Micronuclei in Exfoliated Oral Epithelial Cells in Tobacco Users and Controls with Various Oral Lesions: A Study from Gujarat, India

Abstract

To assess and compare cytogenic damage in the form of micronuclei in various oral lesions according to duration and frequency of tobacco use. The present cross sectional study was carried out from October 2015 to October 2016. We included total 420 cases with 60 cases in each of the following subgroups, no tobacco habit with no obvious oral lesion (control) and tobacco habit with no obvious oral lesion, oral sub mucous fibrosis, leukoplakia, melanoplakia, erythroplakia, oral squamous cell carcinoma. Oral mucosal cells were collected from both sides of cheek; slides were prepared and examined for cells with micronuclei. The mean micronuclei index distribution in control group, potentially malignant group, and malignancy group was 1.14, 2.63, and 4.88 respectively and was statistically significant. The mean micronuclei index in control group, smoking tobacco and smokeless tobacco group was 1.14, 2.64, and 2.76 and was statistically significant. The mean micronuclei index was significantly higher in those using tobacco, for longer duration and with frequent tobacco use. The mean micronuclei index can be used as a potential screening tool of genotoxic damage and biomarker for epithelial carcinogenesis. The method has practical utility for warning tobacco users that higher than range has a danger of malignant event and therefore this in future can be used as reinforcement to advice of avoiding tobacco before malignancy develops.

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Auditory Lateralization Training Effects on Binaural Interaction Component of Middle Latency Response in Children Suspected to Central Auditory Processing Disorder

Abstract

Many children with central auditory processing disorder (C)APD suffer from spatial processing disorder and benefit from binaural processing training including auditory lateralization training. There are subjective tests for evaluating auditory training effects in children with (C)APD but they rely on patient's attention and cooperation so there is a need for appropriate objective tests. The aim of present study was investigating effects of auditory lateralization training on binaural interaction component (BIC) of middle latency response (MLR). This study was an analytical interventional study. Sixty children suspected to (C)APD (40 boys and 20 girls) were selected based on inclusion criteria and were divided into two groups: control and training group. Auditory lateralization training included 12 formal sessions under headphone by using interaural time difference and performed as a game. MLR (monaural right ear, monaural left ear and binaural) and monaural selective auditory attention test (mSAAT) tests were performed in all the cases. BIC was calculated by subtracting binaural response from summed monaural responses. Covariance test showed that BIC latency decreased and BIC amplitude increased significantly and mSAAT score increased significantly in training group after auditory lateralization training (p value ≤ 0.001). In present study BIC of MLR had potential to show underlying neurophysiologic changes after auditory lateralization training in children suspected to (C)APD objectively. It is in agreement with behavioral improvements after training (mSAAT improvements).

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DNA methylation profiling in nonfunctioning pituitary adenomas

Publication date: Available online 1 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Paulina Kober, Joanna Zbijewska, Nataliia Rusetska, Maria Maksymowicz, Krzysztof Goryca, Jacek Kunicki, Wiesław Bonicki, Janusz Aleksander Siedlecki, Mateusz Bujko
Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood.We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients.NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors.



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DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes

Publication date: Available online 1 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Marco Bugliani, Farooq Syed, Flavia M.M. Paula, Bilal A. Omar, Mara Suleiman, Sandra Mossuto, Francesca Grano, Francesco Cardarelli, Ugo Boggi, Fabio Vistoli, Franco Filipponi, Paolo De Simone, Lorella Marselli, Vincenzo De Tata, Bo Ahren, Decio L. Eizirik, Piero Marchetti
It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival.Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions.DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-βH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-βH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells.These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival.



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Use of the REVERT® total protein stain as a loading control demonstrates significant benefits over the use of housekeeping proteins when analyzing brain homogenates by Western blot: An analysis of samples representing different gonadal hormone states

Publication date: Available online 1 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Z.Z. Kirshner, R.B. Gibbs
Western blot is routinely used to quantify differences in the levels of target proteins in tissues. Standard methods typically use measurements of housekeeping proteins to control for variations in loading and protein transfer. This is problematic, however, when housekeeping proteins also are affected by experimental conditions such as injury, disease, and/or gonadal hormone manipulations. Our goal was to evaluate an alternative and perhaps superior method for conducting Western blot analysis of brain tissue homogenates from rats with distinct physiologically relevant gonadal hormone states. Tissues were collected from the hippocampus, frontal cortex, and striatum of young adult female rats that either were ovariectomized to model surgical menopause, or were treated with the ovatotoxin 4-vinylcyclohexene diepoxide (VCD) to model transitional menopause. Tissues also were collected from rats with a normal estrous cycle killed at proestrus when estradiol levels are high, and at diestrus when estradiol levels are low. Western blot detection of α-tubulin, β-actin, and GAPDH was performed and were compared for sensitivity and reliability with a fluorescent total protein stain (REVERT^®). Results show that the total protein stain was much less variable across samples and had a greater linear range than α-tubulin, β-actin, or GAPDH. The stain was stable and easy to use, and did not interfere with the immunodetection or multiplexed detection of the housekeeping proteins. In addition, we show that normalization of our data to total protein, but not to GAPDH, revealed significant differences in α-tubulin expression in the hippocampus as a function of treatment, and that gel-to-gel consistency in measuring differences between paired samples run on multiple gels was significantly better when data were normalized to total protein than when normalized to GAPDH. These results demonstrate that the REVERT^® total protein stain can be used in Western blot analysis of brain tissue homogenates to control for variations in loading and protein transfer, and provides significant advantages over the use of housekeeping proteins for quantifying changes in the levels of multiple target proteins.



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Increased mitochondrial turnover in the skeletal muscle of fasted, castrated mice is related to the magnitude of autophagy activation and muscle atrophy

Publication date: Available online 1 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Michael L. Rossetti, Jennifer L. Steiner, Bradley S. Gordon
Androgen-deficiency promotes muscle atrophy in part by increasing autophagy-mediated muscle protein breakdown during the fasted state, but factors contributing to this remain undefined. To identify novel factors, mice were subjected to sham or castration surgery. Seven-weeks post-surgery, mice were fasted overnight, refed for 30 min, and fasted another 4.5 h before sacrifice. BNIP3-mediated turnover of mitochondria was increased within the atrophied tibialis anterior (TA) of castrated mice and related to the magnitude of muscle atrophy and autophagy activation (i.e. decreased p62 protein content), thus linking turnover of potentially dysfunctional mitochondria with autophagy-mediated atrophy. Autophagy induction was likely facilitated by AMPK activation as a stress survival mechanism since phosphorylation of AMPK (Thr172), as well as the pro survival kinases Akt (Thr308) and (ERK1/2 Thr202/Tyr204), were increased by castration. Together, these data identify a novel relationship between mitochondrial turnover in the fasted state with autophagy activation and muscle atrophy following androgen depletion.



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A novel tubulin inhibitor STK899704 induces tumor regression in DMBA/TPA induced skin carcinogenesis model

Abstract

Skin cancer is the most common type of cancer. The incidence rate of skin cancer has continuously increased over the past decades. In an effort to discover novel anticancer agents, we identified a novel tubulin inhibitor STK899704 which is structurally distinct from other microtubule-binding agents such as colchicine, vinca alkaloids, and taxanes. STK899704 inhibited microtubule polymerization leading to mitotic arrest, and suppressed the proliferation of various cancer cell lines as well as multidrug-resistance cancer cell lines. In this study, our investigation is further extended into animal model to evaluate the effect of STK899704 on skin carcinogenesis in vivo. Surprisingly, almost 80% of the tumors treated with STK899704 were regressed with a one fifth reduction in tumor volume. Furthermore, the efficacy of STK899704 was nearly two times higher than that of 5-fluorouracil, a widely used skin cancer therapeutic. Overall, our results suggest that STK899704 is a promising anticancer chemotherapeutic that may replace existing therapies, particularly for skin cancer.

This article is protected by copyright. All rights reserved.

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Eicosapentaenoic acid ethyl ester ameliorates atopic dermatitis-like symptoms in special diet-fed hairless mice, partly by restoring covalently bound ceramides in the stratum corneum

Abstract

Skin barrier dysfunction has a key role in the development of atopic dermatitis (AD). Covalently bound ceramides (Cer), which are essential lipids for permeability barrier homeostasis, are reportedly decreased in the stratum corneum (SC) of AD patients. Hairless mice fed a special diet develop pruritic dermatitis resembling human AD. Our previous study found that oral administration of the n-3 polyunsaturated fatty acid α-linolenic acid ameliorated skin barrier dysfunction in AD mice with concomitant increase in serum eicosapentaenoic acid (EPA). In this study, we examined the effects of EPA ethyl ester (EPA-E) on diet-induced AD in hairless mice. Oral administration of EPA-E ameliorated skin barrier dysfunction and pruritus in AD mice. In the SC of AD mice, covalently bound Cer were markedly diminished. EPA-E administration restored the lack of bound Cer. Our findings imply the possible therapeutic clinical application of EPA-E in the treatment of human AD.

This article is protected by copyright. All rights reserved.

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An efficient method for eccrine gland isolation from human scalp

Abstract

We describe a simple and efficient method to isolate eccrine sweat glands from the human scalp. This method is inspired by the hair graft harvesting method used in hair transplantation. Based on the recently described anatomical relationship between the scalp hair follicle and the eccrine gland, we have found that scalp follicular unit grafts are an excellent eccrine gland isolation source, especially for the coiled component. In order to make the gland visible for stereoscopic microdissection, the follicular units need to be previously stained with a vital dye like Methylene Blue or Neutral Red. The simplicity and efficiency of this isolation method should encourage further research into human eccrine sweat gland function which has always been hindered by the difficulty of gland isolation.

This article is protected by copyright. All rights reserved.

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Leiomyoma of the soft palate: Case report and review of articles

Publication date: Available online 1 February 2018
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Fahd Alharbi
Leiomyomas are benign tumors arising from smooth muscle, most commonly seen in uterine myometrium, gastrointestinal tract, skin and lower extremities of middle-aged women. Leiomyomas are uncommon in the oral cavity and leiomyomas of head and neck region account for less than 1% of all leiomyomas. The purpose of this article is to present a case of 18 years old male patient with a history of several months of oral leiomyoma on the right side of the soft palate. The clinical features, differential diagnosis and management of leiomyoma are discussed with review of the literatures.



http://ift.tt/2nr7kHG

Leiomyoma of the soft palate: Case report and review of articles

Publication date: Available online 1 February 2018
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Fahd Alharbi
Leiomyomas are benign tumors arising from smooth muscle, most commonly seen in uterine myometrium, gastrointestinal tract, skin and lower extremities of middle-aged women. Leiomyomas are uncommon in the oral cavity and leiomyomas of head and neck region account for less than 1% of all leiomyomas. The purpose of this article is to present a case of 18 years old male patient with a history of several months of oral leiomyoma on the right side of the soft palate. The clinical features, differential diagnosis and management of leiomyoma are discussed with review of the literatures.



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A rotation flap does not rotate

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Does dietary fluid intake affect skin hydration in healthy humans? A systematic literature review

Abstract

Background

Associations between daily amounts of drinking water and skin hydration and skin physiology receive increasingly attention in the daily life and in clinical practice. However, there is a lack of evidence of dermatological benefits from drinking increased amounts of water.

Materials and methods

Pubmed and Web of Science were searched without any restrictions of publication dates. References of included papers and related reviews were checked. Eligibility criteria were primary intervention and observational studies investigating the effects of fluid intake on skin properties in English, German, Spanish or Portuguese language, including subjects being healthy and 18+ years.

Results

Searches resulted in 216 records, 23 articles were read in full text, and six were included. The mean age of the samples ranged from 24 to 56 years. Overall the evidence is weak in terms of quantity and methodological quality. Disregarding the methodological limitations a slight increase in stratum corneum and "deep" skin hydration was observed after additional water intake, particularly in individuals with lower prior water consumption. Reductions of clinical signs of dryness and roughness were observed. The extensibility and elasticity of the skin increased slightly. Unclear associations were shown between water intake and transepidermal water loss, sebum content, and skin surface pH.

Conclusions

Additional dietary water intake may increase stratum corneum hydration. The underlying biological mechanism for this possible relationship is unknown. Whether this association also exists in aged subjects is unclear. Research is needed to answer the question whether increased fluid intake decreases signs of dry skin.

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Issue Information

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Issue Information

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Alterations of the Gut Microbiota in Hashimoto's Thyroiditis Patients

Thyroid , Vol. 0, No. 0.


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Issue Information - TOC

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Issue Information - Cover

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Editorial echoes

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The Vitamin D3 analogue calcipotriol suppresses CpG-activated TLR9-MyD88 signalling in murine plasmacytoid dendritic cells

Summary

Background

Plasmacytoid dendritic cells (pDCs) are involved in the pathogenesis of psoriasis by secreting interferon-α. Vitamin D3 analogues are widely used to treat psoriasis, and the representative analogue calcipotriol (CAL) uniquely downregulates the cytokine production and chemotactic activity of pDCs. However, the molecular mechanism of action of CAL is not well understood.

Aim

To investigate effects of CAL on the Toll-like receptor 9–myeloid differentiation primary response gene 88 (TLR9-MyD88) signalling pathway, which induces cytokine production, in murine pDCs.

Methods

pDCs were isolated from mouse spleen cells by negative selection or were generated from mouse bone-marrow cells, and were stimulated with CpG-oligodeoxynucleotide (ODN) with or without CAL for 24 h. mRNA expression of TLR9 and MyD88 was assessed by real-time PCR, and the amount of TLR9 was measured by western blotting.

Results

CAL suppressed the CpG-ODN-induced increased expression of MyD88 and TLR9 in pDCs.

Conclusions

CAL may downregulate pDCs by inhibiting TLR9-MyD88 signalling.

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Issue Information - TOC

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Issue Information - Cover

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Editorial echoes

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Comparison of the effectiveness of pulsed dye laser vs pulsed dye laser combined with ultrapulse fractional CO2 laser in the treatment of immature red hypertrophic scars

Summary

Introduction

The objective was to investigate the clinical effect of an adjustable pulse width Pulsed Dye Laser (PDL) vs an adjustable pulse width PDL combined with fractional CO₂ laser in treating immature red hypertrophic scars.

Methods

Fifty-six patients (56 sites)were randomly divided into a treatment group and control group. The control group was treated with the 595 nm PDL at a fluence of 7-15J/cm² and pulse widths of 1.5-3 ms, 7 mm spot size. The treatment group was treated with a fractional CO₂ laser (UltraPulse CO₂: Deep FX, Energy: 30~50 mJ, Frequency: 300 Hz, Density 5%, Scan Shape, and Spot Size were decided by shape and area of scar) after utilizing the 595 nm adjustable pulse width PDL (Fluence: 7-15J/cm², Pulse widths: 1.5-3 ms, Spot size: 7 mm). MEBT/MEBO, previously described as a post-treatment wound ointment, was used after laser treatment. The scars of the treatment group and the control group were evaluated for changes in pigment, height, vascularity, and pliability using the Vancouver Scar Scale (VSS) after two laser treatments.

Results

The total VSS score, as well as the score for melanin, height, vascularity, pliability in both groups, showed an obvious decrease following the treatments. There were statistically significant differences between before treatment and after treatment (P < .05); however, the total score of the VSS, and score of the melanin, height, vascularity, and pliability in the control group decreased more than that of treatment group, and there was a statistically significant difference (P < .05).

Conclusions

The 595 nm adjustable pulse width PDL combined with the fractional CO₂ fractional laser appears to have a beneficial clinical effect on fresh red hypertrophic scars, with no severe adverse reactions seen.

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Tracing Stem Cell Division in Adult Neurogenesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Nina S. Corsini, Juergen A. Knoblich
Neural stem cells in the ventricular-subventricular zone of the adult brain continuously generate differentiated neurons without depleting the stem cell pool. In this issue of Cell Stem Cell, Obernier et al. (2018) present the surprising finding that this occurs through mostly symmetric divisions that either generate two differentiating or two self-renewing daughter cells.

Teaser

Neural stem cells in the ventricular-subventricular zone of the adult brain continuously generate differentiated neurons without depleting the stem cell pool. In this issue of Cell Stem Cell, Obernier et al. (2018) present the surprising finding that this occurs through mostly symmetric divisions that either generate two differentiating or two self-renewing daughter cells.


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Slow Your Roll: Inhibiting SETD7 Activity Permits Ex Vivo Expansion of Muscle Stem Cells

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Ryo Fujita, Colin Crist
Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell, Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.

Teaser

Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell, Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.


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Shaping the Pluripotent Genome: Switches, Borders, and Loops

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Effie Apostolou
Three-dimensional genome organization is largely cell type specific and requires reorganization during cell fate transitions. A recent study in Nature Genetics (Stadhouders et al., 2018) offers important insights into the principles and drivers of such reorganization during reprogramming of somatic cells into pluripotent stem cells.

Teaser

Three-dimensional genome organization is largely cell type specific and requires reorganization during cell fate transitions. A recent study in Nature Genetics (Stadhouders et al., 2018) offers important insights into the principles and drivers of such reorganization during reprogramming of somatic cells into pluripotent stem cells.


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Mentoring the Next Generation: Irving Weissman

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Irving Weissman about his views.



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Meddling with METTLs in Normal and Leukemia Stem Cells

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Gaëlle H. Martin, Christopher Y. Park
Three recent studies independently identified the m⁶A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer.

Teaser

Three recent studies independently identified the m⁶A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer.


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Japan Strengthens Regenerative Medicine Oversight

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Douglas Sipp, Hideyuki Okano
The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy.

Teaser

The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy.


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Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Bo Wang, Xin Rong, Elisa N.D. Palladino, Jiafang Wang, Alan M. Fogelman, Martín G. Martín, Waddah A. Alrefai, David A. Ford, Peter Tontonoz
Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo. Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apc^min mice. These findings identify a critical dietary-responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis.

Graphical abstract

Teaser

Tontonoz and colleagues show that the phospholipid remodeling enzyme Lpcat3 regulates intestinal stem cells and progenitor cells by stimulating cholesterol biosynthesis. Furthermore, enhancing cholesterol availability, either by providing it in the diet or through genetic manipulation, promotes tumorigenesis in Apc^min/+ mice.


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Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Kirsten Obernier, Arantxa Cebrian-Silla, Matthew Thomson, José Ignacio Parraguez, Rio Anderson, Cristina Guinto, José Rodas Rodriguez, José-Manuel Garcia-Verdugo, Arturo Alvarez-Buylla
Somatic stem cells have been identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthood for lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vast majority of B1 cells divide symmetrically. Whereas 20%–30% symmetrically self-renew and can remain in the niche for several months before generating neurons, 70%–80% undergo consuming divisions generating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouples self-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consuming symmetric differentiation divisions can explain the levels of neurogenesis observed throughout life.

Graphical abstract

Teaser

Obernier et al. show that juvenile/adult neural stem cells (NSCs) generate progeny or self-renew through symmetric divisions. The prevailing consuming symmetric divisions progressively deplete NSCs, yet this mechanism enables lifelong generation of large numbers of neurons for the olfactory bulb while decoupling proliferation from differentiation.


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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Publication date: 1 February 2018
Source:Cell Stem Cell, Volume 22, Issue 2
Author(s): Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine




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Models including plasma levels of sphingomyelins and phosphatidylcholines as diagnostic and prognostic biomarkers of endometrial cancer

Publication date: Available online 31 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Tamara Knific, Katja Vouk, Špela Smrkolj, Cornelia Prehn, Jerzy Adamski, Tea Lanišnik Rižner
In endometrial cancer, biomarkers for preoperative identification of patients with low risk for disease progression would enable stratification according to the extent of surgery needed, and would avoid the complications that can be associated with radical surgery. A panel of proteins, amino acids, enzymes, and miRNA has been investigated as potential biomarkers for endometrial cancer. At the time of the manuscript submission targeted metabolomics/lipidomics approaches have not been applied to biomarker research in endometrial cancer. Using electrospray ionization–tandem mass spectrometry we quantified 163 metabolites in 126 plasma samples (61 patients with endometrial cancer, 65 control patients). Three single phosphatidylcholines were identified with significantly decreased levels in patients with endometrial cancer. A diagnostic model was defined as the ratio between acylcarnitine C16 and phosphatidylcholine PCae C40:1, the ratio between proline and tyrosine, and the ratio between the two phosphatidylcholines PCaa C42:0 and PCae C44:5; which provided sensitivity of 85.25%, specificity of 69.23%, and AUC of 0.837. Addition of smoking status further improved the constructed diagnostic model (AUC = 0.855). The presence of the major prognostic factors of deep myometrial invasion and lymphovascular invasion were also associated with altered metabolite concentrations. A prognostic model for deep myometrial invasion included the ratio between two hydroxysphingomyelins SMOH C14:1 and SMOH C24:1, and the ratio between two phosphatidylcholines PCaa C40:2 and PCaa C42:6, which provided sensitivity of 81.25%, specificity of 86.36%, and AUC of 0.857. The model for lymphovascular invasion included the ratio between two phosphatidylcholines PCaa C34:4 and PCae C38:3, and the ratio between acylcarnitine C16:2 and phosphatidylcholine PCaa C38:1, which provided sensitivity of 88.89%, specificity of 84.31%, and AUC of 0.935.

Graphical abstract

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Membrane progesterone receptors β and γ have potential as prognostic biomarkers of endometrial cancer

Publication date: Available online 17 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Maša Sinreih, Tamara Knific, Peter Thomas, Snježana Frković Grazio, Tea Lanišnik Rižner
Endometrial cancer (EC) is one of the most common malignancies in women worldwide. EC is linked to chronic exposure to estrogens that is unopposed by protective effects of progesterone. Progesterone modulates gene expression via classical nuclear receptors, and has rapid effects via the less characterized membrane-bound progesterone receptors (mPRs) of the progestin and adipoQ receptor (PAQR) family. The presence of mPRs in EC has not been investigated to date. The aims of this study were to examine PAQR7, PAQR8 and PAQR5, which encode for mPRα, mPRβ and mPRγ, respectively, for their expression and localization in EC tissue and adjacent control endometrium. Our results reveal decreased expression of PAQR7 and PAQR8, and unaltered expression of PAQR5 in EC versus control tissue. Expression of PAQR5 was decreased in EC with higher FIGO stage versus stage IA. Immunohistochemistry revealed lower levels of mPRα and mPRβ, but higher levels of mPRγ, in EC versus control tissue. There was greater decrease in mPRβ levels in tumors with lymphovascular invasion. The analysis of the expression data associates higher PAQR5 mRNA and mPRβ protein levels with favorable patient prognosis. Immunohistochemistry showed diverse localizations of mPRs in control and cancer endometrium. In control endometrium, mPRα and mPRβ were localized mostly at the cell membranes, while mPRγ was localized in the cytoplasm and/or nucleus. In cancer endometrium, mPRα and mPRβ were detected at the cell membrane or in the cytoplasm, or both, while mPRγ was only localized in the cytoplasm. Taken together, these results imply that mPRs are involved in EC pathogenesis through effects on the development or progression of cancer. The potential role of mPRβ and mPRγ as prognostic biomarkers needs to be further assessed on a larger number of samples.

Graphical abstract

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Periodontal diseases and adverse pregnancy outcomes: Is there a role for vitamin D?

Publication date: Available online 16 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Anne Marie Uwitonze, Peace Uwambaye, Moses Isyagi, Chrispinus H. Mumena, Alice Hudder, Afrozul Haq, Kamrun Nessa, Mohammed S. Razzaque
Studies have shown a relationship between maternal periodontal diseases (PDs) and premature delivery. PDs are commonly encountered oral diseases which cause progressive damage to the periodontal ligament and alveolar bones, leading to loss of teeth and oral disabilities. PDs also adversely affect general health by worsening of cardiovascular and metabolic diseases. Moreover, maternal PDs are thought to be related to increasing the frequency of preterm-birth with low birth weight (PBLBW) in new-borns. Prematurity and immaturity are the leading causes of prenatal and infant mortality and is a major public health problem around the world. Inflamed periodontal tissues generate significantly high levels of proinflammatory cytokines that may have systemic effects on the host mother and the fetus. In addition, the bacteria that cause PDs produce endotoxins which can harm the fetus. Furthermore, studies have shown that microorganisms causing PDs can get access to the bloodstream, invading uterine tissues, to induce PBLBW. Another likely mechanism that connects PDs with adverse pregnancy outcome is maternal vitamin D status. A role of inadequate vitamin D status in the genesis of PDs has been reported. Administration of vitamin D supplementation during pregnancy could reduce the risk of maternal infections and adverse pregnancy outcomes. As maternal PDs are significant risk factors for adverse pregnancy outcome, preventive antenatal care for pregnant women in collaboration with the obstetric and dental professions are required.



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Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells—A study in PCOS patients

Publication date: Available online 12 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Muskaan Belani, Abhilash Deo, Preeti Shah, Manish Banker, Pawan Singal, Sarita Gupta
Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%–80% of obese PCOS and 20%–25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS.

Graphical abstract

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Progesterone arrested cell cycle progression through progesterone receptor isoform A in pancreatic neuroendocrine neoplasm

Publication date: Available online 11 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Samaneh Yazdani, Atsuko Kasajima, Yoshiaki Onodera, Keely May McNamara, Kazue Ise, Yasuhiro Nakamura, Tomoyoshi Tachibana, Fuyuhiko Motoi, Michiaki Unno, Hironobu Sasano
In pancreatic neuroendocrine neoplasms (Pan-NEN) progesterone signaling has been shown to have both inhibitory and stimulatory effects on cell proliferation. The ability of progesterone to inhibit tumor proliferation is of particular interest and is suggested to be mediated through the less abundantly expressed progesterone receptor (PR) isoform A (PRA). To date the mechanistic processes underlying this inhibition of proliferation remain unclear. To examine the mechanism of PRA actions, the human Pan-NEN cell line QGP-1, that endogenously expresses PR isoform B (PRB) without PRA, was transfected with PRA. PRA transfection suppressed the majority of cell cycle related genes increased by progesterone including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2). Importantly, following progesterone administration cell cycle distribution was shifted to S and G2/M phases in the naïve cell line but in PRA-transfected cells, this effect was suppressed. To see if these mechanistic insights were confirmed in patient samples PRA, PRB, CCNA2, CCNB, CDK1 and CDK2 immunoreactivities were assessed in Pan-NEN cases. Higher levels of cell cycle markers were associated with higher WHO grade tumors and correlations between the markers suggested formation of cyclin/CDK activated complexes in S and G2/M phases. PRA expression was associated with inverse correlation of all cell cycle markers. Collectively, these results indicate that progesterone signals through PRA negatively regulates cell cycle progression through suppressing S and G2/M phases and downregulation of cell cycle phases specific cyclins/CDKs.



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Vitamin D attenuates pressure overload-induced cardiac remodeling and dysfunction in mice

Publication date: Available online 11 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Liang Zhang, Xiao Yan, Yun-Long Zhang, Jie Bai, Tesfaldet Habtemariam Hidru, Qing-Shan Wang, Hui-Hua Li
Vitamin D (VD) and its analogues play critical roles in metabolic and cardiovascular diseases. Recent studies have demonstrated that VD exerts a protective role in cardiovascular diseases. However, the beneficial effect of VD on pressure overload-induced cardiac remodeling and dysfunction and its underlying mechanisms are not fully elucidated. In this study, cardiac dysfunction and hypertrophic remodeling in mice were induced by pressure overload. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by H&E and Masson's trichrome staining. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein levels of signaling mediators were examined by western blotting while mRNA expression of hypertrophic and fibrotic markers was examined by qPCR analysis. Oxidative stress was detected by dihydroethidine staining. Our results showed that administration of VD3 significantly ameliorates pressure overload-induced contractile dysfunction, cardiac hypertrophy, fibrosis and inflammation in mice. In addition, VD3 treatment also markedly inhibited cardiac oxidative stress and apoptosis. Moreover, protein levels of calcineurin A, ERK1/2, AKT, TGF-β, GRP78, cATF6, and CHOP were significantly reduced whereas SERCA2 level was upregulated in the VD3-treated hearts compared with control. These results suggest that VD3 attenuates cardiac remodeling and dysfunction induced by pressure overload, and this protective effect is associated with inhibition of multiple signaling pathways.



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Selective estrogen receptor modulator ormeloxifene suppresses embryo implantation via inducing miR-140 and targeting insulin-like growth factor 1 receptor in rat uterus

Publication date: Available online 10 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Vijay Kumar Sirohi, Kanchan Gupta, Rohit Kumar, Vinay Shukla, Anila Dwivedi
Ormeloxifene, the non-steroidal SERM contraceptive, inhibits endometrial receptivity and embryo implantation via countering nidatory estrogen. However, the molecular mechanism of ormeloxifene action responsible for its contraceptive efficacy still remains unclear. Herein, we aimed to identify the miRNAs modulated under the influence of ormeloxifene and to explore their role in endometrial receptivity and embryo implantation. By doing microRNA sequencing analysis, a total of 168 miRNAs were found to be differentially expressed in uterine tissue of ormeloxifene-treated rats, on day 5 (10:00 h) of pregnancy i.e. peri-implantation period. Out of differentially expressed miRNAs, miR-140 expression was found to be elevated in ormeloxifene administered groups and was selected for detailed investigation. In-vivo gain-of-function of miR-140 resulted in a significant reduction of implantation sites indicating its role in embryo implantation. The experiment on delayed implantation showed that estradiol caused down-regulation of miR-140. It also suppressed the attachment and outgrowth of BeWo spheroids to RL95-2 endometrial cells. In transwell migration assay, miR-140 was found to be involved in suppression of migration and invasion of endometrial epithelial cells. The ormeloxifene treatment caused up-regulation of miR-140 along with down-regulated expression of its target IGF1R in endometrial epithelial and stromal cells which also led to the suppression of downstream effectors integrin β3 and FAK. In mimic miR-140 receiving horn, the reduced expression of IGF1R was observed along with suppressed downstream integrin β3 and FAK similar to that observed in uteri of ormeloxifene- treated rats. Taken together, these findings suggest that ormeloxifene-induced inhibition of embryo implantation occurs via inducing miR-140 and altering its target IGF1R in rat uterus.

Graphical abstract

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Effect of vitamin D supplementation on serum sclerostin levels in chronic kidney disease

Publication date: Available online 10 January 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Ashok Kumar Yadav, Vivek Kumar, Debasish Banerjee, Krishan Lal Gupta, Vivekanand Jha
Vitamin D deficiency, cardiovascular disease and abnormal bone mineral metabolism are common in chronic kidney disease (CKD). Abnormal bone mineral metabolism has been linked to vascular calcification in CKD. Sclerostin has emerged as an important messenger in cross talk between bone-vascular axis. We analyzed sclerostin in subjects who participated in the randomized, double blind, placebo controlled trial investigating the effect of cholecalciferol supplementation on vascular function in non­diabetic CKD stage G3-4 and vitamin D ≤ 20 ng/ml [CTRI/2013/05/003648]. Patients were randomized (1:1) to receive either two directly observed oral doses of 300,000 IU of cholecalciferol or matching placebo at baseline and 8 weeks. Of the 120 subjects enrolled, 58 in the cholecalciferol group and 59 in the placebo group completed the study. At baseline, serum levels of sclerostin were similar in both groups (cholecalciferol - median;190pg/ml, IQR;140–260 pg/ml and placebo - median;180 pg/ml, IQR; 140–240 pg/ml, p = 0.67). 16 weeks after cholecalciferol supplementation, there was no change in level of sclerostin (mean change;1.10 pg/ml, 95%CI; −27.34 to 29.34 pg/ml, p = 0.25). However, a significant decrease in sclerostin level was noted in the placebo group (mean change; −31.94 pg/ml, 95%CI; −54.76 to −9.13 pg/ml, p = 0.002). Change (Δ) in sclerostin level at 16 weeks correlated negatively with Δ eGFR (r = −0.20, p = 0.03) and positively with Δuric acid (r = 0.37, p < 0.001) but not with Δ25(OH) D (r = 0.06, p = 0.54), Δ iPTH (r = − 0.03, p = 0.78) ΔFGF23 (r = − 0.08, p = 0.38) and Δ125 (OH)2 D (r = − 0.04, p = 0.65). In conclusion, high dose cholecalciferol supplementation did not change sclerostin levels in non-diabetic stage 3–4 CKD subjects.



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Development of a multivariate model of the six-minute walked distance to predict functional exercise capacity in hypertension

Publication date: Available online 31 January 2018
Source:Journal of Bodywork and Movement Therapies
Author(s): Rodrigo de Assis Ramos, Fernando Silva Guimarães, Yannis Dionyssiotis, Dorothea Tsekoura, Jannis Papathanasiou, Arthur de Sá Ferreira
BackgroundHypertension is associated with deterioration of musculoskeletal function and functional capacity. Existing prediction models for assessment of the 6-min walk test (6MWT) do not capture the disease-related functional capacity. This study developed a multivariate prediction model of the measured 6-min walked distance (6MWDM) in hypertension and proposed target-values based on optimal therapeutic aims.MethodsSeventy-six patients (38 men, 56.1 ± 14.3 years, systolic pressure 156.7 ± 17.5 mmHg, diastolic pressure 92.9 ± 6.9 mmHg) underwent anamnesis, physical examination, and laboratory analysis. Functional capacity was assessed using the 6MWT, being the 6MWDM considered as the dependent variable. Independent variables included sex (S, coded 'male' = 1, 'female' = 0), age (A), body height (H), body mass, mean blood pressure (MBP), and physical activity (IPAQ, coded 1–5). Target-values were derived from theoretical scenarios of optimal blood pressure and physical activity, separately and combined.ResultsPatients walked 324.5 ± 10.1 m in the average of two trials 30-min apart. Pearson's correlation coefficient showed moderate-to-weak significant associations between 6MWDM and all independent variables. The final multivariate model was 6MWDP = 611.347–4.446 × MBP + 267.630 × H – 1.511 × A + IPAQcode + Scode (adjusted R² = 0.680, SE of bias = 6.3 m), suggesting that clinical, anthropometric, and hemodynamic information determines functional capacity. Predicted values yielded a group-average of 325 ± 87 m. Target-values under the optimal scenario resulted in 420 ± 60 m.ConclusionsSex (men), higher body height, higher physical activity, lower mean blood pressure, and lower age are independently correlated with higher 6MWDM in patients with hypertension. Target-values can be estimated for therapeutic aims related to hemodynamics and lifestyle.



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A descriptive analysis of shoulder muscle activities during individual stages of the Turkish Get-Up exercise

Publication date: Available online 31 January 2018
Source:Journal of Bodywork and Movement Therapies
Author(s): Eric St-Onge, Andrew Robb, Tyson A.C. Beach, Samuel J. Howarth
The Turkish Get-Up (TGU) is a complex and multi-planar exercise; the performer begins in a supine lying position, progresses toward upright standing through a series of 7 stages while holding a mass overhead in one hand, and returns to the original supine lying position through a reversal of the same 7 stages. A descriptive analysis of shoulder muscle activity during the TGU may provide insight toward its use in training and rehabilitation contexts. Our objectives were to: (1) describe the activity patterns from a subset of muscles that span the glenohumeral joint during individual stages of the TGU, and (2) interpret these patterns through comparisons between left- and right-side muscles, and between the up and down phases of the TGU. Twelve individuals with at least one-year experience performing the TGU were included in this study. Surface electromyographic (EMG) recordings were bilaterally obtained from 8 glenohumeral muscle groups while participants performed ten trials of the TGU with a kettlebell in their right hand. Instants representing the start and end of each TGU stage were identified from a synchronized video for each trial, and EMG activities for each muscle were integrated over the duration of each stage. Average integrated EMG and within-participant coefficients of variation were calculated. Overall, the greatest muscular demand occurred during the second (press to elbow support) and fifth (leg sweep) stages. Activities from muscles on the ipsilateral side to the kettlebell (right-side) were greater during stages when the contralateral upper limb did not contribute to supporting the body; however, contralateral (left-side) muscles were invoked during stages when the non-kettlebell-bearing forearm or hand contributed to supporting the body. The results suggest the importance of training both phases of the TGU to gain the most benefit from the exercise and highlights the asymmetric nature of the exercise, which may be particularly relevant for athletes engaged in activities with rotational demands.



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The Audiology of Otosclerosis

Diagnostic audiologic procedures for otosclerosis are effective tools in identifying this condition. Audiometric data usually demonstrate a conductive hearing loss at the early stages of otosclerosis. Modern middle ear analysis procedures are becoming more popular in the better diagnosis of otosclerosis. In clinical practice, cochlear otosclerosis can also be observed. Audiologic rehabilitation of otosclerosis includes fitting of hearing aids and implantable hearing devices. Current hearing technology enables patients who do not pursue surgical correction to function well and significantly improve their communication and quality of life. Otosclerosis may also be associated with annoying tinnitus, and tinnitus management is important in the rehabilitation process.

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Stapedectomy Versus Stapedotomy

Stapedectomy and stapedotomy represent the state-of-the-art surgical procedures in addressing the conductive hearing loss caused by otosclerosis. Their high rates of success and long-term stability have been demonstrated repeatedly in many studies. In comparing the short- and long-term results of the 2 procedures, it is evident that stapedotomy confers better hearing gain at high frequencies and lower complication rates. Modified stapes mobilization procedures may represent the next major development in stapes surgery in a selected patient population.

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Contents

Publication date: January 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 1





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Update of the systematic review of palliative radiation therapy fractionation for bone metastases

Publication date: Available online 1 February 2018
Source:Radiotherapy and Oncology
Author(s): Shayna E. Rich, Ronald Chow, Srinivas Raman, K. Liang Zeng, Stephen Lutz, Henry Lam, Maurício F. Silva, Edward Chow
PurposeRadiation therapy is an effective modality for pain management of symptomatic bone metastases. We update the previous meta-analyses of randomized trials comparing single fraction to multiple fractions of radiation therapy in patients with uncomplicated bone metastases.MethodsA literature search was conducted in Ovid Medline, Embase, and Cochrane Central Register. Ten new randomized trials were identified since 2010, five with adequate and appropriate data for inclusion, resulting in a total of 29 trials that were analyzed. Forest plots based on each study's odds ratios were computed using a random effects model and the Mantel–Haenszel statistic.ResultsIn intention-to-treat analysis, the overall response rate was similar in patients for single fraction treatments (61%; 1867/3059) and those for multiple fraction treatments (62%; 1890/3040). Similarly, complete response rates were nearly identical in both groups (23% vs 24%, respectively). Re-treatment was significantly more frequent in the single fraction treatment arm, with 20% receiving additional treatment to the same site versus 8% in the multiple fraction treatment arm (p < 0.01). No significant difference was seen in the risk of pathological fracture at the treatment site, rate of spinal cord compression at the index site, or in the rate of acute toxicity.ConclusionSingle fraction and multiple fraction radiation treatment regimens continue to demonstrate similar outcomes in pain control and toxicities, but re-treatment is more common for single fraction treatment patients.



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Editorial Board

Publication date: January 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 1





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The world needs new knowledge

Publication date: January 2018
Source:Radiotherapy and Oncology, Volume 126, Issue 1
Author(s): Michael Baumann




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Low temperature diamond growth arising from ultrafast pulsed-laser pretreatment

Publication date: Available online 1 February 2018
Source:Carbon
Author(s): Halina Krzyżanowska, William F. Paxton, Mesut Yilmaz, Anthony Mayo, John Kozub, Mick Howell, Justin Gregory, James E. Butler, Weng Poo Kang, Richard Mu, Jimmy L. Davidson, Norman H. Tolk
At temperatures significantly lower than normal growth temperatures using the hot filament chemical vapor diamond deposition approach, we have observed growth of high quality diamond films resulting from the application of in situ ultrafast pulsed-laser irradiation as a pretreatment step, on a conventionally abraided Si substrate surface. Low-temperature growth is seen to occur only where the sample was pretreated by laser irradiation. This effect is correlated with the formation, above a particular laser fluence threshold, of laser induced periodic nanostructures on the silicon substrate surface, with characteristic lengths significantly less than the laser wavelength, λ. The origin of these previously observed features will be discussed. Diamond growth samples were characterized using scanning electron microscopy and micro-Raman spectroscopy. This work strongly indicates that appropriate ultrafast-laser pretreatment shows promise as a means of promoting high-quality low-temperature CVD diamond growth in predetermined patterns, thus, demonstrating potential as a technique for the fabrication of diamond-based devices and selective diamond growth on semiconductor substrates.

Graphical abstract

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Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jennifer Yin Yee Kwan, Jie Su, Shao Hui Huang, Laleh S. Ghoraie, Wei Xu, Biu Chan, Kenneth W. Yip, Meredith Giuliani, Andrew Bayley, John Kim, Andrew J. Hope, Jolie Ringash, John Cho, Andrea McNiven, Aaron Hansen, David Goldstein, John de Almeida, Hugo J. Aerts, John N. Waldron, Benjamin Haibe-Kains, Brian O'Sullivan, Scott V. Bratman, Fei-Fei Liu
PurposeDistant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPC); yet there are few reliable predictors of DM in this disease. The role of quantitative imaging (i.e. radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that associate with a higher risk of developing DM.MethodsRadiotherapy planning CT scans were retrieved for all non-metastatic p16-positive OPC patients treated with radiotherapy or chemoradiotherapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume (GTV). Biomarkers included four representative radiomic features from tumor first order statistics, shape, texture, and wavelet groups as well as a combined four-feature signature. Univariable Cox proportional hazards models for DM risk were identified. Discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed.ResultsThere were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up of five years. On univariable analysis, top results included the four representative radiomic features (C-index=0.670-0.686; p<0.001), the radiomic signature (C-index=0.670; p<0.001), tumor stage (C-index=0.633; p<0.001), tumor diameter (C-index=0.653; p<0.001), and tumor volume (C-index=0.674; p<0.001); which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index=0.701-0.714; p<0.05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index=0.663-0.796), such as patients with stage III disease.ConclusionsRadiomic biomarkers appear to classify DM risk for patients with non-metastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in assignment of DM risk in future HPV-related OPC clinical trials.



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The impact of HIV infection on survival and acute toxicities from chemoradiation therapy for cervical cancer patients in a limited resource setting

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Surbhi Grover, Memory Bvochora-Nsingo, Alyssa Yeager, Sebathu Chiyapo, Rohini Bhatia, Emily MacDuffie, Priya Puri, Dawn Balang, Sarah Ratcliffe, Mohan Narasimhamurthy, Elliphine Gwangwava, Sylvia Tsietso, Mukendi K.A. Kayembe, Doreen Ramogola-Masire, Scott Dryden-Peterson, Umesh Mahantshetty, Akila N. Viswanathan, Nicola M. Zetola, Lilie L. Lin
PurposeCervical cancer is the leading cause of cancer death for women in sub-Saharan Africa. Human immunodeficiency virus (HIV) infection increases the risk of cervical cancer. However, prospective data on the outcomes of cervical cancer patients with HIV infection treated with curative intent are limited.MethodsWomen with locally advanced cervical cancer with or without HIV infection initiating radical chemoradiation therapy (CRT) in Botswana were enrolled in a prospective observational cohort study from July 2013 through January 2015.ResultsOf 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122/143) had stage II/III cervical cancer, and 67% (96/143) were HIV-infected. All HIV-infected patients were on anti-retroviral treatment (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The two-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54-74%) and 66% for HIV-uninfected women (95% CI 49-79%) (p=0.70). Factors associated with better two-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, p=0.003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, p=0.04), and age <40 years vs. 40-59 years (HR 2.17, 95% CI 1.05-4.47, p=0.03).ConclusionsHIV status had no effect on two-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status.



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Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma

Publication date: Available online 1 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Soumon Rudra, Caressa Hui, Yuan Rao, Pamela Samson, Alexander Lin, Xiao Chang, Christina Tsien, Sandra Fergus, Dan Mullen, Deshan Yang, Dinesh Thotala, Dennis Hallahan, Jian Li Campian, Jiayi Huang
ObjectiveAcute severe lymphopenia (ASL) in glioblastoma (GBM) patients after radiation therapy (RT) and concurrent temozolomide (TMZ) predicts for poorer overall survival (OS). This study aims to evaluate whether reduction in radiation treatment volume can reduce risk of ASL.MethodsA total of 210 patients with supratentorial/non-metastatic GBM were treated with RT+TMZ from 2007-2016 and had laboratory data on total lymphocyte counts (TLC). Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. TLCs were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. ASL was defined as any TLC<500 cells/μL within 3 months (by week 12) of initiating RT. Multivariate analysis (MVA) for OS was performed with Cox regression and with logistic regression for ASL. Propensity-score matching was performed to adjust for variability between cohorts. ASL, progression-free survival (PFS), and OS were compared using Kaplan-Meier method.ResultsLFRT patients had higher gross tumor volume (GTV) than SFRT patients yet lower brain dose-volume parameters including volume receiving 25Gy (V25Gy: 41% vs 53%, respectively, P<0.01). TLC at week 12 was significantly higher for LFRT than SFRT (median: 1100 cells/μL vs. 900 cells/μL, respectively, P=0.02). On MVA, ASL was an independent predictor of OS, and brain V25Gy was an independent predictor of ASL. ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P=0.12). In a propensity-matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P=0.58) and OS (median: 16.2 vs 13.9 months, respectively, P=0.69) were not significantly different.ConclusionLFRT is associated with less lymphopenia after RT+TMZ and does not adversely affect PFS or OS. Brain V25Gy is confirmed as an important dosimetric predictor for ASL.



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Report of transient events in a cocaine-dependent volunteer who received iTBS

Publication date: Available online 31 January 2018
Source:Brain Stimulation
Author(s): Vaughn R. Steele, Andrea M. Maxwell, Thomas J. Ross, Khaled Moussawi, Osama O. Abulseoud, Elliot A. Stein, Betty Jo Salmeron




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Pallidal deep brain stimulation modulates excessive cortical high β phase amplitude coupling in Parkinson disease

Publication date: Available online 31 January 2018
Source:Brain Stimulation
Author(s): Mahsa Malekmohammadi, Nicholas AuYong, Joni Ricks-Oddie, Yvette Bordelon, Nader Pouratian
ObjectiveDeep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are equally efficacious in the management of Parkinson disease (PD). Studies of STN-DBS have revealed a therapeutic reduction in excessive cortical β-γ phase-amplitude coupling (PAC). It is unclear whether this is specific to STN-DBS and potentially mediated by modulation of the hyperdirect pathway or if it is a generalizable mechanism seen with DBS of other targets. Moreover, it remains unclear how cortical signals are differentially modulated by movement versus therapy. To clarify, the effects of GPi-DBS and movement on cortical β power and β-γ PAC were examined.MethodsRight sensorimotor electrocorticographic signals were recorded in 10 PD patients undergoing GPi-DBS implantation surgery. We evaluated cortical β power and β-γ PAC during blocks of rest and contralateral hand movement (finger tapping) with GPi-DBS off and on.ResultsMovement suppressed cortical low β power (P = 0.008) and high β-γ PAC (P = 0.028). Linear mixed effect modeling (LMEM) showed that power in low and high β bands are differentially modulated by movement (P = 0.022). GPi-DBS also results in a significant suppression of high β-γ PAC but without power modulation in either β sub-band (P = 0.008). Cortical high β-γ PAC is significantly correlated with severity of bradykinesia (Rho = 0.59, P = 0.045) and changes proportionally with therapeutic improvement (Rho = 0.61, P = 0.04).ConclusionsSimilar to STN-DBS, GPi-DBS reduces motor cortical β-γ PAC, like that also reported with dopaminergic mediations, suggesting it is a generalizable symptom biomarker in PD, independent of therapeutic target or proximity to the hyperdirect pathway.



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Post-operative deep brain stimulation assessment: Automatic data integration and report generation

Publication date: Available online 1 February 2018
Source:Brain Stimulation
Author(s): Andreas Husch, Mikkel V. Petersen, Peter Gemmar, Jorge Goncalves, Niels Sunde, Frank Hertel
BackgroundThe gold standard for post-operative deep brain stimulation (DBS) parameter tuning is a monopolar review of all stimulation contacts, a strategy being challenged by recent developments of more complex electrode leads.ObjectiveProviding a method to guide clinicians on DBS assessment and parameter tuning by automatically integrating patient individual data.MethodsWe present a fully automatic method for visualization of individual deep brain structures in relation to a DBS lead by combining precise electrode recovery from post-operative imaging with individual estimates of deep brain morphology utilizing a 7T-MRI deep brain atlas.ResultsThe method was evaluated on 20 STN DBS cases. It demonstrated robust automatic creation of 3D-enabled PDF reports visualizing electrode to brain structure relations and proved valuable in detecting miss placed electrodes.DiscussionAutomatic DBS assessment is feasible and can conveniently provide clinicians with relevant information on DBS contact positions in relation to important anatomical structures.



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Challenges in vascular tissue engineering for diabetic patients

Publication date: Available online 1 February 2018
Source:Acta Biomaterialia
Author(s): Jhilmil Dhulekar, Agneta Simionescu
Hyperglycemia and dyslipidemia coexist in diabetes and result in inflammation, degeneration, and impaired tissue remodeling, processes which are not conducive to the desired integration of tissue engineered products into the surrounding tissues. There are several challenges for vascular tissue engineering such as non-thrombogenicity, adequate burst pressure and compliance, suturability, appropriate remodeling responses, and vasoactivity, but, under diabetic conditions, an additional challenge needs to be considered: the aggressive oxidative environment generated by the high glucose and lipid concentrations that lead to the formation of advanced glycation end products (AGEs) in the vascular wall. Extracellular matrix-based scaffolds have adequate physical properties and are biocompatible, however, these scaffolds are altered in diabetes by the formation AGEs and impaired collagen degradation, consequently increasing vascular wall stiffness. In addition, vascular cells detect and respond to altered stimuli from the matrix by pathological remodeling of the vascular wall. Due to the immunomodulatory effects of mesenchymal stem cells (MSCs), they are frequently used in tissue engineering in order to protect the scaffolds from inflammation. MSCs together with antioxidant treatments of the scaffolds are expected to protect the vascular grafts from diabetes-induced alterations. In conclusion, as one of the most daunting environments that could damage the ECM and its interaction with cells is progressively built in diabetes, we recommend that cells and scaffolds used in vascular tissue engineering for diabetic patients are tested in diabetic animal models, in order to obtain valuable results regarding their resistance to diabetic adversities.Statement of SignificanceAlmost 25 million Americans have diabetes, characterized by high levels of blood sugar that binds to tissues and disturbs the function of cardiovascular structures. Therefore, patients with diabetes have a high risk of cardiovascular diseases. Surgery is required to replace diseased arteries with implants, but these fail after 5–10 years because they are made of non-living materials, not resistant to diabetes. New tissue engineering materials are developed, based on the patients' own stem cells, isolated from fat, and added to extracellular matrix-based scaffolds. Our main concern is that diabetes could damage the tissue-like implants. Thus we review studies related to the effect of diabetes on tissue components and recommend antioxidant treatments to increase the resistance of implants to diabetes.

Graphical abstract

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Microbial nanowires – electron transport and the role of synthetic analogues

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Rhiannon C.G. Creasey, A. Bernardus Mostert, Tuan Nguyen, Bernardino Virdis, Stefano Freguia, Bronwyn Laycock
Electron transfer is central to cellular life, from photosynthesis to respiration. In the case of anaerobic respiration, some microbes have extracellular appendages that can be utilised to transport electrons over great distances. Two model organisms heavily studied in this arena are Shewanella oneidensis and Geobacter sulfurreducens. There is some debate over how, in particular, the Geobacter sulfurreducens nanowires (formed from pilin nanofilaments) are capable of achieving the impressive feats of natural conductivity that they display. In this article, we outline the mechanisms of electron transfer through delocalised electron transport, quantum tunnelling, and hopping as they pertain to biomaterials. These are described along with existing examples of the different types of conductivity observed in natural systems such as DNA and proteins in order to provide context for understanding the complexities involved in studying the electron transport properties of these unique nanowires. We then introduce some synthetic analogues, made using peptides, which may assist in resolving this debate. Microbial nanowires and the synthetic analogues thereof are of particular interest, not just for biogeochemistry, but also for the exciting potential bioelectronic and clinical applications as covered in the final section of the review.Statement of SignificanceSome microbes have extracellular appendages that transport electrons over vast distances in order to respire, such as the dissimilatory metal-reducing bacteria Geobacter sulfurreducens. There is significant debate over how G. sulfurreducens nanowires are capable of achieving the impressive feats of natural conductivity that they display: This mechanism is a fundamental scientific challenge, with important environmental and technological implications.Through outlining the techniques and outcomes of investigations into the mechanisms of such protein-based nanofibrils, we provide a platform for the general study of the electronic properties of biomaterials. The implications are broad-reaching, with fundamental investigations into electron transfer processes in natural and biomimetic materials underway. From these studies, applications in the medical, energy, and IT industries can be developed utilising bioelectronics.

Graphical abstract

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The degradation and transport mechanism of a Mg-Nd-Zn-Zr stent in rabbit common carotid artery: a 20-month study

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Jian Zhang, Haiyan Li, Wu Wang, Hua Huang, Jia Pei, Haiyun Qu, Guangyin Yuan, Yongdong Li
Mg-based stent is a promising candidate of the next generation fully degradable vascular stents. The latest progress includes the CE approval of the Magmaris WE43 based drug eluting stent. However, so far, the long term (more than 1 year implantation) in vivo degradation and the physiological effects caused by the degradation products were still unclear. In this study, a 20 month observation was carried out after the bare Mg-Nd-Zn-Zr (abbr. JDBM) stent prototype was implanted into the common carotid artery of New Zealand white rabbit in order to evaluate its safety, efficacy and especially degradation behavior. The degradation of the main second phase Mg12Nd was also studied. Results showed that the bare JDBM stent had good safety and efficacy with a complete re-endothelialization within 28 days. The JDBM stent struts were mostly replaced in situ by degradation products in 4 month. The important finding was that the volume and Ca concentration of the degradation products decreased in the long term, eliminating the clinicians' concern of possible vessel calcification. In addition, the alloying elements Mg and Zn in the stent could be safely metabolized as continuous enrichment in any of the main organs were not detected although Nd and Zr showed an abrupt increase in spleen and liver after 1 month implantation. Collectively, the long term in vivo results showed the rapid re-endothelialization of JDBM stent and the long term safety of the degradation products, indicating its great potential as the backbone of the fully degradable vascular stent.Statement of SignificanceMg-based stent is a promising candidate of the next generation fully degradable stents, especially after the recent market launch of one of its kind (Magmaris). However the fundamental question about the long term degradation and metabolic mechanism of Mg-based stent and its degradation products remain unanswered. We implanted our patented Mg-Nd-Zn-Zr bare stent into the common carotid artery of rabbits and conducted a 20 months observation. We found that the Ca containing degradation products could be further degraded in vivo. All the alloying elements showed no continuous enrichment in the main organs of rabbits. These findings eliminate the clinicians' concern of possible vessel calcification and element enrichment after the implantation of Mg alloy based stents to some extent.

Graphical abstract

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Computational 3D Imaging to Quantify Structural Components and Assembly of Protein Networks

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Pouyan Asgharzadeh, Bugra Özdemir, Ralf Reski, Oliver Röhrle, Annette I. Birkhold
Traditionally, protein structures have been described by the secondary structure architecture and fold arrangement. However, the relatively novel method of 3D confocal microscopy of fluorescent-protein-tagged networks in living cells allows resolving the detailed spatial organization of these networks. This provides new possibilities to predict network functionality, as structure and function seem to be linked at various scales. Here, we propose a quantitative approach using 3D confocal microscopy image data to describe protein networks based on their nano-structural characteristics. This analysis is constructed in four steps: (i) Segmentation of the microscopic raw data into a volume model and extraction of a spatial graph representing the protein network. (ii) Quantifying protein network gross morphology using the volume model. (iii) Quantifying protein network components using the spatial graph. (iv) Linking these two scales to obtain insights into network assembly. Here, we quantitatively describe the filamentous temperature sensitive Z protein network of the moss Physcomitrella patens and elucidate relations between network size and assembly details. Future applications will link network structure and functionality by tracking dynamic structural changes over time and comparing different states or types of networks, possibly allowing more precise identification of (mal)functions or the design of protein-engineered biomaterials for applications in regenerative medicine.Statement of significanceProtein networks are highly complex and dynamic structures that play various roles in biological environments. Analyzing the detailed spatial structure of these networks may lead to new insight into biological functions and malfunctions. Here, we propose a tool set that extracts structural information at two scales of the protein network and allows therefore to address questions such as "how is the network built?" or "how networks grow?".

Graphical abstract

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The rheological properties of native sericin

Publication date: Available online 1 February 2018
Source:Acta Biomaterialia
Author(s): James Sparkes, Chris Holland
Unlike spider silk, spinning silkworm silk has the added intricacy of being both fibre and micron-thick glue-like coating. Whilst the natural flow properties of the fibre feedstock fibroin are now becoming more established, our understanding of the coating, sericin is extremely limited and thus presents both a gap in our knowledge and a hindrance to successful exploitation of these materials. In this study we characterise sericin feedstock in its native state from the silkworm Bombyx mori, and by employing both biochemical, rheological and spectroscopic tools, define a natural gold standard. Our results demonstrate that native sericin behaves as a viscoelastic shear thinning fluid, but that it does so at a considerably lower viscosity than its partner fibroin, and that its upper critical shear rate (onset of gelation) lies above that of fibroin. Together these findings provide the first evidence that in addition to acting as a binder in the construction of the cocoon, sericin is capable of lubricating the flow of fibroin within the silk gland, which has implications for future processing, modelling and biomimetic efforts of these materials.Statement of SignificanceThis study addresses one of the major gaps in our knowledge regarding natural silk spinning by providing rigorous rheological characterisation of the other major protein involved – sericin. This allows progress in silk flow modelling, biomimetic system design, and in assessing the quality of bioinspired and waste sericin materials by providing a better understanding of the native, undegraded system.

Graphical abstract

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Interplay Between Stiffness and Degradation of Architectured Gelatin Hydrogels Leads to Differential Modulation of Chondrogenesis In Vitro and In Vivo

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Melika Sarem, Neha Arya, Miriam Heizmann, Axel T. Neffe, Andrea Barbero, Tim P. Gebauer, Ivan Martin, Andreas Lendlein, V. Prasad Shastri
The limited capacity of cartilage to heal large lesions through endogenous mechanisms has led to extensive effort to develop materials to facilitate chondrogenesis. Although physical-chemical properties of biomaterials have been shown to impactin vitro chondrogenesis, whether these findings are translatable in vivo is subject of debate. Herein, architectured 3D hydrogel scaffolds (ArcGel) (produced by crosslinking gelatin with ethyl lysine diisocyanate (LDI)) were used as a model system to investigate the interplay between scaffold mechanical properties and degradation on matrix deposition by human articular chondrocytes (HAC) from healthy donorsin vitroandin vivo. Using ArcGel scaffolds of different tensile and shear modulus, and degradation behavior; in this study, we compared the fate ofex vivoengineered ArcGels-chondrocytes constructs, i.e. the traditional tissue engineering approach, with thede novoformation of cartilaginous tissue in HAC laden ArcGels in an ectopic nude mouse model. While the softer and fast degrading ArcGel (LNCO3) was more efficient at promoting chondrogenic differentiationin vitro, upon ectopic implantation, the stiffer and slow degrading ArcGel (LNCO8) was superior in maintaining chondrogenic phenotype in HAC and retention of cartilaginous matrix. Furthermore, surprisingly thede novoformation of cartilage tissue was promoted only in LNCO8. Since HAC cultured for only three days in the LNCO8 environment showed upregulation of hypoxia-associated genes, this suggests a potential role for hypoxia in the observed in vivo outcomes. In summary, this study sheds light on how immediate environment (in vivoversusin vitro) can significantly impact the outcomes of cell-laden biomaterials.Statement of SignificanceIn this study, 3D architectured hydrogels (ArcGels) with different mechanical and biodegradation properties were investigated for their potential to promote formation of cartilaginous matrix by human articular chondrocytesin vitroandin vivo.Two paradigms were explored (i)ex vivoengineering followed byin vivoimplantation in ectopic site of nude mice and (ii) shortin vitroculture (3 days) followed by implantation to inducede novocartilage formation. Softer and fast degrading ArcGel were better at promoting chondrogenesisin vitro,while stiffer and slow degrading ArcGel were strikingly superior in both maintaining chondrogenesisin vivoand inducingde novoformation of cartilage. Our findings highlight the importance of the interplay between scaffold mechanics and degradation in chondrogenesis.

Graphical abstract

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Adhesive free-standing multilayer films containing sulfated levan for biomedical applications

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Tiago D. Gomes, Sofia G. Caridade, Maria P. Sousa, Sara Azevedo, Muhammed Y. Kandur, Ebru T. Öner, Natália M. Alves, João F. Mano
This work is the first reporting the use of layer-by-layer to produce adhesive free-standing (FS) films fully produced using natural-based macromolecules: chitosan (CHI), alginate (ALG) and sulfated levan (L-S). The deposition conditions of the natural polymers were studied through zeta potential measurements and quartz crystal microbalance with dissipation monitoring analysis. The properties of the FS films were evaluated and compared with the control ones composed of only CHI and ALG in order to assess the influence of levan polysaccharide introduced in the multilayers. Tensile tests, dynamic mechanical analysis and single lap shear strength tests were performed to evaluate the mechanical properties of the prepared FS. The presence of L-S conferred both higher tensile strength and shear strength to the developed FS. The results showed an adhesion strength 4 times higher than the control (CHI/ALG) FS films demonstrating the adhesive character of the FS films containing L-S. Morphological and topography studies were carried out revealing that the crosslinking reaction granted the L-S based FS film with a higher roughness and surface homogeneity. Preliminary biological assays were performed by cultivating myoblasts cells on the surface of the produced FS. Both crosslinked and uncrosslinked FS films containing L-S were cytocompatible and myoconductive.Statement of SignificanceSutures remain as the "gold standard" for wound closure and bleeding control; however they still have limitations such as, high infection rate, inconvenience in handling, and concern over possible transmission of blood-borne disease through the use of needles. One of the challenges of tissue engineering consist on the design and development of biocompatible tissue adhesives and sealants with high adhesion properties to repair or attach devices to tissues. In this work, the introduction of sulfated levan (L-S) on multilayered free-standing membranes was proposed to confer adhesive properties. Moreover, the films were myoconductive even in the absence of crosslinking just by the presence of L-S. This study provides a promising strategy to develop biological adhesives and for cardiac tissue engineering applications.

Graphical abstract

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Self-sensibilized polymeric prodrug co-delivering MMP-9 shRNA plasmid for combined treatment of tumors

Publication date: Available online 31 January 2018
Source:Acta Biomaterialia
Author(s): Qiao Tang, Xin Ma, Yi Zhang, Xiang Cai, Wei Xue, Dong Ma
Polymeric prodrugs are of immense interest as anticancer drug-delivery system owing to their superior drug stability during circulation and satisfactory drug loading capacity. However, they are usually less effective than free drugs due to imperfect degradable characteristics or active sites blockage. A polymeric prodrug (HPAA-MTX) with chemotherapeutic self-sensibilization effect consisting of glutathione (GSH)-triggered hyperbranched poly(amido amine) (HPAA) and methotrexate (MTX) was designed and synthesized in this work. This prodrug not only showed better inhibition effect on the tumor cells proliferation compared with free MTX, but also displayed selective sensibilization to tumor cells rather than normal cells. Meanwhile, HPAA-MTX was also explored as a MMP-9 shRNA plasmid delivery vector due to their rich amino group of HPAA, accompanying with MTX for simultaneous inhibiting tumor cells proliferation and migration. As expected, HPAA-MTX possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9 protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and MTX/MMP-9 co-delivery strategy, this HPAA-MTX/MMP-9 co-delivery system exhibited significantly improved therapeutic efficacy to breast cancer in a combined manner which was confirmed through in vitro and in vivo assays. The strategy established in this study provided a facile "all-in-one" platform to integrate the drug/gene co-delivery strategy and self-sensibilization effect into one single nanocomposite for potential cancer treatment.Statement of significanceA cationic polymeric prodrug with chemotherapeutic self-sensibilization effect was designed and showed better inhibition effect on tumor cells proliferation compared with its free drug, as well displayed the selective sensibilization effect to tumor cells rather than normal cells. Moreover, the prodrug could also deliver MMP-9 shRNA plasmid for a combined therapy. As expected, the prodrug possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9 protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and the drug/gene co-delivery strategy, this prodrug exhibited significantly improved therapeutic efficacy to breast cancer in a combined manner.

Graphical abstract

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Parámetros de cuantificación metabólica en la práctica clínica. ¿Es el momento de incluirlos en los informes?

Publication date: Available online 1 February 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): J. Mucientes, L. Calles, B. Rodríguez, M. Mitjavila
Las técnicas de valoración cualitativa han sido el estándar tradicional de valoración diagnóstica en los estudios PET con ¹⁸F-FDG. Desde los inicios de la técnica se han buscado parámetros cuantitativos, más exactos y con mejor precisión diagnóstica, que puedan ofrecer información relevante en cuanto al comportamiento, agresividad o pronóstico de los tumores. Cada vez hay más estudios con evidencia de alta calidad sobre la utilidad de diferentes parámetros metabólicos distintos al SUV máximo, cuyo uso es controvertido, a pesar de ser ampliamente utilizado en la práctica clínica, y del que muchos médicos desconocen todavía su significado real. El objetivo de este trabajo ha sido revisar los conceptos clave de estos parámetros metabólicos que pueden ser relevantes en la práctica habitual durante los próximos años. Se ha visto que existe mayor evidencia en la valoración del metabolismo de una lesión de forma completa a través de parámetros volumétricos que reflejan de forma más adecuada la carga tumoral que presenta un paciente. Básicamente, estos parámetros calculan el volumen de tumor que cumple unas características determinadas. Para ello se ha utilizado un software, disponible en la mayor parte de las estaciones de trabajo y procesado de estudios PET, que ha permitido calcular estos volúmenes utilizando criterios más o menos complejos. Los métodos de segmentación más simples, basados en umbrales, están disponibles en la mayor parte de los equipos, son fáciles de calcular y han demostrado en muchos trabajos tener un importante significado pronóstico.Qualitative techniques have traditionally been the standard for the diagnostic assessment with ¹⁸F-FDG PET studies. Since the introduction of the technique, quantitative parameters have been sought, more accurate and with better diagnostic precision, that may offer relevant information of the behavior, aggressiveness or prognosis of tumors. Nowadays, more and more studies with high quality evidence show the utility of other metabolic parameters different from the SUV maximum, which despite being widely used in clinical practice is controversial and many physicians still do not know its real meaning. The objective of this paper has been to review the key concepts of these metabolic parameters that could be relevant in normal practice in the future. It has been seen that there is more evidence in the complete evaluation of the metabolism of a lesion, through volumetric parameters that more adequately reflect the patient's tumor burden. Basically, these parameters calculate the volume of tumor that fulfills certain characteristics. A software available in the majority of the workstations has been used for this purpose and it has allowed to calculate these volumes using more or less complex criteria. The simplest threshold-based segmentation methods are available in most equipments, they are easy to calculate and they have been shown in many studies to have an important prognostic significance.



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Reply to: professionalisation rather than monopolisation is the future of emergency medicine in Europe

No abstract available

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History of anaesthesia: Nurse anaesthesia practice in the G7 countries (Canada, France, Germany, Italy, Japan, the United Kingdom and the United States of America)

Many factors determine whether nurses, physicians or both administer anaesthesia in any country. We examined the status of nurse-administered anaesthesia in the Group of Seven (G7) countries (Canada, France, Germany, Italy, Japan, the United Kingdom and the United States of America) and explored how historical factors, mixing global and local contexts (such as professional relations, medical and nursing education, social status of nurses, demographics and World Wars in the 20th century), help explain observed differences. Nearly equal numbers of physicians and nurses are currently engaged in the delivery of anaesthesia care in the United States but, remarkably, although the introduction or re-introduction of nurse anaesthesia in the 20th century was attempted in all the other G7 countries (except Japan), it has been successful only in France because of the cooperation with the United States during World War II.

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Reply to: emergency medicine is about collaboration, not monopolisation

No abstract available

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Does the β-receptor antagonist esmolol have analgesic effects?: A randomised placebo-controlled cross-over study on healthy volunteers undergoing the cold pressor test

BACKGROUND Esmolol may attenuate the sympathetic response to pain and reduce postoperative opioid consumption. It is not clear whether esmolol has an analgesic effect per se. OBJECTIVES The aim of this study was to evaluate the analgesic effect of esmolol in the absence of anaesthetics and opioids. We tested the hypothesis that esmolol would reduce the maximum pain intensity perceived during the cold pressor test (CPT) by 2 points on a 0 to 10 numeric pain rating scale (NRS) compared to placebo. DESIGN Randomised, placebo-controlled cross-over study. SETTING Postoperative recovery area, Örebro University Hospital. Study period, November 2013 to February 2014. PARTICIPANTS Fourteen healthy volunteers. Exclusion criteria included ongoing medication, pregnancy and breastfeeding and participation in other medical trials. INTERVENTIONS At separate study sessions, participants received interventions: esmolol (0.7 mg kg−1 bolus over 1 min followed by infusion at 10 μg kg−1 min−1); 0.9% normal saline bolus then remifentanil infusion at 0.2 μg kg−1 min−1 and 0.9% normal saline bolus and infusion according to a random sequence. All infusions were administered over 30 min. MAIN OUTCOME MEASURES Perceived maximum pain intensity score, pain tolerance and haemodynamic changes during CPT, and occurrence of side-effects to interventions compared to placebo, respectively. RESULTS Esmolol did not reduce perceived pain intensity or pain tolerance during the CPT. The NRS-max score was similar for esmolol, 8.5 (±1.4) and placebo, 8.4 (±1.3). The mean difference was 0.1 [95% confidence interval (−1.2 to 1.4)], P value equal to 0.83. Remifentanil significantly reduced NRS-max scores, 5.4 (±2.1) compared to placebo, [mean difference −3.1 (95% confidence interval (−4.4 to −1.8)), P 

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Anaesthesiology and ethics: Can the anaesthesiologist ameliorate simply and rapidly the assessment of decision-making capacity in the elderly?

No abstract available

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Standardised noxious stimulation-guided individual adjustment of remifentanil target-controlled infusion to prevent haemodynamic responses to laryngoscopy and surgical incision: A randomised controlled trial

BACKGROUND The surgical plethysmographic index (SPI) is one of the available indexes of the nociception–antinociception (NAN) balance. Individually adjusting the NAN balance to prevent somatic responses to noxious stimulation remains a challenge. OBJECTIVES To assess whether guiding remifentanil administration according to the SPI response to a calibrated noxious stimulus (NANCAL) can blunt the haemodynamic response to tracheal intubation and surgical incision. DESIGN Randomised multicentre study. SETTING Two Belgian university hospitals from January 2014 to April 2015. PATIENTS After ethic review board approval and informed consent, 48 American Society of Anesthesiologists I or II adult patients scheduled for surgery under general anaesthesia were enrolled. INTERVENTIONS Patients were randomly assigned to a SPI group, where remifentanil effect-site concentration was adjusted according to NANCAL, or a control group, where it was fixed at 4 ng ml−1. Propofol concentration was always adjusted to maintain the bispectral index close to 40. NANCAL consisted of a 100 Hz, 60 mA electrical tetanic stimulation during 30 s at the wrist before tracheal intubation and before surgical incision. MAIN OUTCOME MEASURES The primary endpoint was the efficacy of the NANCAL-guided remifentanil administration to prevent the haemodynamic response to tracheal intubation and surgical incision. The secondary aim was to compare the ability of SPI, analgesia nociception index, pupil diameter and mean arterial pressure response to NANCAL to predict the haemodynamic response to tracheal intubation and surgical incision. RESULTS Our SPI response to NANCAL-based correcting scheme for remifentanil administration was not superior to a fixed remifentanil concentration at blunting the haemodynamic response to tracheal intubation or surgical incision. Among all tested NAN balance indices, only mean arterial pressure had significant predictive ability with regard to the haemodynamic response to surgical incision. CONCLUSION Further research is needed to define the best NANCAL stimulus and the best remifentanil correcting scheme to help individualised tailoring of antinociception for each specific subpopulation of surgical patients. TRIAL REGISTRATION Clinicaltrials.gov NCT: 02884310; http://ift.tt/2B2PCiQ.

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