P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.

Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.

Posttraumatic stress disorder after treatment for breast cancer: prevalence of diagnosis and use of the PTSD Checklist-Civilian Version (PCL-C) as a screening instrument.

The presence of a posttraumatic stress disorder (PTSD) diagnosis in women (n = 82) diagnosed with Stage 0-IIIA breast cancer was assessed 6 to 72 months after cancer therapy. The PTSD Checklist-Civilian Version (PCL-C) and the PTSD module for the Structured Clinical Interview for DSM-IV, Nonpatient Version, PTSD module (SCID-NP-PTSD) were administered in a telephone interview. SCID-NP-PTSD results indicated prevalence rates of 6% and 4% for current and lifetime PTSD, respectively. Use of the recommended cutoff score of 50 on the PCL-C to determine diagnosis of current cancer-related PTSD resulted in a sensitivity of .60 and a specificity of .99 with 2 false-negative diagnoses. In conclusion, PTSD can be precipitated by diagnosis and treatment of breast cancer, and the PCL-C can be a cost-effective screening tool for this disorder.

Head injury in the presence of alcohol intoxication.

The difficulty of distinguishing between serious head injury and intoxication is presented in the case of an injured patient whose signs and symptoms were attributed to alcohol withdrawal. This report emphasizes the need for a high level of suspicion for all trauma patients, for all health care providers to be familiar with common forms of life-threatening trauma, and how to distinguish between altered levels of consciousness resulting from alcohol intoxication versus intracranial disorders. This case may also demonstrate that a person's wealth and social influence and an institution's orientation to a medical specialty can affect care giver's decisions.

Therapeutic strategies for cancer pain management.

Clinical issues related to treating the oncology pain patient have gained considerable attention in the medical and health care literature. Addressed are management strategies which focus specifically on cognitive-behavioral, psychosocial, and pharmacologic approaches to treating the oncology pain patient. Each strategy possesses unique qualities that can benefit the care and management of the cancer patient and provide a better understanding of the disease entity and the patient's ability to develop coping strategies that may be effective in understanding and confronting pain associated with cancer.

Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties.

A new beta-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition C11H16N2O4S (M.W. = 272.18) and possesses a distinctive UV absorption (lambda max = 297 nm, epsilon = 7,900). Its beta-lactam is unusually sensitive to hydrolysis above pH8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations.