One reason for the well-known fact that the complex Langevin (CL) method sometimes fails to converge or converges to the wrong limit has been identified long ago: it is insufficient decay of the ...probability density either near infinity or near poles of the drift, leading to boundary terms that spoil the formal argument for correctness. To gain a deeper understanding of this phenomenon, in a previous paper Phys. Rev. D 99, 014512 (2019) we have studied the emergence of such boundary terms thoroughly in a simple model, where analytic results can be compared with numerics. Here we continue this type of analysis for more physically interesting models, focusing on the boundaries at infinity. We start with Abelian and non-Abelian one-plaquette models, and then we proceed to a Polyakov chain model and finally to high density QCD and the 3D XY model. We show that the direct estimation of the systematic error of the CL method using boundary terms is in principle possible.
Iridium oxide based electrodes are among the most promising candidates for electrocatalyzing the oxygen evolution reaction, making it imperative to understand their chemical/electronic structure. ...However, the complexity of iridium oxide's electronic structure makes it particularly difficult to experimentally determine the chemical state of the active surface species. To achieve an accurate understanding of the electronic structure of iridium oxide surfaces, we have combined synchrotron-based X-ray photoemission and absorption spectroscopies with ab initio calculations. Our investigation reveals a pre-edge feature in the O K-edge of highly catalytically active X-ray amorphous iridium oxides that we have identified as O 2p hole states forming in conjunction with Ir(III). These electronic defects in the near-surface region of the anionic and cationic framework are likely critical for the enhanced activity of amorphous iridium oxides relative to their crystalline counterparts.
Alloying provides a means by which to tune a metal catalyst's electronic structure and thus tailor its performance; however, mean-field behaviour in metals imposes limits. To access unprecedented ...catalytic behaviour, materials must exhibit emergent properties that are not simply interpolations of the constituent components' properties. Here we show an emergent electronic structure in single-atom alloys, whereby weak wavefunction mixing between minority and majority elements results in a free-atom-like electronic structure on the minority element. This unusual electronic structure alters the minority element's adsorption properties such that the bonding with adsorbates resembles the bonding in molecular metal complexes. We demonstrate this phenomenon with AgCu alloys, dilute in Cu, where the Cu d states are nearly unperturbed from their free-atom state. In situ electron spectroscopy demonstrates that this unusual electronic structure persists in reaction conditions and exhibits a 0.1 eV smaller activation barrier than bulk Cu in methanol reforming. Theory predicts that several other dilute alloys exhibit this phenomenon, which offers a design approach that may lead to alloys with unprecedented catalytic properties.
We study the deconfinement transition line in QCD for quark chemical potentials up to μq ∼ 5 T ( μB ∼ 15 T ). To circumvent the sign problem we use the complex Langevin equation with gauge ...cooling. The plaquette gauge action is used with two flavors of naive Wilson fermions at a relatively heavy pion mass of roughly 1.3 GeV. A quadratic dependence describes the transition line well on the whole chemical potential range.
The canonical WNT signaling pathway is crucial for intestinal stem cell renewal and aberrant WNT signaling is an early event in colorectal cancer (CRC) development. Here, we show for the first time ...that WNT2 is one of the most significantly induced genes in CRC stroma as compared to normal stroma. The impact of stromal WNT2 on carcinoma formation or progression was not addressed so far. Canonical WNT/β-catenin signaling was assessed using a 7TGP-reporter construct. Furthermore, effects of WNT2 on fibroblast migration and invasion were determined using siRNA-mediated gene silencing. Tumor cell invasion was studied using organotypic raft cultures and in vivo significance was assessed via a xenograft mouse model. We identified cancer-associated fibroblasts (CAFs) as the main source of WNT2. CAF-derived WNT2 activated canonical signaling in adenomatous polyposis coli/β-catenin wild-type colon cancer cells in a paracrine fashion, whereas no hyperactivation was detectable in cell lines harboring mutations in the adenomatous polyposis coli/β-catenin pathway. Furthermore, WNT2 activated autocrine canonical WNT signaling in primary fibroblasts, which was associated with a pro-migratory and pro-invasive phenotype. We identified FZD8 as the putative WNT2 receptor in CAFs. Three-dimensional organotypic co-culture assays revealed that WNT2-mediated fibroblast motility and extracellular matrix remodeling enhanced cancer cell invasion of cell lines even harboring mutations in the adenomatous polyposis coli/β-catenin pathway. Thus, suggesting a tumor-promoting influence on a broad range of CRC. In line, WNT2 also promotes tumor growth, invasion and metastasis in vivo. Moreover, high WNT2 expression is associated with poor prognosis in human CRC. The identification of the pro-malignant function of stromal derived WNT2 in CRC classifies WNT2 and its receptor as promising stromal targets to confine cancer progression in combination with conventional or targeted therapies.
The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal ...cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-β (TGFβ) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFβ/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFβ to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFβ was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.
Summary
Background
Long‐term outcome of chronic hepatitis C patients with successful viral eradication seems to be promising.
Aim
To evaluate mortality, incidence of hepatocellular carcinoma (HCC), ...liver failure and liver transplantation in sustained virological responders (SVR) and non‐SVR patients with different stages of fibrosis.
Methods
Seven hundred and fourteen patients with a follow‐up of 7.2 (1–21.1) years (age: 51.4 ± 12.0 years, 276 female, IFN‐monotherapy: n = 19, IFN/RBV: n = 122, peg‐IFN/RBV: n = 573, SVR: 551, non‐SVR: 163) were studied. Two hundred and ten of 540 patients with a liver biopsy prior to treatment had advanced stages of fibrosis (Metavir F3/F4).
Results
Forty‐eight patients died during follow‐up, 15 with SVR and 33 without (P < 0.001). Five‐ and 10‐year mortality rates were 1.8% (10/551) and 2.7% (15/551) in the SVR group and 8.6% (14/163) and 19.1% (31/163) in the non‐SVR patients (P < 0.001). In 29 patients, decompensation of liver disease SVR: 9 (1.6%) vs. non‐SVR: 20 (12.3%); P < 0.001 occurred and in 29 patients, HCC developed during follow‐up SVR: 10 (1.8%) vs. non‐SVR: 19 (11.7%); P < 0.001. Non‐SVR was an independent predictor for developing (i) HCC HR: 2.36 (95% CI: 1.07–5.23; P = 0.034, (ii) liver‐related complications HR: 2.62; (95% CI: 1.18–5.81; P = 0.018 and (iii) mortality (HR: 3.46; 95% CI: 1.91–6.29; P < 0.001). For patients with early stages of fibrosis (F0–F2), a survival benefit of SVR patients could not be demonstrated.
Conclusions
Successful anti‐viral therapy decreases mortality, incidence of hepatocellular carcinoma and liver failure in patients with advanced fibrosis. However, hepatocellular carcinoma development or liver failure are not prevented completely, and further follow‐up of patients is advisable.
The activated tumor stroma participates in many processes that control tumorigenesis, including tumor cell growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) represent the major ...cellular component of the stroma and are the main source for connective tissue components of the extracellular matrix and various classes of proteolytic enzymes. The signaling pathways involved in the interactions between tumor and stromal cells and the molecular characteristics that distinguish normal 'resting' fibroblasts from cancer-associated or '-activated' fibroblasts remain poorly defined. Recent studies emphasized the prognostic and therapeutic significance of CAF-related molecular signatures and a number of those genes have been shown to serve as putative therapeutic targets. We have used immuno-laser capture microdissection and whole-genome Affymetrix GeneChip analysis to obtain transcriptional signatures from the activated tumor stroma of colon carcinomas that were compared with normal resting colonic fibroblasts. Several members of the Wnt-signaling pathway and gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and transforming growth factor-β (TGFβ) pathway activation were induced in CAFs. The putative TGFβ-target IGFBP7 was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. We show here that in contrast to its tumor-suppressor function in epithelial cells, IGFPB7 can promote anchorage-independent growth in malignant mesenchymal cells and in epithelial cells with an EMT phenotype when IGFBP7 is expressed by the tumor cells themselves and can induce colony formation in colon cancer cells co-cultured with IGFBP7-expressing CAFs by a paracrine tumor-stroma interaction.
Summary
Background
The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin (PEG/RBV) therapy in patients with chronic hepatitis C (CHC). Recently, a dinucleotide frame shift ...variant in ss469415590 (TT or ΔG) was described, which generates the novel interferon lambda 4 protein (IFNL4). IFNL4 ss469415590 (ΔG) allele carriers have an impaired clearance of HCV infection and response to IFN‐α therapy. In this study, we compared the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC.
Aim
To compare the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC.
Methods
A total of 754 PEG/RBV patients treated (male/female = 484/270; Caucasians: 98.8%; mean age: 42.8 CI 95%: 42.0–43.6 y; genotype (GT)1: n = 435, GT2: n = 23, GT3: n = 185, GT4: n = 114) were investigated. Liver fibrosis was assessed by liver biopsy in 456 patients. Single nucleotide polymorphisms (SNPs) in ss469415590, rs12979860 and rs8099917 were analysed by RT‐PCR system.
Results
Of the patients, 12.9% (n = 97) had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% (n = 387) were heterozygous (TT/ΔG) and 35.8% (n = 270) had TT/TT. IFNL4 polymorphism was independently associated with SVR in GT1 (OR: 2.539, CI 95%: 1.629–3.021, P < 0.001) and GT4 (OR: 12.573, CI 95%: 3.427–46.133, P < 0.001), but not in GT3 (OR: 1.514, CI 95%: 0.933–2.458, P = 0.093).
IFNL4 correlated strongly with rs12979860 (ρ = 0.988, P < 0.001), but only moderately with rs8099917 (ρ = 0.598, P < 0.001).
Conclusions
These findings underscore the role of IFNL4 for treatment response in patients with CHC genotypes 1 and 4. However, due to its strong correlation with rs12979860 in IL28B, there is no benefit in additional testing for IFNL4 for treatment prediction in Caucasian patients. By contrast, IFNL4 improves prediction of response to interferon‐based therapies, if SNP rs8099917 is used.
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