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Blockade of the human epidermal growth factor receptor 3 (HER3) and of the downstream phosphatidylinositide 3-kinase (PI3K)/AKT pathway is a prerequisite for overcoming drug resistance and to develop novel treatments for cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2low cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G1 cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers.

Plasma glucose and insulin concentrations and in vivo and in vitro estimates of insulin action were compared in hypertriglyceridemic apolipoprotein C-III transgenic mice (mean +/- SE triglyceride concentration = 11.8 +/- 0.9 mmol/l) and their normotriglyceridemic (1.1 +/- 0.1 mmol/l) littermates. There were no differences in the glucose (8.9 +/- 0.2 vs. 9.3 +/- 0.5 mmol/l) or insulin (172 +/- 21 vs. 203 +/- 17 pmol/l) concentrations of the transgenic and control mice, respectively. Steady-state plasma glucose concentrations at the end of a 150-min period of physiological hyperinsulinemia were also similar in transgenic (6.2 +/- 0.5 mmol/l) and control mice (6.7 +/- 0.5 mmol/l). As the steady-state plasma insulin levels were essentially identical in the two groups (approximately 1000 pmol/l), these results show that whole body insulin-mediated glucose disposal was unchanged in the transgenic mice. Finally, values for isoproterenol-stimulated lipolysis, insulin-inhibition of lipolysis, and insulin-stimulated glucose disposal were similar in adipocytes isolated from transgenic and control mice. It can be concluded from these data that insulin resistance does not develop in hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene.

Blockade of the human epidermal growth factor receptor 3 (HER3) and of the downstream phosphatidylinositide 3-kinase (PI3K)/AKT pathway is a prerequisite for overcoming drug resistance and to develop novel treatments for cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2(low) cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G1 cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers.

Cosmetic ingredients previously considered "inert" have potential to provide a biologic effect to skin. In a cosmeceutical formulation, the boundary between an "active" and "inert" ingredient may be obscured. For this reason, the cosmeceutical distributor must find a nonambiguous method to demonstrate the efficacy of a new ingredient. For a product to be successful in the marketplace, the benefits of the product must clearly be communicated to the consumer, and the consumer must be satisfied with product performance.

One approach to drug discovery involves the targeting of abnormal protein-protein interactions that lead to pathology. We present a new technology allowing the detection of such interactions within the cytoplasm in a yeast-based system. The interaction detection is based on the sequestration of a translation termination factor involved in stop codon recognition. This sequestration inhibits the activity of the factor, thereby permitting the translation of a reporter gene harboring a premature stop codon. This novel cytoplasmic protein-protein interaction (CPPI) detection system should prove to be useful in the characterization of proteins as well as in partner identification, interaction mapping, and drug discovery applications.

Background: After lung transplantation, filamentous fungi and more particularly Aspergillus fumigatus are commonly isolated, although the origin of contamination is unclear., Methods: To investigate the fungal flora in bronchoscopic fluids, we retrospectively reviewed 20 cases of lung transplant recipients. Using sequence-specific DNA primers analysis, we typed the clinical strains of A. fumigatus isolated from 6 lung transplant recipients. For 4 of them, the strains of this species were isolated from their environment., Results: At least once 90% of patients had filamentous fungi, and A. fumigatus was the most frequently isolated. Bronchial colonization was detected in 14 patients, invasive bronchial mycosis was diagnosed in 4 others, and no case of invasive pulmonary fungal infection was detected. Genome typing of the 47 clinical strains revealed that a given patient could be affected by several different strains. A very extensive polymorphism existed among the 38 environmental strains. Origin of contamination at home was possible in 1 case and in the hospital in 3 cases., Conclusions: Bronchial colonization is frequent after lung transplantation. Although the clinical strains show a polymorphism, it is less widespread than the polymorphism of environmental strains. The origin of acquisition may be in the patient's community.

Effects of p-aminobenzoic acid (PABA) and of 4-[(2-oxo-3-bornylidene)methyl]-phenyl trimethylammonium methylsulfate (OMM), two components used in sunscreen formulations, on the mutagenicity of UVB irradiation are compared in three genetic assay systems. A haploid strain of Saccharomyces cerevisiae XV185-14C was used to measure reverse mutations at three loci. The diploid strain D5 of Saccharomyces cerevisiae was used to screen for reciprocal mitotic recombination. The induction of forward mutations was measured in Chinese hamster V79 cells. Our results indicate that UVB irradiation induced HGPRT- mutants in V79 cells, reverse mutations in Saccharomyces cerevisiae strain XV185-14C, and mitotic crossing over and other genetic alterations in Saccharomyces cerevisiae strain D5. V79 Chinese hamster lung cells were the most sensitive to UVB irradiation, followed by Saccharomyces cerevisiae haploid strain XV185-14C and the diploid strain D5. PABA and OMM were both capable of protecting all three types of cells from UVB irradiation regarding both lethality and induction of various types of genetic alterations. At higher concentrations (above 10(-5) M), OMM was more effective in its photoprotective effect toward UVB irradiation than PABA.