Clinician, dental student and orthognathic patient perception of black and white silhouette lateral profile dimensions of ideal chin position in a chinese population

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Zhiwei Jiang, Long Tan, Lingling Hu, Chaowei Wang, Huiming Wang, Zhijian Xie
Objectives.This study aimed to investigate differences in influence of chin prominence and length on perception of facial esthetics in Chinese dental clinicians, orthoganthic patients, and dental students.Study Design.The male and female silhouette lateral profiles were modified to obtain 28 facial profiles by altering chin prominence and length by 3 mm in the sagittal and vertical planes. Images were rated by 70 clinicians, 30 orthognathic patients, and 100 dental students on a 7-point Likert scale.Results.Perceived attractiveness is highest when the male chin prominence (MCP) was -3 mm to 3 mm, and the female chin prominence (FCP) was 3 mm. In contrast, male chin length (MCL) (0 mm to 3 mm) and female chin length (FCL) (0 mm) were considered the most attractive. In the sagittal and vertical profiles, MCP (-9 mm), FCP (-9 mm), FCL (-9 mm), and MCL (-9 mm) were ranked least attractive.Conclusions.The overall direction of esthetic opinion is similar in the orthoganthic patients, clinicians and dental students. The greater the retrusion or protrusion of the chin and the shorter or longer of the chin length, the less the rates of facial esthetics and the greater the desire for surgery.



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MRI-based determination of occlusal splint thickness for temporomandibular joint disk derangement: a randomized controlled clinical trial

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Ayman F. Hegab, Ahmed Hossni Youssef, Hossam I. Abd Al hameed, Khaled Said Karam
Objective: This prospective study examined a method using magnetic resonance imaging (MRI) to assess the appropriate effective occlusal splint vertical thickness in management of disk derangement. Study Design: Patients were diagnosed as having internal disk displacement of the TMJ and were divided into two groups. Group I (Disk Displacement with Reduction-DDR): This group was subdivided randomly into 2 subgroups. Subgroup IA (control group): patients treated using 3-mm-thick splints. Subgroup IB (study group): patients treated using MRI-based splint thickness. Group II (Disk Displacement without Reduction-DDNR): This group was subdivided randomly into 2 subgroups. Subgroup IIA (control group): patients treated using 3-mm-thick splints. Subgroup IIB (study group): patients treated using MRI-based splint thickness. The primary outcome variables were maximum voluntary mouth opening (MVMO) and visual analogue scale (VAS) for pain. The secondary outcome variable was joint sounds. The final sample was composed of 162 subjects (Group I = 90 and Group II = 72). Results: Statistical analysis showed significant improvement of the clinical outcomes in subgroups IB and IIB as compared to that in subgroups IA and IIA. Conclusion: On the basis of MRI measurements and clinical outcome, the current study recommended 4 mm and 6mm vertical splint thickness for DDR and DDNR respectively for 1 year.



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A novel ROGDI gene mutation is associated with kohlschutter-tonz syndrome

Publication date: Available online 12 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Nalini Aswath, Sankar Narayanan Ramakrishnan, Nithya Teresa, Arvind Ramanathan
BackgroundKohlschutter-tonz syndrome (KTS) is a rare neurodegenerative disorder that presents with seizures, developmental regression and characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta besides dysmorphologies. Genetic analysis has identified loss of function mutations within the coding region of ROGDI gene, which indeed has been reported in KTS patients of European or Jewish decent. In the present study, we have investigated the genetic status of ROGDI in a fourteen year old South Indian patient of Dravidian race born to consanguineous parents, who was clinically diagnosed with KTS.MethodsIn order to confirm the clinical diagnosis of KTS in the patient, primers were designed flanking each of the eleven exons of ROGDI gene. 50ng of chromosomal DNA extracted from peripheral blood of the patient and his parents were then used to amplify with the above primers and were subjected to direct sequencing with the same primers.ResultGenetic analysis identified a novel homozygous nonsense mutation in the exon 6 of ROGDI gene that caused premature termination of ROGDI translation resulting in truncation and loss of function of the ROGDI protein. Taken together, the clinical presentation and loss of function mutation in ROGDI gene confirms the clinical diagnosis of KTS.



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Mitteilungen des Bundesverbandes Deutscher Pathologen e.V.

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Tinnitus-related fear: Mediating the effects of a cognitive behavioural specialised tinnitus treatment

Publication date: Available online 12 October 2017
Source:Hearing Research
Author(s): Rilana F.F. Cima, Gerard van Breukelen, Johan W.S. Vlaeyen
ObjectiveCognitive behavioural treatment (CBT) for the reduction of tinnitus complaints have been shown to be effective; however the specific mechanisms of change are yet to be unveiled. Reductions in tinnitus-related fear have been indicated to be an important factor in alleviating tinnitus suffering. The role of tinnitus-related fear has been proposed as a mediator explaining the cognitive behavioural treatment effects on tinnitus severity, tinnitus-related impairment and general quality of life of tinnitus patients.MethodsA two-group, single-centre RCT was carried out with adult tinnitus patients (n=492), with 3 follow-up assessments up to 12 months after randomization. Patients were randomly assigned to Usual Care (UC) or Specialised cognitive behavioral stepped Care (SC). A repeated-measures design, with group as a between subjects factor, and time as the within-subject factor, was used in an intention-to-treat analysis. Mixed regressions for assessing mediation effects were performed with general health, tinnitus distress, tinnitus related impairment as the dependent variables and tinnitus related fear as the mediator variable.ResultsTinnitus-related fear appears to mediate part of the treatment benefits of specialized care, as compared to usual care, with respect to increased quality of life ratings, and decreased tinnitus severity and tinnitus related impairments.ConclusionsThe effectiveness of cognitive behavioural treatment approaches might be partly explained by significant reductions in tinnitus-related fear. These results are relevant in that currently, though CBT approaches in tinnitus management have been proven to lead to decreased suffering of tinnitus patients, the psychological mechanisms causing these benefits are still to be discovered.



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Overexpression of microRNA-495 improves the intestinal mucosal barrier function by targeting STAT3 via inhibition of the JAK/STAT3 signaling pathway in a mouse model of ulcerative colitis

Publication date: Available online 12 October 2017
Source:Pathology - Research and Practice
Author(s): Xian-Qun Chu, Jing Wang, Guang-Xiang Chen, Guan-Qi Zhang, De-Yong Zhang, Yong-Yan Cai
We aim to investigate the role of microRNA-495 (miR-495) in the intestinal mucosal barrier by indirectly targeting signal transducer and activator of transcription 3 (STAT3) through the Janus kinase-signal transducer and activator of transcription (JAK)/STAT3 signaling pathway in a mouse model of ulcerative colitis (UC). BALB/c mice were selected for establishing a mice model of UC, and intestinal tissues of normal and UC mice were collected. ELISA was conducted for detecting levels of TNF-α, IL-6, IFN-γ and IL-10. The levels of SOD, MPO, MDA and NO were tested in the intestinal tissues. Dual luciferase reporter gene assay was applied to determine whether miR-495 directly targets STAT3. Cells were cultured, transfected and assigned into: normal group, blank group, NC group, miR-495 mimic group, miR-495 inhibitor group, siRNA-STAT3 group and miR-495 inhibitor+siRNA-STAT3 group. MTT was used for testing cell proliferation, flow cytometry for cell cycle and apoptosis. Northern blotting and Western blotting were performed to detect miR-495 expression and expressions of STAT3, JAK and Claudin-1. Results show that the UC group had higher expression levels of TNF-α, IL-6, IFN-γ, MPO, MDA, NO, STAT3 and JAK and lower expression levels of IL-10, SOD, miR-495 and Claudin-1, compared to the normal group. Dual luciferase reporter gene assay confirmed that STAT3 was the target gene of miR-495. The miR-495 mimic and siRNA-STAT3 groups had higher expressions of Claudin-1, higher cell proliferation and increased amount of cells in S phase, but lower expressions of STAT3 and JAK, decreased amount of cells in G0/G1 phase and cell apoptotic rate compared with the blank, NC groups. We also found that the miR-495 inhibitor+siRNA-STAT3 group had reduced miR-495 expression. No significant differences were found in mRNA and protein expressions of STAT3, JAK and Claudin-1, cell proliferation, apoptosis and cycle amongst the miR-495 inhibitor+siRNA-STAT3 groups. Our study provides evidence that miR-495 improves the intestinal mucosal barrier function by targeting STAT3 through inhibiting the JAK/STAT3 signaling pathway in UC mice.



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Incisions et technique opératoire de base du lifting cervicofacial

Publication date: Available online 12 October 2017
Source:Annales de Chirurgie Plastique Esthétique
Author(s): F. Boucher, S. Guerid, E. Delay
Le lifting cervicofacial est l'une des interventions les plus emblématiques de la chirurgie esthétique et cette intervention a un peu plus de 100 ans. Dans les chapitres qui vont venir au cours de ce rapport, de nombreux points techniques seront précisés. Une technique de base reproductible, fiable et s'adressant aux plus grands nombres est présentée afin de débuter cette chirurgie dans des conditions optimales. La gestion préopératoire et postopératoire est également exposée. Le but de ce chapitre est de préciser les incisions et la technique opératoire de base du lifting cervicofacial, avec la description des suspensions du SMAS et du platysma, ainsi que celle des procédés complémentaires que sont la lipoaspiration et la lipostructure. Ce chapitre permettra de comprendre les éléments plus complexes qui viendront se greffer au cours des différents chapitres suivants.Cervicofacial lifting is one of the most iconic procedure of plastic surgery and is about hundred years old. In the following chapters of this report, numerous technical points will be specify. A baseline reliable and reproducible technique, appealing to the largest possible audience is presented in order to begin this surgery in optimum conditions. Pre- and postoperative management is also exposed. The aim of this chapter is to precise incisions and baseline operative technique of cervicofacial lifting, with description of SMAS and platysma suspensions as well as complementary procedures like liposuccion and lipofilling. This chapter will lay the foundation of more complex elements that will be described in the various following chapters.



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Animal models for analyzing metabolic syndrome-associated liver diseases

Metabolic syndrome (MS) is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases affecting the entire body. The hepatic manifestations of MS include nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH). NASH is known to progress to liver cirrhosis and hepatocellular carcinoma (HCC). Excellent animal models for determining the mechanism of pathogenesis and establishing therapeutic treatment of NASH/HCC are strongly required worldwide. We recently reported that two previously established mouse models of obesity and diabetes mellitus, namely, Tsumura-Suzuki Obese Diabetes (TSOD) mice and MSG mice, developed MS-associated NASH and that their clinical course and pathological characteristics closely mimicked those of human MS–NASH patients. Interestingly, most of the mice developed HCC with advancing age, and the pathological and functional characteristics of this condition were identical to those of human HCC. We further established a novel mouse model of HCC based on type 1 diabetes (DIAR–nSTZ mice) and reported its histopathological features. By comparing various aspects of these mouse models, specific and useful characteristics in a suitable model of MS-associated liver diseases, including hepato-carcinogenesis, can be highlighted.

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The re-emerging importance of radiologic–pathologic correlation in reaching the pathology diagnosis

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Cyclophilin A expression and its prognostic significance in lung adenocarcinoma

Cyclophilin A (CypA) has been reported to be upregulated in malignant tumors. CypA expression is thought to be associated with acquisition of tumor growth and anti-apoptotic function. Although upregulation of CypA has been reported in lung adenocarcinoma, its clinicopathological significance and roles in malignant progression remain unclear. Here we investigated the implications of CypA expression for outcome in patients with lung adenocarcinoma. Lung adenocarcinoma specimens from 198 cases were selected and reclassified according to the World Health Organization classification (4th edition) and the Noguchi classification. CypA expression was assessed by immunohistochemistry, and the H-score was calculated on the basis of intensity and proportion. The specificity of the antibody used was confirmed by Western blotting and the cut-off point was determined from the ROC curve. Sixty-seven cases (33.8%) had low CypA expression (CypA-L group) and 131 (66.2%) had high CypA expression (CypA-H group). Many cases of adenocarcinoma in situ were CypA-L, and advanced adenocarcinomas tended to be classified as CypA-H. Clinically, patients with CypA-H tumors showed a significantly poorer prognosis than those with CypA-L tumors. This is the first investigation of the implications of the CypA expression level in terms of the clinical characteristics of resected lung adenocarcinomas.

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The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs

Summary

Objective

Older antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, evidence for newer AED is sparse. We quantified risks of SJS/TEN in association with use of all AEDs in the United Kingdom.

Methods

In a matched case-control study of 480 previously validated SJS/TEN cases (1995–2013) we used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and calculated absolute risks of SJS/TEN within separate cohorts of new users of 28 AEDs. We assessed causality between drugs and SJS/TEN in each exposed case, using an adapted version of the algorithm of drug causality for epidermal necrolysis (ALDEN) score.

Results

We observed a strong association between SJS/TEN and new use of carbamazepine (OR 92.57, 95% CI 19.89–∞), phenytoin (OR 49.96, 95% CI 10.13–∞), and lamotrigine (OR 26.90, 95% CI 4.88–∞), where causality, according to the ALDEN score, was very probable or probable for most exposed cases. Absolute risks for SJS/TEN were highest for phenytoin (45.86 cases/100,000 exposed), lamotrigine (44.17 cases/100,000 exposed), and carbamazepine (20.38 cases/100,000 exposed). Despite increased ORs for valproate (40,941 exposed), gabapentin (116,037 exposed), pregabalin (59,967 exposed), and clobazam (4,300 exposed), ALDEN suggested no causal association. There were no observed cases of SJS/TEN among new users of levetiracetam (n = 96,77), clonazepam (n = 18,075), or topiramate (n = 11,307).

Significance

The results of our study are consistent with those of previous studies of SJS/TEN, which found increased risks of SJS/TEN in new use of carbamazepine, phenytoin, and lamotrigine. Despite frequent use, no ALDEN-score confirmed cases were observed in new users of valproate, gabapentin, pregabalin, levetiracetam, topiramate, or clonazepam.

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A systematic review of land use regression models for volatile organic compounds

Publication date: December 2017
Source:Atmospheric Environment, Volume 171
Author(s): Heresh Amini, Masud Yunesian, Vahid Hosseini, Christian Schindler, Sarah B. Henderson, Nino Künzli
Various aspects of land use regression (LUR) models for volatile organic compounds (VOCs) were systematically reviewed. Sixteen studies were identified published between 2002 and 2017. Of these, six were conducted in Canada, five in the USA, two in Spain, and one each in Germany, Italy, and Iran. They were developed for 14 different individual VOCs or groupings: benzene; toluene; ethylbenzene; m-xylene; p-xylene; (m/p)-xylene; o-xylene; total BTEX; 1,3-butadiene; formaldehyde; n-hexane; total hydro carbons; styrene; and acrolein. The models were based on measurements ranging from 22 sites in El Paso (USA) to 179 sites in Tehran (Iran). Only four studies in Rome (Italy), Sabadell (Spain), Tehran, and Windsor (Canada) met the Cocheo's criterion of having at least one passive sampler per 3.4 km² of study area. The range of R² values across all models was from 0.26 for 1,3-butadiene in Dallas (USA) to 0.93 for benzene in El Paso. The average R² values among two or more studies of the same VOCs were as follows: benzene (0.70); toluene (0.60); ethylbenzene (0.66); (m/p)-xylene (0.65); o-xylene (0.61); total BTEX (0.66); 1,3-butadiene (0.46); and formaldehyde (0.56). The common spatial predictors of studied VOC concentrations were dominated by traffic-related variables, but they also included proximity to ports in the USA, number of chimneys in Canada, altitude in Spain, northern latitudes in Italy, and proximity to sewage treatment plants and to gas filling stores in Iran. For the traffic-related variables, the review suggests that large buffers, up to 5,000 m, should be considered in large cities. Although most studies reported logical directions of association for predictors, some reported inconsistent results. Some studies included log-transformed predictors while others divided one variable by another. Only six studies provided the p-values of predictors. Future work may incorporate chemistry-transport models, satellite observations, meteorological variables, particularly temperature, consider specific sources of aromatic vs aliphatic compounds, or may develop hybrid models. Currently, only one national model has been developed for Canada, and there are no global LUR models for VOCs. Overall, studies from outside North America and Europe are critically needed to describe the wide range of exposures experienced by different populations.

Graphical abstract

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Effects of submicron ammonium sulfate particles on the growth and yield of komatsuna (Brassica rapa L. var. perviridis)

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Akira Motai, Satoshi Nakaba, I. Wuled Lenggoro, Makoto Watanabe, Yoshiharu Wada, Takeshi Izuta
The aim of this study was to determine the effects of submicron ammonium sulfate (AS) particles on komatsuna (Brassica rapa L. cv. Hakkei) plants. First, we optimized a leaf-washing method to measure the amount of AS particles deposited on the leaf surface of the plants. Then, we used this method to determine the retention time of particles deposited on the leaf surface of the plants. We also investigated the effects of AS particles on the growth and yield of the plants. Almost all the AS particles deposited on the leaf surface were removed within 1 min washing time with ultrapure water, and ion leaching from the leaf was relatively slow but continuous during the leaf-washing procedure. On the basis of these results, we determined that 1 min was a suitable washing time to remove most of the AS particles while minimizing the influence of ion leaching from the leaf. The amount of particulate SO4²⁻ deposited on the leaf surface decreased over time, probably because AS particles deposited on the leaf surface deliquesced, allowing ions such as SO4²⁻ in the deliquescence solution to be absorbed into the leaf. The plants were grown and exposed to AS particles for 16 days in naturally lit phytotrons. The daily mean increase in the concentration of SO4²⁻ in PM2.5 by the exposure to AS particles was 22.5 μg m⁻³ in the phytotrons. The growth and yield of the plants were significantly reduced by the exposure to AS particles. The exposure to AS particles did not affect the leaf concentrations of nitrogen and chlorophyll, but significantly reduced stomatal conductance. Therefore, stomatal closure is one of the reasons for the AS particle-induced reductions in the growth and yield of komatsuna plants.



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Editorial board

Publication date: November 2017
Source:Atmospheric Environment, Volume 169





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Impacts of ozone air pollution and temperature extremes on crop yields: Spatial variability, adaptation and implications for future food security

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Amos P.K. Tai, Maria Val Martin
Ozone air pollution and climate change pose major threats to global crop production, with ramifications for future food security. Previous studies of ozone and warming impacts on crops typically do not account for the strong ozone-temperature correlation when interpreting crop-ozone or crop-temperature relationships, or the spatial variability of crop-to-ozone sensitivity arising from varietal and environmental differences, leading to potential biases in their estimated crop losses. Here we develop an empirical model, called the partial derivative-linear regression (PDLR) model, to estimate the spatial variations in the sensitivities of wheat, maize and soybean yields to ozone exposures and temperature extremes in the US and Europe using a composite of multidecadal datasets, fully correcting for ozone-temperature covariation. We find generally larger and more spatially varying sensitivities of all three crops to ozone exposures than are implied by experimentally derived concentration-response functions used in most previous studies. Stronger ozone tolerance is found in regions with high ozone levels and high consumptive crop water use, reflecting the existence of spatial adaptation and effect of water constraints. The spatially varying sensitivities to temperature extremes also indicate stronger heat tolerance in crops grown in warmer regions. The spatial adaptation of crops to ozone and temperature we find can serve as a surrogate for future adaptation. Using the PDLR-derived sensitivities and 2000–2050 ozone and temperature projections by the Community Earth System Model, we estimate that future warming and unmitigated ozone pollution can combine to cause an average decline in US wheat, maize and soybean production by 13%, 43% and 28%, respectively, and a smaller decline for European crops. Aggressive ozone regulation is shown to offset such decline to various extents, especially for wheat. Our findings demonstrate the importance of considering ozone regulation as well as ozone and climate change adaptation (e.g., selecting heat- and ozone-tolerant cultivars, irrigation) as possible strategies to enhance future food security in response to imminent environmental threats.

Graphical abstract

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Temporal multiscaling characteristics of particulate matter PM10 and ground-level ozone O3 concentrations in Caribbean region

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Thomas Plocoste, Rudy Calif, Sandra Jacoby-Koaly
A good knowledge of the intermittency of atmospheric pollutants is crucial for air pollution management. We consider here particulate matter PM10 and ground-level ozone O3 time series in Guadeloupe archipelago which experiments a tropical and humid climate in the Caribbean zone. The aim of this paper is to study their scaling statistics in the framework of fully developed turbulence and Kolmogorov's theory. Firstly, we estimate their Fourier power spectra and consider their scaling properties in the physical space. The power spectra computed follows a power law behavior for both considered pollutants. Thereafter we study the scaling behavior of PM10 and O3 time series. Contrary to numerous studies where the multifractal detrended fluctuation analysis is frequently applied, here, the classical structure function analysis is used to extract the scaling exponent or multifractal spectrum ζ(q); this function provides a full characterization of a process at all intensities and all scales. The obtained results show that PM10 and O3 possess intermittent and multifractal properties. The singularity spectrum MS(α) also confirms both pollutants multifractal features. The originality of this work comes from a statistical modeling performed on ζ(q) and MS(α) by a lognormal model to compute the intermittency parameter μ. By contrast with PM10 which mainly depends on puffs of Saharan dust (synoptic-scale), O3 is more intermittent due to variability of its local precursors. The results presented in this paper can help to better understand the mechanisms governing the dynamics of PM10 and O3 in Caribbean islands context.

Graphical abstract

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Characterization of atmospheric black carbon and co-pollutants in urban and rural areas of Spain

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): M. Becerril-Valle, E. Coz, A.S.H. Prévôt, G. Močnik, S.N. Pandis, A.M. Sánchez de la Campa, A. Alastuey, E. Díaz, R.M. Pérez, B. Artíñano
A one-year black carbon (BC) experimental study was performed at three different locations (urban traffic, urban background, rural) in Spain with different equivalent BC (eBC) source characteristics by means of multi-wavelength Aethalometers. The Aethalometer model was used for the source apportionment study, based on the difference in absorption spectral dependence of emissions from biomass burning (bb) and fossil fuel (ff) combustion. Most studies use a single bb and ff absorption Ångström exponent (AAE) pair (AAEbb and AAEff), however in this work we use a range of AAE values associated with fossil fuel and biomass burning based on the available measurements, which represents more properly all conditions. A sensitivity analysis of the source specific AAE was carried out to determine the most appropriate AAE values, being site dependent and seasonally variable. Here we present a methodology for the determination of the ranges of AAEbb and AAEff by evaluating the correlations between the source apportionment of eBC using the Aethalometer model with four biomass burning tracers measured at the rural site. The best combination was AAEbb = [1.63–1.74] and AAEff = [0.97–1.12]. Mean eBC values (±SD) obtained during the period of study were 3.70 ± 3.73 μg m⁻³ at the traffic urban site, 2.33 ± 2.96 μg m⁻³ at the urban background location, and 2.61 ± 5.04 μg m⁻³ in the rural area. High contributions of eBC to the PM10 mass were found (values up to 21% in winter), but with high eBC/PM10 variability. The hourly mean eBCff and eBCbb concentrations varied from 0 to 51 μg m⁻³ and from 0 to 50 μg m⁻³ at the three sites, respectively, exhibiting distinct seasonal and daily patterns. The fossil fuel combustion was the dominant eBC source at the urban sites, while biomass burning dominated during the cold season (88% of eBCbb) in the rural area. Daily PM2.5 and PM10 samples were collected using high-volume air samplers and analyzed for OC and EC. Analysis of biomass burning tracers and organic (OC) and elemental (EC) carbon in the rural area indicate that biomass combustion is the main source, while OC and EC indicate a lower influence of this source at the urban site.



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Observations of biomass burning tracers in PM2.5 at two megacities in North China during 2014 APEC summit

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Zhisheng Zhang, Jian Gao, Leiming Zhang, Han Wang, Jun Tao, Xionghui Qiu, Fahe Chai, Yang Li, Shulan Wang
To evaluate the effectiveness of biomass burning control measures on PM2.5 reduction, day- and nighttime PM2.5 samples were collected at two urban sites in North China, one in Beijing (BJ) and the other in Shijiazhuang (SJZ), during the 2014 Asia-Pacific Economic Cooperation (APEC) summit. Typical biomass burning aerosol tracers including levoglucosan (LG), Mannosan (MN), and water-soluble potassium (K⁺), together with other water-soluble ions and carbonaceous species were determined. The levels of biomass burning tracers dropped dramatically during the APEC period when open biomass burning activities were well controlled in North China, yet they increased sharply to even higher levels during the post-APEC period. Distinct linear regression relationships between LG and MN were found with lower LG/MN ratios from periods with much reduced open biomass burning activities. This was likely resulted from the reduced open crop residues burning and increased residential wood burning emissions, as was also supported by the simultaneous decrease in K⁺/LG ratio. The positive matrix factorization and air quality model simulation analyses suggested that PM2.5 concentration produced from biomass burning sources was reduced by 22% at BJ and 46% at SJZ during the APEC period compared to pre-APEC period, although they increased to higher levels after APEC mainly due to increased residential biomass burning emissions in winter heating season. Biomass burning was also found to be the most important contributor to carbonaceous species that might cause significant light extinction in this region. This study not only suggested implementing biomass burning controls measures were helpful to reduce PM2.5 in North China, but also pointed out both open crop residues burning and indoor biomass burning activities could make substantial contributions to PM2.5 and its major components in urban areas in North China.



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Paula Moynihan: 'We really need to look at a holistic, systemic approach'

Jonathan Lewney, Associate Editor for the BDJ Portfolio, interviews Professor Paula Moynihan. Paula is Professor of Nutrition & Oral Health at Newcastle University School of Dental Sciences, Director of Newcastle University Centre for Oral Health Research, and Director of the World Health Organisation Collaborating Centre for Nutrition and Oral Health. In December 2016, Paula was elected Vice-President of the International Association of Dental Research (IADR), which means she will become IADR President in 2019.

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Oral health: Treating refugees

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Honours, awards, appointments

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Unsupported conclusions

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Essential courses this November

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Health policy: Hospital cutbacks

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The Dentistry Show and the BDA announce major new collaboration

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Oral surgery: The drug holiday

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NHS FP17 form printing error

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Dental radiography: Short roots

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Perspectives: 'Patients with 40-60/day habits are now few and far between'

What impact has the smoking ban had on dental patients, ten years down the line? asks Kate Quinlan.

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Erratum: Quick release mechanism

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Top 5 most talked-about BDJ articles of the year

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Alternative sugars: Honey

Elaine Gardner, British Dietetic Association (BDA) Spokesperson, discusses the sugar content in honey and provides related oral health advice.

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Book Review: Evidence-Based Caries Prevention

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Spotting the signs

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Parental perception of oral health-related quality of life of Syrian refugee children

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Oral surgery II: Part 2. The maxillary sinus (antrum) and oral surgery

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Focal infection revisited – the swinging of the pendulum

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Articaine: friend or foe?

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Sclerotherapy for the Management of Seromas

A new review examines the potential role sclerotherapy may play in the management of seromas.
ePlasty, Open Access Journal of Plastic Surgery

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Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer-Predisposing Mutations in Pheochromocytomas and Paragangliomas

Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.

Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.

Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio.

Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315–24. ©2017 AACR.

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On OX40 and PD-1 Combination: Why Should OX40 Be First in Sequence?

The larger fraction of patients treated with immune checkpoint inhibitors remain nonresponding eventually. Combination of checkpoint inhibitor and costimulatory antibodies is thought additive, but for such effect, they may require to be given in the right sequence. Clin Cancer Res; 23(20); 5999–6001. ©2017 AACR.

See related article by Messenheimer et al., p. 6165

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Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood–brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo.

Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non–tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models.

Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.

Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215–26. ©2017 AACR.

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Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes

Gastrointestinal (GI) cancers are among the most deadly malignancies. Although serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumors of each primary anatomical site but also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumors and their interaction with the tumor microenvironment would further affect development of combination therapy, including immunotherapy. Currently, immune checkpoint blockade attracts the most intense research, and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers. Clin Cancer Res; 23(20); 6002–11. ©2017 AACR.

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Highlights of This Issue

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T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk

Adoptive therapy with T-cell receptor (TCR)–engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. Clin Cancer Res; 23(20); 6012–20. ©2017 AACR.

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Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.

Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.

Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.

Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267–78. ©2017 AACR.

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The c.1085A>G Genetic Variant of CSF1R Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages

Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.

Experimental designs: CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.

Results: A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC₅₀ of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC₅₀ of 10 to 100 nmol/L range.

Conclusions: The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021–30. ©2017 AACR.

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Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics

Purpose: Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages, leaving no effective treatments. Currently, immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis.

Experimental Design: We analyzed level 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number, and somatic mutation) from The Cancer Genome Atlas (TCGA) and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy-number alteration, and somatic gene mutation.

Results: Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals, including PD-1 and CTLA4, that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy-number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression, and epigenetic regulations, however, seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation.

Conclusions: Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities. Clin Cancer Res; 23(20); 6363–73. ©2017 AACR.

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Increased IFN{gamma}+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy

Purpose: Low-dose DNA-demethylating agent decitabine therapy is effective in a subgroup of cancer patients. It remains largely elusive for the biomarker to predict therapeutic response and the underlying antitumor mechanisms, especially the impact on host antitumor immunity.

Experimental Design: The influence of low-dose decitabine on T cells was detected both in vitro and in vivo. Moreover, a test cohort and a validation cohort of advanced solid tumor patients with low-dose decitabine-based treatment were involved. The activation, proliferation, polarization, and cytolysis capacity of CD3⁺ T cells were analyzed by FACS and CCK8 assay. Kaplan–Meier and Cox proportional hazard regression analysis were performed to investigate the prognostic value of enhanced T-cell activity following decitabine epigenetic therapy.

Results: Low-dose decitabine therapy enhanced the activation and proliferation of human IFN⁺ T cells, promoted Th1 polarization and activity of cytotoxic T cells both in vivo and in vitro, which in turn inhibited cancer progression and augmented the clinical effects of patients. In clinical trials, increased IFN⁺ T cells and increased T-cell cytotoxicity predicted improved therapeutic responses and survival in the test cohort and validation cohort.

Conclusions: We find that low-dose decitabine therapy promotes antitumor T-cell responses by promoting T-cell proliferation and the increased IFN⁺ T cells may act as a potential prognostic biomarker for the response to decitabine-based antitumor therapy. Clin Cancer Res; 23(20); 6031–43. ©2017 AACR.

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Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.

Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEX^mGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8⁺ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.

Results: Treatment with OncoVEX^mGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3⁺/CD8⁺) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8⁺ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEX^mGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEX^mGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8⁺ anti-AH1 T cells and systemic efficacy.

Conclusions: The data support a dual MOA for OncoVEX^mGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8⁺-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.

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Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.

Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.

Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.

Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044–53. ©2017 AACR.

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Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

Purpose: Drugs targeting DNA repair and cell-cycle checkpoints have emerged as promising therapies for small-cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations.

Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse-phase protein array (RPPA) to identify predictive markers of primary resistance. We further established AZD1775 acquired resistance models to identify mechanism of acquired resistance. Combination regimens were tested to overcome primary and acquired resistance to AZD1775 in in vitro and in vivo SCLC models.

Results: High-throughput proteomic profiling demonstrate that SCLC models with primary resistance to AZD1775 express high levels of AXL and phosphorylated S6 and that WEE1/AXL or WEE1/mTOR inhibitor combinations overcome resistance in vitro and in vivo. Furthermore, AXL, independently and via mTOR, activates the ERK pathway, leading to recruitment and activation of another G2-checkpoint protein, CHK1. AZD1775 acquired resistance models demonstrated upregulation of AXL, pS6, and MET, and resistance was overcome with the addition of AXL (TP0903), dual-AXL/MET (cabozantinib), or mTOR (RAD001) inhibitors.

Conclusions: AXL promotes resistance to WEE1 inhibition via downstream mTOR signaling and resulting activation of a parallel DNA damage repair pathway, CHK1. These findings suggest rational combinations to enhance the clinical efficacy of AZD1775, which is currently in clinical trials for SCLC and other malignancies. Clin Cancer Res; 23(20); 6239–53. ©2017 AACR.

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PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors

Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.

Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.

Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.

Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor–treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054–61. ©2017 AACR.

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Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.

Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.

Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN^High and GLN^Low, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN^High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN^High cultures are CD133^neg and display a mesenchymal signature in contrast to CD133^pos GLN^Low GBM cells.

Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292–304. ©2017 AACR.

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Pediatric Phase I Trial and Pharmacokinetic Study of Trebananib in Relapsed Solid Tumors, Including Primary Tumors of the Central Nervous System ADVL1115: A Children's Oncology Group Phase I Consortium Report

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK).

Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.

Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.

Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

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miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/{beta}-catenin Complex in Lung Adenocarcinoma

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.

Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA–protein complex and HDGF/DDX5/β-catenin complex.

Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK–Ras-c–Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF–β-catenin–c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA–FAK–Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin–c-Myc, which suppresses miR-296-3p and further activates PRKCA–FAK–Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.

Conclusions: Our study provides a novel mechanism that the miR-296-3p–PRKCA–FAK–Ras–c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336–50. ©2017 AACR.

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Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging.

Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach.

Results: We showed that this method produced highly reproducible CNA results (r = 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted NGS were comparable with WES (r = 0.86) and aCGH (r = 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.

Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care. Clin Cancer Res; 23(20); 6070–7. ©2017 AACR.

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Genomics of Immunotherapy-Associated Hyperprogressors--Response

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T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower-grade Gliomas: A TCGA/TCIA Project

Purpose: Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes.

Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2–FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate–substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular–radiographic associations. A separate institutional cohort (n = 82) was analyzed to validate the T2–FLAIR mismatch sign.

Results: Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ = 0.234 (0.111–0.358)], T2–FLAIR mismatch sign [ = 0.728 (0.538–0.918)], lesion margins [ = 0.292 (0.135–0.449)], and peritumoral edema [ = 0.173 (0.096–0.250)]. All 15 cases that were positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2–FLAIR mismatch sign [ = 0.747 (0.536–0.958)]; all 10 cases positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.00001; PPV = 100%, NPV = 76%).

Conclusions: Among lower-grade gliomas, T2–FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q non-codeleted molecular subtype. Clin Cancer Res; 23(20); 6078–85. ©2017 AACR.

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Platinum or nonplatinum in recurrent ovarian cancer: that is the question

Future Oncology, Ahead of Print.


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Trabectedin mechanism of action and platinum resistance: molecular rationale

Future Oncology, Ahead of Print.


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When nonplatinum is the answer: the role of trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer

Future Oncology, Ahead of Print.


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Managing relapsed ovarian cancer in a rapidly evolving landscape

Future Oncology, Ahead of Print.


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Update on relapsed ovarian cancer treatment: from new consensus to daily clinical practice

Future Oncology, Ahead of Print.


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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Publication date: Available online 12 October 2017
Source:Cancer Cell
Author(s): Wenjie Ge, Kunming Zhao, Xingwen Wang, Huayi Li, Miao Yu, Mengmeng He, Xuting Xue, Yifu Zhu, Cheng Zhang, Yiwei Cheng, Shijian Jiang, Ying Hu
Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo. Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.

Graphical abstract

Teaser

Ge et al. show that iASPP, a known p53 inhibitor, functions independently of p53 to compete with Keap1 for Nrf2 binding, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation and antioxidative transactivation. The iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance.


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Monocytes and granulocytes reduce CD38 expression levels on myeloma cells in patients treated with daratumumab

Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma (MM) cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of MM cells and non-tumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed. Results: In both trials daratumumab reduced CD38 expression on MM cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on non-tumor immune cells, including NK-, T- B-cells and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of MM cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high MM cells can contribute to CD38 reduction. In addition, we discovered that daratumumab-CD38 complexes and accompanying cell membrane were actively transferred from MM cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins including CD49d, CD56, and CD138. Conclusion: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.

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CAR T therapy targeting ICAM-1 eliminates advanced human thyroid tumors

Purpose: Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. Experimental Design: ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and 'off-tumor' toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases. Results: ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR-T cells mediated profound tumor killing that resulted in long term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models. Conclusions: Our findings are the first demonstration of CAR T therapy for metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies.

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Establishment of a chronic activity-based anorexia rat model

Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Linda Frintrop, Stefanie Trinh, Johanna Liesbrock, Lisa Paulukat, Martien J. Kas, Rene Tolba, Kerstin Konrad, Beate Herpertz-Dahlmann, Cordian Beyer, Jochen Seitz
BackgroundAnorexia nervosa (AN) is often a chronic eating disorder characterised by body image disturbance and low body weight often associated with starvation-induced amenorrhoea and excessive exercise. Activity-based anorexia (ABA) is an animal model representing many somatic aspects of this psychiatric illness. We systematically manipulated the extent and length of starvation and animal age to find the optimal parameters to study chronic starvation.New methodsWistar rats had 24h/day running wheel access and received 40% of their baseline food intake until a 20% or 25% weight reduction was reached (acute starvation). This body weight was then maintained for two weeks (chronic starvation). The rats of different ages of 4 or 8 weeks were used to represent early and late adolescent animals, respectively. The complete absence of a menstrual cycle was defined as the primary outcome parameter.ResultsAcute starvation caused a disruption of the oestrous cycle in 58% of the animals. During chronic starvation, a complete loss of the oestrous cycle could be found. Furthermore, 4-week-old rats exhibited higher levels of hyperactivity and amenorrhoea than 8-week-old animals. A 20% starvation level led to 90% loss of cycle, while a 25% starvation level triggered complete loss.Comparison with existing methodsMost current ABA models focus on acute starvation, while most patients are chronically ill.ConclusionsThe optimal parameters to achieve complete amenorrhoea included early adolescence, chronic starvation and 25% weight loss. The new ABA model allows studying the effects of chronic AN on underlying behavioural, hormonal and brain pathobiology.



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Stimuli to differentiate the neural response at successive stages of visual processing using the VEP from human visual cortex

Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Valentine L. Marcar, Lutz Jäncke
BackgroundClarifying the enigmatic relationship between stimulus property, neural response and the evoked potential is essential if non-invasive functional imaging is to make a meaningful contribution to the understanding of how maturational or degenerative processes influence brain activity. Visual cortex has proven a favourite target to elucidate this relationship. However, to date most studies involving the visual system have yielded inconsistent results or have been strongly criticised.New methodWe developed a set of three visual stimuli, two of which either had the same low- or high spatial frequency characteristic. Adult volunteers viewed these as pattern reversing stimuli while the scalp electric potential was recorded using a 10-10 array of electrodes.ResultsEstablished processing mechanisms of the primate visual system enabled us to link the amplitude of the N75 and P100 to the size of the neural population processing the temporal luminance contrast, and the amplitude of the N135 and P240 to the size of the neural processing the spatial luminance contrast in our stimuli. Calculating the distribution of current source density enabled us to identify the neural source of each VEP component.ConclusionsDemonstrating a direct relationship between the temporal- and spatial luminance contrast properties of our stimuli and the size of the neural population involved provides a better understanding of the nature of the relationship between stimulus property, neural response and the VEP. It also shows that EEG can contribute in a significant manner to the study of the influence of maturational or degenerative processes on brain activity.



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Pediatric Auditory Brainstem Implantation: Surgical, Electrophysiologic, and Behavioral Outcomes.

Objectives: The objectives of this study were to demonstrate the safety of auditory brainstem implant (ABI) surgery and document the subsequent development of auditory and spoken language skills in children without neurofibromatosis type II (NFII). Design: A prospective, single-subject observational study of ABI in children without NFII was undertaken at the University of North Carolina at Chapel Hill. Five children were enrolled under an investigational device exemption sponsored by the investigators. Over 3 years, patient demographics, medical/surgical findings, complications, device mapping, electrophysiologic measures, audiologic outcomes, and speech and language measures were collected. Results: Five children without NFII have received ABIs to date without permanent medical sequelae, although 2 children required treatment after surgery for temporary complications. All children wear their device daily, and the benefits of sound awareness have developed slowly. Intra-and postoperative electrophysiologic measures augmented surgical placement and device programming. The slow development of audition skills precipitated limited changes in speech production but had little impact on growth in spoken language. Conclusions: ABI surgery is safe in young children without NFII. Benefits from device use develop slowly and include sound awareness and the use of pattern and timing aspects of sound. These skills may augment progress in speech production but progress in language development is dependent upon visual communication. Further monitoring of this cohort is needed to better delineate the benefits of this intervention in this patient population. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Vincent A. de Weger, Frederik E. Stuurman, Jeroen J.M.A. Hendrikx, Johannes J. Moes, Emilia Sawicki, Alwin D.R. Huitema, Bastiaan Nuijen, Bas Thijssen, Hilde Rosing, Marianne Keessen, Marja Mergui-Roelvink, Jos H. Beijnen, Jan H.M. Schellens, Serena Marchetti
IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.



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Second language acquisition of intonation: Peak alignment in American English

Publication date: January 2018
Source:Journal of Phonetics, Volume 66
Author(s): Calbert Graham, Brechtje Post
The objective of the present study was to investigate (1) whether, and to what degree, late bilinguals of different L1 backgrounds are comparable to native speakers in the phonetic implementation of tonal targets in their L2, (2) whether they exhibit general patterns of acquisition irrespective of the typological closeness of their L1 to their L2, and (3) whether learners' choice of accent contours and the alignment of the high tone (H^∗) proceeds in parallel with proficiency in the L2. More specifically, we examined the acquisition of the nuclear contour composition and the H^∗ alignment of the American English (L)H^∗L- (i.e. pitch accent and boundary tone combination) in initial-stressed and final-stressed words by Japanese and Spanish late bilingual speakers at varying proficiency levels in American English. Our results show that the L1 Spanish speakers were more comparable than the L1 Japanese speakers to the native English speakers in the phonological aspect of intonation (choice of pitch accent contour). In terms of peak alignment, we found that the late bilinguals generally tended to realise significantly later alignment than the native speakers, although the precise manifestation of this varied according to the L1 background of speakers and the stress pattern of words.



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A concealed giant peritonsillolith masquerading as oropharyngeal tumor

Publication date: Available online 12 October 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Boon Chye Gan, Irfan Mohamad, Norhafiza Mat Lazim




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Democrats’ Bill Requires Sleep Apnea Testing For Engineers

NEWARK, N.J. –  Democratic lawmakers from New York and New Jersey are introducing legislation Thursday to force federal transportation officials to implement a rule to test train engineers for sleep apnea.

Minority Leader Chuck Schumer of New York and New Jersey U.S. Sen. Cory Booker announced the legislation a week after the National Transportation Safety Board said that the engineers involved in crashes in Hoboken and Brooklyn were suffering from undiagnosed sleep apnea.

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Erratum to “Cancer-related Fatigue in Adolescents and Young Adults: A Systematic Review of the Literature” [Crit. Rev. Oncol. Hematol. 118 (2017) 63–69]

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120
Author(s): E. Nowe, Y. Stöbel-Richter, A. Sender, K. Leuteritz, M. Friedrich, K. Geue




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Patterns and drivers of health care use in long-term childhood cancer survivors: A systematic review

Publication date: Available online 12 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): J. Van Breeschoten, R. De Abreu Lourenco, C. Signorelli, M. Haas, R.J. Cohn, C.E. Wakefield, J.E. Fardell
BackgroundChildhood cancer survival is increasing. But cancer and treatment late-effects can lead to ongoing health care use. We summarised the literature on the patterns and drivers of health care use among childhood cancer survivors.MethodPubmed, Embase and Medline were searched for studies reporting health care use in childhood cancer survivors.ResultsWe included 22 studies, covering 88787 experiences of health care use. The proportion of survivors using follow-up care, physician visits, specialist visits, hospitalisations, dental care and screening services varied (36.4% to 88.8%). Participation in screening was below recommendations (11.5% to 81%). Drivers of increased health care use included higher income, private health insurance, attending follow-up care, chronic health conditions, prior radiotherapy, being female and older age.ConclusionSociodemographic and clinical factors result in differences in health care use. Future research could investigate whether such use is appropriate and how survivors might be engaged to receive care appropriate to manage their needs.



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Profiling of Sulfate-Reducing Bacteria in an Offshore Oil Reservoir Using Phospholipid Fatty Acid (PLFA) Biomarkers

Abstract

PLFA analysis was conducted to profile microorganisms and trace sulfate-reducing bacteria (SRB) in water samples from an offshore oil reservoir. From the results of spiked phospholipid standards, more than 90% of the phospholipids were recovered before the treatment of fatty acid methyl ester (FAME) derivatization while the relative standard deviations (RSD) were below 8.0%. The water samples from the injection well and four producing wells exhibited various reducing conditions and were further subjected to PLFA analysis. Fourteen kinds of phospholipid fatty acids were detected in the five wellbores and the concentrations of total fatty acids ranged from 368.4 to 3468.9 ng/L. Possible SRB biomarkers and significant phospholipid fatty acids associated with SRB including C14:0, i-C15:0, a-C15:0, C15:0, C16:1 (cis-9), C17:0, C18:1 (cis-9), C18:1 (cis-11) and C18:0 were selected for determining the presence of SRB species and evaluating the sulfate-related microbial biomass. The possible existence of SRB genera Desulfobacter, Desulfotomaculum, Desulfovibrio, and sulfur-oxidizing bacteria (SOB) in the reservoir were proposed based on PLFA profiles. The highest biomass was found in the most reducing well where very limited SOB biomarkers were found. Results indicated that the presence of SRB and SOB species was closely associated with the redox environment of the reservoir wellbores. The species distribution patterns were interpreted to elucidate the biological souring process.

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Cutting the Holy Dome: The Evolution of Vertical Alar Resection

Abstract

Introduction

Dome division or vertical dome division (VDD) is a tip plasty technique that is effective when applied appropriately to suitable patients. For 15 years, we have used VDD and made modifications as needed. In classical VDD, the dome area is cut and left to heal, but experience shows that additional components are needed to complement dome division, such as sutures or grafts. In this study, we retrospectively analysed our rhinoplasty patients in whom we used vertical alar resection (VAR) to assess the advantages and disadvantages of this technique. To our knowledge, this is one of the most exhaustive studies of VDD, including over 3000 patients.

Materials and Methods

This retrospective case series reviewed the charts of 3965 patients who underwent VAR between 2000 and 2015. All patients were operated on by the senior surgeon. Dome division was used for various reasons, including a deformed tip area in revision rhinoplasties, droopy nose, wide tip, pinched nose, tip asymmetry, and overprojected nasal tip. Patients were excluded if they had septal deviation that enabled tip rotation, or a dorsum problem that caused tip asymmetry.

Results

The study included 3965 patients (3172 women and 793 men) who underwent open rhinoplasty from 2000 to 2015. The mean patient age was 28.3 years (range 18–50 years). The mean clinical follow-up duration was 11.2 years.

Conclusion

In conclusion, this technique is capable of modifying all parameters of the nasal tip (projection, rotation, and volume), as required, at the same time, addressing many tip problems.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Abdominal Contouring Outcomes in Class III Obesity: Analysis of the ACS-NSQIP Database

Abstract

Background

Obesity may increase the risk of complications following abdominal contouring. The aim of this study is to evaluate panniculectomy outcomes in patients with class III obesity (BMI > 40 kg/m²).

Methods

The American College of Surgeon's National Surgical Quality Improvement Program ACS-NSQIP (2010–2014) was used to identify patients who underwent panniculectomy. Class III obesity patients were identified. Demographics, comorbidities and postoperative outcomes were evaluated. Risk-adjusted multivariate logistic regression analyses were performed to assess impact of class III obesity on panniculectomy outcomes.

Results

A total of 4497 panniculectomies were identified. Of these, 545 (12.1%) were performed in patients with class III obesity. This group was older (mean age 50.3 vs. 45.9, p < 0.01) with a higher proportion of men (23.4 vs. 12.4%, p < 0.01). Class III obesity group also had higher rates of comorbidities (p < 0.01). Postoperatively, class III obesity patients experienced much higher rates of wound complications (17.8 vs. 6.8%), sepsis (3.3 vs. 0.8%), venous thromboembolism (1.5 vs. 0.7%) and medical complications (6.4 vs. 1.8%), p < 0.05. Additionally, this group had higher rates of unplanned reoperation (9.2 vs. 3.7%) and 30-day readmissions (3.5 vs. 1.0%), p < 0.01. On risk-adjusted multivariate regression analyses, class III obesity was independently associated with increased risk of wound complications (OR 2.22, p < 0.01), sepsis (OR 3.53, p < 0.01), medical adverse events (OR 1.98, p < 0.05), unplanned reoperation (OR 1.62, p < 0.05) and 30-day readmission (OR 2.30, p < 0.05).

Conclusion

Class III obesity patients are at significantly increased risk of adverse outcomes following abdominal contouring. Plastic surgeons should consider these risks for counseling and preoperative risk optimization.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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A Comparative Study of Full-Thickness Blepharotomy Versus Transconjunctival Eyelid Lengthening in the Correction of Upper Eyelid Retraction in Graves’ Orbitopathy

Abstract

Background

The study was designed to compare the outcome of full-thickness blepharotomy and transconjunctival eyelid lengthening in the correction of upper eyelid retraction (UER) in patients with Graves' orbitopathy (GO).

Methods

This is a prospective randomized interventional study. Following ophthalmic examination, determination of the ocular surface disease index (OSDI) and photography, 27 patients with UER were randomly assigned to either graded full-thickness blepharotomy (G1) or transconjunctival Müller muscle recession and graded disinsertion of the levator palpebrae superioris muscle (G2). Six months later, patients were reevaluated. Digital images were analyzed with the assistance of customized software. A standardized "normal range" of upper eyelid height and contour was calculated based on healthy controls. The outcome of the two groups was compared.

Results

Forty-seven eyelids of 27 patients (19 female) with UER were included. Twenty-seven eyelids (15 patients) were allocated to G1 and 20 eyelids (12 patients) to G2. On average, surgery lasted 37.46 ± 5.73 min in G1 and 32.70 ± 8.39 min in G2. Based on the margin reflex distance, 93% of the eyelids in G1 and 85% in G2 were within the normal range after surgery. The corresponding figures for lid contour were 63 and 55%. Both groups displayed significant improvement in OSDI scores. No significant difference was observed in the overall comparison.

Conclusions

The two surgical techniques were equally effective in the treatment of UER from GO. Postoperative contour outcomes were considerably worse in patients with severe UER than in patients with mild or moderate UER, regardless of group.

Level of Evidence II

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

Study registered on ClinicalTrial.gov number: NCT01999790

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Comparison of Dexamethasone–Dimenhydrinate and Dexamethasone–Ondansetron in Prevention of Nausea and Vomiting in Postoperative Patients

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Autologous Buccal Micro-Mucosa Free Graft combined with Posterior Scrotal Flap Transfer for Vaginoplasty in Male-To-Female Transsexuals: A Pilot Study

Abstract

Background

The inverted peno-scrotal flap method is considered the standard method of vaginoplasty in male-to-female genital reassignment surgery. Though with numerous advantages, the method has its limitations regarding skin texture, lack of inherent lubrication, and that the tissues for creating the labia depend on the amount of tissues remaining after vaginoplasty. Our purpose was to describe the procedure and outcome of vaginoplasty applying a new technique: autologous buccal micro-mucosa free graft combined with posterior scrotal flap transfer, which could solve some of the problems the previous methods had.

Methods

Nine male-to-female transsexual patients received our new method of vaginoplasty from July 2010–October 2015. We described the details of the surgical procedure and evaluated the long-term anatomical and functional outcomes.

Results

In a mean clinical follow-up period of 25.3 months and phone interview follow-up of 50.3 months, we observed that the neovaginas in the nine cases were all of sufficient volume, lined with mucosa, with natural mucosal discharge. The oral donor sites resulted in no visible scars or malfunction. Eight patients experienced uneventful postoperative periods, while one patient suffered from scrotal flap prolapse. All the patients were sexually active and reported sexual satisfaction, with no need of lubrication.

Conclusion

The reported technique achieves the outcomes of creating a neovagina of sufficient volume, without serious stenosis in long-term follow-up. The neovagina is lined with mucosa and has appropriate lubrication as well as good sexual sensation. The reported method is easy and economical to perform and retains enough tissues for vulvoplasty to achieve a superior cosmetic appearance, with rare risk of complications and donor area malfunction. Additionally, this technique is feasible and advantageous to the patients who have insufficient peno-scrotal skin for neovaginal lining as well as those with unfavorable previous vaginoplasty. All of these indicate that this technique is a promising option for vaginoplasty in male-to-female transsexual surgery.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Outcome of In Situ Septoplasty and Extracorporeal Subtotal Septal Reconstruction in Crooked Noses: A Randomized Self-Controlled Study

Abstract

Importance

Severe dorsal deviations in crooked noses are treated by either in situ septoplasty with asymmetric spreader grafts (ISS) or extracorporeal subtotal septal reconstruction (ECS). To our knowledge, except one retrospective study, there is no other that compares the objective and subjective results of these two treatment modalities.

Objective

The aim of this study was to compare the aesthetic and functional outcomes of ECS and ISS in crooked noses.

Design, Setting and Participants

This study was carried out on 40 patients (ISS in 20 patients and ECS in 20 patients) who underwent external rhinoplasty surgery due to crooked noses between May 2014 and January 2016. While performing rhinoplasty on the patients, the decision of whether to use the ECS or ISS technique was randomized in a sequential fashion.

Main Outcomes and Measures

Surgical outcomes were assessed and compared using the anthropometric measurement of photographs with Rhinobase software. Subjective assessments of nasal obstruction and aesthetic satisfaction were evaluated with a visual analog scale.

Results

There was a significant difference between rhinion deviation angle, supratip deviation angle (SDA) and tip deviation angle pre- and postoperatively in the ECS group, whereas in the ISS group, except SDA, all other postoperative angles were significantly improved from preoperative values (p = 0.218). The nasal tip projection in the ECS and ISS groups was 29.48, 31.5 preoperatively and 29.78, 31.26 postoperatively. The mean postoperative nasal tip projection value (p > 0.005) did not change significantly compared to the preoperative value in both groups. The mean postoperative value of nasolabial (p = 0.226) angle did not change significantly compared to the mean preoperative one in the ECS group. However, in the ISS group, the mean postoperative value of nasolabial (p = 0.001) angle significantly improved compared to the mean preoperative value. There was significant improvement in both groups, while improvements in both functional and aesthetic outcomes were much higher in the extracorporeal group. None of the patients had postoperative nasal obstruction that required revision surgery. One patient underwent revision rhinoplasty due to an irregularity on the nasal dorsum in the ECS group.

Conclusions and Relevance

This is the first study that compares subjective and objective aesthetic and functional outcomes of crooked nose surgery according to two common septoplasty techniques in a randomized self-controlled fashion. This study was effective in both objectively and subjectively comparing the functional and aesthetic aspect of the patients submitted to two common different techniques of treatment of nasal deviations in crooked nose patients.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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