Prevalence and type distribution of human papillomavirus infections in Danish patients diagnosed with vulvar squamous cell tumors and precursors

Objective: To study the prevalence and type distribution of human papillomavirus (HPV) in patients with vulvar high-grade precancerous lesions and vulvar squamous cell carcinoma (VSCC). Methods: Formalin-fixed and paraffin-embedded (FFPE) tissue samples from Danish patients diagnosed with vulvar precancerous lesions or VSCC in the period from 2010 to 2012 were obtained. HPV-DNA detection was carried out by the use of polymerase chain reaction (PCR) using GP5+/GP6+ primers and genotyped by sequencing. A systematic literature search on the PubMed database was performed to investigate the prevalence and genotype distribution worldwide. Results: In the present study population (n = 149) 52 vulvar high-grade squamous intraepithelial lesions (HSIL), 2 differentiated vulvar intraepithelial neoplasia (dVIN), and 95 VSCC cases were identified. HPV was detected in 85 patients (57.0%). Overall, a higher proportion of the vulvar high-grade precancerous lesions were HPV positive compared to VSCC (83.6% vs. 42.1%, p < 0.001). Additionally, HSIL had a significantly higher HPV-positive rate compared to keratinizing VSCC (84.6% vs. 33.3%, p < 0.001). However, the HPV positivity was comparable between HSIL and non-keratinizing VSCC (84.6% vs. 82.4%, p = 0.825). One dVIN was HPV positive whereas the other was HPV negative. HPV-16 was the most common HPV type (68.2%), followed by HPV-33 (18.8%) and HPV-18 (8.2%). Conclusions: Most vulvar HSIL and non-keratinizing VSCCs appear to be HPV associated. However, we find a high HPV association in keratinizing VSCC, which needs to be further studied. HPV-16 remains the predominant genotype, but HPV-33 also seems to play a role in the development of VSCC

Integrin-linked kinase controls retinal angiogenesis and is linked to wnt signaling and exudative vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR

Modeling multi-modal traffic in cities

We propose a new functional form for the 3D-MFD. The 3D-MFD links the number of cars and buses in an urban network to the total travel production. The parameters of the functional form are derived from the structure and topology of the road and bus network. The physical interactions of vehicles are described by a single parameter. We apply the methodology to two empirical data sets from London and Zurich, and discuss policy relevant applications of the functional form

HPV16 E6 and E7 upregulate interferon-induced antiviral response genes ISG15 and IFIT1 in human trophoblast cells

Human papillomavirus (HPV) is suggested to infect trophoblasts in the placenta, and HPV infections are reported to be more prevalent in pregnancies with adverse outcomes. Results are however controversial, and studies investigating the molecular consequences of placental HPV infections are lacking. We studied HPV DNA localization in the placenta in cases of spontaneous abortion/spontaneous preterm delivery as well as in elective abortion/normal full-term delivery. Using in vitro assays, we investigated downstream effects of HPV16 E6 and E7 expression in trophoblast cells at the gene expression level in order to gain increased biological insight into the interaction between HPV and the cellular host. Fluorescent in situ hybridization (FISH), combined with fluorescent immunohistochemistry (FIHC) to target the trophoblast marker CK7 clearly showed, that HPV DNA resides within syncytiotrophoblast cells in the placenta. In vitro HPV16 E6 and E7-transfected trophoblasts were analyzed by RNA sequencing, and results were validated by reverse transcription real time polymerase chain reaction (RT-qPCR) for selected genes in cell lines, as well as in patient material. We show that HPV16 E6 and E7 upregulate interferon-induced antiviral response genes ISG15 and IFIT1 in a human trophoblast cell line two-days post-transfection. This is a response that is not observed when assessing the gene expression levels of the same genes in HPV16-positive placenta samples. Investigations on viral activity find that HPV16 E6 and E7 are not transcribed in patients, possibly suggesting that HPV16 syncytiotrophoblast infection may be latent. We conclude that HPV localizes to syncytiotrophoblast cells of the placenta, and that active expression of HPV16 E6 and E7 induce an immediate interferon-induced antiviral response in trophoblast cells, which is not present in HPV-positive placenta samples, suggesting latent infection

Human Papillomavirus Infection as a Possible Cause of Spontaneous Abortion and Spontaneous Preterm Delivery

Based on the current literature, we aimed to provide an overview on Human Papillomavirus prevalence in normal pregnancies and pregnancies with adverse outcome. We conducted a systematic literature search in PubMed and Embase. Data extracted from the articles and used for analysis included HPV prevalence, pregnancy outcome, geographical location, investigated tissue types, and HPV detection methods. The overall HPV prevalence in normal full-term pregnancies was found to be 17.5% (95% CI; 17.3–17.7) for cervix, 8.3% (95% CI; 7.6–9.1) for placental tissue, 5.7% (95% CI; 5.1–6.3) for amniotic fluid, and 10.9% (95% CI; 10.1–11.7) for umbilical cord blood. Summary estimates for HPV prevalence of spontaneous abortions and spontaneous preterm deliveries, in cervix (spontaneous abortions: 24.5%, and preterm deliveries: 47%, resp.) and placenta (spontaneous abortions: 24.9%, and preterm deliveries: 50%, resp.), were identified to be higher compared to normal full-term pregnancies (P<0.05 and P<0.0001). Great variation in HPV prevalence was observed between study populations of different geographical locations. This review demonstrates an association between spontaneous abortion, spontaneous preterm delivery, and the presence of HPV in both the cervix and the placenta. However, a reliable conclusion is difficult to draw due to the limited number of studies conducted on material from pregnancies with adverse outcome and the risk of residual confounding

Capturing network properties with a functional form for the multi-modal macroscopic fundamental diagram

In urban road networks, the interactions between different modes can clearly impact the overall travel production. Although those interactions can be quantified with the multi-modal macroscopic fundamental diagram; so far, no functional form exists for this diagram to explicitly capture operational and network properties. In this paper, we propose a methodology to generate such functional form, and we show its applicability to the specific case of a bi-modal network with buses and cars. The proposed functional form has two components. First, a three dimensional lower envelope limits travel production to the theoretical best-case situation for any given number of vehicles for the different modes. The lower envelopes parameters are derived from topology and operational features of the road network. Second, a smoothing parameter quantifies how interactions between all vehicle types reduce travel production from the theoretical best-case. The smoothing parameter is estimated with network topology and traffic data. In the case no traffic data is available, our functional form is still applicable. The lower envelope can be approximated assuming fundamental parameters of traffic operations. For the smoothing parameter, we show that it always hold similar values even for different networks, making its approximation also possible. This feature of the proposed functional form is an advantage compared to curve fitting, as it provides a reasonable shape for the multi-modal macroscopic fundamental diagram irrespective of traffic data availability. The methodology is illustrated and validated using simulation and empirical data sets from London and Zurich

Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR