Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions.

Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines

Dysplasia epiphysealis hemimelica of the talus

Dysplasia epiphysealis hemimelica is a rare developmental disorder with unknown etiology affecting epiphysis in childhood. The lesion is an osteochondroma arising from the epiphysis and increasing in size until skeletal maturity is reached. Surgical treatment is mandatory when symptoms such as pain, joint impingement or deformation are present, and yields good results when the mass is juxtaarticular or extraarticular. In those cases where articular symptoms are not present and only mass evolution is observed, surgical treatment is not recommended before skeletal maturity has been reached. A case of DEH located in the talus and successfully treated with surgery is presented

A note on clinical presentations of amebic liver abscess: an overview from 62 Thai patients

BACKGROUND: Amebic liver abscess is a tropical disease with a wide spectrum of clinical presentations. Given the often nonspecific nature of the complaints related to amebic abscess, a retrospective review of patients with confirmed disease to recognize the most common patterns of presentation is useful. Here, we study the clinical presentations of 62 Thai patients with amebic liver abscess. We also compare the clinical presentations of Anti HIV seronegative and Anti HIV seropositive patients. METHODS: A retrospective case review was carried out for 62 Thai patients who had been diagnosed with amebic liver abscess. Clinical information was collected, including symptoms and signs, location and number of abscesses. The Anti HIV serology laboratory investigation was also reviewed. RESULTS: According to our study, the common clinical symptoms and signs are abdominal pain (85.5 %), fever and chills (74.2 %), and abdominal tenderness (69.4 %). The location of the abscess was predominantly in the right lobe (74.2 %), and most of patients had a single abscess (77.4 %). Similar trends in clinical presentations were observed in both Anti HIV seropositive and Anti HIV seronegative subjects. CONCLUSIONS: In conclusion, the clinical presentations of our amebic liver abscess patients were similar to those in previous reports. A similarity to those in the pyogenic liver abscess patients can be observed. Nevertheless, we could not detect important significant differences in the clinical presentations between Anti HIV seropositive and Anti HIV seronegative groups of patients

Searching for sterile neutrinos in ice

Oscillation interpretation of the results from the LSND, MiniBooNE and some other experiments requires existence of sterile neutrino with mass $\sim 1$ eV and mixing with the active neutrinos $|U_{\mu 0}|^2 \sim (0.02 - 0.04)$. It has been realized some time ago that existence of such a neutrino affects significantly the fluxes of atmospheric neutrinos in the TeV range which can be tested by the IceCube Neutrino Observatory. In view of the first IceCube data release we have revisited the oscillations of high energy atmospheric neutrinos in the presence of one sterile neutrino. Properties of the oscillation probabilities are studied in details for various mixing schemes both analytically and numerically. The energy spectra and angular distributions of the $\nu_\mu-$events have been computed for the simplest $\nu_s-$mass, and $\nu_s - \nu_\mu$ mixing schemes and confronted with the IceCube data. An illustrative statistical analysis of the present data shows that in the $\nu_s-$mass mixing case the sterile neutrinos with parameters required by LSND/MiniBooNE can be excluded at about $3\sigma$ level. The $\nu_s- \nu_\mu$ mixing scheme, however, can not be ruled out with currently available IceCube data.Comment: 41 pages, 16 figures. Accepted for publication in JHEP. Minor changes from the previous versio

Membrane Docking Geometry of GRP1 PH Domain Bound to a Target Lipid Bilayer: An EPR Site-Directed Spin-Labeling and Relaxation Study

The second messenger lipid PIP3 (phosphatidylinositol-3,4,5-trisphosphate) is generated by the lipid kinase PI3K (phosphoinositide-3-kinase) in the inner leaflet of the plasma membrane, where it regulates a broad array of cell processes by recruiting multiple signaling proteins containing PIP3-specific pleckstrin homology (PH) domains to the membrane surface. Despite the broad importance of PIP3-specific PH domains, the membrane docking geometry of a PH domain bound to its target PIP3 lipid on a bilayer surface has not yet been experimentally determined. The present study employs EPR site-directed spin labeling and relaxation methods to elucidate the membrane docking geometry of GRP1 PH domain bound to bilayer-embedded PIP3. The model target bilayer contains the neutral background lipid PC and both essential targeting lipids: (i) PIP3 target lipid that provides specificity and affinity, and (ii) PS facilitator lipid that enhances the PIP3 on-rate via an electrostatic search mechanism. The EPR approach measures membrane depth parameters for 18 function-retaining spin labels coupled to the PH domain, and for calibration spin labels coupled to phospholipids. The resulting depth parameters, together with the known high resolution structure of the co-complex between GRP1 PH domain and the PIP3 headgroup, provide sufficient constraints to define an optimized, self-consistent membrane docking geometry. In this optimized geometry the PH domain engulfs the PIP3 headgroup with minimal bilayer penetration, yielding the shallowest membrane position yet described for a lipid binding domain. This binding interaction displaces the PIP3 headgroup from its lowest energy position and orientation in the bilayer, but the headgroup remains within its energetically accessible depth and angular ranges. Finally, the optimized docking geometry explains previous biophysical findings including mutations observed to disrupt membrane binding, and the rapid lateral diffusion observed for PIP3-bound GRP1 PH domain on supported lipid bilayers

Synthesis and Biological Evaluation of Phenanthrenes as Cytotoxic Agents with Pharmacophore Modeling and ChemGPS-NP Prediction as Topo II Inhibitors

In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC50 0.08–1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a–b and for the carbonyl group of 5-OCOCH3 in 7a–b, important for their cytotoxic properties. The SAR for moderately active 5a–b (5-OCH3), and highly active 6a–b and 7a–b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a–b as topoisomerase II inhibitors