Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist

Vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis that are up-regulated by hypoxia. We evaluated the effects of DNA-binding small molecules on hypoxia-inducible transcription of VEGF. A synthetic pyrrole-imidazole polyamide designed to bind the hypoxia response element (HRE) was found to disrupt hypoxia-inducible factor (HIF) binding to HIRE. In cultured HeLa cells, this resulted in a reduction of VEGF mRNA and secreted protein levels. The observed effects were polyamide-specific and dose-dependent. Analysis of genome-wide effects of the HIRE-specific polyamide revealed that a number of hypoxia-inducible genes were down-regulated. Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis

Optical Resonances in Reflectivity near Crystal Modes with Spatial Dispersion

We study the effect of spatial dispersion of crystal modes on optical properties such as the reflectivity $R$. As an example for isotropic media, we investigate the simplest model for phonons in ionic crystals and compare with previous results for highly anisotropic plasmons, which are now understood from a more general point of view. As a consequence of the wave vector dependence of the dielectric function small changes in the lineshape are predicted. Beyond that, if the frequency of minimal $R$ is near a pole of the dispersionless dielectric function, the relative amplitude of dips in $R$ with normal and anomalous dispersion differ significantly, if dissipation and disorder are low.Comment: 4 pages, 7 eps figures, minor change

Lower uterine segment placental thickness in women with abnormally invasive placenta.

Introduction Ultrasound signs of abnormal placental invasion are subjective in nature. We tested the hypothesis that placental thickness in the lower uterine segment is increased when there is abnormally invasive placenta (AIP) in women with a low‐lying placenta. Material and methods Retrospective analysis of data of placental thickness in women with ultrasound evidence of major placenta previa or a low‐lying anterior placenta was done. The diagnosis of AIP was confirmed both intraoperatively and on histopathology for those managed by partial myometrial excision with uterine conservation or by hysterectomy. Results In all, 131 records were available for analysis after exclusion of 33 cases due to unsuitable images and eight cases without pregnancy outcomes. The diagnosis of AIP was confirmed in 28 (21.4%) of the 131 cases. The lower segment placental thickness was significantly higher in women with AIP (median = 50.3 mm, IQR: 42.7‐64.3) than in those with normal placentation (median = 30.9 mm, IQR: 22.9‐42.2, P < 0.001). Logistic regression analysis showed that previous cesarean section and placental thickness on ultrasound were independent predictors for AIP. Conclusions Lower uterine segment placental thickness is increased in women with AIP compared with those with noninvasive placentation. This association constitutes a pragmatic objective sign and may be of clinical value in improving prenatal detection of AIP in women with placental implantation in the lower uterine segment. Prospective studies are necessary to ascertain lower segment placental thickness as a predictor for AIP

Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors

In SS, metastases develop late with high mortality. Patients with SS should be followed for >10 year

Scans for signatures of selection in Russian cattle breed genomes reveal new candidate genes for environmental adaptation and acclimation

Domestication and selective breeding has resulted in over 1000 extant cattle breeds. Many of these breeds do not excel in important traits but are adapted to local environments. These adaptations are a valuable source of genetic material for efforts to improve commercial breeds. As a step toward this goal we identified candidate regions to be under selection in genomes of nine Russian native cattle breeds adapted to survive in harsh climates. After comparing our data to other breeds of European and Asian origins we found known and novel candidate genes that could potentially be related to domestication, economically important traits and environmental adaptations in cattle. The Russian cattle breed genomes contained regions under putative selection with genes that may be related to adaptations to harsh environments (e.g., AQP5, RAD50, and RETREG1). We found genomic signatures of selective sweeps near key genes related to economically important traits, such as the milk production (e.g., DGAT1, ABCG2), growth (e.g., XKR4), and reproduction (e.g., CSF2). Our data point to candidate genes which should be included in future studies attempting to identify genes to improve the extant breeds and facilitate generation of commercial breeds that fit better into the environments of Russia and other countries with similar climates

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.Broad Institute of MIT and Harvard. SPARC ProgramBurroughs Wellcome Fun

Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median=48.1%; 95% confidence interval=27.3%-56.5%; P=0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2=0.88, P=0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging maybe used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas

Cardiac maladaptation in term pregnancies with preeclampsia

Objectives: To study biventricular cardiac changes with conventional echocardiography and new echocardiographic speckle tracking technologies such strain, twist and torsion in pregnant women with preeclampsia at term and normotensive control term pregnant women. Study design: For this prospective single centre case-control study, we consecutively recruited 30 women with preeclampsia at term as cases and 40 healthy control term pregnant women. All women underwent transthoracic echocardiographic examination at the time point of inclusion into the study. Main outcome measures: Signs of systolic and/or diastolic cardiac maladaptation to the increased volume load associated with pregnancy. Results: Conventional echocardiography revealed mild left sided diastolic impairment in the form of significantly increased E/E' in preeclampsia (7.58 ± 1.72 vs. 6.18 ± 1.57, p = 0.001) compared to normotensive controls, but no evidence of systolic impairment. With speckle tracking analysis, significant decreases in left ventricular global (−13.32 ± 2.37% vs. −17.61 ± 1.89%, p < 0.001), endocardial (−15.64 ± 2.79% vs. −19.84 ± 2.35%, p < 0.001) and epicardial strain (−11.48 ± 2.15% vs. −15.73 ± 1.66%, p < 0.001) as well as left ventricular longitudinal strain rate (−0.84 ± 0.14 s−1 vs. −0.98 ± 0.12 s−1, p < 0.001) and left ventricular early diastolic strain rate (0.86 ± 0.30 s−1 vs. 1.24 ± 0.26 s−1, p < 0.001) could be observed in women with term preeclampsia. Conclusions: The findings of this study demonstrate that pregnant women with term preeclampsia with minimal functional changes on conventional echocardiography, demonstrated significant subclinical myocardial changes on speckle tracking analysis

Comparison of vitrified and unvitrified Eocene woody tissues by TMAH thermochemolysis – implications for the early stages of the formation of vitrinite

Samples of vitrified and unvitrified Eocene woody plant tissues collected from the Fossil Forest site, Geodetic Hills, Axel Heiberg Island, have been characterized by TMAH thermochemolysis. All samples are gymnosperm-derived, are of very low maturity and all share the same post-depositional geologic history. Differences in the distributions of products observed from vitrified and unvitrified samples suggest that vitrification of woody tissue is associated with modification of the lignin C3 side chain, following loss of all or most of the carbohydrate present in the precursor woody tissues. The key driver of vitrification appears to be physical compression of the tissue following biological removal of cellulosic materials

Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling