Publication date: Available online 10 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Nicolas Jonckheere, Romain Vasseur, Isabelle Van Seuningen
RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.
http://ift.tt/2jfaD0E
Τρίτη 10 Ιανουαρίου 2017
The cornerstone K-RAS mutation in pancreatic adenocarcinoma: from cell signaling network, target genes, biological processes to therapeutic targeting
Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis
Publication date: Available online 10 January 2017
Source:Neurobiology of Aging
Author(s): Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases (MNDs)-related genes. Known variants in ANG, OPTN, SETX and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in one patient. Additionally, 18 patients harbored 1–3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG and OPTN variants were 32%, 11%, 2%, 2%, 1% and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.
http://ift.tt/2jeVoox
Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2
Publication date: Available online 9 January 2017
Source:Neurobiology of Aging
Author(s): Yuriko Katsumata, Peter T. Nelson, Sally R. Ellingson, David W. Fardo
Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the GRN, TMEM106B, ABCC9, and KCNMB2 genes, which were reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer's Disease Genetics Consortium (ADGC), linked to autopsy-derived neuropathological outcomes from the National Alzheimer's Coordinating Center (NACC). Of the 3,251 subjects included in the study, 271 (8.3%) were identified as an HS-Aging case. The significant gene-based association between the ABCC9 gene and HS-Aging appeared to be driven by a region in which a significant haplotype-based association was found. We tested this haplotype as an expression Quantitative Trait Locus (eQTL) using two different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, indicating a possible toxic gain of function.
http://ift.tt/2jeX9lH
Ageing retinal function is improved by near infrared light (670 nm) that is associated with corrected mitochondrial decline
Publication date: Available online 10 January 2017
Source:Neurobiology of Aging
Author(s): Chrishne Sivapathasuntharam, Sobha Sivaprasad, Christopher Hogg, Glen Jeffery
Ageing is associated with cellular decline and reduced function, partly mediated by mitochondrial compromise. However, aged mitochondrial function is corrected with near infrared light (670 nm) that improves their membrane potentials and adenosine triphosphate production (ATP) and also reduces age related inflammation. We ask if 670 nm light can also improve declining retinal function. Electroretinograms (ERG) were measured in 2, 7 and 12 month old C57BL/6 mice. Significant age related declines were measured in the photoreceptor generated a-wave and the post-receptoral b-wave. 7 and 12 month old mice were exposed to 670 nm for 15 minutes daily over 1 month. These showed significant improved retinal function in both waves of approximately 25%, but did not reach levels found in 2 month old animals. Our data suggest, 670 nm light can significantly improve aged retinal function, perhaps by providing additional ATP for photoreceptor ion pumps or reduced aged inflammation. This may have implications for the treatment of retinal ageing and age related retinal disease, such as macular degeneration.
http://ift.tt/2j4xlvh
Accuracy and reproducibility of measurements on plaster models and digital models created using an intraoral scanner
Abstract
Aim
The purpose of the present study was to evaluate the accuracy and reproducibility of measurements made on digital models created using an intraoral color scanner compared to measurements on dental plaster models.
Methods
This study included impressions of 28 volunteers. Alginate impressions were used to make plaster models, and each volunteers' dentition was scanned with a TRIOS Color intraoral scanner. Two examiners performed measurements on the plaster models using a digital caliper and measured the digital models using Ortho Analyzer software. The examiners measured 52 distances, including tooth diameter and height, overjet, overbite, intercanine and intermolar distances, and the sagittal relationship. The paired t test was used to assess intra-examiner performance and measurement accuracy of the two examiners for both plaster and digital models. The level of clinically relevant differences between the measurements according to the threshold used was evaluated and a formula was applied to calculate the chance of finding clinically relevant errors on measurements on plaster and digital models.
Results
For several parameters, statistically significant differences were found between the measurements on the two different models. However, most of these discrepancies were not considered clinically significant. The measurement of the crown height of upper central incisors had the highest measurement error for both examiners. Based on the interexaminer performance, reproducibility of the measurements was poor for some of the parameters.
Conclusions
Overall, our findings showed that most of the measurements on digital models created using the TRIOS Color scanner and measured with Ortho Analyzer software had a clinically acceptable accuracy compared to the same measurements made with a caliper on plaster models, but the measuring method can affect the reproducibility of the measurements.
http://ift.tt/2j1OfdN
Consumption of Low-Calorie Sweeteners among Children and Adults in the United States
Publication date: Available online 10 January 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Allison C. Sylvetsky, Yichen Jin, Elena J. Clark, Jean A. Welsh, Kristina I. Rother, Sameera A. Talegawkar
BackgroundConsumption of low-calorie sweeteners (LCSs) has increased markedly during the past several decades, yet the prevalence of LCS consumption in recent years is currently unknown.ObjectiveThe aim of this study was to describe LCS consumption in the United States and to characterize consumption by sociodemographic subgroups, source, frequency, eating occasion, and location.DesignCross-sectional study using National Health and Nutrition Examination Survey data from 2009 to 2012. The prevalence of LCS consumption was assessed using two 24-hour dietary recalls, while the frequency (number of times per day), occasion (meal vs snack vs alone), and location of LCS consumption (at home vs away from home) was assessed using data from the one, in-person, 24-hour dietary recall.ParticipantsNational Health and Nutrition Examination Survey participants (2 years old or older) either in 2009-2010 (n=9,047) or in 2011-2012 (n=7,939). After excluding participants with implausible energy intake (n=44), the final sample size was 16,942.Main outcome measuresThe primary outcome was the proportion of individuals consuming one or more foods, beverages, or packets containing LCSs during at least one of their two dietary recalls.Statistical analyses performedData were weighted to provide national estimates and Stata frequency procedures for complex survey design were used for all analyses.ResultsOur findings were that 25.1% of children and 41.4% adults reported consuming LCSs. Most LCS consumers reported use once daily (80% of children, 56% of adults) and frequency of consumption increased with body weight in adults. LCS consumption was higher in females compared with males among adults, and in obese individuals, compared with overweight and normal-weight individuals. Individuals of non-Hispanic white race/ethnicity also had higher prevalence of consumption compared with non-Hispanic blacks and Hispanics and those in the highest tertile of income had higher LCS consumption compared with individuals of middle or low income across LCS product categories in adults, and for LCS beverages and LCS foods in children. Most LCS consumers reported consuming LCS with meals (64% of adults, 62% of children) and the majority of LCS consumption occurred at home (71% and 72% among adults and children, respectively).ConclusionsLCS consumption is highly prevalent in the United States, among both children and adults. Well-controlled, prospective trials are required to understand the health impact of this widespread LCS exposure.
http://ift.tt/2jrfVFS
Breastfeeding in Infancy Is Associated with Body Mass Index in Adolescence: A Retrospective Cohort Study Comparing American Indians/Alaska Natives and Non-Hispanic Whites
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Anna Zamora-Kapoor, Adam Omidpanah, Lonnie A. Nelson, Alice A. Kuo, Raymond Harris, Dedra S. Buchwald
BackgroundAmerican Indians and Alaska Natives have the highest obesity prevalence in the United States, but the influence of early childhood variables on body mass index (BMI; calculated as kg/m2) is not well understood. Previous studies have investigated the association between breastfeeding in infancy and offspring BMI, but rarely included American Indians and Alaska Natives.ObjectiveThis study investigated the association between breastfeeding in infancy and BMI in American Indians and Alaska Native and non-Hispanic white adolescents and young adults.DesignLongitudinal analysis based on data from the National Longitudinal Study of Adolescent to Adult Health (1994 to 2008).ParticipantsAdolescent respondents who self-identified as American Indians and Alaska Native or non-Hispanic white, and whose parents completed the parental questionnaire, reported their height and weight. The final sample included 655 American Indians and Alaska Native and 10,305 non-Hispanic white respondents.Statistical analyses performedGeneralized estimating equations were used to measure the mean differences, 95% CIs, and P values of the association between breastfeeding in infancy and offspring BMI in adolescence, stratifying by race, and adjusting for demographic and socioeconomic variables.ResultsThe length of breastfeeding was inversely associated with BMI in both populations. American Indians and Alaska Natives that were breastfed for 6 to 12 months or for more than 12 months had a mean BMI of 2.69 (95% CI −3.46 to −1.92; P<0.01) and 1.54 (95% CI −2.75 to −0.33; P<0.05) units lower than those that were never breastfed. Non-Hispanic whites that were breastfed for 3 to 6 months, 6 to 12 months, or more than 12 months had a mean BMI of 0.71 (95% CI −0.93 to −0.50; P<0.01), 0.68 (95% CI −0.87 to −0.50; P<0.01), and 0.85 (95% CI −1.09 to −0.62; P<0.01) units lower than those that were never breastfed. The association between the length of breastfeeding and offspring BMI varied by race (P<0.01).ConclusionsBreastfeeding in infancy is associated with lower mean BMI. Future research should investigate causal pathways and whether interventions promoting breastfeeding in American Indians and Alaska Natives can prevent increasing BMI.
http://ift.tt/2j1xfnI
Conditions d’accès à l’assistance médicale à la procréation et procréation post-mortem : l’appel des juges à la révision des lois de bioéthique ?
Source:Médecine & Droit
Author(s): Guillaume Monziols
Les conditions légales d'accès à l'assistance médicale à la procréation connaissent quelques atteintes prétoriennes comme si elles n'étaient plus adaptées à la société actuelle. Récemment, l'Assemblée du contentieux du Conseil d'État est venue « égratigner » l'esprit de l'article L. 2141-2 du Code de la santé publique par son arrêt du 31 mai 201611 CE, 31 mai 2016, no 396848 : JurisData no 2016-010489. en enjoignant l'Assistance Publique–Hôpitaux de Paris et l'Agence de la Biomédecine de procéder à l'exportation des gamètes en Espagne d'un homme décédé. Par sa décision, le Conseil d'État s'affranchit de l'interdit légal d'exporter les gamètes déposés en France et destinés à être utilisés, à l'étranger, à des fins qui sont prohibées sur le territoire national : la procréation post-mortem. Pourtant, la prohibition de la procréation post-mortem, ainsi affaiblie par cette décision récente du Conseil d'État, découle d'une volonté clairement affirmée et maintenue du législateur français (Section 1). Cette atteinte prétorienne supplémentaire aux conditions légales d'accès à l'assistance médicale à la procréation, dont la sommation offre des opportunités contraires à notre loi, génère de fait une situation créatrice d'inégalités qui ne peut perdurer (Section 2).The legal requirements for access to medically assisted procreation are experiencing some praetorian damage as if they were no longer adapted to today's society. Recently, the "Assemblée du contentieux du Conseil d'État" came to "scratch" the spirit of Article L. 2141-2 of the Code of public health in its judgment of 31 May 2016 by ordering the Assistance Publique–Hôpitaux of Paris and the Biomedicine Agency to carry out the export of gametes of a deceased man in Spain. In its decision, the Conseil d'État do not respects the legal prohibition of export gametes filed in France and intended to be used abroad, for purposes that are prohibited in the country: the post-mortem procreation. The prohibition of posthumous reproduction, weakened by the recent decision of the Conseil d'État, is the result of a clearly stated and maintained will of the French legislature (Section 1). This additional Praetorian affect against legal conditions of access to medically assisted procreation generates inequalities and creates an unsustainable situation (Section 2).
http://ift.tt/2j4sKJz
Impact of Oncotype DX Breast Recurrence Score testing on adjuvant chemotherapy use in early breast cancer: Real world experience in Greater Manchester, UK
Publication date: Available online 9 January 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): J. Loncaster, A. Armstrong, S. Howell, G. Wilson, R. Welch, A. Chittalia, W.J. Valentine, N.J. Bundred
BackgroundThe National Institute for Health and Clinical Excellence (NICE) recommended the Oncotype DX® Breast Recurrence Score® (RS) assay as an option for informing adjuvant chemotherapy decisions in node-negative, oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer assessed to be at intermediate risk of recurrence based on clinicopathological factors. We evaluated the impact of RS testing on adjuvant chemotherapy decision-making in routine clinical practice in a UK Cancer Network.MethodsRS testing was performed in 201 females with newly diagnosed, ER+, HER2-negative, invasive breast cancer who underwent breast surgery with curative intent, were calculated to have a >3% overall survival benefit at 10 years from adjuvant chemotherapy based on PREDICT, and were considered for adjuvant chemotherapy. The impact of RS testing on adjuvant treatment decisions/associated cost was assessed.ResultsIn all patients, the multi-disciplinary team recommended chemotherapy but the RS result allowed 127/201 patients (63.2%) to avoid unnecessary adjuvant chemotherapy. Amongst ER+, HER2-negative, node-negative patients (eligible for Oncotype DX testing in UK guidelines), 60.3% were spared chemotherapy. In node-positive patients, the assay reduced the use of chemotherapy by 69.2%. The use of RS testing to guide treatment in these 201 patients was associated with significant cost saving (when considering the cost of RS testing for all patients plus chemotherapy and its associated cost for 74 patients).ConclusionsIncorporating RS testing into routine clinical practice for selected node-negative and node-positive breast cancer patients significantly reduces the use of chemotherapy (p<0.001) with its associated morbidity and costs.
http://ift.tt/2jzE1Cg
Neuropeptides encoded within a neural transcriptome of the giant triton snail Charonia tritonis, a Crown-of-Thorns Starfish predator
Source:Peptides
Author(s): U. Bose, S. Suwansa-ard, L. Maikaeo, C.A. Motti, M.R. Hall, S.F. Cummins
Neuropeptides represent a diverse class of signaling molecules originating from neural tissues. These chemical modulators orchestrate complex physiological events including those associated with growth and reproduction. De novo transcriptome sequencing of a cerebral ganglion library of the endangered giant triton snail (Charonia tritonis) was undertaken in an effort to identify key neuropeptides that control or influence its physiology. The giant triton snail is considered a primary predator of the corallivore Acanthaster planci (Crown-of-Thorns Starfish) that is responsible for a significant loss in coral cover on reefs in the Indo-Pacific. The transcriptome library was assembled into contigs, and then bioinformatic analysis was used to identify a repertoire of 38 giant triton snail neuropeptide precursor genes, and various isoforms, that encode conserved molluscan neuropeptides. C. tritonis neuropeptides show overall precursor organization consistent with those of other molluscs. These include those neuropeptides associated with mollusc reproduction such as the APGWamide, buccalin, conopressin, gonadotropin-releasing hormone (GnRH), NKY and egg-laying hormone. These data provide a foundation for further studies targeted towards the functional characterisation of neuropeptides to further understand aspects of the biology of the giant triton snail, such as elucidating its reproductive neuroendocrine pathway to allow the development of knowledge based captive breeding programs.
http://ift.tt/2j4doVy
Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner
Source:Peptides
Author(s): Stephen J. Kentish, Hui Li, Claudine L. Frisby, Amanda J. Page
Food intake is regulated by vagal afferent signals from the stomach. Nesfatin-1 is an anorexigenic peptide produced within the gastrointestinal tract and has well defined central effects. We aimed to determine if nesfatin-1 can modulate gastric vagal afferent signals in the periphery and further whether this is altered in different nutritional states. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks or fasted overnight. Plasma nucleobindin-2 (NUCB2; nesfatin-1 precursor)/nesfatin-1 levels were assayed, the expression of NUCB2 in the gastric mucosa and adipose tissue was assessed using real-time quantitative reverse-transcription polymerase chain reaction. An in vitro preparation was used to determine the effect of nesfatin-1 on gastric vagal afferent mechanosensitivity. HFD mice exhibited an increased body weight and adiposity. Plasma NUCB2/nesfatin-1 levels were unchanged between any of the groups of mice. NUCB2 mRNA was detected in the gastric mucosa and gonadal fat of SLD, HFD and fasted mice with no difference in mRNA abundance between groups in either tissue. In SLD and fasted mice nesfatin-1 potentiated mucosal receptor mechanosensitivity, an effect not observed in HFD mice. Tension receptor mechanosensitivity was unaffected by nesfatin-1 in SLD and fasted mice, but was inhibited in HFD mice. In conclusion, Nesfatin-1 modulates gastric vagal afferent mechanosensitivity in a nutritional state dependent manner.
http://ift.tt/2j4hvAF
Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880
Source:Behavioural Brain Research, Volume 321
Author(s): Mei Han, Rebeca Mejias, Shu-Ling Chiu, Rebecca Rose, Abby Adamczyk, Richard Huganir, Tao Wang
Glutamate receptor interacting proteins 1 and 2 (GRIP1/2) play an important role in regulating synaptic trafficking of AMPA receptor 2/3 (GluA2/3) and synaptic strength. Gain-of-function GRIP1 mutations are implicated in social behavioral deficits in autism. To study mechanisms of Grip1/2-mediated AMPA signaling in the regulation of social behaviors, we performed social behavioral testing on neuron-specific Grip1/2-double knockout (DKO) and wild type (WT) mice that are matched for age, sex, and strain background. We determined the expression profile of key signaling proteins in AMPAR, mGluR, mTOR, and GABA pathways in frontal cortex, striatum, and cerebellum of DKO mice. Compared to WT mice, DKO mice show increased sociability in a modified three-chamber social behavioral test [mean±sem for interaction time in seconds; WT: 44.0±5.0; n=10; DKO: 81.0±9.0; n=9; two factor repeated measures ANOVA: F(1,37)=14.45; p<0.01 and planned t-test; p<0.01] and in a dyadic male–male social interaction test (mean±sem for total time in seconds: sniffing, WT-WT, 18.9±1.1; WT-DKO, 42.5±2.1; t-test: p<0.001; following, WT-WT, 7.7±0.72; WT-DKO,14.4±1.8; t-test: p<0.001). Immunoblot studies identified an increase in phosphorylation at GluA2-Serine 880 (GluA2-pS880) in frontal cortex (mean±sem; WT: 0.69±0.06, n=5; DKO: 0.96±0.06, n=6; t-test; p<0.05) and reduced GABAβ3 expression in striatum (mean±sem; WT: 1.16±0.04, n=4; DKO: 0.95±0.06, n=4; t-test; p<0.05) in DKO mice. GluA2-S880 phosphorylation is known to regulate GluA2synaptic recycling, AMPA signaling strength and plasticity. GABAβ3 has been implicated in the etiology and pathogenesis in autism. These data support an important role of Grip1/2-mediated AMPA signaling in regulating social behaviors and disturbance of glutamate- and GABA-signaling in specialized brain regions in autism-related social behavioral deficits.
http://ift.tt/2j4hCfT
The future excess fraction of occupational cancer among those exposed to carcinogens at work in Australia in 2012
Source:Cancer Epidemiology, Volume 47
Author(s): Renee N. Carey, Sally J. Hutchings, Lesley Rushton, Timothy R. Driscoll, Alison Reid, Deborah C. Glass, Ellie Darcey, Si Si, Susan Peters, Geza Benke, Lin Fritschi
BackgroundStudies in other countries have generally found approximately 4% of current cancers to be attributable to past occupational exposures. This study aimed to estimate the future burden of cancer resulting from current occupational exposures in Australia.MethodsThe future excess fraction method was used to estimate the future burden of occupational cancer (2012–2094) among the proportion of the Australian working population who were exposed to occupational carcinogens in 2012. Calculations were conducted for 19 cancer types and 53 cancer-exposure pairings, assuming historical trends and current patterns continued to 2094.ResultsThe cohort of 14.6 million Australians of working age in 2012 will develop an estimated 4.8 million cancers during their lifetime, of which 68,500 (1.4%) are attributable to occupational exposure in those exposed in 2012. The majority of these will be lung cancers (n=26,000), leukaemias (n=8000), and malignant mesotheliomas (n=7500).ConclusionsA significant proportion of future cancers will result from occupational exposures. This estimate is lower than previous estimates in the literature; however, our estimate is not directly comparable to past estimates of the occupational cancer burden because they describe different quantities – future cancers in currently exposed versus current cancers due to past exposures. The results of this study allow us to determine which current occupational exposures are most important, and where to target exposure prevention.
http://ift.tt/2j1cRTR
Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery
Publication date: Available online 10 January 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Hatef Mehrabian, Kimberly L. Desmond, Sofia Chavez, Colleen Bailey, Radoslaw Rola, Arjun Sahgal, Gregory J. Czarnota, Hany Soliman, Anne L. Martel, Greg J. Stanisz
PurposeThe use of stereotactic radiosurgery (SRS) for the treatment of patients with a few brain metastases has been increasing in clinical practice. Standard anatomical imaging is limited in its ability to evaluate treatment response early after treatment. It can take months before it is clear that a tumor has responded to SRS or not. This study was designed to evaluate if changes in the tumor after SRS can be seen with quantitative MRI early after the treatment.Methods and MaterialsUsing contrast enhanced MRI, a three water compartment tissue model consisting of intracellular (I), extracellular-extravascular (E), and vascular (V) compartments was employed to assess the intra-extracellular water exchange rate constant (kIE), efflux rate constant (kep) and water compartment volume fractions (M0,I,M0,E,M0,V). In this prospective study, 19 patients were MRI-scanned pre-treatment, one-week, and one-month after SRS. The change in model parameters between the pre-treatment and one-week post-treatment scans was correlated to the change in tumor volume between pre-treatment and one-month post-treatment scans.ResultsAt one-week kIE differentiated (p<0.001) tumors that had a partial response (PR) from stable and progressive disease (SD and PD) and a high correlation (R=−0.76,p<0.001) was observed between early changes in thekIE and tumor volume change one-month post-treatment. Other model parameters had lower correlation (M0,E) or no correlation (kep,M0,V).ConclusionsThis is the first study that measured kIE early after SRS, and found that early changes in kIE (one-week after treatment) highly correlated with long term tumor response and could predict the extent of tumor shrinkage at one-month post-SRS.
Teaser
Cells undergoing apoptosis experience increased intracellular to extracellular water exchange rate. A water exchange quantification technique for clinical DCE-MRI was developed and applied to 19 brain metastases patients treated with stereotactic radiosurgery (SRS). The intra-extracellular water exchange rate identified partial response patient within one-week after treatment, and also predicting the extent of tumor shrinkage at one month. Thus, intra-extracellular water exchange rate is a promising biomarker of brain metastases response to SRS.http://ift.tt/2jejFeo
Stereotactic Body Radiotherapy in Octo- and Nonagenarians for the Treatment of Early Stage Lung Cancer
Publication date: Available online 9 January 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Meredith Giuliani, Andrew Hope, Matthias Guckenberger, Frederick Mantel, Heike Peulen, Jan-Jakob Sonke, José Belderbos, Maria Werner-Wasik, Hong Ye, Inga S. Grills
PurposeTo determine the safety and efficacy of lung SBRT in Octo- and Nonagenarians and to compare their outcomes to those of younger patients.MethodsPatients with primary lung cancer treated with SBRT were identified from a multi-institutional (5) database of 1083 cases. Details of patient factors, treatment specifics, toxicity and clinical outcomes were extracted from the database. All events were calculated from the end of radiotherapy. Estimates of local recurrence (LR), regional recurrence (RR), and distant metastases (DM) were calculated using the competing risk method. Cause specific (CSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcomes were compared for those aged <70, 70-79, ≥80. Univariable (UVA) and multivariable analyses (MVA) was performed to determine associations with CSS and OS in patients aged ≥80.ResultsThe median follow-up was 1.7 years (1-10y) and median age 75 (41-94). There were 305 patients age <70 (28%), 448 age 70-79 (41%) and 330 age ≥80 (30%). There was no difference in 2 year LR (4.2% vs 5.4% vs 3.7%, p=0.7), RR (10.4% vs. 7.8% vs 5.3%, p=0.1), DM (12.2% vs 7.7% vs 9.5%, p=0.2) or CSS (90.6% vs 90.3% vs. 90.4%, p=0.6). Those age ≥80 had significantly lower 2 year OS (73.6% vs 67.2% vs 63.3%, p<0.01). The grade 3+ pneumonitis rate was 1.3% vs 1.6% vs 1.5% (p=1.0) in patients ages <70,70-79, ≥80 respectively. The 90 day mortality rates for patients aged <70, 70-79, ≥80 were 1.3%, 2.5%, and 2.4% (P=0.01) respectively. In patients aged ≥80 OS was associated with T-Category (HR1.7; P<0.01).ConclusionSBRT is a safe treatment modality in elderly patients (aged ≥80). Despite larger tumor volumes, the tumor control outcomes were comparable to the younger patients treated with SBRT. All patients with early stage lung cancer, regardless of age, should be considered for treatment o with SBRT.
Teaser
This manuscript explored the safety and efficacy of lung SBRT in Octo- and Nonagenarians. In 1083 patients there were 330 patients age ≥80. Older patients had comparable local, regional and distant control and rates of toxicity to younger patients. Overall survival was significantly lower at 2 years in patients age ≥80. All patients with early stage lung cancer, regardless of age, should be considered for treatment o with SBRT.http://ift.tt/2j104Az
Obituary and Tribute to John “Jack” Francis Fowler, Ph.D., D.Sc. (1925-2016)
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Paul M. Harari, Mark A. Ritter, Albert J. van der Kogel
http://ift.tt/2iY1n1u
Re-evaluation of Ipsilateral Radiation for T1-T2N0-N2b Tonsil Carcinoma at the Princess Margaret Hospital in the HPV Era, 25 Years Later
Publication date: Available online 9 January 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Shao Hui Huang, John Waldron, Scott V. Bratman, Jie Su, John Kim, Andrew Bayley, John Cho, Meredith Giuliani, Andrew Hope, Jolie Ringash, Aaron Hansen, John R. de Almeida, David Goldstein, Bayardo Perez-Ordonez, Ilan Weinreb, Li Tong, Wei Xu, Brian O'Sullivan
Purpose/ObjectiveTo report outcome of ipsilateral radiotherapy (RT-ipsi) for HPV-positive [HPV+] and HPV-negative [HPV–] T1-T2N0-N2b tonsil cancer treated 25 years after our initial historical cohort.Materials/MethodsT1-T2N0-N2b tonsil cancer patients receiving RT-ipsi or bilateral RT (RT-bilat) between 1999-2014 were reviewed. Overall survival (OS), local (LC), regional (RC), and grade 3-4 late toxicity (LT) were compared between RT-ipsi vs RT-bilat within HPV+ and HPV– patients, separately.ResultsHPV status was ascertained in 379/427 (88%) consecutive cases (RT-ipsi: 62 HPV+, 34 HPV–; RT-bilat: 240 HPV+ 240, 41 HPV–). Proportion of ipsilateral RT by N-category for HPV+ and HPV– were: N0: 24/37 (65%) vs 28/48 (74%); N1: 21/49 (43%) vs 4/9 (44%); N2a: 10/39 (26%) vs 1/4 (25%); and N2b: 7/177 (4%) vs 1/24 (4%), respectively. 94/96 (98%) RT-ipsi were treated with RT-alone. Median follow-up was 5.03 years. Respective 5-year OS, LC, RC and LT were similar between RT-ipsi vs RT-bilat for the HPV+ [OS: 89% vs 87%, p=0.55; LC: 97% vs 98%, p=0.65; RC: 98% vs 97%, p=0.27; LT: 17% vs 12%, p=0.83] and HPV– [OS: 63% vs 48%, p=0.27; LC: 90% vs 80%, p=0.19; RC: 94% vs 83%, p=0.14; LT: 15% vs 22%, p=0.36]. Of the 96 RT-ipsi patients, contralateral neck failure (CNF) occurred in 1/52 HPV+ and 1/34 HPV– patients. The 5-year CNF rates were 2% (95%CI: 1-9) [HPV+: 2% (0-14); HPV–: 3% (0-21), p=0.66]. Five local [2 HPV+; 3 HPV–] and no distant failures were seen. Five-year LC, RC and LT were 97% vs 90% (p=0.24), 98% vs 94% (p=0.25), 18% vs 15% (p=0.75) for the HPV+ and HPV– cohort, respectively. Osteoradionecrosis occurred in 9 patients: 6/47 (13%) treated with conventional RT and 3/49 (6%) with IMRT (p=0.32).ConclusionIpsilateral radiation to selected T1-T2N0-N2b tonsil patients results in equally excellent outcomes regardless of tumor HPV status.
Teaser
This study describes results of ipsilateral radiotherapy for T1-T2N0-N2b tonsil cancer in the HPV era, 25 years after the final accrual of our historical 1970-1991 cohort. It shows equally high loco-regional control and survival for HPV-positive and HPV-negative patients receiving ipsilateral versus bilateral radiotherapy. The original principles of case selection for ipsilateral radiotherapy are discussed and remain universally applicable in the current HPV era.http://ift.tt/2i9vRjT
Serological Screening for Genital Herpes: An Evidence Review for the U.S. Preventive Services Task Force [Internet].
To assess the benefits and harms of serologic screening and preventive interventions for genital herpes simplex virus (HSV) infection in asymptomatic adults, adolescents, and pregnant women.
http://ift.tt/2iAK1GK
WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience.
Within the continuum of reproductive health care, antenatal care (ANC) provides a platform for important healthcare functions, including health promotion, screening and diagnosis, and disease prevention. It has been established that, by implementing timely and appropriate evidence-based practices, ANC can save lives.
http://ift.tt/2jzleH4
WHO Guideline: Use of Multiple Micronutrient Powders for Point-of-Use Fortification of Foods Consumed by Infants and Young Children Aged 6–23 Months and Children Aged 2–12 Years.
The use of multiple micronutrient powders for point-of-use fortification of foods has been suggested as an alternative to mitigate or overcome the constraints associated with supplementation and mass fortification. They are intended to increase the vitamin and mineral intake of infants and young children aged 6 to 23 months as well as preschool and school-age children aged 2–12 years.
http://ift.tt/2iAK4T7
Strategies To Improve Mental Health Care for Children and Adolescents [Internet].
To assess the effectiveness of quality improvement, implementation, and dissemination strategies that seek to improve the mental health care of children and adolescents; to examine harms associated with these strategies; and to determine whether effectiveness or harms vary in subgroups based on system, organizational, practitioner, or patient characteristics.
http://ift.tt/2iAX4bp
Randomised controlled trial evaluating the effectiveness and cost-effectiveness of ‘Families for Health’, a family-based childhood obesity treatment intervention delivered in a community setting for ages 6 to 11 years.
The Families for Health intervention did not help overweight and obese children (aged 6–11 years) to manage their weight.
http://ift.tt/2jzaj0m
Wide Area Transepithelial Sample Esophageal Biopsy Combined With Computer Assisted 3-Dimensional Tissue Analysis (WATS3D) For the Detection of High Grade Esophageal Dysplasia and Adenocarcinoma
Intervention: Procedure: Diagnostic Test
Sponsor: CDx Diagnostics
Not yet recruiting - verified January 2017
http://ift.tt/2jegxzn
A Stepped Care Intervention to Reduce Disparities in Mental Health Services Among Cancer Patients and Caregivers
Interventions: Behavioral: Stepped-Care Intervention; Behavioral: Enhanced Usual Care
Sponsor: University of Colorado, Denver
Not yet recruiting - verified January 2017
http://ift.tt/2j0WaHV
Induction Chemotherapy Followed by Radiotherapy Alone or Concurrent Chemoradiotherapy in Nasopharyngeal Carcinoma
Interventions: Drug: Docetaxel; Drug: Cisplatin; Radiation: IMRT/TOMO; Drug: Chemotherapy
Sponsors: Zhejiang Cancer Hospital; Zhejiang Provincial People's Hospital; The Central Hospital of Lishui City; Jinhua Central Hospital; First Affiliated Hospital of Wenzhou Medical Univeristy; Ningbo Medical Center Lihuili Eastern Hospital; Quzhou People's Hospital
Recruiting - verified December 2016
http://ift.tt/2jedXZS
Ranolazine and Microvascular Angina by PET in the Emergency Department: Results From a Pilot Randomized Controlled Trial
Source:Clinical Therapeutics
Author(s): Basmah Safdar, Gail D'Onofrio, James Dziura, Raymond R. Russell, Caitlin Johnson, Albert J. Sinusas
PurposeCoronary microvascular dysfunction (CMD) is a common but underdiagnosed cause of chest pain. Literature is scant regarding effective treatments. We explored the effect of ranolazine on coronary flow reserve (CFR) among symptomatic patients with CMD.MethodsThis pilot double-blinded randomized controlled trial included emergency department patients with chest pain and CMD admitted to an observation unit between June 2014 and November 2015. Participants were assessed by cardiac Rb-82 positron emission tomography and computed tomography imaging at baseline and 30 days. CMD was defined as CFR <2 corrected for rate pressure product or <2.5 uncorrected, with no evidence of obstructive or nonobstructive coronary artery disease or calcification. Patients with infarction, hypertensive urgency, heart failure, or prescribed QTc-prolonging drugs were excluded. Participants were assigned to ranolazine or placebo in a 2:1 ratio. Primary outcome was change in CFR at 30 days.FindingsWe enrolled 31 patients (71% female, mean [SD] age 50 [6] years) with CMD (mean [SD] corrected CFR 1.6 [0.3]). Ranolazine improved CFR at 30 days by 17% (P = 0.005) compared with 0% with placebo (P = 0.67). However, there was no significant difference in the primary outcome as measured by mean change in CFR (0.27 ranolazine compared with 0.06 placebo; 95% CI, −0.08 to 0.62).ImplicationsThe emergency department offers a unique venue to diagnose CMD with acute symptoms. In an exploratory randomized controlled trial of symptomatic patients with CMD and no coronary artery disease, promising results were seem with ranolazine and CFR improving at 30 days. Large robust clinical trials are needed to verify improvement of CMD in a sex-specific model. ClinicalTrials.gov identifier NCT02052011.
http://ift.tt/2iAO9GA
Structural Reconstruction of the Perivascular Space in the Adult Mouse Neurohypophysis during an Osmotic Stimulation
Abstract
Oxytocin (OXT) and arginine vasopressin (AVP), neuropeptides in the neurohypophysis (NH), control lactation and body fluid homeostasis, respectively. Hypothalamic neurosecretory neurons project their axons from the supraoptic and paraventricular nuclei to the NH to make contact with the vascular surface and release OXT and AVP. The neurohypophysial vascular structure is unique, because it has a wide perivascular space between the inner and outer basement membranes. However, the significance of this unique vascular structure remains unclear; therefore, we aimed to elucidate the functional significance of the perivascular space and its activity-dependent changes during salt loading in adult mice. Our results revealed that pericytes were the main resident cells and defined the profile of the perivascular space. Moreover, pericytes sometimes extended their cellular processes or "perivascular protrusions" into neurohypophysial parenchyma between axonal terminals. The vascular permeability of low-molecular-weight (LMW) molecules was higher at perivascular protrusions than at the smooth vascular surface. Axonal terminals containing OXT and AVP were more likely to localize at perivascular protrusions than at the smooth vascular surface. Chronic salt loading with 2% NaCl significantly induced prominent changes in the shape of pericytes, and increased the number of perivascular protrusions and surface area of the perivascular space together with elevations in the vascular permeability of LMW molecules. Collectively, these results indicate that the perivascular space of the NH acts as the main diffusion route for OXT and AVP, and changes in the shape of pericytes and perivascular reconstruction occur in response to increased demand for neuropeptide release.
This article is protected by copyright. All rights reserved.
http://ift.tt/2jzeut6
Molecular profiling of human iPS-derived hypothalamic neurons provides developmental insights to genetic loci for body weight regulation
Abstract
Background/Objectives
Recent data suggests that common genetic risk for metabolic disorders such as obesity may be human-specific and exert effects through the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)-derived neuronal cultures which recapture many features of hypothalamic neurons within the arcuate nucleus. Here we have comprehensively characterized this model across development, benchmarked these neurons to in vivo events, and demonstrate a link between obesity risk variants and hypothalamic development.
Methods
The dynamic transcriptome across neuronal maturation was examined using microarray and RNAseq methods at 9 time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and miRNA control of biological processes. The transcriptomes were compared to those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance assessed with Fisher's exact test.
Results
The human neuronal cultures have a transcriptional and physiological profile of NPY/AGRP ARC neurons. The neuronal transcriptomes were highly correlated with adult hypothalamus as compared to any other brain region from the GTEx. Also, roughly 25% of the transcripts showed substantial changes in expression across neuronal development and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants.
Conclusions
We affirmed the utility of this in vitro human model to study development of key hypothalamic neurons involved in energy balance and show that genes at loci associated with body weight regulation may share a pattern of developmental regulation. These data support the need to investigate early development to elucidate human-specific CNS pathophysiology underlying obesity susceptibility.
This article is protected by copyright. All rights reserved.
http://ift.tt/2iAFNyZ
De-immunized and Functional Therapeutic (DeFT) versions of a long lasting recombinant alpha interferon for antiviral therapy
Source:Clinical Immunology
Author(s): Eduardo F. Mufarrege, Sofía Giorgetti, Marina Etcheverrigaray, Frances Terry, William Martin, Anne S. De Groot
Interferon α (IFN-α) exerts potent antiviral, immunomodulatory, and antiproliferative activity and have proven clinical utility in chronic hepatitis B and C virus infections. However, repeated IFN-α administration induces neutralizing antibodies (NAb) against the therapeutic in a significant number of patients. Associations between IFN-α immunogenicity and loss of efficacy have been described.So as to improve the invivo biological efficacy of IFN-α, a long lasting hyperglycosylated protein (4N-IFN) derived from IFN-α2b wild type (WT-IFN) was developed. However, in silico analysis performed using established in silico methods revealed that 4N-IFN had more T cell epitopes than WT-IFN. In order to develop a safer and more efficient IFN therapy, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of 4N-IFN.Using the OptiMatrix in silico tool in ISPRI, the 4N-IFN sequence was modified to reduce HLA binding potential of specific T cell epitopes. Following verification of predictions by HLA binding assays, eight modifications were selected and integrated in three variants: 4N-IFN(VAR1), (VAR2) and (VAR3). Two of the three variants (VAR1 and VAR3) retained anti-viral function and demonstrated reduced T-cell immunogenicity in terms of T-cell proliferation and Th1 and Th2 cytokine levels, when compared to controls (commercial NG-IFN (non-glycosylated), PEG-IFN, WT-IFN and 4N-IFN).It was previously demonstrated that N-glycosylation improved IFN-α pharmacokinetic properties. Here, we further reduce immunogenicity as measured invitro using T cell assays and cytokine profiling by modifying the T cell epitope content of a protein (de-immunizing). Taking into consideration the present results and previously reported immunogenicity data for commercial IFN-α2b variants, 4N-IFN(VAR1) and 4N-IFN-4N(VAR3) appear to be promising candidates for improved IFN-α therapy of HCV and HBV.
http://ift.tt/2iAGCYE
Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma
Publication date: March 2017
Source:Oral Oncology, Volume 66
Author(s): Alex Panaccione, Yi Zhang, Yanfang Mi, Yoshitsugu Mitani, Guo Yan, Manju L. Prasad, W. Hayes McDonald, Adel K. El-Naggar, Wendell G. Yarbrough, Sergey V. Ivanov
BackgroundMucinous adenocarcinoma of the salivary gland (MAC) is a lethal cancer with unknown molecular etiology and a high propensity to lymph node metastasis. Mostly due to its orphan status, MAC remains one of the least explored cancers that lacks cell lines and mouse models that could help translational and pre-clinical studies. Surgery with or without radiation remains the only treatment modality but poor overall survival (10-year, 44%) underscores the urgent need for mechanism-based therapies.MethodsWe developed the first patient-derived xenograft (PDX) model for pre-clinical MAC studies and a cell line that produces aggressively growing tumors after subcutaneous injection into nude mice. We performed cytogenetic, exome, and proteomic profiling of MAC to identify driving mutations, therapeutic targets, and pathways involved in aggressive cancers based on TCGA database mining and GEO analysis.ResultsWe identified in MAC KRAS (G13D) and TP53 (R213X) mutations that have been previously reported as drivers in a variety of highly aggressive cancers. Somatic mutations were also found in KDM6A, KMT2D, and other genes frequently mutated in colorectal and other cancers: FAT1, NBEA, RELN, RLP1B, and ZFHX3. Proteomic analysis of MAC implied epigenetic up-regulation of a genetic program involved in proliferation and cancer stem cell maintenance.ConclusionGenomic and proteomic analyses provided the first insight into potential molecular drivers of MAC metastases pointing at common mechanisms of CSC propagation in aggressive cancers. The in vitro/in vivo models that we created should aid in the development and validation of new treatment strategies against MAC.
Graphical abstract
http://ift.tt/2joftrB
Use of TNF-inhibitors and ustekinumab for psoriasis during pregnancy: A patient series
Abstract
From 2002 to 2016 a total of seven women with severe refractory psoriasis were exposed to the TNF-inhibitors infliximab and adalimumab or to the IL12/23 inhibitor ustekinumab during one or more pregnancies. Maternal, fetal or teratogenic toxicity were not detected during pregnancy and puerperium. All pregnancies were uneventful and resulted in delivery of 10 healthy children in total, one of the women is due February 2017. Postpartum, five of the women were lactating, but none of the women or newborns developed adverse reactions. Data on safety of treatment during breastfeeding are sparse, but so far appears to be safe due to the lack of absorption across the gastrointestinal lining. Currently biological therapy with either TNF-inhibitors or ustekinumab is not recommended during pregnancy, however in selected women with severe psoriasis these treatment modalities may be considered.
http://ift.tt/2ies1nH
Is myoelectric activity distributed equally within the rectus femoris muscle during loaded, squat exercises?
Publication date: Available online 9 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Leonardo Mendes Leal de Souza, Desirée Barros da Fonseca, Hélio da Veiga Cabral, Liliam Fernandes de Oliveira, Taian Martins Vieira
Myoelectric activity distributed locally within RF was reported for isometric contractions, walking and fatigue. Here we investigate whether myoelectric activity distributes evenly within RF during squat. Surface electromyograms (EMGs) were sampled proximally and distally from RF with arrays of electrodes, while thirteen healthy volunteers performed 10 consecutive squats with 20% and 40% of their body weight. The root mean square (RMS) value, computed separately for thirds of the concentric and eccentric phases, was considered to assess the proximo-distal changes in EMG amplitude during squat. The channels with variations in EMG amplitude during squat associated with shifts in the muscle innervation zone were excluded from analysis. No significant differences were observed between RF regions when considering squat phases and knee joint angles individually (P>0.16) while a significant interaction between phase and knee joint angle with detection site was observed (P<0.005). For the two loads considered, proximal RMS values were greater during the eccentric phase and for the more flexed knee joint position (P<0.001). Our results suggest inferences on the degree of RF activation during squat must be made cautiously from surface EMGs. Of more practical relevance, there may be a potential for the differential adaption of RF proximal and distal regions to squat exercises.
http://ift.tt/2jdCSwG
Validation of a Personalized Curved Muscle Model of the Lumbar Spine during Complex Dynamic Exertions
Publication date: Available online 9 January 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Jaejin Hwang, Gregory G. Knapik, Jonathan S. Dufour, Thomas M. Best, Safdar N. Khan, Ehud Mendel, William S. Marras
Previous curved muscle models have typically examined their robustness only under simple, single-plane static exertions. In addition, the empirical validation of curved muscle models through an entire lumbar spine has not been fully realized. The objective of this study was to empirically validate a personalized biologically-assisted curved muscle model during complex dynamic exertions. Twelve subjects performed a variety of complex lifting tasks as a function of load weight, load origin, and load height. Both a personalized curved muscle model as well as a straight-line muscle model were used to evaluate the model's fidelity and prediction of three-dimensional spine tissue loads under different lifting conditions. The curved muscle model showed better model performance and different spinal loading patterns through an entire lumbar spine compared to the straight-line muscle model. The curved muscle model generally showed good fidelity regardless of lifting condition. The majority of the 600 lifting tasks resulted in a coefficient of determination (R2) greater than 0.8 with an average of 0.83, and the average absolute error less than 15% between measured and predicted dynamic spinal moments. As expected, increased load and asymmetry were generally found to significantly increase spinal loads, demonstrating the ability of the model to differentiate between experimental conditions. A curved muscle model would be useful to estimate precise spine tissue loads under realistic circumstances. This precise assessment tool could aid in understanding biomechanical causal pathways for low back pain.
http://ift.tt/2i9g848
How Meiosis Creates the Single-Copy Genome
Publication date: 9 January 2017
Source:Developmental Cell, Volume 40, Issue 1
Author(s): Mary Herbert, Attila Toth
Genome haploidization involves two meiotic divisions following a single round of DNA replication. In this issue of Developmental Cell, Argüello-Miranda et al. (2017) show that production and packaging of the single-copy genome into gametes during the second meiotic division is coordinated by a conserved casein kinase 1.
Teaser
Genome haploidization involves two meiotic divisions following a single round of DNA replication. In this issue of Developmental Cell, Argüello-Miranda et al. (2017) show that production and packaging of the single-copy genome into gametes during the second meiotic division is coordinated by a conserved casein kinase 1.http://ift.tt/2jdQacS
Ser68 Phosphorylation Ensures Accurate Cell-Cycle-Dependent CENP-A Deposition at Centromeres
Publication date: 9 January 2017
Source:Developmental Cell, Volume 40, Issue 1
Author(s): Kehui Wang, Zhouliang Yu, Yuting Liu, Guohong Li
http://ift.tt/2i9jNik
CENP-A Ubiquitylation Is Required for CENP-A Deposition at the Centromere
Publication date: 9 January 2017
Source:Developmental Cell, Volume 40, Issue 1
Author(s): Yohei Niikura, Risa Kitagawa, Katsumi Kitagawa
http://ift.tt/2jdVQ6u
Mesenchymal MicroRNA Function Branches Out
Publication date: 9 January 2017
Source:Developmental Cell, Volume 40, Issue 1
Author(s): Huojun Cao, Liu Hong, Brad A. Amendt
Significant amounts of microRNAs (miRs) are detected in exosomes, but their function during fetal development is poorly understood. In this issue of Developmental Cell, Hayashi et al. (2017) show that exosomal miRs secreted by mesenchymal cells can regulate epithelial KIT+ progenitor cell expansion during murine salivary gland organogenesis.
Teaser
Significant amounts of microRNAs (miRs) are detected in exosomes, but their function during fetal development is poorly understood. In this issue of Developmental Cell, Hayashi et al. (2017) show that exosomal miRs secreted by mesenchymal cells can regulate epithelial KIT+ progenitor cell expansion during murine salivary gland organogenesis.http://ift.tt/2i9oPvh
CENP-A Modifications on Ser68 and Lys124 Are Dispensable for Establishment, Maintenance, and Long-Term Function of Human Centromeres
Publication date: 9 January 2017
Source:Developmental Cell, Volume 40, Issue 1
Author(s): Daniele Fachinetti, Glennis A. Logsdon, Amira Abdullah, Evan B. Selzer, Don W. Cleveland, Ben E. Black
CENP-A is a histone H3 variant key to epigenetic specification of mammalian centromeres. Using transient overexpression of CENP-A mutants, two recent reports in Developmental Cell proposed essential centromere functions for post-translational modifications of human CENP-A. Phosphorylation at Ser68 was proposed to have an essential role in CENP-A deposition at centromeres. Blockage of ubiquitination at Lys124 was proposed to abrogate localization of CENP-A to the centromere. Following gene inactivation and replacement in human cells, we demonstrate that CENP-A mutants that cannot be phosphorylated at Ser68 or ubiquitinated at Lys124 assemble efficiently at centromeres during G1, mediate early events in centromere establishment at an ectopic chromosomal locus, and maintain centromere function indefinitely. Thus, neither Ser68 nor Lys124 post-translational modification is essential for long-term centromere identity, propagation, cell-cycle-dependent deposition, maintenance, function, or mediation of early steps in centromere establishment.
Teaser
CENP-A is a histone H3 variant important for centromere specification. In this Matters Arising article, using CENP-A gene replacement strategies, Fachinetti, Logsdon et al. provide evidence that the Ser68phos and Lys124ub modifications of CENP-A, previously proposed to regulate CENP-A function, are not required for long-term centromere identity, function, or maintenance.http://ift.tt/2jdVRay
Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis
Publication date: Available online 9 January 2017
Source:Journal of Autoimmunity
Author(s): Caroline Wasén, Minna Turkkila, Apostolos Bossios, Malin Erlandsson, Karin M. Andersson, Linda Ekerljung, Carina Malmhäll, Mikael Brisslert, Sofia Töyrä Silfverswärd, Bo Lundbäck, Maria I. Bokarewa
CD8+ T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8+ T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8+ T cells and cause survivin release to serum.We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8+ T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR.Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8+ T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1−IL-7R+ CD8+ T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype.We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA.
http://ift.tt/2jdMqb6
A comprehensive evaluation for the treatment of lupus nephritis
Publication date: Available online 9 January 2017
Source:Journal of Autoimmunity
Author(s): Evangelia Zampeli, Dennis M. Klinman, M. Eric Gershwin, Haralampos M. Moutsopoulos
Systemic lupus is the prototypic human autoimmune disease. It is a kaleidoscope of autoreactivities, with clear indications of both a genetic and environmental basis. Indeed, it is a disease that can manifest in virtually every tissue and organ and can also be found spontaneously in a number of animal species, including dogs, cats and horses. Moreover, there are multiple murine models of lupus, the first of which, New Zealand Black (NZB) mice, were discovered in 1959. Despite an enormous effort from scientists in multiple disciplines, the etiology of lupus remains elusive and the introduction of new therapies has been disappointing. Fortunately, significant advances have occurred to help patients through the general principles of internal medicine, including antibiotics, dialysis, and of course use of steroids and immunosuppressive agents. However, the magic bullet has yet to be discovered. One of the major causes of morbidity in lupus remains lupus nephritis and there has been significant effort and encouragement in understanding the pathogenesis, renal histologic classification, and use of therapeutic protocols to induce and sustain remission of lupus nephritis. Indeed, the first use of evidence-based clinical trials in lupus was initiated by Dr. Alfred D. Steinberg at NIH in pioneering studies involving either oral or intravenous pulses of cyclophosphamide, azathioprine or corticosteroids alone and/or some combination. Cyclophosphamide intravenously proved to be superior and the use of cyclophosphamide in combination with methylprednisolone remained the standard protocol for the treatment of lupus nephritis for decades. Although alternative therapies have been introduced, including mycophenolate mofetil, the use of therapies first pioneered at NIH may still be considered standard of care in the appropriate indications. More targeted therapies are much desired. In this review we provide a comprehensive overview of lupus nephritis and the evolution of clinical treatments.
http://ift.tt/2j3wZ8i
The expression and function of the neonatal Fc receptor in thyrocytes of Hashimoto's thyroiditis
Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Chenxu Zhao, Ying Gao, Lanlan Zhao, Yuan Li, Yang Zhang, Suxia Wang, Hong Zhang, Guizhi Lu, Xiaohui Guo
ObjectiveThyroglobulin (Tg) and thyroid peroxidase (TPO) antibodies (TgAb and TPOAb), which are primarily of the immunoglobulin G (IgG) class, can mediate antibody-dependent cell-mediated cytotoxicity in vitro. However, it is unclear whether any thyrocyte molecules can facilitate the transport and elimination of TgAb and TPOAb. The IgG transport receptor neonatal Fc receptor (FcRn) is a candidate mediator of these processes. In this study, we aimed to evaluate FcRn expression and function in normal and Hashimoto's thyroiditis (HT) thyrocytes.MethodsFcRn expression in primary thyrocyte cultures (four normal and four HT groups) was examined by polymerase chain reaction (PCR) and Western blotting. Localization of FcRn was demonstrated by immunoelectron microscopy. A double immunofluorescence staining method was adopted to detect FcRn and internalized human TgAb IgG. Stimulation experiments were performed to assess the regulation of FcRn expression by T helper cell 1 (Th1) (IFN-γ and TNF-α) and Th2 cytokines (IL-10 and IL-4).ResultsFcRn expression was lower in HT thyrocytes than in normal thyrocytes. FcRn was located in the cytoplasm, membranes, mitochondria and transport vesicles of thyrocytes. Both human IgG and TgAb IgG were internalized by thyrocytes in a pH-dependent manner and co-localized with FcRn in thyrocytes. FcRn expression was downregulated by Th1 and Th2 cytokines in both normal and HT thyrocytes in a dose-dependent manner.ConclusionsOur results suggest that FcRn may be associated with the transport and metabolism of IgG in thyrocytes and that transport is independent of IgG type. FcRn may be involved in HT pathogenesis.
http://ift.tt/2iAhu4l
Microstructure and physical performance of laser-induction nanocrystals modified high-entropy alloy composites on titanium alloy
Publication date: 5 March 2017
Source:Materials & Design, Volume 117
Author(s): Jianing Li, Werner Craeghs, Cainian Jing, Shuili Gong, Feihu Shan
Ultrafine nanocrystals (UNs) modified high-entropy alloy composites (HEACs) were fabricated by laser-melted deposition (LMD) of the yttria partially stabilized ZrO2 (YPSZ) and the FeCoCrAlCu mixed powders on the aviation turbine blade made of the additive manufacturing (AM) TC17 titanium alloy. Such HEACs exhibited the finer microstructure free of micro-crack under an action of YPSZ, also relative stable atomic group of UNs owned the short-range order was produced attached to such HEACs matrix. Formation mechanisms of the AlCu2Zr UNs, amorphous and the nanoscale icosahedral quasicrystals (I-phase) with five-fold symmetry in HEACs were explored extensively by mean of the high resolution transmission electron microscope (HRTEM); also, under the actions of these various phases, such laser-induction HEACs exhibited the better wear performance than that of the FeCoCrAlCu LMD high-entropy alloy. With SiB2 addition, lots of the one-dimensional nanostructure materials (nanorods) were produced, retained UNs can be easily reunited due to a surface effect, retarding growth of nanorods in a certain extent. This research may provide the essential theoretical and experimental basis to improve the quality of the laser 3D print composites.
Graphical abstract
http://ift.tt/2i9dyuW
Design of NiAl2O4 cellular monoliths for catalytic applications
Publication date: 5 March 2017
Source:Materials & Design, Volume 117
Author(s): Nuno M.D. Vitorino, Andrei V. Kovalevsky, Marta C. Ferro, João C.C. Abrantes, Jorge R. Frade
This work focuses on designing highly-porous cellular NiAl2O4-based spinel ceramics through combined suspension emulsification/reactive sintering and further decoration of the pore surfaces by Ni nanoparticles for potential applications in heterogeneous catalysis. Due to kinetic limitations and specific porous structure, the reduction occurs without affecting the integrity of the cellular monoliths. The reaction mechanism, assessed by XRD and TEM/EDS, includes both partial decomposition and reduction, resulting in the formation of metastable Al-enriched phases, mainly NiAl32O49, and metallic Ni phase, respectively. The results suggest that the cellular bulk framework can be decorated with Ni catalyst in a controlled way, by proper selection of the initial cation stoichiometry of the NiAl2O4 spinel and appropriate reduction conditions. In selected conditions the reduction results in Ni nanoparticles of various dimension scales, finely dispersed at the pore surfaces, with a significant fraction below 50nm, as confirmed by TEM/EDS. The results of thermodynamic analysis emphasize that the redox tolerance of the spinel phase is dependent on the Ni:Al activity ratio, suggesting the prospects for tuning the catalytic activity and stability by designing the initial composition and resulting content of metallic Ni and Ni- and Al-containing metastable phases.
Graphical abstract
http://ift.tt/2i96KO4
Carbon-rich superhard ruthenium carbides from first-principles
Publication date: 5 March 2017
Source:Materials & Design, Volume 117
Author(s): Shipeng Zhao, Yali Yang, Jian Lu, Wei Wu, Sheng Sun, Xi Li, Xinluo Zhao, Shixun Cao, Jincang Zhang, Wei Ren
Compounds formed by transition metals and light elements have attracted increasing attention owing to superior functionalities. Here, high throughput first-principles calculations are employed to investigate the crystal structures and physical properties of ruthenium carbides with various stoichiometries. It is found that the R3¯m-Ru2C, R3¯m-RuC, P3¯m1-Ru2C3, P3¯m1-RuC2, P3¯m1-RuC3 and C2/c-RuC4 are the ground states for the respective chemical compositions at ambient pressure, from a systematical investigation of both thermodynamic and mechanical stabilities, as well as phonon dispersions. Further calculations indicate that P3¯m1-RuC3 and P63/mmc-RuC4 are ultra-incompressible with high bulk and shear modulus. Subsequent empirical calculations predict that the carbon-rich P3¯m1-RuC3 and P63/mmc-RuC4 are superhard materials with a large Vickers hardness of 45.1GPa and 41.5GPa, respectively. In addition, a strong covalent CC bonding was observed from the electronic localization function contours of all the ground states, which is crucial for their excellent mechanical properties.
Graphical abstract
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Efficacy and Safety of Switching to Ixekizumab in Etanercept Non-Responders: A Subanalysis from Two Phase III Randomized Clinical Trials in Moderate-to-Severe Plaque Psoriasis (UNCOVER-2 and -3)
Abstract
Background
Patients with psoriasis who have an inadequate response to one biologic may benefit from switching to a new biologic, such as ixekizumab, a high affinity monoclonal antibody that selectively targets interleukin (IL)-17A.
Objective
Our aim was to assess the response to ixekizumab in patients with moderate-to-severe plaque psoriasis who did not respond adequately to etanercept using a post-hoc analysis in two phase III studies.
Methods
For the subanalyses in two phase III trials (UNCOVER-2 and -3), non-response was defined by either failure to have a static physician global assessment (sPGA) of 0/1 in UNCOVER-2 or failure to have at least 75% improvement in psoriasis area and severity index (PASI 75) in UNCOVER-3 at Week 12 of each study. Non-responders treated with twice-weekly etanercept 50 mg in the first 12 weeks received two injections of placebo at Week 12 (4-week wash-out period), followed by ixekizumab every 4 weeks (Q4W) for Weeks 16–60. Non-responders to placebo in the first 12 weeks were administered ixekizumab 160 mg at Week 12, followed by ixekizumab Q4W for Weeks 16–60.
Results
After switching to ixekizumab Q4W, a substantial proportion of patients with moderate-to-severe psoriasis who did not respond to etanercept experienced rapid and durable improvement in all efficacy evaluations. Among sPGA 0/1 (UNCOVER-2) and PASI 75 (UNCOVER-3) non-responders to etanercept, 73.0% achieved sPGA 0/1 and 78.2% achieved PASI 75, respectively, after 12 weeks of ixekizumab treatment. Safety profiles in patients switched from etanercept to ixekizumab were similar to those in patients switched from placebo to ixekizumab.
Conclusion
Patients who were non-responders to etanercept after 12 weeks, as defined by failure to meet sPGA 0/1 (UNCOVER-2) or PASI 75 (UNCOVER-3), achieved high levels of response 12 weeks after switching to ixekizumab.
Studies are registered with ClinicalTrials.gov (NCT01597245 and NCT01646177).
http://ift.tt/2j3jKnW
An integrative analysis of DNA methylation in osteosarcoma
Publication date: Available online 9 January 2017
Source:Pathology - Research and Practice
Author(s): Baohua Huang, Jiangdong Du, Qing Lin, Limei Yu, Liping Yang, Chengming Sun, Jie Li, Xia Zhang
BackgroundThe study aimed to analyze aberrantly methylated genes, relevant pathways and transcription factors (TFs) in osteosarcoma (OS) development.MethodsBased on the DNA methylation microarray data GSE36002 that were downloaded from GEO database, the differentially methylated genes in promoter regions were identified between OS and normal samples. Pathway and function enrichment analysis of differentially methylated genes was performed. Subsequently, protein-protein interaction (PPI) network was constructed, followed by identification of cancer-associated differentially methylated genes and significant differentially methylated TFs.ResultsA total of 1379 hyper-methylation regions and 169 hypo-methylation regions were identified in OS samples compared to normal samples. The differentially hyper-methylated genes were significantly enriched in Neuroactive ligand-receptor interaction pathway and PPAR signaling pathway. The differentially hypo-methylated genes were significantly enriched in toll-like receptor signaling pathway. In PPI network, signal transducers and activators of transcription (STAT3) had high degree (degree=21). MAX interactor 1, dimerization protein (MXI1), STAT3 and T-cell acute lymphocytic leukemia 1 (TAL1) were significant TFs enriched with target genes in OS samples. They were found to be cancer-associated and hyper-methylated in OS samples.ConclusionNeuroactive ligand-receptor interaction, PPAR signaling, and toll-like receptor signaling pathways are implicated in OS. MXI1, STAT3, and TAL1 may be important TFs in OS development.
http://ift.tt/2jptLbB
Reliability of the nociceptive blink reflex evoked by electrical stimulation of the trigeminal nerve in humans
Abstract
Objective
The nociceptive blink reflex (nBR) can be useful to investigate trigeminal nociceptive function. The aim of this study was to estimate the reliability of the nBR evoked by electrical stimulation of the three branches of the trigeminal nerve under the following conditions: over time (test-retest and intrarater reliability) and by two examiners (interrater reliability).
Materials and methods
Twenty-one healthy participants were evaluated in two sessions (24 h apart). The nBR was elicited by a so-called "nociceptive-specific" electrode placed over the entry zone of the right supraorbital (V1R), infraorbital (V2R), mental (V3R), and left infraorbital (V2L) nerve. The outcomes were individual electrical sensory (I 0) and pain thresholds (I P); root mean square (RMS), area-under-the-curve (AUC), and onset latencies of R2 responses (determined twice after a recalibration session); and stimulus-evoked pain on a 0–10 numerical rating scale. Intraclass correlation coefficients (ICCs) and Kappa statistics were computed (α = 5%).
Results
ICCs were fair to excellent in 82% of the psychophysical measures (fair 21%, good 31%, excellent 30%) and in 86% of V1R, V2R, and V2L nBR parameters, whereas 52% of V3R showed poor reliability. ICCs for intrarater reliability were fair to good in 70% of measurements (fair 20%, good 50%) and in 75% of interrater measurements after the recalibration (fair 55%, good 20%). All kappa values showed at least fair agreement and the majority of the nBR measures (93%) presented moderate to excellent reliability.
Conclusion
The nBR and its associated psychophysical measures can be considered a sufficiently reliable test.
Clinical significance
The nBR can be recommended as an electrophysiological technique to assess trigeminal nociceptive function.
http://ift.tt/2jpuU2Q
Ldb1 Regulates Energy Homeostasis During Diet-Induced Obesity
Endocrinology, Early Release.
http://ift.tt/2hbwW5f
Reg2 expression is required for pancreatic islet compensation in response to aging and high fat diet-induced obesity
Endocrinology, Early Release.
http://ift.tt/2inAupX
BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury
Source:Biomaterials, Volume 121
Author(s): Cátia D.F. Lopes, Nádia P. Gonçalves, Carla P. Gomes, Maria J. Saraiva, Ana P. Pêgo
Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies.
http://ift.tt/2ibqHPt
Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells
Source:Biomaterials, Volume 121
Author(s): Kun Ma, Duo Fu, Dongli Yu, Changhao Cui, Li Wang, Zhaoming Guo, Chuanbin Mao
A Sleeping Beauty (SB) transposon system is made of a transposon plasmid (containing gene encoding a desired functional or therapeutic protein) and a transposase plasmid (encoding an enzyme capable of cutting and pasting the gene into the host cell genome). It is a kind of natural, nonviral gene delivery vehicle, which can achieve efficient genomic insertion, providing long-term transgenic expression. However, before the SB transposon system could play a role in promoting gene expression, it has to be delivered efficiently first across cell membrane and then into cell nuclei. Towards this end, we used a nanoparticle-like lipid-based protocell, a closed bilayer of the neutral lipids with the DNA encapsulated inside, to deliver the SB transposon system to cancer cells. The SB transposon system was amplified in situ inside the protocells by a polymerase chain reaction (PCR) process, realizing more efficient loading and delivery of the target gene. To reach a high transfection efficiency, we introduced two targeting moieties, folic acid (FA) as a cancer cell-targeting motif and Dexamethasone (DEX) as a nuclear localization signaling molecule, into the protocells. As a result, the FA enabled the modified targeting protocells to deliver the DNA into the cancer cells with an increased efficiency and the DEX promoted the DNA to translocate to cell nuclei, eventually leading to the increased chromosome insertion efficiency of the SB transposon. In vivo study strongly suggested that the transfection efficiency of FA-modified protocells in the tumor tissue was much higher than that in other tissues, which was consistent with the in vitro results. Our studies implied that with the targeting ligand modification, the protocells could be utilized as an efficient targeting gene carrier. Since the protocells were made of neutral lipids without cationic charges, the cytotoxicity of protocells was significantly lower than that of traditional cationic gene carriers such as cationic liposomes and polyethylenimine, enabling the protocells to be employed in a wider dosage range in gene therapy. Our work shows that the protocells are a promising gene carrier for future clinical applications.
http://ift.tt/2idEfgx
Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways
Source:Biomaterials, Volume 121
Author(s): Xin Liu, Baiyan Sui, Jiao Sun
Silica nanoparticles (SiO2-NPs) has been extensively exploited in biomedical fields and mostly designed to enter the circulatory system, however, few studies focused on the potential adverse effects of SiO2-NPs exposure on the blood-brain barrier (BBB) that serves as a critical barrier between the central nervous system (CNS) and the peripheral circulation. This study attempts to provide an understanding of whether and how SiO2-NPs disrupts the BBB in vitro and in vivo. Through a human BBB model, we found that SiO2-NPs could induce tight junction loss and cytoskeleton arrangement, and increase inflammatory response and the release of vascular endothelial growth factor (VEGF) of brain microvessel endothelial cells (BMECs), which further activates astrocytes to amplify the generation of VEGF and increase the aquaporin-4 expression, and thus causing BBB disruption through a complex immunoregulatory loop between BMECs and astrocytes under SiO2-NPs exposure. Additionally, our data show that inhibition of reactive oxygen species (ROS) and Rho-kinase (ROCK) could effectively protect the SiO2-NPs-induced BBB dysfunction. In vivo studies further confirmed that SiO2-NPs could cause the BBB paracellular opening, oxidative stress and astrocyte activation in brains of Sprague–Dawley (SD) rats. These findings demonstrate that SiO2-NPs could disturb BBB structure and function and induce BBB inflammation, and suggest that these effects may occur through ROS and ROCK-mediated pathways, which not only improve neurotoxicity evaluation for SiO2-NPs but also provide useful information in development of SiO2-NPs in neuro-therapeutics and nanodiagnostics.
http://ift.tt/2ibwd4k
Engineered gadolinium-doped carbon dots for magnetic resonance imaging-guided radiotherapy of tumors
Source:Biomaterials, Volume 121
Author(s): Fengyi Du, Lirong Zhang, Li Zhang, Miaomiao Zhang, Aihua Gong, Youwen Tan, Jiawen Miao, Yuhua Gong, Mingzhong Sun, Huixiang Ju, Chaoyang Wu, Shenqiang Zou
The effectiveness of radiotherapy can decrease due to inaccurate positioning of machinery and inherent radioresistance of tumors. To address this issue, we present a novel theranostic nanoplatform based on gadolinium-doped carbon dots (Gd-doped CDs) designed specifically for magnetic resonance imaging (MRI)-guided radiotherapy of tumors. The Gd-doped CDs (∼18 nm) with dispersibility in water and stable photoluminescence were synthesized via a one-step hydrothermal approach. After tail vein injection of the Gd-doped CDs, they exhibited a relatively long circulation time (∼6 h), enabled efficient passive tumor targeting. Gd-doped CDs accumulate in the kidney and could be cleared out of the body from bladder. Importantly, they exhibited favorable biocompatibility with excellent performance in longitudinal relaxivity rate (r1) of 6.45 mM−1S−1 and radiosensitization enhancements. These results show that Gd-doped CDs are excellent T1 contrast agents and radiosensitizers, possessing great promise for MRI-guided radiotherapy of tumors.
http://ift.tt/2izxOlE
In vitro evaluation of biodegradable lignin-based nanoparticles for drug delivery and enhanced antiproliferation effect in cancer cells
Source:Biomaterials, Volume 121
Author(s): Patrícia Figueiredo, Kalle Lintinen, Alexandros Kiriazis, Ville Hynninen, Zehua Liu, Tomás Bauleth-Ramos, Antti Rahikkala, Alexandra Correia, Tomáš Kohout, Bruno Sarmento, Jari Yli-Kauhaluoma, Jouni Hirvonen, Olli Ikkala, Mauri A. Kostiainen, Hélder A. Santos
Currently, nanosystems have been developed and applied as promising vehicles for different biomedical applications. We have developed three lignin nanoparticles (LNPs): pure lignin nanoparticles (pLNPs), iron(III)-complexed lignin nanoparticles (Fe-LNPs), and Fe3O4-infused lignin nanoparticles (Fe3O4-LNPs) with round shape, narrow size distribution, reduced polydispersity and good stability at pH 7.4. The LNPs showed low cytotoxicity in all the tested cell lines and hemolytic rates below 12% after 12 h of incubation. Additionally, they induced hydrogen peroxide production in a small extent and time-dependent manner, and the interaction with the cells increased over time, exhibiting a dose-dependent cell uptake. Concerning the drug loading, pLNPs showed the capacity to efficiently load poorly water-soluble drugs and other cytotoxic agents, e.g. sorafenib and benzazulene (BZL), and improve their release profiles at pH 5.5 and 7.4 in a sustained manner. Furthermore, the BZL-pLNPs presented an enhanced antiproliferation effect in different cells compared to the pure BZL and showed a maximal inhibitory concentration ranging from 0.64 to 12.4 μM after 24 h incubation. Overall, LNPs are promising candidates for drug delivery applications, and the superparamagnetic behavior of Fe3O4-LNPs makes them promising for cancer therapy and diagnosis, such as magnetic targeting and magnetic resonance imaging.
http://ift.tt/2idKd17
Allele-Specific Wild-Type TP53 Expression in the Unaffected Carrier Parent of Children with Li-Fraumeni Syndrome
Source:Cancer Genetics
Author(s): Jeffrey S. Buzby, Shirley A. Williams, Lana Schaffer, Steven R. Head, Diane J. Nugent
Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is passed from parent to child. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Paradoxically, some mutant TP53 carriers remain unaffected, while their children develop cancer within the first few years of life. To address this paradox, response to UV stress was compared in dermal fibroblasts (dFb) from an affected LFS patient vs. their unaffected carrier parent. UV induction of CDKN1A/p21, a regulatory target of p53, in LFS patient dFb was significantly reduced compared to the unaffected parent. UV exposure also induced significantly greater p53[Ser15]-phosphorylation in LFS patient dFb, a reported property of some mutant p53 variants. Taken together, these results suggested that the unaffected parent dFb may express an increased proportion of wild-type vs. mutant p53. Indeed, a significantly increased ratio of wild-type to mutant TP53 allele-specific expression in the unaffected parent dFb was confirmed by RT-PCR-RFLP and RNA-seq analysis. Hence, allele-specific expression of wild-type TP53 may allow an unaffected parent to mount a response to genotoxic stress more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.
http://ift.tt/2idKMb6
On the nature of the speech perception deficits in children with autism spectrum disorders
Publication date: Available online 9 January 2017
Source:Research in Developmental Disabilities
Author(s): R.S. You, W. Serniclaes, D. Rider, N. Chabane
Previous studies have claimed to show deficits in the perception of speech sounds in autism spectrum disorders (ASD). The aim of the current study was to clarify the nature of such deficits. Children with ASD might only exhibit a lesser amount of precision in the perception of phoneme categories (CPR deficit). However, these children might further present an allophonic mode of speech perception, similar to the one evidenced in dyslexia, characterised by enhanced discrimination of acoustic differences within phoneme categories. Allophonic perception usually gives rise to a categorical perception (CP) deficit, characterised by a weaker coherence between discrimination and identification of speech sounds. The perceptual performance of ASD children was compared to that of control children of the same chronological age. Identification and discrimination data were collected for continua of natural vowels, synthetic vowels, and synthetic consonants. Results confirmed that children with ASD exhibit a CPR deficit for the three stimulus continua. These children further exhibited a trend toward allophonic perception that was, however, not accompanied by the usual CP deficit. These findings confirm that the commonly found CPR deficit is also present in ASD. Whether children with ASD also present allophonic perception requires further investigations.
http://ift.tt/2izumHW
Design and Synthesis of Potent Substrate-based Inhibitors of the Trypanosoma cruzi Dihydroorotate Dehydrogenase
Publication date: Available online 9 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Daniel Ken Inaoka, Maiko Iida, Satoshi Hashimoto, Toshiyuki Tabuchi, Takefumi Kuranaga, Emmanuel Oluwadare Balogun, Teruki Honma, Akiko Tanaka, Shigeharu Harada, Takeshi Nara, Kiyoshi Kita, Masayuki Inoue
Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, is the leading cause of heart disease in Latin America. T. cruzi dihydroorotate dehydrogenase (DHODH), which catalyzes the production of orotate, was demonstrated to be essential for T. cruzi survival, and thus has been considered as a potential drug target to combat Chagas disease. Here we report the design and synthesis of 75 compounds based on the orotate structure. A comprehensive structure-activity relationship (SAR) study revealed two 5-substituted orotate analogues (5u and 5v) that exhibit Kiapp values of several ten nanomolar level and a selectivity of more than 30,000-fold over human DHODH. The information presented here will be invaluable in the search for next-generation drug leads for Chagas disease.
Graphical abstract
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Microbial transformation of intracellular dissolved organic matter from Microcystis aeruginosa and its effect on the binding of pyrene under oxic and anoxic conditions
Abstract
The environmental behaviour and the bioavailability of polycyclic aromatic hydrocarbons (PAHs) are strongly affected by dissolved organic matter (DOM) in aquatic environments. In this study, we investigated the dynamics of the bioavailability and character of the intracellular DOM (IDOM) from Microcystis aeruginosa (M. aeruginosa-IDOM) during 10 days oxic and anoxic incubations by spectroscopy. Subsequently, the binding affinity of pyrene with the initial/altered M. aeruginosa-IDOM was estimated by fluorescence quenching method. The incubation results indicated that changes in dissolved organic carbon (DOC) concentration and selected spectral descriptors of the M. aeruginosa-IDOM under oxic condition were different from those of anoxic condition. The microbial transformation of the M. aeruginosa-IDOM resulted in an enhancement of the organic carbon-normalized binding coefficient (K DOC) of pyrene in both oxic and anoxic treatments. Moreover, only for the oxic condition, Pearson correlation analysis demonstrated that aromaticity (specific UV absorbance at 254 nm, SUVA254), humification degree (humification index, HIX) and the percent distribution of humic-like component 2 (%C2) presented significantly positive correlations with the pyrene K DOC, while the percent distribution of protein-like component 1 (%C1) exhibited a negative correlation with the K DOC. However, no significant correlation was observed between any spectral descriptor and the K DOC under anoxic condition. This result suggested that the binding affinity of pyrene may be primarily influenced by the altered M. aeruginosa-IDOM characteristics associated with the biological transformation. Hence, our results provided potential evidence for resolving the inconsistency in the relationships between DOM characteristics and the binding affinities of PAHs.
http://ift.tt/2izxPpF
The determination and fate of disinfection by-products from ozonation-chlorination of fulvic acid
Abstract
Ozonation of fulvic acid (FA) can result in diverse intermediate oxidation by-products, significantly affecting disinfection by-product (DBP) formation following chlorination. The objective of this study was to provide insight into ozone reaction intermediates and reveal the possible formation pathway of DBPs from ozonation of FA due to the formation of intermediate oxidation by-products. Aldehydes, aromatic acids, short-chain acids, chloroform, and dichloroacetic acid were detected at various ozone dosage additions. Aromatic acids were studied by using solid-phase extraction-ultra high-performance liquid chromatography (SPE-UPLC). This new analytical approach enables the extraction and analysis of highly polar carboxylic acids that are difficult to measure using conventional methods. The results showed that formaldehyde, acetaldehyde, glyoxal, methyl-glyoxal, fumaric, malonic protocatechuic, 3-hydroxybenzoic, and benzoic acid were predominant oxidation by-products. The yields of the four aldehydes increased steadily with ozone dosage. When ozone dosage was 2∼2.5 mg/l, the amount of carboxylic acids was largest, and the total amount of the carboxylic acids was about 5∼10 times higher than that of the aldehydes. Besides, hydroxybenzoic acids are the major precursor, although they have low content in ozone reaction solution, they have a great contribution to the DBP formation. This study provides a new perspective on ozonation natural organic matter, which contributes to understand the other sources of DBPs and thus broadens the knowledge of drinking water treatment.
http://ift.tt/2jy1XWR
Plant species diversity reduces N 2 O but not CH 4 emissions from constructed wetlands under high nitrogen levels
Abstract
Constructed wetlands (CWs) have been widely used for treating wastewater. CWs also are the sources of greenhouse gas (GHG) due to high pollutant load. It has been reported that plant species diversity can enhance nitrogen (N) removal efficiency in CWs for treating wastewater. However, the influence of plant species diversity on GHG emissions from CWs in habitats with high N levels still lack research. This study established four species richness levels (1, 2, 3, 4) and 15 species compositions by using 75 simulated vertical flow CWs microcosms to investigate the effects of plant species diversity on the GHG emissions and N removal efficiency of CWs with a high N level. Results showed plant species richness reduced nitrous oxide (N2O) emission and N (NO3−-N, NH4+-N, and TIN) concentrations in wastewater, but had no effect on methane (CH4) emission. Especially, among the 15 compositions of plant species, the four-species mixture emitted the lowest N2O and had under-depletion of N (DminTIN < 0). The presence of Oenanthe javanica had a significantly negative effect on the N2O emission but had no effect on N removal efficiency. The presence of Rumex japonicus significantly reduced the N (NO3−-N and TIN) concentrations in wastewater but had no effect on the N2O and CH4 emissions. The N concentrations and GHG emissions in the community of R. japonicus × Phalaris arundinacea were as low as those in the four-species mixture. Assembling plant communities with relatively high species richness (four-species mixture) or particular composition (R. japonicus × P. arundinacea) could enhance the N removal efficiency and reduce the GHG emissions from CWs for treating wastewater with a high N level.
http://ift.tt/2izlrGa
Source identification and spatial distribution of heavy metals in tobacco-growing soils in Shandong province of China with multivariate and geostatistical analysis
Abstract
Samples of surface soil from tobacco (Nicotiana tabacum L.) fields were analysed for heavy metals and showed the following concentrations (mean of 246 samples, mg/kg): As, 5.10; Cd, 0.11; Cr, 49.49; Cu, 14.72; Hg, 0.08; Ni, 19.28; Pb. 20.20 and Zn, 30.76. The values of the index of geoaccumulation (I geo) and of the enrichment factor indicated modest enrichment with As, Cd, Cr, Hg, Ni or Pb. Principal component analysis and cluster analysis correctly allocated each investigated element to its source, whether anthropogenic or natural. The results were consistent with estimated inputs of heavy metals from fertilizers, irrigation water and atmospheric deposition. The variation in the concentrations of As, Cd, Cu, Pb and Zn in the soil was mainly due to long-term agricultural practises, and that of Cr and Ni was mainly due to the soil parent material, whereas the source of Hg was industrial activity, which ultimately led to atmospheric deposition. Atmospheric deposition was the main exogenous source of heavy metals, and fertilizers also played an important role in the accumulation of these elements in soil. Identifying the sources of heavy metals in agricultural soils can serve as a basis for appropriate action to control and reduce the addition of heavy metals to cultivated soils.
http://ift.tt/2jy3c87
Cr(VI) reduction and Cr(III) immobilization by resting cells of Pseudomonas aeruginosa CCTCC AB93066: spectroscopic, microscopic, and mass balance analysis
Abstract
The aim of this study was to investigate the mechanism of Cr(VI) reduction and Cr(III) immobilization by resting cells of Pseudomonas aeruginosa using batch experiments and analysis techniques. Data showed that resting cells of this strain (3.2 g/L dry weight) reduced 10 mg/L of Cr(VI) by 86% in Tris-HCl buffer solution under optimized conditions of 5 g/L of sodium acetate as an electron donor, pH of 7.0 and temperature of 37 °C within 24 h. Cr(VI) was largely converted to nontoxic Cr(III), and both soluble crude cell-free extracts and membrane-associated fractions were responsible for Cr(VI) reduction. While remnant Cr(VI) existed only in the supernatant, the content of resultant Cr(III) in supernatant, on cell surface and inside cells was 2.62, 1.06, and 5.07 mg/L, respectively, which was an indicative of extracellular and intracellular reduction of chromate. Scanning electron microscopy analysis combined with energy dispersive X-ray spectroscopy revealed the adsorption of chromium on the bacterial surface. Interaction between Cr(III) and cell surface functional groups immobilized Cr(III) as indicated by Fourier transform infrared analyses and X-ray photoelectron spectroscopy. Transmission electron microscopy revealed Cr(III) precipitates in bacterial interior suggesting that Cr(II) could also be intracellularly accumulated. Thus, it can be concluded that interior and exterior surfaces of resting P. aeruginosa cells were sites for reduction and immobilization of Cr(VI) and Cr(III), respectively. This is further insight into the underlying mechanisms of microbial chromate reduction.
http://ift.tt/2izruuA
Trace element concentrations in muscle tissue of milk shark, ( Rhizoprionodon acutus ) from the Persian Gulf
Abstract
We analyze the heavy metals concentrations in muscle samples of milk shark (Rhizoprionodon acutus) from Persian Gulf. The metals distribution was Zn > Cu > Pb > Cd > Hg. No statistical differences were observed among size or weight by sex (p < 0.05). Metals concentrations in the population de R. acutus from Larak and Lavan islands are homogeneous along the coastal study area. Our study suggest that the results reflect the natural contents of trace metals in this species, and the health risk associated to milk shark consumption in Persian Gulf is relatively low.
http://ift.tt/2jy7VqA
Encaged Chironomus riparius larvae in assessment of trace metal bioavailability and transfer in a landfill leachate collection pond
Abstract
Household wastes may constitute a vector of environmental contamination when buried, in particular through degradation and production of leachates containing significant trace metal (TM) concentrations that may constitute a serious risk to biota. The objectives of this study were to assess the bioavailability and transfer potential of various TMs present in water and sediments in a reservoir receiving landfill leachates. An active biomonitoring approach was adopted consisting of exposing naive laboratory organisms in cages deployed in the field. Aquatic insects such as Chironomus riparius larvae are good candidates since they represent key organisms in the trophic functioning of aquatic ecosystems. The results show that water, suspended particles, and sediments were significantly contaminated by various TMs (As, Cd, Cu, Ni, Pb, and Zn). Their contribution to the transfer of TMs depends, however, on the specific element considered, e.g., Cd in sediments or Pb in both suspended particles and sediments. The internal fate of TMs was investigated according to their fractionation between an insoluble and a cytosolic fraction. This approach revealed different detoxification strategies capable of preventing the induction of deleterious effects at the individual scale. However, the accumulation of several TMs in C. riparius larvae tissues may also represent a significant load potentially transferable to higher trophic levels.
http://ift.tt/2izxMdt
Δευτέρα 9 Ιανουαρίου 2017
Influence of sunflower seed oil or baby lotion on the skin barrier function of newborns: A pilot study
Summary
Background
Skin care influences skin barrier function during the first postnatal weeks. Although the use of natural oils in preterms has been investigated, there are currently no data comparing the effect of sunflower oil to an emollient on barrier development in healthy term newborns.
Methods
In a prospective, randomized clinical study, 50 healthy full-term newborns aged ≤72 h were randomly assigned to two groups: group baby lotion (L, n=22) and sunflower seed oil (SSO, n=24). The skin barrier function was evaluated in three anatomical areas (front, abdomen, and thigh) by noninvasive assessment of transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum, and skin pH at inclusion and after five weeks.
Results
In both groups, skin pH decreased and SCH increased statistically significantly in all measured areas at W5 compared to baseline. TEWL decreased statistically significantly on the forearm in both groups, on the upper leg in group L, and on the abdomen in group SSO.
Conclusions
Both skin care regimes did not harm skin barrier function adaptation in healthy term neonates during the first five weeks of life.
http://ift.tt/2jxRr1t
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
