Recent Use of Pediatric Extrapolation in Pediatric Drug Development in US.

The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials, for drugs developed in both adults and children. However, when scientifically justified, relying on extrapolation may be acceptable. Historically, the FDA's extrapolation approach was based on draft guidance published in 2014, which introduced the categories of full, partial, and no extrapolation. The European Medicines Agency (EMA) took a different view on pediatric extrapolation. To better understand the use of extrapolation to support pediatric drug development and approval, we reviewed the pediatric labeling changes published by the FDA, focusing on the labeling updates between 1/1/2015 and 7/31/2021, the period where the extrapolation approach is in transition to harmonize with the EMA. Within this time window, among the 265 drugs and biological products with pediatric labeling changes, 169 (63.8%) were identified where extrapolation was used. This includes 64 (24.2%) labeling changes, where full extrapolation was used, and 105 (39.6%) labeling changes, where partial extrapolation was used. The major disease areas that extrapolation was used include neuroscience (40/53, 75.5%) and infectious disease (20/28, 71.4%). The extrapolation approach was identified in terms of source population beyond the use of adult as well as extrapolation from clinical trials conducted in the same drug class. The use of extrapolation increased the rates of new and expanded pediatric indication in the period. This review gives the most recent landscape of pediatric labeling changes using extrapolation. With the released ICH (International Council for Harmonization) E11A guidance in April 2022, the paper also provides insights for future pediatric drug development programs.

Extent of safety database in pediatric drug development: types of assessment, analytical precision, and pathway for extrapolation through on-target effects.

Pediatric patients should have access to medicines that have been appropriately evaluated for safety and efficacy through revised labelling. Given this goal, the adequacy of the pediatric clinical development plan and resulting safety database are critical factors to inform a favorable benefit-risk assessment for the intended use of the medicinal product. While extrapolation from adults can be used to support efficacy of drugs in children, there may be a reluctance to use the same approach in safety assessments, wiping out potential gains in trial efficiency through a reduction of sample size. To address this issue, we explore safety review in pediatric trials, including specific types of safety assessments and precision on the estimation of event rates for specific adverse events (AEs) that can be achieved. In addition, we discuss the assessments which can provide a benchmark for the use of extrapolation of safety that focuses on on-target effects. Finally, we explore a unified approach for understanding precision using Bayesian approaches as the most appropriate methodology to describe or ascertain risk in probabilistic terms for the estimate of the event rate of specific AEs.

Sex Estimation of Medial Aspect of the Ischiopubic Ramus in Adults Based on Deep Learning.

OBJECTIVES: To investigate the reliability and accuracy of deep learning technology in automatic sex estimation using the 3D reconstructed images of the computed tomography (CT) from the Chinese Han population. METHODS: The pelvic CT images of 700 individuals (350 males and 350 females) of the Chinese Han population aged 20 to 85 years were collected and reconstructed into 3D virtual skeletal models. The feature region images of the medial aspect of the ischiopubic ramus (MIPR) were intercepted. The Inception v4 was adopted as the image recognition model, and two methods of initial learning and transfer learning were used for training. Eighty percent of the individuals' images were randomly selected as the training and validation dataset, and the remaining were used as the test dataset. The left and right sides of the MIPR images were trained separately and combinedly. Subsequently, the models' performance was evaluated by overall accuracy, female accuracy, male accuracy, etc. RESULTS: When both sides of the MIPR images were trained separately with initial learning, the overall accuracy of the right model was 95.7%, the female accuracy and male accuracy were both 95.7%; the overall accuracy of the left model was 92.1%, the female accuracy was 88.6% and the male accuracy was 95.7%. When the left and right MIPR images were combined to train with initial learning, the overall accuracy of the model was 94.6%, the female accuracy was 92.1% and the male accuracy was 97.1%. When the left and right MIPR images were combined to train with transfer learning, the model achieved an overall accuracy of 95.7%, and the female and male accuracies were both 95.7%. CONCLUSIONS: The use of deep learning model of Inception v4 and transfer learning algorithm to construct a sex estimation model for pelvic MIPR images of Chinese Han population has high accuracy and well generalizability in human remains, which can effectively estimate the sex in adults.

Surface-enhanced Raman scattering from an electromagnetic induced transparency substrate for the determination of hepatocellular carcinoma.

Surface-enhanced Raman scattering (SERS) is a powerful analytical method that is especially suitable for the detection of protein molecules. Detection sensitivity of SERS is directly related to the enhancement factor of the substrate, which is dependent on the strength of a local surface electric field generated by surface plasmonic resonance from substrate. In this study, an electromagnetic induced transparency like (EIT-like) metamaterial was used as the SERS substrate. The corresponding plasmonic resonance structure not only produces stronger optical near field but also reduces the spectral line broadening due to radiation damping. This is very beneficial for SERS process, which is strongly dependent on electric field intensity, to improve the sensitivity of SERS detection. Compared with the single resonance mode substrate, the enhancement factor for SERS with the double-mode substrate was increased by an order of magnitude. The obtained EIT-like substrate was used as a SERS-active substrate to detect Lens culinaris agglutinin (LCA)-reactive fraction of AFP (AFP-L3), a hepatocellular carcinoma (HCC)-specific maker. Experimental results are in good agreement with the clinical diagnosis, which demonstrates the potential application of metamaterials in the SERS-based diagnosis and biosensing.

In vivo two-photon fluorescence lifetime imaging microendoscopy based on fiber-bundle.

Fluorescence lifetime imaging microendoscopy (FLIME) has been reported to investigate the physicochemical microenvironment in biological tissue. In this work, we designed a two-photon (TP) FLIME system based on a fiber-bundle glued with an achromatic mini-objective with 1.4-mm diameter, which was coupled to a standard TP microscope containing a dispersion precompensation module in the laser source. With 840 nm excitation, the field of view and lateral resolution of our system are 390 µm and 1.55 µm, respectively. To examine the capability of imaging in vivo, we obtained Z-stack (0-130 µm) TP-FLIME images from the intestine's surface of a mouse injected with squaraine dye. Further, we utilized the TP-FLIME system to image the kidney, liver, and xenografted tumor at 100-µm depth in vivo with cellular resolution, which features the distribution of cells and tissue structures with better contrast than intensity images. These results demonstrated that the proposed system is capable of measuring fluorescence lifetime in situ and provides a powerful tool to research the deep tissue microenvironment naturally.

Highly stable organic photothermal agent based on near-infrared-II fluorophores for tumor treatment.

BACKGROUND: The aim to develop a highly stable near-infrared (NIR) photoinduced tumor therapy agent stems from its considerable potential for biological application. Due to its long wavelength, biological imaging exhibits a high signal-to-background ratio, deep tissue penetration and maximum permissible light power, which can minimize damage to an organism during photoinduced tumor therapy. RESULTS: A class of stable NIR-II fluorophores (NIR998, NIR1028, NIR980, NIR1030, and NIR1028-S) based on aza-boron-dipyrromethene (aza-BODIPY) dyes with donor-acceptor-donor structures have been rationally designed and synthesized by harnessing the steric relaxation effect and intramolecular photoinduced electron transfer (IPET). These fluorophores exhibit an intense range of NIR-II emission, large Stokes shift (≥ 100 nm), excellent photothermal conversion performance, and superior stability against photobleaching. Among the NIR-II fluorophores, NIR998 possesses better NIR-II emission and photothermal conversion performance. NIR998 nanoparticles (NIR998 NPs) can be encapsulated by liposomes. NIR998 NPs show superior stability in the presence of light, heat, and reactive oxygen nitrogen species than that of indocyanine green NPs, as well as a higher photothermal conversion ability (η = 50.5%) compared to other photothermal agents. Finally, under the guidance of photothermal imaging, NIR998 NPs have been proven to effectively eliminate tumors via their excellent photothermal conversion performance while presenting negligible cytotoxicity. CONCLUSIONS: Utilizing IPET and the steric relaxation effect can effectively induce NIR-II emission of aza-BODIPY dyes. Stable NIR998 NPs have excellent photothermal conversion performance and negligible dark cytotoxicity, so they have the potential to act as photothermal agents in biological applications.

Fluorescence enhancement of small squaraine dye and its two-photon excited fluorescence in long-term near-infrared I&II bioimaging.

Two-photon excited fluorescence (TPEF) plays an important role in bioimaging, the longer excitation wavelength improves its imaging depths, which gives us deeper biological information. Here, we reported the two-photon absorption of a small squaraine dye (SD), and we found that the TPEF of the small SD can be enhanced significantly using albumin, the TPEF of SD in water was enhanced 17.7 times by adding bull serum albumin (BSA) in the solution. Meanwhile, the cell imaging results indicated that the SD can enter cell effectively in less than 30 min and emit bright TPEF. Furthermore, the SD showed excellent stability against photobleaching in near-infrared II (1200 nm). The cytotoxicity experiment showed that the cytotoxicity of SD is relatively low. Our work demonstrates the excellent two-photon effect of SD in cells, potential application value of SD in two-photon bioimaging, protein detection and near infrared sensing.

The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2A with Cutaneous Lichen Amyloidosis in Ethnic Han Chinese.

This study systematically reviewed previous literatures and analyzed the genotype-phenotype relationship between the multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (CLA) and RET/OSMR/IL31RA mutations. RET/OSMR/IL31RA screening was performed on 8 RET-carriers from 3 independent Chinese MEN 2A families. Besides, 51 MEN 2A-CLA patients in 116 RET carriers from literatures were clustered and analyzed. Our results indicated that almost all MEN 2A-CLA patients exhibited CLA which was located in the scapular region and carried RET mutation at codon 634. Meanwhile, we firstly described MEN 2A-CLA here in Chinese Han patient with RET p.C634F mutation.

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors.

AIMS: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. MATERIALS & METHODS: Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. RESULTS: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. CONCLUSION: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice.

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice (Scn5a(+/ΔKPQ)). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a(+/ΔKPQ) mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a(+/ΔKPQ) mice, light phase-restricted feeding shifted the RR and QT rhythms ~12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ~10%. In contrast to WT mice, the QTc interval in Scn5a(+/ΔKPQ) mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a(+/ΔKPQ) mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.

[Clinicopathological factors in risk prediction of lymph node metastasis in papillary thyroid carcinoma].

OBJECTIVE: To explore the relationship between histomorphological factors and lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). METHODS: A total of 153 paraffin-embedded specimens of PTC treated at Beijing Tongren Hospital, Capital Medical University were collected from January 1, 2006 to December 31, 2013 and assessed by hematoxylin and eosin staining. The tumor growth patterns (infiltrative tumor border, lateral tubular growth and intraglandular dissemination), histomorphological characteristics (hobnail features, loss of cohesiveness/polarity (LOCP) and micropapillary structures) and several clinicopathological parameters were evaluated for their values in LNM. RESULTS: Among them, there were infiltrative tumor border (n = 128), lateral tubular growth (n = 34), intraglandular dissemination (n = 30), extrathyroidal extensions (n = 53), hobnail features (n = 37), LOCP (n = 59) and micropapillary structures (n = 70). According to univariate analysis, patient age < 45 years, tumor size of 10 mm or more, infiltratve tumor border, lateral tubular growth, intraglandular dissemination, hobnail features, LOCP and micropapillary structures predicted LNM for PTC (P < 0.05); whereas gender, multifocality and extrathyroidal extensions did not (P > 0.05). According to multivariated analysis, tumor size of 1 cm or more, infiltratve tumor border, hobnail features, LOCP and micropapillary structures were independent predictive factors of LNM for PTC (P < 0.05). After a median follow-up period of 42 months, 4/82 patients suffered from locoregional recurrence. The estimated 5-year locoregional recurrence was 4.88%. Among 4 logcoregional recurrence cases, 3 involved in lymph nodes and 1 in remaining thyroid. Among 3 lymph node metastasis cases, there were hobnail feature (n = 1), LOCP (n = 1) and LOCP and micropapillary structure (n = 1). None of hobnail feature, LOCP or micropapillary structure was found in recurrent case of remaining thyroid. CONCLUSION: Correlated with lymph node metastasis in PTC, hobnail features, LOCP and micropapillary structures may be used as independent predictive factors of LNM so as to improve treatment and follow-up strategies for PTC.

An oxygen vacancy-modulated bifunctional S-NiMoO4 electrocatalyst for efficient alkaline overall water splitting.

S-doped nickel molybdate nanorods grown on nickel foam (S-NiMoO4/NF) were fabricated by a two-step hydrothermal method. The resultant S-NiMoO4/NF exhibited remarkable bifunctional electrocatalytic activity, with overpotentials of 235 mV for the hydrogen evolution reaction and 150 mV for the oxygen evolution reaction at a current density of 50 mA cm-2. Assembled into the two-electrode S-NiMoO4/NF electrolyzer in alkaline electrolytes for overall water splitting, it required only low cell voltages of 1.55 V and 1.63 V to drive 50 mA cm-2 and 100 mA cm-2, respectively. No significant performance degradation occurred during the water electrolysis process. The experimental results confirmed that S-doping induced the increase of the oxygen vacancies, accelerating the reaction kinetics and thus improving the electrocatalytic performance. Meanwhile, more active sites exposure on the surface of S-NiMoO4/NF enhanced the reactivity. This work may guide the development of efficient bifunctional catalysts in alkaline electrolysis through oxygen vacancy regulation.

Are community oncology practices with/without clinical research programs different? A comparison of patient and practice characteristics.

PURPOSE: Expanding access to clinical trials in community settings is a potential approach to addressing disparities in accrual of historically underrepresented populations. However, little is known about the characteristics of practices that do not participate in research. We investigated differences in patient and practice characteristics of US community oncology practices with high vs low engagement in clinical research. METHODS: We included patients from a real-world, nationwide electronic health record-derived, de-identified database who received active treatment for cancer at community oncology practices between 11/1/17 and 10/31/22. We assessed patient and practice characteristics and their associations with high vs low research engagement using descriptive analyses and logistic regression models. RESULTS: Seventy (39.3%) of 178 practices had high research engagement, treated 57.8% of the overall 568,540 patient cohort, and enrolled 3.25% of their patients on cancer treatment trials during the five-year observation period (v 0.27% enrollment among low engagement practices). Practices with low vs high research engagement treated higher proportions of the following patient groups: ages > =75 (24.2% v 21.8%), non-Latinx Black (12.6% v10.3%) or Latinx (11.6% v 6.1%), were within the lowest socioeconomic status quintile (21.9% v 16.5%), and were uninsured or had no documented insurance (22.2% v 13.6%). CONCLUSION: Patient groups historically underrepresented in oncology clinical trials are more likely to be treated at community practices with limited or no access to trials. These results suggest that investments to expand the clinical research footprint among practices with low research engagement could help address persistent inequities in trial representation.

Application of waste derived magnetic acid-base bifunctional CoFe/biochar/CaO as an efficient catalyst for biodiesel production from waste cooking oil.

The loss of active components, weak acid resistance, and low recover efficiency of common Ca-based catalysts limited its further development and application. In this study, to effectively produce biodiesel from waste cooking oil (WCO), a green and recyclable magnetic acid-base bifunctional CoFe/biochar/CaO catalyst was prepared from sargassum and river snail shell waste via hydrothermal method. The catalysts' structure and properties were investigated by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), CO2/NH3 temperature programmed desorption (CO2/NH3 TPD), etc., The prepared catalyst mainly consisted of the carbon skeleton, CoFe alloy, and CaO. CoFe alloy provided catalyst's ferromagnetism for magnetic separation as well as acid sites for transesterification of WCO. Ca and other metal species with nanoscale (∼5.64 nm) were dispersively anchored on sargassum biochar surface, thereby leading to good catalytic activity (99.21% biodiesel yield) and stability (91.70% biodiesel yield after the 5th cycle). In addition, response surface methodology-Box-Behnken design (RSM-BBD) revealed the optimal operational conditions were 16:1 methanol/oil molar ratio, 3 wt% catalyst dosage, 73 °C for 157 min. The maximum biodiesel yield predicted value was 98.29% and the experimental value was 99.21%, indicating good satisfaction of the established model. Moreover, the quality of WCO biodiesel met the ASTM D6751 standards. This study benefits magnetic waste-derived acid-base bifunctional catalysts for the disposal of WCO towards sustainable biodiesel production.

Broadening Eligibility Criteria and Diversity among Patients for Cancer Clinical Trials.

BACKGROUND: Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown. METHODS: Using a nationwide electronic health record-derived deidentified database, we identified a retrospective cohort of patients diagnosed with 22 cancer types between April 1, 2013 and December 31, 2022 who received systemic therapy (N=235,234) for cancer. We evaluated strict versus broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy. We performed logistic regression to estimate odds ratios for exclusion by strict criteria and their association with measures of patient diversity, including sex, age, race or ethnicity, and area-level socioeconomic status (SES); estimated the impact of broadening criteria on the number and distribution of eligible patients; and performed Cox regression to estimate hazard ratios for real-world overall survival (rwOS) comparing patients meeting strict versus broadened criteria. RESULTS: When applying common strict cutoffs for eligibility criteria to patients with complete data and weighting each cancer type equally, 48% of patients were eligible for clinical trials. Female (odds ratio, 1.30; 95% confidence interval [CI], 1.25 to 1.35), older (age 75+ vs. 18 to 49 years old: odds ratio, 3.04; 95% CI, 2.85 to 3.24), Latinx (odds ratio, 1.46; 95% CI, 1.39 to 1.54), non-Latinx Black (odds ratio, 1.11; 95% CI, 1.06 to 1.16), and lower-SES patients were more likely to be excluded using strict eligibility criteria. Broadening criteria increased the number of eligible patients by 78%, with the strongest impact for older, female, non-Latinx Black, and lower-SES patients. Patients who met only broadened criteria had worse rwOS versus those with strict criteria (hazard ratio, 1.31; 95% CI, 1.27 to 1.34). CONCLUSIONS: Data-driven evaluation of clinical trial eligibility criteria may optimize the eligibility of certain historically underrepresented groups and promote access to more inclusive trials. (Sponsored by Flatiron Health.).

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility.

The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1(-/-) hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na(+) channel (Na(V)1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1(-/-) hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1(-/-) hearts was associated with decreased levels of Na(V)1.5 and Na(+) current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans.

A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors.

BACKGROUND: This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. METHODS: In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. RESULTS: Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7% and 43.3% of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. CONCLUSIONS: Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.

Trans-3,4,5,4'-tetramethoxystilbene, a resveratrol analog, potently inhibits angiogenesis in vitro and in vivo.

AIM: Trans-3,4,5,4'-tetramethoxystilbene (DMU-212) has shown strong antiproliferative activities against a variety of cancer cells. The aim of this study was to investigate the anti-angiogenic effects of DMU-212 in vitro and in vivo. METHODS: Human umbilical vein endothelial cells (HUVECs) were used in this study. Cell viability was studied with MTT assay, and cell apoptosis was evaluated using TUNEL assay and morphological observation. The expression of the related genes and proteins was analyzed with qRT-PCR and Western blot, respectively. Angiogenesis of HUVECs were studied using cell migration and capillary-like tube formation assays in vitro, and mouse Matrigel plug assay and chick chorioallantoic membrane (CAM) assay in vivo. The tyrosine kinase activities of VEGFR1 and VEGFR2 were measured using commercial kits. RESULTS: DMU-212 (5-80 µmol/L) significantly inhibited VEGF-stimulated proliferation of HUVECs (IC50 value was approximately 20 µmol/L), and induced apoptosis. Furthermore, DMU-212 concentration-dependently inhibited VEGF-induced migration of HUVECs and capillary-like structure formation in vitro. DMU-212 also inhibited VEGF-induced generation of new vasculature in Matrigel plugs in vivo with significantly decreased area of infiltrating CD31-positive endothelial cells, and inhibited newly formed microvessels in chick CAMs. Moreover, DMU-212 concentration-dependently suppressed VEGF-induced phosphorylation of VEGFR2, and inhibited phosphorylation of multiple downstream signaling components in the VEGFR2 pathway, including c-Src, FAK, Erk1/2, Akt, mTOR, and p70S6K in HUVECs. DMU-212 had no effect on VEGF-induced phosphorylation of VEGFR1. CONCLUSION: DMU-212 is a potent inhibitor of angiogenesis that exerts anti-angiogenic activity at least in part through the VEGFR2 signaling pathway.

Cyclic Olefin Terpolymers with High Refractive Index and High Optical Transparency.

Cyclic olefin copolymer (COC) is one of the most promising optical materials; however, the brittle COC suffers from issues including a low refractive index. In this contribution, by the introduction of high refractive index comonomers including phenoxy substituted α-olefin (C4OAr), p-tolylthio substituted α-olefin (C4SAr) and carbazolyl substituted α-olefins (C4NAr, C3NAr, and C2NAr), the zirconocene mediated terpolymerization of ethylene (E) and tetracyclododecene (TCD) produces the preferred E-TCD-CnNAr (n = 2, 3, and 4) cyclic olefin terpolymers (COT) with tunable compositions (TCD: 11.5- 35.8 mol %, CnNAr: 1.2-5.0 mol %), high molecular weights and high glass transition temperatures (up to 167 °C) in high catalytic activities. Compared to the E-TCD copolymer (COC) material, these COT materials show the comparable thermal decomposition temperature (Td,5% = 437 °C), slightly higher strain at break value (up to 7.4%) and higher tensile strength (up to 60.5 MPa). In particular, these noncrystalline optical COT materials have significantly higher refractive indices of 1.550-1.569 and are more transparent (transmittance: 93-95%), relative to the COC materials, indicative of an excellent optical material.