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Introduction: The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months. Methods: To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. Results: The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550. Moreover, treatment with a MRTX-849/RMC-4550 combination yielded transient tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice and durable shrinkage of mKRC.1 tumors. Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. Discussion: These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors. [ABSTRACT FROM AUTHOR]

Background: ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI‐resistant ROS1+ lung cancers. Methods: Utilizing a primary, patient‐derived TPM3‐ROS1 cell line (CUTO28), we derived an entrectinib‐resistant line (CUTO28‐ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74‐ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK‐2 entrectinib trial to determine the prevalence of MET amplification. Results: CUTO28‐ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28‐ER cells. CUTO28‐ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74‐ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib‐resistant ROS1+ NSCLC STARTRK‐2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Conclusions: Treatment with ROS1‐selective inhibitors may lead to MET‐mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1‐selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET‐driven resistance. [ABSTRACT FROM AUTHOR]

We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the [...]

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1475-4932.2007.00374.x Byline: MARGARET GILES (1), ANH T. LE (1) Keywords: J60; J64 Abstract: This paper examines the employability and labour market aspirations of prisoners. The results suggest that repeat prisoners are less likely to be employed than non-repeat prisoners. However, a large proportion of the employment differential between repeat and non-repeat prisoners is due to differences in coefficients. There is no evidence to suggest that the frequency of incarceration affects individual characteristics that may limit prisoners' labour market aspirations after their release from prison. Author Affiliation: (1)School of Economics and Commerce, University of Western Australia, Crawley, Western Australia, Australia Article note: Correspondence: Tram Le, School of Economics and Commerce, Mail Bag M251 (Economics), University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Email: ale@biz.uwa.edu.au

The conventional wisdom in Australia is that policy aimed at reducing imbalances in the representation of different socioeconomic classes in the tertiary sector should be aimed at encouraging completion of high school. The analyses in this paper suggest, however, that most of the differences in the socioeconomic mix of tertiary students are due to different propensities of high school graduates to pursue tertiary studies. The relatively low rate of university participation among rural students, however, needs to be addressed by encouraging the completion of high school.

This article examines the determinants of school choice (government, Catholic or other independent schools) as well as the success in completing year 12for cohorts of students born in 1961 and 1970. The results show that those attending Catholic and other independent schools have favourable socio-economic backgrounds. Ability has a significant and positive effect on the probability of completing year 12. There is no evidence of unobserved selection effects on the probability of completing year 12 for the 1961 cohort. For the 1970 cohort, there is negative selection into other independent schools and positive selection into Catholic schools. Decomposition results further reveal that selection on the basis of observed characteristics accounts for only a small part of the observed differences in year 12 completion rates across the three school systems. In comparison, selection on the basis of unobserved factors is an important part of the difference in year 12 completion rates. The school effects for both cohorts are much larger than those reported in previous studies.

Two approaches have been used to model unemployment. The first, conventional, approach involves linking the unemployment outcome to observed indices of productivity, structural factors and discrimination such as educational attainment, location and birthplace. The second approach, the inertia model involves using a person's labour market history as a way of including in unemployment models information on the 'unobservables' that influence employability. This paper evaluates the performance of both models of unemployment. The results provide unambiguous support for the inertia model when modelling unemployment. The inertia model has higher explanatory power, higher within-sample prediction rate success and fewer out-of-sample forecasting errors than the conventional model The estimates from the inertia model can be used to provide quite accurate predictions of the risk of becoming unemployed. This is important if individuals at high risk of becoming unemployed are to be targeted for labour market assistance.

Purpose: This study aims to propose a comprehensive model to help understand factors influencing the intention to participate in a destination management system (DMS) amongst tourism stakeholders in Vietnam which are considered as the determinants of the successful implementation of the system. Design/methodology/approach: A survey was conducted to investigate key stakeholders' opinions of participating in a DMS. In total, 301 questionnaires were used for analysis. Partial least squares structural equation modelling (PLS-SEM) was used to assess the measurement and structural models of the study. Findings: Factors that influence various tourism stakeholders' intention to participate in the national DMS in Vietnam have been identified and examined. The results identify the important predictors of the tourism stakeholders' participation in the DMS including information quality, DMS operator readiness, government regulations and technology awareness. Interestingly, technology awareness was ascertained as a significant mediator for the relationship between performance expectancy, social influence, technology competency, competitive pressure and the intention to participate in the DMS. Originality/value: This study has a unique theoretical contribution by developing a comprehensive model to predict the intention to participate in a DMS amongst tourism stakeholders with the modification and combination of three theoretical models and frameworks: the unified theory of acceptance and use of technology (UTAUT) model, technology–organisation–environment (TOE) framework and updated DeLone and McLean information systems (D&M IS) success model. It is expected to be a useful reference source for tourism management departments that want to develop DMSs in Vietnam. This model also can be used as an initial investigation for DMS implementation studies at other destinations. [ABSTRACT FROM AUTHOR]

Transient diode laser absorption spectroscopy has been used to measure three strong vibronic bands in the near infrared spectrum of the C2H, ethynyl, radical not previously observed in the gas phase. The radical was produced by ultraviolet excimer laser photolysis of either acetylene or (1,1,1)-trifluoropropyne in a slowly flowing sample of the precursor diluted in inert gas, and the spectral resolution was Doppler-limited. The character of the upper states was determined from the rotational and fine structure in the observed spectra and assigned by measurement of ground state rotational combination differences. The upper states include a ²Σ+ state at 6696 cm-1, a second ²Σ+ state at 7088 cm-1, and a ²Π state at 7110 cm-1. By comparison with published calculations [R. Tarroni and S. Carter, J. Chem. Phys 119, 12878 (2003); Mol. Phys. 102, 2167 (2004)], the vibronic character of these levels was also assigned. The observed states contain both X ²Σ+ and A 2? electronic characters. Several local rotational level perturbations were observed in the excited states. Kinetic measurements of the time-evolution of the ground state populations following collisional relaxation and reactive loss of the radicals formed in a hot, non-thermal, population distribution were made using some of the strong rotational lines observed. The case of C2H may be a good place to investigate the behavior at intermediate pressures of inert colliders, where the competition between relaxation and reaction can be tuned and observed to compare with master equation models, rather than deliberately suppressed to measure thermal rate constants. [ABSTRACT FROM AUTHOR]