Drug Discovery Today: Disease Models / Model systems for papillomavirus-associated skin disease

Papillomaviruses (PVs) are small, non-enveloped, double-stranded DNA tumor viruses, which target epithelial cells of the skin and mucosa of different vertebrate species, including humans, for infection. To date, more than 230 human papillomavirus (HPV) types are known according to the PapillomaVirus Episteme (PaVE) database and classified into 5 different genera, alpha, beta, gamma, mu and nu [1]. Preclinical model systems that mimic HPV infections are essential tools for investigations on viral etiology and pathophysiological processes of human diseases. Herein, we describe different PV infection model systems in animals, focusing on models for skin carcinogenesis

Raynaud’s Phenomenon after COVID-19 Vaccination: Causative Association, Temporal Connection, or Mere Bystander?

Herein, we report a case of a new-onset Raynaud’s phenomenon (RP), which occurred in an otherwise healthy 31-year-old Caucasian woman, who lacked any known risk factors and associations with possible causes for secondary RP. However, 2 weeks prior to the development of RP, the patient had received her first injection of the COVID-19 vaccine containing ChAdOx1-SARS-COV-2. The patient presented with well-demarcated, white-pale, cold areas involving the middle fingers of both hands and the ring finger of the right hand, which were triggered by exposure to cold environment and accompanied by a sensation of numbness. Infrared thermography revealed notable temperature differences of up to 10.9°C between affected and nonaffected fingers. Coagulation and immunological parameters, including cryoglobulins and pathological autoantibodies, were within the normal range and antibodies to the heparin/platelet factor 4 complex not detectable. It remains unclear if the development of RP in our patient is causally related to antecedent COVID-19 vaccination; however, the temporal connection to the vaccination, the complete absence of RP in her past medical history, and the lack of any risk factors and triggers raise the suspicion of a yet unknown association with the vaccine. Whether a clear association between the development of RP and COVID-19 vaccination exists or whether RP represents a bystander effect needs to be awaited in case observational reports on RP accumulate. Given the steadily rising numbers of people receiving COVID-19 vaccinations, physicians may remain alert to still unrecognized side effects. </jats:p

Abstract 1081: Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models.

Abstract Braf inhibitors are clinically important agents for the treatment of advanced melanoma however secondary cutaneous tumors are a common side effect; non-melanoma skin cancers (NMSCs) arise in 15-30% of patients on Braf inhibitor therapy and 60% of these harbor ras mutations. NMSC also occurs in 40% of organ transplant patients receiving immunosuppressive therapy, and switching from a calcineurin inhibitor-containing regimen to rapamycin reduces the incidence. To examine the effect of rapamycin on ras-driven epidermal squamous cell tumors, we treated mutant K-RasLA2 mice with rapamycin or vehicle by intraperitoneal injection and found that rapamycin prevented the development of squamous skin tumors (0/21 vs 6/24; p=0.04), and also rapidly reduced the tumor size. To explore this effect we employed a syngeneic orthotopic grafting model using H-Ras mutant primary murine keratinocytes to determine if rapamycin could hamper the ability of a Braf inhibitor to enhance squamous skin tumor growth. Similar to results in the K-RasLA2 model, rapamycin alone diminished the growth of tumors (size difference; 334.5 vs 22.3mm3; p=0.03), and decreased the volume even more in the presence of a Braf inhibitor (size difference; 699.6 vs 17.6 mm3; p=0.02). Treatment of established tumors with rapamycin resulted in significant tumor shrinkage even in the continuous presence of a Braf inhibitor. Size reduction was 78.7% and 66.7% in Braf inhibitor untreated and treated groups respectively. In vitro, Braf inhibition enhanced mutant H-Ras-induced activation of the Raf-ERK and mTOR pathways in keratinocytes, while rapamycin addition blocked the activation of signaling pathways and decreased cell proliferation. Taken together, rapamycin prevents murine skin tumor development arising from oncogenic mutations in two distinct types of ras gene alleles, and reduced the tumor size by inhibiting downstream oncogenic pathways. Rapamycin may have clinical application as a chemopreventive and therapeutic agent for patients at high risk to develop ras-driven NMSC, including those receiving Braf inhibitors. Citation Format: Hiroshi Kitagawa, Christophe Cataisson, Alessandra Handisurya, Patricia M. Day, Stuart H. Yuspa, Phillip A. Dennis. Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1081. doi:10.1158/1538-7445.AM2013-1081</jats:p

Bovine papillomavirus type 1 (BPV1) and BPV2 are closely related serotypes

AbstractInfection with bovine papillomavirus type 1 (BPV1) or BPV2 induces fibropapillomas in cows and skin sarcoids in horses. Prophylactic vaccination targeting BPV1 and BPV2 may reduce the incidence of these economically important diseases. The L1 major capsid proteins of BPV1 and BPV2 were expressed in Sf-9 insect cells and both self-assembled into virus-like particles (VLPs). Using conformation-dependent monoclonal antibodies (mAb) both type-specific and shared epitopes were detected. Antisera were raised against BPV1 or BPV2 VLP using alum adjuvant, and their (cross)neutralization capacity was tested by C127 neutralization assays using native BPV1 and BPV2 virions, or by BPV1 pseudovirion assay. Antisera induced by either VLP vaccine were able to robustly (cross-)neutralize heterologous as well as homologous types, indicating that BPV1 and BPV2 are closely related serotypes. These results suggest that a monovalent BPV1 (or BPV2) VLP vaccine may potentially protect against both BPV1 and BPV2 infections and associated diseases

Hypopyon sign as an unusual complication of varicella infection in a girl with atopic dermatitis

SummaryVaricella-zoster virus (VZV) infection, also known as chickenpox, is a common childhood affliction. Generalized small itchy single-standing vesicles on erythematous skin are typical. Both cutaneous and systemic complications of the VZV infection may commonly occur. A three-year-old girl with a previous history of mild atopic dermatitis presented in our Pediatric Dermatology Clinic in poor general condition, with a skin rash predominantly consisting of generalized large blisters with hypopyon sign and erosions. On a closer look, scattered erythematous papules and vesicles were also visible. A positive Tzanck smear from an intact pinhead-sized vesicle and VZV PCR confirmed the clinical diagnosis of chickenpox. Cultures from hypopyon material revealed Staphylococcus aureus superinfection. We report an exceptional, not-yet described complication of chickenpox with hypopyon-forming superinfection in an atopic child. In addition, our case nicely underscores the necessity of early VZV vaccination, which has been available and recommended now for more than 10 years in pediatric vaccination programs to avoid severe complications.</jats:p