Expression of vascular endothelial growth factor and its receptors after mandibular distraction osteogenesis

During distraction osteogenesis, angiogenic activity is essential for new bone formation. This study examined the expression of vascular endothelial growth factor (VEGF) and two of its receptors, Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2), in cellular components after mandibular distraction osteogenesis. Unilateral mandibular distraction (0.5 mm twice per day for 10 days) was performed in six mongrel dogs. Two animals each were killed on days 7, 14 and 28 after completion of distraction. The distracted mandibular segments and contralateral undistracted control segments were harvested and processed for immunohistochemical examination. Seven days after distraction, there was a significant increase in the expression levels of VEGF and its receptors in the osteoblasts, osteocytes and immature fibroblast-like cells compared to control specimens. These levels were maintained for 14 days after distraction in the osteoblasts and fibroblast-like cells. Twenty-eight days after distraction, VEGF and VEGFR-1 were expressed only moderately/weakly in the osteoblasts, and no VEGFR-2 expression was detected in the cellular component of the distracted bone. Throughout the observation period, VEGFR-1 expression was stronger than that of VEGFR-2. The expression patterns of VEGF and its receptors suggest that it plays an important role in osteogenesis, and that osteoblasts and immature fibroblast-like cells of the distracted bone may have an autocrine growth effect during distraction osteogenesis.     

Predictive value of computed tomography in identifying extranodal extension in human papillomavirus‐positive versus human papillomavirus‐negative head and neck cancer

Pathologic extranodal extension (pENE) impacts treatment planning and is an important prognostic indicator for patients with head and neck squamous cell carcinoma (HNSCC). Computed tomography (CT) is a commonly used modality for assessment of radiographic ENE (rENE). To determine the predictive value of CT‐identified rENE in predicting pENE, we performed a systematic review through a search of 4 databases (PubMed, Scopus, Cochrane, and OVID). Meta‐analysis of diagnostic performance based on human papillomavirus (HPV) status was conducted. For HPV‐negative HNSCC, pooled sensitivity, specificity, and accuracy were 60.6%, 93.3%, and 82.6%, respectively. Overall positive predictive value (PPV) was 82.7%. For HPV‐positive HNSCC, pooled sensitivity, specificity, and accuracy were 77.7%, 72.2%, and 63.8%, respectively. Overall PPV was 68.6%. Significant differences were observed in diagnostic performance parameters between the two cohorts. The radiographic characteristics of HPV‐positive and HPV‐negative nodal metastases in HNSCC differ and radiographic evaluation of ENE in HPV‐positive nodes is challenging. Development of refined imaging characteristics of HPV‐positive nodes is needed to improve diagnostic performance.     

Impact of positive surgical margins and their locations after radical prostatectomy: comparison of biochemical recurrence according to risk stratification and surgical modality

Purpose

We investigated the influence of positive surgical margins (PSMs) and their locations on biochemical recurrence (BCR) according to risk stratification and surgical modality.

Methods

A total of 1,874 post-radical-prostatectomy (RP) patients of pT2–T3a between 2000 and 2010 at three tertiary centers, and who did not receive neoadjuvant/adjuvant therapy, were included in this study. Patients were stratified according to BCR risk: low risk (PSA <10, pT2a-b, and pGS ≤6), intermediate risk (PSA 10–20 and/or pT2c and/or pGS 7), and high risk (PSA >20 or pT3a or pGS 8–10). The median follow-up was 43 months.

Results

PSMs were a significant predictor of BCR in both the intermediate- and high-risk-disease groups (P = .001, HR 2.1, 95 % CI 1.3–3.4; P < .001, HR 2.8, 95 % CI 2.0–4.1). Positive apical margin was a significant risk factor for BCR in high-risk disease (P = .003, HR 2.0, 95 % CI 1.2–3.3), but not in intermediate-risk disease (P = .06, HR 1.7, 95 % CI 0.9–3.1). Positive bladder neck margin was a significant risk factor for BCR in both intermediate- and high-risk disease (P < .001, HR 5.4, 95 % CI 2.1–13.8; P = .001, HR 4.5, 95 % CI 1.8–11.4). In subgroup analyses, robotic RP provided comparable BCR-free survival regardless of risk stratification. Patients with PSMs showed similar BCR-free survival between open and robotic RP (log-rank, P = .897).

Conclusions

Post-RP PSMs were a significantly independent predictor of disease progression in high-risk disease as well as intermediate-risk disease. Both positive apical and bladder neck margins are also significant risk factors of BCR in high-risk disease. Patients with PSMs showed similar BCR-free survival between open and robotic surgery.     

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.Key Results: Sotalol attained C_max values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.     

Comparative effectiveness of cycling of tumor necrosis factor-α (TNF-α) inhibitors versus switching to non-TNF biologics in rheumatoid arthritis patients with inadequate response to TNF-α inhibitor using a Bayesian approach

Alternative tumor necrosis factor-α (TNF-α) inhibitors and non-TNF biologics are available as treatment options for rheumatoid arthritis patients who exhibit inadequate response to TNF-α inhibitor (TNF-IR patients). These agents have considerable efficacy compared with placebo, but head-to-head comparisons among these agents have not been performed. The objective of this study was to use Bayesian approach to compare the effectiveness of cycling TNF-α inhibitors versus switching to non-TNF biologics in TNF-IR patients. A systematic review was conducted using MEDLINE and Cochrane library. Key endpoints were the American College of Rheumatology (ACR) responses of 20/50/70 and the health assessment questionnaire (HAQ) score change at six months. Bayesian outcomes were calculated as the probability that OR is greater than one and HAQ score change difference is less than zero. Compared with TNF-α inhibitors, non-TNF biologics were associated with higher ACR response rates; in ACR20, the OR was 1.639 for abatacept [P(OR > 1) = 90.7 %], 1.871 for rituximab [P(OR > 1) = 96.2 %] and 3.52 for tocilizumab [P(OR > 1) = 99.9 %]. Similar trends were shown in the HAQ change comparison; the median differences (MD) were ?0.259 for abatacept [P(MD < 0) = 100 %], ?0.160 for rituximab [P(MD < 0) = 98.2 %], and ?0.200 for tocilizumab [P(MD < 0) = 99.3 %]. In conclusion, switching to non-TNF biologics was more effective than cycling TNF-α inhibitor in TNF-IR patients.     

Enhanced NO2 Sensing Performance of Graphene with Thermally Induced Defects

This paper demonstrates the enhanced NO₂ sensing performance of graphene with defects generated by rapid thermal annealing (RTA). A high temperature of RTA (300–700 °C) was applied to graphene under an argon atmosphere to form defects on sp² carbon lattices. The density of defects proportionally increased with increasing the RTA temperature. Raman scattering results confirmed significant changes in sp² bonding. After 700 °C RTA, I_D/I_G, I_2D/I_G, and FWHM (full width at half maximum)(G) values, which are used to indirectly investigate carbon-carbon bonds’ chemical and physical properties, were markedly changed compared to the pristine graphene. Further evidence of the thermally-induced defects on graphene was found via electrical resistance measurements. The electrical resistance of the RTA-treated graphene linearly increased with increasing RTA temperature. Meanwhile, the NO₂ response of graphene sensors increased from 0 to 500 °C and reached maximum (R = ~24%) at 500 °C. Then, the response rather decreased at 700 °C (R = ~14%). The results imply that rich defects formed at above a critical temperature (~500 °C) may damage electrical paths of sp² chains and thus deteriorate NO₂ response. Compared to the existing functionalization process, the RTA treatment is very facile and allows precise control of the NO₂ sensing characteristics, contributing to manufacturing commercial low-cost, high-performance, integrated sensors.