The
EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible ...expression of a mutant
EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (
EGFR TL). Expression of
EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the
EGFR T790M mutation.
The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non-small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible ...tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M-expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers.
Science and technology always have been interdependent, but never more so than with today’s highly instrumented data collection practices. We report on a long-term study of collaboration between ...environmental scientists (biology, ecology, marine sciences), computer scientists, and engineering research teams as part of a five-university distributed science and technology research center devoted to embedded networked sensing. The science and technology teams go into the field with mutual interests in gathering scientific data. “Data” are constituted very differently between the research teams. What are data to the science teams may be context to the technology teams, and vice versa. Interdependencies between the teams determine the ability to collect, use, and manage data in both the short and long terms. Four types of data were identified, which are managed separately, limiting both reusability of data and replication of research. Decisions on what data to curate, for whom, for what purposes, and for how long, should consider the interdependencies between scientific and technical processes, the complexities of data collection, and the disposition of the resulting data.
Abstract Background Reports of left-sided brain malignancies among interventional cardiologists have heightened concerns regarding physician radiation exposure. This study evaluated the impact of a ...suspended lead suit and robotic system on physician radiation exposure during percutaneous coronary intervention (PCI). Methods Real-time radiation exposure data were prospectively collected from dosimeters worn by operating physicians at the head- and chest-level during consecutive PCI cases. Exposures were compared in three study groups: 1) manual PCI performed with traditional lead apparel; 2) manual PCI performed using suspended lead; and 3) robotic PCI performed in combination with suspended lead. Results Among 336 cases (86.6% manual, 13.4% robotic) performed over 30 weeks, use of suspended lead during manual PCI was associated with significantly less radiation exposure to the chest and head of operating physicians than traditional lead apparel (chest: 0.0 0.1 μSv vs 0.4 4.0 μSv, p < 0.001; head: 0.5 1.9 μSv vs 14.9 51.5 μSv, p < 0.001). Chest-level radiation exposure during robotic PCI performed in combination with suspended lead was 0.0 0.0 μSv, which was significantly less chest exposure than manual PCI performed with traditional lead (p < 0.001) or suspended lead (p = 0.046). In robotic PCI the median head-level exposure was 0.1 0.2 μSv, which was 99.3% less than manual PCI performed with traditional lead (p < 0.001) and 80.0% less than manual PCI performed with suspended lead (p < 0.001). Conclusions Utilization of suspended lead and robotics were observed to result in significantly less radiation exposure to the chest and head of operating physicians during PCI.
Distributed sensing systems for studying scientific phenomena are critical applications of information technologies. By embedding computational intelligence in the environment of study, sensing ...systems allow researchers to study phenomena at spatial and temporal scales that were previously impossible to achieve. We present an ethnographic study of field research practices among researchers in the Center for Embedded Networked Sensing (CENS), a National Science Foundation Science & Technology Center devoted to developing wireless sensing systems for scientific and social applications. Using the concepts of boundary objects and trading zones, we trace the processes of collaborative research around sensor technology development and adoption within CENS. Over the 10-year lifespan of CENS, sensor technologies, sensor data, field research methods, and statistical expertise each emerged as boundary objects that were understood differently by the science and technology partners. We illustrate how sensing technologies were incompatible with field-based environmental research until researchers “unearthed” their infrastructures, explicitly reintroducing human skill and expertise into the data collection process and developing new collaborative languages that emphasized building dynamic sensing systems that addressed human needs. In collaborating around a dynamic sensing model, the sensing systems became embedded not in the environment of study, but in the practices of the scientists.
Abstract As financial pressures drive health care to be more cost-effective and efficient, performing procedures outside the main operating room (MOR) is becoming more common. Pediatric sedation ...units (PSU) have proven both effective and safe at providing anesthesia for children. However, there is limited data available regarding the PSU and its potential application in pediatric otolaryngology. Objective To evaluate the experience of performing pediatric outpatient procedures in a PSU through a parental satisfaction survey. Methods Pediatric otolaryngology procedures performed in the PSU were prospectively recorded in a database. A prospective survey analysis was performed that measured parental satisfaction with scheduling/registration for surgery, nursing care, surgeon care, facility environment, timing/duration, and overall satisfaction. Parents completed this survey for outpatient procedures performed in either the PSU or in the MOR. The same attending surgeon was involved in all cases, with the only independent variable being the location of the surgery. Fifty surveys were collected for each group, and the surveys scores were statistically compared using nonparametric statistical analysis. Results Parental satisfaction was high in both the PSU and OR, with mean overall satisfaction scores of 4.8 and 4.9 (respectively) on an ordinal scale from 1 to 5. Parents reported greater clarity in preoperative information in the MOR (mean 4.8) compared to the PSU (mean 4.6) ( p < 0.006). Also, parents reported that MOR procedures started on time more often than those in the PSU (90–64%, p < 0.002). There were no significant differences between locations in any other survey metrics, with mean satisfaction scores ranging from 4.5 to 5.0. Conclusions The PSU is a satisfactory patient experience for outpatient procedures in pediatric otolaryngology at our institution. However, this parent survey has identified education prior to surgery and timeliness of surgery as two areas to improve to meet the satisfaction standard provided by the OR.
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