PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma

Background Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. Methods We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Results Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Time-resolved microscale temperature measurements of high-power semiconductor lasers

Nonradiative recombination and other heat generation processes affect both the performance and lifetime characteristics of semiconductor diode lasers. This is especially true for high-power devices, where facet heating due to nonradiative recombination can lead to catastrophic optical damage (COD). Here we present for the first time temperature measurements of a semiconductor laser in which the surface temperature profile (and hence the current density profile) of the laser is measured as it evolves in time. The laser studied is a λ=1.55μm 1-cm-long InGaAsP/InP watt-class slab-coupled optical waveguide laser (SCOWL). The ridge width of the SCOWLs examined here is approximately 5 μm. Temperature measurements are taken using multiple microthermocouples with sizes less than 20μm. Surface temperature fluctuations in time are seen to be quite large, as high as 20% of the total temperature increase of the device. Time-resolved measurements allow us to see both positive correlation (in which the temperature rises at the same time across an area of the device) as well as negative correlation (in which part of the device gets hot at the same time as another part of the device gets cold). Negative correlations are likely due to facet heating processes which cause bandgap shrinkage and hence increased current flow to a facet, pulling current away from the center of the device. Time-resolved measurements of the surface temperature profile therefore show promise as a non-destructive method for characterizing the failure mechanisms of a laser, as facet damage over time is otherwise very difficult to measure before the COD runaway process destroys the device. Copyright © 2005 by ASME.link_to_subscribed_fulltex

Submicron thermal imaging of high power slab coupled optical waveguide laser (SCOWL)

Nonradiative power dissipation within and near the active region of a high power single mode slab coupled optical waveguide laser is directly measured by CCD-based thermoreflectance, including its variation with device bias. By examining the high spatial resolution temperature profile at the optical output facets, we quantify heat spreading from the source in the active region both downward to the substrate and upward to the metal top contact. © 2006 by ASME and MIT Lincoln Laboratory.link_to_subscribed_fulltex