69 research outputs found
Dual role of tumor suppressor p53 in regulation of DNA replication and oncogene e6-promoter activity of epidermodysplasia verruciformis-associated human papillomavirus type 8
AbstractHuman papillomavirus 8 (HPV8) is a representative of Epidermodysplasia verruciformis (EV)-associated viruses. Transient assays in the human skin keratinocyte cell line RTS3b have shown that its replication depends in trans on expression of the viral proteins E1 and E2, similarly to other HPVs. Using deletion mutants and cloned subfragments of the noncoding region (NCR) of HPV8 we identified a 65-bp sequence in the 3âČ part of the NCR to be necessary and sufficient to support replication in cis. The origin of replication (ori) of HPV8 is composed of the sequence motifs âCCAACâ (nt 57â73) and M29 (nt 84â112), which are highly conserved among the majority of EV HPVs. Analysis of M29 revealed an unconventional binding site of the E2 protein and an overlapping DNA recognition site of the tumor suppressor protein p53. Both these factors competitively bind to M29. In transient replication assays p53 acted as a potent inhibitor of ori activity, most probably in a DNA-binding-dependent fashion. The minimal ori sequences are also functionally critical for the E6 oncogene promoter P175. In contrast to its effect on replication, p53 stimulated promoter activity depending on its interaction with M29. Our observations suggest that p53 is involved in controlling the balance between DNA replication and gene expression of HPV8
Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis
Background: The failure to mount an effective DNA damage response to repair UV induced cyclobutane pyrimidine dimers (CPDs) results in an increased propensity to develop cutaneous squamous cell carcinoma (cSCC). High-risk patient groups, such as organ transplant recipients (OTRs) frequently exhibit field cancerization at UV exposed body sites from which multiple human papillomavirus (HPV)-associated cSCCs develop rapidly, leading to profound morbidity and increased mortality. In vitro molecular evidence indicates that HPV of genus beta-papillomavirus (ÎČ-PV) play an important role in accelerating the early stages of skin tumorigenesis. Methods: We investigated the effects of UV induced DNA damage in murine models of ÎČ-PV E6 oncoprotein driven skin tumorigenesis by crossing K14-HPV8-E6wt mice (developing skin tumors after UV treatment) with K14-CPD-photolyase animals and by generating the K14-HPV8-E6-K136N mutant mouse strain. Thymine dimers (marker for CPDs) and ÎłH2AX (a marker for DNA double strand breaks) levels were determined in the murine skin and organotypic skin cultures of E6 expressing primary human keratinocytes after UV-irradiation by immunohistochemistry and in cell lines by In Cell Western blotting. Phosphorylation of ATR/Chk1 and ATM were assessed in cell lines and organotypic skin cultures by Western blots and immunohistochemistry. Results: Skin tumor development after UV-irradiation in K14-HPV8-E6wt mice could completely be blocked through expression of CPD-photolyase. Through quantification of thymine dimers after UV irradiation in cells expressing E6 proteins with point mutations at conserved residues we identified a critical lysine in the
A universal constraint between charge and rotation rate for degenerate black holes surrounded by matter
We consider stationary, axially and equatorially symmetric systems consisting
of a central rotating and charged degenerate black hole and surrounding matter.
We show that always holds provided that a continuous sequence of
spacetimes can be identified, leading from the Kerr-Newman solution in
electrovacuum to the solution in question. The quantity is the black
hole's intrinsic angular momentum per unit mass, its electric charge and
the well known black hole mass parameter introduced by Christodoulou and
Ruffini.Comment: 19 pages, 2 figures, replaced with published versio
The unexpected resurgence of Weyl geometry in late 20-th century physics
Weyl's original scale geometry of 1918 ("purely infinitesimal geometry") was
withdrawn by its author from physical theorizing in the early 1920s. It had a
comeback in the last third of the 20th century in different contexts: scalar
tensor theories of gravity, foundations of gravity, foundations of quantum
mechanics, elementary particle physics, and cosmology. It seems that Weyl
geometry continues to offer an open research potential for the foundations of
physics even after the turn to the new millennium.Comment: Completely rewritten conference paper 'Beyond Einstein', Mainz Sep
2008. Preprint ELHC (Epistemology of the LHC) 2017-02, 92 pages, 1 figur
German evidence and consensusâbased (S3) guideline: Vaccination recommendations for the prevention of HPVâassociated lesions
Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view
Phenomenology of the Lense-Thirring effect in the Solar System
Recent years have seen increasing efforts to directly measure some aspects of
the general relativistic gravitomagnetic interaction in several astronomical
scenarios in the solar system. After briefly overviewing the concept of
gravitomagnetism from a theoretical point of view, we review the performed or
proposed attempts to detect the Lense-Thirring effect affecting the orbital
motions of natural and artificial bodies in the gravitational fields of the
Sun, Earth, Mars and Jupiter. In particular, we will focus on the evaluation of
the impact of several sources of systematic uncertainties of dynamical origin
to realistically elucidate the present and future perspectives in directly
measuring such an elusive relativistic effect.Comment: LaTex, 51 pages, 14 figures, 22 tables. Invited review, to appear in
Astrophysics and Space Science (ApSS). Some uncited references in the text
now correctly quoted. One reference added. A footnote adde
Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer
Merkel cell polyomavirus (MCPyV or MCV) is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, Merkel cell carcinoma (MCC). Infection with MCPyV is common in the general population, and a majority of adults shed MCPyV from the surface of their skin. In this study, we quantitated MCPyV DNA in skin swab specimens from healthy volunteers sampled at different anatomical sites over time periods ranging from 3Â months to 4Â years. The volunteers were also tested using a serological assay that detects antibodies specific for the MCPyV virion. There was a positive correlation between MCPyV virion-specific antibody titers and viral load at all anatomical sites tested (dorsal portion of the hands, forehead, and buttocks) (Spearmanâs r 0.644, PÂ <Â 0.0001). The study results are consistent with previous findings suggesting that the skin is primary site of chronic MCPyV infection in healthy adults and suggest that the magnitude of an individualâs seroresponsiveness against the MCPyV virion generally reflects the overall MCPyV DNA load across wide areas of the skin. In light of previous reports indicating a correlation between MCC and strong MCPyV-specific seroresponsiveness, this model suggests that poorly controlled chronic MCPyV infection might be a risk factor in the development of MCC
The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late-Stage T Cells
Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1+ CD57+ CD7â phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter
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