Background: Fragility fractures, especially hip fractures, are a very common complication of osteoporosis in elderly subjects. Sclerostin (SOST) and dickkopf-1 (DKK-1) are inhibitors of the canonical wnt signalling pathway and thus could be involved in the pathogenesis of age-related bone fragility. Objective: To investigate SOST and DKK-1 in a large group of geriatric patients with hip fractures and to relate the wnt inhibitors to age and gender. Methods: This was a cross-sectional study carried out in a department of acute geriatric care in a district hospital in Upper Austria and a hospital in Vienna, Austria. A total of 256 geriatric patients (172 women and 84 men) and 67 young control subjects were selected after exclusion. Medical history was obtained, a comprehensive geriatric assessment was performed and serum levels of SOST, DKK-1 and bone formation markers were analysed. Results: DKK-1 levels increased with age and in the presence of hip fractures. In contrast, SOST levels were lower in patients with hip fractures. When compared to women, men had higher SOST levels but lower DKK-1 levels. Conclusion: Serum levels of the inhibitors of the canonical wnt signalling pathway reflect different biological events and are useful for the study of bone fragility in geriatric patients.

Epidemiological and experimental data implicate cutaneous human papillomavirus infection as co‐factor in the development of cutaneous squamous cell carcinomas (cSCCs), particularly in immunocompromised organ transplant recipients (OTRs). Herein, we established and characterized a skin cancer model, in which Mus musculus papillomavirus 1 (MmuPV1) infection caused cSCCs in cyclosporine A (CsA)‐treated mice, even in the absence of UV light. Development of cSCCs and their precursors were observed in 70% of MmuPV1‐infected, CsA‐treated mice on back as well as on tail skin. Immunosuppression by systemic CsA, but not UV‐B irradiation, was a prerequisite, as immunocompetent or UV‐B–irradiated mice did not develop skin malignancies after infection. In the virus‐driven cSCCs the MmuPV1‐E6/E7 oncogenes were abundantly expressed, and transcriptional activity and productive infection demonstrated. MmuPV1 infection induced the expression of phosphorylated H2AX, but not degradation of proapoptotic BAK in the cSCCs. Transfer of primary cells, established from a MmuPV1‐induced cSCC from back skin, into athymic nude mice gave rise to secondary cSCCs, which lacked viral DNA, demonstrating that maintenance of the malignant phenotype was virus independent. This papillomavirus‐induced skin cancer model opens future investigations into viral involvement, pathogenesis, and cancer surveillance, aiming at understanding and controlling the high incidence of skin cancer in OTRs.

Background Dirofilariosis is a vector-borne parasitosis caused by filarial nematodes of the genus Dirofilaria. In humans, who represent accidental hosts, dirofilariosis is mostly caused by Dirofilaria repens and Dirofilaria immitis. In Austria, the first reported case occurred in 1978. Since then, several (case) reports have been published. Methods A systematic and retrospective review of collected published cases and new, unpublished confirmed cases of human dirofilariosis occurring in Austria was performed. A nematode was extracted from the eyelid of a previously unreported case and subsequently characterized histologically and using molecular biology techniques. Results Data on a total of 39 cases of human dirofilariosis in Austria occurring between 1978 and 2020 are summarized. Over the past four decades the incidence has markedly increased, in particular after 1998. Of the 39 patients, men and women were equally affected, and the mean age was 47.1 years. The area most frequently affected was the head (38.5% of cases). Confined ocular involvement was observed in 23.1% of cases, and nematodes were isolated from the neck/trunk, extremities and the genito-inguinal area in 25.6, 15.4 and 15.4% of patients, respectively. Microfilariae were detected in two cases. Of the 39 patients, only 73.9% tested positive for anti-filarial antibodies and 56.3% for eosinophilia, despite successful isolation of a nematode; consequently, these measures did not represent reliable markers for dirofilariosis. Most patients had a travel history to countries endemic for Dirofilaria species. One patient who had not traveled abroad represented the only autochthonous case recorded to date. Dirofilaria repens was the predominant species, identified in 89.7% of cases. In the newly reported case of subcutaneous dirofilariosis, a live non-gravid Dirofilaria repens adult female of 12 cm length was isolated from the eyelid of the patient, and a video of the extraction is provided. Conclusions The incidence of human dirofilariosis cases has increased strikingly over the last four decades in Austria. More cases can be expected in the foreseeable future due to changes in human behavior and (travel) activities as well as climate changes and the associated alterations in the availability of the natural reservoir, the vectors and the intrinsic characteristics of the parasite.

Cathelicidins have been reported to inhibit human papillomavirus infection in vitro ; however, nothing is known about their activity in vivo . In this study, experimental skin infection with Mus musculus papillomavirus 1 resulted in robust development of cutaneous papillomas in cyclosporine A-treated C57BL/6J mice deficient for the murine cathelicidin-related antimicrobial peptide (CRAMP), in contrast to wild-type controls. Analysis of the underlying mechanisms revealed moderate disruption of virion integrity and lack of interference with viral entry and intracellular trafficking by a synthetic CRAMP peptide. Differences in the immune response to Mus musculus papillomavirus 1 infection were observed between CRAMP-deficient and wild-type mice. These included a stronger reduction in CD4+ and CD8+ T-cell numbers in infected skin, and lack of Mus musculus papillomavirus 1 -specific neutralizing antibodies in response to cyclosporine A in the absence of endogenous CRAMP. CRAMP has modest direct anti-papillomaviral effects in vitro , but exerts protective functions against Mus musculus papillomavirus 1 skin infection and disease development in vivo , primarily by modulation of cellular and humoral immunity.

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Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs.

Interferon beta (IFN-b) is widespread used as a treatment against melanoma to improve its prognosis. Several literature has suggested that the sensitivity of melanoma cells to IFN-b shows wide spectrum through in vivo and in vitro examinations including our previous study that RPMI-7951 and A375 is relatively sensitive to IFN-b, while SK-MEL-5, G361 and SK-MEL-1 is relatively resistant. has been reported to inhibit the tumor growth by inducing the tumor-selective apoptosis. This study was conducted to elucidate the relation with IL-24 in inhibition effects of IFN-b on melanoma cells. Quantitative real-time reverse transcription PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were carried out to detect amounts of IL-24 mRNA and proteins, respectively. Flow cytometry was performed to assess the tumor cell growth and apoptosis of melanoma cells treated with IL-24 using propidium iodide staining. RT-PCR revealed that IL-24 mRNA was induced in 6.0-fold in RPMI-7951, 2.5-fold in A375 cells, 0.7-fold in G361 cells, 7.0-fold in SK-MEL-5 and 1.0fold in SK-MEL-1 cells at day 5 after IFN-b treatment. ELISA revealed that IL-24 protein at day 5 after IFN-b treatment was induced in 4.8-fold in RPMI-7951 and 1.9-fold in A375 cells, but the protein was not detected in either non-treated or treated G361 cells, SK-MEL-5 cells or SK-MEL-1 cells. These results suggested that IFN-b may inhibit melanoma cell proliferation through inducing IL-24 from melanoma cells. A novel immune checkpoint inhibitor, nivolumab, have contributed higher efficacy for patients with metastatic melanoma. Although clinical effects by this agent is usually evaluated by radiologic examinations, this cannot be performed frequently. Circulating tumor DNA (ctDNA) is expected as a realtime biomarker for evaluating tumor burden. We assessed whether ctDNA in melanoma patients treated with nivolumab could be a significant marker superior to serum LDH levels and radiologic images. 5 patients with metastatic melanoma were examined. The profiles of genome status were as follows, BRAF V600E ; 3, BRAF V600K ; one and NRAS Q61K ; one. Levels of BRAF and NRAS ctDNA were determined using droplet digital PCR. In 4 of 5 patients, ctDNA levels were correlated with and preceded the radiologic changes. Moreover in all 5 patients, ctDNA levels changed within 2-4 weeks, which was prior to the first radiologic examination after nivolumab initiation. In 3 of 5 patients, LDH levels did not corresponded to the tumor dynamics. ctDNA could be a significant indicator expecting clinical response to nivolumab treatment in metastatic melanoma patients. 578Immunomodulatory effects of bexarotene on tumor-associated macrophages in patients with mycosis fungoides K Tanita, T Fujimura, Y Sato, C Lyu, Y Kambayashi, S Furudate and S Aiba dematology, Tohoku university graduate school of medicine, Sendai, Japan Tumor-associated macrophages (TAMs) compose the immunosuppressive cancer stroma by various pathways. Since TAMs produce specific chemokines by the stimulation of various factors i...

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