Therapeutic experience with oral finasteride for androgenetic alopecia in female-to-male transgender patients

Summary

Background

Androgenic treatment of female-to-male transgender patients may result in androgenetic alopecia (AGA). Use of 5-alpha-reductase inhibitors are useful as oral treatment of AA in men. There are no previous studies of the use of finasteride in transgender men as treatment of AGA.

Aim

To evaluate the effectiveness and safety of an oral 5α-reductase inhibitor (finasteride) for AA developed in transgender men.

Methods

This single-centre retrospective study enrolled female-to-male transgender patients with a clinical diagnosis of AGA to receive 1 mg of an oral type II 5α-reductase inhibitor for at least 12 months.

Results

In all, 10 patients were included in the study. All the patients received a clinical diagnosis of male-pattern AGA, with 90% classified as stage IV on the Norwood-Hamilton scale. Mean onset of AGA was 3.25 years after the introduction of androgenic treatment, and 70% of the patients had a family history of AGA. All the patients improved one grade on the Norwood–Hamilton scale after a mean of 5.5 months (range 4–6 months) since the start of finasteride treatment. Two patients stopped treatment for economic reasons and one stopped due to dyspepsia. No sexual or other adverse effects were observed. Patients were given periodic physical and analytical examinations by endocrinologists without any significant finding. Mean follow-up of patients was 16.2 months.

Conclusion

AA in transgender men has a delayed onset, and is clinically and therapeutically similar to the common male-pattern-AGA in cis-gender men.

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Seabather's eruption caused by the thimble jellyfish (Linuche aquila) in the Philippines

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Complex autonomic pathways in patients with idiopathic hyperhidrosis

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Clarithromycin, rifampicin and fusidic acid triple combination therapy for chronic folliculocentric pustulosis of the scalp

http://ift.tt/2u8wCis

Serial D-dimer plasma levels in a patient with chronic spontaneous urticaria developing resistance to omalizumab

Summary

Chronic spontaneous urticaria (CSU) is a condition presenting as the spontaneous occurrence of itchy weals with or without angio-oedema for > 6 weeks. A patient with severe chronic spontaneous urticaria who developed resistance to omalizumab is described. The patient's D-dimer plasma levels strictly paralleled the disease activity despite the administration of anti-IgE therapy.

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Comprehensive profiling of H-Ras signalling in angiosarcoma endothelium

Summary

The MS1/SVR system, in which MS1 represents immortalized endothelial cells and SVR represents MS1 cells transformed with oncogenic human–rat sarcoma protein (H-Ras), has been used for around 20 years as a valuable tool to study angiogenesis and carcinogenesis. Despite the use of these cells in numerous studies, a comprehensive profile of the signalling differences due to oncogenic H-Ras transformation has not been performed previously. In this study, we profiled the well-known MS1 and SVR cell lines using a combination of both Western blot and gene chip assays.

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Acquired reactive perforating collagenosis associated with Hodgkin disease

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Systemic lupus erythematosus, following prodromal idiopathic thrombocytopenic purpura, presenting with skin lesions resembling malignant atrophic papulosis

Summary

Systemic lupus erythematosus (SLE) is an autoimmune disease. Its incidence in the UK is approximately 1 per 10 000. Cutaneous involvement, encompassing acute, subacute and chronic disease, occurs in over two-thirds of cases, and can often be the first clue to diagnosis. We describe a highly unusual case of SLE occurring after prodromal idiopathic thrombocytopenic purpura (ITP) and presenting with skin lesions more typical of malignant atrophic papulosis, a rare and often fatal vasculopathy. Such a combination of rare features emphasizes the potential for complexity in this multisystem disease.

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Peanut allergy and isotretinoin: reply to McCarthy et al.

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Treatment of paediatric facial pyogenic granuloma with topical ingenol mebutate

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Effectiveness of Disease Prevention in Community Health Center Dental Programs

Abstract

Purpose of Review

The goal of this paper is to describe and analyze oral health disease prevention at Community Health Center (CHC) dental programs in order to summarize the effectiveness of activities at the individual and community levels.

Recent Findings

Recent efforts to expand oral health prevention and care with children at community health centers have shown positive results. Although there is considerable literature regarding oral health disease prevention aimed at individuals and communities, there are few articles that specifically address preventive oral health programs at CHC.

Summary

CHC dental programs are well positioned to address the prevention of dental diseases as an integral part of care based on their organization and strong community-based orientation. Recent trends in the integration of medical and dental care at CHC support dental disease prevention activities to increase oral health and provide opportunities for further research in monitoring effectiveness of disease prevention in CHC.

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Immune Checkpoint Inhibition in Cancers that Affect the Head and Neck

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Janaki Parameswaran, Barbara Burtness




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Breast Cancer: Biology or Stage?

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Daphna Spiegel




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Radiation Treatment Time and Overall Survival in Locally Advanced Non-small Cell Lung Cancer

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Matthew T. McMillan, Eric Ojerholm, Vivek Verma, Kristin A. Higgins, Sunil Singhal, Jarrod D. Predina, Abigail T. Berman, Surbhi Grover, Cliff G. Robinson, Charles B. Simone
PurposeProlonged radiation treatment (RT) time (RTT) has been associated with worse survival in several malignancies. The present study investigated whether delays during RT are associated with overall survival (OS) in non-small cell lung cancer (NSCLC).Methods and MaterialsThe National Cancer Database was queried for patients with stage III NSCLC who had received definitive concurrent chemotherapy and fractionated RT to standard doses (59.4-70.0 Gy) and fractionation from 2004 to 2013. The RTT was classified as standard or prolonged for each treatment regimen according to the radiation dose and number of fractions. Cox proportional hazards models were used to evaluate the association between the following factors and OS: RTT, RT fractionation, demographic and pathologic factors, and chemotherapeutic agents.ResultsOf 14,154 patients, the RTT was prolonged in 6262 (44.2%). Factors associated with prolonged RTT included female sex (odds ratio [OR] 1.21, P<.0001), black race (OR 1.20, P=.001), nonprivate health insurance (OR 1.30, P<.0001), and lower income (<$63,000 annually, OR 1.20, P<.0001). The median OS was significantly worse for patients with prolonged RTT than that for those with standard RTT (18.6 vs 22.7 months, P<.0001). Furthermore, the OS worsened with each cumulative interval of delay (standard RTT vs prolonged 1-2 days, 20.5 months, P=.009; prolonged 3-5 days, 17.9 months, P<.0001; prolonged 6-9 days, 17.7 months, P<.0001; prolonged >9 days, 17.1 months, P<.0001). On multivariable analysis, prolonged RTT was independently associated with inferior OS (hazard ratio 1.21, P<.0001). Prolonged RTT as a continuous variable was also significantly associated with worse OS (hazard ratio 1.001, P=.0007).ConclusionsDelays during RT appear to negatively affect survival for patients with locally advanced NSCLC. We have detailed the demographic and socioeconomic barriers influencing prolonged RTT as a method to address the health disparities in this regard. Cumulative interruptions of RT should be minimized.



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Postmastectomy Conundrum

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Janet K. Horton




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Meetings

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5





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PMRT: Please Mind Randomized Trials

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Anthony C. Wong, Steven J. Chmura




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Issue Highlights

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5





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A Clarion Call for Large-Scale Collaborative Studies of Pediatric Proton Therapy

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Amy Berrington de Gonzalez, Bhadrasian Vikram, Jeffrey C. Buchsbaum, Florent de Vathaire, Wolfgang Dörr, Daphne Hass-Kogan, Johannes A. Langendijk, Anita Mahajan, Wayne Newhauser, Andrea Ottolenghi, Cecile Ronckers, Reinhard Schulte, Linda Walsh, Torunn I. Yock, Ruth A. Kleinerman




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Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy and Pathologic Risk Groups in Patients With Head and Neck Cancer

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): David I. Rosenthal, Abdallah S.R. Mohamed, Adam S. Garden, William H. Morrison, Adel K. El-Naggar, Mona Kamal, Randal S. Weber, Clifton D. Fuller, Lester J. Peters
PurposeTo present the long-term and final report of a phase 3 trial designed to assess dose-response relationship for postoperative radiation therapy (PORT) and pathologic risk groups in head and neck cancer.Methods and MaterialsPatients who underwent primary surgery for American Joint Committee on Cancer stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and who required PORT were eligible. Patients' primary sites and involved necks were independently assigned to higher- or lower-risk categories based on a cumulative point score representing increasing risk of recurrence. The sites in the lower-risk group were randomized to receive 57.6 or 63 Gy and those in the higher-risk group were randomized to receive 63 or 68.4 Gy, all at 1.8 Gy per fraction.ResultsA total of 264 patients were included. The actuarial 5-year locoregional control rate was 67%. A second primary cancer was documented in 27% of patients. The 5- and 10-year freedom–from–distant metastasis rates were 64% and 60%, respectively, whereas the 5- and 10-year overall survival rates were 32% and 20%, respectively. There was no statistically significant difference in tumor control between different dose levels in both the lower- and higher-risk groups. On multivariate analysis, nonwhite race (P=.0003), positive surgical margins (P=.009), extracapsular extension (ECE, P=.01), and treatment package time (TPT) ≥85 days (P=.002) were independent correlates of worse locoregional control, whereas age ≥57 years (P<.0001), positive surgical margins (P=.01), ECE (P=.026), and TPT ≥85 days (P=.003) were independently associated with worse overall survival.ConclusionsThis long-term report of PORT delivered at 1.8 Gy/d to total doses of 57.6 to 68.4 Gy without chemotherapy for head and neck squamous cell carcinoma demonstrated that increasing dose did not significantly improve tumor control. On multivariate analysis, the only significant treatment variable was TPT. The results confirm that positive surgical margins and/or nodal ECE remains the most significant predictive pathologic factors.



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Why So Challenging to Personalize Radiation Dose?

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Paul M. Harari




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Stereotactic Radiosurgery for Trigeminal Neuralgia Improves Patient-Reported Quality of Life and Reduces Depression

Publication date: 1 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 5
Author(s): Rupesh Kotecha, Jacob A. Miller, Sujith Modugula, Gene H. Barnett, Erin S. Murphy, Chandana A. Reddy, John H. Suh, Gennady Neyman, Andre Machado, Sean Nagel, Samuel T. Chao
PurposeTo characterize quality-of-life (QOL) outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN).Methods and MaterialsThe EuroQOL 5 Dimensions (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected before and after SRS for 50 patients with TN. Pain response and treatment-related facial numbness were classified by Barrow Neurological Institute (BNI) scales. Differences in pooled QOL outcomes were tested with paired t tests and sign tests. The Kaplan-Meier method was used to estimate time-dependent improvements in the EQ-5D index, EQ-5D perceived health status (PHS), PHQ-9 score, and freedom from pain failure (BNI class IV-V) or facial numbness (BNI class III-IV).ResultsFollowing SRS, the 12-month rate of freedom from pain failure was 92% (95% confidence interval [CI], 77%-97%) while the 12-month rate of freedom from facial numbness was 89% (95% CI, 66%-97%). Significant improvements in the EQ-5D index (P<.01), PHS (P=.01), and PHQ-9 (P=.03) were observed, driven by the EQ-5D subscores for self-care and for pain and/or discomfort (P=.02 and P<.01, respectively). At 12 months after SRS, the actuarial rates of improvement in the EQ-5D, PHS, and PHQ-9 were 55% (95% CI, 40%-70%), 59% (95% CI, 40%-76%), and 59% (95% CI, 39%-76%), respectively. The median time to improvement in each of the QOL measures was 9 months (95% CI, 3-36 months) for the EQ-5D index, 5 months (95% CI, 3-36 months) for PHS, and 9 months (95% CI, 3-18 months) for the PHQ-9. On multivariate analysis, only higher prescription dose (86 Gy vs ≤82 Gy) was associated with improvement in the EQ-5D index (hazard ratio, 5.73; 95% CI, 1.85-22.33; P<.01).ConclusionsPatients with TN treated with SRS reported significant improvements in multiple QOL measures, with the therapeutic benefit strongly driven by improvements in pain and/or discomfort and in self-care, along with lower rates of depression. In this analysis, there appears to be a correlation between prescription dose and treatment response as measured by the EQ-5D.



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Aptamer-assisted novel technologies for detecting bacterial pathogens

Publication date: September 2017
Source:Biomedicine & Pharmacotherapy, Volume 93
Author(s): Naser Alizadeh, Mohammad Yousef Memar, Seyyed Reza Moaddab, Hossein Samadi Kafil
Nowadays, all people are at risk of infectious diseases that are mainly caused by bacteria causing infection. There is a permanent demand for an appropriate detection method that is affordable, practical, careful, rapid, sensitive, efficient and economical. Aptamers are single stranded DNA or RNA oligonucleotides, which can be recognized specifically and bind to their target molecules and also, be exploited in diagnostic applications. Recently, aptamer-based systems have offered great potentials in applications for the recognition of several important bacterial pathogens from clinical and food specimens. There are several reports appraising the diagnostic applicability of aptamer-based systems for the detection of pathogens. As for its excellent sensitivity, as well as its rapid and efficient detectability, this technique may be practical to indicate bacterial targets with less sample size and may consume less time than traditional methods These systems offer a promising approach for the sensitive and quick detection of food-borne and clinical agents. This review provides an overview of aptamer-based methods as a novel approach for detecting bacterial pathogens.



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The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance

Publication date: Available online 9 July 2017
Source:Journal of Autoimmunity
Author(s): Kerstin Klein, Mojca Frank-Bertoncelj, Emmanuel Karouzakis, Renate E. Gay, Christoph Kolling, Adrian Ciurea, Nagihan Bostanci, Georgios N. Belibasakis, Lih-Ling Lin, Oliver Distler, Steffen Gay, Caroline Ospelt
Synovial fibroblasts (SF) drive inflammation and joint destruction in chronic arthritis. Here we show that SF possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In SF and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable. Repeated stimulation of SF with LPS resulted in loss of activating histone marks only in promoters of tolerizable genes. The epigenetic landscape at promoters of tolerizable genes was similar in unstimulated SF and monocytes, whereas the basal configuration of histone marks profoundly differed in genes that were non-tolerizable in SF only. Our data suggest that the epigenetic configuration at gene promoters regulates cell-specific LPS-induced responses and primes SF to sustain their inflammatory response in chronic arthritis.



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Recent Advances in Adhesive Bonding: The Role of Biomolecules, Nanocompounds, and Bonding Strategies in Enhancing Resin Bonding to Dental Substrates

Abstract

Purpose of review

To present an overview on the main agents (i.e. biomolecules and nanocompounds) and/or strategies currently available to amplify or stabilize resin-dentin bonding.

Recent findings

According to studies retrieved for full-text reading (2014–2017), there are currently six major strategies available to overcome resin-dentin bond degradation: (1) use of collagen crosslinking agents, which may form stable covalent bonds with collagen fibrils, thus strengthening the hybrid layer; (2) use of antioxidants, which may allow further polymerization reactions over time; (3) use of protease inhibitors, which may inhibit or inactivate metalloproteinases; (4) modification of the bonding procedure, which may be performed by using the ethanol-wet bonding (EWB) technique or by applying an additional adhesive (hydrophobic) coating, thereby strengthening the hybrid layer; (5) laser treatment of the substrate prior to bonding, which may cause specific topographic changes in the surface of dental substrates, increasing bonding efficacy; and (6) reinforcement of the resin matrix with inorganic fillers and/or remineralizing agents, which may positively enhance physicomechanical properties of the hybrid layer.

Summary

With the present review, we contributed to the better understanding of adhesion concepts and mechanisms of resin-dentin bond degradation, showing the current prospects available to solve that problematic. In addition, adhesively-bonded restorations may be benefited by the use of some biomolecules, nanocompounds or alternative bonding strategies in order to minimize bond strength degradation.

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Association between Sugar Intake, Oral Health, and the Impact on Overall Health: Raising Public Awareness

Abstract

Purpose of Review

The role of sugar consumption and oral health refocused largely due to associations between systemic diseases and conditions (type 2 diabetes, obesity) and oral health. This review examines the evidence supporting the impact of sugars on oral diseases and the role of sugars in oral-systemic complications.

Recent Findings

The increased consumption of dietary sugars, including sugar-sweetened beverages, and the increasing percentage of sugars as a component of the US diet affect oral health in the population. It is important for dental professionals to know public health implications and strategies to effectively communicate this risk to patients' oral health.

Summary

Local and state governments experienced success with the regulation of sodas and sugar-sweetened beverages and studies demonstrated that these regulations are largely successful in decreasing consumption among adolescents. It is the role of the dental professional to support these activities to promote healthy dietary choices for patients.

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Eruptive vellus hair cysts of the vulva

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Preparation of an Au-Pt alloy free from artifacts in magnetic resonance imaging

Publication date: Available online 9 July 2017
Source:Magnetic Resonance Imaging
Author(s): Tomonobu Kodama, Ryusuke Nakai, Kenji Goto, Kunihiro Shima, Hiroo Iwata
PurposeWhen magnetic resonance imaging (MRI) is performed on patients carrying metallic implants, artifacts can disturb the images around the implants, often making it difficult to interpret them appropriately. However, metallic materials are and will be indispensable as raw materials for medical devices because of their electric conductivity, visibility under X-ray fluoroscopy, and other favorable features. What is now desired is to develop a metallic material which causes no artifacts during MRI.Materials and methodsIn the present study, we prepared a single-phase and homogeneous Au-Pt alloys (Au; diamagnetic metal, and Pt; paramagnetic metal) by the processing of thermal treatment. Volume magnetic susceptibility was measured with a SQUID Flux Meter and MRI artifact was evaluated using a 1.5-T scanner.ResultsAfter final thermal treatment, an entirely recrystallized homogeneous organization was noted. The Au-35Pt alloy was shown to have a volume magnetic susceptibility of −8.8ppm, causing almost free from artifacts during MRI.ConclusionsWe thus prepared an Au-35Pt alloy which had a magnetic susceptibility very close to that of living tissue and caused much fewer artifacts during MRI. It is promising as a material for spinal cages, intracranial electrodes, cerebral aneurysm embolization coils, markers for MRI and so on.



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Endothelial cells: From innocent bystanders to active participants in immune responses

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): A. Al-Soudi, M.H. Kaaij, S.W. Tas
The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies.



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Circulating CXCL10 is increased in non-segmental vitiligo, in presence or absence of autoimmune thyroiditis

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): Silvia Martina Ferrari, Poupak Fallahi, Giulia Santaguida, Camilla Virili, Ilaria Ruffilli, Francesca Ragusa, Marco Centanni, Alessandro Antonelli
Recently the importance of CXCL10 in the pathogenesis of non-segmental vitiligo (NSV) and autoimmune thyroid disorders (AITD) has been shown. No data are present about chemokines CXCL10 (Th1 prototype) and CCL2 (Th2 prototype) circulating levels in NSV patients with/without thyroiditis (AT).Serum CXCL10 and CCL2 have been measured in 50 consecutive NSV patients, in 40 consecutive patients with NSV and AT (NSV+AT), in 50 sex- and age-matched controls without AT (control 1) and in 40 sex- and age-matched patients with AT without NSV (control 2).Serum CXCL10 levels were significantly higher in control 2, than in control 1 (P=0.001; ANOVA). NSV patients have serum CXCL10 levels significantly higher than control 1, or control 2 (P=0.001). NSV+AT patients have serum CXCL10 levels higher than control 1, or 2 (P<0.001), and than NSV (P=0.01).In conclusion, we first demonstrate high serum CXCL10 in NSV patients, overall in presence of AT and hypothyroidism, suggesting the importance of a common Th1 immune response in their immune-pathogenesis. To evaluate if serum CXCL10 might be used as a clinical marker of NSV and/or AT further studies are needed.



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Biomarkers of disease activity in vitiligo: A systematic review

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): R. Speeckaert, M. Speeckaert, S. De Schepper, N. van Geel
The pathophysiology of vitiligo is complex although recent research has discovered several markers which are linked to vitiligo and associated with disease activity. Besides providing insights into the driving mechanisms of vitiligo, these findings could reveal potential biomarkers. Activity markers can be used to monitor disease activity in clinical trials and may also be useful in daily practice. The aim of this systematic review was to document which factors have been associated with vitiligo activity in skin and blood. A second goal was to determine how well these factors are validated in terms of sensitivity and specificity as biomarkers to determine vitiligo activity. Both in skin (n=42) as in blood (n=66) an adequate number of studies fulfilled the predefined inclusion criteria. These studies used diverse methods and investigated a broad range of plausible biomarkers. Unfortunately, sensitivity and specificity analyses were scarce. In skin, simple histopathology with or without supplemental CD4 and CD8 stainings can still be considered as the gold standard, although more recently chemokine (C-X-C motif) ligand (CXCL) 9 and NLRP1 have demonstrated a good and possibly even better association with progressive disease. Regarding circulating biomarkers, cytokines (IL-1β, IL-17, IFN-γ, TGF-β), autoantibodies, oxidative stress markers, immune cells (Tregs), soluble CDs (sCD25, sCD27) and chemokines (CXCL9, CXCL10) are still competing. However, the two latter may be preferable as both chemokines and soluble CDs are easy to measure and the available studies display promising results. A large multicenter study could make more definitive statements regarding their sensitivity and specificity.



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Spasticity in multiple sclerosis: Contribution of inflammation, autoimmune mediated neuronal damage and therapeutic interventions

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): Robert Patejdl, Uwe K. Zettl
In contrast to other diseases that go along with spasticity (e.g. spinal cord injury), spasticity in chronic autoimmune diseases involving the CNS is complicated by the ongoing damage of neuronal networks that leads to permanent changes in the clinical picture of spasticity.Multiple sclerosis (MS) is the most frequent autoimmune disease of the central nervous system (CNS) and spasticity is one of the most disabling symptoms. It occurs in more than 80% MS patients at some point of the disease and is associated with impaired ambulation, pain and the development of contractures.Besides causing cumulative structural damage, neuroinflammation occurring in MS leads to dynamic changes in motor circuit function and muscle tone that are caused by cytokines, prostaglandins, reactive oxygen species and stress hormones that affect neuronal circuits and thereby spasticity.The situation is complicated further by the fact that therapeutics used for the immunotherapy of MS may worsen spasticity and drugs used for the symptomatic treatment of spasticity have been shown to have the potential to alter immune cell function and CNS autoimmunity itself. This review summarizes the current knowledge on the immunologic pathways that are involved in the development, maintenance, dynamic changes and pharmacological modulation of spasticity in MS.



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Does type-I interferon drive systemic autoimmunity?

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): Cécile Picard, Alexandre Belot
Type-I interferon (IFN)-mediated immune response involves both innate and adaptive immune system and has a pivotal role in antiviral defence. A complex interplay of intracellular signaling pathways and tight regulatory systems drive the IFN activation. The observation of an aberrant stimulation of this system as a common molecular basis in peculiar inherited autoimmune and autoinflammatory disorders led to the concept of "type I interferonopathies". But the precise genetic dissection of this growing spectrum of diseases adds more and more complexity to the comprehension of this concept and a lot of unsolved questions remain such as how type I IFN can drive systemic inflammation in these clinically and genetically heterogeneous diseases.



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Bile Acids and Intestinal Microbiota in Autoimmune Cholestatic Liver Diseases

Publication date: Available online 8 July 2017
Source:Autoimmunity Reviews
Author(s): You Li, Ruqi Tang, Patrick S.C. Leung, M. Eric Gershwin, Xiong Ma
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acids transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses. However, progression of the disease may also affect the composition of gut microbiota, which in turn exacerbates the progression of cholestasis. In addition, the interaction between intestinal microbiota and bile acids is not unidirectional. Bile acids can shape the gut microbiota community, and in turn, intestinal microbes are able to alter bile acids pool. In general, gut microbiota actively communicate with bile acids, and together play an important role in the pathogenesis of PBC and PSC. Targeting the link between bile acids and microbiota offers exciting new perspectives for the treatment of those cholestatic liver diseases. This review highlights current understanding of the interactions between bile acids and intestinal microbiota and their roles in cholestatic liver diseases. Further, we postulate a bile acids-intestinal microbiota-cholestasis triangle, in the pathogenesis of cholestatic liver diseases and potential therapeutic strategies by targeting this triangle.



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THEMIS: Two Models, Different Thresholds

Publication date: Available online 8 July 2017
Source:Trends in Immunology
Author(s): Seeyoung Choi, Richard Cornall, Renaud Lesourne, Paul E. Love
THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR), but the mechanistic underpinnings of THEMIS function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling enabling thymocytes to reach the threshold for positive selection, avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.



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What is the evidence? Preventing psychological violence in the workplace

Publication date: Available online 8 July 2017
Source:Aggression and Violent Behavior
Author(s): Emily Schindeler, Danielle M. Reynald
Although criminology has actively engaged with psychological violence in the context of domestic violence and child abuse, it has been slower coming to the fore when it comes to such violence in the workplace. This is despite the well-documented human, organisational, community and service costs associated with such victimisation. As demonstrated in this review, the bulk of strategies that have been trialled to date has been devised from psychology, management and organisational development perspectives. However, there is a paucity of evidence that any of the interventions that are widely promoted have been subjected to robust evaluations or provided evidence of any long-term reduction in the incidence of violence as a consequence of such interventions. Acknowledging there no easy single recipe, it is timely to consider the potential of alternative approaches including the application of guardianship and related principles from the routine activity approach, which are well-established strategies for prevention of victimisation in a range of contexts as set out in this review.



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Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy

Publication date: Available online 8 July 2017
Source:Radiotherapy and Oncology
Author(s): Victoria Dunne, Mihaela Ghita, Donna M. Small, Caroline B.M. Coffey, Sinead Weldon, Clifford C. Taggart, Sarah O. Osman, Conor K. McGarry, Kevin M. Prise, Gerard G. Hanna, Karl T. Butterworth
Background and purposeTo evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis.Materials and methodsAZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining.ResultsAZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p<0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p>0.5) and histological scoring of radiation induced fibrosis (p>0.5).ConclusionInhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.



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A prospective study of proton reirradiation for recurrent and secondary soft tissue sarcoma

Publication date: Available online 8 July 2017
Source:Radiotherapy and Oncology
Author(s): David M. Guttmann, Melissa A. Frick, Ruben Carmona, Curtiland Deville, William P. Levin, Abigail T. Berman, Chidambaram Chinniah, Stephen M. Hahn, John P. Plastaras, Charles B. Simone
Background and purposeProton reirradiation for sarcoma has not been previously described. We hypothesized that this strategy would provide favorable toxicity and survival outcomes.Material and methodsPatients with soft tissue sarcoma in a previously-irradiated field were enrolled on a prospective trial of proton reirradiation. The primary endpoint was provider-reported acute toxicity. Secondary endpoints included late toxicities, local control, and overall survival.Results23 patients underwent proton reirradiation. Median time between radiation courses was 40.7months (range 10–272). No grade 4–5 toxicities were observed. One patient (4%) experienced acute grade 3 dysphagia. Common grade 2 acute toxicities were fatigue (26%), anorexia (17%), and urinary incontinence (13%). There were two grade 3 late wound infections (10%) and one grade 3 late wound complication (5%). Grade 2 late complications included lymphedema (10%), fracture (5%), and fibrosis (5%). At a median follow-up of 36months, the 3-year cumulative incidence of local failure was 41% (95% CI [20–63%]). Median overall survival and progression-free survival were 44 and 29months, respectively. In extremity patients, amputation was spared in 7/10 (70%).ConclusionsProton reirradiation of recurrent/secondary soft tissue sarcomas is well tolerated. While longer follow-up is needed, early survival outcomes in this high-risk population are encouraging.



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Multiple pro-tumorigenic functions of the human minor Histocompatibility Antigen-1 (HA-1) in melanoma progression

Publication date: Available online 8 July 2017
Source:Journal of Dermatological Science
Author(s): Peng Xu, Jinyuan Ma, Jingjing Ma, Weigang Zhang, Sen Guo, Zhe Jian, Ling Liu, Gang Wang, Tianwen Gao, Guannan Zhu, Chunying Li
BackgroundRemodeling of cytoskeleton plays an important role in development of multiple cancers, including melanoma. As a group of F-actin regulators, the Ras homology (Rho) GTPase-activating proteins (ARHGAPs) were reported by accumulating studies as a set of significant mediators in cell morphology, proliferation, migration and invasion.ObjectiveTo investigate the function of HMHA1 and its encode protein HA-1 in melanoma.MethodsThe mRNA microarray was performed to screen the expression of ARHGAP family genes between melanoma tissues and nevi tissues. QRT-PCR and Western Blot were used to detect the expression of mRNA of HMHA1 and its relevant protein HA-1 respectively. Small interfering RNA was used to knock down the expression of HMHA1. Cell-count kit 8 assays and colony formation assays were used to evaluate the cell proliferative viability of melanoma cells. Flow cytometry was employed to analyze cell apoptosis. Transwell assay and the observation of cell morphology were used to evaluate the invasive and migrating activity of melanoma cells.ResultsIn previous study, we first found that both the mRNA level of HMHA1and the expression of HA-1 were up-regulated in melanoma tissues and cell lines compared with nevi tissues and normal human melanocytes respectively. Blocking HMHA1 expression in melanoma cell lines WM35 and A375 suppressed their proliferation and function of colony forming. Moreover, silencing HMHA1 not only significantly increased cell apoptosis but also suppressed cell migration and invasion.ConclusionOur results demonstrate that HMHA1 significantly promotes melanoma cells proliferation, invasion and migration, and prevents cell apoptosis. Additionally, it can be considered as a new diagnostic marker and drug target of melanoma.



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Effects of low-dose Bisphenol A on calcium ion influx and on genes of proliferation and differentiation in immortalized human gingival cells in vitro: The role of estrogen receptor beta

Publication date: Available online 9 July 2017
Source:Dental Materials
Author(s): Matthias Ehrenmann, Pascal Tomakidi, Elmar Hellwig, Simon Daniel Schulz, Olga Polydorou
ObjectivesRelating to low-dose Bisphenol-A (BPA), there is still a lack of mechanistic studies in oral cells, representing the first targets of BPA by oral intake. The objective of this study was to investigate an assumed mechanistic interrelationship between both low-dose BPA-modulated Calcium ion (Ca²⁺) influx and cell behavior, and the estrogen receptor β (ERβ), in oral mucosal cells.MethodsIndirect immunofluorescence (IIF) was conducted on estrogen receptor beta (ERβ) activity after 1, 3, and 6days in response to 39nM BPA, 15μM BPA, and 200 pM 17β-Estradiol (E2). In addition to Ca²⁺ concentration measurement, qPCR for proliferation and differentiation biomarkers was performed, to examine cell behavior. Fulvestrant-mediated ER inhibition was employed to seek for a mechanistic role of ERβ in regulating BPA-emanating effects.ResultsWhile both E2 and BPA yielded ERβ activation, 39nM BPA and 200 pM E2 did not change MKI67 proliferation marker expression, but reduced transcription of differentiation markers. Conversely, 15μM BPA reduced MKI67 transcription, but significantly increased differentiation gene expression and intracellular Ca²⁺ levels. Fulvestrant-induced ERβ inhibition yielded complete elimination of all E2− and BPA-triggered modulatory effects, suggesting a mechanistic role of activated ERβ for BPA-mediated Ca²⁺ influx and keratinocyte differentiation.SignificanceConcerning cell behavior, these findings provide significant evidence of a threshold-dependent transcription of proliferation and differentiation-related genes as well as Ca²⁺ influx in response to 39nM and 15μM low-dose BPA, which identify a mechanistic role of activated ERβ in oral keratinocytes.



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Data on the no-load performance analysis of a tomato postharvest storage system

Publication date: August 2017
Source:Data in Brief, Volume 13
Author(s): Orhewere B. Ayomide, Oluseyi O. Ajayi, Solomon O. Banjo, Adesola A. Ajayi
In this present investigation, an original and detailed empirical data on the transfer of heat in a tomato postharvest storage system was presented. No-load tests were performed for a period of 96h. The heat distribution at different locations, namely the top, middle and bottom of the system was acquired, at a time interval of 30min for the test period. The humidity inside the system was taken into consideration. Thus, No-load tests with or without introduction of humidity were carried out and data showing the effect of a rise in humidity level, on temperature distribution were acquired. The temperatures at the external mechanical cooling components were acquired and could be used for showing the performance analysis of the storage system.



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A ratiometric two-photon probe for Ca2+ in live tissues and its application to spinal cord injury model

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Hyung Joong Kim, Chang Su Lim, Hyo Won Lee, Hye Sue Lee, Yun Ju Um, Hemant Kumar, Inbo Han, Hwan Myung Kim
Ratiometric imaging with a small-molecule probe is important for the in-situ quantitative analysis of chemical events. We developed a ratiometric two-photon fluorescent probe (SCa1-IREF) derived from dual dyes with different Stokes shifts. This probe has two identical windows: a Ca²⁺-sensing window and an internal reference window, with eliminated FRET interference. SCa1-IREF shows a marked change in the ratio upon response with Ca²⁺, significant two-photon brightness, considerable selectivity for Ca²⁺, and cell loading ability with low cytotoxicity. The ratiometric two-photon microscopy images revealed that this probe could directly and quantitatively estimate Ca²⁺ in live neurons and various tissues including rat spinal cord tissue. The studies of spinal cord injury model revealed that the Ca²⁺ level was significantly affected by elapsed time after injury. These results will provide useful applications for in-situ [Ca²⁺]i imaging and for the development of effective ratiometric probes.



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Laminin-111 enriched fibrin hydrogels for skeletal muscle regeneration

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Madison Marcinczyk, Hady Elmashhady, Muhamed Talovic, Andrew Dunn, Faiz Bugis, Koyal Garg
Laminin (LM)-111 supplementation has improved muscle regeneration in several models of disease and injury. This study investigated a novel hydrogel composed of fibrinogen and LM-111. Increasing LM-111 concentration (50–450 μg/mL) in fibrin hydrogels resulted in highly fibrous scaffolds with progressively thinner interlaced fibers. Rheological testing showed that all hydrogels had viscoelastic behavior and the Young's modulus ranged from 2-6KPa. C2C12 myobalsts showed a significant increase in VEGF production and decrease in IL-6 production on LM-111 enriched fibrin hydrogels as compared to pure fibrin hydrogels on day 4. Western blotting results showed a significant increase in MyoD and desmin protein quantity but a significant decrease in myogenin protein quantity in myoblasts cultured on the LM-111 (450 μg/mL) enriched fibrin hydrogel. Combined application of electromechanical stimulation significantly enhanced the production of VEGF and IGF-1 from myoblast seeded fibrin-LM-111 hydrogels. Taken together, these observations offer an important first step toward optimizing a tissue engineered constructs for skeletal muscle regeneration.



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“In vivo self-assembled” nanoprobes for optimizing autophagy-mediated chemotherapy

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Yao-Xin Lin, Yi Wang, Sheng-Lin Qiao, Hong-Wei An, Jie Wang, Yang Ma, Lei Wang, Hao Wang
Autophagic therapy is regarded as a promising strategy for disease treatment. Appropriate autophagy regulations in vivo play a crucial role in translating this new concept from benchside to bedside. So far, emerging technologies are required to spatially and quantitatively monitor autophagic process in vivo in order to minimize the cytotoxity concerns associated with autophagy-mediated therapy. We successfully demonstrate the "proof-of-concept" study on autophagy-mediated chemotherapy in mice. Here, we describe a photoacoustic (PA) nanoprobe based on "in vivo self-assembly" idea for real-time and quantitative detection of autophagy in mice for the first time. The purpurin-18 (P18) monomer is connected to hydrophilic poly(amidoamine) dendrimer (4^th generation) through a peptide (GKGSFGFTG) that can be cleaved by an autophagy-specific enzyme, i.e., ATG4B, consequently resulting in aggregation of P18 and enhanced PA signals. Based on this aggregation-induced "turn-on" PA signals, we noninvasively determine the ATG4B activity for monitoring autophagy of tumor in vivo. According to the results of PA imaging, we could optimize chemotherapy efficacy through precisely modulating autophagy, which thereby decrease systemic toxicity from chemotherapeutics and autophagy inhibitors. We envision it will pave the way for developing autophagy-based treatment of diseases in the future.



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Kinetics-mediate fabrication of multi-model bioimaging lanthanide nanoplates with controllable surface roughness for blood brain barrier transportation

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Peiyuan Wang, Chengli Wang, Lingfei Lu, Xiaomin Li, Wenxing Wang, Mengyao Zhao, Lidan Hu, Ahmed Mohamed El-Toni, Qin Li, Fan Zhang
Effective delivery of imaging agents or therapeutics to the brain has remained elusive due to the poor blood-brain barrier (BBB) permeability, resulting in the apparent risks of inefficient diagnosis and therapeutic agents for brain disease. Herein, we report on the surface roughness mediated BBB transportation for the first time. The lanthanide-based core/shell/shell structured NaYF4:Yb,Er@NaGdF4:Yb@NaNdF4:Yb nanoplates with controllable surface roughness and multi-model bioimaging features were synthesized and used to evaluate the surface roughness dependent BBB permeability without any surface bio-functionalization. By controlling the kinetics of the shell coating process, the hexagon-disc, multi-petals and six-petals nanoplates with different surface roughness can be obtained. Comparing with the NPs with less Ra and receptor-conjugated NPs, the obtained six-petals nanoplates with highest roughness exhibit excellent performance in BBB transportation and tumor targeting, which lay solid foundation for the diagnosis and the therapy of brain tumor.

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Development of non-pyrogenic magnetosome minerals coated with poly-l-lysine leading to full disappearance of intracranial U87-Luc glioblastoma in 100% of treated mice using magnetic hyperthermia

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Edouard Alphandéry, Ahmed Idbaih, Clovis Adam, Jean-Yves Delattre, Charlotte Schmitt, François Guyot, Imène Chebbi
Magnetic hyperthermia was reported to increase the survival of patients with recurrent glioblastoma by 7 months. This promising result may potentially be further improved by using iron oxide nanoparticles, called magnetosomes, which are synthesized by magnetotactic bacteria, extracted from these bacteria, purified to remove most endotoxins and organic material, and then coated with poly-l-lysine to yield a stable and non-pyrogenic nanoparticle suspension. Due to their ferrimagnetic behavior, high crystallinity and chain arrangement, these magnetosomes coated with poly-l-lysine (M-PLL) are characterized by a higher heating power than their chemically synthesized counterparts currently used in clinical trials. M-PLL-enhanced antitumor efficacy was demonstrated by administering 500–700 μg in iron of M-PLL to intracranial U87-Luc tumors of 1.5 mm³ and by exposing mice to 27 magnetic sessions each lasting 30 min, during which an alternating magnetic field of 202 kHz and 27 mT was applied. Treatment conditions were adjusted to reach a typical hyperthermia temperature of 42 °C during the first magnetic session. In 100% of treated mice, bioluminescence due to living glioblastoma cells fully disappeared 68 days following tumor cell implantation (D68). These mice were all still alive at D350. Histological analysis of their brain tissues revealed an absence of tumor cells, suggesting that they were fully cured. In comparison, antitumor efficacy was less pronounced in mice treated by the administration of IONP followed by 23 magnetic sessions, leading to full tumor bioluminescence disappearance in only 20% of the treated mice.

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Combined photodynamic and antibiotic therapy for skin disorder via lipase-sensitive liposomes with enhanced antimicrobial performance

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Songhee Jeong, Jonghwan Lee, Byeong Nam Im, Hyung Park, Kun Na
A lipase-sensitive singlet oxygen-producible and erythromycin-loaded liposome (LSSPL) was developed for combination antibacterial therapy for skin disorder. The LSSPL was synthesized by coating pullulan-pheophorbide a (PU-Pheo A) conjugates onto erythromycin-loaded liposomes composed of 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) and cholesterol. Lipase activity was chosen as the environmental-stimulus for the controlled release of erythromycin and Pheo A from LSSPL because skin inflammation-inducing Propionibacterium acnes (P. acnes) secrete extracellular lipases. The presence of P. acnes lipases disrupted LSSPLs by selective cleavage of their ester linkages, liberating erythromycin and Pheo A. Along with the antibacterial effect of erythromycin, additional laser irradiation onto Pheo A further achieved the inhibition of P. acnes growth and treatment of P. acnes-infected inflammation in nude mice back skin. Therefore, antimicrobial therapy, using a stimulus-responsiveness moiety, presents a feasible way to treat bacteria-induced skin disorders.



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Selective effect of hydroxyapatite nanoparticles on osteoporotic and healthy bone formation correlates with intracellular calcium homeostasis regulation

Publication date: Available online 8 July 2017
Source:Acta Biomaterialia
Author(s): Rui Zhao, Pengfei Xie, Kun Zhang, Zhurong Tang, Xuening Chen, Xiangdong Zhu, Yujiang Fan, Xiao Yang, Xingdong Zhang
Adequate bone substitutes osseointegration has been difficult to achieve in osteoporosis. Hydroxyapatite of the osteoporotic bone, secreted by pathologic osteoblasts, had a smaller crystal size and lower crystallinity than that of the normal. To date, little is known regarding the interaction of synthetic hydroxyapatite nanoparticles (HANPs) with osteoblasts born in bone rarefaction. The present study investigated the biological effects of HANPs on osteoblastic cells derived from osteoporotic rat bone (OVX-OB), in comparison with the healthy ones (SHM-OB). A selective effect of different concentrations of HANPs on the two cell lines was observed that the osteoporotic osteoblasts had a higher tolerance. Reductions in cell proliferation, ALP activity, collagen secretion and osteoblastic gene expressions were found in the SHM-OB when administered with HANPs concentration higher than 25 µg/ml. In contrast, those of the OVX-OB suffered no depression but benefited from 25-250 µg/ml HANPs in a dose-dependent manner. We demonstrated that the different effects of HANPs on osteoblasts were associated with the intracellular calcium influx into the endoplasmic reticulum. The in vivo bone defect model further confirmed that, with a critical HANPs concentration administration, the osteoporotic rats had more and mechanically matured new bone formation than the non-treated ones, whilst the sham rats healed no better than the natural healing control. Collectively, the observed epigenetic regulation of osteoblastic cell function by HANPs has significant implication on defining design parameters for a potential therapeutic use of nanomaterials.Statement of significanceIn this study, we investigated the biological effects of hydroxyapatite nanoparticles (HANPs) on osteoporotic rat bone and the derived osteoblast. Our findings revealed a previously unrecognized phenomenon that the osteoporotic individuals could benefit from higher concentrations of HANPs, as compared with the healthy individuals. The in vivo bone defect model confirmed that, with a critical HANPs concentration administration, the osteoporotic rats had more mechanically matured new bone formation than the non-treated ones, whilst the sham rats healed no better than the natural healing control. The selective effect of HANPs might be associated with the intracellular calcium influx into the endoplasmic reticulum. Collectively, the observed epigenetic regulation by HANPs has significant implication on defining design parameters for a potential therapeutic use of nanomaterials in a pathological condition.

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Pharmacological and Physical Vessel Modulation Strategies to Improve EPR-mediated Drug Targeting to Tumors

Publication date: Available online 8 July 2017
Source:Advanced Drug Delivery Reviews
Author(s): Tarun Ojha, Vertika Pathak, Yang Shi, Wim Hennink, Chrit Moonen, Gert Storm, Fabian Kiessling, Twan Lammers
Abstract.The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines.

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3D in vitro models of liver fibrosis

Publication date: Available online 8 July 2017
Source:Advanced Drug Delivery Reviews
Author(s): Leo A. van Grunsven
Animal testing is still the most popular preclinical assesment model for liver fibrosis. To develop efficient anti-fibrotic therapies, robust and representative in vitro models are urgently needed. The most widely used in vitro fibrosis model is the culture-induced activation of primary rodent hepatic stellate cells. While these cultures have contributed greatly to the current understanding of hepatic stellate cell activation, they seem to be inadequate to cover the complexity of this regenerative response. This review summarizes recent progress towards the development of 3D culture models of liver fibrosis. Thusfar, only a few hepatic culture systems have successfully implemented hepatic stellate cells (or other non-parenchymal cells) into hepatocyte cultures. Recent advances in bioprinting, spheroid- and precision-cut liver slice cultures and the use of microfluidic bioreactors will surely lead to valid 3D in vitro models of liver fibrosis in the near future.

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Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

Publication date: Available online 8 July 2017
Source:Advanced Drug Delivery Reviews
Author(s): Katharina Maisel, Maria Stella Sasso, Lambert Potin, Melody A. Swartz
Lymphatic vessels are the primary route of communication from peripheral tissues to the immune system; as such, they represent an important component of local immunity. In addition to their transport functions, new immunomodulatory roles for lymphatic vessels and lymphatic endothelial cells have come to light in recent years, demonstrating that lymphatic vessels help shape immune responses in a variety of ways: promoting tolerance to self-antigens, archiving antigen for later presentation, dampening effector immune responses, and resolving inflammation, among others. In addition to these new biological insights, the growing field of immunoengineering has begun to explore therapeutic approaches to utilize or exploit the lymphatic system for immunotherapy.

Graphical abstract

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Nano-technology based carriers for nitrogen-containing bisphosphonates delivery as sensitisers of γδ T cells for anticancer immunotherapy

Publication date: Available online 8 July 2017
Source:Advanced Drug Delivery Reviews
Author(s): Naomi O. Hodgins, Julie Tzu-Wen Wang, Khuloud T. Al-Jamal
Nitrogen containing bisphosphonates (N-BPs) including zoledronate (ZOL) and alendronate (ALD) inhibit farnesyl diphosphate synthase, and have been shown to have a cytotoxic affect against cancer cells as a monotherapy and to also sensitise tumour cells to destruction by γδ T cells. γδ T cells are a subset of human T lymphocytes and have a diverse range of roles in the immune system including the recognition and destruction of cancer cells. This property of γδ T cells can be harnessed for use in cancer immunotherapy through in vivo expansion or the adoptive transfer of ex vivo activated γδ T cells. The use of N-BPs with γδ T cells has been shown to have a synergistic effect in in vitro, animal and clinical studies.N-BPs have limited in vivo activity due to rapid clearance from the circulation. By encapsulating N-BPs in liposomes (L) it is possible to increase the levels of N-BPs at non-osseous tumour sites. L-ZOL and L-ALD have been shown to have different toxicological profiles than free ZOL or ALD. Both L-ALD and L-ZOL led to increased spleen weight, leucocytosis, neutrophilia and lymphocytopenia in mice after intravenous injection. L-ALD was shown to be better tolerated than L-ZOL in murine studies. Biodistribution studies have been performed in order to better understand the interaction of N-BPs and γδ T cells in vivo. Additionally, in vivo therapy studies have shown that mice treated with both L-ALD and γδ T cells had a significant reduction in tumour growth compared to mice treated with L-ALD or γδ T cells alone. The use of ligand-targeted liposomes may further increase the efficacy of this combinatory immunotherapy. Liposomes targeting the αvβ6 integrin receptor using the peptide A20FMDV2 had a greater ability than untargeted liposomes in sensitising cancer cells to destruction by γδ T cells in αvβ6 positive cancer cell lines.

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“Metformin-Resistant” Folic Acid Producing Probiotics or Folic Acid against Metformin’s Adverse Effects like Diarrhea

Publication date: Available online 8 July 2017
Source:Medical Hypotheses
Author(s): Abdullah Olgun
Metformin, first line medication in the treatment of type2 diabetes by millions of patients worldwide, causes gastrointestinal adverse effects (i.e. diarrhea) in approximately 30% of patients, frequently leading to discontinuation. Interestingly, metformin was reported to increase life span in a microscopic worm, Caenorhabditis elegans, by decreasing folate and methionine production of bacteria that this worm uses as a food source. Metformin can be expected to have a similar effect on some microorganisms of human gut microbiota. This can disturb the balance of gut microbiota and cause gastrointestinal adverse effects by altering folate production of some types of bacteria and suppress their growth. Metformin resistant probiotics can be discovered or generated by artificial evolution/selection,and used to prevent these adverse effects. These patients can also be managed with folate supplementation.



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When a Model becomes the Real Thing: A Neuro-Cognitive Account of ‘Demonic’ Possession

Publication date: Available online 8 July 2017
Source:Medical Hypotheses
Author(s): Ivaylo Borislavov Iotchev, Hein Thomas van Schie




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Pleotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications

Publication date: Available online 8 July 2017
Source:Medical Hypotheses
Author(s): Nicholas W. Carris, Srinivas M. Tipparaju, David J. Magness, Kalyan C. Chapalamadugu, Ronald R. Magness
The 2013 American Heart Association Blood Cholesterol Guidelines increased the number of patients recommended for statin therapy in the United States to 56 million. Two common statin side effects are muscle pain, referred to as "statin-associated muscle symptoms", and increased risk for new onset type-2-diabetes mellitus. Up to 25% of statin users report muscle symptoms resulting in many patients being switched to lower dose or lower potency statins, or refusing statins altogether. The most likely signaling mechanisms for statin-associated muscle symptoms overlaps with the proposed mechanism of statin-induced insulin resistance. Metformin has outstanding utility in reducing insulin resistance and preventing type-2-diabetes mellitus, but has not been studied for statin-associated muscle symptom rescue or prevention. The overlapping mechanisms of statin-associated muscle symptoms, statin-induced insulin resistance, and metformin offers the potential to address two common and detrimental side effects of statins. As statins are the single best medication class for preventing cardiovascular events the potential for clinical benefit is large given metabolic syndrome's growing prevalence in the US.Herein we hypothesize that metformin will rescue and prevent patients from statin-associated muscle symptoms. This hypothesis can benefit two patient groups: 1) patients at risk for diabetes who are taking a statin and experiencing muscle symptoms; and 2) patients with diabetes taking metformin who are to be started on a statin. Method to test Group 1) Symptom Rescue: randomized control trial of metformin versus placebo in patients with prediabetes who are already taking a statin, and are experiencing mild-to-moderate muscle symptoms. Method to test Group 2) Symptom Prevention: meta-analysis, of statin randomized control trials, with patient level data, comparing patients taking metformin at baseline to patients not taking metformin when a statin is started. An efficient method to simulate both symptom rescue and symptom prevention is a skeletal muscle cell culture model of statin-associated muscle symptom markers. These experiments would identify if metformin reverses (rescues) or prevents markers of statin-associated muscle symptoms. As metformin is recommended by the American Diabetes Association for type-2-diabetes mellitus prevention, yet not frequently used, validating this hypothesis will lead towards research and practice change including: a) decreases in the frequency of statin-associated muscle symptoms; leading to subsequent increases in statin therapy compliance; b) increases in metformin use in prediabetes with subsequent decrease in the incidence of type-2-diabetes mellitus; and c) decreases in complications of both cardiovascular disease and diabetes due to improved statin compliance and type-2-diabetes mellitus prevention.



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Antrodia camphorata inhibits metastasis and epithelial-to-mesenchymal transition via the modulation of claudin-1 and Wnt/β-catenin signaling pathways in human colon cancer cells

Publication date: 17 August 2017
Source:Journal of Ethnopharmacology, Volume 208
Author(s): You-Cheng Hseu, Yu-Hsien Chao, Kai-Yuan Lin, Tzong-Der Way, Hui-Yi Lin, Varadharajan Thiyagarajan, Hsin-Ling Yang
Ethnopharmacological relevanceAntrodia camphorata (AC) is a well known traditional Chinese medicinal mushroom in Taiwan, has been used to treat various diseases including cancer.Materials and methodsIn this study, we investigated the anti-metastatic and anti-EMT properties of a fermented culture broth of AC in human colon SW480^claudin−1- and metastatic SW620^claudin−1+ cancer cells in vitro.ResultsAC down-regulates claudin-1 and inhibits the proliferation and colony-formation abilities of both SW620^claudin−1+ and SW480^claudin−1- cells. In highly metastatic SW620^claudin−1+ cells, non-cytotoxic concentrations of AC significantly inhibited migration/invasion, accompanied by the down-regulation of MMP-2 and MMP-9 proteins. AC decreased nuclear translocation of Wnt/β-catenin through a GSK3β-dependent pathway. AC consistently inhibited EMT by up-regulating the epithelial and downregulating the mesenchymal marker proteins. In SW480^claudin−1- cells, AC suppressed migration/invasion potentially through the inhibition of the PI3K/AKT/NFκB signaling pathways without altering the expression levels of β-catenin and GSK3β proteins.ConclusionAltogether, this study demonstrates the anti-metastatic and anti-EMT activities of AC, which may contribute to the development of a chemopreventive agent for colon cancer.

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Gastroprotective actions of Taraxacum coreanum Nakai water extracts in ethanol-induced rat models of acute and chronic gastritis

Publication date: 17 August 2017
Source:Journal of Ethnopharmacology, Volume 208
Author(s): Hye Jeong Yang, Min Jung Kim, Dae Young Kwon, Eun Seon Kang, Suna Kang, Sunmin Park
Ethnopharmacological relevanceTaraxacum coreanum Nakai has been traditionally used for treating inflammatory diseases including gastrointestinal diseases.Aim of the studyWe studied whether water extracts of Taraxacum coreanum Nakai (TCN) had a protective effect on acute and chronic gastritis induced by ethanol/HCl in an animal model of gastritis and its mechanism was also explored.Materials and methodsIn the acute study, rats were orally administered 0.15g/mL dextrin (normal-control), 0.15g/mL dextrin (control), 0.05g/mL TCN (TCN-L), 0.15g/mL TCN (TCN-H), or 0.01g/mL omeprazole (orally; positive-control), followed by oral administration of 1mL of 60% ethanol plus 150mM HCl (inducer). In the chronic study, rats were administered 10% diluted inducer in drinking water, and 0.6% dextrin, 0.2% or 0.6% TCN, and 0.05% omeprazole were administered in chow for 4 weeks. Acid content, gastric structure, oxidative stress, and markers of inflammation in the stomach tissue were measured at the end of experiment.ResultsAcute and chronic ethanol/HCl administration caused the inner layer of the stomach to redden, hemorrhage, and edema in the control group; TCN-H reduced these symptoms more effectively than did the omeprazole positive-control. Acid production and total acidity in the stomach increased in the control group, which was markedly suppressed by omeprazole. TCN also reduced the acid production and acidity, but not to the same degree as omeprazole. H-E and PAS staining revealed that in the inner layer of the stomach, cellular structure was disrupted, with an increased nuclear size and thickness, disarrangement, and decreased mucin in the control group. TCN prevented the cellular disruption in the inner layer, and TCN-H was more effective than the positive-control. This was associated with oxidative stress and inflammation. TCN dose-dependently reduced the infiltration of mast cells and TNF-α expression in the inner layer of the stomach, and decreased lipid peroxides by increasing superoxide dismutase and glutathione peroxidase expression.ConclusionsTCN-H acutely and chronically protected against gastritis and gastric ulcer by reducing oxidative stress and inflammation, not by completely suppressing gastric acid production.

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Xiaochaihutang attenuates depressive/anxiety-like behaviors of social isolation-reared mice by regulating monoaminergic system, neurogenesis and BDNF expression

Publication date: 17 August 2017
Source:Journal of Ethnopharmacology, Volume 208
Author(s): Jie Ma, Fang Wang, Jingyu Yang, Yingxu Dong, Guangyue Su, Kuo Zhang, Xing Pan, Ping Ma, Tingshuo Zhou, Chunfu Wu
Ethnopharmacological relevanceXiaochaihutang (XCHT), as a classical herbal formula for the treatment of "Shaoyang syndrome" has been demonstrated to exert an antidepressant effect in multiple animal models of depression as shown in our previous studies. However, the effects of XCHT on social isolation (SI)-reared mice have not been investigated. This study aims to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice, and its implicated mechanisms, including alterations in the monoaminergic system, neurogenesis and neurotrophin expression.Materials and methodsMale C57 BL/6J mice (aged 4 weeks after weaning) were reared isolatedly for 8 weeks and XCHT (0.8, 2.3, 7.0g/kg) were given by gavage once a day. Forced swimming test (FST), tail suspension test (TST), open field test (OFT), elevated-plus maze test (EPM) and intruder-induced aggression test were used to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice after administration of XCHT for 6 weeks. HPLC-MS/MS was performed to quantify the levels of neurotransmitters in the hippocampus by in vivo microdialysis, while western immunoblotting was used to evaluate the action of XCHT on the synthesis, transport and degradation of monoamine neurotransmitters. Immunofluorescence was used to study the effects of XCHT on neurogenesis and neurotrophin expression, including Ki-67, DCX, BrdU and BDNF.ResultsOur results showed that administration of XCHT (0.8, 2.3 and 7.0g/kg) for 6 weeks significantly attenuated the increase in immobility time in TST and FST, improved the anxiety-like behaviors in OFT and EPM, and improved the aggressive behaviors of SI-reared mice. XCHT significantly elevated monoamine neurotransmitters levels and inhibited 5-HT turnover (5-HIAA/5-HT) in hippocampal microdialysates of SI-reared mice. In addition, we found XCHT enhanced monoamine neurotransmitter synthesis enzymes (TPH2 and TH) expressions, inhibited serotonin transporter (SERT) expression and decreased monoamine neurotransmitter degradation enzyme (MAOA) expression in the hippocampus of SI-reared mice for the first time. Moreover, XCHT significantly augmented hippocampal neurogenesis and BDNF expression in hippocampus of SI-reared mice.ConclusionsOur results showed for the first time that XCHT improved depressive/anxiety-like behaviors of SI-reared mice by regulating the monoaminergic system, neurogenesis and neurotrophin expression. The findings indicate that XCHT may have a therapeutic application for early-life stress model of depression and in turn provide further evidence supporting XCHT a novel potential antidepressant from a distinct perspective.

Graphical abstract

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Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Gertraud Maskarinec, Laureen Dartois, Suzette Delaloge, John Hopper, Françoise Clavel-Chapelon, Laura Baglietto
BackgroundMammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent.MethodsDense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses.ResultsOverall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33–1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR1SD=2.25; 95% CI, 1.67–3.04) than in women reporting none (OR1SD=1.41; 95% CI, 1.24–1.60; pheterogeneity=0.002). Similarly, effect modification by FHBC was observed using categories of PMD (pheterogeneity=0.02) with respective ORs of 15.16 (95% CI, 4.23–54.28) vs. 3.14 (95% CI, 1.89–5.22) for ≥50% vs. <10% PMD.ConclusionsThe stronger association between mammographic density and breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density.



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Fifteen Year Results of Radiofrequency Ablation, Using VNUS Closure, for the Abolition of Truncal Venous Reflux in Patients with Varicose Veins

Publication date: Available online 8 July 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): M.S. Whiteley, I. Shiangoli, S.J. Dos Santos, E.B. Dabbs, T.J. Fernandez-Hart, J.M. Holdstock
ObjectivesEndovenous thermal ablation (EVTA) of varicose veins was introduced in the late 1990s with radiofrequency ablation (RFA) using the VNUS Closure device. The results of the original VNUS Closure device for the abolition of truncal venous reflux at 15 years are reported.MethodsA prospective audit of a group of patients treated with VNUS Closure 15 years previously was carried out, using clinical assessment and duplex ultrasound. A total of 189 patients were treated with VNUS Closure between March 1999 and December 2001 and were invited for clinical assessment (subjective and objective) and duplex ultrasonography (DUS) to assess treatment outcome and de novo disease progression. DUS outcome of the treated vein was graded: 1, complete success (complete atrophy); 2, partial success (> 1 patent section; none giving rise to recurrent varicose veins); 3, partial failure (≥ 1 patent sections giving rise to recurrent varicose veins); 4, complete failure.ResultsFifty-eight patients (91 legs, 101 truncal veins) returned for follow-up DUS, giving a 31.5% response rate (many patients had moved or had died in the 15 years). Two truncal veins had been excluded following treatment elsewhere presumably for partial or complete failure. At a mean of 15.4 years post-procedure, 51 (56%) reported no varicose veins, 58 (100%) that they were pleased that they had the procedure and 57 (98%) that they would recommend the procedure. DUS showed 88% of patients achieved success with no clinical recurrence in the originally treated veins. De novo reflux was identified in 47 of 91 legs (51.6%), showing disease progression in veins that were originally competent.ConclusionsRFA with VNUS Closure achieved excellent long-term technical success in treating venous reflux in truncal veins 15 years post-procedure, demonstrated by DUS. This bodes well for the increased use of EVTA in treating truncal vein reflux.



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Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease

Publication date: October 2017
Source:Neurobiology of Aging, Volume 58
Author(s): Amer Ashrafi, Pierre Garcia, Heike Kollmus, Klaus Schughart, Antonio Del Sol, Manuel Buttini, Enrico Glaab
Regulator of G-protein signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson's disease (PD). In the case of PD, the main current options for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects and reduced effectiveness over the long term. Research on new nondopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection end points has not yet been demonstrated. Here, we use the 6-hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA–induced injury and show enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a nondopaminergic target for PD should be approached with caution.



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Evaluation of selective peripheral neurotomies in the treatment of refractory lower limb spasticity in adults

Publication date: Available online 8 July 2017
Source:Alexandria Journal of Medicine
Author(s): Sherif M. Salem, Waleed Fawzy El-Saadany, Wael Ahmed Fouad, Walid A. Abdel Ghany
Background"Selective peripheral neurotomies" (SPNs) are indicated for the treatment of refractory focal and multifocal spasticity of lower limbs in adults.ObjectiveTo evaluate the surgical results of selective peripheral neurotomies in 20 adult patients who had refractory focal & multifocal spasticity of the lower limbs, follow up period of one year.Patients and MethodsProspective study included 20 adult patients who had refractory spasticity of the lower limbs. Preoperative evaluation for muscle tone using Modified Ashworth Score (MAS), muscle power using Medical Research Council Scale (MRCS), functional assessment using Oswestry Functional Scale (OFS) and Range Of Motion (ROM) using manual goniometry were done for all patients. All cases underwent surgery in the form of SPN of tibial, obturator, sciatic and/or femoral nerves. Follow up of the patients was done at 10th day, 3, 6months and one year postoperatively.ResultsThe mean age of patients was 31.35±12.42years. There were statistically significant improvement of muscle tone, muscle power, functional assessment and range of motion between preoperative and one year postoperative values. Improvement of the muscle tone was from a preoperative Mean±SD of 3.60±0.68 on MAS to a postoperative 2.30±0.86 at one year, improvement of muscle power on MRCS was from preoperative Mean±SD 3.75±1.08 to postoperative 4.08±0.69 at one year, There was a functional improvement from a preoperative Mean±SD of 3.0±0.73 on OFS to 3.60±0.60 at one year postoperatively. Also, there was a significant improvement between preoperative ROM Mean±SD 61.25±15.29 and one year postoperatively 72.25±12.19.ConclusionsSelective peripheral neurotomies could effectively improve muscle tone, muscle power, functional performance & range of motion in patients with refractory focal and multifocal spasticity in the lower limbs.



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IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice

Publication date: October 2017
Source:Molecular Immunology, Volume 90
Author(s): Rongguo He, Hui Yin, Baohong Yuan, Tao Liu, Li Luo, Ping Huang, Liangcheng Dai, Kang Zeng
IL-33 is a newly discovered member of the IL-1 family and has been identified as a potent inducer of Th2 type immunity. Emerging evidence imply that IL-33 may also act as an alarm to alert the immune system when released by epithelial barrier tissues during trauma or infection. In this study, we further investigate the potential efficacy of IL-33 on dermal wound healing in streptozotocin–induced diabetic mice. A full-thickness skin wound was generated on the back of diabetic mice and treated with IL-33 or vehicle topically. Our data showed that IL-33 delivery contributed to diabetic wound closure with wounds gaping narrower and exhibiting elevated re-epithelialization. IL-33 promoted the new extracellular matrix (ECM) deposition and angiogenesis formation, which indicates an important role of IL-33 on matrix synthesis and neovascularization. Meanwhile, IL-33 accelerated the development of M2 macrophages in wound sites in vivo, and amplified IL-13-induced polarization of bone marrow-derived macrophages toward a M2 phenotype in vitro. Furthermore, IL-33-amplified M2 macrophages augmented the proliferation of fibroblasts and ECM deposition. All together, these results strongly suggest manipulation of IL-33-mediated signal might be a potential therapeutic approach for diabetic skin wounds.



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Nesfatin-1 inhibits voltage gated K+ channels in pancreatic beta cells.

Publication date: Available online 8 July 2017
Source:Peptides
Author(s): Yuko Maejima, Shoichiro Horita, Daisuke Kobayashi, Miho Aoki, Rie O'hashi, Ryota Imai, Kazuho Sakamoto, Masatomo Mori, Katsuya Takasu, Kazuma Ogawa, Seiichi Takenoshita, Songji Zhao, Akihiro Hazama, Kenju Shimomura
The anorexigenic neuropeptide NEFA/nucleobindin 2 (NUCB2)/nesfatin-1-containing neurons are distributed in the brain regions involved in feeding regulation. In spite of the growing knowledge of its physiological functions through extensive studies, its molecular mechanism of reaction, including its receptor, remains unknown. NUCB2/nesfatin-1 is also involved in various peripheral regulations, including glucose homeostasis. In pancreatic beta-cells, NUCB2/nesfatin-1 is reported to enhance glucose-stimulated insulin secretion (GSIS) but its exact mechanism remains unknown.To clarify this mechanism, we measured the effect of nesfatin-1 on the electrical activity of pancreatic beta-cells. Using mouse primary beta cells, we measured changes in the ATP-sensitive K⁺ (KATP) channel current, the voltage-gated K⁺ (Kv) channel current, and insulin secretion upon application of nesfatin-1.Nesfatin-1 inhibited the Kv channel, but KATP channel activity was unaffected. Nesfatin-1 enhanced insulin secretion to a same level as Kv channel blocker tetraethylammonium (TEA). The effect was not further enhanced when nesfatin-1 and TEA were applied simultaneously. The inhibition binding assay with [¹²⁵I]nesfatin-1 in Kv2.1 channels, major contributor of Kv current in beta cell, expressing HEK239 cells indicated the binding of nesfatin-1 on Kv2.1 channel.Because Kv channel inhibition enhances insulin secretion under high glucose conditions, our present data suggest a possible mechanism of nesfatin-1 on enhancing GSIS through regulation of ion channels rather than its unidentified receptor.



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Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test

Publication date: Available online 8 July 2017
Source:Peptides
Author(s): A. Rizzi, C. Ruzza, S. Bianco, C. Trapella, G. Calo'
Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1–1mgkg⁻¹) and morphine (0.1–10mgkg⁻¹) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01–0.1mgkg⁻¹) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory.



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A novel molecularly imprinted electrochemical sensor modified with carbon dots, chitosan, gold nanoparticles for the determination of patulin

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Wei Guo, Fuwei Pi, Hongxia Zhang, Jiadi Sun, Yinzhi Zhang, Xiulan Sun
In this paper, molecular imprinting technique was applied to the electrochemical sensor. We used 2-oxindole as dummy template, ρ-Aminothiophenol (ρ-ATP) as functional monomers, combined with the high sensitivity of electrochemical detection, to achieve a specific and efficient detection of patulin in fruit juice. In addition, carbon dots and chitosan were used as the modifying material to improve electron-transfer rate, expand the electroactive surface of glassy carbon electrode and enhance strength of the signal. The Au–S bond and hydrogen bond were employed to complete the assembly of the ρ-ATP and 2-oxindole on the surface of the electrode. Then, polymer membranes were formed by electropolymerization in a polymer solution containing ρ-ATP, HAuCl4, tetrabutylammonium perchlorate (TBAP) and the template molecule 2- oxindole. After elution, the specific cavity can adsorb the target patulin. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) measurements were performed to monitor the electropolymerization process and its optimization. Transmission electron microscopy (TEM), Scanning electron microscopy (SEM) and Atomic force microscopy (AFM) analyses were used for characterization. This was the first time that the molecularly imprinted polymer (MIP) technology combined with carbon dots, chitosan and Au nanoparticles modification and was applied in the electrochemical detection of patulin. The linear response range of the MIP sensor was from 1 × 10^–12 to 1 × 10⁻⁹molL⁻¹ and the limit of detection (LOD) was 7.57 × 10^–13molL⁻¹. The sensor had a high-speed real-time detection capability, low sample consumption, high sensitivity, low interference, good stability and could become a new promising method for the detection of patulin.



http://ift.tt/2sZxGAb

Electrochemical peptide sensor for diagnosing adenoma-carcinoma transition in colon cancer

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Jong Min Lim, Myung Yi Ryu, Jong Won Yun, Tae Jung Park, Jong Pil Park
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Therefore, more sensitive and early diagnostic methods for CRC are urgently needed. In this study, an efficient electrochemical biosensor for early diagnosis of adenoma-to-carcinoma progression that employs a series of chemically modified affinity peptides was developed. A series of amino acid-substituted and cysteine-incorporated synthetic peptides with flexible linkers was chemically synthesized and immobilized to a gold sensor layer; performance of the sensor was monitored using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Potential affinity peptides (LRG1 BP1–BP4) specific for the LRG1 biomarker as a target protein were chosen according to a quantitative current decrease and dynamic impedance increase by CV and EIS, respectively. Using EIS, the Kd value of the LRG1 BP3 peptide was found to be 8.3 ± 2.7nM. The applicability of the sensor to detect LRG1 proteins was confirmed in human plasma from colorectal adenomas and carcinomas (n = 20 in each group). The detection of LRG1 in accordance with the ΔRct value (electron-transfer resistance at the electrode surface) of the sensor layer incorporating LRG1 BP3 peptides showed a statistically significant difference (p < 0.001) between adenomas and carcinomas, indicating that the potential use of this biosensing platform for detecting the CRC biomarker, as well as for monitoring the colorectal adenoma-to-carcinoma transition in an electrochemically miniaturized biosensor (e-chem biosensor) in point-of-care testing, is possible.



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An efficient electrochemiluminescence amplification strategy via bis-co-reaction accelerator for sensitive detection of laminin to monitor overnutrition associated liver damage

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Jing Zhao, Wen-Bin Liang, Yan-Mei Lei, Yang-Xue Ou, Ya-Qin Chai, Ruo Yuan, Ying Zhuo
With the world wildly improvement in dietary and nutrition status, it couldn't be ignored that the chronic liver disease (CLD) resulted from the overnutrition. In order to estimate nutrition status for healthy living, an efficient and sensitive electrochemiluminescence (ECL) sandwich immunosensor of laminin (LN), a marker of CLD, was proposed for early diagnosis of CLD. In this work, the anodic ECL behavior of perylene derivative using H2O2 as co-reactant was demonstrated and the possible ECL mechanism was proposed. Furthermore, a significantly amplified ECL response could be obtained via Ag and Fe-Fe2O3 nanoparticles as bis-co-reaction accelerator. As a result, the proposed ECL immunosensor performed good sensitivity and accuracy with a detection limit down to 0.03pg/mL. Moreover, this immunosensor was successfully employed to monitor patient serum, which exhibited an alternative avenue for the early diagnosis of other diseases via proteins, nucleotide sequence, microRNA and cells.



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Electrochemical nucleic acid detection based on parallel structural dsDNA/recombinant azurin hybrid

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Mohsen Mohammadniaei, Taek Lee, Jinho Yoon, Donghyun Lee, Jeong-Woo Choi
Several challenges remained to fabricate a molecular-level nucleic acid biosensor such as surface immobilization control, single mismatch detection and low current response. To overcome those issues, for the first time, authors presented a novel parallel structural dsDNA/recombinant azurin (PSD/rAzu) hybrid structure for the general nucleic acid detection. The PSD was designed and introduced by the optimized 8 Ag⁺ ions to have greater conductivity than the canonical dsDNA, and conjugated with rAzu to develop a general platform for electrochemical detection of miRNAs and viral DNAs with high reproducibility and ultra-sensitivity towards single base pair mutation. Thanks to the bifunctional rAzu as the selective spacer and electrochemical signal mediator, in the presence of the target strand, the imperfect PSD switched rapidly to the upright position where the Ag⁺ ions intercalated between C-C mismatches of dsDNAs at the top of each structure brought further from the electrode surface resulting in a significant electrochemical signal drop of the Ag⁺ ions. The charge transfer (CT) mechanism across the hybrid structure was simply clarified on the basis of the redox potential location of the species. The electrical conductivity of DNAs were measured using scanning tunneling spectroscopy (STS) at the molecular scale and cyclic voltammetry (CV) technique based on the reduction of Ag⁺ ion. The proposed PSD/rAzu hybrid structure with a great capability of single mutation recognition and miRNA expression level profiling in cancer cells holds a very promising platform to be studied for further development of various kinds of nanoscale biosensors, bioelectronic devices.



http://ift.tt/2sDewRf

Selective binding of Pb2+ with manganese-terephthalic acid MOF/SWCNTs: Theoretical modeling, experimental study and electroanalytical application

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Fuxian Cai, Qinghua Wang, Xiaoqian Chen, Weiwei Qiu, Fengping Zhan, Fei Gao, Qingxiang Wang
A nanocomposite of flake-shaped manganese-terephthalic acid MOF/single-walled carbon nanotubes (Mn(TPA)-SWCNTs) was synthesized using manganese chloride, terephthalic acid and SWCNTs as raw materials. Theoretical modeling study shows that the Mn(TPA) component has stronger adsorption ability to lead ion (Pb²⁺) than the other common heavy metal ions, which is in good agreement with the result of electrochemical assay. Then, the Mn(TPA)-SWCNTs were used as a sensing matrix for the voltammetric determination of Pb²⁺. The results displayed that the sensor shows high analytical performance for Pb²⁺ due to the synergy of Mn(TPA) with highly selective binding to Pb²⁺ and SWCNTs with high electronic conductivity. Under the optimal conditions, the Mn(TPA)-SWCNTs-based electrochemical sensor presented a wide linear response over the concentration range from 0.10 to 14.0μM. The limit of detection was achieved to be 38nM. Satisfactory results were also achieved when the Mn(TPA)-SWCNTs-based sensor was utilized for the determination of Pb²⁺ in the practical samples of industrial wastewater and human serum, suggesting great promising of the sensor for practical application.



http://ift.tt/2ttCoK0

An ultrasensitive bioluminogenic probe of γ-Glutamyltranspeptidase in vivo and in human serum for tumor diagnosis

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Shuang Li, Rui Hu, Chenlin Yang, Xin Zhang, Yi Zeng, Shuangqing Wang, Xudong Guo, Yi Li, Xiaopin Cai, Shirui Li, Chengwu Han, Guoqiang Yang
Abnormal expression of γ-Glutamyltranspeptidase (GGT) in living organisms is closely implicated in the development of several human tumors. The GGT levels in tissue and serum have emerged as a potential criterion for tumor diagnosis. However, precise "light up" GGT activity in vivo is still challenging due to the signal interferes of background. Bioluminescence based on the firefly luciferase-catalyzed reaction for light production provides a feasible strategy for GGT detection in vivo. In this report, a bioluminogenic probe, Glu-Luc, was designed and synthesized by connecting D-luciferin with γ-glutamyl group. The cleavage of γ-glutamyl group is triggered by GGT, resulting in the release of D-luciferin, which generates a bright bioluminescence emission in the present of luciferase and ATP. The probe exhibits very high selectivity and sensitivity toward GGT activity from in vitro to in vivo and in clinical samples, which offers a promising tool for investigations of the GGT-overexpressing related biological process including tumor diagnosis and prognosis in living organisms.



http://ift.tt/2tWmAAN

Portable amperometric immunosensor for histamine detection using Prussian blue-chitosan-gold nanoparticle nanocomposite films

Publication date: 15 December 2017
Source:Biosensors and Bioelectronics, Volume 98
Author(s): Xiu-Xiu Dong, Jin-Yi Yang, Lin Luo, Yi-Feng Zhang, Chuanbin Mao, Yuan-Ming Sun, Hong-Tao Lei, Yu-Dong Shen, Ross C. Beier, Zhen-Lin Xu
Histamine (HA) is a biogenic amine that can accumulate to high concentration levels in food as a result of microbial activity and can cause toxic effects in consumers. In this work, a portable electrochemical immunosensor capable of detecting HA with high sensitivity and selectivity was developed. Prussian blue-chitosan-gold nanoparticle (PB-CS-AuNP) nanocomposite films with excellent biocompatibility were synthesized and characterized by scanning electron microscopy and energy dispersive X-ray analysis. The PB-CS-AuNP were coated onto a screen-printed electrode by one-step electrodeposition and used to conjugate the HA ovalbumin conjugate (HA-Ag). HA was determined by a competition between the coating HA-Ag and the HRP labeled HA antibody (HRP-HA-Ab). After careful optimization of assay conditions and Box-Behnken analysis, the developed immunosensor showed a linear range from 0.01 to 100μg/mL for HA in fish samples. The average recoveries from spiked samples ranged from 97.25% to 105%. The biosensor also showed good specificity, reproducibility, and stability, indicating its potential application in monitoring HA in a simple and low cost manner.



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