Molecular bases of the sympathetic regulation of bone mass

The discovery that leptin regulates bone mass through a central relay generated a lot of interest and raised the question about the identity of the neural mediator linking the brain to the skeleton. In this review we discuss the genetic, neuroanatomical and physiological evidence identifying the sympathetic tone as one of the mediator of leptin regulation of bone mass. We also discussed the antagonistic role played by two beta adrenergic receptors in this regulation and the relevance of these results obtained through studies of model organisms to human physiology and pathology.     

Reciprocal regulation of bone and energy metabolism

The finding that fat regulates bone metabolism was viewed as an indication that bone might regulate some aspects of energy metabolism in a feedback loop. The search that started nine years ago for a bone-derived hormone that regulates energy metabolism first took a convoluted path through the identification of a modifier gene. Once this hormone, osteocalcin, was identified, it became clear that bone exerts a profound and complex influence on glucose and fat metabolism. This review highlights the most important salient features of this novel regulation of energy metabolism.     

Role of SRC kinases in Neu-induced tumorigenesis: challenging the paradigm using Csk homologous kinase transgenic mice

Amplification of the HER-2/neu (ErbB2) gene is observed in approximately 30% of human breast cancers, correlating with a poor clinical prognosis. Src kinases are also involved in the etiology of breast cancer, and their activation was suggested to be necessary for Neu-induced oncogenesis. To address whether Src activity is essential for Neu-mediated tumorigenesis, we used a physiologic inhibitor of Src kinase activity, the Csk homologous kinase (CHK), expressed as a mammary tissue-specific transgene. Our data, using a physiologic inhibitor of Src activity (CHK), showed that blocking of Neu-induced Src activity without altering Src expression levels had no significant effects on Neu-mediated mammary tumorigenesis in vivo. This contradicts the current paradigm that activation of Src kinases is essential for Neu-induced oncogenesis. This study is the first to distinguish between the kinase-dependent and kinase-independent actions of Src and shows that its kinase-dependent properties are not requisite for Neu-induced tumorigenesis.     

Genetic alterations of the NRP/B gene are associated with human brain tumors

Nearly all brain tumors develop following the progressive accumulation of genetic alterations of oncogenes and tumor suppressor genes (such as p53 and retinoblastoma protein). Furthermore, aberrations in the nuclear matrix often contribute to genomic instabilities and the development of cancer. We have previously shown that nuclear-restricted protein/brain (NRP/B), a member of the BTB/Kelch repeat family, is a nuclear matrix protein normally expressed in neurons but not in astrocytes, and that it is an early and specific marker of neurons during the development of the central nervous system. Here, we show aberrant expression of NRP/B in human brain tissues. NRP/B is expressed in the cytoplasm of human brain tumor cells (glioblastoma, GBM) arising from astrocytes. NRP/B mutations (13 mutations in the Kelch domains, two in the intervening sequence (IVS) domain and two in the BTB domain) were detected in brain tumor cell lines (A-172, CCF-STTG1, SK-N-SH and U87-MG) and in primary human malignant GBM tissues (eight samples). More importantly, we found that NRP/B mutants, but not wild-type (wt) NRP/B, increased the activation of ERK and consequently promoted cell proliferation, attenuated caspase activation and suppressed the cellular apoptosis induced by the stressful stimulus cisplatin (10 microM). These events were observed to occur via a p53-mediated pathway. In addition, while wt NRP/B was associated with actin, mutations in the Kelch domains of NRP/B led to its reduced binding affinity to actin. Thus, alterations and gene mutations within the NRP/B gene may contribute to brain tumorigenesis by promoting cell proliferation, suppressing apoptosis and by affecting nuclear cytoskeleton dynamics.     

Coupling of RAFTK/Pyk2 kinase with c-Abl and their role in the migration of breast cancer cells

Mitogen-induced changes in the actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several proteins in focal adhesions. In this study, we have investigated the role of RAFTK (also termed Pyk2/CAK-beta), a cytoplasmic tyrosine kinase related to focal adhesion kinase (FAK), in heregulin-mediated signal transduction in breast cancer cells. Stimulation of T47D cells with heregulin (HRG) induced the tyrosine phosphorylation of RAFTK and the formation of a multiprotein complex. Maximal phosphorylation of the proteins participating in this complex occurred within 2 h of HRG stimulation. Analyses of the members of the HRG-stimulated complex revealed that RAFTK associated with p190 RhoGAP (p190), RasGAP, c-Abl as well as with the focal adhesion molecules p130cas and paxillin. c-Abl was found to be associated with RAFTK through the region of RAFTK containing amino acids 419-1009. Site-directed mutagenesis of Y881 aa within the RAFTK sequence abolished the binding of RAFTK to c-Abl, indicating that the tyrosine residue 881 of RAFTK is the c-Abl binding site within the RAFTK molecule. Overexpression of wild-type RAFTK significantly enhanced breast cancer cell invasion, while overexpression of the mutants Tyr402 or Tyr881 of RAFTK inhibited this migration. Therefore, RAFTK serves as a mediator and an integration point between focal adhesion molecules in HRG-mediated signaling in T47D breast cancer cells.     

Minimally invasive surgery for female urinary incontinence: experience with periurethral microballoon implantation

PURPOSE: To assess the effectiveness of periurethral microballoon implantation for management of female urinary incontinence. PATIENTS AND METHODS: A total of 45 women with urinary incontinence (age range 47-88 years) were treated between May 2000 and June 2001. Microballoons were placed in the proximal periurethral tissue using endoscopic instrumentation under local anesthesia. Follow-up assessment including urodynamic study and quality- of-life assessment was performed at 1, 3, and 6 months. RESULTS: Implantation was successful in all cases with no significant adverse effects. Cure was achieved in 60% and improvement in 5%. The failure rate was 35%. Microballoon implantation significantly increased the mean urethral closure pressure, from 35.2 cm H(2)O (SD 14.9; range 15-72 cm H(2)O) to 46.5 cm H(2)O (SD 19.7; range 16-87 cm H(2)O) (P = 0.001). The best predictors of successful outcome in univariate analysis were initial urethral closure pressure (P = 0.047) and degree of incontinence (P < 0.001). CONCLUSIONS: Periurethral microballoon implantation is a useful technique for the management of female urinary incontinence, especially in elderly and inoperable patients. The microballoons do not present the adverse effects associated with other bulking agents.