A Multimodal Approach to the Management of Neuroendocrine Tumour Liver Metastases

Neuroendocrine tumours (NETs) are often indolent malignancies that commonly present with metastatic disease in the liver. Surgical, locoregional, and systemic treatment modalities are reviewed. A multidisciplinary approach to patient care is suggested to ensure all therapeutic options explored

Trans-anal full-thickness endoscopic resection of a rectal neuroendocrine neoplasia performed with TEO(\uae) (Karl-Storz microsurgery device) and laparoscopic ICG-guided lymphatic sampling - video vignette

Rectal neuroendocrine neoplasms (NEN) are increasingly diagnosed worldwide Compared to colonic NEN's, they are commonly smaller, less aggressive, with a low to intermediate grade of differentiation. A 5-year survival rate as high as 88% has been reported[1,2]. The risk of malignancy is closely related to tumour size, depth of invasion and lymph node involvement [1-3]. The incidence of lymph node metastasis increases with tumour (1-10mm 5.4%, 10-20mm 30%, >21mm 70%). The risk of lymph node metastasis increases with tumour depth (12% if submucosa is involved and 56% when the muscolaris propria is involved) [3-5]. This article is protected by copyright. All rights reserved

NADPH oxidase mediates TNF-α-evoked in vitro brain barrier dysfunction: roles of apoptosis and time

The pro-inflammatory cytokine TNF-α severely perturbs the integrity of the blood–brain barrier (BBB). This study explored the specific roles of NADPH oxidase and associated downstream effectors by using human brain microvascular endothelial cells (HBMECs) and human astrocytes (HAs), the key components of BBB, alone or in co-cultures to mimic human BBB. Exposure to TNF-α (6 h) impaired BBB integrity as evidenced by marked decreases in transendothelial electrical resistance and concurrent increases in paracellular flux which appeared to subside with time (24 h). Increased barrier dysfunction concurred with increases in endothelial NADPH oxidase activity, O2radical dot− production, actin stress fibre formation, MMP-2/9 activities and concomitant decreases in antioxidant (CuZn-SOD and catalase) and tight junction (claudin-5 and occludin) protein expressions. Conversely, TNF-α did not affect astrocytic MMP activities and antioxidant enzyme expressions. Unlike BBB damage, rates of HBMEC and HA apoptosis increased by time. Suppression of NADPH oxidase by apocynin or diphenyleneiodonium prevented TNF-α-evoked morphological changes and apoptosis, attenuated endothelial MMP activity and helped retain usual tight junction protein expression and barrier function. In conclusion, HBMECs constitute the main source of oxidative stress and basement-membrane degrading endopeptidases in inflammatory conditions associated with excessive release of TNF-α where targeting NADPH oxidase may prove extremely beneficial in maintaining proper barrier activity through prevention of cytoskeletal and tight junction reorganisations

BRG1 interacts with SOX10 to establish the melanocyte lineage and to promote differentiation

Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and ventral trunk melanoblasts. To define the requirement for the Smarca4 -encoded BRG1 subunit of the SWI/SNF chromatin remodeling complex, we employed in vitro models of melanocyte differentiation in which induction of melanocyte-specific gene expression is closely linked to chromatin alterations. We found that BRG1 was required for expression of Dct, Tyrp1 and Tyr, genes that are regulated by SOX10 and MITF and for chromatin remodeling at distal and proximal regulatory sites. SOX10 was found to physically interact with BRG1 in differentiating melanocytes and binding of SOX10 to the Tyrp1 distal enhancer temporally coincided with recruitment of BRG1. Our data show that SOX10 cooperates with MITF to facilitate BRG1 binding to distal enhancers of melanocyte-specific genes. Thus, BRG1 is a SOX10 co-activator, required to establish the melanocyte lineage and promote expression of genes important for melanocyte function

Mechanical performance and physico-chemical properties of limestone calcined clay cement (LC3) in Malawi

Malawi is one of the least-developed countries in Sub-Saharan Africa with disaster-prone housing infrastructure characterized by poor construction materials. Therefore, there is a need to provide resilient and cost-effective materials, such as limestone calcined clay cement (LC3). However, the exploitation of LC3 in Malawi is limited due to a lack of mineralogical information about the clays and limestone and related strength and durability when used as a cementitious material. In this study, the strength and physico-chemical properties of LC3 systems with 50% and 40% clinker contents (LC3-50 and LC3-40) were investigated. Cement mortar specimens were prepared at water to cement (w/c) ratios of 0.45, 0.5, and 0.6 with varying calcined clay (CC) to limestone (CC/LS) ratios (1:1, 2:1, and 3:1). The effects of CC/LS ratio on the fresh properties, strength, and durability were investigated. The results showed that specimens with 40% Portland cement replacement levels (LC3-40) exhibited higher standard consistency (up to 45%) than LC3-50, porosity in the range of 8.3–13.3%, and maximum water uptake in the range of 3.8–10.9%. On the other hand, LC3-50 samples offered the highest strength of approximately 40 MPa, complying with requirements for pozzolanic cementitious materials, whereas LC3-40 conforms to the strength requirements for masonry cements. This work shows that LC3 systems can be manufactured with local clays and limestone available in Malawi, and used as a sustainable construction material to mitigate carbon emissions as well as boost the local economy

Behind film performance in China’s changing institutional context:The impact of signals

Grounded in signaling theory, this paper investigates the signals reflecting product quality, innovativeness, reputation and cultural background which influence film performance, i.e. film survival (duration on cinema screen) and box office success, in China’s changing institutional context. This market has grown substantially and still possesses potential for further development. However, China’s unique institutional context presents challenges. By examining an expanded range of potential signals, two of which have not previously been examined in the literature, namely imported films and enhanced format film formats such as 3D and IMAX, we develop a conceptual framework and argue that signaling theory needs to be combined with institutional context. Similar to findings for film industries in other countries, we find quality and reputational signals including budget, star power, sequels, and online consumer reviews to be important in China. However, unique results are also revealed. Chinese consumers react to an innovativeness signal in that they are specifically attracted to enhanced format films. Film award nominations and prizes are insignificant reputational signals. Once other signals are taken into account, imported films on average do not perform as well as domestic films. We link these findings to China’s unique institutional setting and offer important implications for management, recognizing the challenges to film companies of competing in an increasingly globalized market. The paper is also of relevance to policymakers given their continued efforts in shaping the development of China’s film industry

In search of negativity bias:An empirical study of perceived helpfulness of online reviews

A basic tenet of psychology is that the psychological effects of negative information outweigh those of positive information. Three empirical studies show that the negativity bias can be attenuated or even reversed in the context of electronic word-of-mouth (eWoM). The first study analyzes a large sample of customer reviews collected from Amazon.com and concludes that negative reviews are no more helpful than positive ones when controlling for review quality The second study follows up with a virtual experiment that confirms the lack of negativity bias in evaluating the helpfulness of online reviews. The third study demonstrates that the negativity effect can be reversed by manipulating the baseline valences. This work challenges the conventional wisdom of “bad is stronger than good” and contributes to the understanding of the eWoM phenomenon

Inhibition of TNF-α protects in vitro brain barrier from ischaemic damage

Cerebral ischaemia, associated with neuroinflammation and oxidative stress, is known to perturb blood–brain barrier (BBB) integrity and promote brain oedema formation. Using an in vitro model of human BBB composed of brain microvascular endothelial cells and astrocytes, this study examined whether suppression of TNF-α, a potent pro-inflammatory cytokine, might attenuate ischaemia-mediated cerebral barrier damage. Radical decreases in transendothelial electrical resistance and concomitant increases in paracellular flux across co-cultures exposed to increasing periods of oxygen-glucose deprivation alone (0.5–20 h) or followed by 20 h of reperfusion (OGD ± R) confirmed the deleterious effects of ischaemic injury on cerebral barrier integrity and function which concurred with reductions in tight junction protein (claudin-5 and occludin) expressions. OGD ± R elevated TNF-α secretion, NADPH oxidase activity, O2radical dot− production, actin stress fibre formation, MMP-2/9 activities and apoptosis in both endothelial cells and astrocytes. Increases in MMP-2 activity were confined to its extracellular isoform and treatments with OGD + R in astrocytes where MMP-9 could not be detected at all. Co-exposure of individual cell lines or co-cultures to an anti-TNF-α antibody dramatically diminished the extent of OGD ± R-evoked oxidative stress, morphological changes, apoptosis, MMP-2/9 activities while improving the barrier function through upregulation of tight junction protein expressions. In conclusion, vitiation of the exaggerated release of TNF-α may be an important therapeutic strategy in preserving cerebral integrity and function during and following a cerebral ischaemic attack

Expression of NADPH Oxidase (NOX) 5 in Rabbit Corneal Stromal Cells

To determine whether NOX 5 is expressed in rabbit corneal stromal cells (RCSC). NADPH oxidases (NOXes) are enzymes that preferentially use NADPH as a substrate and generate superoxide. Several isoforms of NOXes function as multi-protein complexes while NOX5 and DUOXs do not require the accessory proteins for their activity and possess calcium binding EF hands.Human NOX5 primers were used to amplify the rabbit NOX5 by RT-PCR. Amplified product was sequenced to confirm its identity. The protein encoded by the NOX5 was identified by western blot analysis. NOX5 siRNA was used to reduce transcript, protein, and calcium stimulated activity. In silico analyses were performed to establish the putative structure, functions, and evolution of rabbit NOX5.NOX activity was measured in RCSC with NADPH rather than NADH as a substrate. RT-PCR with NOX5 primers amplified 288 bp product using RCSC cDNA, which, when sequenced, confirmed its identity to human NOX5 mRNA. This sequence was used to predict the rabbit (Oryctolagus cuniculus) NOX5 gene. NOX5 siRNA reduced amounts of NOX5 mRNA in RCSC and reduced ionomycin stimulated superoxide production. A protein of about 65 to 70 kDa encoded by the NOX5 was detected by western blot analysis. In silico analysis predicted a putative rabbit NOX5 protein containing 801 amino acids. Motif searches predicted the presence of at least 3 putative EF-hands in N-terminus and a NOX domain in C terminal region.The data document that the NOX5 gene was expressed in cells of lagomorphs unlike rodents, making the rabbit an interesting model to study NOX5 functions. The activity of the rabbit NOX5 was calcium stimulated, a trait of NOX5 in general. NOX5 may also prove to be a useful genetic marker for studying the taxonomic position of lagomorphs and the Glires classification