Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells.

BACKGROUND: Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression. METHODS: In order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine. RESULTS: Under the TNFα overexpression, significant upregulation of two genes was observed: proinflammatory cytokine IL6 gene in melanoma cells A375 and gene for pro-apoptotic ligand TRAIL in colorectal carcinoma cells HT29, both mediated by TNFα/TNFR1 signaling. Malignant melanoma line A375 displayed also increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology (shortened and condensed mitochondria) both in melanoma and colorectal carcinoma cells. Overexpression of TNFα was not linked with significant affection of the subpopulation of cancer stem-like cells in vitro. However, we could demonstrate a decrease in aldehyde dehydrogenase (ALDH) activity up to 50%, which is associated with to the stemness phenotype. CONCLUSIONS: Our in vitro study of direct TNFα influence demonstrates two distinct outcomes in tumor cells of different origin, in non-epithelial malignant melanoma cells of neural crest origin, and in colorectal carcinoma cells derived from the epithelium.

Impact of Smoking on the Survival of Patients With High-risk HPV-positive HNSCC: A Meta-analysis.

BACKGROUND/AIM: High risk Human papillomavirus (hr-HPV) and smoking are independant risk factors for head and neck squamous cell carcinomas (HNSCC). While hr-HPV+ HNSCC has a better prognosis than smoking-associated HNSCC no systematic data are yet available about the combined risk. PATIENTS AND METHODS: We performed a meta-analysis to assess the overall survival of HNSCC patients relative to the hr-HPV and smoking status. A literature review up to November 2019 was conducted in PubMed and Cochrane Library using the search terms 'HPV, Smoking and HNSCC'. RESULTS: Nine out of 748 articles were included, 1,436 out of 2,080 patients were hr-HPV+ The prevalence of hr-HPV+ smokers was 36%. The meta-analysis showed a significantly better 5-year overall survival for HPV+ non-smokers compared to smokers with risk ratio of 1.94 (95% confidence intervaI=1.46-2.58). CONCLUSION: Smoking is a negative prognostic factor for overall survival in patients with hr-HPV+ HNSCC and should thus be an important part of staging and treatment.

Early Onset, Long Illness Duration, Epilepsy Type, and Polypharmacy Have an Adverse Effect on Psychosocial Outcome in Children with Epilepsy.

Epilepsy is often associated with psychosocial comorbidity and this can be more disabling than the seizure activity. Still, these associated conditions are often underdiagnosed and therefore not sufficiently treated. We studied a large pediatric cohort of 371 patients with epilepsy to identify factors associated with negative outcome. We found that patients with early-onset epilepsy, epilepsy of known etiology, and polypharmacy were the most likely to display cognitive impairment. Behavioral problems were particularly prevalent in patients with an epilepsy duration ≥ 5 years. Similarly, early-onset epilepsy, long illness duration, epilepsy of known etiology, and polypharmacy had an adverse effect on school placement and/or social contact. With polypharmacy being the only potentially modifiable factor, it is important to balance between benefits and adverse effects of antiepileptic drugs and consider alternative therapy options in selected patients such as epilepsy surgery, vagal nerve stimulation, and ketogenic diet early-on.