Epigenetic biomarkers in lung cancer Liloglou, Triantafillos; Bediaga, Naiara G; Brown, Benjamin R.B ...
Cancer letters,
01/2014, Letnik:
342, Številka:
2
Journal Article
Recenzirano
Abstract Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an ...unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies.
SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the pathophysiological mechanisms ...underpinning SARS-CoV-2 infection during placentation and early pregnancy are not clear. Here, to shed light on this, we used induced trophoblast stem cells to generate an in vitro early placenta infection model. We identified that syncytiotrophoblasts could be infected through angiotensin-converting enzyme 2 (ACE2). Using a co-culture model of vertical transmission, we confirmed the ability of the virus to infect syncytiotrophoblasts through a previous endometrial cell infection. We further demonstrated transcriptional changes in infected syncytiotrophoblasts that led to impairment of cellular processes, reduced secretion of HCG hormone and morphological changes vital for syncytiotrophoblast function. Furthermore, different antibody strategies and antiviral drugs restore these impairments. In summary, we have established a scalable and tractable platform to study early placental cell types and highlighted its use in studying strategies to protect the placenta.
Familial hypercholesterolemia (FH) is an inherited metabolic disease affecting cholesterol metabolism, with 90% of cases caused by mutations in the LDL receptor gene (LDLR), primarily missense ...mutations. This study aims to integrate six commonly used predictive software to create a new model for predicting LDLR mutation pathogenicity and mapping hot spot residues. Six predictive‐software are selected: Polyphen‐2, SIFT, MutationTaster, REVEL, VARITY, and MLb‐LDLr. Software accuracy is tested with the characterized variants annotated in ClinVar and, by bioinformatic and machine learning techniques all models are integrated into a more accurate one. The resulting optimized model presents a specificity of 96.71% and a sensitivity of 98.36%. Hot spot residues with high potential of pathogenicity appear across all domains except for the signal peptide and the O‐linked domain. In addition, translating this information into 3D structure of the LDLr highlights potentially pathogenic clusters within the different domains, which may be related to specific biological function. The results of this work provide a powerful tool to classify LDLR pathogenic variants. Moreover, an open‐access guide user interface (OptiMo‐LDLr) is provided to the scientific community. This study shows that combination of several predictive software results in a more accurate prediction to help clinicians in FH diagnosis.
OptiMo‐LDLr is an advanced computational model that improves predictions of LDL receptor (LDLr) variant pathogenicity. It outperforms other methods, accurately distinguishing between pathogenic and benign LDLr variants, and identifies critical residues in all domains except the signal peptide and O‐linked domain. OptiMo‐LDLr also visualizes 3D hot spot areas, enhancing understanding of FH and aiding clinicians in managing this genetic condition.
The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory ...M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.
Objectives
Accumulating evidence indicates that aberrant DNA methylation is closely related to oral carcinogenesis, and it has been shown that methylation changes might be used as prognostic ...biomarker in oral squamous cell carcinoma. Oral lichenoid disease (OLD) is the most common oral potentially malignant disorder in our region. The aim of this study was to perform the first wide DNA methylation study in OLD in order to investigate the relevance of DNA methylation changes in this premalignant disorder.
Materials and Methods
Two different Illumina microarray platforms, namely the GoldenGate Cancer Panel I and the HumanMethylation27 DNA Analysis BeadChip, were utilized in the discovery phase to interrogate the methylation profile of 59 OLD cases and 9 healthy individuals. Top‐ranked genes were further validated by pyrosequencing in a second sample set consisting of 160 OLD and 65 controls.
Results
Our results show that the frequency of aberrant DNA methylation is rare in OLD, and this finding was further corroborated by pyrosequencing in the biological validation.
Conclusions
These findings reinforce the notion that molecular alterations associated with oral carcinogenesis do not seem to be common events in OLD, which in turn might explain the low rate of malignization of this disorder.
We obtain an explicit expression for the charge-parity violation (CPV) considering final state interactions (FSI) and the ρ(770) and f0(980) resonances in the B± → π± π+π− decay. In addition, we ...investigate the channel coupled by the strong interaction B± → π± K+ K-. dictated by the CPT constraint. We use our model to fit experimental data of such decays 1, For the interfering resonant contributions to the CP asymmetry, we show that locally CPT constraint seems to be valid in the B± → π± π+π− channel. Our work suggests, in agreement with the CPT constraint, that the CP asymmetry in coupled channels are related and have opposite signs. Our formula for the CP asymmetry fairly fit the LHCb data improving our understanding of the interplay between the FSI and CP violation. For more complete and detailed studies for the channels K± K+ K-, K± π+π−, π± K+ K- and π± π+π− see Ref. 2,
From a sample of 1172 +/- 61 D(+)-->pi(-)pi(+)pi(+) decays, we find gamma(D(+)-->pi(-)pi(+)pi(+))/gamma(D(+)-->K-pi(+)pi(+)) = 0.0311 +/- 0.0018(+0.0016)(-0.0026). Using a coherent amplitude analysis ...to fit the Dalitz plot of these decays, we find strong evidence that a scalar resonance of mass 478(+24)(-23) +/- 17 MeV/c(2) and width 324(+42)(-40) +/- 21 MeV/c(2) accounts for approximately half of all decays.
A search for the rare two-body charmless baryonic decay $B^+ \to p \bar\Lambda$ is performed with $pp$ collision data, corresponding to an integrated luminosity of $3\mbox{\,fb}^{-1}$, collected by ...the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. An excess of $B^+ \to p \bar\Lambda$ candidates with respect to background expectations is seen with a statistical significance of 4.1 standard deviations, and constitutes the first evidence for this decay. The branching fraction, measured using the $B^+ \to K^0_{\mathrm S} \pi^+$ decay for normalisation, is \begin{eqnarray} \mathcal{B}(B^+ \to p \bar\Lambda) & = & ( 2.4 \,^{+1.0}_{-0.8} \pm 0.3 ) \times 10^{-7} \,, \nonumber \end{eqnarray} where the first uncertainty is statistical and the second systematic.
Using data from FOCUS (E831) experiment at Fermilab, we present a model independent partial-wave analysis of the K−π+ S-wave amplitude from the decay D+→K−π+π+. The S-wave is a generic complex ...function to be determined directly from the data fit. The P- and D-waves are parameterized by a sum of Breit–Wigner amplitudes. The measurement of the S-wave amplitude covers the whole elastic range of the K−π+ system.
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