Editorial Board

Publication date: 1 August 2018
Source:NeuroImage, Volume 176





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Likelihood estimation of drug occupancy for brain PET studies

Publication date: September 2018
Source:NeuroImage, Volume 178
Author(s): Martin Schain, Francesca Zanderigo, R. Todd Ogden
Neuroimaging with PET is unique in its capability to measure in vivo the occupancy of a drug. The occupancy is typically obtained by conducting PET measurements before and after administration of the drug. For radioligands for which no reference region exists, however, the only established procedure to estimate the occupancy from these data is via linear regression analysis, forming the basis for the so-called Lassen plot. There are several reasons why simple linear regression analysis is not ideal for analyzing these data, including regression attenuation and correlated errors.Here, we propose the use of Likelihood Estimation of Occupancy (LEO) in such a situation. Similar to the Lassen plot, LEO uses the total distribution volume estimates at baseline and at block condition as input, but estimates the non-displaceable distribution volume (VND) and fractional occupancy (Δ) via direct maximum likelihood estimation (MLE).This study outlines the rationale for using MLE to estimate Δ and VND from PET data, and evaluates its performance in relation to the Lassen Plot via two separate simulation experiments. Finally, LEO and Lassen plot are applied to a PET dataset acquired with [¹¹C]WAY-100635.LEO can exploit the covariance structure of the data to improve the accuracy and precision of the estimates of Δ and VND. Theoretically, the covariance matrix can be extracted from a test-retest dataset for the radioligand at hand. Several procedures to estimate the covariance matrix were considered as part of the simulation experiments, and the effect of the test-retest sample size was also assessed.The results are conclusive in that MLE can be used to estimate Δ and VND from PET data, avoiding the limitations associated with linear regression. The performance of LEO was, naturally, dependent on the procedure used to estimate the covariance matrix, and the test-retest sample size. Given a test-retest sample size of at least 5, but preferably 10 individuals, LEO provides higher accuracy and precision than Lassen plot in the estimation of Δ and VND. We conclude that LEO is valuable in drug occupancy studies.



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Is the encoding of Reward Prediction Error reliable during development?

Publication date: September 2018
Source:NeuroImage, Volume 178
Author(s): Hanna Keren, Gang Chen, Brenda Benson, Monique Ernst, Ellen Leibenluft, Nathan A. Fox, Daniel S. Pine, Argyris Stringaris
Reward Prediction Errors (RPEs), defined as the difference between the expected and received outcomes, are integral to reinforcement learning models and play an important role in development and psychopathology. In humans, RPE encoding can be estimated using fMRI recordings, however, a basic measurement property of RPE signals, their test-retest reliability across different time scales, remains an open question. In this paper, we examine the 3-month and 3-year reliability of RPE encoding in youth (mean age at baseline = 10.6 ± 0.3 years), a period of developmental transitions in reward processing. We show that RPE encoding is differentially distributed between the positive values being encoded predominantly in the striatum and negative RPEs primarily encoded in the insula. The encoding of negative RPE values is highly reliable in the right insula, across both the long and the short time intervals. Insula reliability for RPE encoding is the most robust finding, while other regions, such as the striatum, are less consistent. Striatal reliability appeared significant as well once covarying for factors, which were possibly confounding the signal to noise ratio. By contrast, task activation during feedback in the striatum is highly reliable across both time intervals. These results demonstrate the valence-dependent differential encoding of RPE signals between the insula and striatum, and the consistency of RPE signals or lack thereof, during childhood and into adolescence. Characterizing the regions where the RPE signal in BOLD fMRI is a reliable marker is key for estimating reward-processing alterations in longitudinal designs, such as developmental or treatment studies.



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Extreme weather event may induce Microcystis blooms in the Qiantang River, Southeast China

Abstract

A severe cyanobacterial bloom in the mainstem of a large Chinese river was first reported from China. The Qiantang River is the longest river in the Zhejiang province, southeast China. It provides drinking water supply to ~ 16 million people, including Hangzhou city. Fifteen sites along the Qiantang River (including upper, middle (Fuchunjiang Reservoir), and lower reaches and tributaries) were sampled between August 13 and September 9, 2016 to conduct a preliminary examination of the outbreak of Microcystis blooms. Laboratory investigation revealed that Microcystis spp. are dominant in the Fuchunjiang Reservoir (an overflow reservoir on the mainstem of the Qiantang River) with an extremely high cell density of 2.3 × 10⁸ cells/L, leading to a severe bloom in the mainstem of the Qiantang River. Investigations of the meteorological, hydrological, and nutrient characteristics associated with the bloom indicated that extremely dry (6.8 mm rainfall from August 13 to September 9, 2016) and hot (32 consecutive days of temperatures > 30 °C from July 20 to August 31, 2016) weather might be the key factors triggering the bloom. Additionally, the extremely low flow of the tributary, Lanjiang River (142 ± 56 m³/s from August 13 to September 9), and its high nutrient background, favored the bloom. While nutrient reductions are important, the most immediate and effective management approach might be to implement appropriate minimal flow conditions to mitigate the blooms.

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Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): James D. Lord, S. Alice Long, Donna M. Shows, Jerill Thorpe, Katherine Schwedhelm, Janice Chen, Mariko Kita, Jane H. Buckner
Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.



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Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): Nithya Lingampalli, Jeremy Sokolove, Lauren J. Lahey, Jess D. Edison, William R. Gilliland, V. Michael Holers, Kevin D. Deane, William H. Robinson
The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.



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Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): James D. Lord, S. Alice Long, Donna M. Shows, Jerill Thorpe, Katherine Schwedhelm, Janice Chen, Mariko Kita, Jane H. Buckner
Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.



https://ift.tt/2IQ6BfG

Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis

Publication date: Available online 26 May 2018
Source:Clinical Immunology
Author(s): Nithya Lingampalli, Jeremy Sokolove, Lauren J. Lahey, Jess D. Edison, William R. Gilliland, V. Michael Holers, Kevin D. Deane, William H. Robinson
The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.



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Impaired spatial processing in a mouse model of fragile X syndrome

Publication date: 17 September 2018
Source:Behavioural Brain Research, Volume 350
Author(s): Mohamed Ghilan, Luis E.B. Bettio, Athena Noonan, Patricia S. Brocardo, Joana Gil-Mohapel, Brian R. Christie
Fragile X syndrome (FXS) is the most common form of inherited intellectual impairment. The Fmr1^−/y mouse model has been previously shown to have deficits in context discrimination tasks but not in the elevated plus-maze. To further characterize this FXS mouse model and determine whether hippocampal-mediated behaviours are affected in these mice, dentate gyrus (DG)-dependent spatial processing and Cornu ammonis 1 (CA1)-dependent temporal order discrimination tasks were evaluated. In agreement with previous findings of long-term potentiation deficits in the DG of this transgenic model of FXS, the results reported here demonstrate that Fmr1^−/y mice perform poorly in the DG-dependent metric change spatial processing task. However, Fmr1^−/y mice did not present deficits in the CA1-dependent temporal order discrimination task, and were able to remember the order in which objects were presented to them to the same extent as their wild-type littermate controls. These data suggest that the previously reported subregional-specific differences in hippocampal synaptic plasticity observed in the Fmr1^−/y mouse model may manifest as selective behavioural deficits in hippocampal-dependent tasks.



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Role of Cervical Vestibular Evoked Myogenic Potentials (cVEMP) as Outcome-Measure of Glycerol Test

Abstract

Diagnosis of Meniere's disease is mainly clinical although many tests have been studied for efficacy in diagnosis of Meniere's disease. Glycerol test is a functional test to identify hydrops in Meniere's disease and can be done with PTA, Speech audiometry, otoacoustic emission, EcochG and cVEMP as its outcome measures. The study aimed to compare two outcome measures of glycerol test to identify Meniere's disease; to determine whether the stage of Meniere's disease affected glycerol outcomes; and to attempt to identify independent variables that could predict outcomes of glycerol test. 26 ears of 20 Meniere's disease participants were evaluated using PTA-based and cVEMP-based glycerol tests. Each test identified ten of 26 ears with Meniere's disease; and high agreement was noted in the two outcome measures. The stage of Meniere's disease based on four frequency hearing threshold average was not associated with outcome of glycerol test, but staging of Meniere's disease based on symptom duration was associated with glycerol test results. As the duration of symptoms increased there was lesser chance of positive outcomes on glycerol test; but intermediate stages of Meniere's disease showed positive outcomes. Variables such as age, gender, severity of hearing loss, duration of symptoms and pre-glycerol cVEMP measurements could not predict glycerol test outcomes. PTA-based and cVEMP- based glycerol tests hold promise in the test battery for identification of Meniere's disease. Positive findings on the test lead to confirmatory diagnosis but a negative glycerol test does not rule out Meniere's disease.

https://ift.tt/2GTMibh

Authors response to communication about mathematical modeling of gonadotropin-releasing hormone signaling

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Amitesh Pratap, Kathryn L. Garner, Margaritis Voliotis, Krasimira Tsaneva-Atanasova, Craig A. McArdle




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The increase in fiber size in male rat gastrocnemius after chronic central leptin infusion is related to activation of insulin signaling

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Emma Burgos-Ramos, Sandra Canelles, Amaia Rodríguez, Laura M. Frago, Javier Gómez-Ambrosi, Julie A. Chowen, Gema Frühbeck, Jesús Argente, Vicente Barrios
Insulin potentiates leptin effects on muscle accrual and glucose homeostasis. However, the relationship between leptin's central effects on peripheral insulin sensitivity and the associated structural changes remain unclear. We hypothesized that central leptin infusion modifies muscle size through activation of insulin signaling. Muscle insulin signaling, enzymes of fatty acid metabolism, mitochondrial respiratory chain complexes, proliferating cell nuclear antigen (PCNA) and fiber area were analyzed in the gastrocnemius of chronic central infused (L), pair-fed (PF) and control rats. PCNA-positive nuclei, fiber area, GLUT4 and glycogen levels and activation of Akt and mechanistic target of rapamycin were increased in L, with no changes in PF. Acetyl-CoA carboxylase-β mRNA levels and non-esterified fatty acid and triglyceride content were reduced and carnitine palmitoyltransferase-1b expression and mitochondrial complexes augmented in L. These results suggest that leptin promotes an increase in muscle size associated with improved insulin signaling favored by lipid profile.



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Editorial Board

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470





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Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Lara Faggi, Andrea Giustina, Giovanni Tulipano
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved. Membrane proteins, including growth factor receptors, are valuable targets of AMPK. The inhibition of the mTOR-p70S6 kinase signalling pathway plays a role in the suppressive effect of metformin on pituitary tumor cell growth. Metformin did not affect the MTT reduction activity in energetic stress conditions. Finally, metformin was still able to induce AMPK activation and to inhibit cell growth in cells treated with forskolin and in transfected cells overexpressing GHRH-receptor and treated with GHRH. Hence, adenylyl cyclase over-activation does not account for the lack of response of some human pituitary tumors to AMPK-activating compounds in vitro.



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Estrogen-induced transcription factor EGR1 regulates c-Kit transcription in the mouse uterus to maintain uterine receptivity for embryo implantation

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Mira Park, Hye-Ryun Kim, Yeon Sun Kim, Seung Chel Yang, Jung Ah Yoon, Sang Woo Lyu, Hyunjung Jade Lim, Seok-Ho Hong, Haengseok Song
Early growth response 1 (Egr1) is a key transcription factor that mediates the action of estrogen (E2) to establish uterine receptivity for embryo implantation. However, few direct target genes of EGR1 have been identified in the uterus. Here, we demonstrated that E2 induced EGR1-regulated transcription of c-Kit, which plays a crucial role in cell fate decisions. Spatiotemporal expression of c-Kit followed that of EGR1 in uteri of ovariectomized mice at various time points after E2 treatment. E2 activated ERK1/2 and p38 to induce EGR1, which then activated c-Kit expression in the uterus. EGR1 transfection produced rapid and transient induction of c-KIT in a time- and dose-dependent manner. Furthermore, luciferase assays to measure c-Kit promoter activity confirmed that a functional EGR1 binding site(s) (EBS) was located within −1 kb of the c-Kit promoter. Site-directed mutagenesis and chromatin immunoprecipitation-PCR for three putative EBS within −1 kb demonstrated that the EBS at -818/-805 was critical for EGR1-dependent c-Kit transcription. c-Kit expression was significantly increased in the uterus on day 4 and administration of Masitinib, a c-Kit inhibitor, effectively interfered with embryo implantation. Collectively, our results showed that estrogen induces transcription factor EGR1 to regulate c-Kit transcription for uterine receptivity for embryo implantation in the mouse uterus.



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Molecular profiles of oxyphilic and chief cell parathyroid adenoma

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Ming Lu, Hanna Kjellin, Omid Fotouhi, Linkiat Lee, Inga-Lena Nilsson, Felix Haglund, Anders Höög, Janne Lehtiö, Catharina Larsson
ContextParathyroid adenomas may be composed of chief cells (conventional or water-clear), oxyphilic cells or a mixture of both cells. The molecular background is rarely studied.ObjectiveTo molecularly characterize parathyroid adenomas of different cell type composition.Design: Chief and oxyphilic cell adenomas were compared in a cohort of 664 sporadic cases. Extensive analyses of parathyroid tissues were performed in subgroup. Gene expressions of known parathyroid-related genes were quantified by qRT-PCR. Protein expression profiles determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS) were compared between each type of parathyroid adenomas. Selected proteins were analysed by Western blot and immunohistochemistry.ResultsPatients with oxyphilic cell adenoma were found to be older at the time of operation than chief cell adenoma cases but did not differ in gender, serum calcium or tumor weight. The gene expression of CASR, VDR, FGFR1, CYP27B1, CYP24A1, PTHLH, GCM2, NDUFA13, CDKN1B, MEN1 and CNND1 did not differ between the groups. VDR protein levels were weaker in oxyphilic adenomas. The proteomic studies identified a set of novel dysregulated proteins of interest such as nuclear receptor subfamily 2 group C member 2 (TR4), LIM domain only protein 3 (LMO3) and calcium-binding protein B (S100B). LMO3 and S100B showed higher expression in oxyphilic adenoma and may be involve in parathyroid tumorgenesis through the p53 pathway. TR4 showed different subcellular localisation between adenoma and normal rim.ConclusionChief and oxyphilic cell parathyroid adenomas have partly overlapping but also distinct molecular profiles. The calmodulin-eEF2K, TR4 and p53 pathways may be involved in the tumor development.



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Activation of Nrf2 might reduce oxidative stress in human granulosa cells

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Nana Akino, Osamu Wada-Hiraike, Hiromi Terao, Harunori Honjoh, Wataru Isono, Houju Fu, Mana Hirano, Yuichiro Miyamoto, Michihiro Tanikawa, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Katsutoshi Oda, Kei Kawana, Tomoyuki Fujii, Yutaka Osuga
Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs.Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs. Human luteinized GCs were isolated and cultured, and hydrogen peroxide (H2O2) or Dimethylfumarates (DMF), an activator of Nrf2, were added to GCs to analyze the relationship between Nrf2 and antioxidants by quantitative RT-PCR. The mRNA levels of Nrf2, catalase, superoxide dismutase 1 (SOD1), and 8-Oxoguanine DNA glycosylase (OGG1) were elevated by H2O2, and DMF treatment showed similar but pronounced effects through activation of Nrf2. To determine the relationship of Nrf2 and the generation of antioxidants, siRNAs were used and quantitative RT-PCR were conducted. Decreased expression of Nrf2 resulted in a decreased level of these antioxidant mRNA. Intracellular levels of ROS were investigated by fluorescence of 8-hydroxy-2′-deoxyguanosine and fluorescent dye, 2′,7′-dichlorodihydrofluorescein diacetate after H2O2 and/or DMF treatment, and DMF treatment quenched intracellular ROS generation by H2O2.These results show that activation of Nrf2 might lead to alleviate OS in human GCs, and this could provide novel insight to conquer the age-related fertility decline that is mainly attributed to the accumulation of aberrant OS.



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Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Jie Lu, Blake K. Montgomery, Grégoire P. Chatain, Alejandro Bugarini, Qi Zhang, Xiang Wang, Nancy A. Edwards, Abhik Ray-Chaudhury, Marsha J. Merrill, Russell R. Lonser, Prashant Chittiboina
BackgroundPre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with ¹⁸F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased ¹⁸F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas.MethodsClinical data was analyzed for efficacy of CRH in improving ¹⁸FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells.ResultsCRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation.ConclusionIncreased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated ¹⁸F-FDG PET could improve microadenoma detection.



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Regulation of NADPH oxidase NOX4 by delta iodolactone (IL-δ) in thyroid cancer cells

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Lisa Thomasz, Romina Oglio, Leonardo Salvarredi, Marina Perona, Luciano Rossich, Silvia Copelli, Mario Pisarev, Guillermo Juvenal
IntroductionIodine is not used only by the thyroid to synthesize thyroid hormones but also directly influences a number of thyroid parameters such as thyroid proliferation and function. Several iodinated lipids, biosynthesized by the thyroid, were postulated as intermediaries in the action of iodide. Among these, iodolactone (IL-δ) and 2-iodohexadecanal (2-IHDA) have shown to inhibit several thyroid parameters. The antiproliferative effect of IL-δ is not restricted to the thyroid gland. IL-δ exhibits anti-tumor properties in breast cancer, neuroblastoma, glioblastoma, melanoma and lung carcinoma cells suggesting that IL-δ could be used as a chemotherapeutic agent. Moreover in a colon cancer cell line (HT-29), IL-δ induced cell death, and this effect was mediated by reactive oxygen species (ROS) generation. The aim of the present study was to analyze the sources of reactive oxygen species induced by IL-δ and to explore the contribution of ROS induced by IL-δ on cell proliferation and apoptosis.Methodology and resultsCancer thyroid follicular (WRO) and papilar (TPC-1) cells lines were treated with IL-δ. Proliferation and apoptosis was analyzed. IL-δ caused a significant loss of cell viability on WRO and TPC-1 cells in a concentration dependent manner and induced apoptosis after 3 h of treatment. Furthermore, IL-δ (10 μM) increased ROS production (39% WRO and 20% TPC-1). The concomitant treatment of WRO and TPC-1 cells with Trolox or NAC plus IL-δ abrogated the augment of ROS induced by IL-δ exposure. Additionally Trolox and NAC reversed the effect of IL-δ on cell proliferation and apoptosis. Only in WRO cells IL-δ upregulates NADPH oxidase NOX4 expression, and siRNA targeted knock-down of NOX4 attenuates ROS production, apoptosis (p < 0.05) and the inhibitory effect of IL-δ on cell proliferation and PCNA expression (p < 0.05).ConclusionsThe antiproliferative and pro-apoptotic effect of IL-δ is mediated by different mechanisms and pathway involving different sources of ROS generation depending on the cellular context.

Graphical abstract

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Mathematical modeling of gonadotropin-releasing hormone signaling

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): George Fink




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Retraction notice to: "Role of Mammalian sirtuin 1 (SIRT1) in lipids metabolism and cell proliferation of goose primary hepatocytes" MCE Volume 382, Issue 1, 25 January 2014, Pages 282-291

Publication date: 15 July 2018
Source:Molecular and Cellular Endocrinology, Volume 470
Author(s): Chunchun Han, Huofu Wan, Shuang Ma, Dandan Liu, Fang He, Jiwen Wang, Zhixiong Pan, Hehe Liu, Liang Li, Hua He, Hongyong Xu, Shouhai Wei, Feng Xu




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Editorial - Endocrine Tumor

Publication date: 5 July 2018
Source:Molecular and Cellular Endocrinology, Volume 469
Author(s): Shioko Kimura, Anthony Glover




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MENIN loss as a tissue-specific driver of tumorigenesis

Publication date: 5 July 2018
Source:Molecular and Cellular Endocrinology, Volume 469
Author(s): Janet W.Y. Li, Xianxin Hua, Diane Reidy-Lagunes, Brian R. Untch
The MEN1 gene encodes MENIN, a tumor suppressor that plays a role in multiple cellular processes. Germline and somatic mutations in MEN1 have been identified in hereditary and sporadic tumors of neuroendocrine origins suggesting context-specific functions. In this review, we focus on the development of mutational Men1 in vivo models, the known cellular activities of MENIN and efforts to identify vulnerabilities in tumors with MENIN loss.



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Editorial Board

Publication date: 15 June 2018
Source:Molecular and Cellular Endocrinology, Volume 468





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Targeting RAW 264.7 macrophages (M1 type) with Withaferin-A decorated mannosylated liposomes induces repolarization via downregulation of NF-κB and controlled elevation of STAT-3

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Manoj Kumar Neog, Farhath Sultana, Mahaboobkhan Rasool
In the present study, we intend to gain an insight into the mechanism of Withaferin-A (WA), a steroidal lactone with reference to repolarization of RAW 264.7 macrophages (M1 to M2 type). We found that successful internalization of WA via mannosylated liposomal delivery system (ML-WA) reduced the RAW 264.7 macrophage (M1) mediated pro-inflammatory cytokines (IL-1β, IL-6, IL-23, and TNF-α) through the attenuation of transcription factor NF-κB-p65 expression. Whereas, ML-WA treatment induced a controlled upregulation of p-STAT3, and ablated the key oxidative stress markers (NO, iNOS, and ROS) in M1 → M2 RAW 264.7 macrophage repolarization, which suggested the recalibration of M1 macrophage metabolic function. Further, the elevated expression of M2 macrophage associated CD163 over the M1 macrophage related CD86 concluded that ML-WA induces an anti-inflammatory response by repolarizing the M1 → M2 RAW 264.7 macrophage.



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Predicted miRNA-mRNA-mediated posttranscriptional control associated with differences in cervical and thoracic thymus function

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Amanda F. Assis, Jie Li, Paula B. Donate, Janaína A. Dernowsek, Nancy R. Manley, Geraldo A. Passos
A secondary cervical thymus (CT) is present in the neck region in about 50% of human and mice. CT in mice is an independent and functional organ, which can be colonized by T lymphocyte progenitors and generate thymocytes that are selected by the T cell receptor repertoire following the positive and negative selection. However, CT and the main thoracic thymus (TT) have been shown in mice to have significant functional differences. In this study, we use transcriptional profiling to compare mRNA or miRNAs expression patterns in murine CT and TT. We used these data to perform functional enrichment of the expression signatures and reconstruction of posttranscriptional miRNA-mRNA interaction networks. For this purpose, we compared the transcriptome profiling of paired RNA samples of whole CTs, TTs and parathyroid gland (PT), which was used as an external group, from Foxn1-GFP;Pth-Cre;R26dTomato transgenic mice that differentially label CT and TT. As expected, CT and TT featured comprehensive transcriptome similarity and this suggests that these organs are subjected to correlated transcriptional control. Nevertheless, significant differences were also observed between TT and CT, characterized by 107 differentially expressed (DE) mRNAs, and in 13 DE miRNAs, that in turn established interactions. These results suggest that functional similarity between TT and CT is reflected in their transcriptional activity and that CT functional uniqueness might be under posttranscriptional control.



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Genomic organization and adaptive evolution of IGHC genes in marine mammals

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Lili Li, Xinghua Rong, Guiting Li, Yingying Wang, Bingyao Chen, Wenhua Ren, Guang Yang, Shixia Xu
Immunoglobulins are important elements of the adaptive immune system that bind to an immense variety of microbial antigens to neutralize infectivity and specify effector functions. In the present study, the immunoglobulin heavy chain constant region (IGHC) genes from marine mammals were identified and compared with those of their terrestrial relatives to explore their genomic organization and evolutionary characteristics. The genomic organization of marine mammal IGHC genes was shown to be conservative with other eutherian mammals. Stronger signals of positive selection on IGHC were revealed in terrestrial mammals than that in marine mammals with the branch-site model, displaying different selective pressure, which might suggest their divergent adaptations to contrasted environments.



https://ift.tt/2KX4Olx

Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Yi Li, Haitao Li, Shuai Liu, Pinhua Pan, Xiaoli Su, Hongyi Tan, Dongdong Wu, Lemeng Zhang, Chao Song, Minhui Dai, Qian Li, Zhi Mao, Yuan Long, Yongbin Hu, Chengping Hu
Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema.Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1β, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1β and TGF-β1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1β maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1β in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1β secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients.



https://ift.tt/2LA7whZ

TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Gang Chi, Xin-Xia Feng, Ying-Xia Ru, Ting Xiong, Yuan Gao, Han Wang, Zhen-Long Luo, Ran Mo, Fang Guo, Yong-Pei He, Gui-Mei Zhang, De-An Tian, Zuo-Hua Feng
Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl4) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4⁺CD25⁺ Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl4/CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.



https://ift.tt/2KVtNpw

Polyglutamine binding protein 1 (PQBP1) inhibits innate immune responses to cytosolic DNA

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Jessica L. Shannon, Molly S. Murphy, Uma Kantheti, Jordan M. Burnett, Marina G. Hahn, Tyler J. Dorrity, Constantinos J. Bacas, Ethan B. Mattice, Kathryna D. Corpuz, Brianne R. Barker
Recent studies have highlighted the importance of immune sensing of cytosolic DNA of both pathogen and host origin. We aimed to examine the role of DNA sensors interferon-γ-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) in responding to cytosolic DNA. We show IFI16 and cGAS can synergistically induce IFNb transcriptional activity in response to cytoplasmic DNA. We also examined the role of polyglutamine binding protein 1 (PQBP1), a protein predominantly expressed in lymphoid and myeloid cells that has been shown to lead to type I interferon production in response to retroviral infection. We show PQBP1 associates with cGAS and IFI16 in THP-1 cells. Unexpectedly, knockout of PQBP1 in THP-1 cells causes significantly increased type I IFN production in response to transfected cytosolic nucleic acids or DNA damage, unlike what is seen in response to retroviral infection. Overexpression of PQBP1 in HEK293 T cells impairs IFI16/cGAS-induced IFNb transcriptional activity. In human cancer patients, low expression of PQBP1 is correlated with improved survival, the opposite correlation of that seen with cGAS or IFI16 expression. Our findings suggest that PQBP1 inhibits IFI16/cGAS-induced signaling in response to cytosolic DNA, in contrast to the role of this protein in response to retroviral infection.

Graphical abstract

https://ift.tt/2LA7iHF

Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Karthik Chandiran, Rebecca Lawlor, Antonio Pannuti, Gabriela Gonzalez Perez, Janani Srinivasan, Todd E. Golde, Lucio Miele, Barbara A. Osborne, Lisa M. Minter
The transmembrane receptor, Notch1 plays an important role during the differentiation of CD4 T cells into T helper (Th) subsets in the presence of appropriate cytokines, including differentiation into Th1 cells. MicroRNAs have also been shown to be important regulators of immune responses, including negatively regulating cytokine production by Th1 cells. The miR-29 family of microRNAs can act to inhibit tbx21 and ifng transcription, two important pro-inflammatory genes that are abundantly expressed in Th1 cells. Here we show that Notch1 may prime CD4 T cells to be responsive to Th1-polarizing cues through its early repressive effects on the miR-29 family of microRNAs. Using a combination of cell lines and primary cells, we demonstrate that Notch1 can repress miR-29a, miR-29b, and miR-29c transcription through a mechanism that is independent of NF-κB. We further show that this repression is mediated by canonical Notch signaling and requires active Mastermind like (MAML) 1, but this process is superseded by positive regulation of miR-29 in response to IFNγ at later stages of CD4 T cell activation and differentiation. Collectively, our data suggest an additional mechanism by which Notch1 signaling may fine-tune Th1 cell differentiation.

Graphical abstract

https://ift.tt/2KWhx88

Predicted miRNA-mRNA-mediated posttranscriptional control associated with differences in cervical and thoracic thymus function

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Amanda F. Assis, Jie Li, Paula B. Donate, Janaína A. Dernowsek, Nancy R. Manley, Geraldo A. Passos
A secondary cervical thymus (CT) is present in the neck region in about 50% of human and mice. CT in mice is an independent and functional organ, which can be colonized by T lymphocyte progenitors and generate thymocytes that are selected by the T cell receptor repertoire following the positive and negative selection. However, CT and the main thoracic thymus (TT) have been shown in mice to have significant functional differences. In this study, we use transcriptional profiling to compare mRNA or miRNAs expression patterns in murine CT and TT. We used these data to perform functional enrichment of the expression signatures and reconstruction of posttranscriptional miRNA-mRNA interaction networks. For this purpose, we compared the transcriptome profiling of paired RNA samples of whole CTs, TTs and parathyroid gland (PT), which was used as an external group, from Foxn1-GFP;Pth-Cre;R26dTomato transgenic mice that differentially label CT and TT. As expected, CT and TT featured comprehensive transcriptome similarity and this suggests that these organs are subjected to correlated transcriptional control. Nevertheless, significant differences were also observed between TT and CT, characterized by 107 differentially expressed (DE) mRNAs, and in 13 DE miRNAs, that in turn established interactions. These results suggest that functional similarity between TT and CT is reflected in their transcriptional activity and that CT functional uniqueness might be under posttranscriptional control.



https://ift.tt/2LzHvQ0

Genomic organization and adaptive evolution of IGHC genes in marine mammals

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Lili Li, Xinghua Rong, Guiting Li, Yingying Wang, Bingyao Chen, Wenhua Ren, Guang Yang, Shixia Xu
Immunoglobulins are important elements of the adaptive immune system that bind to an immense variety of microbial antigens to neutralize infectivity and specify effector functions. In the present study, the immunoglobulin heavy chain constant region (IGHC) genes from marine mammals were identified and compared with those of their terrestrial relatives to explore their genomic organization and evolutionary characteristics. The genomic organization of marine mammal IGHC genes was shown to be conservative with other eutherian mammals. Stronger signals of positive selection on IGHC were revealed in terrestrial mammals than that in marine mammals with the branch-site model, displaying different selective pressure, which might suggest their divergent adaptations to contrasted environments.



https://ift.tt/2KX4Olx

Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3 inflammasome activation

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Yi Li, Haitao Li, Shuai Liu, Pinhua Pan, Xiaoli Su, Hongyi Tan, Dongdong Wu, Lemeng Zhang, Chao Song, Minhui Dai, Qian Li, Zhi Mao, Yuan Long, Yongbin Hu, Chengping Hu
Acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by its acute onset, diffuse alveolar damage, intractable hypoxemia, and non-cardiogenic pulmonary edema.Acute lung injury(ALI) can trigger persistent lung inflammation and fibrosis through activation of the NLRP3 inflammasome and subsequent secretion of mature IL-1β, suggesting that the NLRP3 inflammasome is a potential therapeutic target for ALI, for which new therapeutic approaches are needed. Our present study aims to assess whether pirfenidone,with anti-fibrotic and anti-inflammatory properties, can improve LPS-induced inflammation and fibrosis by inhibiting NLRP3 inflammasome activation. Male C57BL/6 J mice were intratracheally injected with LPS to induce ALI. Mice were administered pirfenidone by oral gavage throughout the entire experimental course. The mouse macrophage cell line (J774 A.1) was incubated with LPS and ATP, with or without PFD pre-treatment. We demonstrated that PFD remarkably ameliorated LPS-induced pulmonary inflammation and fibrosis and reduced IL-1β and TGF-β1 levels in bronchoalveolar lavage fluid(BALF). Pirfenidone substantially reduced NLRP3 and ASC expression and inhibited caspase-1 activation and IL-1β maturation in lung tissues. In vitro, the experiments revealed that PFD significantly suppressed LPS/ATP-induced production of reactive oxygen species (ROS) and decreased caspase-1 activation and the level of IL-1β in J774 A.1 cells. Taken together, the administration of PFD reduced LPS-induced lung inflammation and fibrosis by blocking NLRP3 inflammasome activation and subsequent IL-1β secretion. These findings indicated that PFD can down-regulate NLRP3 inflammasome activation and that it may offer a promising therapeutic approach for ARDS patients.



https://ift.tt/2LA7whZ

TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Gang Chi, Xin-Xia Feng, Ying-Xia Ru, Ting Xiong, Yuan Gao, Han Wang, Zhen-Long Luo, Ran Mo, Fang Guo, Yong-Pei He, Gui-Mei Zhang, De-An Tian, Zuo-Hua Feng
Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl4) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4⁺CD25⁺ Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl4/CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.



https://ift.tt/2KVtNpw

Polyglutamine binding protein 1 (PQBP1) inhibits innate immune responses to cytosolic DNA

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Jessica L. Shannon, Molly S. Murphy, Uma Kantheti, Jordan M. Burnett, Marina G. Hahn, Tyler J. Dorrity, Constantinos J. Bacas, Ethan B. Mattice, Kathryna D. Corpuz, Brianne R. Barker
Recent studies have highlighted the importance of immune sensing of cytosolic DNA of both pathogen and host origin. We aimed to examine the role of DNA sensors interferon-γ-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) in responding to cytosolic DNA. We show IFI16 and cGAS can synergistically induce IFNb transcriptional activity in response to cytoplasmic DNA. We also examined the role of polyglutamine binding protein 1 (PQBP1), a protein predominantly expressed in lymphoid and myeloid cells that has been shown to lead to type I interferon production in response to retroviral infection. We show PQBP1 associates with cGAS and IFI16 in THP-1 cells. Unexpectedly, knockout of PQBP1 in THP-1 cells causes significantly increased type I IFN production in response to transfected cytosolic nucleic acids or DNA damage, unlike what is seen in response to retroviral infection. Overexpression of PQBP1 in HEK293 T cells impairs IFI16/cGAS-induced IFNb transcriptional activity. In human cancer patients, low expression of PQBP1 is correlated with improved survival, the opposite correlation of that seen with cGAS or IFI16 expression. Our findings suggest that PQBP1 inhibits IFI16/cGAS-induced signaling in response to cytosolic DNA, in contrast to the role of this protein in response to retroviral infection.

Graphical abstract

https://ift.tt/2LA7iHF

Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Karthik Chandiran, Rebecca Lawlor, Antonio Pannuti, Gabriela Gonzalez Perez, Janani Srinivasan, Todd E. Golde, Lucio Miele, Barbara A. Osborne, Lisa M. Minter
The transmembrane receptor, Notch1 plays an important role during the differentiation of CD4 T cells into T helper (Th) subsets in the presence of appropriate cytokines, including differentiation into Th1 cells. MicroRNAs have also been shown to be important regulators of immune responses, including negatively regulating cytokine production by Th1 cells. The miR-29 family of microRNAs can act to inhibit tbx21 and ifng transcription, two important pro-inflammatory genes that are abundantly expressed in Th1 cells. Here we show that Notch1 may prime CD4 T cells to be responsive to Th1-polarizing cues through its early repressive effects on the miR-29 family of microRNAs. Using a combination of cell lines and primary cells, we demonstrate that Notch1 can repress miR-29a, miR-29b, and miR-29c transcription through a mechanism that is independent of NF-κB. We further show that this repression is mediated by canonical Notch signaling and requires active Mastermind like (MAML) 1, but this process is superseded by positive regulation of miR-29 in response to IFNγ at later stages of CD4 T cell activation and differentiation. Collectively, our data suggest an additional mechanism by which Notch1 signaling may fine-tune Th1 cell differentiation.

Graphical abstract

https://ift.tt/2KWhx88

Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hidenobu Murafuji, Hajime Sugawara, Megumi Goto, Yoshiaki Oyama, Hiroki Sakai, Seiichi Imajo, Toshiyuki Tomoo, Tsuyoshi Muto
A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1–3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (–)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.

Graphical abstract

https://ift.tt/2xhvTxR

Synthesis and hybridizing properties of isoDNAs including 3′-O,4′-C-ethyleneoxy-bridged 5-methyluridine derivatives

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Takashi Osawa, Yuka Hitomi, Sawako Wakita, Han Kim, Yuta Ito, Yoshiyuki Hari
3′,4′-Ethyleneoxy-bridged 5-methyluridine derivatives with methyl groups in the bridge, (R)-Me-3′,4′-EoNA-T and (S)-Me-3′,4′-EoNA-T, were synthesized, and these two analogs and unsubstituted 3′,4′-EoNA-T were successfully incorporated into a 2′,5′-linked oligonucleotide (isoDNA). Their duplex-forming ability with complementary DNA and complementary RNA, and triplex-forming ability with double-stranded DNA, were evaluated by UV-melting experiments. The results indicated that isoDNAs, including these 3′,4′-EoNA analogs, could hybridize exclusively with complementary RNA. In particular, 3′,4′-EoNA-T and (R)-Me-3′,4′-EoNA-T modifications within isoDNA could stabilize the duplexes with complementary RNA compared with unmodified or 3′,4′-BNA-modified isoDNAs.

Graphical abstract

https://ift.tt/2Ly7APA

Rational design of bis-indolylmethane-oxadiazole hybrids as inhibitors of Thymidine phosphorylase

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Muhammad Taha, Umer Rashid, Syahrul Imran, Muhammad Ali
Inhibition of Thymidine phosphorylase (TP) is continuously studied for the design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7-31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC50 value of 3.50±0.01 μM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes.

Graphical abstract

https://ift.tt/2xg3f0b

Developing hybrid molecule therapeutics for diverse enzyme inhibitory action: active role of coumarin-based structural leads in drug discovery

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Aliya Ibrar, Syeda Aaliya Shehzadi, Faiq Saeed, Imtiaz Khan
Hybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin-based compounds with enhanced enzyme inhibitory profile.

Graphical abstract

https://ift.tt/2Ly7ese

Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

Publication date: Available online 26 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Michael Remesic, Giorgia Macedonio, Adriano Mollica, Frank Porreca, Victor Hruby, Yeon Sun Lee
In an effort to improve biphalin's potency and efficacy at the µ-(MOR) and δ-opioid receptors (DOR), a series of cyclic biphalin analogues 1 – 5 with a cystamine or piperazine linker at the C-terminus were designed and synthesized by solution phase synthesis using Boc-chemistry. Interestingly, all of the analogues showed balanced opioid agonist activities at all opioid receptor subtypes due to enhanced κ-opioid receptor (KOR) activity. Our results indicate that C-terminal flexible linkers play an important role in KOR activity compared to that of the other cyclic biphalin analogues with a hydrazine linker. Among them, analogue 5 is a potent (Ki = 0.27, 0.46, and 0.87 nM; EC50 = 3.47, 1.45, and 13.5 nM at MOR, DOR, and KOR, respectively) opioid agonist with high efficacy. Based on the high potency and efficacy at the three opioid receptor subtypes, the ligand is expected to have a potential synergistic effect on relieving pain and further studies including in vivo tests are worthwhile.

Graphical abstract

https://ift.tt/2IRqRto

Persistent 3′-phosphate termini and increased cytotoxicity of radiomimetic DNA double-strand breaks in cells lacking polynucleotide kinase/phosphatase despite presence of an alternative 3′-phosphatase

Publication date: August 2018
Source:DNA Repair, Volume 68
Author(s): Sri Lakshmi Chalasani, Ajinkya S. Kawale, Konstantin Akopiants, Yaping Yu, Mesfin Fanta, Michael Weinfeld, Lawrence F. Povirk
Polynucleotide kinase/phosphatase (PNKP) has been implicated in non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs). To assess the consequences of PNKP deficiency for NHEJ of 3′-phosphate-ended DSBs, PNKP-deficient derivatives of HCT116 and of HeLa cells were generated using CRISPR/CAS9. For both cell lines, PNKP deficiency conferred sensitivity to ionizing radiation as well as to neocarzinostatin (NCS), which specifically induces DSBs bearing protruding 3′-phosphate termini. Moreover, NCS-induced DSBs, detected as 53BP1 foci, were more persistent in PNKP ^−/− HCT116 cells compared to their wild-type (WT) counterparts. Surprisingly, PNKP-deficient whole-cell and nuclear extracts were biochemically competent in removing both protruding and recessed 3′-phosphates from synthetic DSB substrates, albeit much less efficiently than WT extracts, suggesting an alternative 3′-phosphatase. Measurements by ligation-mediated PCR showed that PNKP-deficient HeLa cells contained significantly more 3′-phosphate-terminated and fewer 3′-hydroxyl-terminated DSBs than parental cells 5–15 min after NCS treatment, but this difference disappeared by 1 h. These results suggest that, despite presence of an alternative 3′-phosphatase, loss of PNKP significantly sensitizes cells to 3′-phosphate-terminated DSBs, due to a 3′-dephosphorylation defect.



https://ift.tt/2ISl0UO

Antinuclear antibodies and cancer: A literature review

Publication date: July 2018
Source:Critical Reviews in Oncology/Hematology, Volume 127
Author(s): Alexandru Vlagea, Sandra Falagan, Gerardo Gutiérrez-Gutiérrez, Juan Moreno-Rubio, María Merino, Francisco Zambrana, Enrique Casado, María Sereno
Antinuclear antibodies (ANAs) are a spectrum of autoantibodies targeted to various nuclear and cytoplasmic components of the cells. They are very useful as serological markers for different autoimmune disease, like systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), scleroderma, polymyositis, or mixed connective tissue disease. In these years, an increasing attention has been focussed in the relationship between tumours and autoimmunity. Different authors have demonstrated that ANAs are presented, not only in autoimmune diseases, also in serum of patients with different types of cancers. These data suggested that ANAs could be involved in the pathogenesis of cancer as well as other premalignant disease. In this review, we are going to describe all data reported about the presence of these antibodies in samples from patients with cancer as well as the potential role of some of these proteins in early detection and prognosis.



https://ift.tt/2J9qIF6

The unfolded protein response as a target for anticancer therapeutics

Publication date: July 2018
Source:Critical Reviews in Oncology/Hematology, Volume 127
Author(s): Mengxiong Wang, Mary E. Law, Ronald K. Castellano, Brian K. Law
The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells, responsible for protein synthesis, folding, sorting, and transportation. ER stress is initiated when the unfolded or misfolded protein load exceeds the capacity of the ER to properly fold protein. Tumor microenvironmental conditions, such as nutrient deprivation, hypoxia, and oxidative stress perturb protein folding and trigger chronic ER stress. Cancer cells can tolerate mild ER stress, however, persistent and severe ER stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis, or immunogenic cell death. Based on this rationale, many drugs have been developed for triggering irremediable ER stress in cancer cells by targeting various processes in the secretory pathway. This review discusses the mechanisms of protein targeting to the ER, the key signaling cassettes that are involved in the ER stress response, and their correlation with cancer formation and progression. Importantly, this review discusses current experimental and FDA approved anti-cancer drugs that induce ER stress, and emerging targets within the secretory pathway for the development of new anticancer drugs.



https://ift.tt/2sd0Xcg

Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond

Publication date: July 2018
Source:Cancer Treatment Reviews, Volume 68
Author(s): Jean-Luc Raoul, Masatoshi Kudo, Richard S. Finn, Julien Edeline, Maria Reig, Peter R. Galle
The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.



https://ift.tt/2kuAdAN

Asymptomatic Pulmonary Artery Intimal Sarcoma with Chest Wall Metastasis as an Initial Manifestation: An Autopsy Case

Pulmonary artery intimal sarcoma (PAIS) is a rare mesenchymal malignancy arising in the pulmonary trunk or proximal pulmonary artery and shows intraluminal growth. Clinical manifestations in PAIS are predominantly related to the pulmonary artery embolism, so cases with initial symptoms related to an extrapulmonary metastasis are unusual. The present report describes an 82-year-old man without any cardiopulmonary symptoms who was detected with an abnormal shadow on chest radiography during a routine health checkup. Contrast medium-enhanced chest computed tomography revealed an enhancing mass in the right pulmonary artery, pulmonary nodules, and a chest wall tumor corresponding to the abnormal shadow observed using chest radiography. A core needle biopsy for the chest wall tumor determined a pathological diagnosis of unclassified sarcoma. The patient was diagnosed with PAIS on the basis of clinical, radiological, and pathological correlations. He was scheduled to receive supportive care, but died of respiratory failure 1 year from the first visit. An autopsy revealed the pleomorphic sarcoma occupying the entire lumen of the right pulmonary artery with the only site of extrapulmonary metastasis in the chest wall. We should be aware of rare cases of asymptomatic PAIS found through routine health checkups.

https://ift.tt/2IOpgbV

MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients

Publication date: July 2018
Source:European Journal of Cancer, Volume 98
Author(s): Michael Constantin Kirchberger, Selma Ugurel, Johanna Mangana, Markus Valentin Heppt, Thomas Kurt Eigentler, Carola Berking, Dirk Schadendorf, Gerold Schuler, Reinhard Dummer, Lucie Heinzerling
BackgroundMelanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma.Patients and methodsIn this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%).ResultsPatients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.ConclusionsImmune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.



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Overweight is associated to a better prognosis in metastatic colorectal cancer: A pooled analysis of FFCD trials

Publication date: July 2018
Source:European Journal of Cancer, Volume 98
Author(s): Thomas Aparicio, Michel Ducreux, Roger Faroux, Emilie Barbier, Sylvain Manfredi, Thierry Lecomte, Pierre-Luc Etienne, Laurent Bedenne, Jaafar Bennouna, Jean-Marc Phelip, Eric François, Pierre Michel, Jean-Louis Legoux, Mohamed Gasmi, Gilles Breysacher, Philippe Rougier, Aimery De Gramont, Come Lepage, Olivier Bouché, Jean-François Seitz
BackgroundPrevious studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.Patients and methodsA pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5–24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy.ResultsThe rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991–1999 period) to 41.5% (2000–2006 period) and 44.8% (2007–2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80–0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01–1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87–1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients.ConclusionOverweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.



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Liver–Microbiome Axis in Health and Disease

Publication date: Available online 26 May 2018
Source:Trends in Immunology
Author(s): Timon E. Adolph, Christoph Grander, Alexander R. Moschen, Herbert Tilg
The intestinal and hepatobiliary tract exhibits host-specific commensal colonization. The resident microbiota has emerged as a key player in intestinal and hepatic diseases. Alcoholic and nonalcoholic fatty liver diseases (ALD/NAFLD), primary sclerosing cholangitis (PSC), liver cirrhosis, and some of their clinical complications, such as hepatic encephalopathy (HE), have been linked to a microbial signature, as also observed for severe liver inflammation in alcoholic hepatitis. In turn, the liver impacts, and communicates with, the microbiota through hepatic mediators, such as bile acids or inflammatory signals. Therefore, a liver–microbiome bidirectional crosstalk appears to be critical in health and various liver diseases and could be therapeutically targeted, such as by fecal microbiota transplantation.



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Workflow and efficiency in MRI-based high-dose-rate brachytherapy for cervical cancer in a high-volume brachytherapy center

Publication date: Available online 26 May 2018
Source:Brachytherapy
Author(s): Hayeon Kim, Christopher J. Houser, Ronny Kalash, Carly A. Maceil, Brett Palestra, Deborah Malush, Sushil Beriwal
PurposeWe report the clinical workflow and time required for MRI-based image-guided brachytherapy (MR-IGBT) of cervical cancer patients in a high-volume brachytherapy center with 10 years of experiences to provide a practical guideline for implementing MR-IGBT into clinical use.Methods and MaterialsWe recorded the time and workflow of each procedure step within the 40 consecutive ring and tandem applicator fractions of MR-IGBT by our multidisciplinary team. We divided the entire procedure into four sections based on where the procedure was performed: (1) applicator insertion under sedation, (2) MR imaging, (3) planning, and (4) treatment delivery. In addition, we compared the current procedure time to the initial procedure time when first implementing MR-IGBT in 2007–2008 via a retrospective review.ResultsMean total procedure time was 149.3 min (SD 17.9, ranges 112–178). The multidisciplinary team included an anesthesia team, radiologist, radiation oncologist, nurses, radiation therapists, MRI technicians, dosimetrists, and physicists. The mean procedure time and ranges for each section (min) were as follows: (1) 56.2 (28.0–103.0), (2) 31.0 (19.0–70.0), (3) 44.3 (21.0–104.0), and (4) 17.8 (9.0–34.0). Under current setting, the combined mean procedure time for MR imaging and planning was 63.2 min. In comparison, the same procedure took 137.7 min in 2007–2008 period, which was significantly longer than the current workflow (p < 0.001).ConclusionsA skilled and dedicated multidisciplinary team is required for an efficient clinical workflow and delivery of MR-IGBT. Over the years, we have improved efficiency with clinical experience and continuous efforts in staff education.



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Removal of heavy metals from aluminum anodic oxidation wastewaters by membrane filtration

Abstract

Aluminum manufacturing has been reported as one of the largest industries and wastewater produced from the aluminum industry may cause significant environmental problems due to variable pH, high heavy metal concentration, conductivity, and organic load. The management of this wastewater with a high pollution load is of great importance for practitioners in the aluminum sector. There are hardly any studies available on membrane treatment of wastewater originated from anodic oxidation. The aim of this study is to evaluate the best treatment and reuse alternative for aluminum industry wastewater using membrane filtration. Additionally, the performance of chemical precipitation, which is the existing treatment used in the aluminum facility, was also compared with membrane filtration. Wastewater originated from anodic oxidation coating process of an aluminum profile manufacturing facility in Kayseri (Turkey) was used in the experiments. The characterization of raw wastewater was in very low pH (e.g., 3) with high aluminum concentration and conductivity values. Membrane experiments were carried out with ultrafiltration (PTUF), nanofiltration (NF270), and reverse osmosis (SW30) membranes with MWCO 5000, 200–400, and 100 Da, respectively. For the chemical precipitation experiments, FeCl₃ and FeSO₄ chemicals presented lower removal performances for aluminum and chromium, which were below 35% at ambient wastewater pH ~ 3. The membrane filtration experimental results show that, both NF and RO membranes tested could effectively remove aluminum, total chromium and nickel (>90%) from the aluminum production wastewater. The RO (SW30) membrane showed a slightly higher performance at 20 bar operating pressure in terms of conductivity removal values (90%) than the NF 270 membrane (87%). Although similar removal performances were observed for heavy metals and conductivity by NF270 and SW30, significantly higher fluxes were obtained in NF270 membrane filtration at any pressure that there were more than three times the flux values in SW30 membrane filtration. Due to the lower heavy metal (<65%) and conductivity (<30%) removal performances of UF membrane, it could be evaluated as pretreatment followed by NF filtration to protect and extend NF membrane life. The water treated by both NF and RO could be recycled back into the process to be reused with economic and environmental benefits.

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The possible effects of anthropogenic acoustic pollution on marine mammals’ reproduction: an emerging threat to animal extinction

Abstract

For about 119 species of cetaceans and other aquatic animals, sound is the key source of learning about the environment, navigation, communication, foraging, and avoiding predators. However, in the recent era, the introduction of large quantities of anthropogenic noise into the ocean has significantly altered the ocean's acoustic environment. The anthropogenic noises travel very long distances, blanketing enormous areas. This can affect cetaceans, either by direct killing or compromising hearing, navigation, communication, predation, as well as normal behaviors. It has been suggested that acoustic pollution could possibly negatively affect cetacean reproduction, which is harmful for endangered and threatened species. However, it is still unknown how acoustic pollution can suppress cetacean reproduction. This is the first comprehensive review article, which focuses on the possible consequences affecting the reproduction of marine mammals resulting from acoustic pollution.

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Characterization of potassium hydroxide modified anthracite particles and enhanced removal of 17α-ethinylestradiol and bisphenol A

Abstract

Anthracite is a natural inorganic-organic hybrid environmentally friendly material, which often is used as a filter medium in water treatment. In this study, we processed anthracite particles using potassium hydroxide (KOH) with different concentrations. The anthracites, before and after treatments, were characterized by Brunauer-Emmett-Teller analysis, scanning electron microscopy, Fourier transform infrared spectrometer, X-ray diffraction, X-ray photoelectron spectroscopy, and Boehm titration. The specific surface area and the amount of total alkalinity of anthracite were 23.73 m² g⁻¹ and 0.38 mmol g⁻¹ (increased by 101 and 217%, respectively) for 4 M KOH treatments, but decreased to 10.09 m² g⁻¹ and 0.12 mmol g⁻¹ for 10 M KOH treatments. We selected 4 M KOH-modified anthracite particles to remove 17α-ethinylestradiol (EE2) and bisphenol A (BPA) from water with unmodified anthracite used in control experiments. The pseudo-second-order model fitted well for the whole adsorption process, and intraparticle diffusion was not the unique rate-controlling step. The equilibrium adsorption data fitted well with the Langmuir-Freundlich model, and the adsorption capacities of EE2 and BPA on anthracite particles after 4 M KOH treatments were 0.7914 and 0.4327 mg g⁻¹ (increased by 138 and 97%, respectively), because the active sites markedly increased. The ligand exchange, hydrogen bonds, and π-π electron donor-acceptor interactions were the main adsorption mechanisms. The 4 M KOH-modified anthracite could be promising in large-scale applications, both as filter medium and adsorbent for organic contaminants.

https://ift.tt/2IQHmKb

Zooplankton sensitivity and phytoplankton regrowth for ballast water treatment with advanced oxidation processes

Abstract

The ballasting and de-ballasting of ships are two necessary operations with ballast water that provide stability for safe navigation. Empty ships must ballast tanks with water, which contains living organisms and subsequently carries them away from their original distribution. De-ballasting represents an input of still viable zooplankton, phytoplankton, and microorganisms in the destination port, leading to the introduction of alien species, and consequently, the introduction of organisms will alter the local biodiversity. Ballast water treatment is necessary to comply with the International Maritime Organization (IMO) for the maximum viable organisms permitted. It is known that UVC eliminates microorganisms, but there are few studies on the other taxonomical groups, such as phytoplankton and zooplankton. The advance oxidation processes (AOPs) with UV-C can be a good alternative to manage the problem of ballast water, primarily for microorganisms. However, for larger organisms, there is more resistance, and, a stage with filtration (by physical filtration or hydrocyclone) is usually required. The filter can fail, or certain zooplankton organisms can escape across the filter and go to the AOPs or UVC reactor. According to the taxonomic group, there can be a different sensitivity to the treatment, and one could survive and generate a risk. The AOPs tested were natural solar radiation (RAD), UV/H₂O₂, UV/TiO₂, UV/TiO₂/H₂O₂, and UV/TiO₂/H₂O₂/RAD. Natural sea water was pumped and treated with the AOPs. The vital zooplankton organisms counted were polychaetes, cladocerans, ostracods, nauplii and calanoid, cyclopoid, and harpacticoid copepods. For the phytoplankton, the abundance was estimated, and the photosystem II efficiency was determined. To evaluate the phytoplankton regrowth after the treatments, the treated water was stored and populations counted for 20 days. The most effective treatment for the zooplankton groups was UVC/H₂O₂. Regarding the sensitivity, the cyclopoid copepods were the most resistant. The nauplii and polychaetes were more likely to be killed by the AOPs, greatly decreasing the risk from nauplii due to their abundance and ease of passing through the filters with their smaller size. Phytoplankton regrowth was observed in all treatments, and it even reached abundance values higher than in the intake water. For instance, additional dark conditions and retreatment on days 3 or 5 are suggested for any treatment.

https://ift.tt/2xpLfkf

Disrupting mating of Lobesia botrana using sex pheromone aerosol devices

Abstract

Pheromone-mediated mating disruption (MD) is widely used as a control tool to manage the European grapevine moth (EGVM), Lobesia botrana. Most of the MD formulations are "passive" reservoir dispensers, which need to be used at a rather large number of units per hectare. A promising alternative is represented by automatic aerosol devices, releasing pheromone puffs at programmed time intervals. Herein, we investigated the effectiveness of MD aerosol product Isonet® L MisterX841 in reducing EGVM infestation on grape in comparison to the reference MD product Isonet® L and the grower's standard. Experiments were carried out over 2 years in two different study sites of Aragon region (Spain). EGVM male catches were monitored using traps baited with the female sex pheromone. The effectiveness of MD formulations against the three generations of EGVM was assessed by determining the percentage of infested bunches and the number of nests per bunch. As expected, a much greater amount of male catches in the grower's standard over Isonet® L MisterX841 and Isonet ® L was observed. No significant differences about EGVM male catches were found in vineyards where Isonet® L MisterX841 and Isonet® L were used. EGVM-infested bunches, as well as number of nests per bunch, were higher in the grower's standard, if compared to vineyards where we tested Isonet® L MisterX841 and Isonet® L. However, the employ of the latter led to a lower EGVM bunch infestation, if compared to Isonet® L MisterX841. Overall, the MD approach proposed here is effective against EGVM. These aerosol devices require a lower number of units per hectare if compared to hand-applied dispensers, saving labor costs and contributing to reduce plastic disposal in agricultural settings.

https://ift.tt/2IN0AAs

Green separation and characterization of fatty acids from solid wastes of leather industry in supercritical fluid CO 2

Abstract

Considerable tannery waste is generated by leather industry around the world. Recovery of the value-added products as natural fats from the solid wastes gained interest of many researchers. In this study, supercritical fluid separation method was applied for the fatty acid isolation from leather industry solid wastes. Pre-fleshing wastes of the double-face lambskins were used as natural fat source. Only supercritical CO₂ was used as process media without any solvent additive in high-pressure view cell equipment. The effect of different conditions was investigated for the best separation influence. The parameters of pressure (100 to 200 bar), temperature (40 to 80 °C), and time (1 to 3 h) were considered. Extraction yields and fat yields of the parameters were statistically evaluated after the processes. Maximum 78.57 wt% fat yield was obtained from leather industry fleshings in supercritical fluid CO₂ at 200 bar, 80 °C, and 2 h. Morever, conventional Soxhlet and supercritical CO₂ extracted fatty acids were characterized by using gas chromatography (GC) coupled with mass spectrometry (MS) and flame ionization detector (FID). Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) characterizations were also done. The results showed that supercritical fluid CO₂ extraction was highly effective for the fat separation as green solvent and leather industry tannery wastes could be used for the value-added products.

https://ift.tt/2IO0bK1

Preparation and characterization of CS/β-CD/Nano-ZnO composite porous membrane optimized by Box-Behnken for the adsorption of Congo red

Abstract

In this paper, an effective chitosan/beta-cyclodextrin/nanometer zinc oxide (CS/β-CD/Nano-ZnO) composite porous membrane was synthesized by sol-gel and polymer-assisted inverting method. Preparation conditions of CS/β-CD/Nano-ZnO were investigated by single-factor and Box-Behnken response surface methodology optimizing triethoxyvinylsilane (JH-V151), beta-cyclodextrin (β-CD), and nanometer zinc oxide (Nano-ZnO), and applied to study the adsorption characteristics of Cong red (CR) from aqueous solution using batch experiments. The optimum preparation conditions were determined that the volume fraction of JH-V151 alcohol solution was 11%, the ratio of β-CD to CS was 5.35, and the ratio of Nano-ZnO's mass to solution's volume was 0.36%. Different characterization methods including field-emission scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, UV-visible spectroscopy, and Universal Materials Tester were used to prove the appearance, crystallinity, functional groups, swelling degree, transmittance, and tensile property of CS/β-CD/Nano-ZnO. The optimized batch experimental parameters were 50 mg L⁻¹, 4 h, 7.0, 0.5 g L⁻¹, and 55.0 °C as initial concentration, contact time, pH, adsorbent dose, and temperature, respectively. The maximum adsorption capacity on CR reached 96.33 mg g⁻¹, which is 4.34 times with respect to CS. The batch experimental data were best described by a pseudo-second-order kinetics model and Langmuir isotherm model (R² = 0.9965, theoretical saturated adsorption capacity 147.28 mg g⁻¹). The values ∆G were − 2.09, − 4.73, and − 7.37 kJ mol⁻¹ at 298, 308, and 318 K temperatures, respectively. The ∆H value was 76.68 kJ mol⁻¹, indicating the endothermic and spontaneous adsorption in nature. The ∆S value was 0.26 kJ mol⁻¹ K⁻¹, a signal of entropy increase during adsorption. The adsorption capacity decreased only by 5.8% after six recycling runs, which indicated the reusability of CS/β-CD/Nano-ZnO. Therefore, the CS/β-CD/Nano-ZnO composite porous membrane is a promising membrane material for the efficient removal of CR from any water at large and economic scales at moderate concentration.

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Long non-coding RNA CASC15 promotes tongue squamous carcinoma progression through targeting miR-33a-5p

Abstract

Long non-coding RNAs (lncRNAs) have gained a lot of attention because they participate in several human disorders, including tumors. This study determined the role of LncRNA CASC15 (cancer susceptibility candidate 15) in the development of tongue squamous cell carcinoma (TSCC). Here, we identified that CASC15 expression was upregulated in TSCC samples and cell lines. We showed that overexpression of CASC15 promoted cell proliferation, cycle, and migration in TSCC. In addition, we revealed that miR-33a-5p expression was downregulated in TSCC tissues and cell lines. Moreover, we showed that the expression of CASC15 was negatively related with miR-33a-5p expression in TSCC tissues. Ectopic expression of miR-33a-5p suppressed cell proliferation, cycle, and migration in TSCC. Elevated expression of CASC15 suppressed miR-33a-5p expression and promoted ZEB1 expression in SCC4 cell. Ectopic expression of CASC15 promoted TSCC cell proliferation, cycle, and migration through targeting miR-33a-5p. These results suggested that lncRNA CASC15 and miR-33a-5p might be exploited as new markers of TSCC and were potential treatment targets for TSCC patients.

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Supercritical carbon dioxide extract of Cinnamomum cassia bark: toxicity and repellency against two stored-product beetle species

Abstract

The extract from Cinnamomum cassia Presl bark was obtained with supercritical CO₂ fluid extraction (SFE). Chemical components of the SFE extract were characterized by GC-MS spectrometry. The repellency and contact toxicity of the SFE extract were evaluated against the adults of Tribolium castaneum and Lasioderma serricorne along with those of its two main compounds. The results of GC-MS analysis indicated that 33 volatile constituents were identified from the extract. The main components included trans-cinnamaldehyde (32.1%), 3,3-dimethylhexane (10.6%) and 2,4-di-tert-butylphenol (7.9%). Testing results showed that the SFE extract had potent contact toxicity against T. castaneum and L. serricorne with LD₅₀ values of 3.96 and 23.89 μg/adult, respectively. LD₅₀ values of trans-cinnamaldehyde against T. castaneum and L. serricorne were 5.78 and 3.24 μg/adult, respectively. Additionally, percentage repellency values of the SFE extract and trans-cinnamaldehyde against T. castaneum and L. serricorne were rather high (PR = 100% and PR > 90%, respectively) at 78.63 and 15.73 nL/cm² at 2 h post-exposure. 2,4-Di-tert-butylphenol showed some repellency against both beetle species. Considering its insecticidal and repellent effects, the SFE extract from C. cassia bark might be used in integrated pest management programs for T. castaneum and L. serricorne.

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Transition to drug co-use among adolescent cannabis users: The role of decision-making and mental health

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Catalina Lopez-Quintero, Karen Granja, Samuel Hawes, Jacqueline C. Duperrouzel, Ileana Pacheco-Colón, Raul Gonzalez
BackgroundCo-use of cannabis and drugs other than cannabis (DOTC) influences the risk of experiencing cannabis disorders. Accordingly, we explored whether speed of transition to drug co-use, the number of DOTC used, and/or being an experimental cannabis-only user, a regular cannabis-only user, or a regular cannabis user who co-uses DOTC (i.e., cannabis-plus user) were associated with decision-making (DM), mental health disorder symptoms, or cannabis use-related characteristics.MethodsWe analyzed baseline data from a sub-sample of 266 adolescent (ages 14 to 16) cannabis users (CU) participating in an ongoing longitudinal study. Assessments included semi-structured interviews, self-report questionnaires, and measures of drug use, DM (measured via the Iowa Gambling Task), mental health disorders, and cannabis use-related problems.ResultsEndorsing a larger number of mood disorders symptoms was associated with being a regular cannabis-plus user rather than a regular cannabis-only user (AOR = 1.08, C.I.95% 1.01, 1.15). Poorer DM was associated with a faster transition to co-use, such that for each one unit increase in DM performance, the years to onset of drug co-use increased by 1% (p = 0.032). Endorsing a larger number of cannabis use-related problems was positively associated with endorsing a larger number of DOTC used (p = 0.001).ConclusionsThis study provides new evidence on the process of drug co-use among CU. Specifically, mood disorder symptoms were associated with use of DOTC among regular CU. Furthermore, poorer DM was associated with a faster transition to drug co-use. Poorer DM and mood disorder symptoms may aggravate or accelerate the onset of adverse consequences among adolescent CU.



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Perceived family relationship quality and use of poly-tobacco products during early and late adolescence

Publication date: October 2018
Source:Addictive Behaviors, Volume 85
Author(s): Tzu Tsun Luk, Man Ping Wang, Lok Tung Leung, Jianjiu Chen, Yongda Wu, Tai Hing Lam, Sai Yin Ho
BackgroundThe role of family relationship in adolescent use of emerging tobacco products, which have become increasingly popular, is unknown. We examined the associations of perceived family relationship quality with current use of poly-tobacco products including cigarettes, electronic cigarettes (e-cigarettes), waterpipe and smokeless tobacco in adolescents.MethodsData from a representative sample of 42,250 US grade 7–12 equivalent students (mean ± SD age 14.6 ± 1.9 years; 51.3% boys) from 75 randomly selected secondary schools in Hong Kong (2012−13) were analysed. Logistic regressions yielded adjusted odds ratios (AORs) for current (past 30-day) use of cigarettes, e-cigarettes, waterpipe, smokeless tobacco and poly-tobacco (≥2 products) in relation to perceived family relationship quality, adjusted for age, sex, perceived family affluence, parental education, family structure, parental and sibling smoking and secondhand smoke exposure at home. Subgroup analyses were conducted to compare the associations in early (aged ≤14 years) versus late (>14) adolescents.ResultsThe odds of current use increased with worse perceived family relationship quality with AORs (95% confidence interval) of up to 2.92 (2.32–3.68) for cigarettes, 7.28 (4.71–11.2) for e-cigarettes, 5.04 (3.44–7.40) for waterpipe, 8.09 (4.87–13.4) for smokeless tobacco and 5.25 (3.45–8.01) for poly-tobacco products use (all P for trend <.001). The associations for all tobacco use outcomes were stronger in early than late adolescents (all P for interaction <.001).ConclusionsDose-response relationships were found between negatively perceived family relationship quality and current poly- and individual tobacco product use by Hong Kong Chinese secondary students. The associations were stronger for alternative tobacco products and in early adolescents.



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Editorial Board

Publication date: September 2018
Source:Addictive Behaviors, Volume 84





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Comparing intrafamilial child sexual abuse and commercial sexual exploitation of children: A systematic literature review on research methods and consequences

Publication date: Available online 26 May 2018
Source:Aggression and Violent Behavior
Author(s): Kelly Selvius, Miriam D.S. Wijkman, Anne-Marie Slotboom, Jan Hendriks
ContextChild sexual abuse is known to have a major negative impact on its victims' lives. Knowledge on the consequences of commercial sexual exploitation of children (CSEC), however, is still relatively unexplored and therefore treatment cannot be tailored for these victims.ObjectivesThis review aims to compare research on consequences of CSEC with those of intrafamilial child sexual abuse (ICSA), with particular attention to the research methods that are used.MethodsThe search on seven databases resulted in 1698 studies. Out of these studies, eighteen studies matched the inclusion criteria and were therefore included in this review. Fourteen studies focused on ICSA and four on CSEC.ResultsThe most notable difference in methodologies was the time between the sexual abuse and interviewing of the victims. This led to a variation in focus of consequences. For ICSA, most studies focused on mental health consequences while for CSEC, the majority focused on physical health consequences, in particular sexually transmitted diseases.ConclusionsFurther research on consequences of CSEC is greatly needed. Longitudinal research should focus on comparing the presence of various consequences (mental health, physical health, sexual behavior and daily functioning) in victims of CSEC, victims of ICSA and a non-sexually abused control-group.



https://ift.tt/2krtGH1

Editorial Board

Publication date: May–June 2018
Source:Aggression and Violent Behavior, Volume 40





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Reduction of the molecular chaperone binding immunoglobulin protein (BiP) accentuates the effect of aging on sleep-wake behavior

Publication date: September 2018
Source:Neurobiology of Aging, Volume 69
Author(s): Nirinjini Naidoo, Jingxu Zhu, Raymond J. Galante, Jie Lian, Ewa Strus, Amy Lee, Brendan T. Keenan, Allan I. Pack
Sleep and wake quality, quantity, and architecture become modified with aging. Sleep and wake quality decline coinciding with increased fragmentation of both states across aging. We have previously shown that this age-related decline in sleep-wake quality is associated with increased endoplasmic reticular (ER) stress and decreased expression of the major ER chaperone binding immunoglobulin protein (BiP). BiP, also known as glucose-regulated protein 78, plays a key role in controlling the cellular response to ER stress, acting as a regulator of a protein homeostatic signaling pathway known as the unfolded protein response. Induction of BiP during cellular stress is part of an adaptive prosurvival mechanism. Here, using mice heterozygous for BiP, we investigated the effect of reduced BiP expression on sleep-wake behavior across aging; complete knockdown of BiP is embryonic lethal. We report that BiP heterozygosity accentuates the aging sleep-wake phenotype. Sleep and wake fragmentation was more pronounced in the BiP heterozygotes across the 3 ages examined. In mice lacking 1 functional copy of BiP, we observed an age-related significant reduction in wake bout duration and increase in wake bout numbers during the active period, as well as an increase in non rapid eye movement and rapid eye movement bout numbers accompanied by reduced bout durations of both non rapid eye movement and rapid eye movement during the sleep period. In addition, we observed increased ER stress in orexin neurons and occurrence of aggregates immunopositive for orexin at the terminals and projections of orexin neurons in the middle-aged BiP heterozygotes. Taken together, our data indicate that a reduction in the molecular chaperone BiP impacts sleep architecture across aging and that orexin processing is likely to be affected.



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