96 research outputs found
The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time
Peer reviewedPreprin
In Vivo Imaging of HIF-Active Tumors by an Oxygen-Dependent Degradation Protein Probe with an Interchangeable Labeling System
Hypoxia-inducible factor (HIF) functions as a master transcriptional regulator for adaptation to hypoxia by inducing adaptive changes in gene expression for regulation of proliferation, angiogenesis, apoptosis and energy metabolism. Cancers with high expression of the alpha subunit of HIF (HIFα) are often malignant and treatment-resistant. Therefore, the development of a molecular probe that can detect HIF activity has great potential value for monitoring tumor hypoxia. HIF prolyl hydroxylases (HPHDs) act as oxygen sensors that regulate the fate of HIFα protein through its oxygen-dependent degradation (ODD) domain. We constructed a recombinant protein PTD-ODD-HaloTag (POH) that is under the same ODD regulation as HIFα and contains protein transduction domain (PTD) and an interchangeable labeling system. Administration of near-infrared fluorescently labeled POH (POH-N) to mouse models of cancers allowed successful monitoring of HIF-active regions. Immunohistochemical analysis for intratumoral localization of POH probe revealed its specificity to HIF-active cells. Furthermore, lack of the PTD domain or a point mutation in the ODD domain abrogated the specificity of POH-N to HIF-active cells. Overall results indicate that POH is a practical probe specific to HIF-active cell in cancers and suggest its large potential for imaging and targeting of HIF-related diseases
The Elg1 Clamp Loader Plays a Role in Sister Chromatid Cohesion
Mutations in the ELG1 gene of yeast lead to genomic instability, manifested in high levels of genetic recombination, chromosome loss, and gross chromosomal rearrangements. Elg1 shows similarity to the large subunit of the Replication Factor C clamp loader, and forms a RFC-like (RLC) complex in conjunction with the 4 small RFC subunits. Two additional RLCs exist in yeast: in one of them the large subunit is Ctf18, and in the other, Rad24. Ctf18 has been characterized as the RLC that functions in sister chromatid cohesion. Here we present evidence that the Elg1 RLC (but not Rad24) also plays an important role in this process. A genetic screen identified the cohesin subunit Mcd1/Scc1 and its loader Scc2 as suppressors of the synthetic lethality between elg1 and ctf4. We describe genetic interactions between ELG1 and genes encoding cohesin subunits and their accessory proteins. We also show that defects in Elg1 lead to higher precocious sister chromatid separation, and that Ctf18 and Elg1 affect cohesion via a joint pathway. Finally, we localize both Ctf18 and Elg1 to chromatin and show that Elg1 plays a role in the recruitment of Ctf18. Our results suggest that Elg1, Ctf4, and Ctf18 may coordinate the relative movement of the replication fork with respect to the cohesin ring
Clinical use of biomarkers of survival in pulmonary fibrosis
<p>Abstract</p> <p>Background</p> <p>Biologic predictors or biomarkers of survival in pulmonary fibrosis with a worse prognosis, more specifically in idiopathic pulmonary fibrosis would help the clinician in deciding whether or not to treat since treatment carries a potential risk for adverse events. These decisions are made easier if accurate and objective measurements of the patients' clinical status can predict the risk of progression to death.</p> <p>Method</p> <p>A literature review is given on different biomarkers of survival in interstitial lung disease, mainly in IPF, since this disease has the worst prognosis.</p> <p>Conclusion</p> <p>Serum biomarkers, and markers measured by medical imaging as HRCT, pertechnegas, DTPA en FDG-PET are not ready for clinical use to predict mortality in different forms of ILD. A baseline FVC, a change of FVC of more than 10%, and change in 6MWD are clinically helpful predictors of survival.</p
Tumour macrophages as potential targets of bisphosphonates
Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use
Telomerase promoter mutations in cancer: an emerging molecular biomarker?
João Vinagre, Vasco Pinto and Ricardo Celestino contributed equally to
the manuscript.Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the “alternative mechanism of telomere lengthening” (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and non-neoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target
Supernova remnants: the X-ray perspective
Supernova remnants are beautiful astronomical objects that are also of high
scientific interest, because they provide insights into supernova explosion
mechanisms, and because they are the likely sources of Galactic cosmic rays.
X-ray observations are an important means to study these objects.And in
particular the advances made in X-ray imaging spectroscopy over the last two
decades has greatly increased our knowledge about supernova remnants. It has
made it possible to map the products of fresh nucleosynthesis, and resulted in
the identification of regions near shock fronts that emit X-ray synchrotron
radiation.
In this text all the relevant aspects of X-ray emission from supernova
remnants are reviewed and put into the context of supernova explosion
properties and the physics and evolution of supernova remnants. The first half
of this review has a more tutorial style and discusses the basics of supernova
remnant physics and thermal and non-thermal X-ray emission. The second half
offers a review of the recent advances.The topics addressed there are core
collapse and thermonuclear supernova remnants, SN 1987A, mature supernova
remnants, mixed-morphology remnants, including a discussion of the recent
finding of overionization in some of them, and finally X-ray synchrotron
radiation and its consequences for particle acceleration and magnetic fields.Comment: Published in Astronomy and Astrophysics Reviews. This version has 2
column-layout. 78 pages, 42 figures. This replaced version has some minor
language edits and several references have been correcte
PI3Kinase signaling in glioblastoma
Glioblastoma (GBM) is the most common primary tumor of the CNS in the adult. It is characterized by exponential growth and diffuse invasiveness. Among many different genetic alterations in GBM, e.g., mutations of PTEN, EGFR, p16/p19 and p53 and their impact on aberrant signaling have been thoroughly characterized. A major barrier to develop a common therapeutic strategy is founded on the fact that each tumor has its individual genetic fingerprint. Nonetheless, the PI3K pathway may represent a common therapeutic target to most GBM due to its central position in the signaling cascade affecting proliferation, apoptosis and migration. The read-out of blocking PI3K alone or in combination with other cancer pathways should mainly focus, besides the cytostatic effect, on cell death induction since sublethal damage may induce selection of more malignant clones. Targeting more than one pathway instead of a single agent approach may be more promising to kill GBM cells
May the Force Be With You: The Light and Dark Sides of the Microbiota–Gut–Brain Axis in Neuropsychiatry
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Hitomi Constraints on the 3.5 keV Line in the Perseus Galaxy Cluster
© 2017. The American Astronomical Society. All rights reserved. High-resolution X-ray spectroscopy with Hitomi was expected to resolve the origin of the faint unidentified E ≈ 3.5 keV emission line reported in several low-resolution studies of various massive systems, such as galaxies and clusters, including the Perseus cluster. We have analyzed the Hitomi first-light observation of the Perseus cluster. The emission line expected for Perseus based on the XMM-Newton signal from the large cluster sample under the dark matter decay scenario is too faint to be detectable in the Hitomi data. However, the previously reported 3.5 keV flux from Perseus was anomalously high compared to the sample-based prediction. We find no unidentified line at the reported high flux level. Taking into account the XMM measurement uncertainties for this region, the inconsistency with Hitomi is at a 99% significance for a broad dark matter line and at 99.7% for a narrow line from the gas. We do not find anomalously high fluxes of the nearby faint K line or the Ar satellite line that were proposed as explanations for the earlier 3.5 keV detections. We do find a hint of a broad excess near the energies of high-n transitions of S xvi (E ≃ 3.44 keV rest-frame) - a possible signature of charge exchange in the molecular nebula and another proposed explanation for the unidentified line. While its energy is consistent with XMM pn detections, it is unlikely to explain the MOS signal. A confirmation of this interesting feature has to wait for a more sensitive observation with a future calorimeter experiment
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