The vascular endothelial growth factor (VEGF) family is central to cancer angiogenesis. However, targeting VEGF as an anti-cancer therapeutic approach has shown success for some tumor types but not ...others. Here we examine the expression of the expanded VEGF family in prostate cancer, including the Semaphorin (Sema) family members that compete with VEGFs for Neuropilin binding and can themselves have pro- or anti-angiogenic activity.
First, we used multivariate statistical methods, including partial least squares and clustering, to examine VEGF/Sema gene expression variability in previously published prostate cancer microarray datasets. We show that unlike some cancers, such as kidney cancer, primary prostate cancer is characterized by both a down-regulation of the pro-angiogenic members of the VEGF family and a down-regulation of anti-angiogenic members of the Sema family. We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive. In contrast to primary prostate tumors, prostate cancer metastases showed increased expression of key pro-angiogenic VEGF family members and further repression of anti-angiogenic class III Sema family members. Given the lack of success of VEGF-targeting molecules so far in prostate cancer, this suggests that the reduction in anti-angiogenic Sema signaling may potentiate VEGF signaling and even promote resistance to VEGF-targeting therapies. Inhibition of the VEGF 'accelerator' may need to be accompanied by promotion of the Sema 'brake' to block cancer angiogenesis. To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples. The simulations suggest that loss of Sema expression promotes angiogenesis by lowering plexin signaling, not by potentiating VEGF signaling via relaxation of competition.
The combined analysis of bioinformatic data with computational modeling of ligand-receptor interactions demonstrated that enhancement of angiogenesis in prostate cancer metastases may occur through two different routes: elevation of VEGFA and reduction of class 3 Semaphorins. Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.
Angiogenesis is essential to both ovulation and the formation of the corpus luteum. The thrombospondin (THBS) family of glycoproteins plays diverse roles in regulation of angiogenesis, but the role ...of these vascular regulators in ovulation and luteinization remain to be elucidated. Using the cynomolgus macaque as a model for human ovulation, we demonstrated that levels of THBS1 mRNA and protein in preovulatory follicle granulosa cells increased after the ovulatory gonadotropin surge, with peak levels just before the expected time of ovulation. THBS1 treatment of monkey ovarian microvascular endothelial cells
in vitro
stimulated migration, proliferation, and capillary sprout formation, consistent with a pro-angiogenic action of THBS1. Injection of an anti-THBS1 antibody into monkey preovulatory follicles reduced rates of follicle rupture and oocyte release in response to an ovulatory gonadotropin stimulus when compared with control IgG-injected follicles. Interestingly, two of three oocytes from anti-THBS1 antibody injected follicles were germinal vesicle intact, indicating that meiosis failed to resume as anticipated. Follicles injected with anti-THBS1 antibody also showed reduced granulosa cell layer expansion, endothelial cell invasion, and capillary formation when compared to control IgG-injected follicles. Overall, these findings support a critical role for THBS1 in follicular angiogenesis, with implications for both successful ovulation and corpus luteum formation.
Cytokines and cardiovascular disease Mehra, Vishal C.; Ramgolam, Vinod S.; Bender, Jeffrey R.
Journal of leukocyte biology,
October 2005, Volume:
78, Issue:
4
Journal Article
Peer reviewed
The role of cytokines in the pathogenesis of cardiovascular disease is increasingly evident since the identification of immune/inflammatory mechanisms in atherosclerosis and heart failure. In this ...review, we describe how innate and adaptive immune cascades trigger the release of cytokines and chemokines, resulting in the initiation and progression of atherosclerosis. We discuss how cytokines have direct and indirect effects on myocardial function. These include myocardial depressant effects of nitric oxide (NO) synthase‐generated NO, as well as the biochemical effects of cytokine‐stimulated arachidonic acid metabolites on cardiomyocytes. Cytokine influences on myocardial function are time‐, concentration‐, and subtype‐specific. We provide a comprehensive review of these cytokine‐mediated immune and inflammatory cascades implicated in the most common forms of cardiovascular disease.
Shallow cores in bright, massive galaxies are commonly thought to be the result of scouring of stars by mergers of binary supermassive black holes. Past investigations have suggested correlations ...between the central black hole mass and the stellar light or mass deficit in the core, using proxy measurements of M sub(BH) or stellarmass-to-light ratios ( Upsilon ). Drawing on a wealth of dynamical models which provide both M sub(BH) and Upsilon , we identify cores in 23 galaxies, of which 20 have direct, reliable measurements of M sub(BH) and dynamical stellar mass-to-light ratios ( Upsilon sub(*,dyn)). These cores are identified and measured using Core-Sersic model fits to surface brightness profiles which extend out to large radii (typically more than the effective radius of the galaxy); for approximately one-fourth of the galaxies, the best fit includes an outer (Sersic) envelope component.We find that the core radius is most strongly correlated with the black hole mass and that it correlates better with total galaxy luminosity than it does with velocity dispersion. The strong core-size-M sub(BH) correlation enables estimation of black hole masses (in core galaxies) with an accuracy comparable to the M sub(BH-sigma) relation (rms scatter of 0.30 dex in log M sub(BH)), without the need for spectroscopy. The light and mass deficits correlate more strongly with galaxy velocity dispersion than they do with black hole mass. Stellar mass deficits span a range of 0.2-39 M sub(BH), with almost all (87%) being <10 M sub(BH); the median value is 2.2 M sub(BH).
Objective
To assess the cost‐effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage.
Design
Within‐trial economic ...evaluation and model‐based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost‐effectiveness acceptability curves. Analyses were performed from the perspective of the UK’s National Health Service (NHS).
Setting
Twenty‐eight UK NHS early pregnancy units.
Sample
A cohort of 711 women aged 16–39 years with ultrasound evidence of a missed miscarriage.
Methods
Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets.
Main outcome measures
Cost per additional successfully managed miscarriage and quality‐adjusted life years (QALYs).
Results
For the within‐trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7–12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI −0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26–£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model‐based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model‐based evidence suggests that the intervention is a less effective but less costly strategy than surgical management.
Conclusions
The within‐trial analysis found that based on cost‐effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage.
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The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.
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The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.
We report R 6 4300 VLT SINFONI adaptive optics integral field K-band spectroscopy of the nucleus of the Seyfert 1 galaxy NGC 3227 at a spatial resolution of 0".085 (7 pc). We present the morphologies ...and kinematics of emission lines and absorption features and give the first derivation of a black hole mass in a Seyfert 1 nucleus from stellar dynamics (marginally resolving the black hole's sphere of influence). We show that the gas in the nucleus has a mean column density of order 10 super(24) cm super(-2) and that it is geometrically thick, in agreement with the standard "molecular torus" scenario. We discuss possible heating processes responsible for maintaining the vertical height of the torus. We also resolve the nuclear stellar distribution and find that within a few parsecs of the AGN there has been an intense starburst, the most recent episode of which began 640 Myr ago but has now ceased. The current luminosity of stars within 30 pc of the AGN, 63 x 10 super(9) L sub( ), is comparable to that of the AGN. We argue that the star formation has been occurring in the obscuring material. Finally, we apply Schwarzschild orbit superposition models to our full two-dimensional data and derive the mass of the black hole, paying careful attention to the input parameters, which are often uncertain. Our models yield a 1 s range for the black hole mass of M sub(BH) = 7 x 10 super(6)-2 x 10 super(7) M sub( ).
Reproductive management programs that synchronize ovulation can ovulate a smaller than normal follicle, potentially resulting in inadequate progesterone (P4) concentrations after artificial ...insemination (AI). Ovulation of the dominant follicle of the first follicular wave with human chorionic gonadotropin (hCG) treatment can produce an accessory corpus luteum and increase circulating P4 concentrations. This manuscript reports the results of 2 separate analyses that evaluated the effect of hCG treatment post-AI on fertility in lactating dairy cows. The first study used meta-analysis to combine the results from 10 different published studies that used hCG treatment on d 4 to 9 post-AI in lactating dairy cows. Overall, pregnancies per artificial insemination (P/AI) were increased 3.0% by hCG treatment post-AI 34% (752/2,213) vs. 37% (808/2,184); Control vs. hCG-treated, respectively. The second study was a field research trial in which lactating Holstein cows (n=2,979) from 6 commercial dairy herds were stratified by parity and breeding number and then randomly assigned to one of 2 groups: control (no further treatment, n=1,519) or hCG Chorulon i.m.: 2,000IU (in 3 of the herds) or 3,300IU (in 3 herds); n=1,460 on d 5 after a timed AI (ovulation synchronized with Ovsynch, Presynch-Ovsynch, or Double-Ovsynch). In a subset of cows, the hCG profile and P4 changes were determined. Treatment with hCG increased P4 (4.3 vs. 5.3ng/mL on d 12). Pregnancies per AI were greater in cows treated with hCG (40.8%; 596/1,460) than control (37.3%; 566/1,519) cows. Interestingly, an interaction among treatment and parity was observed; primiparous cows had greater P/AI after hCG (49.7%; 266/535) than controls (39.5%; 215/544). In contrast, older cows receiving hCG (35.7%; 330/925) had similar P/AI to controls (36.0%; 351/975).Thus, targeted use of hCG on d 5 after TAI enhances fertility about 3.0% (based on meta-analysis) to 3.5% (based on our field trial). Surprisingly, this fertility-enhancing effect of hCG was very large in first-lactation cows but not observed in older cows in the field study. Future research is needed to confirm these intriguing results and to determine why older cows did not have improved fertility after hCG treatment.
New photometric and long-slit spectroscopic observations are presented for NGC 7113, PGC 1852, and PGC 67207 which are three bright galaxies residing in low-density environments. The ...surface-brightness distribution is analysed from the K
S
-band images taken with adaptive optics at the Gemini North Telescope and the ugriz-band images from the Sloan Digital Sky Survey while the line-of-sight stellar velocity distribution and line-strength Lick indices inside the effective radius are measured along several position angles. The age, metallicity, and α-element abundance of the galaxies are estimated from single stellar-population models. In spite of the available morphological classification, images show that PGC 1852 is a barred spiral which we do not further consider for mass modelling. The structural parameters of the two early-type galaxies NGC 7113 and PGC 67207 are obtained from a two-dimensional photometric decomposition and the mass-to-light ratio of all the (luminous and dark) mass that follows the light is derived from orbit-based axisymmetric dynamical modelling together with the mass density of the dark matter halo. The dynamically derived mass that follows the light is about a factor of 2 larger than the stellar mass derived using stellar-population models with Kroupa initial mass function. Both galaxies have a lower content of halo dark matter with respect to early-type galaxies in high-density environments and in agreement with the predictions of semi-analytical models of galaxy formation.
Objectives
To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding.
Design
Economic evaluation alongside a ...large multi‐centre randomised placebo‐controlled trial.
Setting
Forty‐eight UK NHS early pregnancy units.
Population
Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac.
Methods
An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages.
Main outcome measures
Cost per additional live birth at ≥34 weeks of gestation.
Results
Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673).
Conclusions
The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s).
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Progesterone treatment is likely to be cost‐effective in women with early pregnancy bleeding and a history of miscarriage.
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Progesterone treatment is likely to be cost‐effective in women with early pregnancy bleeding and a history of miscarriage.
We present the first results of an analysis of the properties of the molecular gas in the nuclear regions (r 300 pc) of a sample of six nearby galaxies, based on new high-spatial-resolution ...observations obtained in the K-band with the near-infrared integral field spectrograph SINFONI at the Very Large Telescope. We derive 2D distributions of the warm molecular and ionized gas from the H2, Brγ and He i emission lines present in the spectra of the galaxies. We find a range of morphologies, including bar- and ring-like distributions and either centrally peaked or off-centre emission. The morphologies of the molecular and the ionized gas are not necessarily coincident. The observed emission-line ratios point towards thermal processes as the principal mechanism responsible for the H2 excitation in the nuclear and circumnuclear regions of the galaxies, independently of the presence of an active nucleus. We find that a rescaling of the H2 2.12 μm emission-line luminosity by a factor β 1200 gives a good estimate (within a factor of 2) of the total (cold) molecular gas mass. The galaxies of the sample contain large quantities of molecular gas in their centres, with total masses in the ∼105-108 M range. Nevertheless, these masses correspond to less than 3 per cent of the stellar masses derived for the galaxies in these regions, indicating that the presence of gas should not affect black hole mass estimates based on the dynamical modelling of the stars. The high spatial resolution provided by the SINFONI data allowed us to resolve a circumnuclear ring (with a radius of ∼270 pc) in the galaxy NGC 4536. The measured values of the Brγ equivalent width and the He i/Brγ emission-line ratio suggest that bursts of star formation occurred throughout this ring as recently as 6.5 Myr ago.
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