Publication date: Available online 19 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Mohammadhossein Khorraminejad-Shirazi, Mohammad Farahmandnia, Bahareh Kardeh, Alireza Estedlal, Sina Kardeh, Ahmad Monabati
In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and NAD+ are practical ways to be employed for achieving more optimal results in stem cell-based transplantation therapies.
http://ift.tt/2znRtwS
Πέμπτη 19 Οκτωβρίου 2017
Ageing and Stem cell therapy: AMPK as an applicable pharmacological target for Rejuvenation of Aged Stem Cells and achieving higher efficacy in stem cell therapy
PLDT (planarian light/dark test): an invertebrate assay to quantify defensive responding and study anxiety-like effects
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Ashenafi Mebratu Zewde, Frances Yu, Sunil Nayak, Christopher Tallarida, Allen B. Reitz, Lynn G. Kirby, Scott M. Rawls
BackgroundPlanarians, like rodents, instinctively spend more time in dark versus light environments when given a choice. This behavioral phenomenon is called negative phototaxis, which may reflect defensive responding related to an anxiety-like phenotype.New methodWe propose a planarian light/dark test, designated PLDT, to predict anxiogenic- or anxiolytic-like effects. Experimentally, we placed a planarian at the midline of a Petri dish, containing test compound or water, that was split evenly into light and dark compartments and determined time spent in the light over 10min.ResultsA clinically-approved benzodiazepine agonist (clorazepate; 10μM) increased time spent in the light whereas an inverse benzodiazepine agonist (FG-7142; 1, 10μM) produced the opposite response. Fluoxetine (1μM) or ethanol (1%), as well as the 'bath salt' cathinone S-mephedrone (300μM), enhanced time spent in the light. Planarians exposed to predator (frog) odor spent more time in the dark.Comparison with existing methodsThe light/dark box (LDB) test in rodents is used to screen putative medications for possible anxiolytic and anxiogenic effects. Our results showing that time spent in the light by planarians is enhanced by common anxiety-relieving drugs (e.g. benzodiazepine agonist, ethanol, fluoxetine) and decreased by anxiogenic substances (e.g. predator odor, benzodiazepine inverse agonist) reveal directionally similar effects in the established (LDB) and new (PLDT) assays.ConclusionOur data identify the PLDT as a cost-effective, invertebrate assay for quantifying the effects of practically any water-soluble substance on defensive responding and for studying and teaching anxiety-like responses in a living organism.
http://ift.tt/2yDqkcb
Nano-scale precipitation and phase growth in Mg-Gd binary alloy: An atomic-scale investigation using HAADF-STEM
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): Jingxu Kent Zheng, Ruichun Luo, Xiaoqin Zeng, Bin Chen
In the present study, nanoscale precipitation and phase growth in Mg-15Gd(wt%) binary alloy are comprehensively studied by atomic-resolution high angle annular dark field - scanning transmission electron microscopy (HAADF-STEM). Various nanoscale precipitate structures, including βH, β′, βT′, βM and β′′-like structure, assembled by the "basic unit" as building block, are observed, reconstructed and discussed in detail. In the early stage of precipitation, the precipitate growth basically follows y (nm)=1.53x−2.68 (nm) and protrusions start to grow when the size of a precipitate reaches a threshold value. Long-range diffusion of Gd solute preferentially proceeds along <101¯0>Mg directions and protrusions are formed. A large number of fine β′ precipitates exist and act as the key strengthening structures. The formation of precipitate-free zones in the over-age condition is attributed to the intertwining of precipitates.
Graphical abstract
http://ift.tt/2l1PxYQ
Oxidation–nitridation-induced recrystallization in a near-α titanium alloy
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): Tomonori Kitashima, Toru Hara, Yang Yang, Yuka Hara
The oxidation resistance of titanium alloys is an important property for high-temperature applications. Here, the oxidation–nitridation-induced recrystallization at the oxide–metal interface of a near-α titanium alloy substrate was analyzed using electron-backscatter diffraction and scanning transmission electron microscopy after oxidation tests at 750°C for 500h in air. Oxidation–nitridation-induced recrystallization was promoted by the enrichment of nitrogen at the interface, and grains comprising Ti2N and Ti3AlN grew from the interface with the inhomogeneous distribution of nitrogen.
Graphical abstract
http://ift.tt/2l2e9QV
Evaluation of novel temperature-stable viscoelastic polyurea foams as helmet liner materials
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): B.J. Ramirez, V. Gupta
Viscoelastic polyurea foams with densities of 98, 170, and 230kg/m3 were manufactured and integrated into helmet shells and tested using the NOCSAE and FMVSS 218 standards for football and motorcycle helmets, respectively. For football helmet testing, a Riddell Revolution helmet shell was used. The helmets with a foam liner thickness of 28mm were dropped using a NOCSAE medium headform (4.9kg) from heights ranging from 0.305 to 1.524m. All impact tests were done on the crown of the helmet and dropped on a 12.7mm modular elastomer programmer pad. Use of PU98 foam resulted in a reduction of 22% in peak g's and 25% in Severity Index and Head Injury Criteria values when compared to helmets with the original VN600 foams under ambient conditions. These tests were repeated under varying temperatures along with a reduced liner thickness of 22.2mm. In these tests, PU98 foam reduced the peak g's by 18% at 23°C, 26% at −15°C, and 20% at 50°C when compared to VN600 helmets. The FMVSS motorcycle helmet tests demonstrated the success of using an additional layer of polyurea foam liner on top of the existing expanded polystyrene liner in reducing the peak g's by 17%.
Graphical abstract
http://ift.tt/2l2e9jT
High temperature fatigue characteristics of P/M and hot-forged W-Re and TZM for X-ray target of CT scanner
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): Mohd Azhar Harimon, Yukio Miyashita, Yuichi Otsuka, Yoshiharu Mutoh, Shinichi Yamamoto
The fatigue strengths at 1000°C of layered W-Re/TZM, bulk W-Re and bulk TZM for x-ray target materials were successfully evaluated under load-controlled four-point bending by introducing a fatigue failure criterion as two-times increase of initial compliance. The obtained fatigue strengths at 1000°C for layered W-Re/TZM and bulk W-Re were similar and 280MPa and 290MPa at 106cycles, respectively, while that of bulk TZM was 200MPa. During fatigue loading at 1000°C, dominant fatigue damage would be multiple intergranular crack nucleation and propagation, which would induce the increase of compliance. The reasonability of the fatigue failure criterion was confirmed by the fatigue process observations and the results of room temperature fatigue tests of the specimens tested at 1000°C up to the cycles corresponding to the fatigue failure criterion.
Graphical abstract
http://ift.tt/2l2e6od
Morphological evolution and internal strain mapping of pomelo peel using X-ray computed tomography and digital volume correlation
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): B. Wang, B. Pan, G. Lubineau
Cellular microstructures within natural materials enlighten and promote the development of novel materials and structures in the industrial and engineering fields. Characterization of the microstructures and mechanical properties of these natural materials can help to understand the morphology-related mechanical properties and guide the structural optimization in industrial design. Among these natural cellular materials, pomelo peels, having a foam-like hierarchical microstructure, represent an ideal model for developing materials with high energy absorption efficiency. In this work, by combining X-ray tomographic imaging technique and digital volume correlation (DVC), in-situ stepwise uniaxial compression tests were performed to quantify the internal morphological evolution and kinematic responses of pomelo peel samples during compression. Via these experiments, the varying microstructure features and thus diverse resistance to compression from endocarp to exocarp are examined, and the evolution of both bundles bending and large strain domain from endocarp to mesocarp are explored. Based on the experimental results, the microstructure-related mechanical properties of pomelo peels in response to compressive loading that demonstrates nearly linear morphology-mechanics relationship were revealed.
Graphical abstract
http://ift.tt/2l3CGoQ
Controllable hierarchical micro/nano patterns on biomaterial surfaces fabricated by ultrasonic nanocrystalline surface modification
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): Yuan Liang, Haifeng Qin, Nitin Mehra, Jiahua Zhu, Zhengnan Yang, Gary L. Doll, Chang Ye, Yalin Dong
In this work, we have shown that Ultrasonic Nanocrystal Surface Modification (UNSM) cannot only improve the mechanical properties of Ti-based biomaterials but also produce surface texture with hierarchical micro/nanoscale patterns due to its high controllability. After UNSM-treatment the surface texture of Ti-based biomaterial consists of a major microscale structure with widths ranging from 4μm to 200μm, and an embedded nanoscale structure with widths as small as 120nm. With a customized cylinder tip, the average surface roughness (Ra) can be reduced to 0.03μm, comparable to the superfinishing surface. The embedded nanoscale structure originates from the formation of the pile-up, which is determined by the elastic-plastic property of materials. Such hierarchical patterns enable new functions for the treated surface. It is demonstrated that light dispersion and the alteration of wettability can be achieved by controlling surface patterns using UNSM. The capacity of improving mechanical properties, biocompatibility, and hydrophobicity simultaneously, in conjunction with its low-cost and easy-to-operate features, makes it a promising surface engineering technique for biomaterial treatment.
Graphical abstract
http://ift.tt/2l31b5C
Anisotropic Ti-6Al-4V gyroid scaffolds manufactured by electron beam melting (EBM) for bone implant applications
Publication date: 5 January 2018
Source:Materials & Design, Volume 137
Author(s): Arash Ataee, Yuncang Li, Darren Fraser, Guangsheng Song, Cuie Wen
Ti-6Al-4V gyroid scaffolds with high porosities in the range of 82–85% and three different unit cell sizes 2, 2.5 and 3mm were manufactured by electron beam melting (EBM) for bone implant applications. The microstructure, mechanical properties and failure mode of the scaffolds with different sample orientations were evaluated. The as-built struts showed orthogonally orientated martensite α′ needles in columnar grains along the building direction with an average hardness of 3.89GPa and the elastic modulus and yield strength of scaffolds ranged from 637 to 1084MPa and from 13.1 to 19.2MPa, respectively. The elastic modulus and yield strength along the build direction and perpendicular to building direction varied by ~70% and 49%, respectively, depending on the amount of structural anisotropy and unit cell size. The ratio of elastic modulus anisotropy in orthogonal directions was comparable to those of trabecular bone and could be in favor of bone implant applications. Furthermore, as-built scaffolds showed a mixed mode of ductile and brittle behavior under compression, and the dominant failure mode was by forming orthogonal crush bonds at the peak loads with an angle of ~45° with compression axis.
Graphical abstract
http://ift.tt/2yuv5VL
Perceptions of eating disorder diagnoses and body image issues in four male cases in Singapore
Abstract
Background
Despite the increasing number of patients presenting for treatment, little is still known about male eating disorders cases. The current study presents four male eating disorder cases presented to our specialized treatment facility in Singapore.
Case presentation
Cases 1, 2 and 3 are homosexual males in their twenties and thirties who presented with anorexia nervosa and bulimia nervosa. Case 4 is a heterosexual male in his twenties diagnosed with binge eating disorder. All four cases expressed body image dissatisfaction, fat phobia and fear of weight gain. Additionally, all of them sought treatment because of comorbid psychiatric conditions or parental wishes. Premorbid obesity and homosexual orientation may be potential risk factors for males in developing eating disorders.
Conclusions
These findings suggest that more exploration needs to be done for males diagnosed with eating disorders, particularly in the Asian society. A deeper understanding into factors associated with symptom presentation and treatment-seeking behaviors would greatly assist in informing the direction and focus of treatment in the region.
http://ift.tt/2xS4LW9
Statin Use and Breast Cancer Prognosis in Black and White Women
Abstract
Studies show decreased risk of breast cancer recurrence and improved survival with statin use, but data on racial disparities regarding breast cancer prognosis and statin use are lacking. Our objective was to investigate if racial disparities in breast cancer prognosis can be partially explained by differences in pre-diagnosis statin use. Patients were identified from a prospective, multicenter study examining the effects of metabolic factors on breast cancer prognosis in Black and White women. Statin use, prognosis (as measured by Nottingham Prognostic Index), anthropometric, tumor, and socio-demographic characteristics were examined. Five hundred eighty-seven women (487 White, 100 Black) with newly diagnosed primary invasive breast cancer were recruited. Obesity was more prevalent in Black women than White women (47 vs 19%, p < 0.01); both groups had similar low-density lipoprotein (LDL) cholesterol levels (113 ± 41 vs 113 ± 36 mg/dl, p = 0.90). More Black women used statins than White women (18 vs 11%, p = 0.06). Black women had a worse prognosis in an adjusted model than White women (OR 2.13 95% CI 1.23–3.67). Statin use was not associated with prognosis in unadjusted (OR 1.03, 95% CI 0.53–2.0) and adjusted models (OR 1.14, 95% CI 0.56–2.31). In women with newly diagnosed breast cancer, Black women were more likely to be treated with statins than White women, contrary to previous studies. Black women had worse prognosis than White women, but this difference was not explained by differences in pre-diagnosis statin use. Our study suggests that differences in pre-diagnosis statin use do not contribute to racial disparities in breast cancer prognosis.
http://ift.tt/2yCadf4
Factors associated with post-stroke physical activity: a systematic review and meta-analysis
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Shamala Thilarajah, Benjamin F. Mentiplay, Kelly J. Bower, Dawn Tan, Pua Yong Hao, Gavin Williams, Gerald Koh, Ross A. Clark
ObjectiveTo integrate the literature investigating factors associated with post-stroke physical activity.Data SourcesA search was conducted from database inception to June 2016 across nine databases: Cochrane, Medline, ProQuest, Web of Science ISI, PsycInfo, Scopus, Embase, CINAHL and AMED. The reference lists of included articles were screened for secondary literature.Study selectionCohort and cross-sectional studies were included if they recruited community-dwelling stroke survivors and measured factors associated with physical activity.Data ExtractionRisk of bias was evaluated using the Quality in Prognosis Studies checklist. A meta-analysis was conducted for correlates where there were at least two studies that reported a correlation value. Correlation values were used in an effect size measure and converted to a standardised unit with Fisher r to z transformation and conversion back to r method. Results were described qualitatively for studies that could not be pooled.Data Synthesis2161 studies were screened and 26 studies were included. Age (meta r=-0.17; p=<0.001) and gender (meta r=-0.01; p=0.02) were the non-modifiable factors that were found to be associated with post-stroke physical activity. The modifiable factors were physical function (meta r=0.68-0.73; p<0.001), cardiorespiratory fitness (meta r=0.35; p=<0.001), fatigue (meta r=-0.22; p=0.01), falls self-efficacy (meta r=-0.33; p<0.001), balance self-efficacy (meta r=0.37; p<0.001), depression (meta r=-0.58-0.48; p<0.001) and health-related quality of life (meta r=0.38-0.43; p<0.001). The impact of side of infarct, neglect and cognition on post-stroke physical activity were inconclusive.ConclusionsAge, gender, physical function, depression, fatigue, self-efficacy and quality of life were factors associated with post-stroke physical activity. The cause and effect of these relationships are unclear and the possibility of reverse causality needs to be addressed.
http://ift.tt/2yWbv5D
Probiotic strains and mechanistic insights for the treatment of type 2 diabetes
Abstract
Introduction
The intestinal microbial composition appears to differ between healthy controls and individuals with Type 2 diabetes (T2D). This observation has led to the hypothesis that perturbations of the intestinal microbiota may contribute to the development of T2D. Manipulations of the intestinal microbiota may therefore provide a novel approach in the prevention and treatment of T2D. Indeed, fecal transplants have shown promising results in both animal models for obesity and T2D and in human clinical trials. To avoid possible complications associated with fecal transplants, probiotics are considered as a viable alternative therapy. An important, however often underappreciated, characteristic of probiotics is that individual strains may have different, even opposing, effects on the host. This strain specificity exists also within the same species. A comprehensive understanding of the underlying mechanisms at the strain level is therefore crucial for the selection of suitable probiotic strains.
Purpose
The aim of this review is to discuss the mechanisms employed by specific probiotic strains of the Lactobacillus and the Bifidobacterium genuses, which showed efficacy in the treatment of obesity and T2D. Some probiotic strains employ recurring beneficial effects, including the production of anti-microbial lactic acid, while other strains display highly unique features, such as hydrolysis of tannins.
Conclusion
A major obstacle in the evaluation of probiotic strains lays in the great number of strains, differences in detection methodology and measured outcome parameters. The understanding of further research should be directed towards the development of standardized evaluation methods to facilitate the comparison of different studies.
http://ift.tt/2xTvvWd
Effective removal of ammonia nitrogen from waste seawater using crystal seed enhanced struvite precipitation technology with response surface methodology for process optimization
Abstract
Traditional biological treatment was not effective for removing nitrogen from saline wastewater due to the inhibition of high salinity on biomass activity. In this context, a method of removing ammonia nitrogen from waste seawater was proposed by struvite precipitation which was enhanced by seeding technique. The abundant magnesium contained in waste seawater was used as the key component of struvite crystallization without additional magnesium. The effects of pH and P:N molar ratio on ammonia nitrogen removal efficiency were studied. The results showed that optimum pH value was in range of 8.5–10 and the P:N molar ratio should be controlled within 2:1–3:1. XRD and SEM-EDS analyses of the precipitates proved that Ca2+ and excess Mg2+ contained in waste seawater inhibited the struvite crystallization by competing PO43− to form by-products. Then, seeding technique for enhancing the struvite crystallization was investigated, and the results indicated that using preformed struvite as crystal seed significantly improved the ammonia nitrogen removal efficiency, especially when initial ammonia nitrogen concentration was relatively low. Moreover, response surface optimization experiment following a Box-Behnken design was conducted. A response surface model was established, based on which optimum process conditions were determined and interactions between various factors were clarified. At last, economic evaluation demonstrated this proposed method was economic feasible.
http://ift.tt/2yzFE7G
Hair mercury and risk assessment for consumption of contaminated seafood in residents from the coast of the Persian Gulf, Iran
Abstract
The health risks of mercury exposure due to the high consumption of aquatic were assessed for fishermen and non-fishermen families living on the Bandar Abbas, Bushehr, and Mahshahr cities located in the coast of Persian Gulf (Iran). The mean hair mercury concentration of people in Bandar Abbas, Bushehr, and Mahshahr cities was obtained 1.56 ± 0.17, 1.97 ± 0.22, and 5.12 ± 0.3 μg g−1, respectively. Hair mercury concentration in 8.8% of people exceeded the no observed adverse effects level (NOAEL) of 10 μg g−1 declared by the World Health Organization (WHO). The fish and shrimps consumption, place of living, and fisher and non-fisherman family were variables that significantly effected on mercury levels in the hair. The effect of other factors (age, sex, and number of dental amalgam fillings) on hair mercury was not significant. The mean concentrations of mercury in three fish species in Mahshahr exceeded the recommended maximum standard level (0.5 μg g−1) set by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA). The estimated weekly intake (EWI) for mercury in some fish species in Bandar Abbas, Bushehr, and Mahshahr was higher than the provisional tolerable weekly intake (1.6 μg kg−1 bw) set by European Food Safety Authority (EFSA) for some groups. The significant positive correlation between daily mercury intake and hair mercury concentration of people (r = 0.64, P < 0.001) reasserts that the hair mercury concentration could be explained by fish consumption. HQ > 1 was obtained for women in child bearing age in fishermen families in Bandar Abbas and Bushehr cities, children in fishermen families in Bushehr, and for all groups of population except adult in non-fishermen families in Mahshahr. So, the limited consumption of some fish species for these groups of people is recommended. The maximum of allowable fish consumption rate was 0.70 meals/month for Pseudorhombus arsius from Mahshahr fish for women of child bearing age. Also, it is necessary to create and monitor and enforce environmental standards, preventing the entry of pollutants released into the marine aquatic environment without proper early treatment.
http://ift.tt/2x9W8C7
Distribution of mesotocin-immunoreactive neurons in the brain of the male native Thai chicken
Source:Acta Histochemica
Author(s): Boonyarit Kamkrathok, Tom E. Porter, Mohamed E. El Halawani, Yupaporn Chaiseha
Mesotocin (MT), a homolog of oxytocin (OT) in mammals, is a nonapeptide neurohypophysial hormone that is mainly synthesized in specific neuronal groups within the hypothalamus and released from the posterior pituitary gland in amphibian, reptilian, and avian species. MT is associated with the neuroendocrine regulation of reproductive cycle and maternal behaviors in female native Thai chickens. Male birds exhibit parental behaviors as well. However, there are limited data regarding the role(s) of the MTergic system in males. Thus, the objective of this study was to elucidate the localization of the MT neuronal groups in the brain of male native Thai chickens. The distributions of MT-immunoreactive (-ir) neurons and fibers in the brain were studied utilizing immunohistochemistry technique. The results revealed that MT-ir neurons and fibers were distributed throughout the brain and extensively in the diencephalon. MT-ir neurons and fibers were predominantly located within the nucleus supraopticus, pars ventralis (SOv), nucleus preopticus medialis (POM), nucleus ventrolateralis thalami (VLT), nucleus paraventricularis magnocellularis (PVN), and regio lateralis hypothalami (LHy), suggesting that MT neurons in these nuclei might be involved in the reproductive activities and/or parental behavior in the male chickens. In addition, the numbers of MT-ir neurons within the SOv and POM were significantly higher than those of the VLT, PVN, and LHy. More importantly, the number of MT-ir neurons in the SOv was high in the male brain when compared with the female brain, indicating that the MTergic system in the SOv might play a significant role in male reproductive activities in this equatorial species.
http://ift.tt/2yB9AjS
Probiotic strains and mechanistic insights for the treatment of type 2 diabetes
Abstract
Introduction
The intestinal microbial composition appears to differ between healthy controls and individuals with Type 2 diabetes (T2D). This observation has led to the hypothesis that perturbations of the intestinal microbiota may contribute to the development of T2D. Manipulations of the intestinal microbiota may therefore provide a novel approach in the prevention and treatment of T2D. Indeed, fecal transplants have shown promising results in both animal models for obesity and T2D and in human clinical trials. To avoid possible complications associated with fecal transplants, probiotics are considered as a viable alternative therapy. An important, however often underappreciated, characteristic of probiotics is that individual strains may have different, even opposing, effects on the host. This strain specificity exists also within the same species. A comprehensive understanding of the underlying mechanisms at the strain level is therefore crucial for the selection of suitable probiotic strains.
Purpose
The aim of this review is to discuss the mechanisms employed by specific probiotic strains of the Lactobacillus and the Bifidobacterium genuses, which showed efficacy in the treatment of obesity and T2D. Some probiotic strains employ recurring beneficial effects, including the production of anti-microbial lactic acid, while other strains display highly unique features, such as hydrolysis of tannins.
Conclusion
A major obstacle in the evaluation of probiotic strains lays in the great number of strains, differences in detection methodology and measured outcome parameters. The understanding of further research should be directed towards the development of standardized evaluation methods to facilitate the comparison of different studies.
http://ift.tt/2xTvvWd
Measuring alcohol use across the transition to adulthood: Racial/ethnic, sexual identity, and educational differences
Source:Addictive Behaviors, Volume 77
Author(s): Jessica N. Fish, Amanda M. Pollitt, John E. Schulenberg, Stephen T. Russell
BackgroundPatterns of alcohol use change from adolescence to adulthood and may differ based on race/ethnicity, sexual identity, and education. If alcohol use measures do not operate consistently across groups and developmental periods, parameter estimates and conclusions may be biased.ObjectivesTo test the measurement invariance of a multi-item alcohol use measure across groups defined by race/ethnicity, sexual identity, and college education during the transition to adulthood.MethodsUsing three waves from the National Longitudinal Study of Adolescent to Adult Health, we tested configural, metric, and scalar invariance of a 3-item alcohol use measure for groups defined by race/ethnicity, sexual identity, and college education at three points during the transition to adulthood. We then assessed longitudinal measurement invariance to test the feasibility of modeling developmental changes in alcohol use within groups defined by these characteristics.ResultsOverall, findings confirm notable variability in the construct reliability of a multi-item alcohol use measure during the transition to adulthood. The alcohol use measure failed tests of metric and scalar invariance, increasingly across ages, both between- and within-groups defined by race/ethnicity, sexual identity, and college education, particularly among females.ConclusionsMeasurement testing is a critical step when utilizing multi-item measures of alcohol use. Studies that do not account for the effects of group or longitudinal measurement non-invariance may be statistically biased, such that recommendations for risk and prevention efforts could be misguided.
http://ift.tt/2l2j2d1
Energy efficiency of ambulation–A comparison of various orthopaedic possibilities
Publication date: Available online 19 October 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Jerin Mathew, Kavitha Raja, Febin P. Baby, B. Basima
BackgroundIn most developing countries, accessibility for people using walking aids is limited due to architectural and environmental barriers. As observed from anecdotal accounts, even a minor orthopaedic injury/disorder may restrict a person's ambulation due to fatigue associated with using walking aids. Hence this study was undertaken with the following objective.Objectiveto estimate the magnitude of energy consumption using energy expenditure index (EEI) during gait under different conditions.DesignRepeated measures design (within subjects study).SettingSchool.ParticipantsTen healthy, typical young adults between 17 and 25 years of age.Outcome measureEnergy Expenditure Index (EEI) was estimated for each of the conditions of the study using consistent measurement procedures.Resultsthe energy consumption with immobilization is greater (anke-16.2%, knee-36.7% and ankle and kee-49.2%) than typical self-selected ambulation. During on ground ambulation the energy cost was greatest for axillary crutches than standard walker with ankle and knee immobilized being the highest in relation to typical ambulation (78.2% greater). Axillary crutches were more efficient than walker during stair climbing.Conclusionfor young adults a standard walker may be the right option for over-ground ambulation, when a lower limb joint in immobilized; with axillary crutch use during stair climbing.
http://ift.tt/2gpv0Id
Artificial 137 Cs and natural 40 K in mushrooms from the subalpine region of the Minya Konka summit and Yunnan Province in China
Abstract
A study on 137Cs pollution and activity concentrations of 40K in mushrooms of the genera Cortinarius, Leccinum, Russula, Tricholoma, Tylopilus, and Xerocomus from two neighboring regions in southwest China in 2010–2013 revealed different patterns of pollution with 137Cs, which seemed to be highly dependent on climate conditions. Tricholoma matsutake was collected in Yunnan before and after the Fukushima Dai-ichi nuclear accident and showed similar contamination with 137Cs. Mushrooms from the elevation of 2800–3480 m above sea level on the east slope of Minya Konka and forest topsoil showed higher contamination with 137Cs than mushrooms from the highlands of Yunnan. In detail, the activity concentration of 137Cs in caps of mushrooms from Minya Konka were in the range 62 ± 6–280 ± 150 Bq kg−1 dry biomass and from Yunnan at < 4.4–83 ± 3 Bq kg−1 dry biomass. The climate in the region of the Minya Konka is much colder than in Yunnan, which seems to favor deposition of 137Cs at higher altitudes from global atmospheric circulation. The activity concentration of 40K in mushrooms and soils highly exceeded that of 137Cs. The assessed annual effective doses for 137Cs in 1 kg of consumed mushrooms of the genera Leccinum and Xerocomus in Yunnan were low, i.e., in the range < 0.0043–0.049 ± 0.004 μSv, while those for 40K were 0.26 ± 0.02–0.81 ± 0.09 μSv.
http://ift.tt/2x8JJOt
Rare-earth elements in human colostrum milk
Abstract
Rare-earth elements (REEs) are used in a growing number of applications, and their release to environment has increased over the decades. Knowledge of REEs in human milk and factors that could possibly influence their concentration is scarce. This study evaluated the concentrations of 16 REEs (Ce, Eu, Er, Gd, La, Nd, Pr, Sc, Sm, Dy, Ho, Lu, Tb, Tm, Y, and Yb) in human colostrum milk collected from Polish women (n = 100) with the ICP-OES technique. The concentrations (mean ± SD) of Pr (41.9 ± 13.2 μg L−1), Nd (11.0 ± 4.0 μg L−1), La (7.1 ± 5.2 μg L−1), and Er (2.2 ± 0.8 μg L−1) were found above detection limits. The total mean ± SD concentration of detected REEs was 60.9 ± 17.8 μg L−1. Current smokers displayed significantly increased Nd concentrations compared to women who had never smoked. No other associations between REEs in colostrum milk and age, diet in pregnancy (food supplement use and frequency of fish, meat, and vegetable consumption) or place of living (urban/rural) were found. This study adds to general understanding of the occurrence and turnover of REEs in women and human fluids.
http://ift.tt/2ioVdLn
Clinical Thyroidology High-Impact Articles
FREE ACCESS through November 30, 2017.
Read Now:
Does Normal TSH Mean Euthyroidism in L-T4 Treatment?
Jacques Orgiazzi
The Increased Incidence of Thyroid Cancer Is Worldwide
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Stephen W. Spaulding
Active Surveillance of Small, Low-Risk Papillary Thyroid Cancers Can Be a Safe Alternative to Surgery in Selected Patients
Angela M. Leung
Age Cutoff of 45 Years May Not Be Appropriate for Papillary Thyroid Cancer Staging
Masha J. Livhits, Michael W. Yeh Read Now
Postoperative Thyroglobulin and Neck Ultrasound Are Useful for Risk Restratification and Decision to Perform 131I Ablation
Stephanie A. Fish
How Often Does a Thyroid Cancer Patient Need to Undergo Surveillance with Cervical Ultrasound?
Martin Biermann
Lymph Node Mapping with Ultrasound Is Highly Useful in the Preoperative Workup of Patients with Thyroid Cancer
Martin Biermann
Lateral Lymph-Node Dissection for Papillary Thyroid Cancer Should Be Limited to Clinically Positive Compartments
Masha J. Livhits, Michael W. Yeh
Radiofrequency Ablation Is a Treatment Option for Low-Risk Papillary Thyroid Microcarcinoma
Wendy Sacks
The post Clinical Thyroidology High-Impact Articles appeared first on American Thyroid Association.
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Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization
Abstract
Background
Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort.
Patients and methods
Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed.
Results
Sixty-one patients were included, of which 16.4% were underexposed (mean Cmin < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis Cmin > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis.
Conclusion
This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.
http://ift.tt/2hQR5Qs
LAMP3 regulates hepatic lipid metabolism through activating PI3K/Akt pathway
Source:Molecular and Cellular Endocrinology
Author(s): Xiaoyu Liao, Lingyu Song, Linlin Zhang, Hui Wang, Qiang Tong, Jing Xu, Gangyi Yang, Shiming Yang, Hongting Zheng
Lysosome associated membrane protein 3 (LAMP3), a highly glycosylated protein, is one member of the LAMPs family. LAMPs family plays a critical role in the autolysosome fusion process. Autophagy was recently confirmed to regulate hepatic lipolysis. However, the physiological function of LAMP3 in lipid metabolism is not clear. In the current study, we discovered that the LAMP3 expression level was higher in the liver tissues of non-alcoholic fatty liver disease (NAFLD) patients and high-fat diet and ob/ob mice than in the matched control groups. LAMP3 expression was also obviously increased in hepatocellular carcinoma (HCC) cells treated with free fatty acids. Moreover, marked accumulation of intracellular lipid droplets and triglycerides (TG) was observed after LAMP3 overexpression in HCC cells. Further study showed that LAMP3 overexpression activated Akt and upregulated the expression of the lipogenic enzymes FASN and SCD-1 in HepG2 cells. Additionally, the increased TG content induced by LAMP3 overexpression was attenuated by treatment with a PI3K/Akt pathway inhibitor. Our findings demonstrated that LAMP3 is an important regulator of hepatic lipid metabolism, which provides a line of evidence for taking LAMP3 as a drug target in lipid metabolism disorder-associated diseases, such as NAFLD and obesity.
http://ift.tt/2io5dVp
Cryoconites from Alpine glaciers: Radionuclide accumulation and age estimation with Pu and Cs isotopes and 210Pb
Source:Journal of Environmental Radioactivity
Author(s): T. Wilflinger, H. Lettner, A. Hubmer, P. Bossew, B. Sattler, H. Slupetzky
Cryoconites ("cold dust", derived from the Greek) are aeolian sediments accumulated on glacier surfaces. In cryoconites from the surface of the Stubacher Sonnblickkees, a temperate Austrian glacier, extremely high activity concentrations of artificial and natural radionuclides were found. Artificial radionuclides stem from two clearly distinguishable sources, global fallout from the nuclear weapons testing era deposited over a period of years until roughly 1966 and the fallout from Chernobyl in 1986, which was essentially deposited as a single input during one week. Anthropogenic radionuclides identified were 137Cs, 134Cs, 238Pu, 239+240Pu, 90Sr, 241Am, 60Co, 125Sb, 154Eu, and 207Bi. The naturally occurring radionuclides detected were the long-lived radon decay product 210Pb, the primordial radionuclide 4 K and the cosmogenic 7Be.Isotopic ratios of 134Cs/137Cs and 239+240Pu/238Pu were used to separate the nuclide inventory into the contributions of the two aforementioned sources, which show varying degrees of mixing and provide information on the mixing age of the cryoconites. Since isotopic ratios of Pu often have high uncertainties due to low absolute concentrations, age estimation based on this method can be quite inaccurate. Additional information about the age of cryoconites was obtained through analysis of 210Pb, which is constantly deposited over time.
http://ift.tt/2yu3Qef
HMGA1 is a novel transcriptional regulator of the FoxO1 gene
Abstract
Purpose
The forkhead transcription factor (FoxO1) is a master transcriptional regulator of fundamental cellular processes ranging from cell proliferation and differentiation to inflammation and metabolism. However, despite its relevance, the mechanism(s) underlying FoxO1 gene regulation are largely unknown. We have previously shown that the chromatin factor high-mobility group A1 (HMGA1) plays a key role in the transcriptional regulation of glucose-responsive genes, including some that are involved in FoxO1-mediated glucose metabolism. Here we investigated the impact of HMGA1 on FoxO1 gene expression.
Methods
FoxO1 protein and gene expression studies were performed by Western blot analysis combined with qRT-PCR of material from human cultured cells and EBV-transformed lymphoblasts, and from primary cultured hepatocytes from wild-type and Hmga1 –/– mice. Reporter gene assays and chromatin immunoprecipitation for binding of HMGA1 to the endogenous FoxoO1 locus were performed in cells overexpressing HMGA1 and in cells pretreated with siRNA targeting HMGA1.
Results
HMGA1 increased FoxO1 mRNA and protein expression in vitro, in cultured HepG2 and HEK-293 cells by binding FoxO1 gene promoter, thereby activating FoxO1 gene transcription. Forced expression of HMGA1 in primary cultured hepatocytes from Hmga1 –/– mice and in EBV-transformed lymphoblasts from subjects with reduced expression of endogenous HMGA1 increased FoxO1 mRNA and protein levels.
Conclusion
These findings may contribute to the understanding of FoxO1 gene regulation and its role in metabolism.
http://ift.tt/2yCJpvk
Thyroid reoperation using intraoperative neuromonitoring
Abstract
Purpose
Thyroid reoperations are at a high risk of recurrent laryngeal nerve (RLN) injury. The aim of the study was to investigate whether the use of intraoperative neuromonitoring (IONM) can aid in the RLN identification and minimize the risk of its injury, in comparison with visual RLN identification.
Methods
This was a retrospective cohort study of patients who underwent thyroid reoperations with and without the use of IONM. Primary endpoint was the RLN identification rate; secondary: the prevalence of RLN injury, the frequency of total thyroidectomies, and the course of the RLN.
Results
The study involved 61 patients undergoing thyroid reoperation among whom 24 were operated on with visual RLN identification only, while 37 procedures used IONM. In the non-monitored reoperations, 44.4% of the RLN were visually identified, as opposed to 91.6% in the IONM group (p < 0.001). Transient paresis occurred in three nerves with visualization (6.6%), and in one in IONM group 1.6% (p = 0.185). Permanent paresis occurred in the group with visualization (6.6%), as opposed to none with neuromonitoring. The extent of resection in both groups was significantly different (p = 0.043). Total, near-total thyroidectomies, Dunhill operations and subtotal thyroidectomies were performed in 71, 17, 4, and 8% in the visualization group, and in 94, 0, 3, and 3%, respectively, in the IONM group. A non-anatomical RLN course was observed in 80% of the reoperations with IONM.
Conclusions
Thyroid reoperation should be performed using IONM, because it allows for a significantly improved RLN identification rate and a significantly more radical resection.
http://ift.tt/2gREm08
HMGA1 is a novel transcriptional regulator of the FoxO1 gene
Abstract
Purpose
The forkhead transcription factor (FoxO1) is a master transcriptional regulator of fundamental cellular processes ranging from cell proliferation and differentiation to inflammation and metabolism. However, despite its relevance, the mechanism(s) underlying FoxO1 gene regulation are largely unknown. We have previously shown that the chromatin factor high-mobility group A1 (HMGA1) plays a key role in the transcriptional regulation of glucose-responsive genes, including some that are involved in FoxO1-mediated glucose metabolism. Here we investigated the impact of HMGA1 on FoxO1 gene expression.
Methods
FoxO1 protein and gene expression studies were performed by Western blot analysis combined with qRT-PCR of material from human cultured cells and EBV-transformed lymphoblasts, and from primary cultured hepatocytes from wild-type and Hmga1 –/– mice. Reporter gene assays and chromatin immunoprecipitation for binding of HMGA1 to the endogenous FoxoO1 locus were performed in cells overexpressing HMGA1 and in cells pretreated with siRNA targeting HMGA1.
Results
HMGA1 increased FoxO1 mRNA and protein expression in vitro, in cultured HepG2 and HEK-293 cells by binding FoxO1 gene promoter, thereby activating FoxO1 gene transcription. Forced expression of HMGA1 in primary cultured hepatocytes from Hmga1 –/– mice and in EBV-transformed lymphoblasts from subjects with reduced expression of endogenous HMGA1 increased FoxO1 mRNA and protein levels.
Conclusion
These findings may contribute to the understanding of FoxO1 gene regulation and its role in metabolism.
http://ift.tt/2yCJpvk
Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis
Abstract
Purpose
To assess the effectiveness and safety of myoinositol for patients with PCOS.
Methods
In this meta-analysis, data from randomized controlled trials are obtained to assess the effects of myoinositol vs. placebo or western medicine in women with PCOS. The study's registration number is CRD42017064563. The primary outcomes included total testosterone, estradiol (E2) and the homeostatic model assessment (HOMA) of insulin resistance.
Result
Ten trials involving 573 patients were included. The meta-analysis results show that: compared with the control group, myoinositol may improve HOMA index (WMD −0.65; 95% CI −1.02, −0.28; P = 0. 0005) and increase the E2 level (WMD 16.16; 95% CI 2.01, 30.31; P = 0. 03); while there is no enough strong evidence that the myoinositol has an effect on the total testosterone level (WMD −16.11; 95% CI −46.08, 13.86; P = 0. 29).
Conclusion
Based on current evidence, myoinositol may be recommended for the treatment of PCOS with insulin resistance, as well as for improving symptoms caused by decreased estrogen in PCOS.
http://ift.tt/2iodclc
Dielectric spectroscopy study of water hyacinth collected from different media
Publication date: 15 February 2018
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 191
Author(s): Ragab Mahani, Fatma Atia, Mohammed M. Al Neklawy, Amin Fahem
X-ray fluorescence (XRF) study has been shown that the water hyacinth plant is an effective tool for the removals of heavy metals (As, Ba, Cr, Cu, Ni, Pb, Rb, Sr, Zn and Zr) and metal oxides (SiO2, K2O, CaO, Al2O3, Fe2O3, MgO, Na2O, MnO, P2O5, SO3 and TiO2) from agriculture (media 1) and agriculture wastewaters drainage polluted with municipal wastewater (media 2). As a general description, the heavy metals and metal oxides were found at higher levels in the plant collected from media 1 than those in the plant collected from media 2. Similarly, these pollutants were found at higher levels in the plant roots than those in the plant shoots. The dielectric properties were investigated for the plant samples before (control) and after treating by microwave heating power. They were found at higher values in the control roots than those in the control shoots. Furthermore, the properties were found at relatively higher values in the control roots collected from media 1 (ε′=13 at 103Hz) than those in the control roots collected from media 2 (ε′=9 at 103Hz). The electrical conductivity of the microwave treated samples remarkably increased due to appearance of OH group through which the plant interacts with heavy metals. Accordingly, the pollutants removing ability could be enhanced upon treating the plant by microwave heating power. The plant-pollutant mixture behaves like highly conductive disordered polymers. The conductivity and dielectric properties of all plant samples are dominated by the media and concentration of pollutants.
Graphical abstract
http://ift.tt/2zC9ybt
Pulsed light reduces the toxicity of the algal toxin okadaic acid to freshwater crustacean Daphnia pulex
Abstract
This constitutes the first study to report on the reduction in toxicity of the dinoflagellate algal toxin okadaic acid after novel pulsed light (PL) treatments where ecotoxicological assessment was performed using a miniaturised format of the conventional in vivo freshwater crustacean Daphnia sp. acute toxicity test. Bivalves accumulate this toxin, which can then enter the human food chain causing deleterious health effects such as diarrhetic shellfish poisoning. This miniaturised toxicological bioassay used substantially less sample volume and chemical reagents. Findings revealed a 24-h EC50 of 25.87 μg/L for PL-treated okadaic acid at a UV dose of 12.98 μJ/cm2 compared to a 24-h EC50 of 1.68 μg/L for the untreated okadaic acid control, suggesting a 15-fold reduction in toxicity to Daphnia pulex. The bioassay was validated in this study and correlated well with the "classic" ISO format (r = 0.98) using the traditional reference chemical potassium dichromate (K2Cr2O7). Reduction by up to 65% in PL-treated okadaic acid concentration was confirmed by LC-MS/MS analysis. Findings from this study have positive ecological, societal and enterprise implications, such as the development of PL technology for the prevention or reduce algal contamination of fisheries and aquaculture industries.
http://ift.tt/2yuiNwI
An exploratory study of creativity and eating disorders
Abstract
Background
We examined whether cognitive rigidity associated with having an eating disorder generalized to creativity.
Method
One hundred twelve participants from the participant pool of an Australian university were given a measure of disordered eating (EDE-Q), asked if they had ever had a diagnosis of an eating disorder (16 reported yes), and given 3 min to generate alternative uses for a paper-clip. The alternative uses task yielded measures of creative fluency, originality, elaboration and flexibility.
Results
A logistic regression found that only lower flexibility predicted a self-reported ED diagnosis. Across the spectrum of disordered eating behaviour there was no association between creativity measures and EDE-Q global scores.
Conclusion
Our results were consistent with previous findings of an association between cognitive inflexibility and having an ED. However we found no evidence that cognitive inflexibility generalized to creativity more broadly. Our results may lend support to Cognitive Remediation Therapy, but further study is required.
http://ift.tt/2yCA4mT
Radiation-induced liver injury mimicking liver metastases on FDG-PET-CT after chemoradiotherapy for esophageal cancer
Abstract
Background
For esophageal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), restaging using F‑18-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT) following nCRT can detect interval metastases, including liver metastases, in almost 10% of patients. However, in clinical practice, focal FDG liver uptake, unrelated to liver metastases, is observed after chemoradiotherapy. This radiation-induced liver injury (RILI) can potentially lead to overstaging.
Methods
A systematic search for potential cases of RILI after (chemo)radiotherapy for esophageal cancer was performed in the electronic reports from all PET-CT scans made between 2006 and 2015 in our hospital. Additional data about potential cases were obtained from the electronic medical records. A literature review of RILI was also performed.
Results
Of 205 patients undergoing nCRT, 6 cases with localized increased FDG uptake in the caudate or left liver lobe following nCRT for esophageal cancer were identified. None of these patients had signs of liver metastases with additional imaging, during surgery, on biopsy, or during follow-up (range 11–46 months). At our institute, the incidence of RILI after neoadjuvant chemoradiotherapy for esophageal cancer was 3%. In the literature, RILI is described in about 8% of patients at the time of restaging. FDG-avid lesions occur in the high radiation dose area, usually corresponding to the caudate or left liver lobe.
Conclusions
FDG accumulation in the caudate or left liver lobe after CRT in the area that received a high radiation dose may be caused by metastases or RILI. Awareness of the pitfall of high FDG uptake in RILI is crucial to avoid misinterpretation and overstaging.
http://ift.tt/2yDLtmq
Use of Probiotics and Oral Health
Abstract
Purpose of Review
The purpose of this study is to critically assess recent studies concerning the use of probiotics to control periodontal diseases, dental caries and halitosis (oral malodour).
Recent Findings
Clinical studies have shown that probiotics when allied to conventional periodontal treatment can ameliorate microbial dysbiosis and produce significant improvement in clinical indicators of disease. However, this effect is often not maintained by the host after the end of probiotic use. Current probiotics also show limited effects in treating caries and halitosis. Novel approaches based up on replacement therapy and using highly abundant health-associated oral species, including nitrate-reducing bacteria, have been proposed to improve persistence of probiotic strains and maintain oral health benefits.
Summary
Probiotics have potential in the management of multifactorial diseases such as the periodontal diseases and caries, by more effectively addressing the host-microbial interface to restore homeostasis that may not be achieved with conventional treatments.
http://ift.tt/2yBPLel
Telotristat ethyl: proof of principle and the first oral agent in the management of well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea
Abstract
Introduction
Metastatic neuroendocrine tumors (NETs) are associated with carcinoid syndrome that is typically characterized by diarrhea, cutaneous flushing and bronchospasm. Treatment with somatostatin analogues (SSA) improves the symptom burden but a significant proportion of patients stop responding to SSA therapy eventually. Novel agents with the potential to effectively control the symptoms are urgently needed.
Methods
This article reviews an in-depth analysis of the phase I-III clinical trials determining the clinical rationale for the use of tryptophan hydroxylase inhibitor, telotristat ethyl in patients with well-differentiated metastatic NETs and uncontrolled carcinoid syndrome.
Discussion
Telotristat ethyl has already been approved for the treatment of inadequately controlled carcinoid syndrome symptoms in metastatic NET patients on SSA therapy. Results from multiple phase I–III clinical studies of telotristat ethyl therapy have reported a significant decrease in the daily bowel movement frequency, increase in quality of life and the subsequent decrease in annual health costs related to carcinoid syndrome symptoms in NET patients.
Future directions
The associated decrease in urinary 5-hydroxyindoleacetic acid (u5-HIAA) provides evidence that telotristat ethyl effectively decreases serotonin production, and therefore, offers a rationale to investigate this agent to mitigate serotonin-mediated complications in this patient population, especially cardiac valvular disease or mesenteric fibrosis.
http://ift.tt/2gRPdHh
Treatment-related sinusoidal obstruction syndrome in children with de novo acute lymphoblastic leukemia during intensification
Abstract
Purpose
Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, has been described following treatment of acute lymphoblastic leukemia (ALL) with the anti-metabolite 6-thioguanine (6-TG). Previous studies incorporating daily 6-TG into maintenance chemotherapy demonstrated a high incidence of SOS, typically presenting after prolonged exposures to 6-TG. 6-TG continues to be used as a single, 14-day burst during intensification; however, SOS associated with brief courses of 6-TG is poorly described. We aim to describe this rare though clinically significant phenomenon.
Methods
Children with 6-TG-related SOS were retrospectively identified from 680 de novo patients with ALL at Texas Children's Cancer Center over 8 years. Clinical characteristics and outcomes are described.
Results
Ten (1.5%) patients were identified with SOS. No predominant sex, ethnicity, or race was noted. SOS was diagnosed 16.5 (6–42) days from starting 6-TG. Isolated thrombocytopenia (IT) was noted in 9/10 patients and presented a median of 5 days prior to SOS. Refractoriness to platelet transfusions was noted in 8/10 patients, presenting a median of 2 days prior to SOS. Most patients were otherwise clinically stable outpatients upon presenting with IT or transfusion refractoriness. Fever was noted in 7/10 patients at diagnosis and 6/10 had documented or suspected infection within 14 days of SOS. Two patients died, while eight fully recovered. Intermediate thiopurine methyltransferase genotype was noted in 5/8 patients with data available.
Conclusion
SOS following short courses of 6-TG in DI is clinically distinct from SOS following prolonged courses of 6-TG in maintenance, particularly in its early presentation and outcomes.
http://ift.tt/2imtUS1
Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis
Abstract
Purpose
To assess the effectiveness and safety of myoinositol for patients with PCOS.
Methods
In this meta-analysis, data from randomized controlled trials are obtained to assess the effects of myoinositol vs. placebo or western medicine in women with PCOS. The study's registration number is CRD42017064563. The primary outcomes included total testosterone, estradiol (E2) and the homeostatic model assessment (HOMA) of insulin resistance.
Result
Ten trials involving 573 patients were included. The meta-analysis results show that: compared with the control group, myoinositol may improve HOMA index (WMD −0.65; 95% CI −1.02, −0.28; P = 0. 0005) and increase the E2 level (WMD 16.16; 95% CI 2.01, 30.31; P = 0. 03); while there is no enough strong evidence that the myoinositol has an effect on the total testosterone level (WMD −16.11; 95% CI −46.08, 13.86; P = 0. 29).
Conclusion
Based on current evidence, myoinositol may be recommended for the treatment of PCOS with insulin resistance, as well as for improving symptoms caused by decreased estrogen in PCOS.
http://ift.tt/2iodclc
Thyroid reoperation using intraoperative neuromonitoring
Abstract
Purpose
Thyroid reoperations are at a high risk of recurrent laryngeal nerve (RLN) injury. The aim of the study was to investigate whether the use of intraoperative neuromonitoring (IONM) can aid in the RLN identification and minimize the risk of its injury, in comparison with visual RLN identification.
Methods
This was a retrospective cohort study of patients who underwent thyroid reoperations with and without the use of IONM. Primary endpoint was the RLN identification rate; secondary: the prevalence of RLN injury, the frequency of total thyroidectomies, and the course of the RLN.
Results
The study involved 61 patients undergoing thyroid reoperation among whom 24 were operated on with visual RLN identification only, while 37 procedures used IONM. In the non-monitored reoperations, 44.4% of the RLN were visually identified, as opposed to 91.6% in the IONM group (p < 0.001). Transient paresis occurred in three nerves with visualization (6.6%), and in one in IONM group 1.6% (p = 0.185). Permanent paresis occurred in the group with visualization (6.6%), as opposed to none with neuromonitoring. The extent of resection in both groups was significantly different (p = 0.043). Total, near-total thyroidectomies, Dunhill operations and subtotal thyroidectomies were performed in 71, 17, 4, and 8% in the visualization group, and in 94, 0, 3, and 3%, respectively, in the IONM group. A non-anatomical RLN course was observed in 80% of the reoperations with IONM.
Conclusions
Thyroid reoperation should be performed using IONM, because it allows for a significantly improved RLN identification rate and a significantly more radical resection.
http://ift.tt/2gREm08
Enzymatic activity induction of GST-family isoenzymes from pesticide mixture used in floriculture
Abstract
Glutathione S-transferases (GSTs) comprise a number of genes that codify for a group of isoenzymes that participate in phase II xenobiotic detoxification by means of conjugation with glutathione, producing hydrosoluble compounds. It has been demonstrated that some pesticides are substrates for GST isoenzymes. Floriculture is one of the main economic activities in the municipalities of Villa Guerrero and Atlacomulco; pesticides, applied as mixtures, are intensively used in this activity. In this study, total GST enzymatic activity and glutathione S-transferases theta 1 (GSTT1) enzymatic activity were calculated for a group of floriculture workers exposed to pesticides and for an unexposed group. The former comprised 169 floriculture workers, while the latter, 96 students. The value of the median GST enzymatic activity in the exposed group was 0.560 and 0.169 μmol/min/mL in the unexposed individuals. GSTT1 activity was 1.234 μmol/min/mL in the exposed group and 0.221 μmol/min/mL in the unexposed group. Mann-Whitney U test showed a significant difference between these groups, for both total GST and GSTT1, p < 0.001. Our results show that exposure to pesticides increases the activities of total GST and GSTT1 enzymes.
http://ift.tt/2zBVkaq
Conserved expression of ultra-conserved noncoding RNA in mammalian nervous system
Publication date: Available online 18 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Junjie Zhou, Ruiyu Wang, Jing Zhang, Liyuan Zhu, Wei Liu, Shuaiyao Lu, Pan Chen, Hanlu Li, Bin Yin, Jiangang Yuan, Boqin Qiang, Pengcheng Shu, Xiaozhong Peng
T-UCRs, a class of long non-coding RNAs that are transcribed from ultra-conserved regions (UCRs), might play an important role in development and diseases. However, the amount of T-UCRs that are conservatively expressed in the developing nervous systems of mice, monkeys and humans is still unknown. In this study, we screened the RNA sequence signals of 481 identified UCRs in an E14.5 mouse brain from the ENCODE database and found 76 UCRs that may be transcribed into T-UCRs. To verify the expression of these potential T-UCRs, we used an RT-PCR experiment and identified that 60 T-UCRs can be expressed in the E14.5 mouse brain. Furthermore, we detected the expression conservation of 76 potential T-UCRs in two comparisons: postnatal day 0 brains of a mouse and a rhesus monkey and neural stem cell of mouse and human by RT-PCR experimentation. It was found that up to 65% of these T-UCRs were expressed in mouse, rhesus monkey and human nervous systems. Next, by testing the spatiotemporal expression pattern of these T-UCRs expressed in mouse, rhesus monkey and human nervous systems, we found that approximately 30% of the T-UCRs showed a relatively high and dynamical expression during mouse brain development. Finally, through biological process and molecular function gene ontology analysis of the host genes of intronic or exonic-antisense T-UCRs, it was discovered that most of the genes were involved in RNA splicing or RNA binding. These results suggest that T-UCRs are likely to participate in nervous system development through RNA processing.
http://ift.tt/2xQGL0F
HER2 in Colorectal Cancer
http://ift.tt/2guYAjc
Job Lock Among Long-term Survivors of Childhood Cancer
http://ift.tt/2yDr4xQ
Brain Metastases in Lung Cancer With Targetable Mutations
http://ift.tt/2yEgHKx
Errors in Table
http://ift.tt/2gv5KnR
Brain Metastases in Lung Cancer With Targetable Mutations—Reply
http://ift.tt/2yC1HwK
Insurance Coverage Among Cancer Patients Under the Affordable Care Act
http://ift.tt/2gvjnn0
Prophylactic Surgery for Stage IV Small Intestinal Neuroendocrine Tumors
http://ift.tt/2yCfm6T
Stem cells and heart disease - brake or accelerator?
Publication date: Available online 18 October 2017
Source:Advanced Drug Delivery Reviews
Author(s): Gustav Steinhoff, Julia Nesteruk, Markus Wolfien, Jana Große, Ulrike Ruch, Praveen Vasudevan, Paula Müller
After two decades of intensive research and attempts of clinical translation, stem cell based therapies for cardiac diseases are not getting closer to clinical success. This review tries to unravel the obstacles and focuses on underlying mechanisms as the target for regenerative therapies. At present, the principal outcome in clinical therapy does not reflect experimental evidence. It seems that the scientific obstacle is a lack of integration of knowledge from tissue repair and disease mechanisms. Recent insights from clinical trials delineate mechanisms of stem cell dysfunction and gene defects in repair mechanisms as cause of atherosclerosis and heart disease. These findings require a redirection of current practice of stem cell therapy and a reset using more detailed analysis of stem cell function interfering with disease mechanisms. To accelerate scientific development the authors suggest intensifying unified computational data analysis and shared data knowledge by using open-access data platforms
Graphical abstract
http://ift.tt/2kYYlP1
Severity strata for five patient-reported outcomes in adults with atopic dermatitis
Abstract
Background
Multiple patient-reported outcomes have been used to assess the burden of atopic dermatitis (AD). Some are disease specific, e.g. the Patient Oriented Eczema Measure (POEM). While others pertain to itch, e.g. Numerical Rating Scale (NRS)-itch, ItchyQoL and 5-D itch, or dermatologic disease in general, e.g. Dermatology Life Quality Index (DLQI). Development of severity strata is essential for proper interpretability of these assessments. We sought to confirm previously developed strata for POEM, DLQI and raw ItchyQoL, and develop strata for the NRS-itch, mean ItchyQOL and 5-D itch scale for use in adults with AD.
Methods
Self-administered questionnaires were completed by 210 adults with AD in a dermatology practice setting. Strata were selected using an anchoring approach based on patient-reported disease severity.
Results
We confirmed the existing strata for POEM (mild=0-7, moderate=8-16, severe=17-28) (kappa=0.440), DLQI (mild=0-5, moderate=6-10, severe=11-30) (kappa=0.398) and NRS-itch (mild=0-3, moderate=4-6, severe=7-10) (kappa=0.499). However, the preferred band for raw ItchyQoL was mild=22-58, moderate=59-74 and severe=75-110 (kappa=0.379) and mean ItchyQOL was mild=1-2.9, moderate=3.0-3.9, severe=4.0-5.0 (kappa=0.374). The preferred band for 5-D itch scale was mild=0-11, moderate=12-17 and severe=18-25 (kappa=0.331).
Conclusions
Existing strata for POEM and DLQI perform well in adult AD. Previously reported strata for VAS-itch performed best for NRS-itch. We identified banding for the raw ItchyQoL for our AD population that varies slightly from the banding published for a more heterogeneous population. Finally, we proposed strata for mean ItchyQOL and 5-D itch scale in adult AD.
This article is protected by copyright. All rights reserved.
http://ift.tt/2xSpERf
Insulin-Like Growth Factor-II mRNA-Binding Protein 3 as a Novel Prognostic Biomarker for Acral Lentiginous Melanoma
Acral lentiginous melanoma (ALM) is a distinctive histopathological subtype of melanoma that typically occurs on the palms, soles, and nail beds. Because of their anatomical locations, ALMs are typically diagnosed at late stages, resulting in a poor prognosis.1 Insulin-like growth factor-2 mRNA-binding protein 3 (IMP-3) plays significant roles in cell proliferation, migration, and adhesion by enhancing IGF-2 protein expression in malignant tumours.2 We evaluated the associations between IMP-3 expression and clinicopathological features, including the western blot profile, Ki-67 index, BRAF mutation, and long-term survival, among patients with ALM.
This article is protected by copyright. All rights reserved.
http://ift.tt/2l0QTTB
Seasonality of hair loss: a time series analysis of Google Trends data 2004 to 2016
Hair loss is a frequently encountered dermatologic complaint that often generates psychological distress. Prior studies have demonstrated a seasonal pattern to hair loss. Maximal proportions of telogen hair have been found to occur in the summer, whereas lowest rates of telogen hairs occur in the winter. Additionally, a recent study demonstrated that maximal hair shedding occurs in August and September, and that the percentage of hairs in the anagen phase peaks at the beginning of spring.
This article is protected by copyright. All rights reserved.
http://ift.tt/2xQJBI1
Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Sampark S. Thakkar, Parth Thakor, Arabinda Ray, Hiren Doshi, Vasudev R. Thakkar
Benzothiazole analogues are of interest due to their potential activity against malarial and microbial infections. In search of suitable antimicrobial and antimalarial agents, we report here the synthesis, characterization and biological activities of benzothiazole analogues (J 1-J 10). The molecules were characterized by IR, Mass, 1H NMR, 13C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains; the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds J 1, J 2, J 3, J 5 and J 6 were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR, computational and in vitro studies were carried out to examine their candidatures as lead dihydrofolate reductase inhibitors.
Graphical abstract
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Editorial board
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
http://ift.tt/2xQIUK1
Axially substituted silicon(IV) phthalocyanine and its quaternized derivative as photosensitizers towards tumor cells and bacterial pathogens
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): İpek Ömeroğlu, Esra Nur Kaya, Meltem Göksel, Vesselin Kussovski, Vanya Mantareva, Mahmut Durmuş
Axially di-(alpha,alpha-diphenyl-4-pyridylmethoxy) silicon(IV) phthalocyanine (3) and its quaternized derivative (3Q) were synthesized and tested as photosensitizers against tumor and bacterial cells. These new phthalocyanines were characterized by elemental analysis, and different spectroscopic methods such as FT-IR, UV–Vis, MALDI-TOF and 1H NMR. The photophysical properties such as absorption and fluorescence, and the photochemical properties such as singlet oxygen generation of both phthalocyanines were investigated in solutions. The obtained values were compared to the values obtained with unsubstituted silicon(IV) phthalocyanine dichloride (SiPcCl2). The addition of two di-(alpha,alpha-diphenyl-4-pyridylmethanol) groups as axial ligands showed an improvement of the photophysical and photochemical properties and an increasement of the singlet oxygen quantum yield (ΦΔ) from 0.15 to 0.33 was determined. The photodynamic efficacy of synthesized photosensitizers (3 and 3Q) were evaluated with promising photocytotoxicity (17% cell survival for 3 and 28% for 3Q) against the cervical cancer cell line (HeLa). The photodynamic inactivation of pathogenic bacterial strains Streptococcus mutans, Staphylococcus aureus, and Pseudomonas aeruginosa suggested a high susceptibility with quaternized derivative (3Q). The both Gram-positive bacterial strains were fully photoinactivated with 11μM 3Q and mild light dose 50J.cm−2. In case of P. aeruginosa the effect was negligible for concentrations up to 22μM 3Q and light dose 100J.cm−2. The results suggested that the novel axially substituted silicon(IV) phthalocyanines have promising characteristic as photosensitizer towards tumor cells. The quaternized derivative 3Q has high potential for photoinactivation of pathogenic bacterial species.
Graphical abstract
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Discovery of berberine based derivatives as anti-influenza agent through blocking of neuraminidase
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Gansukh Enkhtaivan, Pandurangan Muthuraman, Doo Hwan Kim, Bhupendra Mistry
In this study, we investigated the antiviral activity of newly synthesized berberine derivatives (BD) against influenza virus infection using several strains in in vitro and in silico. The CPE reduction, pre-incubation, NA activity inhibition and molecular docking assays were used for antiviral evaluation. The anti-influenza activities of BDs were stronger than plant-derived pure commercial berberine, and some of the BDs were more potent than control drug Oseltamivir. The cytotoxicity level was observed in the range 63.16–1639μg/mL for synthesized BDs. Additionally, BDs were detected as able to block influenza viral particles. We targeted neuraminidase one of the influenza surface protein for further probing. Moreover, BDs registered competitive NA inhibition activity comparing with Oseltamivir. The active site of viral NA subunit was fully blocked by BD as the same location as Oseltamivir. The binding energies between influenza NA subunit and BD-5 were higher than Oseltamivir. More H-bonds and NA residues were occupied by BD for stronger binding ability than Oseltamivir. These results indicated that BD inhibits various strains of influenza virus by blocking of viral NA subunit.
Graphical abstract
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Picomolar inhibition of β-galactosidase (bovine liver) attributed to loop closure
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Jessica B. Pickens, Feng Wang, Susanne Striegler
In an effort to examine similarities in the active sites of glycosidases within the GH35 family, we performed a structure-activity-relationship study using our recently described library of galactonoamidines. The kinetic evaluation based on UV/Vis spectroscopy disclosed inhibition of β-galactosidase (bovine liver) in the picomolar concentration range indicating significantly higher inhibitor affinity than previously determined for β-galactosidase (A. oryzae). Possible alterations in the secondary protein structure or folding were excluded after further examination of the inhibitor binding using CD spectroscopy. Molecular dynamics studies suggested loop closing interactions as a rationale for the disparity of the active sites in the β-galactosidases under investigation.
Graphical abstract
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Nrf2 activators from Glycyrrhiza inflata and their hepatoprotective activities against CCl4-induced liver injury in mice
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Yan Lin, Yi Kuang, Kai Li, Shuang Wang, Shuai Ji, Kuan Chen, Wei Song, Xue Qiao, Min Ye
Glycyrrhiza inflata (licorice) has been used to treat liver diseases for a long history. However, the bioactive compounds are still not clear. In this work, 77 compounds, including 9 new ones, were isolated from the EtOAc extract of the roots and rhizomes of G. inflata. The Nrf2 activation activities of all compounds were screened using ARE-luciferase reporter assay on HepG2C8 cells. The results indicated a number of chalcones were potent Nrf2 activators, including 11 (licochalcone A, 4.07-fold), 12 (licochalcone B, 5.17-fold), and 19 (echinatin, 4.09-fold). Further studies indicated that 11, 12 and 19 remarkably attenuated CCl4-induced acute liver injury in mice (10 or 50mg/kg, 7days, ig.). These compounds could be promising hepatoprotective natural agents.
Graphical abstract
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Identification of highly selective and potent orexin receptor 1 antagonists derived from a dual orexin receptor 1/2 antagonist based on the structural framework of pyrazoylethylbenzamide
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Aya Futamura, Dai Nozawa, Yuko Araki, Yunoshin Tamura, Seiken Tokura, Hiroshi Kawamoto, Yuichi Tokumaru, Sora Kakihara, Takeshi Aoki, Norikazu Ohtake
The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2.01nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2.
Graphical abstract
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Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Noemi D. Paguigan, Mohammed H. Al-Huniti, Huzefa A. Raja, Austin Czarnecki, Joanna E. Burdette, Mariana González-Medina, José L. Medina-Franco, Stephen J. Polyak, Cedric J. Pearce, Mitchell P. Croatt, Nicholas H. Oberlies
Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2–6, with 4 being new to literature) were isolated from Xylaria cubensis. Six fluorinated analogues (7–12) were synthesized, each in a single step using the isolated natural products and Selectflour, so as to examine the effects of fluorine incorporation on the bioactivities of this structural class. The isolated and synthesized compounds were screened for activity against a panel of cancer cell lines (MDA-MB-435, MDA-MB-231, OVCAR3, and Huh7.5.1) and for antifungal activity against Microsporum gypseum. A comparison of the chemical space occupied by the natural and fluorinated analogues was carried out by using principal component analysis, documenting that the isolated and fluorinated analogues occupy complementary regions of chemical space. However, the most active compounds, including two fluorinated derivatives, were centered around the chemical space that was occupied by the parent compound, griseofulvin, suggesting that modifications must preserve certain attributes of griseofulvin to conserve its activity.
Graphical abstract
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Methyl propiolate and 3-butynone: Starting points for synthesis of amphiphilic 1,2,3-triazole peptidomimetics for antimicrobial evaluation
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Thomas A. Bakka, Morten B. Strøm, Jeanette H. Andersen, Odd R. Gautun
A library of 29 small 1,4-substituted 1,2,3-triazoles was prepared for studies of antimicrobial activity. The pharmacophore model investigated with these substrates was based on small peptidomimetics of antimicrobial peptides and antimicrobials isolated from marine organisms from sub-arctic regions. Using methyl 1,2,3-triazole-carboxylates and 1,2,3-triazole methyl ketones prepared through "click" chemistry we were able to synthesize the different cationic amphiphiles through three steps or less. Several structural modifications to the lipopohilic side and hydrophilic sides of the amphiphiles were investigated and compared with regards to antimicrobial activity and cytotoxicity in particular. The most promising amphiphile 10f displayed minimum inhibitory concentrations (MICs) between 4–16µg/mL against Gram-positive Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalacticae, and Gram-negative Escherichia coli and Pseudomonas aeruginosa. The decent level of antimicrobial activity and biofilm inhibition, short synthesis, and accessible reagents, makes this type of amphiphilic mimics interesting leads for further development.
Graphical abstract
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meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Karen Reyes-Melo, Abraham García, Antonio Romo-Mancillas, Elvira Garza-González, Verónica M. Rivas-Galindo, Luis D. Miranda, Javier Vargas-Villarreal, Juan Manuel J. Favela-Hernández, María del Rayo Camacho-Corona
Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26–31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies.
Graphical abstract
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Facile alkylation of 4-nitrobenzotriazole and its platelet aggregation inhibitory activity
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Dhandeep Singh, Om Silakari
We explored the facile alkylation of 4-nitrobenzotriazole under basic conditions and the synthesized derivatives were tested for their potential ADP induced platelet aggregation inhibition activity in comparison with standard drug ticagrelor (selective P2Y12 inhibitor). The nitro group at 4-position is highly activating toward alkylation reactions (under strong basic conditions) and resulted in formation of degradation product like 3-nitrobenzene-1,2-diamine which make isolation of alkyl products very difficult. We optimized the reaction under mild basic condition (potassium carbonate and DMF) which is devoid of any degradation product. This is perhaps the first report of 4-nitrobenzotriazole derivatives possessing platelet aggregation inhibitory activity. Generally activity increases with increase in length of alkyl chain and 1-alkyl positional isomers were found to be more potent than 2-alkyl isomers. The benzoyl derivative was found to be the most potent [compound 22; (4-Nitro-1H-benzotriazol-1-yl)(phenyl)methanone; IC50=0.65±0.10mM] which may be attributed to electronegative oxygen atom and aromatic ring. Benzyl derivatives [compound 20; 1-Benzyl-4-nitro-1H-benzotriazole; IC50=0.81±0.08mM, compound 21; 2-Benzyl-4-nitro-2H-benzotriazole; IC50=0.82±0.19mM] and sulfonyl derivative [compound 23; 1-[(4-Methylphenyl)sulfonyl]-4-nitro-1H-benzotriazole; IC50=0.82±0.19mM] are also found to be highly active. Furthermore, all compounds possess P2Y12 binding affinity as confirmed by VASP/P2Y12 phosphorylation assay.
Graphical abstract
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Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran–oxindole derivatives as potent p53-MDM2 inhibitors
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Changjin Ji, Shengzheng Wang, Shuqiang Chen, Shipeng He, Yan Jiang, Zhenyuan Miao, Jian Li, Chunquan Sheng
p53–MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran–oxindole p53–MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships. Among them, compound B14 bearing a novel spiroindole–thiopyranopyridone scaffold exhibited potent MDM2 inhibitory activity as well as antitumor activity, which could effectively induce the apoptosis of A549 cancer cells. It represents a promising lead compound for the development of novel antitumor agents.
Graphical abstract
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Triple reuptake inhibitors: Design, synthesis and structure–activity relationship of benzylpiperidine–tetrazoles
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Suresh Paudel, Xiao Min, Srijan Acharya, Daulat Bikram Khadka, Goo Yoon, Kyeong-Man Kim, Seung Hoon Cheon
Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine–tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.
Graphical abstract
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Constructing novel dihydrofuran and dihydroisoxazole analogues of isocombretastatin-4 as tubulin polymerization inhibitors through [3+2] reactions
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Ming-Yu Song, Chen-Yu Cao, Qiu-Rui He, Qing-Miao Dong, Ding Li, Jiang-Jiang Tang, Jin-Ming Gao
[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47μM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32µM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly. Immunohistochemistry studies and cell cycle distribution analysis indicated that 6g severely disrupted microtubule network and significantly arrested most cells in the G2/M phase of the cell cycle in PC-3 cells. In addition, molecular docking studies showed that two chiral isomers of 6g can bind efficiently and similarly at colchicine binding site of tubulin.
Graphical abstract
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Structural evidence for the DPPH radical-scavenging mechanism of 2-O-α-d-glucopyranosyl-l-ascorbic acid
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Akihiro Tai, Atsuko Iomori, Hideyuki Ito
2-O-α-d-Glucopyranosyl-l-ascorbic acid (AA-2G) exhibits biological activities after enzymatic hydrolysis to ascorbic acid (AA) by α-glucosidase. We have found that AA-2G per se exerted radical-scavenging activity toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH radical). The radical-scavenging property of AA-2G was greatly different from that of AA; that is, the reaction rate with DPPH radical of AA-2G was far slower than that of AA, but the long-lasting radical-scavenging ability per one molecule of AA-2G was superior to that of AA. We purified key intermediates for the characteristic radical-scavenging reaction of AA-2G and carried out time-course studies of the radical-scavenging reactions of the intermediates, AA-2G and AA to determine both the reaction rate and stoichiometry of AA-2G with DPPH radical. One mole of AA-2G quenched 2.7mol of DPPH radical over a period of 120min, while one mole of AA quenched 1.9mol of the radical. The high reaction stoichiometry of AA-2G against DPPH radical was associated with adduct formation of AA-2G with DPPH radical. The radical-scavenging reaction mechanism of AA-2G consists of the following three steps: (1) At an early stage of the reaction, AA-2G scavenged DPPH radical to generate AA-2G radical, (2) AA-2G radical immediately reacted with an additional DPPH radical to give two types of AA-2G–DPPH adducts and (3) AA-2G–DPPH adducts slowly quenched the other DPPH radical to generate several reaction products. Our results suggest the practical value of AA-2G, even before being converted into AA, as a beneficial antioxidant in food and cosmetic applications.
Graphical abstract
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Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Hiroaki Yamagishi, Takayuki Inoue, Yutaka Nakajima, Jun Maeda, Hiroaki Tominaga, Hiroyuki Usuda, Takeshi Hondo, Ayako Moritomo, Fumihiro Nakamori, Misato Ito, Koji Nakamura, Hiroki Morio, Yasuyuki Higashi, Masamichi Inami, Shohei Shirakami
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.
Graphical abstract
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Identification of pyrazolopyrimidine arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Afjal H. Miah, Aurelie C. Champigny, Rebecca H. Graves, Simon T. Hodgson, Jonathan M. Percy, Panayiotis A. Procopiou
A novel 4-aminoindazole sulfonamide hit (13) was identified as a human CCR4 antagonists from testing a focussed library of compounds in the primary GTPγS assay. Replacing the indazole core with a pyrazolopyrimidine, and introduction of a methoxy group adjacent to the sulfonamide substituent, resulted in the identification of pyrazolopyrimidine 37a, which exhibited good binding affinity in the GTPγS assay (pIC50=7.2), low lipophilicity (clogP=2.2, chromlogD7.4=2.4), high LE (0.41), high solubility (CLND solubility ≥581µM), and an excellent PK profile in both the rat (F=62%) and the dog (F=100%). Further SAR investigation of the pyrazolopyrimidine suggested that substitution at N1 is tolerated, providing a suitable vector to modulate the properties, and increase the potency in a lead optimisation campaign.
Graphical abstract
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Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[e][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation
Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Md. Saifuzzaman, Rick Morrison, Zhaohua Zheng, Stephanie Orive, Justin Hamilton, Philip E. Thompson, Jasim M.A. Al-rawi
A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH2 in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent.The products were evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kδ was somewhat more tolerant of this substitution particularly where 8-(4-methoxylphenyl) substituents were present (IC50s∼2–3μM). Good activities against PDE3 were also obtained for compounds, with particular members of the 7-(2-pyridinyl) methoxy series 19 showing good inhibition (IC50s∼2–3μM), comparable to previously described analogues. A piperazinyl derivative 26a effectively inhibited ADP-induced platelet aggregation with an IC50 of 8μM.
Graphical abstract
http://ift.tt/2l4IQoX
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Summary Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an un...
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