Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Cerebrospinal fluid shunt dynamics in patients with idiopathic adult hydrocephalus syndrome.

The objective was to assess CSF dynamics of different shunt constructions in patients with adult hydrocephalus syndrome and correlate these findings to clinical outcome, neuroradiology, and the specifications of the shunts provided by the manufacturer. Thirty four patients with idiopathic adult hydrocephalus (normal pressure hydrocephalus) syndrome were included in a prospective, consecutive case series. A differential pressure valve (Cordis Hakim standard system) was used in 28 patients and a variable resistance valve (Cordis Orbis-Sigma) in six. A constant pressure infusion method was used; CSF pressure and conductance were determined before surgery. Three months after shunt placement CSF pressure, the "pressure v flow" curve, and gravity induced flow were measured. There was no difference between mean preoperative and postoperative resting CSF pressures in patients with Hakim shunts. The opening pressures of the Hakim shunts were higher than the value proposed by the manufacturer. A pronounced gravity effect induced CSF flow and decrease of the CSF pressure. In functioning variable resistance valves, CSF dynamics normalised postoperatively. There was no gravity effect and the characteristics shaped "pressure v flow" curve was sometimes seen. Six patients (three differential pressure valves, three variable resistance valves) had non-functioning shunts. Four of these patients were improved after the operation but improvement was transient in three. In all patients, there was no relation between the width of the ventricles and clinical improvement or CSF pressure. In conclusion, the differential pressure valve system does not behave according to the specifications provided by the manufacturer. A decrease in CSF pressure in patients with this shunt was solely due to the effect of gravity. Eleven percent of the differential pressure valves and 50% of the variable resistance valves were non-functioning. In the functioning variable resistance valves, the antisiphon system seems to be effective

Steps toward Determination of the Size and Structure of the Broad-Line Region in Active Galactic Nuclei. XII. Ground-based Monitoring of 3C 390.3

Results of a ground-based optical monitoring campaign on 3C 390.3 in 1994-1995 are presented. The broadband fluxes (B, V , R, and I), the spectrophotometric optical continuum flux Fλ(5177 Å), integrated emission-line fluxes of Hα, Hβ, Hγ, He I λ5876, and He II λ4686 all show a nearly monotonic increase with episodes of milder short-term variations superposed. The amplitude of the continuum variations increases with decreasing wavelength (4400-9000 Å). The optical continuum variations follow the variations in the ultraviolet and X-ray with time delays, measured from the centroids of the crosscorrelation functions, typically around 5 days, but with uncertainties also typically around 5 days; zero time delay between the high-energy and low-energy continuum variations cannot be ruled out. The strong optical emission lines Hα, Hβ, Hγ, He I λ5876 respond to the high-energy continuum variations with time delays typically about 20 days, with uncertainties of about 8 days. There is some evidence that He II λ4686 responds somewhat more rapidly, with a time delay of around 10 days, but again, the uncertainties are quite large (~8 days). The mean and rms spectra of the Hα and Hβ line profiles provide indications for the existence of at least three distinct components located at ±4000 and 0 km s-1 relative to the line peak. The emission-line proÐle variations are largest near line center