Microphase Separation Induced by Differential Interactions in Diblock Copolymer/Homopolymer Blends

Phase behavior of diblock copolymer/homopolymer blends (AB/C) is investigated theoretically. The study focuses on a special case where all three binary pairs, A/B, B/C and C/A, are miscible. Despite the miscibility of the binary pairs, a closed-loop immiscible region exists in the AB/C blends when the A/C and B/C pair interactions are sufficiently different. Inside the closed-loop, the system undergoes microphase separation, exhibiting different ordered structures. This phenomenon is enhanced when the homopolymer (C) interacts more strongly to one of the blocks (A or B).Comment: 19 pages, 7 figures, submitted to J. Chem. Phy

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Wolbachia in the flesh: symbiont intensities in germ-line and somatic tissues challenge the conventional view of Wolbachia transmission routes

Symbionts can substantially affect the evolution and ecology of their hosts. The investigation of the tissue-specific distribution of symbionts (tissue tropism) can provide important insight into host-symbiont interactions. Among other things, it can help to discern the importance of specific transmission routes and potential phenotypic effects. The intracellular bacterial symbiont Wolbachia has been described as the greatest ever panzootic, due to the wide array of arthropods that it infects. Being primarily vertically transmitted, it is expected that the transmission of Wolbachia would be enhanced by focusing infection in the reproductive tissues. In social insect hosts, this tropism would logically extend to reproductive rather than sterile castes, since the latter constitute a dead-end for vertically transmission. Here, we show that Wolbachia are not focused on reproductive tissues of eusocial insects, and that non-reproductive tissues of queens and workers of the ant Acromyrmex echinatior, harbour substantial infections. In particular, the comparatively high intensities of Wolbachia in the haemolymph, fat body, and faeces, suggest potential for horizontal transmission via parasitoids and the faecal-oral route, or a role for Wolbachia modulating the immune response of this host. It may be that somatic tissues and castes are not the evolutionary dead-end for Wolbachia that is commonly thought

Dually investigated: the effect of a pressure headcollar on the behaviour, discomfort and stress of trained horses

The Dually™ is a control headcollar designed to improve equine behaviour during handling challenges by applying greater pressure than a standard headcollar. Previous research indicated it did not improve compliance in naïve horses but did result in higher Horse Grimace Scale scores (HGS) indicative of discomfort. However, subjects had not been trained to step forward to release the pressure applied by the headcollar. The current study aimed to determine the effect of training on behaviour and physiology of horses wearing the Dually™ headcollar during handling challenges. To this end, subjects received three training sessions prior to completing two handling tests in which they crossed distinct novel obstacles, one wearing a Dually™ with a line attached to the pressure mechanism and one attached to the standard ring as a control. Behaviour was coded by hypothesis blind researchers: time to cross the obstacle and proactive refusal (moving away from the obstacle) were recorded as indicators of compliance and the Horse Grimace Scale was used to measure discomfort caused by each configuration of the device. Infrared thermography of ocular temperature, heart rate variability (RMSSD and low/high frequency ratios (LF/HF)) and salivary cortisol were measured as indicators of arousal. Data from the previous study on Naïve horses was also included to compare responses to the Dually in Naïve and Trained horses. Training resulted in a decrease in RMSSD (p = 0.002) and an increase in LF/HF (p=0.012), compared to rest, indicating arousal. As per the original study, horses did not complete the tests more quickly in the Dually, compared to control (p=0.698). Trained horses from this study tended to be more proactive in the Dually compared to Controls (p=0.066) and significantly more so than Naïve horses from the previous study (p=0.002) suggesting that behaviour becomes less desirable during early Dually training. Yet, stress and HGS indicators were not higher in the Dually compared to Control during testing. Results suggest the Dually has a negative effect on behaviour but not on stress or discomfort during short handling challenges. Further research is warranted to determine the long-term effect of Dually experience on behaviour and welfare

Epithelial Tissues Have Varying Degrees of Susceptibility to KrasG12D-Initiated Tumorigenesis in a Mouse Model

Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, KrasG12D, broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the KrasG12D mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes KrasG12D-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer

The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.Peer reviewe

Hypertonic Stress Induces VEGF Production in Human Colon Cancer Cell Line Caco-2: Inhibitory Role of Autocrine PGE2

Vascular Endothelial Growth Factor (VEGF) is a major regulator of angiogenesis. VEGF expression is up regulated in response to micro-environmental cues related to poor blood supply such as hypoxia. However, regulation of VEGF expression in cancer cells is not limited to the stress response due to increased volume of the tumor mass. Lipid mediators in particular arachidonic acid-derived prostaglandin (PG)E2 are regulators of VEGF expression and angiogenesis in colon cancer. In addition, increased osmolarity that is generated during colonic water absorption and feces consolidation seems to activate colon cancer cells and promote PGE2 generation. Such physiological stimulation may provide signaling for cancer promotion. Here we investigated the effect of exposure to a hypertonic medium, to emulate colonic environment, on VEGF production by colon cancer cells. The role of concomitant PGE2 generation and MAPK activation was addressed by specific pharmacological inhibition. Human colon cancer cell line Caco-2 exposed to a hypertonic environment responded with marked VEGF and PGE2 production. VEGF production was inhibited by selective inhibitors of ERK 1/2 and p38 MAPK pathways. To address the regulatory role of PGE2 on VEGF production, Caco-2 cells were treated with cPLA2 (ATK) and COX-2 (NS-398) inhibitors, that completely block PGE2 generation. The Caco-2 cells were also treated with a non selective PGE2 receptor antagonist. Each treatment significantly increased the hypertonic stress-induced VEGF production. Moreover, addition of PGE2 or selective EP2 receptor agonist to activated Caco-2 cells inhibited VEGF production. The autocrine inhibitory role for PGE2 appears to be selective to hypertonic environment since VEGF production induced by exposure to CoCl2 was decreased by inhibition of concomitant PGE2 generation. Our results indicated that hypertonicity stimulates VEGF production in colon cancer cell lines. Also PGE2 plays an inhibitory role on VEGF production by Caco-2 cells exposed to hyperosmotic stress through EP2 activation

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-B-induced IL-8 expression by sequestering NF-B within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3NF-BIL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.P 25599(VLID)183891