Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

BACKGROUND: Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. METHODS AND FINDINGS: Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. CONCLUSION: Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies

The Jumping Ability of Wild Age-0 Brook Trout

Understanding the ability of Brook Trout Salvelinus fontinalis to jump vertical plunges is essential to fish conservation efforts aiming to protect native species. This information is useful for management strategies that seek to limit the movement of Brook Trout in areas where they have been introduced and pose a risk to native species. It is also useful for strategies seeking to maintain or restore connectivity within the native range of Brook Trout. While previous efforts have described the jumping ability of hatchery-reared Brook Trout, additional work is needed to determine the maximum jump height of wild Brook Trout less than 100 mm in length. Our objective was to determine the maximum jump height of wild Brook Trout ranging from 50-99 mm in length (69.6 mm mean total length) by exposing fish to vertical plunges of varying heights while maintaining a plunge pool depth of 50 cm. Fish successfully passed over plunge heights of 0, 10, and 20 cm but did not pass a 30 cm plunge height. This suggests that wild Brook Trout in the size class we evaluated cannot jump a 30 cm fall. We anticipate this information will aid management agencies in designing impassable barriers and, conversely, toward efforts that seek to facilitate the ability of Brook Trout to move freely within their native range

Delayed presentation of retained acrylic intraocular lens (IOL) fragment after uncomplicated cataract surgery

Purpose: To report a case of delayed presentation of a severed acrylic single-piece intraocular lens (IOL) haptic fragment causing corneal edema after uneventful phacoemulsification surgery. Observations: An 85-year-old male presented with inferior corneal decompensation six months after a reportedly uneventful phacoemulsification in his left eye. A distal haptic fragment of an acrylic single-piece posterior chamber intraocular lens was found in the inferior anterior chamber angle. Intraoperative examination revealed that the dislocated fragment originated from the temporal haptic, the remainder of which was adherent to the anterior surface of the capsular bag. The clipped edge of the haptic fragment showed a clean, flat surface, suggesting it was severed by a sharp object. The findings were considered consistent with cutting of the fragment during implantation presumably from improper lens loading, improper implantation technique, or defective implantation devices. Conclusions and Importance: This is the first case report of a foldable acrylic intraocular lens severed during routine uncomplicated cataract surgery that was not noted at the time of the surgery or in the immediate postoperative period. Delayed presentation of severed IOL fragments should be considered in cases of late onset corneal edema post-operatively, when other causes have been ruled out. Careful implantation technique and thorough examination of the intraocular lens after implantation to assess for lens damage intraoperatively is essential to avoid such rare complications

Differences in sequences encoding the carboxyl-terminal domain of the epidermal growth factor receptor correlate with differences in the disease potential of viral erbB genes.

Eleven recently isolated erbB-transducing viruses as well as avian erythroblastosis virus (AEV)-R (ES4) and AEV-H have been characterized for the type of disease they cause, their ability to transform fibroblasts in culture, their ability to cause disease in pedigrees of chicken that differ in susceptibility to erbB-induced erythroblastosis, and the structure of their erbB genes. Differences in each of the biological parameters correlated with differences in erbB sequences encoding the C-terminal domain of the epidermal growth factor receptor (EGFR). Seven viruses were strain restricted in their ability to induce erythroblastosis and did not transform fibroblasts. These seven viruses contained v-erbB genes encoding the complete C terminus of the EGFR. AEV-R and AEV-H were not pedigree restricted in their ability to induce erythroblastosis and could transform fibroblasts. These viruses contain v-erbB genes that lack codons for the immediate C terminus of the EGFR. Three viruses caused angiosarcoma and one caused fibrosarcoma. The angiosarcoma and fibrosarcoma-inducing viruses were not strain restricted and did not cause erythroblastosis. The v-erbB genes of each of these viruses contained extensive internal deletions or 3' truncations in sequences encoding the C-terminal domain of the EGFR