Wnt signalling in adenomas of familial adenomatous polyposis patients

BACKGROUND: Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP). METHODS: We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients. RESULTS: We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were downregulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively). CONCLUSION: Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours

Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata

Aims Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown. Methods and results We detected enhanced FAP expression in type IV-V human aortic atheromata (n = 12), compared with type II-III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R2= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01). Conclusion Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous cap

Multi-Cancer Computational Analysis Reveals Metastasis-Associated Variant of Desmoplastic Reaction Involving INHBA and THBS2

Despite extensive research, the details of the metastasis-associated biological mechanisms are largely unknown. Here, we analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype. We conclude that there is one shared &#x201c;core&#x201d; metastasis-associated gene expression signature corresponding to a specific variant of desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. It has several features, such as coordinated expression of particular collagens, mainly COL11A1 and other genes, mainly THBS2 and INHBA. The universally prominent presence of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-&#x3b2; signaling, because activin A is a member of the TGF-&#x3b2; superfamily consisting of an INHBA homodimer. It is accompanied by the expression of several transcription factors related to epithelial-mesenchymal transition, but not of SNAI1, and expression of E-cadherin is not downregulated. It is reversible, as evidenced by its absence in many matched metastasized samples, but its presence indicates that metastasis has occurred. Therefore, these results can be used for developing high-specificity biomarkers, as well as potential multi-cancer metastasis-inhibiting therapeutics targeting the corresponding biological mechanism

On relaxation phenomena in a two-component plasma

The relaxation of temperatures and velocities of the components of a quasi-equilibrium two-component homogeneous completely ionized plasma is investigated on the basis of a generalization of the Chapman-Enskog method applied to the Landau kinetic equation. The generalization is based on the functional hypothesis in order to account for the presence of kinetic modes of the system. In the approximation of a small difference of the component temperatures and velocities, it is shown that relaxation really exists (the relaxation rates are positive). The proof is based on the arguments that are valid for an arbitrary two-component system. The equations describing the temperature and velocity kinetic modes of the system are investigated in a perturbation theory in the square root of the small electron-to-ion mass ratio. The equations of each order of this perturbation theory are solved with the help of the Sonine polynomial expansion. Corrections to the known Landau results related to the distribution functions of the plasma and relaxation rates are obtained. The hydrodynamic theory based on these results should take into account a violation of local equilibrium in the presence of relaxation processes.Comment: 18 page

Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.We acknowledge the following sources of research funding: NIH U19 A1063603 (DRS, SMK), NIH DK46335 (JWK) and NIH R01AG19259 (JNB)info:eu-repo/semantics/publishedVersio

Optimization of Radio and Computational Resources for Energy Efficiency in Latency-Constrained Application Offloading

Providing femto-access points (FAPs) with computational capabilities will allow (either total or partial) offloading of highly demanding applications from smart-phones to the so called femto-cloud. Such offloading promises to be beneficial in terms of battery saving at the mobile terminal (MT) and/or latency reduction in the execution of applications, whenever the energy and/or time required for the communication process are compensated by the energy and/or time savings that result from the remote computation at the FAPs. For this problem, we provide in this paper a framework for the joint optimization of the radio and computational resource usage exploiting the tradeoff between energy consumption and latency, and assuming that multiple antennas are available at the MT and the serving FAP. As a result of the optimization, the optimal communication strategy (e.g., transmission power, rate, precoder) is obtained, as well as the optimal distribution of the computational load between the handset and the serving FAP. The paper also establishes the conditions under which total or no offloading are optimal, determines which is the minimum affordable latency in the execution of the application, and analyzes as a particular case the minimization of the total consumed energy without latency constraints.Comment: Accepted to be published at IEEE Transactions on Vehicular Technology (acceptance: November 2014

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects