The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a ...link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.
Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), ...which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes.
Banked ascites supernatants from patients with newly diagnosed advanced EOC were analysed for mtDNA, neutrophil elastase, and activation of healthy donor neutrophils and platelets. TCGA was mined for expression of SELP and ELANE.
The highest quartile of ascites mtDNA correlated with reduced progression-free survival (PFS) and a higher likelihood of disease progression within 12-months following primary surgery (n = 68, log-rank, p = 0.0178). NETs were detected in resected tumours. Ascites supernatants chemoattracted neutrophils, induced NETs, and activated platelets. Ascites exposure rendered neutrophils suppressive, based on abrogation of ex vivo stimulated T cell proliferation. Increased SELP mRNA expression correlated with worse overall survival (n = 302, Cox model, p = 0.02).
In this single-centre retrospective analysis, ascites mtDNA correlated with worse PFS in advanced EOC. Mitochondrial and other DAMPs in ascites may activate neutrophil and platelet responses that facilitate metastasis and obstruct anti-tumour immunity. These pathways are potential prognostic markers and therapeutic targets.
Bio-food materials are heterogeneous in structure with cellular diversity, where the majority of the water is located in the intracellular spaces. Understanding of the nature of the microscopic ...behaviour of water transport is crucial to enhance the energy efficiency in food processing and obtain the better quality of processed food. In this research, apoplastic and symplastic transport of cellular water in the bio-food material during drying was investigated using
H-NMR-T
relaxometry. We found that intracellular water (ICW) migrates from intracellular spaces to the intercellular spaces by progressive rupturing the cell membranes while drying at a higher temperatures (60 °C-70 °C). In this case, apoplastic process dominates the transport process. However, at lower temperature (45 °C), cell membranes do not rupture and therefore ICW migrates from cell to the neighbouring cell through micro-capillaries, where the symplastic process dominates the mass transfer at different stages of drying.
Background: Gabapentin has been introduced as an effective agent for post‐operative pain control. This study aimed to test the effects of pre‐ and post‐incision administration of different doses of ...gabapentin on post‐operative morphine requirement and pain following lumbar laminectomy.
Methods: In this randomized clinical trial, 175 patients were allocated into seven groups of 25 patients each to receive placebo or gabapentin 600, 900 or 1200 mg pre‐ or post‐incision. Total patient‐controlled intravenous morphine consumption during the first 24 post‐operative hours, and the time to the first demand for morphine were recorded. Pain score at rest (visual analogue scale) was recorded every 30 min in the first 4 h and then every 2 h until 24 h post‐operatively. Side‐effects were observed.
Results: In the first 12 h, morphine consumption was less, pain scores were lower and the time to the first demand for analgesia was longer in groups receiving gabapentin 900 or 1200 mg either pre‐ or post‐incision, compared with placebo and gabapentin 600 mg (P<0.001). There was no difference between gabapentin 900 and 1200 mg. Pain score, morphine consumption and time to the first demand for analgesia in equal pre‐ or post‐incision doses of gabapentin were not significantly different. No differences in the side‐effects were observed between groups.
Conclusion: Gabapentin 900 or 1200 mg, administered either pre‐ or post‐incision, was found to be effective in pain management following lumbar laminectomy. Similar doses of gabapentin provide the same post‐operative analgesia whether administered pre‐ or post‐incision.
Abstract
The political settlements framework argues that the distribution of organizational power is important for understanding the economic and political effects of institutions and policies. ...Institutions and policies describe rules that in turn determine resource allocation, and these can affect different types of organizations in very different ways. Organizations can be expected to support, resist or distort particular institutions or policies depending on their interests and capabilities. The distribution of organizational power can therefore determine the institutions and policies that are likely to persist as well as the ones most likely to be developmental in that context. This directs our attention to the importance of accurately identifying the relative power and capabilities of relevant organizations that describe a particular political settlement and how these may be changing over time. The articles in African Affairs that have used the political settlements framework demonstrate its usefulness. In this overview we examine the motivations behind the development of the framework and some of the challenges of applying it in the context of dynamic interactions between institutions and organizations. We also discuss the most appropriate definition of a political settlement, the questions the framework is most suited to answer and the challenges ahead for developing the framework and its applications.
Customer satisfaction has become the primary target for each successful running business currently. They have the true potential in uplifting a tiny business overnight to completely shutting down a ...brand. Real time analysis of customer opinion (sentiment) is the backbone of this success. Thus this piece of research tries to focus light on the challenges encountered by businesses in four categories of opinion mining. Natural Language Processing with machine learning algorithms works wonders for opinion mining. What is important is the correct choice of opinion mining for a specific type of business as each one of them demands an idiosyncratic approach. The research indeed shares a quick infusion for businesses to safeguard. Countless advice is beared by businesses to have real time analysis, but this research endeavor by showcasing its ideal infusion.
Colorectal Cancer (CRC) ranks third among all cancer-related deaths around the globe. Chemotherapy may prolong the survival of CRC patients to some extent, but its clinical use is associated with ...grave side effects on overall health. Contrary to chemotherapy, the use of plant-derived therapeutic molecules offered advantages because of their reduced toxicity. Polyphenol is a group of phytochemicals that impart many therapeutic benefits in the treatment of diabetes, cardiovascular disease and cancer. Various signaling pathways, including Wnt/β-catenin, MAPK/PI3K and TGF-β/Smad, play very important roles in the development and progression of CRC. Polyphenols inhibit CRC progressions by modulating these signaling pathways e.g. curcumin and resveratrol impede cancer cell proliferation by inhibiting Wnt signaling. Because of their lower aqueous solubility, the therapeutic efficacy of polyphenols is not fully exploited. In order to increase their bioavailability and efficacy, the nanoformulations of polyphenols have been formulated and investigated against various CRC test models. The main objective of this review is to explore the potential roles of polyphenols and their nanoformulations in the treatment of colorectal cancer.
We used PubMed, Web of Science, ScienceDirect, Google Scholar and Scopus electronic databases by searching the keywords: nanoparticles, polyphenols, colorectal cancer, cell signaling pathways. Mostly, the articles were retrieved directly from the journals licensed to the library of Qassim University, Saudi Arabia.
Literature analysis has shown that the polyphenols contain several important bioactive compounds, which showed potential effectiveness against CRC. Incorporating polyphenols into nanoparticles further enhanced their bioavailability and efficacy. The findings from various studies demonstrated that polyphenol-nanoformulations accelerated the apoptosis in CRC cells by upregulating the levels of caspases and Bax, whereas inhibiting the CRC cell proliferation by downregulating the expression of Bcl-2 and ERK1/2.
This review provides a valuable resource on the important anti-CRC role of polyphenols and their nanoformulations. This review will expand our knowledge about the anti-CRC roles of polyphenols and their mechanisms of action through the multiple cell signaling pathways.
Underground water in many regions of the world is contaminated with high concentrations of arsenic and the resulting toxicity has created a major environmental and public health problem in the ...affected regions. Chronic arsenic exposure can cause many diseases, including various physical and psychological harms. Although the physical problems caused by arsenic toxicity are well reported in literature, unfortunately the consequences of arsenic exposure on mental health are not adequately studied. Therefore we conducted a review of the available literature focusing on the social consequences and detrimental effects of arsenic toxicity on mental health. Chronic arsenic exposures have serious implications for its victims (i.e. arsenicosis patients) and their families including social instability, social discrimination, refusal of victims by community and families, and marriage-related problems. Some studies conducted in arsenic affected areas revealed that arsenic exposures are associated with various neurologic problems. Chronic arsenic exposure can lead to mental retardation and developmental disabilities such as physical, cognitive, psychological, sensory and speech impairments. As health is defined by the World Health Organization as "a state of complete physical, mental and social wellbeing", the social dimensions have a large impact on individual's mental health. Furthermore studies in China und Bangladesh have shown that mental health problems (e.g. depression) are more common among the people affected by arsenic contamination. Our study indicates various neurological, mental and social consequences among arsenic affected victims. Further studies are recommended in arsenic-affected areas to understand the underlying mechanisms of poor mental health caused by arsenic exposure.
Mechanical properties of nanoconfined water layers are still poorly understood and continue to create controversy, despite their importance for biology and nanotechnology. We report on dynamic ...nanomechanical measurements of water films compressed to a few single molecular layers. We show that the mechanical properties of nanoconfined water layers change significantly with their dynamic state. In particular, we observed a sharp transition from viscous to elastic response even at extremely slow compression rates, indicating that mechanical relaxation times increase dramatically once water is compressed to less than 3-4 molecular layers.
This observational study assessed the prevalence of co-existing type 2 inflammatory conditions T2Cs; asthma, atopic dermatitis (AD), allergic rhinitis, and chronic rhinosinusitis with nasal polyps ...(CRSwNP) in patients with moderate-to-severe (M/S) type 2 asthma, M/S CRSwNP, or M/S AD, in the real-world setting. Data from 761 physicians in the US and EUR5 were sourced from Adelphi Disease-Specific Programmes covering patients with M/S asthma (
n
= 899), M/S CRSwNP (
n
= 683), and M/S AD (
n
= 1497). At least one T2C was identified in 66%, 69%, and 46% of M/S asthma, M/S CRSwNP, and M/S AD cohorts, respectively, and 24%, 36% and 16% had at least two T2Cs; trends were similar in the US and EUR5. In patients with M/S asthma or M/S CRSwNP, T2Cs commonly presented as mild or moderate. The comorbidity burden suggests that an integrated treatment approach is warranted to address underlying type 2 inflammation in patients with M/S type 2 diseases.
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