Client protein activation by Hsp90 involves a plethora of cochaperones whose roles are poorly defined. A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. The identification of these Hsp90 cochaperone activators adds to the complex roles of cochaperones in regulating the ATPase-coupled conformational changes of the Hsp90 chaperone cycle.

Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

The neuropsychological performance of 85 women with early stage breast cancer scheduled for chemotherapy, 43 women scheduled for endocrine therapy and/or radiotherapy and 49 healthy control subjects was assessed at baseline (T1), postchemotherapy (or 6 months) (T2) and at 18 months (T3). Repeated measures analysis found no significant interactions or main effect of group after controlling for age and intelligence. Using a calculation to examine performance at an individual level, reliable decline on multiple tasks was seen in 20% of chemotherapy patients, 26% of nonchemotherapy patients and 18% of controls at T2 (18%, 14 and 11%, respectively, at T3). Patients who had experienced a treatment-induced menopause were more likely to show reliable decline on multiple measures at T2 (OR ¼ 2.6, 95% confidence interval (CI) 0.823 -8.266 P ¼ 0.086). Psychological distress, quality of life measures and self-reported cognitive failures did not impact on objective tests of cognitive function, but were significantly associated with each other. The results show that a few women experienced objective measurable change in their concentration and memory following standard adjuvant therapy, but the majority were either unaffected or even improve over time.

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been implicated in signal transduction through tyrosine kinase-and heterotrimeric G-proteinlinked receptors. We report herein the cloning and characterization of p110␦, a novel class I PI3K. Like p110␣ and p110␤, other class I PI3Ks, p110␦ displays a broad phosphoinositide lipid substrate specificity and interacts with SH2͞SH3 domaincontaining p85 adaptor proteins and with GTP-bound Ras. In contrast to the widely distributed p110␣ and ␤, p110␦ is exclusively found in leukocytes. In these cells, p110␣ and ␦ both associate with the p85␣ and ␤ adaptor subunits and are similarly recruited to activated signaling complexes after treatment with the cytokines interleukin 3 and 4 and stem cell factor. Thus, these class I PI3Ks appear not to be distinguishable at the level of p85 adaptor selection or recruitment to activated receptor complexes. However, distinct biochemical and structural features of p110␦ suggest divergent functional͞regulatory capacities for this PI3K. Unlike p110␣, p110␦ does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity. In addition, the p110␦ catalytic domain contains unique potential proteinprotein interaction modules such as a Pro-rich region and a basic-region leucine-zipper (bZIP)-like domain. Possible selective functions of p110␦ in white blood cells are discussed.Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3Ј OH position of the inositol ring of inositol lipids, generating phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate. PI3K enzymes have been identified in plants, slime molds, yeast, fruit flies, and mammals (1) and play a role in signal transduction via tyrosine kinase-and G-protein-linked receptors (2-5). In addition, PI3Ks have a function in membrane trafficking events, either constitutive or induced upon receptor stimulation (for review, see ref. 6).