Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a major role in the maintenance of extracellular matrix homeostasis and are involved in the process of tumour invasion and metastasis in several malignant tumour entities. The goal of this study is to evaluate the diagnostic value of various circulating MMPs and TIMPs in blood plasma for a non-invasive detection of transitional cell carcinoma of the bladder (TCC). METHODS: In this study the concentrations of MMP1, MMP2, MMP3, MMP9, their inhibitors TIMP1, TIMP2, and the MMP1/TIMP1-complex (MTC1) were quantified in blood plasma with the sandwich enzyme-linked immunosorbent assay (ELISA). Blood plasma samples were investigated from 68 patients (non-metastasized, n = 57 and metastasized, n = 11) with TCC of the bladder and from 79 healthy controls. The mROC program was used to calculate the best two- and three- marker combinations. The diagnostic values for all single markers and the marker combinations were estimated both by the overall diagnostic performance index area under the ROC curve (AUC) and the sensitivity and specificity at cutoff limits with the highest diagnostic accuracy and at the 90% and 95% limits of sensitivity and specificity, respectively. RESULTS: The median MMP2 concentration was elevated in blood plasma in all patient groups with TCC in comparison to the controls (p < 0.001). The concentrations of TIMP1, TIMP2, and MTC1 in plasma probes were significantly lower from patients with non-metastasized TCC compared to the controls. MMP2 tested alone reached the highest sensitivity and specificity at 75%, respectively. The sensitivity and specificity increased when tested in combination with MMP9 and TIMP1 (97%, 94%, respectively). The combination of MMP9 and TIMP1 also showed an improved sensitivity (80%) and specificity (99%) than tested alone. CONCLUSION: MMP2 is a statistically significant marker in blood plasma for bladder cancer detection with an increased diagnostic value in combination with MMP9 and TIMP1. This study showed that the highest sensitivities and specificities are not obtained by testing each marker alone. As shown by the best two-marker combination, which includes MMP9 and TIMP1, the optimized combination does not always include the best single markers

Nitrogen isotope ratios trace high-pH conditions in a terrestrial Mars analog site

This research was financially supported by the Leverhulme Trust to T.W.L. E.E.S. acknowledges start-up funds from the University of St. Andrews. The NASA Astrobiology Institute under Cooperative Agreement no. NNA15BB03A issued through the Science Mission Directorate also provided funds as did a NASA Fellowship in support of C.T. under Cooperative Agreement no. 80NSSC19K1739 issued through the NASA Office of STEM Engagement.High-pH alkaline lakes are among the most productive ecosystems on Earth and prime targets in the search for life on Mars; however, a robust proxy for such settings does not yet exist. Nitrogen isotope fractionation resulting from NH3 volatilization at high pH has the potential to fill this gap. To validate this idea, we analyzed samples from the Nördlinger Ries, a Miocene impact crater lake that displayed pH values up to 9.8 as inferred from mineralogy and aqueous modeling. Our data show a peak in δ15N of +17‰ in the most alkaline facies, followed by a gradual decline to around +5‰, concurrent with the proposed decline in pH, highlighting the utility of nitrogen isotopes as a proxy for high-pH conditions. In combination with independent mineralogical indicators for high alkalinity, nitrogen isotopes can provide much-needed quantitative constraints on ancient atmospheric Pco2 (partial pressure of CO2) and thus climatic controls on early Earth and Mars.Publisher PDFPeer reviewe

Systematic evaluation of the features influencing the accuracy of third order measurements

The aims of this study were to evaluate the relationship of third order measurements on dental casts with those on lateral radiographs, and to identify those incisor features on radiographs which can best explain third order measurements on dental casts. Lateral cephalograms and corresponding dental casts were obtained from 39 untreated Caucasians (12 males, 27 females; mean age 19.5 years; standard deviation 3.7 years) with occlusal relationships considered to be ‘normal'. The upper (U1) and lower (L1) incisors were assessed with reference to the occlusal plane perpendicular which was established on the lateral radiographs, including third order angles (U1TR, L1TR) which were also derived from direct dental cast measurements (U1TA, L1TA). Both single regression and multiple linear regression analysis with stepwise variable selection were performed using third order measurements on casts as the dependent variable and crown axis (U1C, L1C), root axis (U1R, L1R), tip-apex connecting line (U1E, L1E), and radiographic third order measurements as independent variables. Single regression analysis indicated an overall difference of 0.02 degrees between radiographic third order inclination and cast assessment in the maxilla (mandible: −2.83 degrees). A change of 1 degree in radiographic third order inclination would produce a change of 0.65 degrees for U1TA and 0.86 degrees for L1TA assessments. Third order measurements on dental casts can best be explained by a linear combination of U1TR and U1E (maxilla) and of L1TR and L1C (mandible) measurements. This study demonstrates the functional enmeshment between two different third order assessments and the most common incisor features on lateral radiographs. Both methods of third order evaluation show sufficient reliability and are appropriate for routine orthodontic practic

Effect of peri-implant mucosal thickness on esthetic outcomes and the efficacy of soft tissue augmentation procedures: Consensus report of group 2 of the SEPA/DGI/OF workshop

OBJECTIVES The aim of this study was to comprehensively assess the literature in terms of the effect of peri-implant mucosal thickness on esthetic outcomes and the efficacy of soft tissue augmentation procedures to increase the mucosal thickness with autogenous grafts or soft tissue substitutes. MATERIAL AND METHODS Two systematic reviews (SR) were performed prior to the consensus meeting to assess the following questions. Review 1, focused question: In systemically healthy patients with an implant-supported fixed prosthesis, what is the influence of thin as compared to thick peri-implant mucosa on esthetic outcomes? Review 2, focused question 1: In systemically healthy humans with at least one dental implant (immediate or staged implant), what is the efficacy of connective tissue graft (CTG), as compared to absence of a soft tissue grafting procedure, in terms of gain in peri-implant soft tissue thickness (STT) reported by randomized controlled clinical trials (RCTs) or controlled clinical trials (CCTs)? Review 2, focused question 2: In systemically healthy humans with at least one dental implant (immediate or staged implant), what is the efficacy of CTG, as compared to soft tissue substitutes, in terms of gain in peri-implant STT reported by RCTs or CCTs? The outcomes of the two SRs, the consensus statements, the clinical implications, and the research recommendations were discussed and subsequently approved at the consensus meeting during the group and plenary sessions. CONCLUSIONS There was a tendency of superior esthetic outcomes in the presence of a thick mucosa. The connective tissue graft remains the standard of care in terms of increasing mucosa thickness

Human Embryonic Stem Cells and Embryonal Carcinoma Cells Have Overlapping and Distinct Metabolic Signatures

While human embryonic stem cells (hESCs) and human embryonal carcinoma cells (hECCs) have been studied extensively at the levels of the genome, transcriptome, proteome and epigenome our knowledge of their corresponding metabolomes is limited. Here, we present the metabolic signatures of hESCs and hESCs obtained by untargeted gas chromatography coupled to mass spectrometry (GC-MS). Whilst some metabolites are common to both cell types, representing the self-renewal and house-keeping signatures, others were either higher (e.g., octadecenoic acid, glycerol-3-phosphate, 4-hydroxyproline) or lower (e.g., glutamic acid, mannitol, malic acid, GABA) in hESCs (H9) compared to hECCs (NTERA2), these represent cell type specific signatures. Further, our combined results of GC-MS and microarray based gene expression profiling of undifferentiated and OCT4-depleted hESCs are consistent with the Warburg effect which is increased glycolysis in embryonic cells and tumor cells in the presence of O2 while oxidative phosphorylation (OXPHOS) is impaired or even shut down. RNAi-based OCT4 knock down mediated differentiation resulted in the activation of the poised OXPHOS machinery by expressing missing key proteins such as NDUFC1, UQCRB and COX, increase in TCA cycle activity and decreased lactate metabolism. These results shed light on the metabolite layer of pluripotent stem cells and could potentially establish novel metabolic markers of self renewal and pluripotency

Голодомор 1932 –– 1933 рр. в Україні як геноцид

Given its fundamental role in development and cancer, the Wnt-beta-catenin signaling pathway is tightly controlled at multiple levels. RING finger protein 43 (RNF43) is an E3 ubiquitin ligase originally found in stem cells and proposed to inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family. We detected endogenous RNF43 in the nucleus of human intestinal crypt and colon cancer cells. We found that RNF43 physically interacted with T cell factor 4 (TCF4) in cells and tethered TCF4 to the nuclear membrane, thus silencing TCF4 transcriptional activity even in the presence of constitutively active mutants of beta-catenin. This inhibitory mechanism was disrupted by the expression of RNF43 bearing mutations found in human gastrointestinal tumors, and transactivation of the Wnt pathway was observed in various cells and in Xenopus embryos when the RING domain of RNF43 was mutated. Our findings indicate that RNF43 inhibits the Wnt pathway downstream of oncogenic mutations that activate the pathway. Mimicking or enhancing this inhibitory activity of RNF43 may be useful to treat cancers arising from aberrant activation of the Wnt pathwa