Discovery of a novel series of N-hydroxypyridone derivatives protecting astrocytes against hydrogen peroxide-induced toxicity via improved mitochondrial functionality

Publication date: Available online 3 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sarbjit Singh, Ja-Il Goo, Hyojin Noh, Sung Jae Lee, Myoung Woo Kim, Hyejun Park, Hitesh B. Jalani, Kyeong Lee, Chunsook Kim, Won-Ki Kim, Chung Ju, Yongseok Choi
Astrocytes play a key role in brain homeostasis, protecting neurons against neurotoxic stimuli such as oxidative stress. Therefore, the neuroprotective therapeutics that enhance astrocytic functionality has been regarded as a promising strategy to reduce brain damage. We previously reported that ciclopirox, a well-known antifungal N-hydroxypyridone compound, protects astrocytes from oxidative stress by enhancing mitochondrial function. Using the N-hydroxypyridone scaffold, we have synthesized a series of cytoprotective derivatives. Mitochondrial activity assay showed that N-hydroxypyridone derivatives with biphenyl group have comparable to better protective effects than ciclopirox in astrocytes exposed to H2O2. N-hydroxypyridone derivatives, especially 11g, inhibited H2O2-induced detrioration of mitochondrial membrane potential and oxygen consumption rate, and significantly improved cell viability of astrocytes. The results indicate that the N-hydoxypyridone motif can provide a novel cytoprotective scaffold for astrocytes via enhancing mitochondrial functionality.

Graphical abstract

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3,4-dihydropyrimidinone-coumarin analogues as a new class of selective agent against S. aureus: Synthesis, biological evaluation and molecular modeling study

Publication date: Available online 5 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Nirmala S. Naik, Lokesh A. Shastri, Shrinivas D. Joshi, Sheshagiri R. Dixit, Bahubali M. Chougala, S. Samundeeswari, Megharaj Holiyachi, Farzanabi Shaikh, Jyoti Madar, Rashmi Kulkarni, Vinay Sunagar
Bacterial infections are increasingly difficult to combat as bacteria evolve resistance to antibiotic drugs and have severely compromised the arsenal of antibiotic drugs. On the other hand matrix metalloproteinases (MMPs) play a fundamental role in inflammation and extracellular matrix degradation in physiological and pathological conditions. In search of potent antibiotic, taking coumarin and dihydropyrimidinone as lead compound, a green, eco-friendly and efficient protocol has been developed and synthesized the dihydropyrimidin-2(1H)-one/thione derivatives of coumarin 3/4 from substituted 4-formylcoumarins 2 and ethylacetoacetate using urea/thiourea in the presence of catalytic amount of ceric ammonium nitrate is reported. All the synthesized compounds were evaluated for their antibacterial activity against four bacterial strains by broth dilution method. The tested compounds have exhibited promising in vitro potency with low MIC values against the drug susceptive S. aureus strain with low MIC values ranging from 0.2-6.25 μg/mL. The in vivo anti-inflammatory potency of 3a-e and 4a-e by gelatin zymography is comparable to that of tetracycline. Molecular docking study performed for all the synthesized compounds with S. aureus DNA gyrase and results obtained were quite promising.

Graphical abstract

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Development of 111In-labeled Exendin(9-39) Derivatives for Single-Photon Emission Computed Tomography Imaging of Insulinoma

Publication date: Available online 3 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroyuki Kimura, Hirokazu Matsuda, Yu Ogawa, Hiroyuki Fujimoto, Kentaro Toyoda, Naotaka Fujita, Kenji Arimitsu, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji
Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (¹¹¹In)-benzyl-diethylenetriaminepentaacetic acid (¹¹¹In-BnDTPA)-conjugated exendin(9-39), ¹¹¹In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. ^natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50 = 2.5 nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of ¹¹¹In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6% ID/g at 15 min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B = 2.55, T/M = 22.7, T/P = 2.7 at 1 h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1 h after ¹¹¹In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of ¹¹¹In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, ¹¹¹In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30 min post-injection. These results suggest that ¹¹¹In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.

Graphical abstract

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A mathematical model for the determination of forming tissue moduli in needled-nonwoven scaffolds

Publication date: Available online 5 January 2017
Source:Acta Biomaterialia
Author(s): Joao S. Soares, Will Zhang, Michael S. Sacks
Formation of engineering tissues (ET) remains an important scientific area of investigation for both clinical translational and mechanobiological studies. Needled-nonwoven (NNW) scaffolds represent one of the most ubiquitous biomaterials based on their well-documented capacity to sustain tissue formation and the unique property of substantial construct stiffness amplification, the latter allowing for very sensitive determination of forming tissue modulus. Yet, their use in more fundamental studies is hampered by the lack of (1) substantial understanding of the mechanics of the NNW scaffold itself under finite deformations and means to model the complex mechanical interactions between scaffold fibers, cells, and de novo tissue; and (2) rational models with reliable predictive capabilities describing their evolving mechanical properties and their response to mechanical stimulation. Our objective is to quantify the mechanical properties of the forming ET phase in constructs that utilize NNW scaffolds. We present herein a novel mathematical model to quantify their stiffness based on explicit considerations of the modulation of NNW scaffold fiber-fiber interactions and effective fiber stiffness by surrounding de novo ECM. Specifically, fibers in NNW scaffolds are effectively stiffer than if acting alone due to extensive fiber-fiber cross-over points that impart changes in fiber geometry, particularly crimp wavelength and amplitude. Fiber-fiber interactions in NNW scaffolds also play significant role in the bulk anisotropy of the material, mainly due to fiber buckling and large translational out-of-plane displacements occurring to fibers undergoing contraction. To calibrate the model parameters, we mechanically tested impregnated NNW scaffolds with polyacrylamide (PAM) gels with a wide range of moduli with values chosen to mimic the effects of surrounding tissues on the scaffold fiber network. Results indicated a high degree of model fidelity over a wide range of planar strains. Lastly, we illustrated the impact of our modeling approach quantifying the stiffness of engineered ECM after in vitro incubation and early stages of in vivo implantation obtained in a concurrent study of engineered tissue pulmonary valves in an ovine model.Statement of Significance"A mathematical model for the determination of forming tissue moduli in needled-nonwoven scaffolds" Regenerative medicine has the potential to fully restore diseased tissues or entire organs with engineered tissues. Needled-nonwoven scaffolds can be employed to serve as the support for their growth. However, there is a lack of understanding of the mechanics of these materials and their interactions with the forming tissues. We developed a mathematical model for these scaffold-tissue composites to quantify the mechanical properties of the forming tissues. Firstly, these measurements are pivotal to achieve functional requirements for tissue engineering implants; however, the theoretical development yielded critical insight into particular mechanisms and behaviors of these scaffolds that were not possible to conjecture without the insight given by modeling, let alone describe or foresee a priori.

Graphical abstract

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The Effect of Polyanhydride Chemistry in Particle-based Cancer Vaccines on the Magnitude of the Antitumor Immune Response

Publication date: Available online 4 January 2017
Source:Acta Biomaterialia
Author(s): Emad I. Wafa, Sean M. Geary, Jonathan T. Goodman, Balaji Narasimhan, Aliasger K. Salem
The goal of this research is to study the effect of polyanhydride chemistry on the immune response induced by a prophylactic cancer vaccine based on biodegradable polyanhydride particles. To achieve this goal, different compositions of polyanhydride copolymers based on 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG), 1,6-bis-(p-carboxyphenoxy)-hexane (CPH), and sebacic anhydride (SA) were synthesized by melt polycondensation, and polyanhydride copolymer particles encapsulating a model antigen, ovalbumin (OVA), were then synthesized using a double emulsion solvent evaporation technique. The ability of three different compositions of polyanhydride copolymers (50:50 CPTEG:CPH, 20:80 CPTEG:CPH, and 20:80 CPH:SA) encapsulating OVA to elicit immune responses was investigated. In addition, the impact of unmethylated oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODN), an immunological adjuvant, on the immune response was also studied. The immune response to cancer vaccines was measured after treatment of C57BL/6J mice with two subcutaneous injections, seven days apart, of 50 μg OVA encapsulated in particles composed of different polyanhydride copolymers with or without 25 μg CpG ODN. In vivo studies showed that 20:80 CPTEG:CPH particles encapsulating OVA significantly stimulated the highest level of CD8⁺ T lymphocytes, generated the highest serum titers of OVA-specific IgG antibodies, and provided longer protection against tumor challenge with an OVA-expressing thymoma cell line in comparison to formulations made from other polyanhydride copolymers. The results also revealed that vaccination with CpG ODN along with polyanhydride particles encapsulating OVA did not enhance the immunogenicity of OVA. These results accentuate the crucial role of the copolymer composition of polyanhydrides in stimulating the immune response and provide important insights on rationally designing efficacious cancer vaccines.Statement of SignificanceCompared to soluble cancer vaccine formulations, tumor antigens encapsulated in biodegradable polymeric particles have been shown to sustain antigen release and provide long-term protection against tumor challenge by improving the immune response towards the antigen. Treatment of mice with cancer vaccines based on different polyanhydride copolymers encapsulating OVA resulted in stimulation of tumor-specific immune response with different magnitudes. This clearly indicates that polyanhydride chemistry plays a substantial role in stimulating the immune response. Vaccination with 20:80 CPTEG:CPH/OVA, the most hydrophobic formulation, stimulated the strongest cellular and humoral immune responses and provided the longest survival outcome without adding any other adjuvant. The most important finding in this study is that the copolymer composition of polyanhydride particle-based vaccines can have a direct effect on the magnitude of the antitumor immune response and should be selected carefully in order to achieve optimal cancer vaccine efficacy.

Graphical abstract

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Engineered extracellular microenvironment with a tunable mechanical property for controlling cell behavior and cardiomyogenic fate of cardiac stem cells

Publication date: Available online 4 January 2017
Source:Acta Biomaterialia
Author(s): Min-Young Choi, Jong-Tae Kim, Won-Jin Lee, Yunki Lee, Kyung Min Park, Young-Il Yang, Ki Dong Park
Endogenous cardiac stem cells (CSCs) are known to play a certain role in the myocardial homeostasis of the adult heart. The extracellular matrix (ECM) surrounding CSCs provides mechanical signals to regulate a variety of cell behaviors, yet the impact in the adult heart of these mechanical properties of ECM on CSC renewal and fate decisions is mostly unknown. To elucidate CSC mechanoresponses at the individual cell and myocardial level, we used the sol-to-gel transitional gelatin-poly(ethylene glycol)-tyramine (GPT) hydrogel with a tunable mechanical property to construct a three-dimensional (3D) matrix for culturing native myocardium and CSCs. The elastic modulus of the GPT hydrogel was controlled by adjusting cross-linking density using hydrogen peroxide. The GPT hydrogel showed an ability to transduce integrin-mediated signals into the myocardium and to permit myocardial homeostatic processes in vitro, including CSC migration and proliferation into the hydrogel from the myocardium. Decreasing the elastic modulus of the hydrogel resulted in upregulation of phosphorylated integrin-mediated signaling molecules in CSCs, which were associated with significant increases in cell spreading, migration, and proliferation of CSCs in a modulus-dependent manner. However, increasing the elastic modulus of hydrogel induced the arrest of cell growth but led to upregulation of cardiomyocyte-associated mRNAs in CSCs. This work demonstrates that tunable 3D-engineered microenvironments created by GPT hydrogel are able to control CSC behavior and to direct cardiomyogenic fate. Our system may also be appropriate for studying the mechanoresponse of CSCs in a 3D context as well as for developing therapeutic strategies for in situ myocardial regeneration.Statement of SignificanceThe extracellular matrix (ECM) provides a physical framework of myocardial niches in which endogenous cardiac stem cells (CSCs) reside, renew, differentiate, and replace cardiac cells. Interactions between ECM and CSCs might be critical for the maintenance of myocardial homeostasis in the adult heart. Yet most studies done so far have used irrelevant cell types and have been performed at the individual cell level, none able to reflect the in vivo situation. By the use of a chemically defined hydrogel to create a tunable 3D microenvironment, we succeeded in controlling CSC behavior at the myocardial and individual cell level and directing the cardiomyogenic fate. Our work may provide insight into the design of biomaterials for in situ myocardial regeneration as well as for tissue engineering.

Graphical abstract

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Efficient tuning of siRNA dose response by combining mixed polymer nanocarriers with simple kinetic modeling

Publication date: Available online 4 January 2017
Source:Acta Biomaterialia
Author(s): Chad T. Greco, Victoria G. Muir, Thomas H. Epps III, Millicent O. Sullivan
Two of the most prominent challenges that limit the clinical success of siRNA therapies are a lack of control over cargo release from the delivery vehicle and an incomplete understanding of the link between gene silencing dynamics and siRNA dosing. Herein, we address these challenges through the formulation of siRNA polyplexes containing light-responsive polymer mixtures, whose varied compositions and triggered release behavior provide enhanced gene silencing and controlled dose responses that can be predicted by simple kinetic models. Through the straightforward mixing of two block copolymers, the level of gene knockdown was easily optimized to achieve the maximum level of GAPDH protein silencing in NIH/3T3 cells (70%) using a single siRNA dose. The kinetic model was used to describe the dynamic changes in mRNA and protein concentrations in response to siRNA treatment. These predictions enabled the application of a second dose of siRNA to maximally suppress gene expression over multiple days, leading to a further 50% reduction in protein levels relative to those measured following a single dose. Furthermore, polyplexes remained dormant in cells until exposed to the photo-stimulus, demonstrating the complete control over siRNA activity as well as the stability of the nanocarriers. Thus, this work demonstrates that pairing advances in biomaterials design with simple kinetic modeling provides new insight into gene silencing dynamics and presents a powerful strategy to control gene expression through siRNA delivery.Statement of SignificanceOur manuscript describes two noteworthy impacts: (1) we designed mixed polymer formulations to enhance gene silencing, and (2) we simultaneously developed a simple kinetic model for determining optimal siRNA dose responses to maintain silencing over several days. These advances address critical challenges in siRNA delivery and provide new opportunities in therapeutics development. The structure-function relationships of these formulations were established to enable tuning and forecasting of nanocarrier efficiency a priori, leading to siRNA dosing regimens able to maximally suppress gene expression. Our advances are significant because the mixed polymer formulations provide a straightforward and scalable approach to tailor siRNA delivery regimens. Moreover, the implementation of accurate dosing frameworks addresses a major knowledge gap that has hindered clinical implementation of siRNA.

Graphical abstract

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Evidence of structurally continuous collagen fibrils in tendon

Publication date: Available online 5 January 2017
Source:Acta Biomaterialia
Author(s): Rene B. Svensson, Andreas Herchenhan, Tobias Starborg, Michael Larsen, Karl E. Kadler, Klaus Qvortrup, S. Peter Magnusson
Tendons transmit muscle-generated force through an extracellular matrix of aligned collagen fibrils. The force applied by the muscle at one end of a microscopic fibril has to be transmitted through the macroscopic length of the tendon by mechanisms that are poorly understood. A key element in this structure-function relationship is the collagen fibril length. During embryogenesis short fibrils are produced but they grow rapidly with maturation. There is some controversy regarding fibril length in adult tendon, with mechanical data generally supporting discontinuity while structural investigations favor continuity. This study initially set out to trace the full length of individual fibrils in adult human tendons, using serial block face-scanning electron microscopy. But even with this advanced technique the required length could not be covered. Instead a statistical approach was used on a large volume of fibrils in shorter image stacks. Only a single end was observed after tracking 67.5 mm of combined fibril lengths, in support of fibril continuity. To shed more light on this observation, the full length of a short tendon (mouse stapedius, 125 μm) was investigated and continuity of individual fibrils was confirmed. In light of these results, possible mechanisms that could reconcile the opposing findings on fibril continuity are discussed.Statement of SignificanceConnective tissues hold all parts of the body together and are mostly constructed from thin threads of the protein collagen (called fibrils). Connective tissues provide mechanical strength and one of the most demanding tissues in this regard are tendons, which transmit the forces generated by muscles. The length of the collagen fibrils is essential to the mechanical strength and to the type of damage the tissue may experience (slippage of short fibrils or breakage of longer ones). This in turn is important for understanding the repair processes after such damage occurs. Currently the issue of fibril length is contentious, but this study provides evidence that the fibrils are extremely long and likely continuous.

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Upconversion nanoparticles mediated deep-penetrating photodynamic therapy of KillerRed

Publication date: Available online 4 January 2017
Source:Acta Biomaterialia
Author(s): Liuen Liang, Yiqing Lu, Run Zhang, Andrew Care, Tiago A. Ortega, Sergey M. Deyev, Yi Qian, Andrei V. Zvyagin
The fluorescent protein KillerRed, a new type of biological photosensitizer, is considered as a promising substitute for current synthetic photosensitizes used in photodynamic therapy (PDT). However, broad applications of this photosensitiser in treating deep-seated lesions is challenging due to the limited tissue penetration of the excitation light with the wavelength falling in the visible spectral range. To overcome this challenge, we employ upconversion nanoparticles (UCNPs) that are able to convert deep-penetrating near infrared (NIR) light to green light to excite KillerRed locally, followed by the generation of reactive oxygen species (ROS) to kill tumour cells under centimetre-thick tissue. The photosensitizing bio-nanohybrids, KillerRed-UCNPs, are fabricated through covalent conjugation of KillerRed and UCNPs. The resulting KillerRed-UCNPs exhibit excellent colloidal stability in biological buffers and low cytotoxicity in the dark. Cross-comparison between the conventional KillerRed and UCNP-mediated KillerRed PDT demonstrated superiority of KillerRed-UCNPs photosensitizing by NIR irradiation, manifested by the fact that ∼70% PDT efficacy was achieved at 1-cm tissue depth, whereas that of the conventional KillerRed dropped to ∼7%.Statement of SignificanceKillerRed is a protein photosensitizer that holds promise as an alternative for the existing hydrophobic photosensitizers that are widely used in clinical photodynamic therapy (PDT). However, applications of KillerRed to deep-seated tumours are limited by the insufficient penetration depth of the excitation light in highly scattering and absorbing biological tissues. Herein, we reported the deployment of upconversion nanoparticles (UCNPs) to enhance the treatment depth of KillerRed by converting the deep-penetrating near-infrared (NIR) light to upconversion photoluminescence and activating the PDT effect of KillerRed under deep tissues. This work demonstrated clear potential of UCNPs as the NIR-to-visible light converter to overcome the light penetration limit that has plagued PDT application for many years.

Graphical abstract

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Burst-suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy

Publication date: Available online 4 January 2017
Source:Pediatric Neurology
Author(s): Koshi Cherian, Alan Legatt




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Agenesis of the Corpus Callosum and Aicardi Syndrome: a neuroimaging and clinical comparison

Publication date: Available online 4 January 2017
Source:Pediatric Neurology
Author(s): T. Govil-Dalela, A. Kumar, R. Agarwal, H.T. Chugani
ObjectiveAgenesis of the corpus callosum (ACC) can be seen in patients with epilepsy, either in isolation or as part of various neurologic conditions, such as Aicardi syndrome. In this study, we evaluated the clinical and neuroradiological differences between children with non-syndromic ACC and those with Aicardi syndrome.MethodsWe evaluated 31 children with epilepsy and ACC (11 males: 20 females), 14 of whom had Aicardi syndrome (all females). We compared their clinical histories, radiologic and electrophysiologic findings, treatments, and their outcome.ResultsMedian age at seizure onset was lower in the Aicardi syndrome group compared to non-syndromic ACC (2 vs 5 months, p=0.006). The developmental impairment in terms of verbalization and ambulation was significantly worse in patients with Aicardi syndrome. The extent of magnetic resonance imaging (MRI) as well as glucose metabolism positron emission tomography (PET) involvement was more extensive in children with Aicardi syndrome than in non-syndromic ACC. In both groups, the PET scan showed a much more extensive area of involvement than suggested by the MRI scan. Four children underwent epilepsy surgery with significant improvement, but were not seizure free. Outcome was worse in those with PET showing abnormalities in the non-surgical hemisphere despite normal appearance on MRI. All children who did not undergo surgery also continued to have seizures at last follow-up.ConclusionsChildren with Aicardi syndrome have earlier seizure onset, worse developmental outcome and larger areas of brain abnormalities on neuroimaging as compared to non-syndromic ACC patients. PET reveals larger area of abnormalities, compared to MRI. Although epilepsy surgery in ACC may offer some palliative benefit in seizure frequency, none of our patients became seizure free.



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Safety of Transcranial Magnetic Stimulation in Children: A Systematic Review of the Literature

Publication date: Available online 4 January 2017
Source:Pediatric Neurology
Author(s): Corey H. Allen, Benzi M. Kluger, Isabelle Buard
ContextData and best practice recommendations for transcranial magnetic stimulation (TMS) use in adults is largely available. While there is less data in pediatric populations and no published guidelines, its practice in children continues to grow.MethodsWe performed a literature search through PubMed to review all TMS studies from 1985-2016 involving children and documented any adverse events. Crude risks were calculated per session.ResultsFollowing data screening, we identified 42 single pulse (spTMS) and/or paired pulse (ppTMS) TMS studies involving 639 healthy children (HC), 482 children with CNS disorders, and 84 epileptic children (EP). Adverse events (AEs) occurred at rates of 3.42%, 5.97%, and 4.55% respective to population and number of sessions. We also report 23 repetitive TMS (rTMS) studies involving 230 CNS and 24 EP with AE rates of 3.78% and 0.0% respectively. We finally identified three theta-burst stimulation (TBS) studies involving 90 HC, 40 CNS and no EP, with AE rates of 9.78% and 10.11% respectively. Three seizures were found to have occurred in CNS individuals during rTMS, with a risk of 0.14% per session. There was no significant difference in frequency of AEs by group (p = .988) nor modality (p = .928).ConclusionsAvailable data suggests that risk from TMS/TBS in children is similar to adults. We recommend that TMS users in this population follow the most recent adult safety guidelines until sufficient data are available for pediatric specific guidelines. We also encourage continued surveillance through surveys and assessments on a session-basis.



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Common and distinctive patterns of cognitive dysfunction in children with benign epilepsy syndromes

Publication date: Available online 4 January 2017
Source:Pediatric Neurology
Author(s): Dazhi Cheng, Xiuxian Yan, Zhijie Gao, Keming Xu, Xinlin Zhou, Qian Chen
BACKGROUNDChildhood absence epilepsy (CAE) and benign childhood epilepsy with centrotemporal spikes (BECTs) are the most common forms of benign epilepsy syndromes. Although cognitive dysfunctions occur in children with CAE or BECTs, the similarity between their patterns of underlying cognitive impairments is not well understood. To describe these patterns, we examined multiple cognitive functions in children with CAE and BECTs.METHODSIn this study, 43 children with CAE, 47 children with BECTs, and 64 controls were recruited; all received a standardized assessment (i.e., computerized test battery) assessing processing speed, spatial skills, calculation, language ability, intelligence, visual attention and executive function. Groups were compared in these cognitive domains. Simple regression analysis was used to analyze the effects of epilepsy-related clinical variables on cognitive test scores.RESULTSCompared to controls, children with CAE and BECTs showed cognitive deficits in intelligence and executive function, but performed normally in language processing. Impairment in visual attention was specific to patients with CAE, whereas impaired spatial ability was specific to the children with BECTs. Simple regression analysis showed syndrome-related clinical variables did not affect cognitive functions.CONCLUSIONSThis study provides evidence of both common and distinctive cognitive features underlying the relative cognitive difficulties in children with CAE and BECTs. It is suggested that clinicians should pay particular attention to the specific cognitive deficits in children with CAE and BECTs, to allow for more discriminative and potentially more effective interventions.



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Alternating upper limb monoplegia due to ATP1A3 mutation

Publication date: Available online 5 January 2017
Source:Pediatric Neurology
Author(s): Cécile Delorme, Elodie Hainque, Emmanuel Roze




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Association between the 20210G>A prothrombin gene polymorphism and arterial ischemic stroke in children and young adults – two meta-analyses of 3586 cases and 6440 controls in total

Publication date: Available online 4 January 2017
Source:Pediatric Neurology
Author(s): Beata Sarecka-Hujar, Ilona Kopyta, Michal Skrzypek, Joanna Sordyl
BackgroundPrevious data have shown that the 20210G>A polymorphism of the Factor II gene is related to an elevated prothrombin level, which may in turn lead to a procoagulant state. The heterogeneous and multifactorial character of arterial ischemic stroke (AIS) often results in contradictory reports describing the association between the 20210G>A polymorphism and AIS in different populations. We performed a meta-analysis of available data addressing the relation between the FII 20210G>A polymorphism and AIS, both in young adults and children.MethodsWe searched PubMed using appropriate keywords. The inclusion criteria for the study were as follows: case-control study, study population consisting of children, study population consisting of young adults, AIS confirmed by magnetic resonance imaging (MRI) or computed tomography (CT), English language. The exclusion criteria included: lack of genotype or allele frequencies, study design other than a case-control study, outcome definition other than AIS, previously overlapped patient groups. Finally, 30 case-control studies (14 in children and 16 in young adults) were included. Statistical analyses were conducted using R software. Heterogeneity between the studies was evaluated using the Dersimonian and Laird's Q test. In the case of significant between-studies heterogeneity, the pooled odds ratio (OR) was estimated with a random effects model, otherwise a fixed effects model was used.ResultsThe pooled analysis showed that carriers of 20210A allele (GA+AA genotypes) of the prothrombin gene are more common in AIS patients, both in children and young adults, than in controls (p=0.006,OR=1.83 95%CI 1.19-2.80 and p=0.001,OR=1.69 95%CI 1.25-2.28, respectively).ConclusionsThe results of the present meta-analysis have proven that the FII 20210G>A polymorphism is associated with AIS in both paediatric and young adult patients.



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Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan

Publication date: Available online 4 January 2017
Source:Brain and Development
Author(s): Toshiyuki Yamamoto, Keiko Shimojima, Mayumi Matsufuji, Ryuichi Mashima, Eri Sakai, Torayuki Okuyama
BackgroundAspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, aspartylglucosaminidase (AGA). This disorder is rare in the general population except in Finland. Since the most characteristic feature of this disorder is a progressive developmental regression, patients often show no specific symptoms in the initial stages, and thus early diagnosis is often challenging.Case reportWe encountered a 16-year-old boy who began to show difficulties in his speech at the age of 6years. Due to a mild regression in his development, he gradually lost common daily abilities. His diagnosis was first obtained through exome sequencing that identified a novel homozygous mutation in the AGA gene. This result was reasonable because of parental consanguinity. Reduced enzymatic activity of AGA was then confirmed. His urine was retrospectively screened by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and a specific pattern of abnormal metabolites was identified.ConclusionsBecause both exome sequencing and MALDI-TOF-MS screening are adaptable and comprehensive, future combinatory use of these methods would be useful for diagnosis of rare inborn errors of metabolism such as AGU.



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Symmetrical thalamic calcification: A trio whole exome sequencing negative series

Publication date: Available online 4 January 2017
Source:Brain and Development
Author(s): Kathleen Mary Gorman, John James Aird, Judith Conroy, Deirdre Devaney, Michael Farrell, Mary Dolores King
Symmetrical thalamic calcification or bilateral symmetrical thalamic gliosis presents at delivery with hypertonia, fixed flexion contractures and prominent bulbar signs, without preceding perinatal asphyxia. At post-mortem, there is evidence of bilateral symmetrical selective thalamic neuronal encrustation and gliosis. To date, 27 cases are published with no underlying diagnosis identified. Two affected children from singleton pregnancies were reported and therefore, a genetic cause proposed. No previous reports have performed genetic testing to confirm or reject this hypothesis.We report three additional cases of this rare condition, expanding the clinical and pathological phenotype. We performed trio whole exome sequencing, the first in this cohort of patients, and did not identify a pathogenic variant. As postulated in the original report, the likely underlying mechanism is antenatal hypoxia in the third trimester.



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Unilateral blue rubber bleb naevus syndrome with Chiari malformation

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Toll-like receptor (TLR)7 expression in mycosis fungoides and psoriasis: a case–control study

Summary

Background

Toll-like receptors (TLRs) have been implicated in various dermatological diseases. TLR agonists have the capacity to potently activate the innate immune cells of patients with advanced, refractory, cutaneous T-cell lymphoma (CTCL).

Aim

To detect TLR7 gene expression in mycosis fungoides (MF) (a neoplastic skin condition) and to compare it with psoriasis (an inflammatory skin condition) in an attempt to clarify the pathogenic role played by TLR7 in both conditions.

Methods

This case–control study enrolled 28 patients with MF: 30 patients with psoriasis, and 30 age- and sex-matched healthy controls (HCs). A 4-mm punch skin biopsy was obtained from lesional skin of patients and from normal skin of HCs for detection of TLR7 gene expression using real-time PCR.

Results

Mean TLR7 level in patients with MF (0.4 ± 0.23) was significantly lower than in patients with psoriasis (1.49 ± 0.46) and in HCs (1.22 ± 0.44) (P < 0.001), and mean TLR7 level in patients with psoriasis was significantly higher than in HCs (P < 0.03). Based on MF staging, 21.4% of patients had stage Ia, 28.6% had stage Ib, 28.6% had stage IIa and 21.4% had stage IIb disease. Comparing the TLR7 levels in relation to MF staging revealed the lowest mean value was in stage IIb and highest mean value in stage Ia, and this was significant (P < 0.001).

Conclusion

Disturbed innate immunity might play a role in the pathogenesis of neoplastic and inflammatory skin conditions. TLR7 could be useful as a prognostic factor in MF.

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Masthead

Publication date: January–February 2017
Source:Practical Radiation Oncology, Volume 7, Issue 1





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Editorial Board

Publication date: January–February 2017
Source:Practical Radiation Oncology, Volume 7, Issue 1





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Table of Contents

Publication date: January–February 2017
Source:Practical Radiation Oncology, Volume 7, Issue 1





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The Impact of Tumor Biology on Survival and Response to Radiation Therapy among Patients with Non-Small Cell Lung Cancer Brain Metastases

Publication date: Available online 5 January 2017
Source:Practical Radiation Oncology
Author(s): Jacob A. Miller, Rupesh Kotecha, Manmeet S. Ahluwalia, Alireza M. Mohammadi, John H. Suh, Gene H. Barnett, Erin S. Murphy, Michael A. Vogelbaum, Lilyana Angelov, Samuel T. Chao
PurposeTo investigate the natural history and response to radiation therapy among ALK-rearranged, EGFR-mutated, wild-type adenocarcinoma, and squamous cell non-small cell lung cancer (NSCLC) brain metastases.Materials and MethodsPatients with NSCLC brain metastasis diagnosed from 1989–2014 at a single tertiary-care institution were included. The primary outcome was overall survival, while secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. Cox proportional hazards regression was used to model overall survival, while multivariate competing risks regression was used to model secondary outcomes.ResultsWithin the study period, 1920 patients presented with 6312 brain metastases. Squamous histology was associated with poorer median survival compared with adenocarcinomas (5.4 vs. 8.8 mo., p<0.01). Median survival was greatest among ALK+ patients (49.2 mo.), followed by EGFR+ (20.3 mo.), and wild-type adenocarcinomas (10.0 mo., p<0.01). Treatment with EGFR inhibitors (HR 0.66, p<0.01) and VEGF antibodies (HR 0.65, p<0.01) increased survival independent of mutational status.Among 2056 lesions treated with stereotactic radiosurgery, the 12-month cumulative incidence of local failure was significantly greater among squamous cell carcinomas relative to adenocarcinomas (15% vs. 10%, HR 1.26, p=0.04). Patients with ALK+ metastases experienced higher rates of local failure (10%, HR 2.00, p=0.05), distant failure (39%, HR 2.94, p<0.01), and radiation necrosis (18%, HR 5.77, p<0.01), while EGFR+ patients experienced the lowest rates of local failure (5%, HR 0.46, p=0.04) and distant failure (3%, HR 0.13, p=0.04).ConclusionsAdvances in precision medicine have increased survival among select patients with NSCLC. In the present investigation, ALK+ and EGFR+ status were associated with improved survival. However, patients with ALK+ metastases have poor intracranial control relative to EGFR+ metastases, possibly due to limited intracranial penetration of crizotinib compared to EGFR inhibitors. Future investigations are warranted to determine the optimal management of ALK+ brain metastases with the introduction of second-generation ALK inhibitors.



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Pulse sequence considerations for simulation and postimplant dosimetry of prostate brachytherapy

Publication date: Available online 4 January 2017
Source:Brachytherapy
Author(s): Jingfei Ma, Marinus A. Moerland, Aradhana M. Venkatesan, Tharakeswara K. Bathala, Rajat J. Kudchadker, Kristy K. Brock, Steven J. Frank
PurposeThe purpose of this work is to present a brief review of MRI physics principles pertinent to prostate brachytherapy, and a summary of our experience in optimizing protocols for prostate brachytherapy applications.Methods and MaterialsWe summarized essential MR imaging characteristics and their interplays that need to be considered for prostate brachytherapy applications. These include spatial resolution, signal-to-noise ratio, image contrast, artifacts, geometric distortion, specific absorption rate, and total scan time. We further described the optimization of the protocols for three pulse sequences: three-dimensional (3D) fast-spoiled gradient echo sequence for T1-weighted imaging, 3D fast-spin echo sequence for T2-weighted imaging, and 3D fast imaging in steady-state precession sequence for combined T1 and T2-weighed imaging. The utilization of an endorectal coil was also described.ResultsUsing the optimized protocols, we acquired high-quality images of the entire prostate within 3–5 minutes for each sequence. These images display the desired image contrasts and a spatial resolution that is equal to or better than 0.59 mm × 0.73 mm × 1.2 mm. While 3D fast-spoiled gradient echo sequence and 3D fast-spin echo sequence depict radioactive seed markers and anatomic structures separately, 3D fast imaging in steady-state precession sequence demonstrates great promise for imaging both seed markers and prostate anatomy simultaneously in a single acquisition.ConclusionsWe have optimized current MRI protocols and demonstrated that the anatomic structures and positive contrast radioactive seed markers for prostate post-implant dosimetry can be adequately imaged either separately or simultaneously using different pulse sequences within a total scan time of 3–5 minutes each.



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Trends in the use of implantable accelerated partial breast irradiation for ductal carcinoma in situ: Implications of the recent amendments to the American Society for Radiation Oncology consensus guidelines

Publication date: Available online 4 January 2017
Source:Brachytherapy
Author(s): Waqar Haque, Vivek Verma, Anam Haque, E. Brian Butler, Bin S. Teh
PurposeIn 2009, the American Society for Radiation Oncology (ASTRO) published consensus recommendations that stated ductal carcinoma in situ (DCIS) patients were in a "cautionary" group for accelerated partial breast irradiation (APBI) and should not receive APBI outside of a clinical trial. However, very recently, ASTRO placed low-risk DCIS patients in the "suitable" category. Given this recent change, we aimed to use the Surveillance, Epidemiology, and End Results (SEER) database to evaluate past patterns of implantable APBI (IAPBI) utilization in women with DCIS.Methods and MaterialsThe Surveillance, Epidemiology, and End Results database was queried for patients from 2000 to 2012 with DCIS that underwent lumpectomy and adjuvant radiation therapy. Patients receiving IAPBI were differentiated from those receiving whole breast radiation therapy. Trends based on treatment year and patient demographics were collected, and multivariable logistic regression determined factors independently predictive of use of IAPBI.ResultsOf 52,012 eligible patients, 49,450 (95%) underwent external beam radiation and 2562 (5%) received APBI. Though IAPBI utilization steadily increased from 2000 (0.2% of the study population) to 2008 (9.4%), it abruptly declined in 2009 (7.9%, p = 0.009) and yearly thereafter. The 40–49 age group was proportionally most associated with this decline (8.6% in 2008 to 4.3% in 2009). Factors independently associated with IAPBI receipt included increasing age, hormone receptor negative status, and women living in the South.ConclusionsPatterns of IAPBI administration in DCIS are described. These trends are important to consider as a benchmark going forward, in light of the very recent change in ASTRO recommendations to include low-risk DCIS patients.



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Anthropometric factors have significant influence on the outcome of the GHRH-arginine test: establishment of normative data for an automated immunoassay specifically measuring 22 kDa human growth hormone

Context

Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion.

Objective

To improve the diagnostic accuracy of GH-releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH.

Design/setting

Prospective multicenter study.

Participants

Eighty-seven patients with hypothalamic–pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when ≥2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with ≥95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI.

Interventions

All participants received GHRH and l-arginine.

Main outcome measures

GH was measured by immunoassay (iSYS, IDS).

Results

In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively.

Conclusion

BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs.

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Increased prevalence of obstructive sleep apnea in patients with Cushings syndrome compared with weight- and age-matched controls

Objective

Diabetes mellitus and obesity are well-known risk factors associated with obstructive sleep apnea (OSA). Cushing's syndrome (CS) is also characterized by obesity and diabetes mellitus. However, the association between CS and OSA remains unclear. Therefore, we investigated the possible associations between CS and OSA in this study.

Patients and methods

Thirty female patients with newly diagnosed active CS and 30 age-, gender- and body mass index (BMI)-matched controls were included in this study. All participants were evaluated by overnight polysomnography. OSA was defined as having an apnea–hypopnea index (AHI) score of ≥5 events/h. Insulin resistance was calculated by homeostasis model assessment (HOMA) scores. Fasting serum cortisol was also determined.

Results

The prevalence of OSA was higher (50% vs 23%, P = 0.003) in patients with CS compared with the control subjects. The mean HOMA (P = 0.046) and AHI (P = 0.028) scores were higher in patients with CS compared with the control subjects. AHI was positively correlated with the HOMA scores (r = 0.281, P = 0.046) in both groups. Linear regression analysis showed that serum cortisol remained as an independent predictor for AHI after controlling for BMI and HOMA score (P < 0.001).

Conclusions

The prevalence of OSA increased in patients with CS compared with control subjects with similar ages and BMI levels. Hypercortisolemia is an independent risk factor for developing OSA. The presence of OSA needs to be considered in patients with CS.

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Ultrasound Measurements of Skeletal Muscle Architecture Are Associated with Strength and Functional Capacity in Older Adults

Publication date: Available online 4 January 2017
Source:Ultrasound in Medicine & Biology
Author(s): Isaac Selva Raj, Stephen R. Bird, Anthony J. Shield
The goal of this study was to determine whether ultrasound measures of muscle architecture can be used to infer strength and functional capacity in older adults. Thirty-six healthy older adults (aged 68.2 ± 5.3 y) undertook isokinetic dynamometry for isometric and isokinetic concentric knee extensor strength, the 6-m fast walk, timed up and go, stair climb and descent and vertical jump tests. Longitudinal brightness-mode ultrasound scans (probe frequency, 10 MHz) of the vastus lateralis, vastus intermedius, rectus femoris and gastrocnemius medialis were obtained, and muscle architecture measures (thickness, fascicle pennation angle and fascicle length) were correlated with the aforementioned strength and functional measures. Quadriceps thickness was a significant (p < 0.05) independent predictor of isometric and isokinetic knee extensor strength (R² ≥ 0.630). Gastrocnemius medialis thickness was a significant independent predictor of 6-m fast walk test (R² = 0.216, p < 0.05), timed up and go test (R² = 0.455, p < 0.01), stair climb power (R² = 0.591, p < 0.01), stair descent power (R² = 0.608, p < 0.01) and vertical jump height (R² = 0.579, p < 0.01). Ultrasound is a safe, non-invasive and efficient tool for inferring the strength and functional capacity of older adults.



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GluR3B Ab’s induced oligodendrocyte precursor cells excitotoxicity via mitochondrial dysfunction

Publication date: Available online 4 January 2017
Source:Brain Research Bulletin
Author(s): Yi Liu, Yan Chen, Wan Tong Du, Xiu Xiang Wu, Fu Xing Dong, Xue Bin Qu, Hong Bin Fan, Rui Qin Yao
Studies have indicated that glutamate receptor subunit 3 peptide B antibodies (GluR3B Ab's) by directing against a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype glutamate receptors (AMPARs) subunit 3 (GluR3B) was involved in the hippocampal neuron damage in the pathogenesis of epilepsy. Glutamate accumulation is critical for oligodendrocyte precursors (OPCs) excitotoxic injury. However, remarkably little is known about whether GluR3B Ab's causes OPCs excitotoxicity, and the underlying mechanisms remain unclear. In this study, we found that the survival rate of OPCs decreased, apoptosis increased and the release of LDH increased with GluR3B Ab's treatment. GluR3B Ab's enhanced the level of intracellular Ca²⁺ and reactive oxygen species (ROS), caused mitochondrial potential collapse measured by JC-1 and promoted mitochondrial cytochrome C release. AMPARs antagonist NBQX reversed OPCs apoptosis caused by GluR3B Ab's. Taken together, these data suggests that AMPAR was involved in GluR3B Ab's-induced OPCs toxicity by mitochondrial dysfunction. The study revealed a new mechanism for OPCs excitotoxicity in many central nervous system diseases such as epilepsy.



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Early Stage Alterations of Catecholamine and Adrenocorticotropic Hormone Levels in Posttraumatic Acute Diffuse Brain Swelling

Publication date: Available online 4 January 2017
Source:Brain Research Bulletin
Author(s): Weiqiang Chen, Jiangtao Sheng, Guoyi Peng, Jinhua Yang, Shousen Wang, Kangsheng Li
Posttraumatic acute diffuse brain swelling (PADBS) is characterized by serious brain bulk enlargement rapidly following trauma and is a major cause of elevated intracranial pressure and thus mortality. The pathogenesis of PADBS is not clearly understood, and the early stage alterations of catecholamine (CA) and adrenocorticotropic hormone (ACTH) levels in PADBS also remain largely unknown. The objective of this study was to investigate CA and ACTH levels in the patients with PADBS in the early stage and discuss the possible roles CA and ACTH in the pathogenesis of PADBS. It is a cross-sectional study. A group of patients with PADBS (n=10) was compared with a group of patients with severe brain injury (SBI) (n=33). A control group of healthy adults (n=25) was also included. Blood samples were obtained to measure levels of epinephrine (EPI), norepinephrine (NE), dopamine (DA), and ACTH as soon as the patients arrived at the neurosurgery department, which was done within 4hours after trauma. Both SBI and PADBS groups of patients had higher levels of EPI, NE, DA, and ACTH than the control group. The PADBS group had significantly higher levels of EPI, NE, and ACTH than the SBI group. CA and ACTH levels are significantly increased in early stage PADBS. These results imply that CA and ACTH may play important roles in the pathogenesis of PADBS. To eliminate the effects of CA and ACTH at the early stage, and thereby protect the hypothalamus and brain stem, might be critical measures for treating patients with PADBS.



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De l’influence de scandales sanitaires sur la réglementation des produits cosmétiques

Publication date: Available online 3 January 2017
Source:Médecine & Droit
Author(s): Laurence Coiffard, Céline Couteau
Les différentes affaires sanitaires qui ont eu lieu en France depuis une quarantaine d'années ont influencé la réglementation des produits cosmétiques. L'influence la plus évidente est celle de « L'affaire du talc Morhange » qui a initié leur réglementation. Par la suite, « L'Affaire du sang contaminé », par le biais de la création de l'Afssaps, a donné aux produits cosmétiques une autorité de tutelle et les fait désormais classer comme des produits de santé. Enfin, plus récemment « L'Affaire Médiator » a entraîné, entre autres, une prise de conscience de la notion de conflits d'intérêt dans le domaine des produits de santé, donc des produits cosmétiques.The various health scandals which have happened in France over the past 40 years have influenced the regulation of cosmetic products. The most obvious influence is the "Talc Morhange Scandal" which triggered their regulation. Then, "the Infected Blood Scandal", through the creation of Afssaps, provided a regulatory authority for cosmetics products and from then onwards, they were classed as health products. Lastly, one of the effects of the more recent "Médiator scandal" was to bring about an awareness concerning the notion of conflicts of interests in the field of health products, therefore including cosmetic products.



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Gene expression signature: a powerful approach for drug discovery in diabetes

Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D.

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Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish

Zebrafish are widely used as model organism. Their suitability for endocrine studies, drug screening and toxicity assessements depends on the extent of conservation of specific genes and biochemical pathways between zebrafish and human. Glucocorticoids consist of inactive 11-keto (cortisone and 11-dehydrocorticosterone) and active 11β-hydroxyl forms (cortisol and corticosterone). In mammals, two 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2) interconvert active and inactive glucocorticoids, allowing tissue-specific regulation of glucocorticoid action. Furthermore, 11β-HSDs are involved in the metabolism of 11-oxy androgens. As zebrafish and other teleost fish lack a direct homologue of 11β-HSD1, we investigated whether they can reduce 11-ketosteroids. We compared glucocorticoid and androgen metabolism between human and zebrafish using recombinant enzymes, microsomal preparations and zebrafish larvae. Our results provide strong evidence for the absence of 11-ketosteroid reduction in zebrafish. Neither human 11β-HSD3 nor the two zebrafish 11β-HSD3 homologues, previously hypothesized to reduce 11-ketosteroids, converted cortisone and 11-ketotestosterone (11KT) to their 11β-hydroxyl forms. Furthermore, zebrafish microsomes were unable to reduce 11-ketosteroids, and exposure of larvae to cortisone or the synthetic analogue prednisone did not affect glucocorticoid-dependent gene expression. Additionally, a dual-role of 11β-HSD2 by inactivating glucocorticoids and generating the main fish androgen 11KT was supported. Thus, due to the lack of 11-ketosteroid reduction, zebrafish and other teleost fish exhibit a limited tissue-specific regulation of glucocorticoid action, and their androgen production pathway is characterized by sustained 11KT production. These findings are of particular significance when using zebrafish as a model to study endocrine functions, stress responses and effects of pharmaceuticals.

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Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.

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Antihyperglycemic activity of the bark methanolic extract of Syzygium mundagam in diabetic rats

Publication date: Available online 3 January 2017
Source:Alexandria Journal of Medicine
Author(s): Rahul Chandran, Thangaraj Parimelazhagan, Blassan P. George
The present study was designed to investigate the free radical defence and antihyperglycemic property of S. mundagam. Petroleum ether, ethyl acetate, methanol and hot water extracts of bark were determined for the total phenolic, tannin, flavonoid content and antioxidant property using DPPH, ABTS⁺, phosphomolybdenum, FRAP, superoxide, nitric oxide and metal chelating assays. The antioxidant response was best observed in ABTS⁺ (109686.87μM TE/g extract), phosphomolybdenum (268.54g AAE/100g extract) and superoxide radical scavenging assays (84.30%). Bark methanol extract was found highly efficient in scavenging the free radicals than other extracts. The higher phenolic content (54.44g GAE/100 extract) could be attributed to this effect. The glucose homeostasis was observed till 180th min in glucose loaded rats treated with the bark methanol extract. The extract could also induce potent hypoglycaemia in STZ induced diabetic rats. The antioxidant defence system could be one of the prime mechanisms of S. mundagam leaf and bark extracts that needs to be studied further for the exact molecular action leading to antidiabetic effect.



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Clinical Practice Guidelines for the Use of Video Capsule Endoscopy

Publication date: Available online 4 January 2017
Source:Gastroenterology
Author(s): Robert A. Enns, Lawrence Hookey, David Armstrong, Charles N. Bernstein, Steven J. Heitman, Christopher Teshima, Grigorios I. Leontiadis, Frances Tse, Daniel Sadowski
Background & AimsVideo capsule endoscopy (CE) provides a noninvasive option to assess the small intestine, but its use with respect to endoscopic procedures and cross-sectional imaging varies widely. The aim of this consensus was to provide guidance on the appropriate use of CE in clinical practice.MethodsA systematic literature search identified studies on the use of CE in patients with Crohn's disease, celiac disease, gastrointestinal bleeding, and anemia. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach.ResultsThe consensus includes 21 statements focused on the use of small-bowel CE and colon capsule endoscopy. CE was recommended for patients with suspected, known, or relapsed Crohn's disease when ileocolonoscopy and imaging studies were negative if it was imperative to know whether active Crohn's disease was present in the small bowel. It was not recommended in patients with chronic abdominal pain or diarrhea, in whom there was no evidence of abnormal biomarkers typically associated with Crohn's disease. CE was recommended to assess patients with celiac disease who have unexplained symptoms despite appropriate treatment, but not to make the diagnosis. In patients with overt gastrointestinal bleeding, and negative findings on esophagogastroduodenoscopy and colonoscopy, CE should be performed as soon as possible. CE was recommended only in selected patients with unexplained, mild, chronic iron-deficiency anemia. CE was suggested for surveillance in patients with polyposis syndromes or other small-bowel cancers, who required small-bowel studies. Colon capsule endoscopy should not be substituted routinely for colonoscopy. Patients should be made aware of the potential risks of CE including a failed procedure, capsule retention, or a missed lesion. Finally, standardized criteria for training and reporting in CE should be defined.ConclusionsCE generally should be considered a complementary test in patients with gastrointestinal bleeding, Crohn's disease, or celiac disease, who have had negative or inconclusive endoscopic or imaging studies.



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Editorial board

Publication date: January 2017
Source:Microbes and Infection, Volume 19, Issue 1





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Determination of glutathione redox potential and pH value in subcellular compartments of malaria parasites

Publication date: Available online 4 January 2017
Source:Free Radical Biology and Medicine
Author(s): Franziska Mohring, Mahsa Rahbari, Bernd Zechmann, Stefan Rahlfs, Jude M. Przyborski, Andreas J. Meyer, Katja Becker
The malaria parasite Plasmodium falciparum is exposed to multiple sources of oxidative challenge during its complex life cycle in the Anopheles vector and its human host. In order to further elucidate redox-based parasite host cell interactions and mechanisms of drug action, we targeted the genetically encoded glutathione redox sensor roGFP2 coupled to human glutaredoxin 1 (roGFP2-hGrx1) as well as the ratiometric pH sensor pHluorin to the apicoplast and the mitochondrion of P. falciparum. Using live cell imaging this allowed for the first time the determination of the pH values of apicoplast (7.12±0.40) and mitochondrion (7.37±0.09) in the intraerythrocytic asexual stages of the parasite. Based on the roGFP2-hGrx1 signals, glutathione-dependent redox potentials of −267mV and −328mV, respectively, were obtained. Employing these novel tools, first studies on the effects of redox-active agents and clinically employed antimalarial drugs were carried out on both organelles.

Graphical abstract

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Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Publication date: Available online 4 January 2017
Source:Free Radical Biology and Medicine
Author(s): Hana Verescakova, Gabriela Ambrozova, Lukas Kubala, Tomas Perecko, Adolf Koudelka, Ondrej Vasicek, Tanja K. Rudolph, Anna Klinke, Steven R. Woodcock, Bruce A. Freeman, Michaela Pekarova
Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1–5min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

Graphical abstract

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Linking lipid peroxidation and neuropsychiatric disorders: focus on 4-hydroxy-2-nonenal

Publication date: Available online 4 January 2017
Source:Free Radical Biology and Medicine
Author(s): Adele Romano, Gaetano Serviddio, Silvio Calcagnini, Rosanna Villani, Anna Maria Giudetti, Tommaso Cassano, Silvana Gaetani
4-hydroxy-2-nonenal (HNE) is considered to be a strong marker of oxidative stress; the interaction between HNE and cellular proteins leads to the formation of HNE-protein adducts able to alter cellular homeostasis and cause the development of a pathological state.By virtue of its high lipid concentration, oxygen utilization, and the presence of metal ions participating to redox reactions, the brain is highly susceptible to the formation of free radicals and HNE-related compounds.A variety of neuropsychiatric disorders have been associated with elevations of HNE concentration. For example, increased levels of HNE were found in the cortex of bipolar and schizophrenic patients, while HNE plasma concentrations resulted high in patients with major depression. On the same line, high brain concentrations of HNE were found associated with Huntington's inclusions. The incidence of high HNE levels is relevant also in the brain and cerebrospinal fluid of patients suffering from Parkinson's disease. Intriguingly, in this case the increase of HNE was associated with an accumulation of iron in the substantia nigra, a brain region highly affected by the pathology.In the present review we recapitulate the findings supporting the role of HNE in the pathogenesis of different neuropsychiatric disorders to highlight the pathogenic mechanisms ascribed to HNE accumulation.The aim of this review is to offer novel perspectives both for the understanding of etiopathogenetic mechanisms that remain still unclear and for the identification of new useful biological markers.We conclude suggesting that targeting HNE-driven cellular processes may represent a new more efficacious therapeutical intervention.



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Anti-DFS70 antibodies in healthy schoolchildren: A follow-up analysis

Publication date: Available online 4 January 2017
Source:Autoimmunity Reviews
Author(s): Francesca Sperotto, Mara Seguso, Nicoletta Gallo, Mario Plebani, Francesco Zulian




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RNA in situ hybridization characterization of non-enzymatic derived bovine intervertebral disc cell lineages suggests progenitor cell potential

Publication date: Available online 4 January 2017
Source:Acta Histochemica
Author(s): Petra Kraus, Rachel Yerden, Victoria Kocsis, Thomas Lufkin
Degeneration of the intervertebral disc (IVD) is a meritorious target for therapeutic cell based regenerative medicine approaches, however, controversy over what defines the precise identity of mature IVD cells and lack of single cell based quality control measures is of concern. Bos taurus and human IVDs are histologically more similar than is Mus musculus. The mature bovine IVD is well suited as model system for technology development to be translated into therapeutic cell based regenerative medicine applications. We present a reproducible non-enzymatic protocol to isolate cell progenitor populations of three distinct areas of the mature bovine IVD. Bovine specific RNA probes were validated in situ and employed to assess fate changes, heterogeneity, stem cell characteristics and differentiation potential of the cultures. Quality control measures with single cell resolution like RNA in situ hybridization to assess culture heterogeneity (PISH) followed by optimization of culture conditions could be translated to human IVD cell culture to increase the safety of cell based regenerative medicine.



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Erratum: Application of intelligent algorithm in the optimization of novel protein regulatory pathway: Mechanism of action of gastric carcinoma protein p42.3

Journal of Cancer Research and Therapeutics 2016 12(3):1212-1212



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Management of the neck in early oral cancers: Is the verdict out?

Vishal U. S. Rao, Prashant H Patil, BV Rajaram

Journal of Cancer Research and Therapeutics 2016 12(3):1114-1116

The management of patients with the clinically negative neck (N0) in early oral cancers awaits a clear mandate despite growing evidence favoring elective neck dissection. Having a general policy of operating all N0 neck may indeed increase the number of unnecessary neck dissection in the true pathological N0 necks, a more commonly encountered scenario. This controversy needs to be looked beyond statistical evidence to address a larger question to "does the neck truly harbor disease," thus, refining the early age old debate. This article highlights the feasibility of wait and watch policy, while elaborating a stringent algorithm to judiciously select patients in whom the neck may be safely observed.

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Application of accelerated failure time models for breast cancer patients' survival in Kurdistan Province of Iran

Asrin Karimi, Ali Delpisheh, Kourosh Sayehmiri

Journal of Cancer Research and Therapeutics 2016 12(3):1184-1188

Context: Breast cancer is the most common cancer and the second common cause of cancer-induced mortalities in Iranian women. There has been a rapid development in hazard models and survival analysis in the last decade. Aims: The aim of this study was to evaluate the prognostic factors of overall survival (OS) in breast cancer patients using accelerated failure time models (AFT). Setting and Design: This was a retrospective-analytic cohort study. Subjects and Materials: About 313 women with a pathologically proven diagnosis of breast cancer who had been treated during a 7-year period (since January 2006 until March 2014) in Sanandaj City, Kurdistan Province of Iran were recruited. Statistical Analysis Used: Performance among AFT was assessed using the goodness of fit methods. Discrimination among the exponential, Weibull, generalized gamma, log-logistic, and log-normal distributions was done using Akaik information criteria and maximum likelihood. Results: The 5 years OS was 75% (95% CI = 74.57–75.43). The main results in terms of survival were found for the different categories of the clinical stage covariate, tumor metastasis, and relapse of cancer. Survival time in breast cancer patients without tumor metastasis and relapse were 4, 2-fold longer than other patients with metastasis and relapse, respectively. Conclusion: One of the most important undermining prognostic factors in breast cancer is metastasis; hence, knowledge of the mechanisms of metastasis is necessary to prevent it so occurrence and treatment of metastatic breast cancer and ultimately extend the lifetime of patients.

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Radioiodine as an adjuvant therapy and its role in follow-up of differentiated thyroid cancer

S Padma, P Shanmuga Sundaram

Journal of Cancer Research and Therapeutics 2016 12(3):1109-1113

Papillary and follicular cancers of thyroid are the most common varieties of differentiated thyroid cancers exhibiting excellent long-term prognosis when carefully managed. Being a slow-growing malignancy, guidelines exist on the staging, preoperative risk stratification, and management of these cancers to increase the overall survival of these patients. Radioactive iodine has a central role in differentiated thyroid malignancies. It has the same physical properties as stable iodine, thus both normal and malignant thyrocytes cannot differentiate radioactive from stable iodine. Differentiated thyroid carcinoma (DTC) cells concentrate cytocidal amounts of Iodine -131 (131 I) by trapping (the function of the sodium iodine symporter, or NIS) and organifying the iodide ion to produce levothyroxine and triiodothyronine. We shall discuss the role of radioiodine in the management and followup of DTC patients.

http://ift.tt/2hT4R82

Clinicopathological correlation of skin tumors: A dermatologist's perspective

Namitha Chathra, Ramesh Bhat

Journal of Cancer Research and Therapeutics 2016 12(3):1124-1126

Background: Tumors of the skin may be encountered by a dermatologist either as presenting complaints or as incidental findings. Certain tumors are easily recognized clinically, while others can only be diagnosed by histopathology. Aims and Objectives: To analyze the pattern of skin tumors through clinical and histopathological correlation and to assess the role of a dermatologist in the treatment of tumors. Materials and Methods: A retrospective analysis of histopathologically-diagnosed skin tumors seen in dermatology outpatient department from May 2011 to June 2013. Results: Forty cases of skin tumors were histopathologically reported during the period under review. Out of this, nine cases were malignant, the nonmelanoma to melanoma ratio being 8:1. Conclusion: Dermatologists are recommended to monitor closely the changing pigmented or hyperkeratotic lesions and poorly healing ulcers to facilitate early diagnosis and effective management.

http://ift.tt/2hUyap0

The Unquiet Mind Cancer: The Metaethical Quandary of Therapies

Rohit Manchanda

Journal of Cancer Research and Therapeutics 2016 12(3):1207-1208



http://ift.tt/2j6lid9

Samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid: A novel agent for bone pain palliation therapy

Hassan Yousefnia, Razieh Enayati, Mohammad Hosntalab, Samaneh Zolghadri, Ali Bahrami-Samani

Journal of Cancer Research and Therapeutics 2016 12(3):1117-1123

Aim: Various phosphonate ligands labeled with β−-emitting radionuclides have shown good efficacy for bone pain palliation. In this study, a new agent for bone pain palliation has been developed. Materials and Methods: Samarium-153-(4-[((bis(phosphonomethyl))carbamoyl)methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (153Sm-BPAMD) complex was prepared using BPAMD ligand and samarium-153 chloride. The effect of various parameters on the labeling yield of 153Sm-BPAMD including ligand concentration, pH, temperature, and reaction time were studied. Production of 153Sm was performed at a research reactor using 152Sm (n, γ)153Sm nuclear reaction. The radiochemical purity of the radiolabeled complex was checked by instant thin layer chromatography. Stability studies of the complex in the final preparation and the presence of human serum were performed up to 48 h. Partition coefficient and hydroxyapatite (HA) binding of the complex were investigated and biodistribution studies using single photon emission computed tomography (SPECT) and scarification were performed after injection of the complex to wild-type mice. Results: 153Sm-BPAMD was prepared in a high radiochemical purity >98% and specific activity of 267 GBq/mmol at the optimal conditions. The complex demonstrated significant stability at the room temperature and in human serum at least for 48 h. HA binding assay demonstrated that at the amount of more than 5 mg, approximately, all radiolabeled complex was bind to HA. At the pH 7.4, log Po/w was − 1.86 ± 0.02. Both SPECT and scarification showed major accumulation of the labeled compound in the bone tissue. Conclusions: The results show that 153Sm-BPAMD has interesting characteristics as an agent for bone pain palliation, however, further biological studies in other mammals are still needed.

http://ift.tt/2hUqQtJ

Diagnostic value of core biopsy histology and cytology sampling of mediastinal lymph nodes using 21-gauge EBUS-TBNA needle

Preyas J Vaidya, Avinandan Saha, Arvind H Kate, Kamlesh Pandey, Vinod B Chavhan, Joerg D Leuppi, Prashant N Chhajed

Journal of Cancer Research and Therapeutics 2016 12(3):1172-1177

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the initial modality of choice in sampling mediastinal lymphadenopathy. It is possible to obtain both cytological and histological samples using both 21-gauge and 22-gauge EBUS-TBNA needles. The current study was undertaken to compare the diagnostic yield of cytology and histology samples obtained by the same EBUS-TBNA 21-gauge needle. Patients and Methods: One hundred sixty-six consecutive patients who underwent EBUS-TBNA with a 21-gauge EBUS-TBNA needle over a period of 3 years were included in this retrospective analysis. The diagnostic yields of EBUS-TBNA histology (EBUS-TBNA-H) and EBUS-TBNA cytology (EBUS-TBNA-C) specimens were compared using the McNemar test. Results: The overall sensitivity and specificity of EBUS-TBNA were 89% and 100%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of EBUS-TBNA were 100% and 53%, respectively. The overall sensitivity and specificity of EBUS-TBNA-H were 85% and 100%, respectively. The PPV and NPV of EBUS-TBNA-H were 100% and 43%, respectively. The overall sensitivity and specificity of EBUS-TBNA-C were 65% and 100%, respectively. The PPV and NPV of EBUS-TBNA-C were 100% and 14%, respectively. The diagnostic yield of EBUS-TBNA-H over EBUS-TBNA-C was statistically significant (P < 0.0001). Conclusion: EBUS-TBNA-H with 21-gauge needle significantly improves the diagnostic yield of EBUS-TBNA. EBUS-TBNA-H improves the NPV of EBUS-TBNA. The combination of EBUS-TBNA-H and EBUS-TBNA-C improves the overall diagnostic yield of EBUS-TBNA.

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Combined prednisolone and pirfenidone in bleomycin-induced lung disease

Preyas J Vaidya, HS Sandeepa, Tejinder Singh, SK Susheel Kumar, Rajat Bhargava, Gopal Ramakrishnan, Prashant N Chhajed

Journal of Cancer Research and Therapeutics 2016 12(3):1198-1202

Bleomycin is a cytostatic drug commonly employed in the treatment of Hodgkin's disease, seminomas, and choriocarcinoma. Bleomycin may induce a chronic pulmonary inflammation that may progress to fibrosis. So far, only corticosteroids have been used in the treatment of bleomycin-induced lung disease with variable results. Pirfenidone is an antifibrotic drug that has been approved for the treatment of idiopathic pulmonary fibrosis. We report two cases of bleomycin-induced lung disease treated successfully with pirfenidone and oral corticosteroids.

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Erratum: The postoperative complication for adenocarcinoma of esophagogastric junction

Journal of Cancer Research and Therapeutics 2016 12(3):1210-1210



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Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation

Xiao Zhao, Guangqin Zhu, Huoming Chen, Ping Yang, Fang Li, Nan Du

Journal of Cancer Research and Therapeutics 2016 12(3):1127-1131

Objective: This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. Materials and Methods: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced. (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas, the secondary endpoint was overall survival(OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan–Meier method and statistical significance was determined using the log-rank test. Results: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Conclusion: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR.sensitive mutation.

http://ift.tt/2hUGh57

Nanothermia: A heterogenic heating approach

Szasz Oliver, Szasz Andras

Journal of Cancer Research and Therapeutics 2016 12(3):1132-1137

Aim of Study: The aim of the study is to show the possible differences on the same temperature and treatment time as control parameter of the variety of local hyperthermia techniques, pointing the possible differences in the local and systemic actions. Materials and Methods: Debate about the apparent locality of malignancy and the problems of the local treatment. Results: Consider the physiological feedback mechanisms, the spread of temperature, and the time which has active role in the spreading. Conclusion: Points that the clinical results depend not only on the temperature but also on the technical solution of the heat delivery.

http://ift.tt/2hUB2T5

Big data in radiation oncology

Nagraj Huilgol

Journal of Cancer Research and Therapeutics 2016 12(3):1107-1108



http://ift.tt/2j6lppc

Questionnaire survey to assess the pattern and characteristics of cell-phone usage among Indian oncologists

Anusheel Munshi, Debanarayan Dutta, Pramod Tike, Jai Prakash Agarwal

Journal of Cancer Research and Therapeutics 2016 12(3):1138-1143

Purpose: Obtain baseline data of cell-phone usage in the medical (MO), surgical (SO) and radiation (RO) oncology community practicing in India. Materials and Methods: Indigenously prepared cell-phone usage related questionnaire was used in the present study after approval by the Institutional Ethics/Scientific Committees. The questionnaire had 41 items and was made to assess the cell-phone usage parameters, utility in clinical practice, awareness, and to compare parameters between oncology specialties. Between November 2009 and January 2010, the questionnaire was sent as an E-mail attachment to 200 oncologists in India. Results: In all, 123 responses were received (61% responders); 84 (68.3%) were RO. The median age of responders was 35 years. Overall, 80% felt handicapped without cell-phone. The Mean cell-phone score, an index to assess overall usefulness over a score of 1–10, was 6.46 (median 7, standard deviation 1.709). There was no significant difference between RO, MO and SO in duration of usage (P = 0.235), number of cell-phones (P = 0.496), call duration per day (P = 0.490) and dependence on cell-phone (P = 0.574). Age of starting cell-phone usage was earlier in RO (P = 0.086). Professional usage was significantly more by MO and SO compared to RO (P < 0.001); however, the former were less aware of any potential cell-phone hazards compared to RO (P < 0.007). Conclusion: The results of the first such questionnaire based study have been presented. Most oncologists consider cell-phones a useful tool in patient care. More RO are aware of potential cell-phone hazards compared to non-RO's.

http://ift.tt/2hUuKTj

Polymorphisms of glucose-regulated protein 78 and clinical relevance of neuroblastoma: Risk and prognosis

Jiao Zhang, Jiaxiang Wang, Qiuliang Liu, Jingyao Gao, Qi Wang

Journal of Cancer Research and Therapeutics 2016 12(3):1178-1183

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Glucose/regulated protein 78 (GRP78) is a stress-associated protein. It has been reported that overexpression of GRP78 occurs in various human cancers, and GRP78 polymorphisms have effect on the expression of GRP78 with possible function of predicting clinical outcome. Upregulation of GRP78 has been detected in NB. However, little is known about the relationship of GRP78 polymorphisms and the susceptibility of NB. Aim: To investigate whether GRP78 polymorphisms were associated with the risk and clinical characteristics of NB. Materials and Methods: Two GRP78 polymorphisms rs391957 (C>T) and rs430397 (G>A) were detected in 105 NB cases and 145 healthy controls using the polymerase chain reaction fragment length polymorphism technique. Results: Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of NB. In NB cases, the variant T allele was significantly associated with tumor International Neuroblastoma Staging System stage (P = 0.027), but not with MYCN amplification (P = 0.056). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of NB. The rs430397 polymorphism was not associated with the clinicopathological characteristics of NB. Conclusion: These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as the markers to predict the risk and poor prognosis of NB.

http://ift.tt/2j6nFwC

Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver

Lajos Balogh, András Polyák, Zita Pöstényi, Veronika Kovács-Haász, Miklós Gyöngy, Julianna Thuróczy

Journal of Cancer Research and Therapeutics 2016 12(3):1153-1159

Aim of Study: Is to show the intrahepatic temperature development in anesthetized pig. Materials and Methods: Temperature development in the liver of anesthetized pig is measured to study the thermal effects of capacitive coupled energy transfer. The treatment was made by modulated electrohyperthermia (mEHT, trade name: oncothermia ®), controlled by a fluoroptical temperature sensing positioned by the ultrasound-guided process. Various fits of coupling were studied. Results: The intrahepatic temperature at the end of the treatment ranged 40.5–44.8°C, while the skin temperature ranged 36.8–41.8°C depending on the coupling arrangement. Conclusion: mEHT is a feasible method to deliver deep heat to the liver of an anesthetized pig.

http://ift.tt/2hUrRC6

Cellular and spectroscopic characterization of cancer stem cell-like cells derived from A549 lung carcinoma

Murali M. S. Balla, Raghumani S Ningthoujam, Mukesh Kumar, Jayant R Bandekar, Badri N Pandey

Journal of Cancer Research and Therapeutics 2016 12(3):1144-1152

Background: Cancer stem cells (CSCs) are increasingly being realized to play a significant role in the mechanism of chemo-, radio-resistance, and metastasis of cancer. However, studies for spectral markers of CSCs using Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopy are limited in the literature. Materials and Methods: In the present study, CSCs obtained from single cell assay of human lung adenocarcinoma (A549) cells were characterized using CD44+/CD24−/low phenotype expression, Hoechst 33342 dye efflux assay, and expression of stemness genes. Spectral changes in cancer cells and clones enriched with CSCs were studied by FT-IR and CD spectroscopy. Results: The changes in FT-IR spectra of clones enriched with CSCs showed the difference in the secondary protein structure as compared to nonstem cancer cells. Moreover, A549 clone cells showed higher C-O band of carbohydrates and deoxyribose ring vibrations of Z-form of DNA. These results were further corroborated with CD spectroscopy that showed increased alpha helix proteins and difference in DNA conformation in clones enriched with CSCs. FT-IR studies also showed higher imidazole-metal interactions in clones enriched with CSCs. These results are in agreement with higher activity of one of the metalloproteins that is, superoxide dismutase in clones enriched with CSCs and their increased radioresistance. Conclusions and General Significance: Overall, these observations provide novel FT-IR and CD spectroscopy signatures in A549 clones enriched with CSCs, which may have implications in the quantifying magnitude of CSCs as prognostic markers in cancer therapy.

http://ift.tt/2hUzLv2

Long-term outcomes of peripheral blood stem cell transplantation for 38 patients with peripheral T-cell lymphoma

Jian Bo, Yu Zhao, Songsong Zhang, Wenrong Hua, Shuhong Wang, Chunji Gao, Quanshun Wang, Honghua Li, Li Yu

Journal of Cancer Research and Therapeutics 2016 12(3):1189-1197

Objective: In this study, to investigate clinical characteristics, response, outcome, and prognosis of peripheral blood stem cell transplantation (PBSCT) for patients with peripheral T-cell lymphoma (PTCL). Methods: This study retrospectively analyzed the efficacy of PBSCT in 38 patients with PTCL. Kaplan–Meier methods were used in survival analysis, and the Cox regression model was applied in multivariate analysis. There were ten clinical parameters were analyzed. Results: The 2-year overall survival (OS) was 46%, and the 5-year OS was 34% after a median follow-up of 40 months. The patients who received allogeneic PBSCT (allo-PBSCT) had a higher nonrelapse mortality than autologous PBSCT (auto-PBSCT), but they could achieve a longer-term disease-free survival in the former, which OS could achieve 40%. Survival analysis with Kaplan–Meier method showed the pretransplant disease status, B symptoms, serum lactate dehydrogenase (LDH) in early (>275 U/L), Eastern Cooperative Oncology Group (ECOG) score (>1), prognostic index for PTCL score (>2) were all prognostic factors for posttransplant OS. Pretransplant disease status is the only prognostic factor for allo-PBSCT. Conclusion: The key was to reducing transplant-related mortality of allo-PBSCT by reduced-intensity conditioning. Factors such as level of early serum LDH, extranodal involvement, B symptoms, ECOG score, Ann Arbor stage, and pretransplant disease status were all related to the prognosis of patients treated with PBSCT. Allo-PBSCT maybe suggested as the first line therapy for late-stage PTCL patients who could reach treatment remission before transplantation.

http://ift.tt/2j6wsyI

Spectrum of complex chromosomal aberrations in a myelodysplastic syndrome and a brief review

Bani Bandana Ganguly, Tuphan Kanti Dolai, Rajib De, Nitin N Kadam

Journal of Cancer Research and Therapeutics 2016 12(3):1203-1206

Myelodysplastic syndrome (MDS) is a heterogeneous premalignant condition characterized by cytopenia, ineffective hematopoiesis, dysplastic marrow, and risk of progression to acute myeloid leukemia. Cytogenetic abnormalities, including del(3q/5q/7q/11q/12p/20q), monosomy 5/7, trisomy 8/19, i(17q), and -Y, are the indicators of diagnosis and risk stratification. The present case with bicytopenia detected with highly complex chromosome rearrangements with variability in numerical and structural combinations. Chromosome analysis was carried out following unstimulated marrow culture and G-banding. In addition to known MDS-aberrations, der(9p), der(12) dic(12;?19), +15, −18, and ring and marker chromosomes were recorded having, at least, nine abnormal chromosomes/cell. To our knowledge, this is the first case with all MDS-aberrations in one single individual. The case has been discussed in relevance to current MDS research. In the present case, i(17q)/-17, der(12p), del(5q26), del(7q36), and del(20q11) indicate possible alterations in TP53, ETV6, IDH2, EZH2, and SRSF2 genes, which are responsible for pathomechanism, genetic instability, clonal evolution, and advancement of disease condition.

http://ift.tt/2j6wre9

Brain metastasis from nonnasopharyngeal head and neck squamous cell carcinoma: A case series and review of literature

Sarbani Ghosh-Laskar, Jai Prakash Agarwal, Prahlad H Yathiraj, Prasad Tanawade, Rajendra Panday, Tejpal Gupta, Ashwini Budrukkar, Vedang Murthy

Journal of Cancer Research and Therapeutics 2016 12(3):1160-1163

Background: Brain metastasis from primary head and neck squamous cell carcinoma (HNSCC) is infrequent and probably under-reported thereby leading to paucity of information. Methods: Archives of two institutes in India were studied from 2005 to 2013 and relevant information regarding patient demographics, treatment details, and follow-up was obtained for patients having brain metastasis (BM) from HNSCC. Data were analyzed using SPSS software version 20 (IBM Corporation, NY, USA). Results: Metastasis to the brain was detected in 17 patients with an HNSCC primary. The median age for diagnosis of index primary was 55 years (range (R) - 32–71 years) with 88% (15/17) being male. Oral cavity was the most common site of primary disease with 35% (6/17) followed by larynx (24%), oropharynx (18%), and hypopharynx (18%). The median stage at presentation was IVA (47%) and two (12%) were metastatic to the brain at presentation. Human papillomavirus analysis was not available for any of the patients. Neurological symptoms were complained of in 94% patients. The median BM-free-interval was 15 months (R - 1–67 months, SE ± 5.2). While 88% had multiple brain metastases, 82% also had extracranial metastasis and in 53% of patients, the index primary was not controlled. The median overall survival of all patients after the development of BM was 2 months (R - 0.5–6 months, SE ± 0.4). Conclusion: BM in HNSCC is mostly multiple, associated with extracranial metastasis and can occur in patients without locoregional relapse or residual disease and carries a dismal outcome.

http://ift.tt/2hUCrc6

Polymer-decorated anisotropic silica nanotubes with combined shape and surface properties for guest delivery

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Guo Liang Li, Jinglei Hu, Hongqiang Wang, Christine Pilz-Allen, Junpeng Wang, Tao Qi, Helmuth Möhwald, Dmitry G. Shchukin
We report on amphiphilic diblock copolymer-decorated anisotropic silica nanotubes with well-defined dual functions of shape and surface properties in one nanocontainer. Amphiphilic poly(lactic acid)-block-poly(ethylene glycol) (PLA-b-PEG) diblock copolymers are covalently grafted to the surface of mesoporous silica nanotubes via silane chemistry and esterification. The released percentage of probe molecules from the resultant silica-g-(PLA-b-PEG) hybrid nanocontainer is around 40% over a release time of 48 h, in contrast to 90% from bare silica nanotubes prior to surface modification. The diblock copolymer-decorated anisotropic nanocontainers with large aspect ratio lead to enhanced viability of NIH 3T3 fibroblast cells. A theoretical model based on the free energy cost for cell membranes to encapsulate nanocontainers is utilized to understand the cytotoxicity. This work demonstrates that the release dynamics of the active molecules and the interaction of hybrid nanocontainers with cell membranes can be regulated by the synergistic effect of nanocontainer shape and surface properties.

Graphical abstract

http://ift.tt/2iG49bu

Amphiphilic polypeptide-polyoxazoline graft copolymer conjugate with tunable thermoresponsiveness: Synthesis and self-assembly into various micellar structures in aqueous and nonaqueous media

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Avijit Bose, Somdeb Jana, Anupam Saha, Tarun K. Mandal
A "grafting onto" approach based on two different controlled ring-opening polymerization (ROP) techniques is developed to synthesize polytyrosine-graft-poly(2-ethyl-2-oxazoline) (PTyr-g-PEtOx) copolymer conjugates of varying main backbone and pendent chain lengths. This approach consists of syntheses of propargyl functionalized polytyrosine (PTyr-O-Pr) by ROP of tyrosine N-carboxyanhydride and azide functional poly(2-ethyl-2-oxazoline) (PEtOx-N3) by cationic ROP separately followed by their grafting using CuAAC reaction to afford the final graft copolymer conjugate (GCC). Owing to the presence of pendent hydrophiphilic PEtOx block, PTyr-g-PEtOx GCC exhibits LCST-type reversible phase transition behavior in water, which is tunable with respect to its concentration and the lengths of the main backbone and the pendent block. Again, the amphiphilic PTyr-g-PEtOx GCC molecules undergo self-assembly into spherical unit micelles and their consequent secondary aggregations into compound micelles both in aqueous and non-aqueous media. Upon increasing the solution temperature above LCST, micelles/compound micelles of PTyr-g-PEtOx GCC undergo further aggregation into higher order micellar agglomerates without any disruption of micellar structures as observed from DLS study. A hydrophobic dye (nile red) can easily be encapsulated into the hydrophobic PTyr core of the PTyr-g-PEtOx micelles in water, which remains stable without any release of the dye even when the temperature is increased above the LCST of the GCC.

Graphical abstract

http://ift.tt/2iG1VsJ

Kinetics of the temperature-induced volume phase transition in poly(2-(2-methoxyethoxy)ethyl methacrylate) hydrogels of various topologies

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Marcin Pastorczak, Lidia Okrasa, Jeong Ae Yoon, Tomasz Kowalewski, Krzysztof Matyjaszewski
Hydrogels based on thermo-responsive 2-(2-methoxyethoxy)ethyl methacrylate (pMEO2MA) are regarded as bioinert replacements of poly (N-isopropylacrylamide) in many biomedical applications. Here, we study kinetics of temperature-induced volume phase transitions (VPT) of pMEO2MA-based hydrogels of various network architecture during their water sorption and desorption processes by means of dielectric spectroscopy. Maxwell-Wagner-Sillars (MWS) polarization processes of two distinct origins develop in the course of VPT in the hydrogels. In the hydrogel with bare pMEO2MA network we observe MWS process resulted probably from interfacial polarization on microheterogeneities in the hydrogel and an additional MWS polarization linked to formation of the so-called dense skin-layer. In the hydrogel with its network grafted with dangling chains we observe only the microheterogeneities-related process; the process associated with formation of the skin-layer is not present, possibly due to more effective water diffusion out of the hydrogel. We determine relaxation times related to rearrangements of the polymer networks and to the diffusion of water during the hydrogel VPT in the both directions of the transition.

Graphical abstract

http://ift.tt/2iFS2er

Dual-layered nanocomposite substrate membrane based on polysulfone/graphene oxide for mitigating internal concentration polarization in forward osmosis

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Sungil Lim, Myoung Jun Park, Sherub Phuntsho, Leonard D. Tijing, Grace M. Nisola, Wang-Geun Shim, Wook-Jin Chung, Ho Kyong Shon
A novel thin-film composite (TFC) forward osmosis (FO) membrane with dual-layered substrate membrane was fabricated by a double-blade casting technique using different polysulfone (PSf) concentrations for top (15 wt%) and bottom (7 wt%) substrate layers. Graphene oxide (GO) was incorporated in the substrate layer, and the dual casting approach resulted in a membrane support with a highly porous bottom structure and a dense top skin layer on which the polyamide active layer was effectively formed. The dual-layered TFC PSf/GO membrane (TFC-PSfdGO) exhibited high water permeability, and ion selectivity was enhanced by the presence of well dispersed hydrophilic GO in the PSf substrate. The TFC-PSfdGO also exhibited the lowest specific reverse salt flux (Js/Jv = 0.19 g L^-1) and a more favorable structural parameter (S = 130 μm) compared to GO-free membranes. Using deionized water as feed solution and 1 M NaCl as draw solution (DS), TFC-PSfdGO had Jv = 33.8 L m⁻² h⁻¹ and Js = 6.9 g⁻² h⁻¹ under AL-FS mode, and Jv = 61.5 L m⁻²h⁻¹ and Js = 14.0 g⁻² h⁻¹ under AL-DS mode. The potential of TFC-PSfdGO for commercial application was further evaluated by fabricating it with a fabric backing support (denoted as TFC-PSfdGOf). Compared to TFC-PSfdGO, TFC-PSfdGOf exhibited only 14% decline in its water flux. The overall results reveal that, fabrication of TFC substrate membrane via dual-blade casting approach along with GO incorporation produced high-performance TFC FO membranes which likely reduced the internal concentration polarization effects.

Graphical abstract

http://ift.tt/2iG1cYk