerful, noninvasive, continuous technique for monitoring cardiac function in the clinical setting.

Effects of pre-incubation egg storage on embryonic functions and growth.

The effect of pre-incubation storage on physiological functions of chick embryos during the last half of incubation and the relationship to embryonic growth were studied. In the first experiment, eggs were stored for 20 or 30 days, respectively, and the developmental patterns of oxygen consumption (MO2), heart rate (fH) and O2 pulse of individual embryos were examined. The MO2 of stored eggs increased at significantly lower rate than the control between day 12 and 17 of incubation, and the stored eggs had a significantly lower plateau MO2 between day 17 and 19. The decrease in MO2 of some stored eggs was correlated with late incubation mortality. Pre-incubation storage also resulted in significant changes in the developmental patterns of fH and O2 pulse. In the second experiment, the eggs were stored for 10 and 20 days, respectively, to also examine the effect of short-term storage on the development of MO2 in relation to embryo growth. Pre-incubation storage for 10 days had no significant effect, but 20 days storage shifted developmental patterns of MO2, wet mass, dry mass and embryo water fraction to the right of the control. Furthermore, MO2 was significantly lower than expected on the basis of embryo mass after day 17 of incubation. Prolonged pre-incubation storage caused not only a rightward shift in MO2 pattern due to retarded growth, but also severe depression of MO2 during the last stages of prenatal development.

Developmental patterns of O2 consumption, heart rate and O2 pulse in unturned eggs.

The effects of failure to turn eggs on the developmental patterns of oxygen consumption (MO2), heart rate (fH) and O2 pulse during the second half of incubation of individual chicken eggs were examined. The MO2 of unturned eggs increased at a significantly lower rate than the control toward the end of prenatal incubation, and the plateau MO2 between day 17 and 19 was significantly lower than the control. Lack of turning also resulted in significant changes in the developmental patterns of fH and O2 pulse. It is suggested that the effects of lack of egg-turning on the developmental patterns of MO2 may be attributable to lower embryonic growth rate in addition to impairment of gas exchange through the chorioallantoic gas exchanger.

Blood pressures and heart rate during larval development in the anuran amphibian Xenopus laevis.

Heart rate and blood pressure were measured in lightly anesthetized developing Xenopus laevis from hatching (body mass approximately 3 mg) to the end of metamorphosis (< or = 1 g). Blood pressures in the conus arteriosus, truncus arteriosus, and ventricle were measured by a servo-null micropressure system. Heart rate was determined from blood pressure recordings, and cardiac cycles were videotaped through a dissecting microscope. Heart rate varied from 50 to 150 beats/min and showed a negative correlation with body mass, with a slope less than predicted from allometric equations based on adult vertebrates. Mean truncus pressures showed a positive correlation with body mass, increasing from 4 mmHg in a 25-mg larva to 9 mmHg in a 1-g larva. The pressure waveform during ventricular systole was similar in all developmental stages examined, whereas those in conus and truncus varied with development. Conus pressures differed distinctly from truncus pressure during diastole in all larvae examined, suggesting the existence of functional valves between conus and truncus as early as stage 46 of the Nieuwkoop-Faber larval staging system. Although the developmental patterns of heart rate and blood pressure in X. laevis showed significant correlation with body mass, body mass explained less than one-half of the variation in these variables. Therefore developmental factors other than body mass, such as changes in heart mass and the addition of new resistance vessels, may influence heart rate and blood pressure during development in X. laevis.

Cardiac output and peripheral resistance during larval development in the anuran amphibian Xenopus laevis.

Stroke volume (SV) and cardiac output (CO) were measured in anesthetized larvae of Xenopus laevis from hatching (3 mg) to the end of metamorphosis (approximately 1 g). CO and SV were calculated from videotaped images of the intact beating heart. SV increased from 2.4 x 10(-3) microliters at 3 mg body mass to 7.6 microliters at 1 g. CO increased from 0.25 microliter/min at 3 mg to 623 microliters/min at 1 g. With use of CO, along with arterial pressures from another study [P.-C. L. Hou and W. W. Burggren. Am. J. Physiol. 269 (Regulatory Integrative Comp. Physiol. 38): R1120-R1125, 1995], peripheral resistance and cardiac work were also calculated. Resistance decreased rapidly from 701 peripheral resistance units (PRU, mmHg.s.mm-3) at 3 mg body mass to 79 PRU at 20 mg and gradually declined toward 0.9 PRU at 1 g. Cardiac work increased from 0.06 dyn.mm at 3 mg body mass to 1.27 dyn.mm at 20 mg and then climbed sharply to 717 dyn.mm at 1 g. The general pattern of change in hemodynamic variables (except heart rate) during larval development is similar in Xenopus laevis and chick embryos, suggesting a common pattern for hemodynamic development in vertebrate embryos/larvae.

Interaction of allometry and development in the mouse Mus musculus: heart rate and hematology.

The contribution of body mass changes to developmental adjustments in heart rate and hematology has been investigated in the mouse Mus musculus. Both resting heart rate (fH) and hematological variables including erythrocyte concentration, hemoglobin concentration, blood oxygen capacity, hematocrit, mean corpuscular hemoglobin and mean corpuscular volume, changed considerably during the increase in body mass from birth (1g) to adulthood (maximum of 50 g). There were two phases of change, one characteristic of preweaned mice (approximately less than 10 g) and the other of postweaned mice (approximately 10-50 g). In preweaned mice resting fH was about 1/2 of the value predicted on the basis of interspecific allometric data from mammals. fH increased steadily until body mass reached 10 g, then began to decrease with further mass increase at the same rate as predicted from interspecific allometric data. Erythrocyte concentration, hematocrit, hemoglobin concentration and blood oxygen capacity were all significantly lower in preweaned mice compared with postweaned mice. It is suggested that the progressive heart rate increase in very young mice may be to increase cardiac output to compensate for the neonatal anemia. After weaning, hematological variables showed little or no further change with increasing body mass. Collectively, these data indicate that during the early phases of postnatal growth, developmental factors other than body mass have the greatest influence on heart rate and hematology, and allometric data derived from interspecific studies on adults have little predictive value in neonates. After weaning, however, body mass is the major influence on these variables, and allometric data derived from interspecific studies on adults are reasonably accurate as predictors. We conclude that interspecific allometric studies must be properly regarded as the study of adult animals of different body sizes, and that untested assumptions about the applicability of these data to intraspecific studies of immature specimens should be made with extreme caution.