Truncated p110 ERBB2 induces mammary epithelial cell migration, invasion and orthotopic xenograft formation, and is associated with loss of phosphorylated STAT5.

Truncated-ERBB2 isoforms (t-ERBB2s), resulting from receptor proteolysis or alternative translation of the ERBB2 mRNA, exist in a subset of human breast tumors. t-ERBB2s lack the receptor extracellular domain targeted by therapeutic anti-ERBB2 antibodies and antibody-drug conjugates, including trastuzumab, trastuzumab-DM1 and pertuzumab. In clinical studies, expression of t-ERBB2 in breast tumors correlates with metastasis as well as trastuzumab resistance. By using a novel immuno-microarray method, we detect a significant t-ERBB2 fraction in 18 of 31 (58%) of immunohistochemistry (IHC)3+ ERBB2+ human tumor specimens, and further show that t-ERBB2 isoforms are phosphorylated in a subset of IHC3+ samples (10 of 31, 32%). We investigated t-ERBB2 biological activity via engineered expression of full-length and truncated ERBB2 isoforms in human mammary epithelial cells (HMECs), including HMEC and MCF10A cells. Expression of p110 t-ERBB2, but not p95m (m=membrane, also 648CTF) or intracellular ERBB2s, significantly enhanced cell migration and invasion in multiple cell types. In addition, only expression of the p110 isoform led to human breast epithelial cell (HMLE) xenograft formation in vivo. Expression of t-ERBB2s did not result in hyperactivation of the phosphoinositide kinase-3/AKT or mitogen-activated protein kinase signaling pathways in these cells; rather, phosphoproteomic array profiling revealed attenuation of phosphorylated signal transducer and activator of transcription 5 (STAT5) in p110-t-ERBB2-expressing cells compared to controls. Short hairpin-mediated silencing of STAT5 phenocopied p110-t-ERBB2-driven cell migration and invasion, while expression of constitutively active STAT5 reversed these effects. Thus, we provide novel evidence that (1) expression of p110 t-ERBB2 is sufficient for full transformation of HMEC, yielding in vivo xenograft formation, and (2) truncated p110 t-ERBB2 expression is associated with decreased phosphorylation of STAT5.

Spawning dynamics and biomass estimates of an anchovy Engraulis australis population in contrasting gulf and shelf environments.

The spawning biomass of Australian anchovy Engraulis australis in gulf and shelf waters of South Australia was compared using the daily egg production method (DEPM). The total survey area was 128 700 km2 with recorded spawning areas in gulf and shelf waters of 4898 and 44 618 km2, respectively. High egg densities in the warm, shallow gulf waters were produced by small, young (<1 year old) E. australis that spawned relatively small batches of eggs (c. 855) approximately every 3 days. In cooler, deeper shelf waters, where larger, older E. australis are found, lower egg densities occurred despite individuals producing much larger batches of eggs (c. 15,572) approximately every 7 days. In shelf waters, the highest densities were recorded at inshore sampling stations. Spawning appeared to peak between 0000 and 0100 hours. Females were more abundant than males in samples from both gulf and shelf waters with sex ratios of 0.61 and 0.56, respectively. The spawning biomass of E. australis in shelf waters was 101 522 t, whereas the estimate for gulf waters was 25 374 t. Due to the differences in mean size of the spawning females, however, c. 6x10(9)E. australis were present in each region. The results support the hypothesis that variability in habitat conditions may directly influence E. australis reproduction. A large reserve of young fish in the relatively stable gulf environment may increase the resilience of the E. australis population in South Australia to unfavourable interannual changes in offshore environmental conditions.

Simian varicella virus gene 61 encodes a viral transactivator but is non-essential for in vitro replication.

Simian varicella virus (SVV) is closely related to varicella-zoster virus (VZV), the causative agent of chickenpox and shingles. The SVV and VZV gene 61 polypeptides are homologs of the HSV-1 ICP0, a viral transactivator which appears to play a role in viral latency and reactivation. In this study, the molecular properties of the SVV 61 were characterized. The SVV open reading frame (ORF) 61 encodes a 54.1-kDa polypeptide with 37% amino acid identity to the VZV 61. Homology to the HSV-1 ICP-0 is limited to a conserved RING finger motif at the amino terminus of the protein. A nuclear localization sequence (nls) at the carboxy-terminus directs the SVV 61 to the cell nucleus, while a SVV 61nls(-) mutant is confined to the cell cytoplasm. The SVV 61 transactivates its own promoter as well as SVV immediate early (IE, ORF 62), early (ORFs 28 and 29), and late (ORF 68) gene promoters in transfected Vero cells. The RING finger and nls motifs are required for efficient SVV 61 transactivation. The SVV 61 has no effect on the ability of the major SVV transactivator (IE62) to induce SVV promoters. Generation and propagation of a SVV gene 61 deletion mutant demonstrated that the SVV 61 is non-essential for in vitro replication. SVV gene 61 is expressed in liver, lung, and neural ganglia of infected monkeys during acute simian varicella.

Psychotherapeutic injury: reshaping the implied contract as an alternative to malpractice.

Despite the enormous number of Americans who seek psychiatric aid for their emotional problems, malpractice actions against psychiatrists are surprisingly rare. In this Article, Professors Feldman and Ward suggest that this stage of affairs is caused not by the extraordinary competence of the psychiatric profession, but rather by the particularly severe legal obstacles that confront injured psychiatric patients. The elements of the traditional tort cause of action--especially causation--are not easily proved by plaintiffs claiming psychiatric injury. Moreover, recent cases show that courts are growing even more unsympathetic to those patients who suffer most grievously from unscrupulous psychiatrists. To remedy this problem, the authors reach to the historical origins of medical malpractice liability, and advocate the revival of an implied contract to treat with skill and care. By imposing a fiduciary obligation on the psychiatrist in the performance of this contract, the authors overcome the obstacles of proof that arise from traditional tort law. This alternative approach should bring a new balance to the law of psychiatric malpractice, in which aggrieved patients will be compensated for thier injuries, but innovative practitioners will not be unduly deterred from medical experimentation.