An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. ...Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine.
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to ...highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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•Epithelial NOTCH1 signaling drives metastasis in serrated CRC•Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1•TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis•Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.
Prime editing enables the installation of virtually any combination of point mutations, small insertions or small deletions in the DNA of living cells. A prime editing guide RNA (pegRNA) directs the ...prime editor protein to the targeted locus and also encodes the desired edit. Here we show that degradation of the 3' region of the pegRNA that contains the reverse transcriptase template and the primer binding site can poison the activity of prime editing systems, impeding editing efficiency. We incorporated structured RNA motifs to the 3' terminus of pegRNAs that enhance their stability and prevent degradation of the 3' extension. The resulting engineered pegRNAs (epegRNAs) improve prime editing efficiency 3-4-fold in HeLa, U2OS and K562 cells and in primary human fibroblasts without increasing off-target editing activity. We optimized the choice of 3' structural motif and developed pegLIT, a computational tool to identify non-interfering nucleotide linkers between pegRNAs and 3' motifs. Finally, we showed that epegRNAs enhance the efficiency of the installation or correction of disease-relevant mutations.
CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in ...neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.
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•CXCR2 signaling is upregulated in myeloid cells in human pancreatic cancer•Cxcr2 loss reduces metastasis and inhibition prolongs tumor-free survival in mice•Neutrophils/MDSCs play a key role in the establishment of the metastatic niche•CXCR2 inhibition enhances T cell entry and confers sensitivity to anti-PD1 therapy
Steele et al. show that CXCR2 is important in immune modulation of pancreatic cancer and that inhibition of CXCR2 reduces metastasis and improves response to gemcitabine and anti-PD1. Peptide inhibitor, but not germline deletion of Cxcr2, improved survival, revealing differential effects in early and late tumors.
Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic ...disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.
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•Macrophages functionally contribute to the squamous subtype of human PDAC•Inhibition of CSF1R alters the TME and results in an enhanced T cell immune response•Loss of macrophages rewires PDAC gene expression and switches subtype•Macrophage inhibition induces changes markedly different to neutrophil targeting
Candido et al. find that CSF-1R+ macrophages play a vital role in pancreatic tumor maintenance, suppression of T cells, and tumor gene networks based on transcriptome analysis. In an autochthonous model, CSF-1R inhibition alters the gene expression programs that influence subtype specification of PDAC and extends survival.
Applying surface texture to piston liners may provide an effective means of controlling friction and hence improving engine efficiency. However, little is understood about the mechanisms by which ...pockets affect friction, primarily because of a lack of reliable experimental measurements. To address this, the influence of surface texture on film thickness and friction force was measured simultaneously in a convergent-divergent bearing, under conditions that closely replicate an automotive piston ring-liner conjunction. Film thicknesses were measured using a modified version of the ultra-thin film optical interferometry approach, enabling film thicknesses <50nm to be measured under transient, mixed lubrication conditions. This involved using the out-of-contact curvature of the specimens in place of a spacer layer and analysing multiple interference fringes to avoid fringe ambiguity. Tests were performed on both a textured sample (with features oriented normal to the direction of sliding) and a non-textured reference sample, while angular velocity, applied normal load and lubricant temperature were controlled in order to study the effect of varying lubrication regime (as typically occurs in service). Results showed that the presence of surface pockets consistently enhances fluid film thickness in the mixed lubrication regime by approximately 20nm. Although this is only a modest increase, the effect on friction is pronounced (up to 41% under these conditions), due to the strong dependence of friction on film thickness in the mixed regime. Conversely, in the full film regime, texture caused a reduction in film thickness and hence increased friction force, compared with the non-textured reference. Both textured and non-textured friction values show nearly identical dependence on film thickness, (showing that, under these conditions, texture-induced friction reduction results entirely from the change in film thickness). These results are important in providing film thickness data to validate piston-ring lubrication models and also in helping to understand the effect of surface roughness on texture performance.
•Under full film lubrication conditions, the effect of surface texture is shown to reduce film thickness, which causes an increase in lubricant shear rate and hence increases friction.•Under mixed and boundary conditions, the effect of surface texture is shown to increase film thickness, causing a reduction in asperity contact and hence reduces friction. Although this film thickness increase is small (~28%), its effect on friction is significant (~41% in this study), due to steep gradient of the Stribeck curve in this regime.
The British Society of Gastroenterology guidelines on the management of cholangiocarcinoma were originally published in 2002. This is the first update since then and is based on a comprehensive ...review of the recent literature, including data from randomised controlled trials, systematic reviews, meta-analyses, cohort, prospective and retrospective studies.
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. ...However, little is known about Arc’s molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties to retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.
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•The neuronal gene Arc encodes a protein that forms virus-like capsids•Arc protein exhibits similar biochemical properties as retroviral Gag proteins•Endogenous Arc protein is released from neurons in extracellular vesicles (EVs)•Arc EVs and capsids can mediate intercellular transfer of Arc mRNA in neurons
The neuronal protein Arc is evolutionarily related to retrotransposon Gag proteins and forms virus-like capsid structures that can transfer mRNA between cells in the nervous system.
Imaging of liver cancer Ben Ariff Claire R Lloyd Sameer Khan Mohamed Shariff Andrew V Thillainayagam Devinder S Bansi Shahid A Khan Simon D Taylor-Robinson Adrian KP Lim
World journal of gastroenterology,
03/2009, Letnik:
15, Številka:
11
Journal Article
Odprti dostop
Improvements in imaging technology allow exploitation of the dual blood supply of the liver to aid in the identification and characterisation of both malignant and benign liver lesions. Imaging ...techniques available include contrast enhanced ultrasound, computed tomography and magnetic resonance imaging. This review discusses the application of several imaging techniques in the diagnosis and staging of both hepatocellular carcinoma and cholangiocarcinoma and outlines certain characteristics of benign liver lesions. The advantages of each imaging technique are highlighted, while underscoring the potential pitfalls and limitations of each imaging modality.
To shed light on the mechanisms with which surface texture improves the tribological performance of piston–liner contacts, we have measured the transient friction response as individual pockets pass ...through a reciprocating sliding contact. Tests were performed at different sliding speeds and results compared to those from a non-textured, reference specimen under different lubrication regimes. At low speed when the contact is in the boundary regime, friction force falls abruptly as each pocket leaves the contact zone, before gradually returning to an approximately steady-state value. This suggests that each pocket acts to temporarily increase the film thickness, which then decays to its non-textured value as oil is squeezed out. At higher speeds, friction is seen to reduce in a stepwise fashion, since the period between pockets being entrained is less than the time taken for the film to decay. In addition, friction results obtained when the contact is operating in the middle of the mixed regime point to a temporary film thickness collapse as the pocket enters the contact, and this agrees with recent modelling predictions. At higher speeds, the compound effect of successive pockets is to shift the contact to the right on Stribeck curve. These results imply that each pocket gives rise to an increase in film thickness that is both short-lived and small in magnitude (we estimate a few tens of nm). However, the resulting effect on friction can be significant (up to 82 % in this study) for two reasons: (1) provided the pocket frequency is sufficiently high, each successive pocket entrainment builds the film up without there being time for it to reduce back to its steady-state value; (2) when the contact is in the mixed regime, the Stribeck curve is at its steepest and friction is therefore most sensitive to film thickness changes. This has important practical implications in that pocket spacing on piston liners should be varied as a function of reciprocating sliding speed.
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