Migraine: Stigma in Society

Abstract

Migraine is a prevalent disease with a substantial socioeconomic impact. However, stigma affects social attitude toward migraine, accruing additional burden on individuals with migraine and isolating them from a society that should be supporting them.

Purpose of this Review

This review will discuss the following concepts: (1) the emergence of stigma toward migraine and its impact on medical care; (2) internalized stigma among those with migraine and its detrimental effect on quality of life and patient-physician relationships; (3) the structural impact of stigma on research funding, workplace support, and specialized care; and (4) strategies for "rebranding" the disease and alleviating stigma toward migraine.

Recent Findings

Recent literature on condition rebranding offers strategies on how to define and communicate migraine to the public.

Summary

Rebranding of migraine to alleviate societal stigma is paramount. This involves use of unified language, education, and advocacy.

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Physiological and comparative proteomic analyses of saline-alkali NaHCO 3 -responses in leaves of halophyte Puccinellia tenuiflora

Abstract

Aims

Soil alkalization imposes severe ion toxicity, osmotic stress, and high pH stress to plants, inhibiting their growth and productivity. NaHCO₃ is a main component of alkaline soil. However, knowledge of the NaHCO₃-responsive proteomic pattern of alkaligrass is still lacking. Alkaligrass (Puccinellia tenuiflora) is a monocotyledonous halophyte pasture widely distributed in the Songnen Plain in Northeastern China. This study aims to investigate the NaHCO₃-responsive molecular mechanisms in the alkaligrass plants.

Methods

An integrative approach including photosynthetic and redox physiology, and comparative proteomics was used.

Results

NaHCO₃ decreased photosynthesis, but increased nonphotochemical quenching, increased membrane electrolyte leakage of alkaligrass, and increased proline and glycine betaine concentrations in leaves. In addition, the NaHCO₃ stress increased Na⁺ concentration and decreased K⁺/Na⁺ ratio in leaves, while Ca²⁺ and Mg²⁺ concentrations were maintained, contributing to signaling and homeostasis of ion and enzyme activity. Furthermore, O₂⁻ generation rate and H₂O₂ concentration were increased, and the activities of ten antioxidant enzymes and antioxidant concentrations were changed in response to the NaHCO₃ stress. Proteomics revealed 90 NaHCO₃-responsive proteins, 54% of which were localized in chloroplasts. They were mainly involved in signaling, photosynthesis, stress and defense, carbohydrate and energy metabolism, as well as protein synthesis, processing and turnover. Some protein abundances did not correlate well with their activities, implying that the enzyme activities were affected by NaHCO₃-induced post-translational modifications.

Conclusions

To cope with the NaHCO₃ stress, alkaligrass deployed multiple strategies, including triggering phospholipase D (PLD)-mediated Ca²⁺ signaling pathways, enhancing diverse reactive oxygen species (ROS) scavenging pathways, and regulating chloroplast protein synthesis and processing.

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Tree size and leaf traits determine the fertility island effect in Prosopis pallida dryland forest in Northern Peru

Abstract

Aims

To assess the fertility island effect of Prosopis pallida in the North Peruvian dry forests and analyze if it is influenced by tree size and structural and/or chemical leaf traits.

Methods

We measured the soil nutrient concentrations under and outside the tree canopy in five populations that differ in mean annual temperature and annual rainfall in North Peru. We also measured tree size (height, stem diameter, and crown area), leaf structure (leaf mass per area (LMA) and leaf dry matter content), and leaf nutrient concentrations (C, N, P, Mn, Fe, Cu, and Zn).

Results

The concentration of most soil nutrients was higher under the P. pallida canopy. Tree size affected positively the soil C, N, and P concentrations, while leaf structural traits such as LMA were negatively related to the soil C, N, and P concentrations. The relationships between the nutrient concentrations in the leaf and soil were only significant for P and Mn. The tree size effect was greater in those populations where the temperature was lower, suggesting the fertility island effect can be increased or weakened by climatic factors.

Conclusions

P. pallida have a significant though limited fertility island effect regulated by plant traits and influenced by climatic factors.

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Strong host specificity of a root hemi-parasite ( Santalum acuminatum ) limits its local distribution: beggars can be choosers

Abstract

Aims

Santalum acuminatum (quandong) is a root hemi-parasite with a very wide distribution across southern Australia. Despite its very wide distribution, along the Jurien Bay chronosequence, it only occurs on the young Quindalup dunes, and it is absent on older dunes. The soils and local vegetation community change across the 10 km chronosequence, with higher species diversity correlated with lower soil phosphorus (P) levels. Here, we aimed to test whether the distribution of quandong on the dune systems can be explained by different neighbours (potential hosts) or different soil P concentrations across the chronosequence.

Methods

Quandongs were grown in pots with 18 potential hosts for a year at three P levels, reflecting conditions across the chronosequence. Hemi-parasite growth and neighbour response were measured through the assessment of biomass, root mass ratios, haustorial size and frequency, δ¹⁵N and δ¹³C isotope signatures, as well as amino acid composition of xylem sap.

Results

Effects of neighbour species on the growth of quandongs were stronger when they were paired with Acacia saligna than when grown with other legumes and non-legumes, indicating strong host specificity. Quandong growth with all other species was significantly less than when grown with A. saligna or without a host, indicating strong competition with a conspecific neighbour. Soil P concentration had little effect on quandong growth.

Conclusion

Host specificity and competition from non-hosts comprise main drivers for the distribution of quandong across the Jurien Bay chronosequence, rather than soil P availability. Our results show the importance of host specificity and how it may restrict the distribution of hemi-parasitic plants in different plant communities along a steep ecological gradient.

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Enhancement of gasworks groundwater remediation by coupling a bio-electrochemical and activated carbon system

Abstract

Here, we show the electrical response, bacterial community, and remediation of hydrocarbon-contaminated groundwater from a gasworks site using a graphite-chambered bio-electrochemical system (BES) that utilizes granular activated carbon (GAC) as both sorption agent and high surface area anode. Our innovative concept is the design of a graphite electrode chamber system rather than a classic non-conductive BES chamber coupled with GAC as part of the BES. The GAC BES is a good candidate as a sustainable remediation technology that provides improved degradation over GAC, and near real-time observation of associated electrical output. The BES chambers were effectively colonized by the bacterial communities from the contaminated groundwater. Principal coordinate analysis (PCoA) of UniFrac Observed Taxonomic Units shows distinct grouping of microbial types that are associated with the presence of GAC, and grouping of microbial types associated with electroactivity. Bacterial community analysis showed that β-proteobacteria (particularly the PAH-degrading Pseudomonadaceae) dominate all the samples. Rhodocyclaceae- and Comamonadaceae-related OTU were observed to increase in BES cells. The GAC BES (99% removal) outperformed the control graphite GAC chamber, as well as a graphite BES and a control chamber both filled with glass beads.

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Binding of Sb(III) by Sb-tolerant Bacillus cereus cell and cell-goethite composite: implications for Sb mobility and fate in soils and sediments

Abstract

Purpose

Adsorption onto mineral and bacterial surfaces can profoundly affect the mobility and fate of dissolved ions in soils; however, currently, there is a poor understanding of antimony (Sb) adsorption onto mixture of these two sorbents. This study aims at investigating the adsorption of Sb(III) to an antimony-tolerant soil bacterium Bacillus cereus and cell-goethite binary composite under anaerobic condition.

Materials and methods

Adsorption isotherms and adsorption edges (pH 3–10) were conducted to explore the adsorption capacity of Sb(III) to goethite, bacteria, and the cell-goethite composite. X-ray photoelectron spectroscopy (XPS) was applied to determine the surface functional groups that are responsible for Sb adsorption.

Results and discussion

Scanning electron microscope shows that nano-particulate goethite is strongly adsorbed onto the cell surfaces to give a mineral film. The cell-goethite composite displays an additive Sb adsorption behavior, i.e., composite adsorptivity is the sum of the individual end-member metal adsorptivities (i.e., the additivity rule). Sb(III) adsorption to goethite, Bacillus cereus cells, and the cell-goethite composite is independent of pH. Using high-resolution XPS spectra, we identify the ferric hydroxyl functional groups of goethite and the carboxyl and amino/amide groups of bacteria responsible for Sb binding to the binary solid products. Moreover, the molecular binding mechanisms are very similar between the composite and the isolated end-member bacteria and mineral phases.

Conclusions

Sb(III) adsorption to the bacteria-goethite conforms to a component-additive rule. Goethite component plays a more important role in Sb binding to the bacteria-mineral composite. New findings of this research suggest that it should be careful to use the universal adsorption rule for cations as previously suggested, to simulate anion adsorption to organo-iron oxide composite.

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Multimodal neuroimaging study reveals dissociable processes between structural and functional networks in patients with subacute intracerebral hemorrhage

Abstract

Emerging evidence has revealed widespread stroke-induced brain dysconnectivity, which leads to abnormal network organization. However, there are apparent discrepancies in dysconnectivity between structural connectivity and functional connectivity studies. In this work, resting-state fMRI and structural diffusion tensor imaging were obtained from 26 patients with subacute (10–14 days) intracerebral hemorrhage (ICH) and 20 matched healthy participants (patients/controls = 21/18 after head motion rejection). Graph theoretical approaches were applied to multimodal brain networks to quantitatively compare topological properties between both groups. Prominent small-world properties were found in the structural and functional brain networks of both groups. However, a significant deficit in global integration was revealed in the structural brain networks of the patient group and was associated with more severe clinical manifestations of ICH. Regarding ICH-related nodal deficits, reduced nodal interconnectivity was mainly detected in motor-related regions. Moreover, in the functional brain network, topological properties were mostly comparable between patients with ICH and healthy participants. Beyond the prominent small-world architecture in multimodal brain networks, there are dissociable alterations between structural and functional brain networks in patients with ICH. These findings highlight the potential for using aberrant network metrics as neural biomarkers for evaluation of the severity of ICH.

Graphical abstract

Intracerebral hemorrhage (ICH) also known as cerebral bleed, a major type of stroke, would significantly affect brain structure and function. Using multimodal neuroimaging, Zhang et al. investigate the ICH-related dysconnectivity in structural and functional brain networks and show a significantly disintegrated structural brain network with a preserved functional network topology in subacute phase (10–14 days).

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Quantifying mode mixing and leakage in multivariate empirical mode decomposition and application in motor imagery–based brain-computer interface system

Abstract

Improper selection of the number and the amplitude of noise channels in noise-assisted multivariate empirical mode decomposition (NA-MEMD) would induce mode mixing and leakage in the obtained intrinsic mode functions (IMF), which would degrade the performance in applications like brain-computer interface (BCI) systems based on motor imagery. A measurement (ML-index) using no prior knowledge of the underlying components of the original signals was proposed to quantify the amount of mode mixing and leakage of IMFs. Both synthetic signals and electroencephalography (EEG) recordings from motor imagery experiments were used to test the validity. The BCI classification performance using NA-MEMD with the optimal parameters selected based on the ML-index was compared with the performance under the non-optimal parameter condition and the performance using the conventional filtering method. Test on synthetic signals demonstrated the ML-index can effectively quantify the amount of mode mixing and leakage, and help to improve the accuracy of extracting the underlying components. Test on EEG recordings showed the BCI classification performance can be significantly improved under the optimal parameter condition. This study provided a method to quantify the amount of mode mixing and leakage in IMFs and realized the optimization of the parameters associated with noise channels in NA-MEMD.

Graphical abstract

One of the synthetic multivariate signals comprised four components oscillating at different rates (middle column). Noise-assisted multivariate empirical mode decomposition (noise-assisted MEMD) was used to extract different components. Mode mixing issue occurred under the non-optimal parameter condition (left column). The issue was alleviated under the optimal parameter condition (right column) which can be obtained with the proposed method in this study.

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Identification and evaluation of novel anchoring proteins for cell surface display on Saccharomyces cerevisiae

Abstract

The development of arming yeast strains as whole-cell biocatalysts involves a selection of effective anchoring proteins to display enzymes and proteins on yeast cell surface. To screen for novel anchoring proteins with improved efficiency, a bioinformatics pipeline for the identification of glycosylphosphatidylinositol-anchored cell wall proteins (GPI-CWPs) suitable for attaching passenger proteins to the cell surface of Saccharomyces cerevisiae has been developed. Here, the C-terminal sequences (CTSs) of putative GPI-CWPs were selected based on the criteria that the sequence must contain a serine/threonine-rich (S/T) region of at least 30% S/T content, a total threonine content of at least 10%, a continuous S/T stretch of at least 130 amino acids in length, and a continuous T-rich region of at least 10 amino acids in length. Of the predicted 790 proteins, 37 putative GPI-CWPs were selected from different yeast and fungal species to be evaluated for their performance in displaying yeast-enhanced green fluorescent protein and β-glucosidase enzyme. This led to the identification of five novel anchoring proteins with higher performance compared to α-agglutinin used as benchmark. In particular, the CTS of uncharacterized protein in Kluyveromyces lactis, namely 6_Kl, is the most efficient anchoring protein of the group. The CTS of 6_Kl protein provided a β-glucosidase activity of up to 23.5 U/g cell dry weight, which is 2.8 times higher than that of the CTS of α-agglutinin. These identified CTSs could be potential novel anchoring protein candidates for construction of efficient arming yeasts for biotechnology applications in the future.

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Using multi-integrated biomarker indexes approach to assess marine quality and health status of marine organism: a case study of Ruditapes philippinarum in Laizhou Bay, China

Abstract

With the progress of technology and the deepening of understanding of biological monitoring, much more attention has been paid to the multiple evaluation of marine pollution monitoring. In view of this, our study aimed at establishing a multi-integrated biomarker indexes approach to evaluate marine condition systematically and comprehensively. In the current study, sampling was conducted in Laizhou Bay, China (S1, S2, and S3) in May, August, and October of 2015. And then, multi-integrated biomarker indexes approach was applied to assess marine PAHs pollution, select appropriate biomarkers, and evaluate marine environmental quality and health status of the clams of Ruditapes philippinarum. As the results showed, S2 was the most PAHs-polluted site while S1 was the least polluted site, and the levels of tPAHs in seawater and sediments ranged from 69.78 to 315.30 ng/L and 163.19 to 565.17 ng/g d.w., respectively. And all three sampling sites had different sources of PAHs. IBR represented DNA damage (F value), the expression of SOD, EROD activity, GST activity, and LPO could be served as biomarkers to monitor the PAHs pollution in Laizhou Bay. And MPI suggested the quality of all three sites: S1 was generally favorable, S2 was moderately polluted, and S3 was lightly polluted. BRI values showed that the order of health status of R. philippinarum was S1 > S3 > S2.

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Prospective Detection of Germline Mutation of Fumarate Hydratase in Women With Uterine Smooth Muscle Tumors Using Pathology-based Screening to Trigger Genetic Counseling for Hereditary Leiomyomatosis Renal Cell Carcinoma Syndrome: A 5-Year Single Institutional Experience

Pathology-based screening of uterine smooth muscle tumors (uSMT) for morphology suggestive of fumarate hydratase deficiency (FH-d morphology) has been proposed as a method to identify women at increased risk for hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome. For 5 years our clinical diagnostic practice has evaluated all women with any type of uSMT for FH-d morphology (defined, at low magnification, as staghorn shaped blood vessels and alveolar pattern edema and, at high magnification, as tumor macronucleoli surrounded by a halo and cytoplasmic eosinophilic globules) and, when present, used the pathology report to advise genetic counseling to further evaluate for HLRCC syndrome. We now report the results of this prospective screening strategy, with emphasis on the incidence and clinicopathologic features of FH-d morphology in uSMT, the rate of patient uptake of referral to genetic counseling, and the results of genetic testing for FH germline mutation. Among 2060 women with a uSMT, FH-d morphology was reported in 1.4% (30 women). Ten women elected to undergo FH genetic testing and 6 of 10 (60%) had a FH germline mutation: 5 were pathogenic mutations and 1 was a mutation variant of unknown significance. Therefore, the screening program led to a confirmed genetic diagnosis of HLRCC syndrome in 0.24% of all women with any type of uSMT. The women with a pathogenic mutation were ages 24 to 40 years. Although the majority of leiomyoma with bizarre nuclei exhibited FH-d morphology, the uSMT were conventional leiomyomas with FH-d morphology in 2 of 5 women found to have a pathogenic FH germline mutation. Relying on an abnormal FH immunostain result to trigger genetic counseling referral would have resulted in 2 of 5 (40%) cases with pathogenic FH germline mutation but normal FH immunoexpression going undetected, both of which were missense type mutations. There was no difference in the incidence of pathogenic FH germline mutation between FH-d morphology uSMT with an abnormal versus a normal FH immunostain result. Overall, this study demonstrates that prospective morphology-based screening, integrated with referral for genetic counseling, can result in the diagnosis of HLRCC syndrome in otherwise unselected women with uSMT. We conclude that this strategy should be incorporated in the routine pathologic examination of all uterine smooth muscle tumors. Conflicts of Interest and Source of Funding: Dr. J.T.R. reports that his spouse receives salary/stock options from Merck & Co. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Joseph T. Rabban, MD, MPH, 1825 4th Street, M-2359, UCSF Pathology Department, San Francisco, CA 94158 (e-mail: joseph.rabban@ucsf.edu). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Orchard management under the effects of climate change: implications for apple, plum, and almond growing

Abstract

The authors analyzed certain species and varieties of fruit tree in which applied crop technology is used and also undergoes the effects of climate change. The aim is to extend productive crop varieties, resistant to disease and pests, in order to obtain superior yields. The research was conducted in orchards located in northwestern Romania (on 8.59 ha), intensively cultivated with apple, plum, and almond species. The blooming period of the species and fruit production was studied in 2009, the first year of the farm's commercial production, and then compared to figures from 2016 to see the changes that occurred. Climatic conditions were studied throughout the period of existence of the farm (2002–2016). To determine the influence of the climatic factor on the blooming and production periods, respectively, every year is considered having pre-blooming, blooming, and ripening periods. It was found that climate change influences the annual biological cycle of the trees: the vegetative rest period of the trees shortens, the tree vegetation begins earlier in the spring, and the blooming period is advanced by as much as 10 days compared to normal cultivated varieties. All these factors have direct repercussions on the quantity of production.

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Comparison of different sequential extraction procedures for mercury fractionation in polluted soils

Abstract

Three sequential extraction procedures (SEPs), modified Tessier, modified BCR, and CIEMAT, were compared for mercury fractionation in polluted soils. With satisfactory total mercury recovery, the modified Tessier and modified BCR SEPs were comparable with each other in terms of extraction efficiency in equivalent mercury fractions, whereas both SEPs were not as efficient as the CIEMAT SEP. However, the CIEMAT SEP might underestimate the oxidizable mercury fractions due to the humic and fulvic complexes instead of the organic matter of the other two SEPs. For mercury bioavailability identification, based on Pearson correlation analysis, all fractions in each SEP were significantly correlated with mercury uptake in Ipomoea aquatica, causing difficulty in comparison. Partial correlation analysis indicated that the mobile mercury fractions extracted by the first step in all three SEPs had a positive correlation with mercury uptake by plant, while mercury bound to organic matter extracted by both modified Tessier and modified BCR SEPs presented negative correlation with mercury uptake by plant which was in contrast to CIEMAT SEP. Meanwhile, clearly positive correlations between mercury fractions extracted by the former three steps of CIEMAT SEP and mercury uptake in Ipomoea aquatica were observed, demonstrating that CIEMAT SEP provided more accurate results related to Hg bioavailability than did the other two SEPs.

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Algae turf scrubber and vertical constructed wetlands combined system for decentralized secondary wastewater treatment

Abstract

Water shortage is a current problem faced by many regions. The deterioration of water bodies driven by the directly discard of untreated wastewater worsens the water shortage and implies in more costly treatments to meet local standards for water quality. In rural areas, the problem is even worse, once conventional centralized treatment plants do not encompass them. Decentralized treatment systems must present low-cost, local availability, standards-meeting efficiency, and simplified operation. The present study examines the combined use of algae turf scrubber and down-flow vertical constructed wetlands for a University's sanitary wastewater treatment. After a hydraulic detention time of 21 days, the unit was able to reach 49%, 48%, 98%, 82%, 99.2%, 70.1%, 44%, 83%, 72%, 86%, 69%, 95%, and 99.9% for conductivity, total soluble solids, turbidity, apparent color, N-NH₃, total nitrogen, P-soluble, total carbon, chemical oxygen demand, inorganic carbon, TOC, Escherichia coli, and total coliforms. In accord to the Brazilian standard ABNT 13969/97, the treated effluent is eligible for reuse in floor and sidewalks washing, garden irrigation, and landscaping purposes.

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Effect of auditory status on visual emotion recognition in adolescents.

Related Articles

Effect of auditory status on visual emotion recognition in adolescents.

Cochlear Implants Int. 2019 Feb 06;:1-11

Authors: Warner-Czyz AD, Evans D, Turkstra L, Scheppele M, Song C, Evans JL

Abstract
Adolescents with severe to profound hearing loss who wear cochlear implants (CIs) experience significantly more peer problems compared to peers with typical hearing (TH). Differences in peer social dynamics may relate to perception not only of message content, but also message intent based on a speaker's emotion from visual (e.g. facial expressions) and auditory (e.g. prosody) cues. Pediatric CI users may experience greater difficulty with auditory emotion recognition due to an impoverished signal representation provided by the device, but the effect of auditory status on visual emotion recognition yields conflicting results.
OBJECTIVES: The current study examined accuracy and speed of visual emotion recognition in adolescents with CIs and peers with TH.
METHODS: Participants included 58 adolescents (10-18 years) stratified by auditory status: 34 CI users and 24 TH peers. Participants identified the intended emotion (i.e. happiness, sadness, anger, fear, disgust, and surprise) of static images of faces displayed on a computer screen.
RESULTS: No significant differences by auditory status emerged for response accuracy, response time to all trials, or response time to correct trials. Type of emotion significantly affected both accuracy and response time.
CONCLUSION: Adolescents with CIs show similar accuracy and response time in recognizing static facial expressions compared to TH peers. Future studies should explore the association between visual emotion recognition and social well-being to determine the relationship between emotion recognition and overall quality of life in adolescents with CIs.

PMID: 30727860 [PubMed - as supplied by publisher]

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Effect of EDTA and NTA on cadmium distribution and translocation in Pennisetum purpureum Schum cv. Mott

Abstract

The primary objective of this research was to investigate the cadmium (Cd) distribution in Pennisetum purpurem (Napier grass) in the presence of 30 mg/L of Cd and different types and concentrations of chelating agents (ethylenediaminetetraacetic acid disodium dihydrate (EDTA), nitrilotriacetic acid (NTA), and EDTA-NTA mixtures). Plant samples were collected every 15 d during a 105-d experimental period. Accumulation of Cd in each part of the plant was determined using atomic absorption spectrometer (AAS), and the distribution of Cd was determined by laser ablation inductively coupled plasma mass spectrometer (LA-ICP-MS) and synchrotron radiation micro X-ray fluorescence (SR-micro-XRF). The highest concentrations of Cd accumulation of 889 ± 53 mg kg⁻¹ in the underground part (roots) and 265 ± 26 mg kg⁻¹ in the aboveground part (stems and leaves) in the presence of 1:1 M ratio of Cd:EDTA after 30 d of exposure were observed. Plants grown in the presence of either NTA or EDTA-NTA mixtures showed significant lower Cd accumulation levels. The LA-ICP-MS analysis showed that Cd was primarily accumulated in the aboveground part (stems and leaves), especially in the xylem and intercalary meristem. In addition, translocation factor was very low. Thus, P. purpurem could be considered as a candidate plant for cadmium phytostabilization.

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Rapid and versatile pre-treatment for quantification of multi-walled carbon nanotubes in the environment using microwave-induced heating

Abstract

The concerns regarding potential environmental release and ecological risks of multi-walled carbon nanotubes (MWCNTs) rise with their increased production and use. As a result, there is the need for an analytical method to determine the environmental concentration of MWCNTs. Although several methods have been demonstrated for the quantification of well-characterized MWCNTs, applying these methods to field samples is still a challenge due to interferences from unknown characteristics of MWCNTs and environmental media. To bridge this gap, a recently developed microwave-induced heating method was investigated for the quantification of MWCNTs in field samples. Our results indicated that the microwave response of MWCNTs was independent of the sources, length, and diameter of MWCNTs; however, the aggregated MWCNTs were not able to convert the microwave energy to heat, making the method inapplicable. Thus, a pre-treatment process for dispersing bundled MWCNTs in field samples was crucial for the use of the microwave method. In the present paper, a two-step pre-treatment procedure was proposed: the aggregated MWCNTs loaded environmental samples were first exposed to high temperature (500 °C) and then dispersed by using an acetone-surfactant solution. A validation study was performed to evaluate the effectiveness of the pre-treatment process, showing that an 80–120% recovery range of true MWCNT loading successfully covered the microwave-measured MWCNT mass.

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Limitations imposed by conventional fine bubble diffusers on the design of a high-loaded membrane bioreactor (HL-MBR)

Abstract

The operation of membrane bioreactors (MBRs) at higher than usual mixed liquor suspended solids (MLSS) concentrations may enhance the loading rate treatment capacity while minimizing even further the system's footprint. This requires operating the MBR at the highest possible MLSS concentration and biomass activity (e.g., at high loading rates and low solid retention times (SRTs)). Both a negative effect of the MLSS concentrations and a positive effect of the SRT on the oxygen transfer have been reported when using conventional fine bubble diffusers. However, most of the evaluations have been carried out either at extremely high SRTs or at low MLSS concentrations eventually underestimating the effects of the MLSS concentration on the oxygen transfer. This research evaluated the current limitations imposed by fine bubble diffusers in the context of the high-loaded MBR (HL-MBR) (i.e., high MLSS and short SRT—the latter emulated by concentrating municipal sludge from a wastewater treatment plant (WWTP) operated at a short SRT of approximately 5 days). The high MLSS concentrations and the short SRT of the original municipal sludge induced a large fraction of mixed liquor volatile suspended solids (MLVSS) in the sludge, promoting a large amount of sludge flocs that eventually accumulated on the surface of the bubbles and reduced the free water content of the suspension. Moreover, the short SRTs at which the original municipal sludge was obtained eventually appear to have promoted the accumulation of surfactants in the sludge mixture. This combination exhibited a detrimental effect on the oxygen transfer. Fine bubble diffusers limit the maximum MLSS concentration for a HL-MBR at 30 g L⁻¹; beyond that point is either not technically or not economically feasible to operate; an optimum MLSS concentration of 20 g L⁻¹ is suggested to maximize the treatment capacity while minimizing the system's footprint.

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Taking the bait: species taking oral rabies vaccine baits intended for raccoons

Abstract

Raccoon rabies in eastern USA is managed by strategically distributing oral rabies vaccine (ORV) baits. The attractiveness, palativity, density, and non-target species bait take affect ORV effectiveness. We examined raccoon and non-target species differences in investigating/removing fish-meal polymer and coated sachet baits applied to simulate two aerial bait distribution densities. Bait densities of 150 baits/km² and 75 baits/km² were evaluated, respectively, in zones expected to have high and low raccoon densities. Three primary non-target species visited baits: coyotes, white-tailed deer, and feral swine. The proportion of bait stations visited by raccoons during 1 week observation periods ranged from 50 to 70%, exceeding non-target species visitation. Raccoon take rates for visited baits averaged from 59 to 100%. Raccoon visitation was similar for both bait densities, indicating a proportionally greater quantity of baits were taken in the higher bait density zone. Coyote visitation rates ranged from 16 to 26%, with take rates for visited baits between 46 and 100%. Coyotes were expected to take baits intended for raccoons, because similar baits are applied to vaccinate coyotes. Deer regularly investigated but rarely took baits. Feral swine were in low abundance in the high bait density zone (higher human density) and visited ≤ 1% of baits there but visited baits at frequencies similar to coyotes and deer in the low-density zone and were likely to take encountered baits (63–100%). Non-target bait consumption could be a concern in some circumstances for achieving sufficient raccoon sero-conversion rates.

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Dramatic decreases of all haemorrhagic coagulation factors by acquired inhibitors after extended left lobectomy.

Related Articles

Dramatic decreases of all haemorrhagic coagulation factors by acquired inhibitors after extended left lobectomy.

Int J Surg Case Rep. 2019 Jan 30;55:140-144

Authors: Sakuraoka Y, Suzuki T, Mtsumoto T, Tanaka G, Shimizu T, Shiraki T, Kyongha P, Mori S, Iso Y, Kato M, Aoki T, Kubota K

Abstract
INTRODUCTION: Acquired inhibition of coagulation factors is a rare disease, and the diagnosis is often difficult and delayed. We experienced a deficiency in all coagulation factors after hepatobiliary surgery.
CASE PRESENTATION: Extended left liver resection was undertaken and hepaticojejunostomy was performed in a 70-year-old man. He had suffered from a high fever caused by cholangitis for 35 days. The major cause was a narrowing of the hepaticojejunostomy, and reconstruction was carried out. Twenty-four days later, there was a sudden massive bleed from his nose and the surgical site. Steroid pulse therapy was used as a treatment because cross mixing and some blood tests revealed the patient was experiencing an inhibition of all coagulation factors, and consequently the levels of coagulation factors dramatically recovered.
DISCUSSION: We considered malignancy and surgical damages to be the underlying cause. The reported treatment and examination will help clinicians explore additional reasons for massive bleeding after a severe physical injury.
CONCLUSION: We have described the first case of acquired inhibition of all coagulation factors associated with extended left lobectomy.

PMID: 30731301 [PubMed - as supplied by publisher]

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Primary hepatic neuroendocrine tumours-Case series of a rare malignancy.

Related Articles

Primary hepatic neuroendocrine tumours-Case series of a rare malignancy.

Int J Surg Case Rep. 2019 Jan 30;55:145-148

Authors: Chen N, Slater K

Abstract
INTRODUCTION: Primary hepatic neuroendocrine tumours (PHNET) were first described by Edmondson et al. in 1958 and are rare, accounting for only 0.3% of all neuroendocrine tumours. Only several hundred cases have been reported.
PRESENTATION OF CASE: We present two cases. The first is a 65-year-old asymptomatic male referred with a liver lesion on ultrasound performed to investigate a mildly elevated Alanine Aminotransferase (ALT). Hepatitis serology and tumour markers were normal. He had an unremarkable colonoscopy and gastroscopy. CT and MRI revealed a single liver lesion adjacent to the gallbladder suspicious for malignancy. He underwent a segment IVb/V liver resection. Histology was consistent with a 65 mm grade 2 PHNET. Subsequent Dotatate PET/CT scans have been normal at 5 years. The second is an asymptomatic 73-year-old male referred with fluctuating hepatic enzymes and a history of alcohol overuse. Imaging revealed a suspicious lesion in segment III of the liver. He underwent a left lateral liver resection. Histology revealed an 18 mm grade 1 PHNET. A subsequent Dotatate PET/CT was normal with no new disease at six months.
DISCUSSION: PHNET, albeit rare are in the differential diagnosis for primary hepatic malignancies. Tumour markers are usually normal and radiological imaging can mimic other hypervascular hepatic tumours. Surgery is the only curative treatment for localised disease to date.
CONCLUSION: PHNET needs to be considered in asymptomatic patients with hypervascular hepatic lesions. More research is required before other adjunct treatment options can be suggested.

PMID: 30731302 [PubMed - as supplied by publisher]

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Solid pseudopapillary neoplasm of the pancreas showing marked distal atrophy: A case report.

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Solid pseudopapillary neoplasm of the pancreas showing marked distal atrophy: A case report.

Int J Surg Case Rep. 2019 Jan 30;55:136-139

Authors: Tsujie M, Wakasa T, Mizuno S, Ishikawa H, Manabe H, Koyama T, Kitani K, Satoi S, Inoue K, Fukuda S, Kawasaki T, Yukawa M, Ohta Y, Inoue M

Abstract
INTRODUCTION: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm, affecting primarily young females. Because SPNs are of low-malignancy, they rarely obstruct the main pancreatic duct (MPD) and cause atrophy of the distal pancreas even if their tumor sizes are large.
PRESENTATION OF CASE: A 35-year-old female was referred to our hospital due to pancreatic tumor. Imaging findings showed the presence of well-defined round tumor in the body of the pancreas with 25-mm in diameter. The pancreas parenchyma distal to the tumor was markedly atrophic, and MPD dilatation was not observed. The lesion was diagnosed as SPN by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), and central pancreatectomy was performed. Intraoperative frozen section of the distal atrophic pancreas showed no evidence of acinar cells, indicating exocrine dysfunction. Therefore, we closed distal pancreas stump instead of reconstruction. In the distal atrophic parenchyma, scattered foci of islets of Langerhans and the vestige of dilated MPD were observed. She has shown neither endocrine nor exocrine insufficiency after surgery.
DISCUSSION: SPNs are usually found without atrophic change of distal pancreas. To the best of our knowledge, this is the first report of SPN in which exocrine dysfunction of atrophic pancreas was demonstrated pathologically and central pancreatectomy without anastomosis of distal pancreas was chosen for the surgical treatment.
CONCLUSION: We reported a very rare case of SPN with marked distal parenchymal atrophy. We successfully performed central pancreatectomy without reconstruction.

PMID: 30731300 [PubMed - as supplied by publisher]

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Jejuno-jejunal intussusception in a post-lung transplant patient from a gastrojejunostomy tube: A case report.

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Jejuno-jejunal intussusception in a post-lung transplant patient from a gastrojejunostomy tube: A case report.

Int J Surg Case Rep. 2019 Jan 31;55:129-131

Authors: Harano T, Sanchez PG, Bauza G, McDyer JF, D'Cunha J

Abstract
INTRODUCTION: Gastro-jejunostomy tube is used for post-pyloric feeding for critical-ill patient who cannot tolerate oral alimentation. Jejuno-jejunal intussusception is a rare complication of gastrojejunostomy tube.
PRESENTATION OF CASE: A 39-year-old male with history of severe combined immunodeficiency, Achalasia and end-stage lung disease underwent double lung transplantation. After lung transplantation, he required gastrojejunostomy(GJ) tube placement due to his esophageal disease. Four days after gastrojejunostomy tube placement, he developed jejuno-jejunal intussusception. A 15 cm segment of thickened and enlarged bowel, which consisted of the intussusception were identified laparoscopically. Surgical reduction was performed without bowel resection.
DISCUSSION: Intussusception is uncommon in adults compared to pediatric population. In this rare case, the jejunal limb of the GJ tube placed in jejunum was the cause of jejunojejunal intussusception serving as the lead point. The GJ tube should not be placed farther down from ligaments of Treiz to prevent jejuno-jejunal intussusception.
CONCLUSIONS: A heightened index of suspicion for this rare complication should exist with a presenting patient has signs of proximal bowel obstruction and CT evidence of intussusception.

PMID: 30731299 [PubMed - as supplied by publisher]

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Adjunctive antimicrobial photodynamic therapy using methylene blue/ethanol formulation in experimental periodontitis in diabetic rats: short-term results

Abstract

The aim of this study was to evaluate the effect of an MB experimental formulation (ethanol 20%) in aPDT used as an adjuvant to scaling and root planing (SRP) in the periodontal treatment of diabetic rats. Forty male Wistar rats received streptozotocin-intraperitonial injections to induce diabetes. After 14 days, 5 animals were allocated in the non-ligate group (NLG), and 35 animals received ligature at the first right mandibular molar to induce periodontitis. After 7 days, the ligature was removed and the animals were randomized into 4 groups: LG (without treatment, n = 5), SRPG (SRP, n = 10), aPDTW (SRP+aPDT-MB/water, n = 10), and aPDTEt (SRP + aPDT-MB/water/ethanol/carboxymethylcellulose, n = 10). Animals were euthanized after 7 days. Data of bone loss (BL) area, degree of inflammatory cell response, and collagen fibers percentages were statistically analyzed (p < 0.05). Percentage of animals that presented mild and severe inflammatory infiltrate was 10% and 40% for SRPG, 20% and 30% for aPDTW, and 50% and 0% for aPDTEt, respectively. BL area (mm²) was statistically higher in the LG (0.39 ± 0.15) than NLG (0.05 ± 0.02). aPDTEt showed the lowest value of BL (0.08 ± 0.03), followed by aPDTW (0.21 ± 0.15) and SRPG (0.31 ± 0.18). Statistical differences were verified between aPDTEt and SRPG. In relation to the LG, aPDTEt, aPDTW, and SRPG recovered the equivalent 80%, 46%, and 20% of the BL. aPDTEt showed collagen content statistically higher than SRPG and LG, and presented higher mean values than NLG (p > 0.05). Our findings showed aPDTEt presented promising results. aPDT using MB/ethanol can have potential as an adjunctive periodontal treatment in diabetics.

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epilepsy treatment; +32 new citations

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Revisiting the Sequence Method for Baroreflex Analysis.

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Revisiting the Sequence Method for Baroreflex Analysis.

Front Neurosci. 2019;13:17

Authors: Silva LEV, Dias DPM, da Silva CAA, Salgado HC, Fazan R

Abstract
The sequence method is an important approach to assess the baroreflex function, mainly because it is based on the spontaneous fluctuations of beat-by-beat arterial pressure (for example, systolic arterial pressure or SAP) and pulse interval (PI). However, some studies revealed that the baroreflex effectiveness index (BEI), calculated through the sequence method, shows an intriguing oscillatory pattern as function of the delay between SAP and PI. It has been hypothesized that this pattern is related to the respiratory influence on SAP and/or PI variability, limiting the SAP ramps to 3 or 4 beats of length. In this study, this hypothesis was tested by assessing the sequence method using raw (original) and filtered series. Results were contrasted to the well-established transfer function, estimated between SAP and PI. Continuous arterial pressure recordings were obtained from healthy rats (N = 61) and beat-by-beat series of SAP and PI were generated. Low-pass (LP) and high-pass (HP) filtered series of SAP and PI were created by filtering the original series with a cutoff frequency of 0.8 Hz. Original series were analyzed by either the sequence method or cross-spectral analysis (transfer function) at low- (LF) and high- (HF) frequency bands, while filtered series were evaluated only by the sequence method. Baroreflex sensitivity (BRS) and BEI of original series, calculated by sequence method, was highly (85-90%) determined by HP series, with no significant association between original and LP series. A high correlation (>0.7) was found between the BRS estimated from original series (sequence method) and HF band (transfer function), as well as for LP series (sequence method) and LF band (transfer function). These findings confirmed the hypothesis that the sequence method quantifies only the high-frequency components of the baroreflex, neglecting the low-frequency influences, such as the Mayer waves. Therefore, we propose using both the original and LP filtered time series for a broader assessment of the baroreflex function using the sequence method.

PMID: 30728765 [PubMed]

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Endovascular treatment of infectious pseudoaneurysm of the internal carotid artery.

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Endovascular treatment of infectious pseudoaneurysm of the internal carotid artery.

World Neurosurg. 2019 Feb 04;:

Authors: OuYang M, Huang X, Wang Y

PMID: 30731201 [PubMed - as supplied by publisher]

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Pharmacotherapeutic options for patients with refractory breast cancer.

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Pharmacotherapeutic options for patients with refractory breast cancer.

Expert Opin Pharmacother. 2019 Feb 07;:1-11

Authors: Fedele P, Ciccarese M, Surico G, Cinieri S

Abstract
INTRODUCTION: The development of resistance to therapy is a concern in all three subtypes of breast cancer (BC). Yet, outcomes of patients with BC have improved in the past few years thanks to a molecularly targeted approach and a greater understanding of the many mechanisms through which cancer cells adapt to evade drug therapies. Indeed, there have been a number of different and active treatment strategies for hormone receptor positive (HR+ and Her2 positive BC although triple-negative breast cancer treatment remains problematical because of the early onset of resistance to treatments and the limited availability of targeted treatment options. Areas covered: Herein, the authors present the various pharmacotherapeutic options for refractory breast cancer including their perspectives on these options. Expert opinion: In recent years, there has been significant progress in our understanding of the biological mechanisms that cause resistance to BC treatments. The targeted therapeutic approach particularly has improved patient outcomes for those with refractory BC, but some unresolved issues still remain. In particular, we need to identify biomarkers of resistance to better tailor treatments, toxicities, and costs. Moreover, we need to determine the best sequence of treatments in refractory BC patients.

PMID: 30730767 [PubMed - as supplied by publisher]

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Specific drug delivery efficiently induced human breast tumor regression using a lipoplex by non-covalent association with anti-tumor antibodies.

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Specific drug delivery efficiently induced human breast tumor regression using a lipoplex by non-covalent association with anti-tumor antibodies.

J Nanobiotechnology. 2019 Feb 06;17(1):25

Authors: Lin YL, Tsai NM, Chen CH, Liu YK, Lee CJ, Chan YL, Wang YS, Chang YC, Lin CH, Huang TH, Wang CC, Chi KH, Liao KW

Abstract
BACKGROUND: A cationic liposome-PEG-PEI complex (LPPC) was employed as a carrier for achieving targeted delivery of drug to human epidermal growth factor receptor-2 (HER2/neu)-expressing breast cancer cells. LPPC can be easily loaded with an anti-tumor drug and non-covalently associated with an anti-tumor antibody such as Herceptin that is clinically used to rapidly form immunoparticles within 1 h.
RESULTS: Drug-loaded LPPC have an average size about 250 nm and a zeta potential of about 40 mV. Herceptin was complexed onto surface of the LPPC to form the drug/LPPC/Herceptin complexes. The size of curcumin/LPPC/Herceptin complexes were 280 nm and the zeta potentials were about 23 mV. Targeting ability of this delivery system was demonstrated through specific binding on surface of cells and IVIS images in vivo, which showed specific binding in HER2-positive SKBR3 cells as compared to HER2-negative Hs578T cells. Only the drug/LPPC/Herceptin complexes displayed dramatically increased the cytotoxic activity in cancer cells. Both in vitro and in vivo results indicated that Herceptin adsorbed on LPPC directed the immunocomplex towards HER2/neu-positive cells but not HER2/neu-negative cells. The complexes with either component (curcumin or doxorubicin) used in the LPPC-delivery system provided a better therapeutic efficacy compared to the drug treatment alone and other treatment groups, including clinical dosages of Herceptin and LipoDox, in a xenografted model.
CONCLUSIONS: LPPC displays important clinical implications by easily introducing a specific targeting characteristic to drugs utilized for breast cancer therapy.

PMID: 30728015 [PubMed - in process]

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miRNA-7a-2-3p Inhibits Neuronal Apoptosis in Oxygen-Glucose Deprivation (OGD) Model.

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miRNA-7a-2-3p Inhibits Neuronal Apoptosis in Oxygen-Glucose Deprivation (OGD) Model.

Front Neurosci. 2019;13:16

Authors: Zhang ZB, Tan YX, Zhao Q, Xiong LL, Liu J, Xu FF, Xu Y, Bobrovskaya L, Zhou XF, Wang TH

Abstract
Neuronal apoptosis is a major pathological hallmark of the neonatal hypoxic-ischemic brain damage (HIBD); however, the role of miR-7a-2-3p in the regulation of HIBD remains unknown. The purpose of this study was to explore the possible roles of miR-7a-2-3p in brain injury using a hypoxia-ischemia model in rats and oxygen-glucose deprivation (OGD) model in vitro. Firstly, we established the hypoxia-ischemia (HI) model and verified the model using Zea Longa scores and MRI in rats. Next, the changes of miR-7a-2-3p were screened in the ischemic cortex of neonatal rats by qRT-PCR at 12, 48, and 96 h after HIBD. We have found that the expression of miR-7a-2-3p in the HI rats decreased significantly, compared with the sham group (P < 0.01). Then, we established the OGD model in PC12 cells, SH-SY5Y cells and primary cortical neurons in vitro and qRT-PCR was used to confirm the changes of miR-7a-2-3p in these cells after the OGD. In order to determine the function of miR-7a-2-3p, PC12 cells, SH-SY5Y cells and rat primary cortical neurons were randomly divided into normal, OGD, mimic negative control (mimic-NC) and miR-7a-2-3p groups. Then, Tuj1+ (neuronal marker) staining, TUNEL assay (to detect apoptotic cells) and MTT assay (to investigate cell viability) were performed. We have found that the number of PC12 cells, SH-SY5Y cells and cortical neurons in the miR-7a-2-3p groups increased significantly (P < 0.01) in comparison to the OGD groups. The survival of cortical neurons in the miR-7a-2-3p group was improved markedly (P < 0.01), while the apoptosis of neurons in the miR-7a-2-3p group was significantly decreased (P < 0.01), compared with the normal group. Lastly, we investigated the target genes of miR-7a-2-3p by using the prediction databases (miRDB, TargetScan, miRWalk, and miRmap) and verified the target genes with qRT-PCR in the HI rats. Bioinformatics prediction showed that Vimentin (VIM), pleiomorphic adenoma gene 1(PLAG1), dual specificity phosphatase 10 (DUSP10), NAD(P)H dehydrogenase, quinone 1 (NQO1) and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) might be the targets of miR-7a-2-3p and the qRT-PCR confirmed that VIM increased in the HI rats (P < 0.01). In conclusion, miR-7a-2-3p plays a crucial role in the hypoxic-ischemic injury, and is associated with regulation of VIM.

PMID: 30728764 [PubMed]

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Maternal Supplementation With Avocado (Persea americana Mill.) Pulp and Oil Alters Reflex Maturation, Physical Development, and Offspring Memory in Rats.

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Maternal Supplementation With Avocado (Persea americana Mill.) Pulp and Oil Alters Reflex Maturation, Physical Development, and Offspring Memory in Rats.

Front Neurosci. 2019;13:9

Authors: de Melo MFFT, Pereira DE, Moura RL, da Silva EB, de Melo FALT, Dias CCQ, Silva MDCA, de Oliveira MEG, Viera VB, Pintado MME, Dos Santos SG, Soares JKB

Abstract
Avocado (Persea americana Mill.) is an oleaginous fruit source of fatty acids with high levels of neuroprotective phytocomplexes. The objective of this study was to evaluate the development of reflex and somatic maturation, fatty acid profiles in the brain, and memory in different stages of life in the offspring of dams supplemented with avocado pulp and oil during gestation and lactation. The dams were randomly divided into three groups (n = 15 pups/group), and recieved by gavage supplementation: control group (CG)-distilled water; Avocado Oil (AO)-3,000 mg avocado oil/kg animal weight, and Avocado Pulp (AP)-3,000 mg avocado pulp/kg animal weight. We performed the following tests: Analysis of Somatic Development and Ontogeny of Postnatal Reflex (T0 to T21), the Open Field Habituation Test and the Object Recognition Test (ORT) in the adolescent (T45) and adult (T90) phases. The cerebral fatty acids content was evaluated at times T0, T21, T45, and T90. The results were analyzed using the statistical program GraphPad Prism and significant statistics were considered when p < 0.05. Acceleration of reflex maturation and reflex ontogeny was observed in the offspring of AO and AP fed dams, with the results being more pronounced in the pulp fed group (p < 0.05). All groups presented a decrease in the ambulation parameter in the second exposure to the Open Field Habituation Test, at T45 and T90 (p < 0.05). In the ORT, the AO and AP offspring presented memory improvements in the short and long term in the adult and adolescent phases (p < 0.05). The results of the brain fatty acid profiles presented higher polyunsaturated fatty acids (PUFA) content in the AO and AP groups at T21, T45, and T90. The docosahexaenoic fatty acid (DHA) content was higher at T21 (AO and AP), at T45 (AO and AP), and at T90 (AP) (p < 0.05). The arachidonic acid (ARA) content was higher at T45 (AO and AP), and at T90 (AO) (p < 0.05). Maternal supplementation with avocado oil and pulp anticipates reflex maturation and somatic postnatal development, and improves memory during the adolescent and adult phases.

PMID: 30728763 [PubMed]

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The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury.

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The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury.

Front Neurosci. 2019;13:07

Authors: Mohamadpour M, Whitney K, Bergold PJ

Abstract
Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4-8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.

PMID: 30728762 [PubMed]

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Corrigendum: Interglial Crosstalk in Obesity-Induced Hypothalamic Inflammation.

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Corrigendum: Interglial Crosstalk in Obesity-Induced Hypothalamic Inflammation.

Front Neurosci. 2019;13:3

Authors: Rahman MH, Kim MS, Lee IK, Yu R, Suk K

Abstract
[This corrects the article DOI: 10.3389/fnins.2018.00939.].

PMID: 30728761 [PubMed - in process]

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Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation.

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Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation.

Front Neurosci. 2018;12:1058

Authors: Carnagarin R, Kiuchi MG, Ho JK, Matthews VB, Schlaich MP

Abstract
The autonomic nervous system (ANS) has a significant influence on the structural integrity and electrical conductivity of the atria. Aberrant activation of the sympathetic nervous system can induce heterogeneous changes with arrhythmogenic potential which can result in atrial tachycardia, atrial tachyarrhythmias and atrial fibrillation (AF). Methods to modulate autonomic activity primarily through reduction of sympathetic outflow reduce the incidence of spontaneous or induced atrial arrhythmias in animal models and humans, suggestive of the potential application of such strategies in the management of AF. In this review we focus on the relationship between the ANS, sympathetic overdrive and the pathophysiology of AF, and the potential of sympathetic neuromodulation in the management of AF. We conclude that sympathetic activity plays an important role in the initiation and maintenance of AF, and modulating ANS function is an important therapeutic approach to improve the management of AF in selected categories of patients. Potential therapeutic applications include pharmacological inhibition with central and peripheral sympatholytic agents and various device based approaches. While the role of the sympathetic nervous system has long been recognized, new developments in science and technology in this field promise exciting prospects for the future.

PMID: 30728760 [PubMed]

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Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication.

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Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication.

Front Neurosci. 2018;12:1035

Authors: Gonçalves CA, Rodrigues L, Bobermin LD, Zanotto C, Vizuete A, Quincozes-Santos A, Souza DO, Leite MC

Abstract
Based on the concept of the tripartite synapse, we have reviewed the role of glucose-derived compounds in glycolytic pathways in astroglial cells. Glucose provides energy and substrate replenishment for brain activity, such as glutamate and lipid synthesis. In addition, glucose metabolism in the astroglial cytoplasm results in products such as lactate, methylglyoxal, and glutathione, which modulate receptors and channels in neurons. Glucose has four potential destinations in neural cells, and it is possible to propose a crossroads in "X" that can be used to describe these four destinations. Glucose-6P can be used either for glycogen synthesis or the pentose phosphate pathway on the left and right arms of the X, respectively. Fructose-6P continues through the glycolysis pathway until pyruvate is formed but can also act as the initial compound in the hexosamine pathway, representing the left and right legs of the X, respectively. We describe each glucose destination and its regulation, indicating the products of these pathways and how they can affect synaptic communication. Extracellular L-lactate, either generated from glucose or from glycogen, binds to HCAR1, a specific receptor that is abundantly localized in perivascular and post-synaptic membranes and regulates synaptic plasticity. Methylglyoxal, a product of a deviation of glycolysis, and its derivative D-lactate are also released by astrocytes and bind to GABAA receptors and HCAR1, respectively. Glutathione, in addition to its antioxidant role, also binds to ionotropic glutamate receptors in the synaptic cleft. Finally, we examined the hexosamine pathway and evaluated the effect of GlcNAc-modification on key proteins that regulate the other glucose destinations.

PMID: 30728759 [PubMed]

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Spontaneous Rectus Sheath Hematoma: An Uncommon Cause of Acute Abdominal Pain.

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Spontaneous Rectus Sheath Hematoma: An Uncommon Cause of Acute Abdominal Pain.

Am J Case Rep. 2019 Feb 07;20:163-166

Authors: Ben Selma A, Genese T

Abstract
BACKGROUND A clinical condition that is often misdiagnosed, rectus sheath hematoma (RSH) is usually seen in the context of blunt abdominal trauma and/or anticoagulation therapy, rarely occurring spontaneously. We present a case of spontaneous rectus sheath hematoma (SRSH) without obvious risk factors and review the literature regarding diagnosis modalities and management. The aim of this case presentation is to highlight this rare clinical condition and emphasize the role of the physical exam in determining the appropriate treatment approach.   CASE REPORT A 50-year-old woman presented to the emergency room with right-sided pelvic pain for one day. Her medical history was specifically notable for recent coughing due to acute bronchitis, as well as the use of NSAIDs. Physical examination revealed marked tenderness in the hypogastric and right lower quadrant, with guarding and fullness in the same area. Laboratory investigation showed mild anemia and normal coagulation tests. Computed tomography demonstrated a right rectus muscle hematoma measuring 8.5×8.5 cm and extending into the lower abdomen and the extraperitoneal space, without active contrast extravasation. Close monitoring of vital signs and hemoglobin hematocrit levels along with supportive care with fluid resuscitation and pain control were initiated and the patient remained stable throughout her hospital stay. CONCLUSIONS Prompt recognition and management of SRSH are crucial. Physical examination is a key part of this process and imaging is the mainstay of diagnosis. Management remains for the most part supportive, although surgery or vascular embolization is required for uncontrolled hematomas with hemodynamic instability.

PMID: 30728345 [PubMed - in process]

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2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma.

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2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma.

Eur J Med Chem. 2019 Jan 22;166:291-303

Authors: Viswanathan A, Kute D, Musa A, Konda Mani S, Sipilä V, Emmert-Streib F, Zubkov FI, Gurbanov AV, Yli-Harja O, Kandhavelu M

Abstract
Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound R234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC50 value ranging 87 μM - 107 μM. Molecular docking simulations of the synthesized compounds into the active site of tyrosine receptor kinase A (TrkA), demonstrated a strong binding affinity with R234 and concurs well with the obtained biological results. R234 was found to be a negative regulator of PI3K/Akt/mTOR pathway and an enhancer of p53 expression. In addition, R234 treated GBM cells exhibited the downregulation of cyclins, cyclin-dependent kinases and other key molecules involved in cell cycle such as CCNE, E2F, CCND, CDK6, indicating that R234 induces cell cycle arrest at G1/S. R234 also exerted its apoptotic effects independent of caspase3/7 activity, in both cell lines. In U87 cells, R234 induced oxidative effects whereas LN229 cells annulled oxidative stress. The study thus concludes that R234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs.

PMID: 30731398 [PubMed - as supplied by publisher]

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Kinase inhibitor library screening identifies synergistic drug combinations effective in sensitive and resistant melanoma cells.

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Kinase inhibitor library screening identifies synergistic drug combinations effective in sensitive and resistant melanoma cells.

J Exp Clin Cancer Res. 2019 Feb 06;38(1):56

Authors: Margue C, Philippidou D, Kozar I, Cesi G, Felten P, Kulms D, Letellier E, Haan C, Kreis S

Abstract
BACKGROUND: Melanoma is the most aggressive and deadly form of skin cancer with increasing case numbers worldwide. The development of inhibitors targeting mutated BRAF (found in around 60% of melanoma patients) has markedly improved overall survival of patients with late-stage tumors, even more so when combined with MEK inhibitors targeting the same signaling pathway. However, invariably patients become resistant to this targeted therapy resulting in rapid progression with treatment-refractory disease. The purpose of this study was the identification of new kinase inhibitors that do not lead to the development of resistance in combination with BRAF inhibitors (BRAFi), or that could be of clinical benefit as a 2nd line treatment for late-stage melanoma patients that have already developed resistance.
METHODS: We have screened a 274-compound kinase inhibitor library in 3 BRAF mutant melanoma cell lines (each one sensitive or made resistant to 2 distinct BRAFi). The screening results were validated by dose-response studies and confirmed the killing efficacies of many kinase inhibitors. Two different tools were applied to investigate and quantify potential synergistic effects of drug combinations: the Chou-Talalay method and the Synergyfinder application. In order to exclude that resistance to the new treatments might occur at later time points, synergistic combinations were administered to fluorescently labelled parental and resistant cells over a period of > 10 weeks.
RESULTS: Eight inhibitors targeting Wee1, Checkpoint kinase 1/2, Aurora kinase, MEK, Polo-like kinase, PI3K and Focal adhesion kinase killed melanoma cells synergistically when combined with a BRAFi. Additionally, combination of a Wee1 and Chk inhibitor showed synergistic killing effects not only on sensitive cell lines, but also on intrinsically BRAFi- and treatment induced-resistant melanoma cells. First in vivo studies confirmed these observations. Interestingly, continuous treatment with several of these drugs, alone or in combination, did not lead to emergence of resistance.
CONCLUSIONS: Here, we have identified new, previously unexplored (in the framework of BRAFi resistance) inhibitors that have an effect not only on sensitive but also on BRAFi-resistant cells. These promising combinations together with the new immunotherapies could be an important step towards improved 1st and 2nd line treatments for late-stage melanoma patients.

PMID: 30728057 [PubMed - in process]

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Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest.

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Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest.

Pharmacology. 2019 Feb 07;103(5-6):250-256

Authors: Usugi E, Ishii K, Hirokawa Y, Kanayama K, Matsuda C, Uchida K, Shiraishi T, Watanabe M

Abstract
BACKGROUND: Pirfenidone (PFD), which is an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis, induces G0/G1 cell cycle arrest in fibroblasts. We hypothesized that PFD-induced G0/G1 cell cycle arrest might be achieved in other types of cells, including cancer cells. Here we investigated the effects of PFD on the proliferation of pancreatic cancer cells (PCCs) in vitro.
METHOD: Human skin fibroblasts ASF-4-1 cells and human prostate stromal cells (PrSC) were used as fibroblasts. PANC-1, MIA PaCa-2, and BxPC-3 cells were used as human PCCs. Cell cycle and apoptosis were analyzed using flow cytometer.
RESULTS: First, we confirmed that PFD suppressed cell proliferation of ASF-4-1 cells and PrSC and induced G0/G1 cell cycle arrest. Under these experimental conditions, PFD also suppressed cell proliferation and induced G0/G1 cell cycle arrest in all PCCs. In PFD-treated PCCs, expression of p21 was increased but that of CDK2 was not clearly decreased. Of note, PFD did not induce significant apoptosis among PCCs.
CONCLUSIONS: These results demonstrated that the antifibrotic agent PFD might have antiproliferative effects on PCCs by inducing G0/G1 cell cycle arrest. This suggests that PFD may target not only fibroblasts but also PCCs in the tumor microenvironment of pancreatic cancer.

PMID: 30731453 [PubMed - as supplied by publisher]

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Genomic and GeneChip Expression Profiling Reveals the Inhibitory Effects of Amorphophalli Rhizoma in TNBC cells.

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Genomic and GeneChip Expression Profiling Reveals the Inhibitory Effects of Amorphophalli Rhizoma in TNBC cells.

J Ethnopharmacol. 2019 Feb 04;:

Authors: Wu C, Chen M, Zhang Q, Yu L, Zhu J, Gao X

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Amorphophalli Rhizoma has been widely used as an adjuvant treatment for advanced or metastatic breast cancer, pancreatic cancer, hepatoma, and malignant lymphoma, but its molecular mechanism of action for treatment of metastatic triple-negative breast cancer (TNBC) is generally poorly understood.
AIM OF THE STUDY: To investigate genomic changes related to the inhibitory effect of Amorphophalli Rhizoma and to elucidate the molecular mechanism of this inhibition in MDA-MB-231 TNBC cells.
MATERIALS AND METHODS: Gene chip analysis was employed to explore genomic changes caused by Amorphophalli Rhizoma in TNBC cells. Potential classical signaling pathways, upstream regulators, functions, regulatory effects and gene interaction networks were analyzed by Ingenuity Pathway Analysis (IPA). Real-time quantitative PCR (RT-qPCR) and RNA interference (RNAi) assays were used to clarify the roles of potential target genes.
RESULTS: In total, 536 significantly upregulated and 648 significantly downregulated genes were identified between the group treated with Amorphophalli Rhizoma extract and that treated with vehicle. Many of these differentially expressed genes (DEGs) in TNBC cells are involved in DNA replication, recombination and repair, the cell cycle, and cellular assembly and organization. Attenuation of KNL1, OLFML2A, RTKN2 and SGO1 gene expression by Amorphophalli Rhizoma significantly induced cell cycle arrest and suppressed cell proliferation and migration.
CONCLUSIONS: The inhibitory effects of Amorphophalli Rhizoma in TNBC cells likely occur through regulation of the spindle checkpoint, chromosomal and centrosomal instability, and cell membrane stability.

PMID: 30731183 [PubMed - as supplied by publisher]

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Involvement of ERK1/2-mediated ELK1/CHOP/DR5 pathway in 6-(methylsulfinyl)hexyl isothiocyanate-induced apoptosis of colorectal cancer cells.

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Involvement of ERK1/2-mediated ELK1/CHOP/DR5 pathway in 6-(methylsulfinyl)hexyl isothiocyanate-induced apoptosis of colorectal cancer cells.

Biosci Biotechnol Biochem. 2019 Feb 07;:1-10

Authors: Yano S, Wu S, Sakao K, Hou DX

Abstract
6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabi. Although 6-MSITC is reported to have cancer chemopreventive activities in rat model, the molecular mechanism is unclear. In this study, we investigated the anticancer mechanisms using two types of human colorectal cancer cells (HCT116 p53+/+ and p53-/-). 6-MSITC caused cell cycle arrest in G2/M phase and induced apoptosis in both types of cells in the same fashion. Signaling data revealed that the activation of ERK1/2, rather than p53, is recruited for 6-MSITC-induced apoptosis. 6-MSITC stimulated ERK1/2 phosphorylation, and then activated ERK1/2 signaling including ELK1 phosphorylation, and upregulation of C/EBP homologous protein (CHOP) and death receptor 5 (DR5). The MEK1/2 inhibitor U0126 blocked all of these molecular events induced by 6-MSITC, and enhanced the cell viability in both types of cells in the same manner. These results indicated that ERK1/2-mediated ELK1/CHOP/DR5 pathway is involved in 6-MSITC-induced apoptosis in colorectal cancer cells. Abbreviations: CHOP: C/EBP homologous protein; DR5: death receptor 5; ELK1: ETS transcription factor; ERK1/2: extracellular signal-regulated kinase 1/2; JNK: Jun-N-terminal kinase; MAPK: mitogen-activated protein kinase; MEK1/2: MAP/ERK kinase 1/2; 6-MSITC: 6-(methylsulfinyl)hexyl isothiocyanate; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP: poly(ADP-ribose) polymerase.

PMID: 30730256 [PubMed - as supplied by publisher]

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PKCβ1 regulates meiotic cell cycle in mouse oocyte.

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PKCβ1 regulates meiotic cell cycle in mouse oocyte.

Cell Cycle. 2019 Feb 07;:1-18

Authors: Yi ZY, Liang QX, Meng TG, Li J, Dong MZ, Hou Y, Ouyang YC, Zhang CH, Schatten H, Sun QY, Qiao J, Qian WP

Abstract
PKCβI, a member of the classical protein kinase C family, plays key roles in regulating cell cycle transition. Here, we report the expression, localization and functions of PKCβI in mouse oocyte meiotic maturation. PKCβI and p-PKCβI (phosphor-PKCβI) were expressed from germinal vesicle (GV) stage to metaphase II (MII) stage. Confocal microscopy revealed that PKCβI was localized in the GV and evenly distributed in the cytoplasm after GV breakdown (GVBD), and it was concentrated at the midbody at telophase in meiotic oocytes. While, p-PKCβI was concentrated at the spindle poles at the metaphase stages and associated with midbody at telophase. Depletion of PKCβI by specific siRNA injection resulted in defective spindles, accompanied with spindle assembly checkpoint activation, metaphase I arrest and failure of first polar body (PB1) extrusion. Live cell imaging analysis also revealed that knockdown of PKCβI resulted in abnormal spindles, misaligned chromosomes, and meiotic arrest of oocytes arrest at the Pro-MI/MI stage. PKCβI depletion did not affect the G2/M transition, but its overexpression delayed the G2/M transition through regulating Cyclin B1 level and Cdc2 activity. Our findings reveal that PKCβI is a critical regulator of meiotic cell cycle progression in oocytes. Abbreviations: PKC, protein kinase C; COC, cumulus-oocyte complexes; GV, germinal vesicle; GVBD, germinal vesicle breakdown; Pro-MI, first pro-metaphase; MI, first metaphase; Tel I, telophase I; MII, second metaphase; PB1, first polar body; SAC, spindle assembly checkpoint.

PMID: 30730241 [PubMed - as supplied by publisher]

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Nanomaterials and microbes' interactions: a contemporary overview.

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Nanomaterials and microbes' interactions: a contemporary overview.

3 Biotech. 2019 Mar;9(3):68

Authors: Singh J, Vishwakarma K, Ramawat N, Rai P, Singh VK, Mishra RK, Kumar V, Tripathi DK, Sharma S

Abstract
Use of nanomaterials in the field of science and technology includes different fields in food industry, medicine, agriculture and cosmetics. Nanoparticle-based sensors have wide range of applications in food industry for identification and detection of chemical contaminants, pathogenic bacteria, toxins and fungal toxins from food materials with high specificity and sensitivity. Nanoparticle-microbe interactions play a significant role in disease treatment in the form of antimicrobial agents. The inhibitory mechanism of nanoparticles against different bacteria and fungi includes release of metal ions that interacts with cellular components through various pathways including reactive oxygen species (ROS) generation, pore formation in cell membranes, cell wall damage, DNA damage, and cell cycle arrest and ultimately inhibits the growth of cells. Nanoparticle-based therapies are growing to study the therapeutic treatments of plant diseases and to prevent the growth of phytopathogens leading to the growing utilization of engineered nanomaterials. Hence, with this background, the present review focuses thoroughly on detailed actions and responses of nanomaterials against different bacteria and fungi as well as food sensing and storage.

PMID: 30729092 [PubMed]

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Upregulated Interleukin 21 Receptor Enhances Proliferation and Epithelial-Mesenchymal Transition Process in Benign Prostatic Hyperplasia.

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Upregulated Interleukin 21 Receptor Enhances Proliferation and Epithelial-Mesenchymal Transition Process in Benign Prostatic Hyperplasia.

Front Endocrinol (Lausanne). 2019;10:4

Authors: Xu D, Chen P, Xiao H, Wang X, DiSanto ME, Zhang X

Abstract
Background: Interleukins (ILs) and related chronic inflammation have been found to contribute to the development of benign prostatic hyperplasia (BPH) in recent decades. As a late member of the ILs family, IL-21 receptor (IL-21R) can modulate cell proliferation, however, IL-21R activity in the prostate has not been examined. The current study aimed to elucidate a potential role of IL-21R in the development of BPH. Material and Methods: Human prostate tissues, cell lines and rats were used. QRT-PCR, Western blot, and immunohistochemistry, along with hematoxylin and eosin, Masson's trichrome, and immunofluorescent staining were performed. BPH-1 cells with IL-21R silenced were cultured or co-cultured with macrophages (active THP-1, AcTHP-1). Apoptosis and cell cycle phases were determined via flow cytometry. Epithelial-mesenchymal transition (EMT) processes were also examined. In vivo, rat prostatitis was induced with intraprostatic injected lipopolysaccharide (LPS). Results: IL-21R was highly expressed in human as well as rat prostate, mainly in the epithelial compartment. BPH concomitant with prostatitis significantly upregulated the expression of IL-21R. Knockdown of IL-21R induced cell apoptosis and cycle arrest at G0/G1 phase, and blocked the EMT process in BPH-1 cells. When IL-21R silenced BPH-1 cells were co-cultured with AcTHP-1 cells, these aforementioned processes and IL-21R change were completely reversed. Prostatic hyperplasia was observed with IL-21R upregulated in LPS induced prostatitis rats. More specifically, the expression of apoptosis, cyclin, and EMT proteins in this rat model are altered in a manner consistent with that seen in the cell line model. Conclusions: Our novel data demonstrates the expression and functional activities of IL-21R in the mechanism for development of BPH. IL-21R mainly localized in prostate epithelium and it was upregulated in hyperplastic prostate tissues. IL-21R enhanced proliferation of BPH-1 cells, via inhibiting cell apoptosis, and modulating cell cycles, as well as the EMT process, in response to inflammatory stimuli.

PMID: 30728806 [PubMed]

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FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression.

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FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression.

Sci Rep. 2019 Feb 06;9(1):1505

Authors: Varghese V, Magnani L, Harada-Shoji N, Mauri F, Szydlo RM, Yao S, Lam EW, Kenny LM

Abstract
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.

PMID: 30728402 [PubMed - in process]

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Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 human breast cancer cells via cell cycle arrest, anti-angiogenesis and induction of apoptosis.

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Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 human breast cancer cells via cell cycle arrest, anti-angiogenesis and induction of apoptosis.

Sci Rep. 2019 Feb 06;9(1):1514

Authors: Razak NA, Abu N, Ho WY, Zamberi NR, Tan SW, Alitheen NB, Long K, Yeap SK

Abstract
Eupatorin has been reported with in vitro cytotoxic effect on several human cancer cells. However, reports on the mode of action and detail mechanism of eupatorin in vitro in breast cancer disease are limited. Hence, eupatorin's effect on the human breast carcinoma cell line MCF-7 and MDA-MB-231 was investigated. MTT assay showed that eupatorin had cytotoxic effects on MCF-7 and MDA-MB-231 cells but was non-toxic to the normal cells of MCF-10a in a time-dose dependent manner. At 24 h, the eupatorin showed mild cytotoxicity on both MCF-7 and MDA-MB-231 cells with IC50 values higher than 20 μg/mL. After 48 h, eupatorin at 5 μg/mL inhibited the proliferation of MCF-7 and MDA-MB-231 cells by 50% while the IC50 of MCF-10a was significantly (p < 0.05) high with 30 μg/mL. The concentration of eupatorin at 5 μg/mL induced apoptosis mainly through intrinsic pathway by facilitating higher fold of caspase 9 compared to caspase 8 at 48 h. The cell cycle profile also showed that eupatorin (5 μg/mL) exerted anti-proliferation activity with the cell cycle arrest of MCF-7 and MDA-MB-231 cells at sub Gθ/G1 in a time-dependent manner. In addition, wound healing assay showed an incomplete wound closure of scratched MDA-MB-231 cells, and more than 60% of the MDA-MB-231 cells were prevented to migrate and invade the membrane in the Boyden chamber after 24 h. Eupatorin also inhibited angiogenic sprouting of new blood vessels in ex vivo mouse aorta ring assay. In gene expression assay, eupatorin up-regulated pro-apoptotic genes such as Bak1, HIF1A, Bax, Bad, cytochrome c and SMAC/Diablo and blocked the Phospho-Akt pathway. In conclusion, eupatorin is a potent candidate to induce apoptosis and concurrently inhibit the invasion, migration and angiogenesis of MDA-MB-231 and MCF-7 cells through inhibition of Phospho-Akt pathway and cell cycle blockade.

PMID: 30728391 [PubMed - in process]

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Human papillomavirus E6/E7 and lncRNA TMPOP2 mutually upregulated gene expression in cervical cancer cells.

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Human papillomavirus E6/E7 and lncRNA TMPOP2 mutually upregulated gene expression in cervical cancer cells.

J Virol. 2019 Feb 06;:

Authors: He H, Liu X, Liu Y, Zhang M, Lai Y, Hao Y, Wang Q, Shi D, Wang N, Luo XG, Ma W, Zhang TC

Abstract
TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remains largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus HPV16/18 E6 and E7 in cervical cancer cell CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53-response elements in the TMPOP2 promoter to repress the transcription of TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor miRNAs miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the lncRNA TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities.IMPORTANCE: Type 16 and type 18 HPVs are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of lncRNAs in cervical cancer although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings to the oncogenic activities of human papillomaviruses and lncRNAs.

PMID: 30728257 [PubMed - as supplied by publisher]

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TES functions as a Mena-dependent tumor suppressor in gastric cancer carcinogenesis and metastasis.

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TES functions as a Mena-dependent tumor suppressor in gastric cancer carcinogenesis and metastasis.

Cancer Commun (Lond). 2019 Feb 06;39(1):3

Authors: Wang DD, Chen YB, Zhao JJ, Zhang XF, Zhu GC, Weng DS, Pan K, Lv L, Pan QZ, Jiang SS, Wang LL, Xia JC

Abstract
BACKGROUND: In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC.
METHODS: We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC.
RESULTS: TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low Mena expression.
CONCLUSIONS: We believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.

PMID: 30728082 [PubMed - in process]

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Long non-coding RNA LINC00346 promotes pancreatic cancer growth and gemcitabine resistance by sponging miR-188-3p to derepress BRD4 expression.

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Long non-coding RNA LINC00346 promotes pancreatic cancer growth and gemcitabine resistance by sponging miR-188-3p to derepress BRD4 expression.

J Exp Clin Cancer Res. 2019 Feb 06;38(1):60

Authors: Shi W, Zhang C, Ning Z, Hua Y, Li Y, Chen L, Liu L, Chen Z, Meng Z

Abstract
BACKGROUND: Long non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. However, its biological function in pancreatic cancer has not yet been determined. In this study, we attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer.
METHODS: The effects of overexpression and knockdown of LINC00346 on the proliferation, cell cycle progression, apoptosis, and gemcitabine resistance were investigated. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation assay were performed to search for potential microRNAs (miRs) that can interact with LINC00346.
RESULTS: Overexpression of LINC00346 significantly enhanced the proliferation, colony formation, and tumorigenesis of pancreatic cancer cells. Conversely, knockdown of LINC00346 suppressed pancreatic cancer cell proliferation and caused a cell-cycle arrest at the G2/M-phase. Depletion of LINC00346 also enhanced gemcitabine sensitivity in pancreatic cancer cells both in vitro and in vivo. Mechanistic investigation revealed that LINC00346 acted as a sponge for miR-188-3p and blocked the repression of BRD4 by miR-188-3p in pancreatic cancer cells. Clinical evidence indicated a negative correlation between LINC00346 and miR-188-3p in pancreatic cancer specimens. Rescue experiments showed that LINC00346 attenuated the growth-suppressing and chemosensitizing effects of miR-188-3p on pancreatic cancer cells. In addition, silencing of BRD4 significantly inhibited LINC00346-induced pancreatic cancer cell proliferation and colony formation.
CONCLUSIONS: LINC00346 shows the ability to promote pancreatic cancer growth and gemcitabine resistance, which is in part mediated by antagonization of miR-188-3p and induction of BRD4. Targeting LINC00346 may improve gemcitabine-based therapeutic efficacy.

PMID: 30728036 [PubMed - in process]

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