The impact of SARS-Covid-19 pandemic on peripheral nerve surgery - A single centre report.

OBJECTIVE: SARS-Cov-19 pandemic totally changed daily routine work in German hospitals. As hospital capacity was reduced, many surgeries were postponed or even cancelled. On March 25th 2020 the German Society of Neurosurgery (DGNC) published a statement in which urgent non-elective surgeries were defined for each neurosurgical domain, whereas elective interventions were deferred. The present work examines the impact of these Covid strategies focusing on patients with peripheral lesions who were conducted to our department during this period of time. METHODS: All patients who underwent any peripheral nerve surgery at our department from January 2018 until December 2022, were included. The complete range of surgeries including peripheral nerve lesions was examined encompassing compression syndromes, traumatic lesions of brachial plexus, traumatic lesions and tumors of single peripheral nerves. The numbers of surgical procedures were compared before, during and after pandemic. Pearson correlation coefficient was analysed. RESULTS: From 2018 to 2022 the total number of surgical procedures involving peripheral nerves included 2422 procedures. Compression syndromes made up the largest proportion (1433 operations, 59%), followed by peripheral nerve lesions (445 operations, 18%), peripheral nerve tumors (344 operations, 14%) and lesions of the brachial plexus (142 operations, 6%). The average was 40,5 interventions per month, the range was 7-63. Two declines in the number of peripheral nerve surgeries were noted during this period. The first was in April and May 2020 with an average drop of 65% and 41% respectively. In these months the average number of operations was 37. The second decrease was from October 2021 until January 2022, where number of surgeries was reduced by 16%, 36%, 83% and 18% with an average number of 50 operations. Both declines showed a significant and strong correlation with the lower number of compression syndrome treatments (r = 0.952, p < 0.001 and r = 0.968, p < 0.001), while no drop and no significant correlation was found in the treatment of traumatic peripheral nerve injuries (p = 0.769, r = 0.095 and p = 0.243, r = 0.366) and traumatic brachial plexus injuries (p = 0.787, r = 0.088 and p = 0.780, r = 0.09). A weak significant correlation was seen in the treatment numbers of peripheral nerve tumors (p = 0.017, r = 0.672 and p = 0.015, r = 0.67). CONCLUSION: Covid-19 pandemic lead to a significant decrease in the number of nerve decompressions, since, according to the German Society of Neurosurgery, those were considered as elective surgeries.

Primary tumor-derived systemic nANGPTL4 inhibits metastasis.

Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.

Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity.

Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards 'normal' liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.