Semisynthesis and antibacterial activities of nidulin derivatives
Semisynthesis and antibacterial activities of nidulin derivatives, Published online: 17 December 2018; doi:10.1038/s41429-018-0133-0
Semisynthesis and antibacterial activities of nidulin derivatives
Polymeric cyclodextrin–based nanoparticles are currently undergoing clinical trials as nanotherapeutics. Using a non-covalent approach, we decorated two cross-linked cyclodextrin polymers of different molecular weights with an RGD peptide derivative to construct a novel carrier for the targeted delivery of doxorubicin. RGD is the binding sequence for the integrin receptor family that is highly expressed in tumour tissues. The assembled host–guest systems were investigated using NMR and DLS techniques. We found that, in comparison with free doxorubicin or the binary complex doxorubicin/cyclodextrin polymer, the RGD units decorating the cyclodextrin-based nanosystems improved the selectivity and cytotoxicity of the complexed doxorubicin towards cultured human tumour cell lines. Our results suggest that the nanocarriers under study may contribute to the development of new platforms for cancer therapy.
We examined how legacies of afforestation affect soil food webs using the composition, structure, and diversity of soil nematode communities along a prairie restoration chronosequence.
Vegetation and soil nematode surveys were conducted across a restoration chronosequence of tree removal (2, 5, and 20 years) in a former plantation in Riding Mountain National Park, Canada, established on a Great Plains rough fescue prairie. Nematodes were extracted using sugar-gradient centrifugation, counted and assigned to feeding groups.
Remaining plantation and recently restored prairies were characterized by bacterial feeding nematodes whereas the oldest restored prairie and control prairie were dominated by plant-root feeders. Nematode diversity did not reach the level observed in the prairie even 20 years following the removal of trees. Nematode community diversity and structure was strongly correlated with the composition of restored plant communities. Invasion of restored prairies by exotic grasses corresponded with a strong decline in the diversity of plant-root feeders.
Legacies of afforestation can impact prairie soils years after trees have been removed and can lead to shifts in feeding structure and a loss of diversity in the soil food web. As grasslands continue to decline globally, considering soil faunal communities may help evaluate the outcomes of ecosystem restoration and maintain their key functions.
Litter decomposition is of great concern as it plays a key role in regulating global carbon cycle and nutrient budgets, especially in tropical forests where it is very fast. Therefore, we studied the decomposition and subsequent changes in element concentrations and amounts of 11 tropical leaf litter.
Fresh litters were characterized in terms of elemental, proximate features, as well as organic carbon compositions by 13C-NMR spectroscopy. Controlled litterbag decomposition was carried out for 180 days in the laboratory, bags were retrieved at three dates and analyzed for mass loss and concentration of nitrogen (N), potassium (K), sodium (Na), carbon (C), magnesium (Mg), manganese (Mn), iron (Fe), phosphorus (P), zinc (Zn), and percentage of ash, extractives, cellulose and lignin.
Terminalia arjuna showed highest mass loss, while the lowest was observed in Shorea robusta showing significant positive correlation with litter initial K, Mg, Fe and di-O-alkyl C, O-alkyl C, while significant negative correlation with Mn, lignin and Methoxyl C, Alkyl C. Trajectories shows that Fe, Mg, K, Mn, Zn and Na concentrations increased in most of the litter types, except Terminalia arjuna and Toona ciliata, where Fe, Mg, K concentrations decreased during decomposition. Surprisingly, in most of the species with the exception of Terminalia arjuna, N concentrations decreased at a faster rate than C concentrations, resulting in an increase in C/N ratios. Expectedly, lignin progressively increased, while cellulose decreased.
Observed differences in decomposition rate and dynamics of chemical changes among litters were strongly affected by the litter type, decomposition time and their interactions.
The mean biomass ATP concentration in aerobic soils is around 10–11 μmol ATP g−1 biomass C, within a fairly narrow range. It is much lower in short-term incubated laboratory waterlogged soils. However, the biomass ATP concentration in waterlogged paddy soils under field conditions remains unknown. This is investigated.
Soil microbial biomass C (biomass C), ATP, biomass ATP and heavy metal (Cd, Zn, and Cu) concentrations in soil and rice were measured in a Chinese paddy soil growing rice. Soils and plants were analyzed at day 0, 30, 75 and 90, over the 90 day growing period with inputs of inorganic fertilizer, or biochar and manure singly or in combination.
Both biomass C and ATP concentrations increased, range from 14.9–30.5% for microbial biomass C and 115.8–160.1% for ATP, from initial values until the end of the experiment following manure or biochar addition. An important result was that the biomass ATP concentration increased throughout the growth period. There were also significant negative correlations (p < 0.05) between total and available Cd and these three microbial parameters, despite the low levels of Cd. Over the same period, total plant Cd concentrations increased, and soil Cd decreased. This suggests that the rice acted as a bioaccumulator. The microbial biomass was then in a continually decreasingly toxic environment and responded rapidly by increasing its size.
These results demonstrate clear differences in microbial energy dynamics between aerobic and anaerobic microbial populations. Both ATP and biomass C are useful bioindicators of the effects of cadmium contamination on microbial processes in waterlogged soil.
The endophytic fungus Epichloë bromicola forms mutualistic symbiotic associations with wild barley (Hordeum brevisubulatum) in the saline-alkali areas of northwestern China. E. bromicola enhances the tolerance of H. brevisubulatum to salt stress. Because plant polyamine metabolism is closely related to microbial infection and tolerance to diverse abiotic stresses, we hypothesized that in symbiotic plants polyamine modification may result from E. bromicola infection, and that improved tolerance to abiotic stress by the presence of this endophyte might be related to polyamine modification. Our focus in this study was to investigate whether E. bromicola affects polyamine metabolism in host plants under salt stress.
E. bromicola infected (E+) and endophyte free (E-) wild barley plants were subjected to NaCl treatments (0, 100, 200 and 300 mM). Dry weight, diamine putrescine (Put), triamine spermidine (Spd) and tetramine spermine (Spm) content and the content of their free, soluble conjugated and insoluble bound forms were measured after 21 d exposure to stress.
E. bromicola infection led to significant amelioration of salt stress in H. brevisubulatum. The presence of the endophyte significantly increased dry weight, spermidine and spermine content, but decreased putrescine content and the putrescine: (spermidine + spermine) ratio. E. bromicola infection also lowered the proportion of putrescine in total polyamines, but increased the proportion of spermidine and spermine in total polyamines. Furthermore, E. bromicola infection significantly increased the proportion of insoluble bound forms of polyamines, and decreased the proportion of free forms of polyamines and soluble conjugated forms of polyamines.
H. brevisubulatum salinity stress tolerance induced by E. bromicola infection correlated with enhanced conversion of putrescine to spermidine and spermine, as well as improved shift ability from free forms and soluble conjugated forms of polyamines to insoluble bound forms of polyamines.
We aimed to determine the effect of Piriformospora indica inoculation on maize maximum root growth pressure (σmax) and root elongation rate (ER) over a wide range of water potentials.
The maximum axial force (Fmax) exerted by the P. indica-inoculated and non-inoculated roots of maize (Zea mays L. cv. Maxima) seedlings were measured under control (osmotic potential of zero) and PEG-induced water stress (i.e., osmotic potentials of −0.1, −0.2, −0.3 and − 0.4 MPa) conditions. After measuring root diameter (d), σmax was calculated by dividing the Fmax by the corresponding root cross-sectional area. To test the toxicity of PEG-6000 on root growth, the effect of osmotic potentials induced by PEG-6000 on ER was compared with the corresponding matric potentials in two soils.
The establishment of a mutualistic relationship between maize roots and P. indica exerted a temporary stress on plants leading to greater lag time for force development (Tlag) and the time to reach Fmax (Tmax) in inoculated plants. However, root colonization resulted in greater Fmax, σmax and ER especially under moderate and severe water stresses. Severe water stress decreased σmax, Fmax, d, Tmax and ER.
P. indica inoculation can moderate adverse influences of stressful conditions on growth and elongation of plant roots especially during the initial growth stages by enhancing osmotic adjustment and/or by changing cell wall mechanical characteristics.
Emission of greenhouse gas is a global environmental problem. In recent years, China has been facing growing international pressure because of its large energy consumption and elevated greenhouse gas emissions. As the capital of China, Beijing is central to the study of carbon emission reduction since its carbon emissions have ranked at the forefront nationwide. The existing literature mainly revolves around carbon emissions of a few specific years, and there is a lack of trend study of multiple years in Beijing. This paper, based on the input-output method, calculates carbon emissions in Beijing by carbon footprints; the changing trend analysis was carried out by researching available statistical data of three years, 2002, 2007, and 2012, from the perspective of the entire city of Beijing and from that of urban and rural residents' consumption. The reasons for the changing trends of total carbon emission in Beijing have also been analysed using the Structural Decomposition Analysis (SDA) model. Results show that the total direct carbon footprint as well as the urban and rural direct carbon footprints of residents' consumption in Beijing is all increasing gradually. The direct carbon footprint of urban residents' consumption is mainly produced by electricity, gasoline, and heating power, while that of rural residents' consumption is mainly produced by raw coal and electricity. The indirect carbon footprint of residents' consumption in Beijing is increasing gradually, and that of urban areas is higher than that of rural areas. The compositions of indirect carbon footprints of rural and urban residents' consumption are consistent, and both come mainly from the transportation and communication industry, housing, food, culture, education, entertainment, etc. The SDA results show that the per capita consumption level is the main driving factor for the increase of the indirect carbon footprint of Beijing residents' consumption, and the intensity of CO2 emission is the main inhibiting factor. Finally, suggestions for reducing carbon emissions from urban and rural perspectives have been put forward.
Erosive tooth wear (ETW) has become a crucial oral health problem over the decades in China.
To explore the prevalence and risk indicators of ETW among adolescents in Guangzhou, south China.
A cross‐sectional survey of 720 participants was conducted in Guangzhou, using an equal‐sized, stratified, multistage random sampling approach. The participants were from two different age groups(12‐ and 15‐year‐olds), 360 per group. The ratio of males to females was 1:1 in each group. ETW was recorded utilizing the basic erosive wear examination (BEWE) index as the dependent variable. Independent variables included age, gender, region, socioeconomic status, dietary factors, oral health measures and others.
The prevalence rates (weighted) of ETW and dentin exposure (DE) were 56.1% and 26.2% among adolescents in Guangzhou, with mean teeth (weighted) of 1.8±2.5 and 0.6±1.5, respectively. No matter the prevalence or the mean teeth, the 15‐year‐olds were higher than the 12‐year‐olds; the mean teeth of ETW of males was higher than that of females; the mean teeth of ETW and DE of the adolescents of low socioeconomic status were higher than those of high socioeconomic status. Medium to high risk levels were found for 10.1%. In the multiple regression model, age, gender and taking acidic foods/drinks before sleep were associated with ETW.
Moderate ETW in the permanent dentition was common among adolescents in Guangzhou. However, the teeth involved were low. Dietary factors and demographics were the main risk indicators.
This article is protected by copyright. All rights reserved.
Publication date: Available online 15 December 2018
Source: Cortex
Author(s): Javier Bernacer, Ivan Martinez-Valbuena, Martin Martinez, Nuria Pujol, Elkin Luis, David Ramirez-Castillo, Maria A. Pastor
According to the theory of value-based decision making, subjects tend to choose the most valuable among a set of options. However, agents may not be consistent when facing the same decision several times. In this paper, Shannon's entropy (H) is employed as a measure of behavioral inconsistency: it is a central measure of information theory that, applied to decision making, allows the estimation of behavioral preferences among a set of options. We scanned (functional magnetic resonance imaging, fMRI) 24 young (18-25 year) subjects (14 female) while performing a decision-making task, where monetary rewards were devalued by physical effort (minutes running in the treadmill) and risk. Twenty different pairs of options were presented nine times each, and H was calculated for each pair and subject. Behavioral analyses showed that subjective value (SV) significantly explained agents' preferences only in pairs with a low inconsistent response. Averaged response time positively correlated with H, confirming entropy as an indicator of choice difficulty. Group analyses on fMRI data revealed a cluster in the paracingulate cortex as the neural correlate of H. Besides, BOLD signal in the posterior cingulate correlated with the SV of the pair only in consistent decisions, confirming that SV loses its explanatory power on highly inconsistent decisions. Finally, the anterior and central cingulate were especially recruited when predicting a secured effortless reward, compared with a secured reward that involved a maximum effort. Our study shows that different regions of the cingulate cortex are involved in choice inconsistency, SV and processing effort costs.
Publication date: Available online 15 December 2018
Source: Cortex
Author(s): Joost Heutink, Gera de Haan, Jan-Bernard Marsman, Mart van Dijk, Christina Cordes
Although much research has been devoted to the neural correlates of motion perception, the processing of speed of motion is still a topic of discussion. Apart from patient LM, no in-depth clinical research has been done in the past 20 years on this topic. In the present study, we investigated patient TD, who suffered from the rare disorder akinetopsia due to bilateral lesions of V5 after stroke. By means of a Random-Dot-Kinematogram (RDK) in which speed was varied systematically, it was found that TD was impaired in perceiving the direction of movement at speeds exceeding 9 deg/s. Our study suggests that V5 plays an important role in processing high-speed visual motion and further implies that V5 does not play a crucial role in processing low-speed visual motion. A remarkable finding, which has not been shown before, was that TD always reported the opposite direction of the actual movement at a speed of 24 deg/s. This suggests a form of the continuous wagon wheel illusion, which might have been caused by intact brain areas operating at different sampling rates than area V5.
Publication date: Available online 15 December 2018
Source: Cortex
Author(s): Candice C. Morey
Reports of rare patients who seem to lack the ability to retain certain types of information across brief delays have long sustained the popular idea that newly-perceived verbal, visual, and spatial information is initially recorded in separate, specialized short-term memory buffers. However, evidence from these same cases includes puzzling details that question explanations based on isolated deficits to a specialized storage system. We highlight consistent findings from patients with deficient auditory short-term memory that warrant further investigation and may challenge the specialized store account, including that short-term recognition memory performance appears to be much stronger than recall, and not so obviously impaired. We also describe the substantial problems for the broader memory system caused by assuming that the patients' deficits are focused in a specialized module. We suggest that a sensory-motor integration account of the patient cases may adequately explain these patterns, and therefore presents a path toward incorporating into the embedded processes framework greater clarity about how domain-specific phenomena in immediate memory tasks arise. We further contend that applying ideas about sensory-motor recruitment could improve working memory theory.
Publication date: Available online 15 December 2018
Source: Cortex
Author(s): Marine Lunven, Gilles Rode, Clémence Bourlon, Christophe Duret, Raffaella Migliaccio, Emmanuel Chevrillon, Michel Thiebaut de Schotten, Paolo Bartolomeo
Visual neglect is a frequent and disabling consequence of right hemisphere damage. Previous work demonstrated a probable role of posterior callosal dysfunction in the chronic persistence of neglect signs. Prism adaptation is a non-invasive and convenient technique to rehabilitate chronic visual neglect, but it is not effective in all patients. Here we aimed to assess the hypothesis that prism adaptation improves left neglect by facilitating compensation through the contribution of the left, undamaged hemisphere. We assessed the relationship between prism adaptation effects, cortical thickness and white matter integrity in a group of 14 patients with unilateral right-hemisphere strokes and chronic visual neglect. Results showed that patients who benefitted from prism adaptation had thicker cortex in temporo-parietal, prefrontal and cingulate areas of the left, undamaged hemisphere. Additionally, these patients had a higher fractional anisotropy value in the body and genu of the corpus callosum. Results from normal controls show that these callosal regions connect temporo-parietal, sensorimotor and prefrontal areas. Finally, shorter time intervals from the stroke tended to improve patients' response to prism adaptation. We concluded that prism adaptation may improve left visual neglect by promoting the contribution of the left hemisphere to neglect compensation. These results support current hypotheses on the role of the healthy hemisphere in the compensation for stroke-induced, chronic neuropsychological deficits, and suggest that prism adaptation can foster this role by exploiting sensorimotor/prefrontal circuits, especially when applied at early stages post-stroke.
Publication date: Available online 15 December 2018
Source: Behavioural Brain Research
Author(s): E. Tobias Krause, Joergen B. Kjaer, Anissa Dudde, Lars Schrader, Loc Phi-van
The serotonin transporter gene (5-HTT) is involved in the regulation of the neural serotonin. Polymorphisms in the 5-HTT gene have been described in many species to be involved in physiological processes and emotions. A functional polymorphism in the 5´-flanking region of the 5-HTT gene is known from chickens, with a deletion-allele (D), which is associated with an increased 5-HTT expression, in comparison to the wild-type-allele (W). In domestic populations, the majority of hens carry the W-allele. The regulatory changes of the 5-HTT are accompanied in chickens, as in humans, by modulations of fear. Beside these effects on fear, the understanding of potential functional consequences on the social behaviour in the gregarious chicken is lacking. Thus, we here investigated whether the 5-HTT polymorphism with three genotypes (WW, WD, DD), is not only linked to fear-related behaviour, but affects also socio-positive and -negative behaviours of adult hens. Our data confirmed the effects on fear-related behaviour. WW hens showed highest levels of fear. Interestingly, no differences in the social behaviours were present between the hens of the different 5-HTT genotypes. We further discuss implications for potential evolutionary pathways via natural selection and / or artificial selection through domestication of the 5-HTT polymorphism, which might have enabled a stable social lifestyle in the wild ancestors of modern chickens.
Publication date: Available online 15 December 2018
Source: Behavioural Brain Research
Author(s): Emil Trofimiuk, Przemysław Wielgat, Jan J. Braszko, Halina Car
The glutamate N-methyl-D-aspartate receptor (NMDAR) non-selective antagonist, ketamine, has been recently repurposed as a rapidly acting antidepressant, catalyzing the vigorous investigation of glutamate-signaling modulators as novel therapeutic agents for depressive disorders. Beneficial effects of this drug in the quick-acting treatment of depression are recognized. The long-term effects of ketamine have not been known, including the cognitive sphere. It is well acknowledged that prolonged exposure to stress induces depression and cognitive impairment.
It seemed reasonable to ask how the long-term ketamine administration would affect stressed animals in the aspect of cognitive functions. In the current study we tested whether it is possible for ketamine, used in prolonged-regimen in rats, to alleviate stress-evoked memory deficits?
Stressed (restraint 2 h daily for 21 days) and non-stressed rats (6-weeks-old) were treated with ketamine for 21 days and next subjected to a battery of behavioral tests: for the assessment of working and reference spatial memory (Morris water maze (MWM) and Barnes maze (BM)), stereotypy (stereotypy test - ST), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM).
Ketamine administration resulted in a significant stereotype behaviour in rats tested in ST.
Stressed rats (6-weeks-old) displayed a significant decline in the spatial working and reference memory. The effect of chronic ketamine administration depended on the type of test and differed between control rats and animals simultaneously exposed to chronic stress. However, in the MWM the impact was quite unequivocal, as we observed an improvement in spatial memory in stressed animals and a deterioration in non-stressed animals after ketamine administration. In the BM, the effect of ketamine changed in successive attempts, from favorable in the initial period to negative at the end of the test in the group of stressed animals and without a significant impact on control animals. We found no significant effects of ketamine on locomotor performance and on the level of anxiety.
Taken together, these findings demonstrate that ketamine potently abolishes or prevents some kinds of stress-induced memory impairments and cognitive decline in rats, although in some circumstances, it could even increase damage to memory, especially in unstressed animals.
It seems that the prolonged use of ketamine in the prevention of stress-induced memory declines can fulfill its role.
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Precision Medicine in Pediatric Cancer: Current Applications and Future Prospects.
High Throughput. 2018 Dec 13;7(4):
Authors: Ahmed AA, Vundamati DS, Farooqi MS, Guest E
Abstract
Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the survival of patients with leukemia and solid tumors. This review discusses the current status of pediatric precision oncology and the different clinical scenarios in which it can be effectively applied.
PMID: 30551569 [PubMed]
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Antiemetic use of olanzapine in patients with advanced cancer: results from an open-label multicenter study.
Support Care Cancer. 2018 Dec 14;:
Authors: Harder S, Groenvold M, Isaksen J, Sigaard J, Frandsen KB, Neergaard MA, Mondrup L, Herrstedt J
Abstract
INTRODUCTION: The antipsychotic drug olanzapine is effective against chemotherapy-induced nausea and targets multiple receptors known to be involved in the emetic reflex arch. The drug has a mean half-life of 30 h, which allows for a single daily administration and is therefore of interest in patients with advanced cancer suffering from nausea.
OBJECTIVES: To investigate the antiemetic effect and tolerability of olanzapine in patients with advanced cancer not receiving chemotherapy or irradiation.
METHODS: Patients with advanced cancer (no curable treatment options) with at least "moderate" nausea and/or one emetic episode within the last 24 h were included if they had not received chemotherapy or irradiation (last 2 weeks) and had no reversible causes of nausea/vomiting. Patients were administered 10 mg olanzapine daily for 5 days (the first day subcutaneously and the following 4 days orally). Nausea, vomiting, and adverse effects were assessed daily for 7 days. The primary efficacy parameter was nausea after 24 h.
RESULTS: Forty patients from four centers were included and all evaluable after 24 h. Thirty-six patients experienced some degree of improvement. The mean two-item N/V score (0-100) at baseline was 66 and improved to 21 and 24 after 24 h and 7 days, respectively. During the course of the study, the dose of olanzapine was reduced in three patients due to adverse events. Five patients were withdrawn from the study primarily due to progression of malignant disease or per patient's request.
CONCLUSIONS: Olanzapine appears effective and tolerable as an antiemetic in patients with advanced cancer. Future research should examine a lower dose (5 or 2.5 mg), preferably in a randomized controlled trial.
PMID: 30552594 [PubMed - as supplied by publisher]
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EG-VEGF silencing inhibits cell proliferation and promotes cell apoptosis in pancreatic carcinoma via PI3K/AKT/mTOR signaling pathway.
Biomed Pharmacother. 2019 Jan;109:762-769
Authors: Yan X, Hui Y, Hua Y, Huang L, Wang L, Peng F, Tang C, Liu D, Song J, Wang F
Abstract
OBJECTIVE: Pancreatic carcinoma (PC), one of the most prevalent and malignant tumors, has a poor prognosis and a high mortality rate. EG-VEGF, a vascular endothelial growth factor from endocrine glands, also termed as PROK1, has a high positive expression rate in PC tissues and is involved in the pathogenesis of various tumors. However, the expression and potential role of EG-VEGF in PC has not been thoroughly explored. The aim of this study was to better clarify the expression and potential role of EG-VEGF in pancreatic carcinoma.
METHODS: Immunohistochemical staining, western blotting, and RT-qPCR analysis were performed to detect the EG-VEGF level in PC tissues and cells. Subsequently, two short hairpin RNA (shRNA) lentiviral expression vector, shPROK1-1/shPROK1-2, were transfected into PANC-1 and BxPC-3 PC cell lines. MTT assay was used to determine cell proliferation. Meanwhile, flow cytometry assay was conducted to measure cell cycle and cell apoptosis. The protein levels of PI3K/AKT/mTOR pathway-related genes were also determined by western blotting.
RESULTS: EG-VEGF was aberrantly expressed in PC samples, as compared with paracancerous samples. Knockdown of PROK1 notably decreased the protein level of EG-VEGF, indicating a successful downregulation model of EG-VEGF. EG-VEGF silencing remarkably attenuated cell proliferation, while also induced G0/G1 arrest and magnified the extent of cell apoptosis. Further, EG-VEGF knockdown significantly inhibited PI3K/AKT/mTOR signaling pathway by downregulating p-PI3K, p-AKT, and p-mTOR levels.
CONCLUSION: This study identified the high-expression of EG-VEGF in pancreatic carcinoma tissues and cells, and demonstrated that EG-VEGF silencing inhibits the proliferation of PC cells and promotes apoptosis via regulating PI3K/AKT/mTOR pathway. Thus, EG-VEGF may become an essential target for the therapy of pancreatic cancer in the future.
PMID: 30551529 [PubMed - in process]
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Oral medicine: Today's future can become tomorrow's reality.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Nov;126(5):409-414
Authors: Miller CS, Peterson DE
Abstract
There have been strategic clinical, educational, and research advances in the field of Oral Medicine over the past several decades. In many cases, Oral Medicine experts are contributing the lead role in these advances nationally and internationally. In addition, American Board of Dental Specialty recognition of Oral Medicine as a specialty in 2015 has positioned Oral Medicine professionals to substantively enhance the delivery of oral health care to medically complex patients as well. It is now important and timely to capitalize on this contemporary foundation, to advance the field of Oral Medicine in the United States for the next generation of Oral Medicine specialists and practitioners. This article provides the results of analyses of the present dynamics and economic opportunities, as well as solutions to existing perceived barriers.
PMID: 30551842 [PubMed - in process]
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Salivary gland tumors: Molecular characterization and therapeutic advances for metastatic disease.
Head Neck. 2018 Dec 15;:
Authors: Schvartsman G, Pinto NA, Bell D, Ferrarotto R
Abstract
Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
PMID: 30552848 [PubMed - as supplied by publisher]
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Darpp-32 and t-Darpp protein products of PPP1R1B: old dogs with new tricks.
Biochem Pharmacol. 2018 Dec 12;:
Authors: Avanes BA, Lenz G, Momand J
Abstract
The PPP1R1B gene is located on chromosome 17q12 (39,626,208-39,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (Dopamine and cAMP Regulated Phosphoprotein), discovered in the early 1980s, is a protein whose phosphorylation is upregulated in response to cAMP in dopamine-responsive tissues in the brain. It's phosphorylation profile modulates its ability to bind and inhibit Protein Phosphatase 1 activity, which, in turn, controls the activity of hundreds of phosphorylated proteins. PPP1R1B knockout mice exhibit subtle learning defects. In 2002, the second protein product of PPP1R1B was discovered in gastric cancers: t-Darpp (truncated Darpp-32). The start codon of t-Darpp is amino acid residue 37 of Darpp-32 and it lacks the domain responsible for modulating Protein Phosphatase 1. Aside from gastric cancers, t-Darpp and/or Darpp-32 is overexpressed in tumor cells from breast, colon, esophagus, lung and prostate tissues. More than one research team has demonstrated that these proteins, through mechanisms that to date remain cloudy, activate AKT, a protein whose phosphorylation leads to cell survival and blocks apoptosis. Furthermore, in Her2 positive breast cancers (an aggressive form of breast cancer), t-Darpp/Darpp-32 overexpression causes resistance to the frequently-administered anti-Her2 drug, trastuzumab (Herceptin), likely through AKT activation. Here we briefly describe how Darpp-32 and t-Darpp were discovered and report on the current state of knowledge of their involvement in cancers. We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter.
PMID: 30552871 [PubMed - as supplied by publisher]
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FDA Approval Summary: Pertuzumab for adjuvant treatment of HER2-positive early breast cancer.
Clin Cancer Res. 2018 Dec 14;:
Authors: Howie LJ, Scher NS, Amiri-Kordestani L, Zhang L, King-Kallimanis BL, Choudhry Y, Schroeder J, Goldberg KB, Kluetz PG, Ibrahim A, Sridhara R, Blumenthal GM, Pazdur R, Beaver JA
Abstract
On December 20, 2017, the Food and Drug Administration granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4 months median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% (n=171) in the pertuzumab arm and 8.7% (n=210) for placebo (HR 0.82; 95% CI: 0.67, 1.00; p=0.047). The proportion of IDFS events in patients with HR-negative disease was 8.2% (n=71) and 10.6% (n=91) in the pertuzumab and placebo arms, respectively (HR 0.76, 95% CI: 0.56, 1.04). The proportion of IDFS events for patients with node positive disease was 9.2% (n=139) and 12.1% (n=181) in the pertuzumab and placebo arms, respectively (HR 0.77, 95% CI: 0.62, 0.96). Adverse reactions in ≥ 30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence.
PMID: 30552112 [PubMed - as supplied by publisher]
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Acute Pancreatitis Caused by Ampullary Duodenum Adenoma in a Patient with Adenomatous Polyposis Coli with Billroth II Reconstruction After Distal Gastrectomy.
Am J Case Rep. 2018 Dec 15;19:1495-1498
Authors: Iemoto T, Sanuki T, Ose T, Yoshie T, Tanaka K, Sasaki A, Abe S, Abe T, Miki M, Futai R, Inoue Y
Abstract
BACKGROUND Adenomatous polyposis coli is an autosomal dominant hereditary disorder. Duodenal adenocarcinoma and adenoma, which are extracolonic lesions, not only affect the prognosis of patients but also cause acute pancreatitis. CASE REPORT We present the case of a 73-year-old male. He had undergone proctocolectomy for familial adenomatous polyposis and distal gastrectomy (Billroth II reconstruction with Braun anastomosis) for gastric ulcer; he presented with acute pancreatitis caused by ampullary duodenum adenoma. Double-balloon endoscopy showed 2 adenomatous polyps in the major papilla and descending limb of the duodenum. Based on the findings of endoscopy and biopsy, the duodenal polyps were diagnosed as adenomas and classified as Spigelman stage II. CONCLUSIONS Our case report suggests that duodenal surveillance is necessary for patients with adenomatous polyposis coli. In addition, surveillance using double-balloon endoscopy is useful for patients with an altered gastrointestinal anatomy.
PMID: 30552312 [PubMed - in process]
The tethered effect of vestibular schwannoma tumor shrinkage following stereotactic radiosurgery in secondary trigeminal neuralgia.
World Neurosurg. 2018 Dec 12;:
Authors: Izumi M, Higuchi Y, Yakufujiang M, Motoshima T, Horiguchi K, Aoyagi K, Nagano O, Serizawa T, Iwadate Y, Yamakami I
PMID: 30553070 [PubMed - as supplied by publisher]
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Corrigendum to 'Intraventricular Epithelioid Glioblastoma: A Case Report' [World Neurosurgery 112 (2018) 257-263].
World Neurosurg. 2018 Dec 11;:
Authors: Nitta N, Moritani S, Fukami T, Yoshimura Y, Hirai H, Nozaki K
PMID: 30551971 [PubMed - as supplied by publisher]
Publication date: January 2019
Source: Neoplasia, Volume 21, Issue 1
Author(s): Yongjun Cha, Sun Young Kim, Hyun Yang Yeo, Ji Yeon Baek, Moon Ki Choi, Kyung Hae Jung, Seung Myung Dong, Hee Jin Chang
Aberrant promoter methylation plays a vital role in colorectal carcinogenesis. However, its role in treatment responses is unclear, especially for metastatic disease. Here, we investigated the association between promoter methylation and treatment outcomes of irinotecan-based chemotherapy in 102 patients with metastatic colorectal cancer. Promoter methylation was examined by methylation-specific polymerase chain reaction for three loci (CHFR, WRN, and SULF2) associated with chemotherapy response and five CpG island methylator phenotype (CIMP)–specific markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1). Association between CHFR methylation and in vitro sensitivity to irinotecan was also evaluated. Promoter methylation of CHFR, WRN, and SULF2 was identified in 16 (15.7%), 24 (23.5%), and 33 (32.4%) patients, respectively. CIMP status was positive in 22 (21.6%) patients. CHFR methylation was associated with a significantly longer time to progression (TTP) (median: 8.77 vs. 4.43 months, P = .019), with trends favoring higher overall survival (OS) (median: 22.83 vs. 20.17 months, P = .300) and response rates (31.3% vs. 17.4%, P = .300). For patients with unmethylated CHFR, TTP (median: 5.60 vs. 3.53, P = .020) and OS (median: 20.57 vs. 9.23, P = .006) were significantly different according to CIMP status. Colorectal cancer cell lines with CHFR methylation demonstrated increased sensitivity to irinotecan. Both CHFR overexpression and combination with 5-aza-2′-deoxycytidine reversed irinotecan sensitivity in CHFR-methylated cell lines, whereas CHFR knockdown in unmethylated cells restored sensitivity to irinotecan. These data suggest that CHFR methylation may be associated with favorable treatment outcomes of irinotecan-based chemotherapy in patients with metastatic colorectal cancer.
Bundle payment model in spine surgery: Current challenges and opportunities, a systematic review.
World Neurosurg. 2018 Dec 12;:
Authors: Dietz N, Sharma M, Alhourani A, Ugiliweneza B, Wang D, Nuño MA, Drazin D, Boakye M
Abstract
INTRODUCTION: Bundled payments offer a lump sum for management of particular conditions over a specified time period that has the potential to reduce healthcare payments. Additionally, bundled payments represent a shift toward patient-centered reimbursement that has the upside of improved care coordination among providers and may lead to improved outcomes.
AIM: To review the challenges and sources of payment variation and opportunities for restructuring bundled payments plans in context of spine surgery.
MATERIALS AND METHODS: We reviewed the current landscape of episodes of care over the past 10 years. We completed a search using PRISMA guidelines and the PICO model in PubMed and Ovid databases to identify studies that met our search criteria.
RESULTS: A total of 10 studies met search criteria that were retrospective in design. The primary recipient of reimbursement was the hospital associated with the index procedure (59.7-77% of the bundled payment), followed by surgeon reimbursement (12.8-14%) and post-acute care rehabilitation (3.6-7.3%). On average, the index hospitalization was $32,467, ranging from $11,880 to $107,642, depending on number of levels fused, complications, and malignancy. Readmission was shown to increase the 90-day payment by 50%-200% for uncomplicated fusion.
CONCLUSION: The implementation of spine surgery in bundled payment models offers opportunity for healthcare cost reduction. Patient heterogeneity, complications, and index hospitalization pricing are among factors that contribute to the challenge of payment variation. Development of standard care pathways, multi-disciplinary coordination between inpatient and outpatient postoperative care, and empowerment of patients are also key elements of progress in the evolution of bundled payments in spine surgery. We anticipate more individualized risk-adjusted prediction models of payment for spine surgery, contributing to more manageable variation in payment and favorable models of bundled payments for payers and providers.
PMID: 30553071 [PubMed - as supplied by publisher]
A Second course of stereotactic image-guided robotic radiosurgery for patients with cerebral metastasis.
World Neurosurg. 2018 Dec 12;:
Authors: Jiang X, Wang H, Song Y, Wang X, Li F, Dong Y, Wang J, Chen H, Yuan Z
Abstract
OBJECTIVES: The purpose of this research was to study the outcome of brain metastases in a cohort of patients undergoing a second course of stereotactic image-guided robotic radiosurgery, and to identify predictors corelated with survival.
METHODS: A total of 63 patients with primary malignancies underwent a second course of Cyberknife radiosurgery for intracranial progression, including recurrence and new metastases after initial stereotactic radiosurgery (SRS). Overall survival (OS) and control rate were calculated by Kaplan-Meier. A Cox proportional hazards model was used to analyze predictive factors for survival.
RESULTS: With a median follow-up duration of 12 months following second SRS, the median OS of the second course of radiosurgery were 18 months. On multivariate analysis, sum of total plan target volume (tPTV) (HR 2.112, 95%CI 1.069-4.173) and minimum dose (HR 1.990, 95%CI 1.017-3.892) were associated with OS significantly. Median intracranial progression free survival (IPFS) was 23 months. 6-month and 12-month local control rates of the targets were 97.0% and 94.4%, respectively. Univariate analysis revealed that only tumor number significantly influenced IPFS (P=0.012). 9 (14.2%) patients developed brain necrosis. Median time to brain necrosis in regions where brain necrosis occurred after single course of SRS was not reached, compared to16 months for those treated with repeat SRS (P=0.041).
CONCLUSIONS: A second course of Cyberknife radiosurgery appears to be an effective salvage option for brain progression following initial SRS. The tPTV shows prediction for OS. Tumor volume of initial SRS may influence selection of the potential population that may benefit from salvage radiosurgery.
PMID: 30553069 [PubMed - as supplied by publisher]
A case of completely isolated advanced enteric duplication cyst cancer performed partial pancreatectomy.
Int J Surg Case Rep. 2018 Nov 27;54:83-86
Authors: Nakashima S, Yamada T, Sato G, Sakai T, Chinen Y, Itakura H, Kato R, Ueda M, Tsuda Y, Ohta K, Matsuyama J, Ikenaga M
Abstract
INTRODUCTION: Enteric duplication cysts are rare and, in addition, isolated enteric duplication cysts are lower morbidity prevalence rate. These cysts lack a connection to the gastrointestinal tract or the adjacent mesenteric vasculature and have only been reported in 10 case reports. In these reports, only two reports were cases with malignant transformation. Our case was a report for the advanced cancer of the isolated enteric duplication cyst.
CASE PRESENTATION: The patient was a 43 year-old woman with slightly abdominal pain and mass formation. The abdominal contrast-enhanced computed tomography showed 130 × 100 × 90 mm huge cystic mass existed in right upper peritoneal cavity. The cystic mass had thickened wall and many enhanced nodules. As these imaging findings suggested a tumor originated from pancreas and the preoperative diagnose was suspect of mucinous cystic neoplasm. In operative findings, the tumor originated from pancreatic head and did not attach to gastrointestinal tract. Final pathology indicated the cyst was an isolated advanced enteric duplication cyst cancer and not originated from pancreas.
CONCLUSION: We experienced an extremely rare case of completely isolated advanced enteric duplication cyst cancer. Unique to this case, the preoperative diagnosis was suspect of mucinous cystic neoplasm arising from pancreas head and partial pancreatectomy was performed. However, in the pathological findings, this cyst diagnosed advanced enteric duplication cyst cancer.
PMID: 30553095 [PubMed - as supplied by publisher]
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Involvement of the uridine cytidine kinase 2 enzyme in cancer cell death: A molecular crosstalk between the enzyme and cellular apoptosis induction.
Biomed Pharmacother. 2019 Jan;109:1506-1510
Authors: Malami I, Abdul AB
Abstract
Apoptosis is a series of molecular signalling regulating normal cellular growth and development. Cells resistance to apoptosis, however, leads to uncontrolled proliferation. Research involving cancer cell death is one of the most important targeted areas in the discovery of novel anticancer therapy. There are several biochemical pathways that are liked towards cancer cell death of which, uridine-cytidine kinase 2 (UCK2) was recently linked to cell apoptosis induction. UCK2 is responsible for the phosphorylation of uridine and cytidine to their corresponding monophosphate in a salvage pathway of pyrimidine nucleotides biosynthesis. Cytotoxic ribonucleoside analogues that target UCK2 enzyme activity are currently being investigated in clinical trials useful for cancer treatment. Whilst findings have clearly shown that these antimetabolites inhibit cancer development in clinical settings, they have yet to establish linking cytotoxic nucleoside analogues to cancer cell death. In this present review, we propose the probable molecular crosstalk involving UCK2 protein and cancer cell death through cell cycle arrest and triggering of apoptosis involving proteins, MDM2 and the subsequent activation of p53.
PMID: 30551402 [PubMed - in process]
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Metformin increases antitumor activity of MEK inhibitor binimetinib in 2D and 3D models of human metastatic melanoma cells.
Biomed Pharmacother. 2019 Jan;109:2548-2560
Authors: Ryabaya O, Prokofieva A, Akasov R, Khochenkov D, Emelyanova M, Burov S, Markvicheva E, Inshakov A, Stepanova E
Abstract
Melanoma is one of the most aggressive and treatment-resistant tumors that responsible for majority of skin-cancer related deaths. Here we propose a combination of MEK inhibitor binimetinib with metformin as a promising therapy against human melanoma cells in vitro, including BRAF -mutated A375, Mel Z, and Mel IL cells, and NRAS-mutated Mel MTP and Mel Me cells. Additionally, we obtained two close to clinical practice models of melanoma progression. The first one was vemurafenib-resistant Mel IL/R melanoma cells with acquired resistance to BRAF inhibition-targeted therapy, and the second one was tumor spheroids, which are 3D in vitro model of small-size solid tumors in vivo. The cytotoxicity of binimetinib and metformin was synergistic in both 2D and 3D melanoma culture and mediated through apoptotic pathway. The combination reduced the number of melanoma-formed colonies, inhibited cell invasion and migration, and led to G0/G1 cell cycle arrest through cyclin D/CDK4/CDK6 pathway. The mechanism of metformin and binimetinib synergy in melanoma cells was associated with increased activation of p-AMPKα and decreased p-ERK, but not with alterations in p-mTOR. In summary, the combination of metformin and binimetinib resulted in stronger anti-proliferative effects on melanoma cells compared to binimetinib alone, and therefore could be promising for clinical applications.
PMID: 30551515 [PubMed - in process]
The role of histone deacetylase inhibitors in metastatic breast cancer.
Breast. 2018 Dec 06;43:130-134
Authors: Zucchetti B, Shimada AK, Katz A, Curigliano G
Abstract
Histone deacetylase inhibitors (HDACi) are a relatively new class of drug that plays an important role in the epigenetic and non-epigenetic regulation in cancer, inducing death, apoptosis and cell cycle arrest in cancer cells. Although HDACi are approved only for hematologic malignancies, there are several trials in the breast cancer setting with promising results. In this review, we summarize the latest studies with HDACi in breast cancer from the emerging data in the translational research until its possible applicability in the clinical practice.
PMID: 30553187 [PubMed - as supplied by publisher]
FH535 inhibits proliferation and migration of colorectal cancer cells by regulating CyclinA2 and Claudin1 gene expression.
Gene. 2018 Dec 12;:
Authors: Tu X, Hong D, Jiang Y, Lou Z, Wang K, Jiang Y, Jin L
Abstract
Wnt signaling pathway plays a major role in the progression of colorectal cancer (CRC). Small molecules which can cut off this signal transduction can be promising anti-cancer drugs for CRC therapy. Therefore, we aimed to investigate the mechanisms of FH535, an inhibitor of the Wnt signaling pathway, on inhibiting proliferation and migration of colorectal cancer cells DLD-1 and SW620. We found that FH535 could significantly suppress the growth of DLD-1 and SW620 cells in a concentration-dependent and time-dependent manner. The results of cell cycle tests showed that FH535 could significantly induce G2/M arrest in colorectal cancer cells. Transwell and Wound-healing assays revealed that FH535 notably inhibited cell migration. Moreover, we found that FH535 down-regulated β-catenin and CyclinA2 expressions while up-regulating Claudin-1 expression at both mRNA and protein levels, which may contribute to the FH535-induced inhibitory effect on proliferation and migration in human colorectal cancer cells. Our study revealed that FH535 inhibited proliferation and migration of colorectal cancer cells by regulating CyclinA2 and Claudin1 gene expression, which enriches regulatory network of FH535 and may contribute to being promising anti-cancer drugs for CRC therapy.
PMID: 30552982 [PubMed - as supplied by publisher]
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BRD4 interacts with PML/RARα in acute promyelocytic leukemia.
Front Med. 2018 Dec;12(6):726-734
Authors: Luo Q, Deng W, Wang H, Fan H, Zhang J
Abstract
Bromodomain-containing 4 (BRD4) has been considered as an important requirement for disease maintenance and an attractive therapeutic target for cancer therapy. This protein can be targeted by JQ1, a selective small-molecule inhibitor. However, few studies have investigated whether BRD4 influenced acute promyelocytic leukemia (APL), and whether BRD4 had interaction with promyelocytic leukemia-retinoic acid receptor α (PML/RARα) fusion protein to some extent. Results from cell viability assay, cell cycle analysis, and Annexin-V/PI analysis indicated that JQ1 inhibited the growth of NB4 cells, an APL-derived cell line, and induced NB4 cell cycle arrest at G1 and apoptosis. Then, we used co-immunoprecipitation (co-IP) assay and immunoblot to demonstrate the endogenous interaction of BRD4 and PML/RARα in NB4 cells. Moreover, downregulation of PML/RARα at the mRNA and protein levels was observed upon JQ1 treatment. Furthermore, results from the RT-qPCR, ChIP-qPCR, and re-ChIP-qPCR assays showed that BRD4 and PML/RARα co-existed on the same regulatory regions of their target genes. Hence, we showed a new discovery of the interaction of BRD4 and PML/RARα, as well as the decline of PML/RARα expression, under JQ1 treatment.
PMID: 30552662 [PubMed - in process]
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Downregulation of EIF5A2 by miR-221-3p inhibits cell proliferation, promotes cell cycle arrest and apoptosis in medulloblastoma cells.
Biosci Biotechnol Biochem. 2018 Dec 14;:1-9
Authors: Yang Y, Cui H, Wang X
Abstract
Recently, miR-221-3p expression has been reported to be down-regulated in medulloblastoma (MB), but its functional effects remains unclear. In this study, quantitative real-time PCR (qRT-PCR) revealed significantly decreased miR-221-3p in MB cell lines. Transfection of miR-221-3p mimics reduced, or inhibitor increased cell proliferation in MB cells using MTT assay. Flow cytometry analysis indicated miR-221-3p overexpression promoted, while knockdown alleviated G0/G1 arrest and apoptosis. Luciferase reporter assay confirmed miR-221-3p directly targets the EIF5A2 gene. Moreover, restoration of EIF5A2 in the miR-221-3p-overexpressing DAOY cells significantly alleviated the suppressive effects of miR-221-3p on cell proliferation, cell cycle and apoptosis. Furthermore, miR-221-3p overexpression decreased CDK4, Cyclin D1 and Bcl-2 and increased Bad expression, which was reversed by EIF5A2 overexpression. These results uncovered the tumor suppressive role of miR-221-3p in MB cell proliferation at least in part via targeting EIF5A2, suggesting that miR-221-3p might be a potential candidate target for diagnosis and therapeutics of MB.
PMID: 30551723 [PubMed - as supplied by publisher]
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EG-VEGF silencing inhibits cell proliferation and promotes cell apoptosis in pancreatic carcinoma via PI3K/AKT/mTOR signaling pathway.
Biomed Pharmacother. 2019 Jan;109:762-769
Authors: Yan X, Hui Y, Hua Y, Huang L, Wang L, Peng F, Tang C, Liu D, Song J, Wang F
Abstract
OBJECTIVE: Pancreatic carcinoma (PC), one of the most prevalent and malignant tumors, has a poor prognosis and a high mortality rate. EG-VEGF, a vascular endothelial growth factor from endocrine glands, also termed as PROK1, has a high positive expression rate in PC tissues and is involved in the pathogenesis of various tumors. However, the expression and potential role of EG-VEGF in PC has not been thoroughly explored. The aim of this study was to better clarify the expression and potential role of EG-VEGF in pancreatic carcinoma.
METHODS: Immunohistochemical staining, western blotting, and RT-qPCR analysis were performed to detect the EG-VEGF level in PC tissues and cells. Subsequently, two short hairpin RNA (shRNA) lentiviral expression vector, shPROK1-1/shPROK1-2, were transfected into PANC-1 and BxPC-3 PC cell lines. MTT assay was used to determine cell proliferation. Meanwhile, flow cytometry assay was conducted to measure cell cycle and cell apoptosis. The protein levels of PI3K/AKT/mTOR pathway-related genes were also determined by western blotting.
RESULTS: EG-VEGF was aberrantly expressed in PC samples, as compared with paracancerous samples. Knockdown of PROK1 notably decreased the protein level of EG-VEGF, indicating a successful downregulation model of EG-VEGF. EG-VEGF silencing remarkably attenuated cell proliferation, while also induced G0/G1 arrest and magnified the extent of cell apoptosis. Further, EG-VEGF knockdown significantly inhibited PI3K/AKT/mTOR signaling pathway by downregulating p-PI3K, p-AKT, and p-mTOR levels.
CONCLUSION: This study identified the high-expression of EG-VEGF in pancreatic carcinoma tissues and cells, and demonstrated that EG-VEGF silencing inhibits the proliferation of PC cells and promotes apoptosis via regulating PI3K/AKT/mTOR pathway. Thus, EG-VEGF may become an essential target for the therapy of pancreatic cancer in the future.
PMID: 30551529 [PubMed - in process]
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Effects of 5-Aza on p-Y1472 NR2B related to learning and memory in the mouse hippocampus.
Biomed Pharmacother. 2019 Jan;109:701-707
Authors: Zhang X, Xie Y, Xu W, Liu X, Jiang S, Bao M, Xie W, Jia X, Bade R, Gong K, Yan S, Zhang C, Shao G
Abstract
BACKGROUND: We have previously reported that 5-Aza-2-deoxycytidine (5-Aza-cdR) can repress protein serine/threonine phosphatase-1γ (PP1γ) expression and activity in the mouse hippocampus and affect the behaviour of mice in a water maze. It is well known that the phosphorylation of N-methyl-d-aspartate receptor 2B subunit (NR2B) plays a role in behaviour. In this study, we examined whether 5-Aza-cdR affects NR2B phosphorylation at tyrosine 1472 (p-Y1472 NR2B) and whether it affected the responses of the mice in a passive avoidance test.
METHODS: 5-Aza-cdR (10 μM) was administered to mice via intracerebroventricular injection (i.c.v). The learning and memory behaviour of the mice were evaluated by measuring their response in a step-down type passive avoidance test 24 h after the injection. The mRNA level of NR2B was measured by real-time PCR. NR2B and p-Y1472 NR2B protein expression in the mouse hippocampus was detected by western blot and immunofluorescence. CDK5 activity was detected by the ADP-Glo™ + CDK5/p35 Kinase Enzyme System. To further clarify whether the 5-Aza-cdR effects on behaviour were dependent on cellular proliferation or not, the effect of 5-Aza-cdR on the expression level of NR2B, the phosphorylation level of p-Y1472 NR2B, cell viability and the cell cycle were analysed using the immortalized mouse hippocampal neuronal cells neural cell line HT22 treated with 10 μM 5-Aza-cdR compared with an untreated control group.
RESULTS: After injection with 5-Aza-cdR, the behaviour of the mice in the step-down test was improved, while their phosphorylation level of p-Y1472 NR2B was increased and their CDK5 activity was decreased in the hippocampus. In vitro experiments showed 10 μM 5-Aza-cdR increased the p-Y1472 NR2B phosphorylation level with inhibition of cell viability and cell cycle arrest.
CONCLUSIONS: Our results suggested that the effect of 5-Aza-cdR on behaviour may be related to the increase in phosphorylation of p-Y1472 NR2B in the hippocampus.
PMID: 30551522 [PubMed - in process]
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In vivo pathogenesis of colon carcinoma and its suppression by hydrophilic fractions of Clematis flammula via activation of TRAIL death machinery (DRs) expression.
Biomed Pharmacother. 2019 Jan;109:2182-2191
Authors: Guesmi F, Ben Hmed M, Prasad S, Tyagi AK, Landoulsi A
Abstract
This work focused on characterizing hydrophilic fractions of Clematis flammula (CFl). The data here clearly demonstrated that hydrolate fractions act as a free radical scavengers and inhibited proliferation of different cell lines in a time- and concentration-dependent manner, transwell, and with a significant cytotoxic effect. Treating cells with CFl had the effect of suppressing cell growth attenuated by ROS generation in colonic carcinoma. Moreover, CFl in HCT116 cells suppressed survival, proliferation, invasion, angiogenesis and metastasis in vitro by inhibiting gene expression. Following CFl treatment, caspases and PARP cleavage were detected. The up- and down-regulated genes obtained from the WBA of the effect of CFl showed that several biological processes were associated with apoptosis and induction of G1 cell cycle arrest. CFl synergizes the effect of TRAIL by down-regulating the expression of cell survival proteins involved in apoptosis compared to cells treated with CFl or TRAIL alone. Our findings showed that CFl sensitizes apoptosis in TRAIL-resistant cells by activating MAPKs, SP1, and CHOP, that induced DR5 expression. Overall, our data showed that CFl is a promising antitumor agent through kinases and transcription factor induction, both of which are required to activate TRAIL receptors. Colon inflammation induced by LPS was inhibited by CFl hydrolate.
PMID: 30551475 [PubMed - in process]
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Chemopreventive mechanisms of galangin against hepatocellular carcinoma: A review.
Biomed Pharmacother. 2019 Jan;109:2054-2061
Authors: Fang D, Xiong Z, Xu J, Yin J, Luo R
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and has a high mortality rate in less developed countries, especially in China. Galangin (GA), one of the most important and naturally active flavonoids, extracted primarily from the root of Alpinia officinarum Hance, has been demonstrated to be effective in the treatment of HCC. It is a substance with defensive actions and a broad range of biological properties, including inhibitory effects on bacteria, fungi, viruses, the control of hypertension and diabetes, and chemoprevention of several cancers. Experiments have shown that GA prevents HCC through multiple anti-cancer mechanisms, anti-genotoxic activity against environmental and dietary carcinogens; anti-proliferative effects through reversal of the Warburg effect in HCC; arrest of the cell cycle in the G0/G1 phase; induction of apoptosis via stimulation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and the mitochondrial-dependent apoptosis pathway; induction of autophagy; and inhibition of angiogenesis, metastasis, and multidrug resistance (MDR). In addition, synergistic effects with other chemotherapy drugs have been demonstrated. Therefore, this review is focused on the anti-HCC mechanisms of GA.
PMID: 30551461 [PubMed - in process]
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MiR-128 suppresses the growth of thyroid carcinoma by negatively regulating SPHK1.
Biomed Pharmacother. 2019 Jan;109:1960-1966
Authors: Cao XZ, Bin H, Zang ZN
Abstract
Accumulating evidences have emphasized the essential roles of differentially expressed miRNAs in papillary thyroid cancer (PTC) and follicular thyroid carcinoma (FTC) progression. MiR-128 has been reported to be down-regulated in multiple cancers to restrain tumor growth. However, the role of miR-128 in the development of PTC and FTC and the underlying mechanism remain to be unclear. In this present study, the results indicated that miR-128 expression was markedly down-regulated in PTC and FTC tissues and various thyroid carcinoma cell lines. Functional analysis indicated that over-expression of miR-128 suppressed PTC and FTC cancer cell growth, induced apoptosis and cell cycle arrest in G0/G1 phase. In addition, miR-128 over-expression markedly inhibited cancer cell migration and invasion. However, the processes above were reversed by silencing miR-128 expressions in thyroid tumor cells. Following, we characterized sphingosine kinase-1 (SPHK1) as a direct target of miR-128 that interacted with the 3'-untranslated region (UTR) of SPHK1, and the results were confirmed by using luciferase-reporter assay. We also observed that SPHK1 expression was decreased and negatively correlated with miR-128 expression in PTC and FTC tissues clinically. Importantly, ectopic expression of SPHK1 significantly abrogated the tumor-suppressive effect induced by miR-128, as supported by the reduced apoptosis, while the enhanced proliferation and metastasis. Finally, over-expressing miR-128 apparently reduced the tumor growth rate and tumor weight in vivo using xenograft tumor model, accompanied with a remarkable decrease of SPHK1. Thus, our study illustrated that miR-128 might be a tumor suppressor microRNA that played an essential role in thyroid carcinoma progression.
PMID: 30551451 [PubMed - in process]
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A novel rutin-fucoidan complex based phytotherapy for cervical cancer through achieving enhanced bioavailability and cancer cell apoptosis.
Biomed Pharmacother. 2019 Jan;109:1181-1195
Authors: Deepika MS, Thangam R, Sheena TS, Sasirekha R, Sivasubramanian S, Babu MD, Jeganathan K, Thirumurugan R
Abstract
Recent studies on flavonoids forming complexes with macromolecules attract researchers due to their enhanced bioavailability as well as chemo-preventive efficacy. In this study, a flavonoid rutin (Ru) is non-covalently complexed with fucoidan (Fu) using the functional groups to obtain a therapeutic polymeric complex overcoming the limitations of bioavailability of rutin. The prepared novel rutin-fucoidan (Ru-Fu) complex is characterized for spectroscopic features, particle size and distribution analysis by DLS. It is shown that the complex displayed the nanostructural features that are different from that of the usual rutin-fucoidan mixture. The studies on drug release profiles at different pH (5.5, 6.8 and 7.4) show that the sustained release of compounds from complex occurs preferentially at the desired endosomal pH (5.5). Further, the chemopreventive potential of Ru-Fu complex is investigated against HeLa cells by cellular apoptotic assays and flow cytometric analysis. It showed that the complex is able to disrupt cell cycle regulation and has the ability to induce cellular apoptosis via nuclear fragmentation, ROS generation and mitochondrial potential loss. In vitro cell viability assay with Ru-Fu complex shows that the complex is biocompatible on normal cells. The hemolysis assay also reveals that the complex does not release hemoglobin from human red blood cells (RBCs). Thus, the study is envisaged to open up interests for developing such formulations against cervical cancer and other cancers.
PMID: 30551368 [PubMed - in process]
Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis.
Epilepsy Res. 2018 Nov 26;149:92-101
Authors: Kamnaksh A, Puhakka N, Ali I, Smith G, Aniceto R, McCullough J, Das Gupta S, Ndode-Ekane XE, Brady R, Casillas-Espinosa P, Hudson M, Santana-Gomez C, Immonen R, Abreu PA, Jones N, Shultz S, Staba RJ, O'Brien TJ, Agoston D, Pitkänen A
Abstract
The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is an international, multicenter, multidisciplinary study aimed at preventing epileptogenesis (EpiBioS4Rx: https://ift.tt/2rFBHvA). One of the study's major objectives is the discovery of diagnostic, prognostic, and predictive plasma protein and microRNA (miRNA) biomarkers that are sensitive, specific, and translatable to the human condition. Epilepsy due to structural brain abnormalities, secondary to neurological insults such as traumatic brain injury (TBI), currently represents ∼50% of all epilepsy cases. In the preclinical EpiBioS4Rx study, TBI was induced in adult male Sprague Dawley rats using a standardized protocol for lateral fluid-percussion injury. Whole blood was collected from the tail vein at baseline and 2, 9 and 30 days post-injury and processed for plasma separation. Biomaterial properties, sample preparation and integrity, and choice of analysis platform can significantly impact measured marker levels and, in turn, interpretation with respect to injury and/or other variables. We present here the results of procedural harmonization for the first 320 rats included in the EpiBioS4Rx study study, from three international research centers, and preliminary proteomic and miRNA analyses. We also discuss experimental considerations for establishing rigorous quality controls with the goal of harmonizing operating procedures across study sites, and delivering high-quality specimens for preclinical biomarker discovery in a rat model of post-traumatic epilepsy (PTE).
PMID: 30553097 [PubMed - as supplied by publisher]
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Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome.
Neurology. 2018 Dec 14;:
Authors: Marafi D, Suter B, Schultz R, Glaze D, Pavlik VN, Goldman AM
Abstract
OBJECTIVE: We characterized the epilepsy features and contribution to cognitive regression in 47 patients with MECP2 duplication syndrome (MDS) and reviewed these characteristics in over 280 MDS published cases.
METHODS: The institutional review board approved this retrospective review of medical records and case histories of patients with MDS.
RESULTS: The average age at enrollment was 10 ± 7 years. Patients with epilepsy were older (13 ± 7 years vs 8 ± 5 years, p = 0.004) and followed for a longer time (11.8 ± 6.5 years vs 6.3 ± 4.2 years, p = 0.003) than patients without a seizure disorder. Epilepsy affected 22/47 (47%) patients with MDS. It was treatment-refractory and consistent with epileptic encephalopathy in 18/22 (82%) cases. Lennox-Gastaut syndrome (LGS) was present in 12/22 (55%) patients and manifested between late childhood and adulthood in 83% of cases. The emergence of neurologic regression coincided with the onset of epilepsy. The MECP2 duplication size and gene content did not correlate with epilepsy presence, type, age at onset, or treatment responsiveness.
CONCLUSION: Epilepsy in MDS is common, often severe, and medically refractory. LGS occurs frequently and may have a late onset. Developmental regression often follows the onset of epilepsy. The MECP2 duplication extent and gene content do not discriminate between patients with or without epilepsy. Our findings inform clinical care and family counseling with respect to early epilepsy recognition, diagnosis, specialty referral, and implementation of aggressive seizure therapy to minimize detrimental effect of uncontrolled seizures on cognitive functions or preexisting neurologic deficits.
PMID: 30552298 [PubMed - as supplied by publisher]
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Intravenously Administered Ganaxolone Blocks Diazepam- Resistant Lithium-Pilocarpine-Induced Status Epilepticus in Rats. Comparison with Allopregnanolone.
J Pharmacol Exp Ther. 2018 Dec 14;:
Authors: Saporito MS, Gruner JA, DiCamillo A, Hinchliffe R, Barker-Haliski M, White HS
Abstract
Ganaxolone (GNX) is the 3β-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following intravenous (IV) administration in treatment resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamics (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer half-life, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other non-anesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to one hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment for this indication.
PMID: 30552296 [PubMed - as supplied by publisher]
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In vivo Preclinical Molecular Imaging of repeated exposure to an NMDA antagonist and a glutaminase inhibitor as potential glutamatergic modulators.
J Pharmacol Exp Ther. 2018 Dec 14;:
Authors: Servaes S, Kara F, Glorie D, Stroobants S, Van Der Linden A, Staelens S
Abstract
Glutamate is the principal excitatory neurotransmitter in the brain and at the base of a wide variety of neuropathologies, including epilepsy, autism, Fragile X and obsessive compulsive disorder. Glutamate has so become the target for novel drugs in treatment and in fundamental research settings. However, much remains unknown on the working mechanisms of these drugs and the effects of chronic administration on the glutamatergic system. This paper investigates the chronic effects of two glutamate modulating drugs with imaging techniques to further clarify their working mechanisms for future research opportunities. Animals were exposed to either Saline (1 mL/kg), MK-801 (0.3 mg/kg) or Ebselen (10 mg/kg) for 7 consecutive days. At the 6th injection, animals underwent a PET/CT with ABP-688 to visualize the mGluR5 receptor. After the 7th injection, animals underwent an MRS scan to visualize Glutamate and Glutamine content. Afterwards, results were verified by mGluR5 immunohistochemistry (IHC). PET/CT analysis revealed that animals receiving chronic MK-801 or Ebselen had a significant (p<0.05) higher BPnd (respectively 2.90±0.47 and 2.87±0.46) when compared to Saline (1.97±0.39) in the caudate putamen. This was confirmed by mGluR5 IHC with 60.83%±6.30% of the area being highlighted for Ebselen and 57.14%±9.23% for MK-801 versus 50.21%±5.71% for the saline group. MRS displayed significant changes on glutamine level, when comparing chronic Ebselen (2.20±0.40 µmol/g) to Control (2.72±0.34 µmol/g). Therefore, although no direct effects on glutamate were visualized, the changes in glutamine suggest changes in the total glutamate-glutamine pool. This highlights the potential of both drugs to modulate glutamateric pathologies.
PMID: 30552293 [PubMed - as supplied by publisher]
Mycobacterium leprae causes leprosy, a dermatoneurological disease which affects the skin and peripheral nerves. One of several cellular structures affected during M. leprae infection is the endoplasmic reticulum (ER). Infection by microorganisms can result in ER stress and lead to the accumulation of unfolded or poorly folded proteins. To restore homeostasis in the cell, the cell induces a series of signaling cascades known as the unfolded protein response called UPR (unfolded protein response). The present work is aimed at investigating the in situ expression of these markers in cutaneous lesions of clinical forms of leprosy and establish possible correlation expression patterns and types of lesion. A total of 43 samples from leprosy patients were analyzed by immunohistochemistry with monoclonal antibodies against GRP78/BiP, PERK, IRE1α, and ATF6. A statistically significant difference between the indeterminate, tuberculoid, and lepromatous clinical forms was detected, with high expression of GRP78/BiP, PERK, IRE1α, and ATF6 in tuberculoid forms (TT) when compared to lepromatous leprosy (LL) and indeterminate (I) leprosy. These results represent the first evidence of ER stress in samples of skin lesions from leprosy patients. We believe that they will provide better understanding of the complex pathogenesis of the disease and facilitate further characterization of the cascade of molecular events elicited during infection.
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