Citations

ABSTRACT Pneumocystis carinii is an opportunistic fungus causing severe pneumonia in immune-compromised hosts. Recent evidence suggests that Pneumocystis exists as separate sex types, though definitive evidence is currently lacking. These studies were undertaken to determine whether Pneumocystis maintains functional meiotic control molecules, which are required for sexual life stages in eukaryotes. Using the Pneumocystis carinii Genome Project database, two partial sequences for meiotic control molecules were detected, namely, PC Ran1 , a presumptive meiotic control kinase, and PC Mei2 , a homologue to a primary activator of meiosis in Schizosaccharomyces pombe . Rapid amplification of cDNA ends was employed to obtain the full open reading frames and to further investigate the functions of these proteins. These presumptive meiotic control molecules were most homologous to molecules present in S. pombe (52% identical and 67% homologous for PC Ran1 and 75% identical and 88% homologous for PC Mei2 by BLAST analysis). Heterologous expression of these Pneumocystis meiotic genes in corresponding temperature-sensitive and knockout strains of S. pombe , respectively, further verified the functions of the PCRan1 and PCMei2 proteins. These proteins were further shown to control downstream components of the meiotic pathway in S. pombe . Lastly, in vitro kinase assays were used to determine that PCRan1p phosphorylates PCMei2p. These experiments represent the first characterization of any proteins in P. carinii involved in meiosis and indicate the presence of a conserved meiotic pathway in Pneumocystis . Elucidation of this pathway will be essential in gaining a greater understanding of this important opportunistic fungal pathogen.

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]