Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

publishedVersio

Patient Safety in Internal Medicine

AbstractHospital Internal Medicine (IM) is the branch of medicine that deals with the diagnosis and non-surgical treatment of diseases, providing the comprehensive care in the office and in the hospital, managing both common and complex illnesses of adolescents, adults, and the elderly. IM is a key ward for Health National Services. In Italy, for example, about 17.3% of acute patients are discharged from the IM departments. After the epidemiological transition to chronic/degenerative diseases, patients admitted to hospital are often poly-pathological and so requiring a global approach as in IM. As such transition was not associated—with rare exceptions—to hospital re-organization of beds and workforce, IM wards are often overcrowded, burdened by off-wards patients and subjected to high turnover and discharge pressure. All these factors contribute to amplify some traditional clinical risks for patients and health operators. The aim of our review is to describe several potential errors and their prevention strategies, which should be implemented by physicians, nurses, and other healthcare professionals working in IM wards

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma(1). The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established(2), but how the microenvironmental effects of UV radiation(3,4) influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model(5) promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists(6). Angiotropism represents a hitherto underappreciated mechanism of metastasis(7) that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression

Villagers, Elections, and Citizenship in Contemporary China

In this article, I assess the state of political citizenship in rural China. After discussing the often local and rural origins of citizenship and the meaning of the term itself, I review the limited reforms that have taken place in the election of high-ranking state leaders and people's congress deputies. I then turn to a more promising avenue of inclusion: the villagers' committee (VC) elections that began in the late 1980s. Here, we see notable efforts to heighten cadre responsiveness and draw rural residents into the local polity. At the same time, sizable obstacles to inclusion remain, not least because many electoral rules and practices do not enfranchise villagers reliably. The inescapable conclusion that villagers enjoy (at best) a partial citizenship needs to be qualified, however, owing to evidence that some rural people are starting to challenge improper elections using the language of rights. Building on a rules consciousness and a sensitivity to government rhetoric that have existed for centuries, as well as exploiting the spread of participatory ideologies and patterns of rule rooted in notions of equality, rights, and the rule of law, these villagers are busy advancing their interests within prevailing limits, forcing open blocked channels of participation, and struggling to make still-disputed rights real. In this regard, certain citizenship practices are emerging even before citizenship has appeared as a fully recognized status, and we may be observing the process by which a more complete citizenship comes about