Citations

Background— Concern regarding risk of late thrombosis after “off-label” treatment with drug-eluting stents has prompted increased use of bare-metal stents (BMS) in current practice. The sequelae of late BMS failures, however, have been poorly characterized. Methods and Results— We performed a retrospective study of 4503 consecutive patients treated with at least 1 BMS and dual antiplatelet therapy between 1994 and 2000. The cumulative incidence of stent thrombosis was 0.5% at 30 days (95% CI, 0.3% to 0.7%), 0.8% at 1 year (95% CI, 0.6% to 1.1%), and 2.0% at 10 years (95% CI, 1.5% to 2.5%). Risk of late (30 days to 1 year) and very late (>1 year) BMS thrombosis was increased among patients considered off label for drug-eluting stent use ( P =0.024). When saphenous vein graft interventions were excluded, however, risk after off-label use was not significantly increased ( P =0.23). Other correlates included vein graft intervention, prior myocardial infarction (MI), peripheral vascular disease, and ulcerated lesion ( P <0.001). Mortality was markedly increased after late and very late BMS thrombosis, particularly during the first 30 days (hazard ratios, 22 [95% CI, 3.1 to 159] and 40 [95% CI, 15 to 107], respectively). The 10-year incidence of clinical restenosis was 18.1% (95% CI, 16.5% to 19.7%), presenting with MI in 2.1% (95% CI, 1.6% to 2.6%). Restenosis presenting with MI was associated with increased mortality compared with no restenosis (hazard ratio, 2.37; P <0.001) and with restenosis with a non-MI presentation (hazard ratio, 2.42; P <0.001). Conclusions— The incidence of BMS thrombosis and of MI caused by restenosis during extended follow-up is significant. Both complications are associated with mortality.

Treatments for myeloma have expanded in the last decade, but it is not clear if the introduction of novel therapies and the increased use of high-dose therapy have translated into better outcome for patients with myeloma. We examined the outcome of 2 groups of patients seen at a single institution, one from time of diagnosis and the other from the time of relapse, to examine the survival trends over time. Among 387 patients relapsing after stem-cell transplantation, a clear improvement in overall survival from the time of relapse was seen, with those relapsing after 2000 having a median overall survival of 23.9 versus 11.8 months (P < .001) for those who relapsed prior to this date. This improvement was independent of other prognostic factors. Patients treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 vs 14.8 months; P < .001). In a larger group of 2981 patients with newly diagnosed myeloma, those diagnosed in the last decade had a 50% improvement in overall survival (44.8 vs 29.9 months; P < .001). In this study, we demonstrate improved outcome of patients with myeloma in recent years, both in the relapsed setting as well as at diagnosis.

Abstract Rationale Patients with a clinicopathological diagnosis of idiopathic pulmonary fibrosis (IPF) may have typical findings of usual interstitial pneumonia (UIP) on computed tomography (CT) or nonspecific or atypical findings, including those often seen in nonspecific interstitial pneumonia. Objectives The aims of this study were to revisit the high-resolution CT findings of IPF and to clarify the correlation between the CT findings and mortality. Methods The study included 98 patients with a histologic diagnosis of UIP and a clinical diagnosis of IPF. Two observers evaluated the CT findings independently and classified each case into one of the following three categories: (1) definite UIP, (2) consistent with UIP, or (3) suggestive of alternative diagnosis. The correlation between the CT categories and mortality was evaluated using the Kaplan-Meier method and the log-rank test, as well as Cox proportional hazards regression models. Measurements and Main Results Thirty-three of the 98 CT scans were classified as definite UIP, 36 as consistent with UIP, 29 as suggestive of an alternative diagnosis. The mean survival was 45.7, 57.9, and 76.9 months, respectively. There was no significant difference in survival among the three categories (all P &gt; 0.05). Traction bronchiectasis and fibrosis scores were significant predictors of outcome (hazard ratios: 1.30 and 1.10, respectively; 95% confidence intervals: 1.18–14.2 and 1.03–1.19, respectively). Conclusions In patients with IPF and UIP pattern on the biopsy, the pattern of abnormality on thin-section CT, whether characteristic of UIP or suggestive of alternative diagnosis, does not influence prognosis. Prognosis is influenced by traction bronchiectasis and fibrosis scores.

Abstract 2-Methoxyestradiol (2ME2), a physiologic metabolite of 17β-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME2 also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME2 could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME2 (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME2 inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME2. In vitro, 2ME2 repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME2 could be an important new therapy in the arsenal to fight metastatic breast cancer. [Cancer Res 2007;67(21):10106–11]

Abstract Androgen receptor (AR) activity is critical for prostate cancer progression. Overexpression of several AR-associated coactivators has been shown to be essential for AR activation during disease progression. The stimuli and signaling pathways leading to overexpression of these coregulators, however, remain largely elusive. Here, we investigated whether androgen signaling, which demarcates critical transitions during prostate cancer disease progression, can affect coregulator expression. We found that expression of four and a half LIM domain protein-2 (FHL2), a key AR coactivator that is overexpressed in prostate cancer and associates with a poor prognosis, is induced strongly by androgens. Androgen induction of this coactivator established a feed-forward mechanism that robustly activated the AR. Stimulation of FHL2 after androgen exposure was time- and dose-dependent and relied on the presence of a functional AR. Androgen induction of FHL2 depended on active transcription of the FHL2 gene, mediated by action of serum response factor (SRF) on its proximal promoter. Loss of SRF, a transcription factor that preferentially regulates the expression of genes involved in mitogenic response and cytoskeletal organization, hampered prostate cancer cell proliferation. These results suggest a novel indirect mechanism of androgen action on FHL2 expression and provide evidence that SRF is an important determinant of AR action in prostate cancer cells. [Cancer Res 2007;67(21):10592–9]

PKC (protein kinase C) isoenzymes are key signalling components involved in the regulation of normal cell proliferation, differentiation, polarity and survival. The aberrant regulation of PKC isoenzymes has been implicated in the development of many human diseases including cancer [Fields and Gustafson (2003) Methods Mol. Biol. 233, 519–537]. To date, however, only one PKC isoenzyme, the aPKC [atypical PKCι (protein kinase Cι)], has been identified as a human oncogene [Regala, Weems, Jamieson, Khoor, Edell, Lohse and Fields (2005) Cancer Res. 65, 8905–8911]. PKCι has also proven to be a useful prognostic marker and legitimate target for the development of novel pharmacological agents for the treatment of cancer. The PKCι gene resides at chromosome 3q26 and is a frequent target of tumour-specific gene amplification in multiple forms of human cancer. PKCι gene amplification in turn drives PKCι overexpression in these cancers. Genetic disruption of PKCι expression blocks multiple aspects of the transformed phenotype of human cancer cells including transformed growth in soft agar, invasion through Matrigel and growth of subcutaneous tumours in nude mice. Genetic dissection of oncogenic PKCι signalling mechanisms demonstrates that PKCι drives transformed growth by activating a PKCι → Rac1 → PAK (p21-activated kinase) → MEK [MAPK (mitogen-activated protein kinase) 1,2/ERK (extracellular-signal-regulated kinase) kinase] 1,2 signalling pathway [Regala, Weems, Jamieson, Copland, Thompson and Fields (2005) J. Biol. Chem. 280, 31109–31115]. The transforming activity of PKCι requires the N-terminal PB1 (Phox-Bem1) domain of PKCι, which serves to couple PKCι with downstream effector molecules. Hence, there exists a strong rationale for developing novel cancer therapeutics that target the PB1 domain of PKCι and thereby disrupt its interactions with effector molecules. Using a novel high-throughput drug screen, we identified compounds that can disrupt PB1–PB1 domain interactions between PKCι and the adaptor molecule Par6 [Stallings-Mann, Jamieson, Regala, Weems, Murray and Fields (2006) Cancer Res. 66, 1767–1774]. Our screen identified the gold compounds ATG (aurothioglucose) and ATM (aurothiomalate) as specific inhibitors of the PB1–PB1 domain interaction between PKCι and Par6 that exhibit anti-tumour activity against NSCLC (non-small-cell lung cancer) both in vitro and in vivo. Structural analysis, site-directed mutagenesis and modelling indicate that ATM specifically targets the PB1 domain of PKCι to mediate its anti-tumour activity [Erdogan, Lamark, Stallings-Mann, Lee, Pellechia, Thompson, Johansen and Fields (2006) J. Biol. Chem. 281, 28450–28459]. Taken together, our recent work demonstrates that PKCι signalling is required for transformed growth of human tumours and is an attractive target for development of mechanism-based cancer therapies. ATM is currently in Phase I clinical trials for the treatment of NSCLC.

Plasma-membrane calcium pumps [PMCAs (plasma-membrane Ca2+-ATPases)] expel Ca2+ from eukaryotic cells to maintain overall Ca2+ homoeostasis and to provide local control of intracellular Ca2+ signalling. Recent work indicates functional versatility among PMCA isoforms, with specific pumps being essential for cochlear hair cell function, sperm motility, feedback signalling in the heart and pre- and post-synaptic Ca2+ regulation in neurons. The functional versatility of PMCAs is due to differences in their regulation by CaM (calmodulin), kinases and other signalling proteins, as well as to their differential targeting and retention in defined plasma membrane domains. The basis for this is the structural diversity of PMCAs. In mammals, four genes encode PMCA isoforms 1–4, and each of these has multiple variants generated by alternative RNA splicing. The alternatively spliced regions are intimately involved in the regulatory interactions and differential membrane localization of the pumps. The alternatively spliced C-terminal tail acts as an autoinhibitory domain by interacting with the catalytic core of the pump. The degree of inhibition and the kinetics of interaction with the major activator CaM differ between PMCA variants. This translates into functional differences in how PMCAs handle Ca2+ signals of different magnitude and frequency. Accumulating evidence thus demonstrates how structural diversity provides functional versatility in the PMCAs.

AbstractConversion Technology (CT) is a streamlined version of somatic cell hybrid preparation that was developed to be amenable for use as a mutation detection method and as a diagnostic tool for individual patients. It is also a powerful research tool. There are two broad categories of potential applications for CT: research applications in gene mapping and identification, and clinical applications in the detection of disease‐causing mutations in individual patients. CT may emerge as the gold standard for both mutation detection and haplotyping. It will likely prove valuable in mutation detection due to its ability to detect mutations that are not amenable to detection by sequencing (e.g., deep intron or promoter mutations). It will likely prove valuable in gene identification projects because genotyping of haploid chromosomes yields unequivocal haplotypes. Curr. Protoc. Hum. Genet. 55:3.6.1‐3.6.38. © 2007 by John Wiley & Sons, Inc.