Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could ...suppress endothelial NO production and may impair vascular function.
To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.
Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.
Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic ...target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.
Urban growth is a major factor of global environmental change and has important impacts on biodiversity, such as changes in species composition and biotic homogenization. Most previous studies have ...focused on effects of urban area as a general measure of urbanization, and on few or single taxa. Here, we analyzed the impacts of the different components of urban sprawl (i.e., scattered and widespread urban growth) on species richness of a variety of taxonomic groups covering mosses, vascular plants, gastropods, butterflies, and birds at the habitat and landscape scales. Besides urban area, we considered the average age, imperviousness, and dispersion degree of urban area, along with human population density, to disentangle the effects of the different components of urban sprawl on biodiversity. The study was carried out in the Swiss Plateau that has undergone substantial urban sprawl in recent decades.Vascular plants and birds showed the strongest responses to urban sprawl, especially at the landscape scale, with non-native and ruderal plants proliferating and common generalist birds increasing at the expense of specialist birds as urban sprawl grew. Overall, urban area had the greatest contribution on such impacts, but additional effects of urban dispersion (i.e., increase of non-native plants) and human population density (i.e., increases of ruderal plants and common generalist birds) were found. Our findings support the hypothesis that negative impacts of urban sprawl on biodiversity can be reduced by compacting urban growth while still avoiding the formation of very densely populated areas.
The European Association of Urology (EAU) non–muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be ...underuse of guideline-recommended care in this potentially curable cohort.
To assess European physicians’ current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines.
Initial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews.
Descriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used.
Guidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71–100%). Cystoscopy (60–97%) and ultrasonography (42–95%) are the most used diagnostic techniques. Using EAU risk classification, 40–69% and 88–100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25–75% of low-risk and 55–98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24h after TURB. Adjuvant intravesical treatment is not given to 6–62%, 2–33%, and 1–20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians.
Although most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice.
Our survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non–muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied.
European urologists claim to apply the European Association of Urology guidelines to the management of non–muscle-invasive bladder cancer, but may not fully adhere to these guidelines in everyday practice. As a community, we urologists need to understand this lack of adherence to guidelines to improve treatment practice.
Noninvasive corneal imaging is essential for the diagnosis and treatment control of various diseases affecting the anterior segment of the eye. This study presents an ultrahigh resolution ...polarization sensitive optical coherence tomography instrument operating in the 840 nm wavelength band that incorporates a conical scanning design for large field of view imaging of the cornea. As the conical scanning introduces a dispersion mismatch depending on the scanning angle, this study implemented variable, location dependent, numerical dispersion compensation in order to achieve high axial resolution throughout the imaged volume. The corneal images were recorded in vivo in healthy volunteers showing various details of corneal structures.
The content of the flavonolignan mixture silymarin and its individual components (silichristin, silidianin, silibinin A, silibinin B, isosilibinin A, and isosilibinin B) in whole and milled milk ...thistle seeds (Silybi mariani fructus) was analyzed with near-infrared spectroscopy. The analytical performance of one benchtop and two handheld near-infrared spectrometers was compared. Reference analysis was performed with HPLC following a Soxhlet extraction (European Pharmacopoeia) and a more resource-efficient ultrasonic extraction. The reliability of near-infrared spectral analysis determined through partial least squares regression models constructed independently for the spectral datasets obtained by the three spectrometers was as follows. The benchtop device NIRFlex N-500 performed the best both for milled and whole seeds with a root mean square error of CV between 0.01 and 0.17%. The handheld spectrometer MicroNIR 2200 as well as the microPHAZIR provided a similar performance (root mean square error of CV between 0.01 and 0.18% and between 0.01 and 0.23%, respectively). We carried out quantum chemical simulation of near-infrared spectra of silichristin, silidianin, silibinin, and isosilibinin for interpretation of the results of spectral analysis. This provided understanding of the absorption regions meaningful for the calibration. Further, it helped to better separate how the chemical and physical properties of the samples affect the analysis. While the study demonstrated that milling of samples slightly improves the performance, it was deemed to be critical only for the analysis carried out with the microPHAZIR. This study evidenced that rapid and nondestructive quantification of silymarin and individual flavonolignans is possible with miniaturized near-infrared spectroscopy in whole milk thistle seeds.
To determine pathologic regulations and potential compensatory mechanisms in the supraspinal locomotor network of patients with progressive supranuclear palsy (PSP) by investigation of brain ...activation during walking and correlation to gait performance.
Twelve patients with PSP were scanned with 18F-FDG-PET during walking and at rest as has been described earlier. Results were compared to age-matched healthy controls (n = 12).
The major results were as follows. (1) At rest, the regional cerebral glucose metabolism (rCGM) in the supraspinal locomotor centers, i.e., the prefrontal cortex, the subthalamic nucleus, and the pedunculopontine/cuneiform nucleus complex, was reduced in PSP. (2) Severity of gait impairment, measured by gait velocity, step length, and progressive supranuclear palsy rating scales/gait, correlated with decrease of rCGM in the prefrontal cortex and subthalamic nucleus. (3) Accordingly, during walking functional activation of the prefrontal cortex, the subthalamic nucleus, the pedunculopontine/cuneiform nucleus complex, and the thalamus was reduced in patients with PSP compared to controls. (4) The precentral gyrus and the vermal cerebellum were activated more strongly during locomotion in PSP.
Gait impairment in PSP is especially associated with dysfunction of the indirect, modulatory prefrontal-subthalamic-pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar drive shows increased activity in PSP. The latter can be interpreted as an attempt of compensation, but may also contribute to a stereotyped gait pattern in PSP.
Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility ...variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their
-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of
< 2.2 × 10
, we identified 35 genes, including
at 11q14.2 (Z = 5.08,
= 3.83 × 10
, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (
< 1.47 × 10
). These data identify one novel locus
) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.
Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk.
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