Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma

Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process

Fluor-schorl, a new member of the tourmaline supergroup, and new data on schorl from the cotype localities

Fluor-schorl, NaFe^(2+) _3Al_6Si_6O_(18)(BO_3)_3(OH)_3F, is a new mineral species of the tourmaline supergroup from alluvial tin deposits near Steinberg, Zschorlau, Erzgebirge (Saxonian Ore Mountains), Saxony, Germany, and from pegmatites near Grasstein (area from Mittewald to Sachsenklemme), Trentino, South Tyrol, Italy. Fluor-schorl was formed as a pneumatolytic phase and in high-temperature hydrothermal veins in granitic pegmatites. Crystals are black (pale brownish to pale greyish-bluish, if distance (r^2 = 0.93). This correlation indicates that Fe^(2+)-rich tourmalines from the investigated localities clearly tend to have a F-rich or F-dominant composition. A further strong positive correlation (r^2 = 0.82) exists between the refined F content and the Y–W (F,OH) distance, and the latter may be used to quickly estimate the F content

The First Definitive Binary Orbit Determined with the Hubble Space Telescope Fine Guidance Sensors: Wolf 1062 (Gliese 748)

The M dwarf binary, Wolf 1062 (Gliese 748), has been observed with the Hubble Space Telescope (HST) Fine Guidance Sensor 3 in the transfer function scan mode to determine the apparent orbit. This is the first orbit defined fully and exclusively with HST, and is the most accurate definitive orbit for any resolved, noneclipsing system. The orbital period is 2.4490 ± 0.0119 yr and the semimajor axis is 01470 ± 00007—both quantities are now known to better than 1%. Using the weighted mean of seven parallax measurements and these HST data, we find the system mass to be 0.543 ± 0.031 M⊙, where the error of 6% is due almost entirely to the parallax error. An estimated fractional mass from the infrared brightness ratio and infrared mass-luminosity relation yields a mass for the primary of 0.37 M⊙, and the secondary falls in the regime of very low mass stars, with a mass of only 0.17 M⊙

Rituximab, B-lymphocyte depletion, and preservation of beta-cell function

BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition

A cross-sectional study of osteocalcin and body fat measures among obese adolescents

Osteocalcin (OCN), a marker of osteoblast activity, has been implicated in the regulation of energy metabolism by the skeleton and thus may affect body fat measures. We examined the relationships of OCN to body fat measures and whether they vary according to markers of energy and vitamin D metabolism. Data was obtained from 58 obese adolescents aged 13–17.9 years (38 females, 8 black or African-American). We calculated total fat mass (FM) [dual X-ray absorptiometry (DXA)] and visceral adipose tissue (VAT) [computerized axial tomography (CT)]. Blood tests included leptin, OCN, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), thyroid function tests, and triglycerides. Markers of glucose metabolism were obtained from fasting and OGTT samples. Adolescents with 25(OH)D<20 ng/mL were considered deficient (n=17/58); none had high PTH (PTH≥65 pg/mL). OCN was associated with lower VAT (−84.27±33.89 mm2) and BMI (−0.10±0.05 kg/m2), not FM (p=0.597) in a core model including age, sex, race, geographic latitude, summer, height z-score, and tanner stage. Adding 25(OH)D deficiency and PTH attenuated the inverse association of OCN to VAT. We found a significant interaction of OCN and 25(OH)D deficiency on FM (0.37±0.18 kg, p=0.041) and BMI (0.28±0.10 kg/m2, p=0.007) in this adjusted model, which was further explained by leptin. Adding A1C to the core model modified the relationship of OCN to VAT (−93.08±35.05 mm2, p=0.011), which was further explained by HOMA-IR. In summary, these findings provide evidence for a relationship between OCN and body fat measures that is dependent on energy metabolism and vitamin D status among obese adolescents

Limitations of Fe^(2+) and Mn^(2+) site occupancy in tourmaline: Evidence from Fe^(2+)- and Mn^(2+)-rich tourmaline

Fe^(2+)- and Mn^(2+)-rich tourmalines were used to test whether Fe^(2+) and Mn^(2+) substitute on the Z site of tourmaline to a detectable degree. Fe-rich tourmaline from a pegmatite from Lower Austria was characterized by crystal-structure refinement, chemical analyses, and Mössbauer and optical spectroscopy. The sample has large amounts of Fe^(2+) (~2.3 apfu), and substantial amounts of Fe^(3+) (~1.0 apfu). On basis of the collected data, the structural refinement and the spectroscopic data, an initial formula was determined by assigning the entire amount of Fe^(3+) (no delocalized electrons) and Ti^(4+) to the Z site and the amount of Fe^(2+) and Fe^(3+) from delocalized electrons to the Y-Z ED doublet (delocalized electrons between Y-Z and Y-Y): X(Na_(0.9)Ca_(0.1)) ^Y(Fe^(2+)_(2.0)Al_(0.4)Mn^(2+)_(0.3)Fe^(3+)_(0.2)) ^Z(Al_(4.8)Fe^(3+)_(0.8)Fe^(2+)_(0.2)Ti^(4+)_(0.1)) ^T(Si_(5.9)Al_(0.1))O_(18) (BO_3)_3^V(OH)_3 ^W[O_(0.5)F_(0.3)(OH)_(0.2)] with α = 16.039(1) and c = 7.254(1) Å. This formula is consistent with lack of Fe^(2+) at the Z site, apart from that occupancy connected with delocalization of a hopping electron. The formula was further modified by considering two ED doublets to yield: ^X(Na_(0.9)Ca_(0.1)) ^Y(Fe^(2+)_(1.8)Al_(0.5)Mn^(2+)_(0.3)Fe^(3+)_(0.3)) ^Z(Al_(4.8)Fe^(3+)_(0.7)Fe^(2+)_(0.4)Ti^(4+)_(0.1)) ^T(Si_(5.9_Al_(0.1))O_(18) (BO_3)_3 ^V(OH)_3 ^W[O_(0.5)F_(0.3)(OH)_(0.2)]. This formula requires some Fe^(2+) (~0.3 apfu) at the Z site, apart from that connected with delocalization of a hopping electron. Optical spectra were recorded from this sample as well as from two other Fe^(2+)-rich tourmalines to determine if there is any evidence for Fe^(2+) at Y and Z sites. If Fe^(2+) were to occupy two different 6-coordinated sites in significant amounts and if these polyhedra have different geometries or metal-oxygen distances, bands from each site should be observed. However, even in high-quality spectra we see no evidence for such a doubling of the bands. We conclude that there is no ultimate proof for Fe^(2+) at the Z site, apart from that occupancy connected with delocalization of hopping electrons involving Fe cations at the Y and Z sites. A very Mn-rich tourmaline from a pegmatite on Elba Island, Italy, was characterized by crystal-structure determination, chemical analyses, and optical spectroscopy. The optimized structural formula is ^X(Na_(0.6)□_(0.4)) ^Y(Mn^(2+)_(1.3)Al_(1.2)Li_(0.5)) ^ZAl_6 ^TSi_6O_(18) (BO_3)_3 ^V(OH)_3 ^W[F_(0.5)O_(0.5)], with α = 15.951(2) and c = 7.138(1) Å. Within a 3σ error there is no evidence for Mn occupancy at the Z site by refinement of Al ↔ Mn, and, thus, no final proof for Mn^(2+) at the Z site, either. Oxidation of these tourmalines at 700–750 °C and 1 bar for 10–72 h converted Fe^(2+) to Fe^(3+) and Mn^(2+) to Mn^(3+) with concomitant exchange with Al of the Z site. The refined ^ZFe content in the Fe-rich tourmaline increased by ~40% relative to its initial occupancy. The refined YFe content was smaller and the distance was significantly reduced relative to the unoxidized sample. A similar effect was observed for the oxidized Mn^(2+)-rich tourmaline. Simultaneously, H and F were expelled from both samples as indicated by structural refinements, and H expulsion was indicated by infrared spectroscopy. The final species after oxidizing the Fe^(2+)-rich tourmaline is buergerite. Its color had changed from blackish to brown-red. After oxidizing the Mn^(2+)-rich tourmaline, the previously dark yellow sample was very dark brown-red, as expected for the oxidation of Mn^(2+) to Mn^(3+). The unit-cell parameter α decreased during oxidation whereas the c parameter showed a slight increase

Does Strategic Planning Improve Organizational Performance? A Meta-Analysis

Strategic planning is a widely adopted management approach in contemporary organizations. Underlying its popularity is the assumption that it is a successful practice in public and private organizations that has positive consequences for organizational performance. Nonetheless, strategic planning has been criticized for being overly rational and for inhibiting strategic thinking. This article undertakes a meta-analysis of 87 correlations from 31 empirical studies and asks, Does strategic planning improve organizational performance? A random-effects meta-an