Restricted skew-morphisms on matrix algebras

LBK

HER2 mediates PSMA/mGluR1-driven resistance to the DS-7423 dual PI3K/mTOR inhibitor in PTEN wild-type prostate cancer models

Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors

Development of anaphylactoid hypersensitivity after adrenocortical failure due to Bordetella pertussis vaccine

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Patient Safety Section Editor: Sorin J. Brull Residual Neuromuscular Blockade and Critical Respiratory Events in the Postanesthesia Care Unit

BACKGROUND: Incomplete recovery of neuromuscular function may impair pulmo-nary and upper airway function and contribute to adverse respiratory events in the postanesthesia care unit (PACU). The aim of this investigation was to assess and quantify the severity of neuromuscular blockade in patients with signs or symp-toms of critical respiratory events (CREs) in the PACU. METHODS: We collected data over a 1-yr period. PACU nurses identified patients with evidence of a predefined CRE during the first 15 min of PACU admission. Train-of-four (TOF) ratios were immediately quantified in these patients using acceleromyography (cases). TOF data were also collected in a control group that consisted of patients undergoing a general anesthetic during the same period who were matched with the cases by age, sex, and surgical procedure. RESULTS: A total of 7459 patients received a general anesthetic during the 1-yr period, of whom 61 developed a CRE. Forty-two of these cases were matched with controls and constituted the study group for statistical analysis. The most common CREs among matched cases were severe hypoxemia (22 of 42 patients; 52.4%) an

Development of a 3D Tissue Culture-Based High-Content Screening Platform That Uses Phenotypic Profiling to Discriminate Selective Inhibitors of Receptor Tyrosine Kinases.

3D tissue cultures provide a more physiologically relevant context for the screening of compounds, compared with 2D cell cultures. Cells cultured in 3D hydrogels also show complex phenotypes, increasing the scope for phenotypic profiling. Here we describe a high-content screening platform that uses invasive human prostate cancer cells cultured in 3D in standard 384-well assay plates to study the activity of potential therapeutic small molecules and antibody biologics. Image analysis tools were developed to process 3D image data to measure over 800 phenotypic parameters. Multiparametric analysis was used to evaluate the effect of compounds on tissue morphology. We applied this screening platform to measure the activity and selectivity of inhibitors of the c-Met and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases in 3D cultured prostate carcinoma cells. c-Met and EGFR activity was quantified based on the phenotypic profiles induced by their respective ligands, hepatocyte growth factor and EGF. The screening method was applied to a novel collection of 80 putative inhibitors of c-Met and EGFR. Compounds were identified that induced phenotypic profiles indicative of selective inhibition of c-Met, EGFR, or bispecific inhibition of both targets. In conclusion, we describe a fully scalable high-content screening platform that uses phenotypic profiling to discriminate selective and nonselective (off-target) inhibitors in a physiologically relevant 3D cell culture setting