Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study

PURPOSE: Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors. METHODS: In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m(2) IV q21d to determine the MTDs of this treatment combination. RESULTS: Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m(2) q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m(2) q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (±fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug–drug interactions with either schedule. CONCLUSIONS: Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m(2) IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug–drug interactions, and shows antitumor activity in patients with advanced solid tumors

Global patterns of diapycnal mixing from measurements of the turbulent dissipation rate

The authors present inferences of diapycnal diffusivity from a compilation of over 5200 microstructure profiles. As microstructure observations are sparse, these are supplemented with indirect measurements of mixing obtained from (i) Thorpe-scale overturns from moored profilers, a finescale parameterization applied to (ii) shipboard observations of upper-ocean shear, (iii) strain as measured by profiling floats, and (iv) shear and strain from full-depth lowered acoustic Doppler current profilers (LADCP) and CTD profiles. Vertical profiles of the turbulent dissipation rate are bottom enhanced over rough topography and abrupt, isolated ridges. The geography of depth-integrated dissipation rate shows spatial variability related to internal wave generation, suggesting one direct energy pathway to turbulence. The global-averaged diapycnal diffusivity below 1000-m depth is O(10?4) m2 s?1 and above 1000-m depth is O(10?5) m2 s?1. The compiled microstructure observations sample a wide range of internal wave power inputs and topographic roughness, providing a dataset with which to estimate a representative global-averaged dissipation rate and diffusivity. However, there is strong regional variability in the ratio between local internal wave generation and local dissipation. In some regions, the depth-integrated dissipation rate is comparable to the estimated power input into the local internal wave field. In a few cases, more internal wave power is dissipated than locally generated, suggesting remote internal wave sources. However, at most locations the total power lost through turbulent dissipation is less than the input into the local internal wave field. This suggests dissipation elsewhere, such as continental margins

TECHNIQUES FOR REARING AND RELEASING NONMIGRATORY CRANES: LESSONS FROM THE MISSISSIPPI SANDHILL CRANE PROGRAM

Captive-reared Mississippi sandhill cranes (Grus canadensis pulla) reared at the Patuxent Wildlife Research Center (patuxent) have been released at the Mississippi Sandhill Crane National Wildlife Refuge (MSCNWR) since 1981. Of 131 birds released through December 1990, 103 were reared by foster parents. The remaining 28 were experimentally hand-reared in 1989 and 1990. After refining release procedures, parent-reared birds have integrated into the wild flock, many have survived, and some have bred. Releases of hand-reared cranes elsewhere in the 1970\u27s were largely unsuccessful. at least in part due to the lack of a lengthy acclimation period. A new hand-rearing protocol holds promise in producing release-worthy birds. The technique employs some features first used in the 1960\u27s (e.g., a costume for the human caretaker and model crane heads used to train chicks to feed). In the mid-1980\u27s, the following features were added: (1) the costumed caretaker was given a visor and feathers, (2) a taxidermic crane head or a hand puppet was held or suspended from the ceiling for use in stimulating chicks to feed, (3) a taxidermic mount of a brooding crane supplied warmth, (4) a full-sized live crane was maintained in an adjacent pen and in visual contact with neonatal young to provide an imprinting model, and (5) a small group of adult (or subadult) cranes was penned adjacent to the outdoor chick pens to provide socialization models. Recent releases of Mississippi sandhill cranes hand-reared according to this protocol and released in Mississippi have had high first-year survival rates. The now-operational technique holds promise for producing large numbers of release-worthy birds

TECHNIQUES FOR REARING AND RELEASING NONMIGRATORY CRANES: LESSONS FROM THE MISSISSIPPI SANDHILL CRANE PROGRAM

Captive-reared Mississippi sandhill cranes (Grus canadensis pulla) reared at the Patuxent Wildlife Research Center (patuxent) have been released at the Mississippi Sandhill Crane National Wildlife Refuge (MSCNWR) since 1981. Of 131 birds released through December 1990, 103 were reared by foster parents. The remaining 28 were experimentally hand-reared in 1989 and 1990. After refining release procedures, parent-reared birds have integrated into the wild flock, many have survived, and some have bred. Releases of hand-reared cranes elsewhere in the 1970\u27s were largely unsuccessful. at least in part due to the lack of a lengthy acclimation period. A new hand-rearing protocol holds promise in producing release-worthy birds. The technique employs some features first used in the 1960\u27s (e.g., a costume for the human caretaker and model crane heads used to train chicks to feed). In the mid-1980\u27s, the following features were added: (1) the costumed caretaker was given a visor and feathers, (2) a taxidermic crane head or a hand puppet was held or suspended from the ceiling for use in stimulating chicks to feed, (3) a taxidermic mount of a brooding crane supplied warmth, (4) a full-sized live crane was maintained in an adjacent pen and in visual contact with neonatal young to provide an imprinting model, and (5) a small group of adult (or subadult) cranes was penned adjacent to the outdoor chick pens to provide socialization models. Recent releases of Mississippi sandhill cranes hand-reared according to this protocol and released in Mississippi have had high first-year survival rates. The now-operational technique holds promise for producing large numbers of release-worthy birds

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Double Spin Asymmetry of Electrons from Heavy Flavor Decays in p+p Collisions at sqrt(s)=200 GeV

We report on the first measurement of double-spin asymmetry, A_LL, of electrons from the decays of hadrons containing heavy flavor in longitudinally polarized p+p collisions at sqrt(s)=200 GeV for p_T= 0.5 to 3.0 GeV/c. The asymmetry was measured at mid-rapidity (|eta|<0.35) with the PHENIX detector at the Relativistic Heavy Ion Collider. The measured asymmetries are consistent with zero within the statistical errors. We obtained a constraint for the polarized gluon distribution in the proton of |Delta g/g(log{_10}x= -1.6^+0.5_-0.4, {mu}=m_T^c)|^2 < 0.033 (1 sigma), based on a leading-order perturbative-quantum-chromodynamics model, using the measured asymmetry.Comment: 385 authors, 17 pages, 15 figures, 5 tables. Submitted to Phys. Rev. D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm