Experimental evidence for Parthanatos-like mode of cell death of heat-damaged human skin fibroblasts in a cell culture-based in vitro burn model.

The cellular mechanisms of burn conversion of heat damaged tissue are center of many studies. Even if the molecular mechanisms of heat-induced cell death are controversially discussed in the current literature, it is widely accepted that caspase-mediated apoptosis plays a central role. In the current study we wanted to develop further information on the nature of the mechanism of heat-induced cell death of fibroblasts in vitro. We found that heating of human fibroblast cultures (a 10 s rise from 37 °C to 67 °C followed by a 13 s cool down to 37 °C) resulted in the death of about 50% of the cells. However, the increase in cell death started with a delay, about one hour after exposure to heat, and reached the maximum after about five hours. The lack of clear evidence for an active involvement of effector caspase in the observed cell death mechanism and the lack of observation of the occurrence of hypodiploid nuclei contradict heat-induced cell death by caspase-mediated apoptosis. Moreover, a dominant heat-induced increase in PARP1 protein expression, which correlated with a time-delayed ATP synthesis inhibition, appearance of double-strand breaks and secondary necrosis, indicate a different type of cell death than apoptosis. Indeed, increased translocation of Apoptosis Inducing Factor (AIF) and Macrophage Migration Inhibitory Factor (MIF) into cell nuclei, which correlates with the mentioned enhanced PARP1 protein expression, indicate PARP1-induced, AIF-mediated and MIF-activated cell death. With regard to the molecular actors involved, the cellular processes and temporal sequences, the mode of cell death observed in our model is very similar to the cell death mechanism via Parthanatos described in the literature.

Self-Reported Baseline Quality of Life Mirrors Treatment-Specific Characteristics of Cancer Patients.

BACKGROUND: Baseline quality of life (bQL) has been shown to be a predictor of the clinical outcome of oncological patients. The primary objective of the present study was to examine the role of bQL as a treatment predictor in oncological patients. METHODS: In this prospective study, all-stage cancer patients registered in the Network Oncology registry were enrolled, and their bQL at diagnosis was evaluated. RESULTS: Five hundred and thirty-eight oncological patients were eligible (median age 64 years). We show that survival-predicting bQL variables such as pain, low physical functioning or financial burden at tumor diagnosis were linked to lower systemic treatment (p = 0.03), reduced surgery (p = 0.007) or reduced oncological treatment compliance (0.01), respectively. Lastly, female gender and older cancer patients exhibited a tempered bQL. CONCLUSION: Our study is one of the first to reveal that bQL at tumor diagnosis is significantly associated with the prediction of oncological treatment with distinctive age- and gender-related patterns. Our results emphasize the need to address the physical, psychosocial, and financial burden of cancer patients prior to their oncological treatment with respect to age and gender. The associations found here pave the way for early integration of patient-reported outcomes into oncological supportive concepts.

The Role of Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (D-DT/MIF-2) in Infections: A Clinical Perspective.

Macrophage migration inhibitory factor (MIF) and its homolog, D-dopachrome tautomerase (D-DT), are cytokines that play critical roles in the immune response to various infectious diseases. This review provides an overview of the complex involvement of MIF and D-DT in bacterial, viral, fungal, and parasitic infections. The role of MIF in different types of infections is controversial, as it has either a protective function or a host damage-enhancing function depending on the pathogen. Depending on the specific role of MIF, different therapeutic options for MIF-targeting drugs arise. Human MIF-neutralizing antibodies, anti-parasite MIF antibodies, small molecule MIF inhibitors or MIF-blocking peptides, as well as the administration of exogenous MIF or MIF activity-augmenting small molecules have potential therapeutic applications and need to be further explored in the future. In addition, MIF has been shown to be a potential biomarker and therapeutic target in sepsis. Further research is needed to unravel the complexity of MIF and D-DT in infectious diseases and to develop personalized therapeutic approaches targeting these cytokines. Overall, a comprehensive understanding of the role of MIF and D-DT in infections could lead to new strategies for the diagnosis, treatment, and management of infectious diseases.