Resistance to anti-HER2 therapies in HER2
breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and ...treatment-resistant cell line models to investigate a mechanism by which HER2
breast cancer can reactivate the HER network under potent HER2-targeted therapies.
Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER
/HER2
BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally.
and
experiments were performed to test alternative therapies for mutant HER2 inhibition.
Genomic analyses revealed that the
L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of
L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines.
L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by
L755S
and
HER2 reactivation through acquisition of the
L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.
.
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a ...potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
A detailed population balance model is used to perform a parametric sensitivity study on the computed particle size distributions (PSDs) for a laminar premixed ethylene burner-stabilised stagnation ...flame. The soot morphology in the post-flame region is studied using computed sintering level distributions, fringe length analysis of the polycyclic aromatic hydrocarbons (PAHs) within the primary soot particles, and TEM-like projections of aggregates. The computed PSDs were sensitive to the minimum particle inception size, the coagulation rate and the inception species concentration. Changes in the particle inception size and the coagulation rate led to an overall shift in the position of the coagulation peak. Only changes in the inception species concentration led to a systematic shift in both the position of the trough between the modes of the bimodal PSD and the coagulation peak at larger diameters. Given the overall model, varying the inception species concentration with each burner-stagnation plate separation was the only means possible to achieve a satisfactory agreement between the experimental and computed PSDs. This study shows that further work is required to better understand the soot precursor chemistry, the inception of soot particles. Additional work may also be needed in the area of experimental mobility sizing for the flame studied here.
Evolution of particle size distribution function (PSDF) was studied in premixed stretch-stabilized flat flames for the first time. The purpose is to demonstrate that stretch-stabilized flames can ...broaden the experimental flame condition space for studying soot formation in a pseudo-one dimensional flow configuration. PSDFs were measured in three series of atmospheric-pressure ethylene–oxygen–argon flames with maximum temperatures around 1980, 2000, and 2160K. The measured PSDFs show a strong effect of flame temperature as nucleation and growth of soot is found to be suppressed towards high temperatures. Simulations using a population balance soot model show reasonably good agreement with the 1980 and 2000K series of flames, but it significantly overpredicts the number density and size of soot in the highest temperature flame. Numerical tests suggest that the discrepancy can be caused by high-temperature reversibility in surface growth and other processes.
The prevalence of fatty liver in children is unknown and its relationship to obesity is poorly defined. The present study of 810 northern Japanese children (4-12 years old) determined the prevalence ...of fatty liver in the pediatric population and its relationship to obesity. Diagnosis of fatty liver was based on established real-time ultrasonographic criteria. The overall prevalence of fatty liver was 2.6% and was higher for boys (3.4%) than for girls (1.8%), although not statistically significant (P = 0.15). Fatty liver was found in children as young as 6 years of age. There was no significant association between the prevalence of fatty liver and height (physical growth). There was a strong positive correlation between fatty liver prevalence and established obesity indices: Rohrer's Index--chi 2 linear trend = 59.2, P < 0.0001; body mass index--chi 2 linear trend = 91.6, P < 0.0001; and age-gender-adjusted Japanese standard index of weight for height--chi 2 linear trend = 93.2, P < 0.0001. However, direct measurement of abdominal subcutaneous fat thickness by ultrasonography was the best predictor of fatty liver: chi 2 linear trend = 159, P < 0.0001. These results indicate that fatty liver may develop very early in life, and there is a direct relationship between degree of obesity and fatty liver in children.
An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-α-aminoazepinone 6b were ...developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic α-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
The author has chosen three major topics in development economics for a discussion on how to teach the subject: the concepts and measurement of development, models of growth and development, and the ...international aspects of economic development. For the concepts of development, it is important to emphasize the coherence of the topics to be studied. In teaching models of growth and development, he suggests that the classical models, the Marxian model, the Harrod-Domar models, and the Neoclassical model be discussed in the context of technology versus capital as a major determinant of growth and development. The role of labor, employment, and human capital would be discussed in the context of the Lewis-Ranis-Fei model, the Harris-Todaro model, and the New Growth theory. The international aspects should be given due emphasis in the economic development syllabus with a thorough discussion on trade, investment, and finance in this connection.
The paper describes the current competition policy framework in Hong Kong: how it came into existence, what business practices are prohibited, and how the enforcement system works. Recent cases in ...the telecommunications industry are used to illustrate the sectoral approach, a unique feature of Hong Kong's competition policy. We argue that a sectoral approach faces two fundamental drawbacks. First, due to having different "rules of the game" for different sectors, the allocation of resources may be distorted in the long run. Second, since the relevant regulatory agencies perform dual roles both as competition policy enforcer and as traditional regulator of natural monopolies, the impartiality of their competition decisions may not be credibly conveyed to the public. We also address other specific problems associated with the sectoral approach, such as the exclusion of structural issues, narrow coverage of sectors, and the lack of public enforcement. We conclude that an overall competition law can better promote competition and economic efficiency in Hong Kong.
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