Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients

Malignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. St...

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Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome

Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here...

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Letter to the Editor concerning “Rod fracture and lengthening intervals in traditional growing rods: is there a relationship?” by P. Hosseini et al. Eur Spine J (2016). doi:10.1007/s00586-016-4786-8

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Appraising laboratory quality and value: What's missing?

Publication date: Available online 20 April 2017
Source:Clinical Biochemistry
Author(s): Paul L. Epner




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The emerging landscape of scientific publishing

Publication date: Available online 20 April 2017
Source:Clinical Biochemistry
Author(s): Clare Fiala, Eleftherios P. Diamandis
We present emerging models of publishing which have grown from the phenomenon of open access, the changing role of peer review in the scientific process and the new position of the impact factor. We juxtapose the new models of paid review, eponymous review, no review, post publication review and light review with the classic model which has dominated for a century, detailing advantages, problems and examples of each model to provide a comprehensive overview of the changing landscape of scientific publishing.



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Performance specifications in extra-analytical phase of laboratory testing: Sample handling and transportation

Publication date: Available online 21 April 2017
Source:Clinical Biochemistry
Author(s): Martina Zaninotto, Adriano Tasinato, Gianni Vecchiato, Angelo Legnaro, Alessio Pinato, Mario Plebani




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Symmetry of fMRI activation in the primary sensorimotor cortex during unilateral chewing

Abstract

Objective

Functional magnetic resonance imaging (fMRI) is one of the most advanced techniques to analyze the cerebral effects on many behavior aspects of the oral system such as chewing and mastication. Studies on imaging of the cerebral representation of chewing demonstrated differential results with respect to cortical lateralization during unilateral chewing. The aim of our study is to clarify the effects of cerebral responses during unilateral chewing.

Material and methods

We used fMRI to compare brain activities during occlusal function in centric occlusion on natural teeth and chewing on a gum located on the right or the left teeth in 15 healthy subjects. Group data were performed by Talairach normalization and in addition by an assignment of activation maxima to individual anatomical landmarks in order to avoid possible loss of spatial preciseness of activation sites by normalization procedures.

Results

Evaluation of group data by Talairach normalization revealed representation sites for occlusal movements in bilateral primary (S1) and secondary (S2) somatosensory cortices, primary motor (M1) and premotor cortices, supplementary motor area (SMA) and medial cingulate gyrus, bilateral anterior cerebellar hemispheres and vermis, insula, orbitofrontal cortex, thalamus, and left pallidum. Right-sided chewing showed no differential activation to left-sided chewing, and both showed activation in areas also involved in bilateral occlusion. Both techniques, the one based on group normalization and the one based on an individual evaluation method, revealed remarkable low differences in activation maximum location in the primary motor, the primary and secondary somatosensory cortices, and the anterior cerebellar lobe. All chewing movements tested involved bilateral sensorimotor activation without a significant lateralization of activation intensities.

Conclusion

Overall, a general lateralization of occlusion movements to the dominant side could not be verified in the present study. Chewing on the left or on the right side of teeth makes no difference for brain representation of chewing.

Clinical relevance

The results describe the basic effects of what we can expect by evaluation of cerebral effects of chewing and mastication. Based on these results, clinical fMRI studies can be performed in different patient groups.

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Transmitted irradiance through ceramics: effect on the mechanical properties of a luting resin cement

Abstract

Objectives

The study aims to characterise the curing behaviour of a light-curing luting composite (Variolink® Aesthetic LC, Ivoclar Vivadent) polymerised at different exposure times (10 s, 20 s) through different ceramics (IPS Empress CAD and IPS e.max CAD, Ivoclar Vivadent) and ceramic thicknesses (no ceramic, 0.5, 1, 1.5 and 2 mm).

Material and method

Curing units' (Bluephase Style, Ivoclar Vivadent) variation in irradiance delivered up to 10-mm exposure distance as well as the incident and transmitted irradiance and radiant exposure up to 6-mm ceramic thickness were assessed on a laboratory-grade spectrometer. A total of 216 (18 groups, n = 12) thin and flat luting composite specimens of 500-μm thickness were prepared and stored after curing in a saturated vapour atmosphere for 24 h at 37 °C. Micro-mechanical properties (Vickers hardness, HV and indentation modulus, Y_HU) were determined by means of an automatic micro-hardness indenter.

Results

Within the study design, the radiant exposure received by the luting composite varied from 2.56 to 24.75 J/cm², showing a high impact on the measured properties. Comparing the effect of the parameters exposure time, ceramic thickness and type, the highest influence on the micro-mechanical parameters was identified for exposure time, while this influence was stronger on HV (p < 0.001, η _P² = 0.452) than on Y_HU (p < 0.001, η _P² = 0.178). The influence of ceramic type was significant but low (η _P² = 0.161 on HV and 0.113 on Y_HU), while the influence of ceramic thickness was the lowest (η _P² = 0.04 and 0.05, respectively).

Conclusions

Slightly higher irradiance values were transmitted through Empress CAD up to a ceramic thickness of 3 mm (p < 0.001), while being comparable with e.max for thicker slices. Differences in translucency between ceramics were reflected in the micro-mechanical properties of the luting composite.

Clinical relevance

The radiant exposure reaching the luting composite is determined by the incident irradiance, exposure time, ceramic type and ceramic thickness. At the analysed incident irradiance, exposure time was the most consistent parameter affecting the micro-mechanical properties of the luting composite, and this effect was strongly reflected in the more translucent ceramic Empress CAD. Within the curing conditions, an exposure time of 20 s is recommended.

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In vivo determination of tooth mobility after fixed orthodontic appliance therapy with a novel intraoral measurement device

Abstract

Objective

Valid measurement systems recording tooth mobility upon displacement within the subtle range of physiological strains are missing. Here, we introduce a novel in vivo measurement device and demonstrate a first clinical application by monitoring tooth mobility changes during retention after fixed multibracket appliance therapy.

Materials and methods

Tooth mobility was measured in vivo on 21 patients (11 female, 10 male; mean age 16.1 ± 3.1 years) by displacing the upper first incisor 0.2 mm lingually for 0.2, 0.5, 1, 2, 5, and 10 s with the novel intraoral device. Measurements were recorded directly after, as much as 2, 7, and 14 days and up to 6 months after appliance debonding.

Results

Device performance was precise and valid in clinical use. Data revealed significant interindividual varying tooth mobility, which was very high during the first 2 days after appliance removal. After 1 week, mobility values decreased, but were generally higher upon short loadings compared to long ones. After 3 months, tooth mobility was significantly lower than directly after debonding. Interestingly, males exhibited significantly less mobility than females.

Conclusions

Our work is the first using an in vivo measurement device capable of performing and recording tooth displacements within this delicate range and in such precision. Furthermore, our findings elucidate tooth mobility changes after multibracket treatment, giving important information for retention periods.

Clinical relevance

Establishment of this novel measurement device in clinical use is an important improvement when approaching the complexity of tooth mobility in vivo regarding different issues like orthodontics, periodontal disease, or bruxism.

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Skin entrance dose with and without lead apron in digital panoramic radiography for selected sensitive body regions

Abstract

Purpose

The aim of this study was to compare the dose at skin level at five significant anatomical regions for panoramic radiography devices with and without lead apron by means of a highly sensitive dosimeter.

Materials and methods

A female RANDO-phantom was exposed in five different digital panoramic radiography systems, and the dose at skin level was assessed tenfold for each measurement region by means of a highly sensitive solid-state-dosimeter. The five measurement regions selected were the thyroid, both female breasts, the gonads, and a central region in the back of the phantom. For each panoramic machine, the measurements were performed in two modes: with and without a commercial lead apron specifically designed for panoramic radiography. Reproducibility of the measurements was expressed by absolute differences and the coefficient of variation. Values between shielded and unshielded doses were pooled for each region and compared by means of the paired Wilcoxon tests (p ≤ 0.05).

Results

Reproducibility as represented by the mean CV was 22 ± 52 % (median 2.3 %) with larger variations for small dose values. Doses at skin level ranged between 0.00 μGy at the gonads and 85.39 μGy at the unshielded thyroid (mean ± SD 15 ± 24 μGy). Except for the gonads, the dose in all the other regions was significantly lower (p < 0.001) when a lead apron was applied. Unshielded doses were between 1.02-fold (thyroid) and 112-fold (at the right breast) higher than those with lead apron shielding (mean: 14-fold ± 18-fold).

Conclusion

Although the doses were entirely very low, we observed a significant increase in dose in the radiation-sensitive female breast region when no lead apron was used. Future discussions on shielding requirements for panoramic radiography should focus on these differences in the light of the linear non-threshold (LNT) theory which is generally adopted in medical imaging.

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A comparison of lower canine retraction and loss of anchorage between conventional and self-ligating brackets: a single-center randomized split-mouth controlled trial

Abstract

Objective

To evaluate the rate of lower canine retraction, anchorage loss, and changes on lower canines and first molars axial inclination using self-ligating and conventional brackets.

Materials and methods

Twenty-five adult patients with a treatment plan involving extractions of four first premolars were selected for this split-mouth trial and had either conventional or self-ligating brackets bonded to lower canines in a block randomization. Retraction was accomplished using 100-g nickel titanium closed-coil springs, which were reactivated each 4 weeks. Oblique radiographs were taken before and after total canine retraction and the cephalograms were superimposed on stable structures of the mandible. Cephalometric points were digitized twice by a single-blinded operator for error control and the average of the points were used to determine the following variables: canine cusp horizontal changes, molar cusp horizontal changes, and angulation changes in canines and molars. Paired t tests were used to analyze the blinded data for group differences.

Results

All patients reached final phase without bracket debonds. No differences were found between the two groups for all variables tested. No serious harm was observed.

Conclusion

Both brackets showed the same rate of canine retraction and loss of anteroposterior anchorage of the molars. No changes were found between brackets regarding the inclination of canines and first molars.

Clinical Relevance

Using self-ligating brackets to retract lower canines will not increase the velocity of tooth movement, does not increase anchorage, and does not decrease tipping.

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Impact of combined CO 2 laser irradiation and fluoride on enamel and dentin biofilm-induced mineral loss

Abstract

Objectives

The caries-protective effects of CO₂ laser irradiation on dental enamel have been demonstrated using chemical demineralization models. We compared the effect of CO₂ laser irradiation, sodium fluoride, or both on biofilm-induced mineral loss (∆Z) and Streptococcus mutans adhesion to enamel and dentin in vitro.

Materials and methods

Ground, polished bovine enamel, and dentin samples were allocated to four groups (n = 12/group): no treatment (C); single 22,600-ppm fluoride (F) varnish (5 % NaF) application; single CO₂ laser treatment (L) with short pulses (5 μs/λ = 10.6 μm); and laser and subsequent fluoride treatment (LF). Samples were sterilized and submitted to an automated mono-species S. mutans biofilm model. Brain heart infusion plus 5 % sucrose medium was provided eight times daily, followed by rinses with artificial saliva. After 10 days, bacterial numbers in biofilms were enumerated as colony-forming units/ml (CFU/ml) (n = 7/group). ∆Z was assessed using transversal microradiography (n = 12/group). Univariate ANOVA with post hoc Tukey honestly-significant-difference test was used for statistical analysis.

Results

Bacterial numbers were significantly higher on dentin than enamel (p < 0.01/ANOVA). On dentin, LF yielded significantly lower CFUs than other groups (p = 0.03/Tukey), while no differences between groups were found for enamel. The lowest ∆Z in enamel was observed for L (mean/SD 2036/1353 vol%×μm), which was not only significantly lower than C (9642/2452 vol%×μm) and F (7713/1489 vol%×μm) (p < 0.05) but also not significantly different from LF (3135/2628 vol%×μm) (p > 0.05). In dentin, only LF (163/227) significantly reduced ∆Z (p < 0.05).

Conclusion/clinical relevance

CO₂ laser irradiation did not increase adhesion of S. mutans in vitro. Laser treatment alone protected enamel against biofilm-induced demineralization, while a combined laser-fluoride application was required to protect dentin.

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In situ Hearing Tests for the Purpose of a Self-Fit Hearing Aid

This study investigated the potential and limitations of a self-fit hearing aid. This can be used in the “developing” world or in countries with large distances between the hearing-impaired subjects and the professional. It contains an on-board tone generator for in situ user-controlled, automated audiometry, and other tests for hearing aid fitting. Twenty subjects with mild hearing losses were involved. In situ audiometry showed a test-retest reliability (SD Audiol Neurotol 2017;22:15-23

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Fewer than half of patients take high intensity statins two years after MI

A substantial proportion of patients prescribed high intensity statins following a heart attack do not continue to regularly take them after they have been discharged from hospital, a study published...

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Time for an overhaul at the World Medical Association

On 21 October 2016 Ketan Desai began his one year tenure as president of the World Medical Association. The WMA is formed and funded by 111 national medical associations and describes itself as “an...

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Irish MP calls for key documents on Pandemrix to be handed to lawyers representing children with narcolepsy

A member of Dáil Éireann, the Irish parliament, has accused the Irish state body responsible for buying vaccines of choosing GlaxoSmithKline’s Pandemrix for its swine flu programme when it knew it...

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The prevalence of acne in Mainland China: a systematic review and meta-analysis

Introduction

Acne, a very common skin disease, can result in psychological distress and sustain impairment in quality of life. Data on the prevalence of acne and the differences in gender, region and age are limited. The aim of this review is to estimate the prevalence of acne in Mainland China comprehensively and to quantify its association with gender, region and age.

Methods

We searched electronic databases with predetermined search terms to identify relevant studies published between 1 January 1996 and 30 September 2016. We pointed out repeated results using Note Express software and evaluated the studies for inclusion. Two independent reviewers extracted the data, followed with statistical analyses using Comprehensive Meta-Analysis software version 2.0. A random effects model was adopted to calculate the overall pooled prevalence and to merge categories, including gender (males and females), region (Northern China and Southern China) and age (primary and secondary students: 7–17 years old; undergraduates: 18–23 years old; overall: no limits of age) for subgroup analyses. Logistic meta-regression analysis was used to clarify the associations between acne and the predictors age, gender and region using OR and their associated 95% CI.

Results

25 relevant studies were included in this meta-analysis. The overall pooled prevalence rates of acne were 39.2% (95% CI 0.310 to 0.479). The prevalence rates in different age groups were 10.2% overall (95% CI 0.059 to 0.171), 50.2% for primary and secondary students (95% CI 0.451 to 0.554), and 44.5% for undergraduates (95% CI 0.358 to 0.534); by gender, the prevalence rates were 35.7% for females (95% CI 0.275 to 0.448) and 39.7% for males (95% CI 0.317 to 0.482); and by region, the prevalence rates were 34.2% for Northern China (95% CI 0.242 to 0.458) and 46.3% for Southern China (95% CI 0.374 to 0.555). The associations between acne and the predictors age, gender and region were statistically significant.

Conclusions

In Mainland China, primary and secondary students exhibited higher prevalence rates than undergraduate students; males had higher prevalence rates of acne than females; and the prevalence rates of acne in Southern China was higher than Northern China.

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Insights into structure and function of high pressure-modified starches with different crystalline polymorphs

Publication date: September 2017
Source:International Journal of Biological Macromolecules, Volume 102
Author(s): Jinrong Wang, Huaping Zhu, Sha Li, Shujun Wang, Shuo Wang, Les Copeland
The effect of high pressure (HP) treatment at 200–600MPa for 30min on properties of three starches with different polymorphs was investigated. HP treatment altered greatly the morphology of wheat starch, especially at 400MPa or higher. The crystallinity of wheat starch decreased from 22.6% for native starch to 3.4% for starch after treatment at 600MPa. The short-range molecular order as measured by FTIR and Raman spectroscopy decreased with increasing treatment pressure. HP treatment had little effect on structural properties of potato and yam starches, except for yam starch after treatment at 600MPa. HP treatment decreased the pasting viscosities of wheat starch except for the treatment at 200MPa, which increased the peak, trough and final viscosities by 6.7, 11.1 and 5.7%, respectively. The peak viscosity of potato and yam starches was increased respectively by 14.0 and 11.3% after HP treatment at 600MPa. HP treatment at 600MPa enhanced greatly the final digestion percentages of wheat and yam starch by 20 and 26.4%, but had little effect on potato starch. The above results showed that wheat starch was more susceptible to the effects of HP treatment than did yam and potato starches, and that C-type yam starch behaved more likely the B-type potato starch to HP treatment.



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Corrigendum to “Structural elucidation of a polysaccharide from Lonicera japonica flowers, and its neuroprotective effect on cerebral ischemia-reperfusion injury in rat” [Int. J. Biol. Macromol. 99 (2017) February (28) 350–357]

Publication date: September 2017
Source:International Journal of Biological Macromolecules, Volume 102
Author(s): Danying Su, Shi Li, Wei Zhang, Jing Wang, Jingjing Wang, Manhua Lv




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Management of a case of myopic foveoschisis with phakic intraocular lens (pIOL) in situ: intraoperative challenges

We describe the case of a 30-year-old man with pathological myopia with a phakic intraocular lens (IOL) (Visian ICL V4c model; STAAR, Monrovia, California, USA) in situ having complaints of metamorphopsia in the left eye with documented myopic foveoschisis on swept-source optical coherence tomography (DRI OCT Triton; Topcon, Tokyo, Japan). The patient underwent pars plana vitrectomy with internal limiting membrane peeling. This report discusses the intraoperative challenges occurring as a result of increased optical aberrations in the presence of a phakic IOL.

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Exogenous Cushing's syndrome due to a Chinese herbalists prescription of ointment containing dexamethasone

Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment. We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing's syndrome. Analysis of the ointment revealed the presence of dexamethasone. Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids.

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Improvement of Prosody Modeling Using Semantic Role Labeling, Hybrid Feature Selection and BPSO–PSO–Optimized RNN

Abstract

A modified Elman-type recurrent neural network (RNN) is used in this study for prosody generation in natural speech synthesis application. To improve the performance of generator, three modifications are applied to the system as compared to a traditional neural model: (a) using semantic role labeling to enrich the word-level features, (b) using hybrid of genetic algorithm and ant colony optimization algorithm for feature selection to reduce the number of input features, and (c) using hybrid of particle swarm optimization (PSO) and binary PSO algorithms for optimization of weights and structure of RNN-based prosody generator model, respectively. Experimental results show the superior performance of proposed model in predicting prosodic information with lower root mean squared error and a lighter model as compared to a traditional neural model.

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The effectiveness of earmuffs on the physiologic and behavioral stability in preterm infants

The use of earmuffs can protect preterm infants against negative effects of high noise levels in the neonatal intensive care unit. This study was aimed at assessing the effectiveness of the earmuffs on the physiologic and behavioral responses in preterm infants.

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Foreign body aspiration in children: A study of children who lived or died following aspiration

Foreign body aspiration (FBA) is a preventable cause of mortality and morbidity in children. We conducted a chart review of children who presented to a university hospital due to FBA in the period 1999 - 2014. Children were either managed with bronchoscopy for removal of the foreign body or died due to FBA. A total of 103 children were seen due to FBA including 27 deaths. The majority of children were boys and were less than 3 years old. Most aspirated foreign bodies were food-related, mainly peanuts.

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Paediatric tracheomalacia - a review of clinical features and comparison of diagnostic imaging techniques

Tracheomalacia is the excessive collapse of the tracheal wall during respiration [1]. In children, it can be classified as primary or secondary in origin. Primary tracheomalacia is due to impaired maturation or deficiency in cartilaginous rings and/or decreased tone of the trachealis muscle. In a healthy child, the tracheal cartilage extends for approximately 320 degrees. In patients with primary tracheomalacia, cartilage may be small or fragmented leading to anterior collapse and the membranous portion of the trachea can account for up to 50% of the circumference.

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Outcomes and Limitations of Hospital-Based Newborn Hearing Screening

Globally, newborn hearing screening (NHS) is variably incorporated into national healthcare systems. The authors reviewed the set-up and evolution process of a hospital-based NHS program in South Korea, where screening costs for low-income families are paid by the National Health Authority.

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Sir Charles Bell: Unheralded laryngologist

Sir Charles Bell is renowned and revered as an outstanding surgeon, anatomist, clinician and teacher and his many contributions to various medical fields have been amply described. What are less well-known are his contributions to the field of laryngology.

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Primary mucosal melanoma of the palatine tonsil: Report of a case and review of the literature

Mucosal melanoma of the palatine tonsil is extremely rare. Due to its poor prognosis, primary tonsillar melanoma requires prompt recognition and treatment.

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Thyroid cancer

Thyroid cancer: Cancer of the gland in front of the neck that normally produces thyroid hormone which is important to the normal regulation of the metabolism of the body. There are 4 major types of thyroid cancer -- papillary, follicular, medullary, and anaplastic. The most common symptom of thyroid cancer is a lump, or nodule, that can be felt in the neck. The only certain way to tell whether a thyroid lump is cancer is by examining the thyroid tissue, obtained using a needle or surgery to obtain a biopsy.

Carcinoma of the thyroid gland is an uncommon cancer but is the most common malignancy of the endocrine (hormone making)system. Differentiated tumors (papillary or follicular) are highly treatable and usually curable. Poorly-differentiated tumors (medullary or anaplastic) are much less common, are aggressive, metastasize early, and have a much poorer prognosis. In spite of its role as a causal agent in common thyroid cancer radiation therapy both with radioactive isotopes (used as medicines) as well as with conventional radiation therapy and with surgery are essential in the management and hopefully the cure of thyroid cancer patients.

Thyroid cancer affects women more often than men, and usually occurs in people between the ages of 25 and 65 years. The incidence of this malignancy has been increasing. Patients with a history of radiation in infancy and childhood for benign conditions of the head and neck have an increased risk of cancer (and other abnormalities) of the thyroid. In this group of patients, malignancies of the thyroid may first appear anywhere between 5 and 20 or more years later. Persons who received radiation to the head or neck in childhood should be examined by a doctor every 1 to 2 years.

Radiation exposure as a consequence of nuclear fall-out has also been associated with a high risk of thyroid cancer, especially in children. Other risk factors for the development of thyroid cancer include a history of goiter, family history of thyroid disease, female gender, and Asian race.

The prognosis for differentiated carcinoma (papillary or follicular) is better for patients younger than 40 years without extension of the tumor beyond the thyroid. Age appears to be the single most important prognostic factor. An elevated serum thyroglobulin level correlates strongly with recurrent tumor when found in patients with differentiated thyroid cancer during postoperative evaluations.

Patients considered to be low risk by the age, metastases, extent, and size risk criteria include women younger than 50 years and men younger than 40 years without evidence of distant metastases. Also included in the low-risk group are older patients with primary tumors less than 5 cm and papillary cancer without evidence of gross extrathyroid invasion. Using these criteria, a retrospective study of 1,019 patients showed that the 20-year survival rate is 98% for low-risk patients and 50% for high-risk patients.

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Variation in brain anatomy in frogs and its possible bearing on their locomotor ecology

Abstract

Despite the long-standing interest in the evolution of the brain, relatively little is known about variation in brain anatomy in frogs. Yet, frogs are ecologically diverse and, as such, variation in brain anatomy linked to differences in lifestyle or locomotor behavior can be expected. Here we present a comparative morphological study focusing on the macro- and micro-anatomy of the six regions of the brain and its choroid plexus: the olfactory bulbs, the telencephalon, the diencephalon, the mesencephalon, the rhombencephalon, and the cerebellum. We also report on the comparative anatomy of the plexus brachialis responsible for the innervation of the forelimbs. It is commonly thought that amphibians have a simplified brain organization, associated with their supposedly limited behavioral complexity and reduced motor skills. We compare frogs with different ecologies that also use their limbs in different contexts and for other functions. Our results show that brain morphology is more complex and more variable than typically assumed. Moreover, variation in brain morphology among species appears related to locomotor behavior as suggested by our quantitative analyses. Thus we propose that brain morphology may be related to the locomotor mode, at least in the frogs included in our analysis.

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Effect of non-coherent infrared light (LED, λ 945 ± 20 nm) on bone repair in diabetic rats—morphometric and spectral analyses

Abstract

Phototherapy using coherent light (lasers) and non-coherent light (light-emitting diodes (LEDs)) has been investigated for the purpose of biomodulation in biological tissues. Several effects can be expected, including pain moderation, biostimulation of cellular tropism, anti-inflammatory effects, regular circulatory stimulation, and tissue repair. The aim of this study was to evaluate the effect of LED (λ945 ± 20 nm, 48 mW) therapy on the regeneration process in femoral lesions of rats (Wistar). Seven irradiation sessions were held, with a 48-h interval between sessions. The animals were euthanised 14, 21, and 28 days after surgery. Bone samples were analysed by histomorphometry, micro X-ray fluorescence spectroscopy, scanning electron microscopy, and optical densitometry. The results demonstrated the effective positive influence of low-intensity LED therapy using the near-infrared region on the tissue repair process in diabetic animals, especially in the early stages of repair (14 and 21 days after surgery). It can be concluded that LED therapy positively influences bone formation in the early stages of the bone repair process in non-diabetic and diabetic animals, without causing changes in the optical density and volume of tissue in the final stages. No influence of LED therapy was observed on the percentage of calcium, percentage of phosphorus, Ca/P ratio, or optical mineral density in non-diabetic animals. However, increased mineral concentration was evident in the diabetic animals treated with the LED during the repair process.

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Photoinactivation effect of eosin methylene blue and chlorophyllin sodium-copper against Staphylococcus aureus and Escherichia coli

Abstract

The use of eosin methylene blue according to Giemsa as photosensitizer is presented for the first time in this paper. The present study evaluated the potential application of chlorophyllin sodium copper salt (CuChlNa) and eosin methylene blue according to Giemsa (EMB) as antimicrobial photosensitizers (aPS) for photodynamic inactivation (PDI) of Staphylococcus aureus (gram-positive) and Escherichia coli (gram-negative) bacteria. The experiments were performed using S. aureus stain ATCC 25923 and E. coli ATCC 25922 in which five aPS concentrations (0.0, 1.0, 2.5, 5.0, 10.0, and 20.0 μM for S. aureus and 0.0, 5.0, 10.0, 20.0, 40.0, and 50.0 μM for E. coli) were prepared and added in 2 mL of a saline solution containing the bacterial inoculum. After aPS incubation, the samples were divided into two groups, one kept in the dark and another submitted to the illumination. Then, the bacterial inactivation was determined 18 h after the incubation at 37 °C by counting the colony-forming units (CFU). The results revealed that both EMB and CuChlNa can be used as aPS for the photoinactivation of S. aureus, while only EMB was able to photoinactivate E. coli. Nevertheless, a more complex experimental setup was needed for photoinactivation of E. coli. The data showed that EMB and CuChlNa presented similar photoinactivation effects on S. aureus, in which bacterial growth was completely inhibited at photosensitizer (PS) concentrations over 5 μM, when samples were previously incubated for 30 min and irradiated by a light dose of 30 J cm⁻² as a result of an illumination of 1 h at 8.3 mW cm⁻² by using a red light at 625 nm with a 1 cm beam diameter and output power of 6.5 mW. In the case of E. coli, bacterial growth was completely inhibited only when combining a PS incubation period of 120 min with concentrations over 20 μM.

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Melanogenesis inhibition in mice using a low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum garnet laser: a pilot study

Abstract

A low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum garnet laser, or laser toning, has yielded favorable outcomes in various benign pigmented disorders. However, the exact mechanism of action of laser toning has not been fully elucidated. We sought to determine the inhibitory effect of laser toning on melanogenesis and to assess how laser passes influence the outcomes. To produce perceptible pigmentation, nine HRM-2 melanin-possessing hairless mice were treated with ultraviolet (UV) B radiation on the dorsal skin. This was followed by zero, two, four, or six passes of laser toning twice in 2 weeks on each designated quadrant. The spectrophotometric values and pigmentation-related protein expressions were measured. Pigment changes were found in the mice skin using the Fontana-Masson stain for histopathological analysis. Four- and six-pass laser toning significantly improved the lightness compared to that in the unirradiated control (p < 0.002). The Fontana-Masson stain showed that melanin was considerably decreased in laser-irradiated skin. As the number of laser passes increased, the expression of tyrosinase decreased (p < 0.008). The following parameters also decreased in proportion to the number of laser passes: MITF, TRP-1, TRP-2, p-ERK, and p-Akt. In contrast, TGF-β increased in proportion to the number of laser passes. However, the changes in these six proteins were not statistically significant. Our study demonstrates that laser toning improves skin pigmentation with increased number of passes in a dose-dependent manner. This effect is mediated by tyrosinase inhibition.

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Information for authors (p/u from previous issue)

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Cover 2 - Masthead (p/u from previous issue)

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Editorial Board (p/u from previous issue)

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Contents

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Future and recent issues (p/u from previous issue and update)

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Brodie abscess of the femoral capital epiphysis in a 2-year-old child caused by Kingella kingae

We report the case of a Brodie abscess of the femoral capital epiphysis from which Kingella kingae was isolated. This is to the best of our knowledge the first report of a Brodie abscess of the femoral capital epiphysis from which K. kingae was isolated.

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Delayed LGI1 seropositivity in voltage-gated potassium channel (VGKC)-complex antibody limbic encephalitis

We utilise a clinical case to highlight why exclusion of voltage-gated potassium channel (VGKC)-complex autoantibody testing in serological evaluation of patients may delay or miss the diagnosis. A 68-year-old man presented with increasing involuntary movements consistent with faciobrachial dystonic seizures (FBDS). Initial evaluation demonstrated VGKC antibody seropositivity with leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) seronegativity. Aggressive immunotherapy with methylprednisolone and plasmapheresis was started early in the course of his presentation. Following treatment with immunotherapy, the patient demonstrated clinical improvement. Repeat serum evaluation 4 months posthospitalisation remained seropositive for VGKC-complex antibodies, with development of LGI1 autoantibody seropositivity. VGKC-complex and LGI1 antibodies remained positive 12 months posthospitalisation. Our findings suggest that clinical symptoms can predate the detection of the antibody. We conclude that when suspicion for autoimmune encephalitis is high in the setting of VGKC autoantibody positivity, regardless of LGI1 or CASPR2 seropositivity, early immunotherapy and repeat testing should be considered.

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Syndrome of inappropriate antidiuretic hormone accompanied by bilateral hypothalamic and anterior thalamic lesions with serum antiaquaporin 4 antibody

We described a rare case of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and severe unconsciousness accompanied by bilateral hypothalamic and anterior thalamic lesions with positive serum antiaquaporin 4 (AQP4) antibody. A 29-year-old man was admitted to our hospital due to the subacute progression of an unconscious state. He was observed to be hyponatraemic secondary to SIADH. Brain MRI showed bilateral hypothalamic and anterior thalamic lesions. Anti-AQP4 antibody was detected in his serum. After the administration of intravenous methylprednisolone pulse therapy, his symptoms improved with complete recovery from SIADH and regression of the hypothalamic and anterior thalamic lesions. The patient was transferred to another hospital for rehabilitation with 20 mg/day of oral prednisolone 127 days after admission. This case highlights the importance of testing for anti-AQP4 antibody in patients with unexplainable SIADH, subacute progressive unconsciousness and bilateral hypothalamic and anterior thalamic lesions.

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Transoesophageal three-dimensional echocardiographic diagnosis of Barlows disease

Description

A 67-year-old man with a year history of palpitations and dyspnoea presented to the physician’s office. His blood pressure was 140/80 mm Hg and pulse was 80 beats/min. Heart auscultation revealed a loud systolic click followed by a holosystolic murmur. The ECG showed sinus rhythm, P wave +/– in V1 and P wave duration 140 ms in DII. The Holter monitoring showed atrial extrasystoles and an episode of atrial tachycardia (figure 1A).

Figure 1

(A) The Holter monitoring showed atrial extrasystoles and an episode of atrial tachycardia. (B) M-mode echocardiogram showed late systolic sagging of the mitral valve. (C) Transoesophageal echocardiogram showed clearly the prolapsing mitral leaflets and severe mitral regurgitation. (D,E) Three-dimensional echocardiographic imaging demonstrated bileaflet prolapse. Mitral model showed prolapse of the P1, P2, P3 and A1, A2, A3.

The transthoracic echocardiogram M-mode showed late systolic sagging of the mitral...

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Direct monitoring of basophil degranulation by using avidin-based probes

We show that fluorescent avidin binds to basophil cell surface upon degranulation and can be used to set up a new basophil activation test (BAT). This new assay provides results comparable to those provided by the CD63 exposure-based BAT, but has the advantage to directly monitor granule exteriorization.

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Steroid Resistance of Airway Type 2 Innate Lymphoid Cells (ILC2s) from Severe Asthma: The Role of Thymic Stromal cell Lymphopoietin (TSLP)

Dexamethasone inhibited CRTH2 and IL5 but promoted IL7Rα expression by ILC2s, which led to the development of steroid resistance This steroid resistance was reversed by MEK and STAT5 inhibitors.

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Asthma: the past, the future, the environment, and the costs

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Vitamin D downregulates the IL-23 receptor pathway in human mucosal ILC3

We have unraveled the detailed mechanisms behind how vitamin D efficiently suppresses IL-23 receptor signaling in gut innate lymphoid cells, providing incitement for vitamin D supplementation as a therapeutic approach in IBD.

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Type 3 innate lymphoid cells induce proliferation of CD94+ NK cells

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Sleeve Gastrectomy Alters Intestinal Permeability in Diet-Induced Obese Mice

Abstract

Background

Increased lipopolysaccharide (LPS) translocation due to altered intestinal permeability has been suggested as a mechanism for obesity-associated insulin resistance. The goal of this study was to assess the effect of sleeve gastrectomy (SG) on intestinal barrier permeability in diet-induced obese mice.

Materials and Methods

Four weeks after surgery, the effects of SG on intestinal permeabilities were assessed ex vivo and in vivo in male C57Bl/6J mice fed a high-fat diet. Gene expression of tight junction proteins and inflammatory cytokines was measured in jejunum, colon, liver, and inguinal adipose tissue. Plasma LPS was quantified by HPLCMS/MS spectrometry.

Results

SG significantly reduced body weight and improved glucose homeostasis, as expected. SG decreased paracellular (p = 0.01) and transcellular permeability (p = 0.03) in the jejunum; and increased mRNA levels of the tight junction proteins Jam A (p = 0.02) and occludin (p = 0.01). In contrast in the distal colon, paracellular permeability tended to be increased (p = 0.07) while transcellular permeability was significantly induced (p = 0.03) after SG. In vivo, the paracellular permeability was significantly increased 3 weeks after SG (p = 0.02). Plasma LPS level were increased after SG (p = 0.03), as well as mRNA levels of adipose and hepatic inflammatory markers (p = 0.02).

Conclusions

SG significantly modifies intestinal permeability in a differential manner between the proximal and distal intestine. These changes promote LPS translocation in plasma, induce a low-grade pro-inflammatory state in adipose tissue and liver, but do not impair the SG-induced glucose homeostasis improvement.

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A survey of memory deduplication approaches for intelligent urban computing

Abstract

Limited memory size is considered as a major bottleneck in data centers for intelligent urban computing. It is shown that there exist a large number of duplicated pages when various processes working with big data are hosted in data centers. Memory deduplication aims to automatically eliminate duplicate data in memory. It is an efficient technique to reduce memory requirement. In memory deduplication, pages with same content are detected and merged into a single copy. Recently, several system-level techniques have been proposed to address this issue, in which content-based page sharing (CBPS) is most widely used, since CBPS can be performed transparently in the hypervisor layer without any modification to guest operating systems of data center. In this paper, we survey several techniques for memory deduplication. We also classify these techniques based on their characteristics to highlight their similarities and differences. The aim of this paper is to provide insights to researchers into working of memory deduplication techniques and also to motivate them to propose better intelligent urban computing systems.

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KCa1.1 channels regulate {beta}1 integrin function and cell adhesion in rheumatoid arthritis fibroblast-like synoviocytes [Research]

Large-conductance calcium-activated potassium channel (KCa1.1; BK, Slo1, MaxiK, KCNMA1) is the predominant potassium channel expressed at the plasma membrane of fibroblast-like synoviocytes isolated from the synovium of patients with rheumatoid arthritis (RA-FLS). It is a critical regulator of RA-FLS migration and invasion and therefore represents an attractive target for the therapy of RA. However, the molecular mechanisms by which KCa1.1 regulates RA-FLS invasiveness have remained largely unknown. Here, we demonstrate that KCa1.1 regulates RA-FLS adhesion through controlling the plasma membrane expression and activation of β₁ integrins, but not α₄, α₅, or α₆ integrins. Blocking KCa1.1 disturbs calcium homeostasis, leading to the sustained phosphorylation of Akt and the recruitment of talin to β₁ integrins. Interestingly, the pore-forming α subunit of KCa1.1 coimmunoprecipitates with β₁ integrins, suggesting that this physical association underlies the functional interaction between these molecules. Together, these data outline a new signaling mechanism by which KCa1.1 regulates β₁ integrin function and therefore invasiveness of RA-FLS.—Tanner, M. R., Pennington, M. W., Laragione, T., Gulko, P. S., Beeton, C. KCa1.1 channels regulate β₁ integrin function and cell adhesion in rheumatoid arthritis fibroblast-like synoviocytes.

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Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration [Research]

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30–40% in the Rpe65^–/– mouse model of Leber congenital amaurosis and reduced the number of TUNEL⁺ cells. Cone survival was significantly improved in Rpe65^–/– and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2^–/– and Rpe65^–/–/Thrb2^–/– mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.—Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

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CB1 cannabinoid receptor drives oocyte maturation and embryo development via PI3K/Akt and MAPK pathways [Research]

Endocannabinoids have been recognized as mediators of practically all reproductive events in mammals. However, little is known about the role of this system in oocyte maturation. In a mouse model, we observed that activation of the cannabinoid receptor (CB)₁ during in vitro oocyte maturation modulated the phosphorylation status of Akt and ERK1/2 and enhanced the subsequent embryo production. In the absence of the CB₁ receptor, in vivo oocyte maturation was impaired and embryo development delayed. The CB₂ receptor was unable to rescue these effects. Finally, we confirmed abnormal oocyte maturation rather than impaired embryonic transport through the oviduct in CB₁ knockouts. Our data suggest that cannabinoid agonists may be useful in vitro maturation supplements. For in vitro fertilization patients intolerant to gonadotropins, this could be a promising and only option.—López-Cardona, A. P., Pérez-Cerezales, S., Fernández-González, R., Laguna-Barraza, R., Pericuesta, E., Agirregoitia, N., Gutiérrez-Adán, A., Agirregoitia, E. CB₁ cannabinoid receptor drives oocyte maturation and embryo development via PI3K/Akt and MAPK pathways.

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Zum Nutzen von Drainagen nach tiefer Rektumanastomose

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Julius-Springer-Preis für Chirurgie 2017 verliehen

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No cooling: Trump’s indifference to climate change has not changed China’s view

Print section Print Rubric:  Donald Trump’s indifference to climate change has not changed China’s view Print Headline:  No cooling Print Fly Title:  Climate change UK Only Article:  standard article Issue:  Why an election offers the chance of a better Brexit Fly Title:  No cooling Location:  BEIJING Main image:  20170422_CNP001_0.jpg RESIDENTS have found something else to blame for the toxic smog that envelops many Chinese cities for much of the year. Until recently the culprits that were usually fingered were the obvious ones: emissions from coal-fired power plants, exhaust fumes from cars and dust from building sites. This year, however, reports began to appear in state-run media that climate change is now reckoned to be a factor, too. Chinese scientists say that in eastern China global ...

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Gold Nanoparticles Induced Endothelial Leakiness Depends on Particle Size and Endothelial Cell Origin

ACS Nano

DOI: 10.1021/acsnano.7b01744

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Correlation between intervertebral disc degeneration, paraspinal muscle atrophy, and lumbar facet joints degeneration in patients with lumbar disc herniation

Abstract

Background

To assess the correlation between lumbar disc degeneration (LDD), multifidus muscle atrophy (LMA), and facet joints degeneration in patients with L4-L5 lumbar disc herniation (LDH).

Methods

Sixty patients with L4-L5 LDH diagnosed by a 1.5 T MRI scanner were enrolled in the study group and another 60 patients with non-specific back pain were enrolled in the control group. LDD, LMA, and facet joints degeneration were examined and analyzed independently by two independent orthopedic surgeons using T2-weighted images. Wilcoxon test was used for analyzing the difference of LDD and facet joints degeneration between L3-L4 and L5-S1 and difference of LMA between the herniated and control groups. Correlation analysis of the three degeneration grades at the same level was determined by Spearman rank correlation test.

Results

In the herniated group, most LMA at L3-L4 level was grade 1 (42, 70.0%); grade 2 (33, 55.0%) at L4-L5 level; and grade 3 (27, 45.0%) at L5-S1 level. LMA and LDD grading were significantly different between L3-L4 and L5-S1 levels (P < 0.05). In the herniation group, the Spearman value for LDD and LMA grading were 0.352 (P < 0.01) at L3-L4 and 0.036 (P > 0.05) at the L5-S1 level. The differences in LMA between the herniated and control groups at the three levels were significant (P < 0.05).

Conclusions

Disc degeneration and multifidus muscles atrophy were positively correlated at the L3-L4 disc level. A lumbar extension muscle strengthening program could be helpful in preventing muscle atrophy and lumbar spinal degeneration.

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Hydrogen production and microbial kinetics of Clostridium termitidis in mono-culture and co-culture with Clostridium beijerinckii on cellulose

Cellulose utilization by hydrogen producers remains an issue due to the low hydrogen yields reported and the pretreatment of cellulose prior to fermentation requires complex and expensive steps. Clostridium termi...

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Growth kinetics, fatty acid composition and metabolic activity changes of Crypthecodinium cohnii under different nitrogen source and concentration

The effect of varying concentrations of the nitrogen source on the growth kinetics, lipid accumulation, lipid and DHA productivity, and fatty acid composition of C. cohnii was elucidated. Growth of C. cohnii was ...

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How bumblebees use lateral and ventral optic flow cues for position control in environments of different proximity

Abstract

Flying insects frequently navigate through environments of different complexity. In this study, buff-tailed bumblebees (Bombus terrestris L.) were trained to fly along tunnels of different widths, from 60 to 240 cm. In tunnel widths of 60 and 120 cm, bumblebees control their lateral position by balancing the magnitude of translational optic flow experienced in the lateral visual field of each eye. In wider tunnels, bumblebees use translational optic flow cues in the ventral visual field to control their lateral position and to steer along straight tracks. Our results also suggest that bumblebees prefer to fly over surfaces that provide strong ventral optic flow cues, rather than over featureless ones. Together, these strategies allow bumblebees to minimize the risk of collision and to maintain relatively straight flight paths in a broad range of environments.

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A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.109

Authors: M A Calegari, A Inno, S Monterisi, A Orlandi, D Santini, M Basso, A Cassano, M Martini, T Cenci, I de Pascalis, F Camarda, B Barbaro, L M Larocca, S Gori, G Tonini & C Barone

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Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.108

Authors: J H Park, H van Wyk, C S D Roxburgh, P G Horgan, J Edwards & D C McMillan

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Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial

Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.111

Authors: Manuela Viviano, Rosa Catarino, Emilien Jeannot, Michel Boulvain, Manuela Undurraga Malinverno, Pierre Vassilakos & Patrick Petignat

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Long-term improvement of breast cancer survivors’ quality of life by a 2-week group physical and educational intervention: 5-year update of the ‘PACThe’ trial

Long-term improvement of breast cancer survivors’ quality of life by a 2-week group physical and educational intervention: 5-year update of the ‘PACThe’ trial

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.112

Authors: Fabrice Kwiatkowski, Marie-Ange Mouret-Reynier, Martine Duclos, François Bridon, Thierry Hanh, Isabelle Van Praagh-Doreau, Armelle Travade, Marie-Paule Vasson, Sylvie Jouvency, Christian Roques & Yves-Jean Bignon

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Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.94

Authors: Didier Meulendijks, Linda M Henricks, Bart A W Jacobs, Abidin Aliev, Maarten J Deenen, Niels de Vries, Hilde Rosing, Erik van Werkhoven, Anthonius de Boer, Jos H Beijnen, Caroline M P W Mandigers, Marcel Soesan, Annemieke Cats & Jan H M Schellens

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Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening

Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening

British Journal of Cancer advance online publication, April 20 2017. doi:10.1038/bjc.2017.107

Authors: M Román, M J Quintana, J Ferrer, M Sala & X Castells

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Master Transcriptional Regulators in Cancer: Discovery via Reverse Engineering Approaches and Subsequent Validation

Reverse engineering of transcriptional networks using gene expression data enables identification of genes that underpin the development and progression of different cancers. Methods to this end have been available for over a decade and, with a critical mass of transcriptomic data in the oncology arena having been reached, they are ever more applicable. Extensive and complex networks can be distilled into a small set of key master transcriptional regulators (MTR), genes that are very highly connected and have been shown to be involved in processes of known importance in disease. Interpreting and validating the results of standardized bioinformatic methods is of crucial importance in determining the inherent value of MTRs. In this review, we briefly describe how MTRs are identified and focus on providing an overview of how MTRs can and have been validated for use in clinical decision making in malignant diseases, along with serving as tractable therapeutic targets. Cancer Res; 77(9); 1–5. ©2017 AACR.

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Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection

Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 1–10. ©2017 AACR.

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Whither Radioimmunotherapy: To Be or Not To Be?

Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two “first-generation,” directly radiolabeled anti-CD20 antibodies, 131iodine-tositumomab and 90yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep “pretargeting” methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities. The dramatically improved therapeutic index of bispecific antibody pretargeting appears to be sufficiently compelling to justify human clinical trials and reinvigorate enthusiasm for radioimmunotherapy in the treatment of malignancies, particularly lymphomas. Cancer Res; 77(9); 1–6. ©2017 AACR.

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Role of CBX4 in the Colorectal Carcinoma Metastasis—Letter

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Role of CBX4 in the Colorectal Carcinoma Metastasis—Response

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Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention.

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Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-kappaB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation, and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC.

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Micellar delivery of miR-34a modulator rubone and paclitaxel in resistant prostate cancer

Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2′-hydroxy-2,4,4′,5,6′-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. PTX and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70 ± 0.10% and 5.34 ± 0.02% for PTX and rubone, respectively, controlling a drug release of 60.20 ± 2.67% and 60.62 ± 4.35% release of PTX and rubone at 24 h. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing PTX concentration. Co-incubation with a miR-34a inhibitor diminished the effect of rubone. PTX IC50 in PC3 and PC3-TXR cells was 55.6 and 2580 nM, respectively, but decreased to 49.8 and 93.2 nM when treated in combination with rubone, demonstrating a reversal of PTX resistance by rubone. Systemic administration of micelles carrying PTX and rubone inhibited orthotopic prostate tumor growth in nude mice, compared to monotherapy, by reversing the expression of miR-34a, SIRT1, Cyclin D1 and E-cadherin. In summary, our results showed how rubone acts as an efficient small molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of PTX in PTX-resistant prostate cancer.

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Immune gene expression is associated with genomic aberrations in breast cancer

The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the 3 major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER positive, 207 HER2 positive, and 191 triple negative (TNBC) cancers from TCGA. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers.

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Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion

New magnetic resonance (MR) molecular imaging techniques offer the potential for non-invasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a 3D dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low and high grade tumors in the TRAMP transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1 and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans, attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL. This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials.

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Epithelial-to-mesenchymal Transition contributes to Immunosuppression in Breast Carcinomas

The Epithelial-to-mesenchymal transition (EMT) is a cell-biological program that confers mesenchymal traits on carcinoma cells and drives their metastatic dissemination. It is, unclear, however, whether activation of EMT in carcinoma cells can change their susceptibility to immune attack. We demonstrate here that mammary tumor cells arising from more epithelial carcinoma cell lines expressed high levels of MHC-I, low levels of PD-L1 and contained within their stroma CD8+ T cells and M1 (anti-tumor) macrophages. In contrast, tumors arising from more-mesenchymal carcinoma cell lines exhibiting EMT markers expressed low levels of MHC-I, high levels of PD-L1 and contained within their stroma regulatory T cells, M2 (pro-tumor) macrophages and exhausted CD8+ T cells. Moreover, the more mesenchymal carcinoma cells within a tumor retained the ability to protect their more epithelial counterparts from immune attack. Lastly, epithelial tumors were more susceptible to elimination by immunotherapy than corresponding mesenchymal tumors. Our results identify immune cells and immunomodulatory markers that can be potentially targeted to enhance the susceptibility of immunosuppressive tumors to various therapeutic regimens.

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EGFR mediates responses to small molecule drugs targeting oncogenic fusion kinases

Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models and human clinical specimens before onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to co-target EGFR to reduce risks of developing drug resistance.

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New Insights into the Tetraspanin Tspan5 Using Novel Monoclonal Antibodies [Cell Biology]

Tspan5 is a member of a subgroup of tetraspanins referred to as TspanC8. These tetraspanins directly interact with the metalloprotease ADAM10, regulate its exit from the endoplasmic reticulum and subsequent trafficking, and differentially regulate its ability to cleave various substrates and activate Notch signaling. The study of Tspan5 has been limited by the lack of good antibodies. This study provides new insights into Tspan5 using new monoclonal antibodies (mAbs), including two mAbs recognizing both Tspan5 and the highly similar tetraspanin Tspan17. Using these mAbs, we show that endogenous Tspan5 associates with ADAM10 in human cell lines and in mouse tissues where it is most abundant such as the brain, the lung, the kidney or the intestine. We also uncover two TspanC8-specific motifs in the large extracellular domain of Tspan5 that are important for ADAM10 interaction and exit from the endoplasmic reticulum. One of the anti-Tspan5 mAb does not recognize Tspan5 associated with ADAM10, providing a convenient way to measure the fraction of Tspan5 not associated with ADAM10. This fraction is minor in the cell lines tested, and increases upon transfection of cells with TspanC8 tetraspanins such as Tspan15 or Tspan33 that inhibit Notch signalling. Finally, two antibodies inhibit ligand-induced Notch signalling, and this effect is stronger in cells depleted of the TspanC8 Tspan14, further indicating that Tspan5 and Tspan14 can compensate for each other in Notch signalling.

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Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss [Cell Biology]

Connexin26 (Cx26) is a gap junction protein that oligomerizes in the cell to form hexameric transmembrane channels called connexons. Cell surface connexons dock between adjacent cells to allow for gap junctional intercellular communication. Numerous autosomal dominant mutations in the Cx26 encoding GJB2 gene lead to many skin disorders and sensorineural hearing loss. Although some insights have been gained into the pathogenesis of these diseases, it is not fully understood how distinct GJB2 mutations result in hearing loss alone or in skin pathologies with comorbid hearing loss. Here, we investigated five autosomal dominant Cx26 mutants (N14K, D50N, N54K, M163V, and S183F) linked to various syndromic or nonsyndromic diseases to uncover the molecular mechanisms underpinning these disease links. We demonstrated that when gap junction deficient HeLa cells expressed the N14K and D50N mutants, they undergo cell death. The N54K mutant was retained primarily within intracellular compartments and displayed dominant or transdominant properties on wild type Cx26 and coexpressed Cx30 and Cx43. The S183F mutant formed some gap junction plaques, but was largely retained within the cell and exhibited only a mild transdominant reduction in gap junction communication when coexpressed with Cx30. The M163V mutant, which causes only hearing loss, exhibited impaired gap junction function and showed no transdominant interactions. These findings suggest that Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes will lead to skin diseases and hearing loss, whereas mutants having reduced channel function but exhibiting no aberrant effects on coexpressed connexins cause only hearing loss. Moreover, cell death inducing GJB2 mutations lead to more severe syndromic disease.

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Key features of an Hsp70 chaperone allosteric landscape revealed by ion mobility native mass spectrometry and double electron-electron resonance [Protein Structure and Folding]

Proteins are dynamic entities that populate conformational ensembles, and most functions of proteins depend on their dynamic character. Allostery, in particular, relies on ligand-modulated shifts in these conformational ensembles. Hsp70s are allosteric molecular chaperones with conformational landscapes that involve large rearrangements of their two domains (viz, the nucleotide-binding domain and substrate-binding domain) in response to adenine nucleotides and substrates. However, it remains unclear how the Hsp70 conformational ensemble is populated at each point of the allosteric cycle and how ligands control these populations. We have mapped the conformational species present under different ligand-binding conditions throughout the allosteric cycle of the E. coli Hsp70 DnaK by two complementary methods, ion mobility mass spectrometry and double electron-electron resonance. Our results obtained under biologically relevant ligand-bound conditions confirm the current picture derived from NMR and crystallographic data of domain docking upon ATP binding and undocking in response to ADP and substrate. Additionally, we find that the helical lid of DnaK is a highly dynamic unit of the structure in all ligand-bound states. Importantly, we demonstrate that DnaK populates a partially docked state in the presence of ATP and substrate and that this state represents an energy minimum on the DnaK allosteric landscape. Because Hsp70s are emerging as potential drug targets for many diseases, fully mapping an allosteric landscape of a molecular chaperone like DnaK will facilitate the development of small molecules that modulate Hsp70 function via allosteric mechanisms.

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Crystal structure and redox properties of a novel cyanobacterial heme-protein with a His/Cys heme axial ligation and a per-arnt-sim (PAS)-like domain [Molecular Biophysics]

Photosystem II (PSII) catalyzes the light-induced water oxidation leading to the generation of dioxygen indispensable for sustaining aerobic life on Earth. The PSII reaction center is composed of D1 and D2 proteins encoded by the psbA and psbD genes, respectively. In cyanobacteria, different psbA genes are present in the genome. The thermophilic cyanobacterium Thermosynechococcus elongatus contains 3 psbA genes, psbA1, psbA2 and psbA3 and a new c-type heme protein, Tll0287, was found to be expressed in a strain expressing the psbA2 gene only, but the structure and function of Tll0287 are unknown. Here we solved the crystal structure of Tll0287 at a 2.0 Å resolution. The overall structure of Tll0287 was found to be similar to some kinases and sensor proteins with a per-arnt-sim (PAS)-like domain, rather than to other c-type cytochromes. The 5th and 6th axial ligands for the heme were Cys and His, instead of the His/Met or His/His ligand pairs observed for most of the c-type hemes. The redox potential, E1/2, of Tll0287 was -255 ± 20 mV versus normal hydrogen electrode at pH values above 7.5. Below this pH value, the E1/2 increased by ≈57 mV/pH unit at 15°C, suggesting the involvement of a protonatable group with a pKred = 7.2 ± 0.3. Possible functions of Tll0287 as a redox sensor under micro-aerobic conditions or a cytochrome subunit of an H2S-oxidising system, are discussed in view of the environmental conditions in which psbA2 is expressed as well as phylogenetic analysis, structural and sequence homologies.

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Effectiveness of Graded Return to Work After Multimodal Rehabilitation in Patients with Mental Disorders: A Propensity Score Analysis

Abstract

Purpose Graded return to work (GRTW) is a strategy aimed at bringing people gradually back to coping with a full workload after an extended period of sick leave. This study aims to determine the effect of GRTW in addition to a multimodal rehabilitation on longer-term work participation in people with chronic mental disorders (CMDs). Methods Patients filled out questionnaires at the start of a multimodal rehabilitation and 15 months later. Balanced groups (GRTW, no GRTW) were formed by propensity score matching based on 27 covariates. The primary outcome measures were the return to work (RTW) status at follow-up and the number of days on sick leave during follow-up. Results From 1062 data sets (GRTW 508, no GRTW 554), 381 pairs were matched (age: 47.8 years; 78% female; 65% affective disorders, 28% neurotic or somatic disorders). At follow-up, 88% of the GRTW group had returned to work compared to only 73% of the controls (RR = 1.22, 1.13–1.31). The mean sick leave duration during the follow-up period was 7.0 weeks in the GRTW group compared to 13.4 weeks in the control group (p < 0.001). Additional explorative analyses showed that these effects were only observed in patients with an unsure or negative subjective RTW prognosis. Conclusions Based on this analysis, GRTW in addition to a multimodal rehabilitation is effective in enhancing successful work participation in people with CMDs. Earlier studies showing larger effects in people with a higher risk of a non-RTW were confirmed.

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Devolutionary genetic algorithms with application to the minimum labeling Steiner tree problem

Abstract

This paper characterizes and discusses devolutionary genetic algorithms and evaluates their performances in solving the minimum labeling Steiner tree (MLST) problem. We define devolutionary algorithms as the process of reaching a feasible solution by devolving a population of super-optimal unfeasible solutions over time. We claim that distinguishing them from the widely used evolutionary algorithms is relevant. The most important distinction lies in the fact that in the former type of processes, the value function decreases over successive generation of solutions, thus providing a natural stopping condition for the computation process. We show how classical evolutionary concepts, such as crossing, mutation and fitness can be adapted to aim at reaching an optimal or close-to-optimal solution among the first generations of feasible solutions. We additionally introduce a novel integer linear programming formulation of the MLST problem and a valid constraint used for speeding up the devolutionary process. Finally, we conduct an experiment comparing the performances of devolutionary algorithms to those of state of the art approaches used for solving randomly generated instances of the MLST problem. Results of this experiment support the use of devolutionary algorithms for the MLST problem and their development for other NP-hard combinatorial optimization problems.

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Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients

Abstract

In renal transplant recipients (RTR), we recently found that low urinary excretion of homoarginine (hArg) is associated with mortality and graft failure. However, it is not known whether such prospective associations also hold true for plasma concentrations of hArg. In the present study, we therefore determined plasma concentrations of hArg in the same cohort, i.e. in 687 RTR (functioning graft ≥1 year), and in 140 healthy donors, before and after kidney donation. Plasma hArg concentrations were significantly lower in RTR compared to healthy controls [1.24 (0.95–1.63) µM vs. 1.58 (1.31–2.03) µM, P < 0.001], and kidney donation resulted in a decrease in plasma hArg concentration to 1.41 (1.10–1.81) µM (P < 0.001). In RTR, multivariable linear regression analysis revealed BMI (β = 0.124), heart rate (β = −0.091), pre-emptive transplantation (β = 0.078), antidiabetic medication (β = −0.091), eGFR (β = 0.272), plasma PTH (β = −0.098), uric acid (β = 0.137), alkaline phosphatase (β = −0.100), HDL (β = −0.111), NT-pro-BNP (β = −0.166), and urinary urea excretion (β = 0.139) as main determinants of plasma hArg (all P < 0.05). In RTR, plasma hArg concentration was inversely associated with all-cause [hazard ratio (HR) 0.59 (95% CI 0.50–0.70), P < 0.001] and cardiovascular mortality [HR 0.50 (0.39–0.66), P < 0.001], both expressed per standard deviation change in log-transformed hArg, independent of potential confounders. To conclude, our results suggest that the kidney is a major hArg production site and an important modulator of hArg homeostasis in the renal and cardiovascular systems. Moreover, low plasma hArg is independently associated with increased risk of cardiovascular mortality in RTR, which corroborates the cardiovascular importance of preserving kidney function after transplantation.

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Autophagy and Ferroptosis—What Is the Connection?

Abstract

Purpose of Review

Autophagy is a conserved intracellular degradation system and plays a dual role in cell death, depending on context and phase. Ferroptosis is a new form of regulated cell death that mainly depends on iron accumulation and lipid peroxidation. In this review, we summarize the processes of autophagy and ferroptosis and discuss their crosstalk mechanisms at the molecular level.

Recent Findings

The original study shows that ferroptosis is morphologically, biochemically, and genetically distinct from autophagy and other types of cell death. However, recent studies demonstrate that activation of ferroptosis is indeed dependent on the induction of autophagy. Additionally, many ferroptosis regulators such as SLC7A11, GPX4, NRF2, p53, HSPB1, CISD1, FANCD2, and ACSL4 have been identified as potential regulators of autophagy.

Summary

This review not only highlights the importance of autophagy as an emerging mechanism of ferroptosis but also raises new insights regarding regulated cell death.

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Regulation of Exercise-Induced Autophagy in Skeletal Muscle

Abstract

Purpose of Review

Physical exercise is a highly effective method to prevent several pathogenic conditions, such as obesity, type 2 diabetes, and cardiovascular diseases, largely due to metabolic adaptations induced by exercise in skeletal muscle. Yet how exercise induces the beneficial effects in muscle remains to be fully elucidated. Autophagy is a lysosomal degradation pathway that regulates nutrient recycling, energy production, and organelle quality control. The autophagy pathway is upregulated in response to stress during exercise and muscle contraction, and may be an important mechanism mediating exercise-induced health benefits.

Recent Findings

A number of studies have indicated that physical exercise induces non-selective autophagy and selective mitophagy in skeletal muscle in animal models and humans. The AMPK-ULK1 and the FoxO3 signaling pathways play an essential role in the activation of the upstream autophagy machinery in skeletal muscle during exercise. The autophagy activity is required for health benefits of exercise, as in different autophagy-deficient mouse lines exercise-induced effects are abolished.

Summary

This review aims to summarize and highlight the most recent findings on the role of autophagy in muscle maintenance, the molecular pathways that upregulate autophagy during exercise, and the potential functions of exercise-induced autophagy and mitophagy in skeletal muscle.

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High-Content Assessment of Cardiac Function Using Heart-on-a-Chip Devices as Drug Screening Model

Abstract

Drug discovery and development continues to be a challenge to the pharmaceutical industry despite great advances in cell and molecular biology that allow for the design of better targeted therapeutics. Many potential drug compounds fail during the clinical trial due to inefficacy and toxicity that were not predicted during preclinical stages. The fundamental problem lies with the use of traditional drug screening models that still largely rely on the use of cell lines or animal cell monolayers, which leads to lack of predictive power of human tissue and organ response to the drug candidates. More physiologically relevant systems are therefore critical in relieving the burden of high failure rates. Emerging knowledge and techniques in tissue engineering and microfabrication have enabled the development of micro-engineered systems — collectively known as organs-on-chips — that may lead to a paradigm shift in preclinical drug screening assays. In this review we explore the technological advances and challenges in the development of heart-on-a-chip models, by addressing current assessment methods for drug-induced cardiotoxicity and providing a perspective on the modifications that should be implemented to realize the full potential of this system.

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The ‘AbdoMAN’: an artificial abdominal wall simulator for biomechanical studies on laparotomy closure techniques

Abstract

Purpose

Incisional hernia remains a frequent complication after abdominal surgery associated with significant morbidity and high costs. Animal and clinical studies have exhibited some limitations. The purpose of this study was to develop an artificial human abdominal wall (AW) simulator in order to enable investigations on closure modalities. We hypothesized that a physical model of the human AW would give new insight into commonly used suture techniques representing a substantial complement or alternative to clinical and animal studies.

Methods

The 'AbdoMAN' was developed to simulate human AW biomechanics. The 'AbdoMAN' capacities include measurement and regulation of intra-abdominal pressure (IAP), generation of IAP peaks as a result of muscle contraction and measurements of AW strain patterns analyzed with 3D image stereo correlation software. Intact synthetic samples were used to test repeatability. A laparotomy closure was then performed on five samples to analyze strain patterns.

Results

The 'AbdoMAN' was capable of simulating physiological conditions. AbdoMAN lateral muscles contract at 660 N, leading the IAP to increase up to 74.9 mmHg (range 65.3–88.3). Two strain criteria were used to assess test repeatability. A test with laparotomy closure demonstrated closure testing repeatability.

Conclusions

The 'AbdoMAN' reveals as a promising enabling tool for investigating AW surgery-related biomechanics and could become an alternative to animal and clinical studies. 3D image correlation analysis should bring new insights on laparotomy closure research. The next step will consist in evaluating different closure modalities on synthetic, porcine and human AW.

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Microcavity Laser Based on a Single Molecule Thick High Gain Layer

ACS Nano

DOI: 10.1021/acsnano.6b08092

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The influence of pump rotation speed on hemodynamics and myocardial oxygen metabolism in left ventricular assist device support with aortic valve regurgitation

Abstract

Aortic valve regurgitation (AR) is a serious complication under left ventricular assist device (LVAD) support. AR causes LVAD-left ventricular (LV) recirculation, which makes it difficult to continue LVAD support. However, the hemodynamics and myocardial oxygen metabolism of LVAD support with AR have not been clarified, especially, how pump rotation speed influences them. An animal model of LVAD with AR was newly developed, and how pump rotation speed influences hemodynamics and myocardial oxygen metabolism was examined in acute animal experiments. Five goats (55 ± 9.3 kg) underwent centrifugal type LVAD, EVAHEART implantation. The AR model was established by placing a vena cava filter in the aortic valve. Hemodynamic values and the myocardial oxygen consumption, delivery, and oxygen extraction ratio (O₂ER) were evaluated with changing pump rotation speeds with or without AR (AR+, AR−). AR+ was defined as Sellers classification 3 or greater. AR was successfully induced in five goats. Diastolic aortic pressure was significantly lower in AR+ than AR− (p = 0.026). Central venous pressure, mean left atrial pressure, and diastolic left ventricular pressure were significantly higher in AR+ than AR− (p = 0.010, 0.047, and 0.0083, respectively). Although systemic flow did not improve with increasing pump rotation speed, LVAD pump flow increased over systemic flow in AR+, which meant increasing pump rotation speed increased LVAD-LV recirculation and did not contribute to effective systemic circulation. O₂ER in AR− decreased with increasing pump rotation speed, but O₂ER in AR+ was hard to decrease. The O₂ER in AR+ correlated positively with the flow rate of LVAD-LV recirculation (p = 0.012). AR caused LVAD-LV recirculation that interfered with the cardiac assistance of LVAD support and made it ineffective to manage with high pump rotation speed.

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