Comparison of high-dose Cisplatin-based chemoradiotherapy and Cetuximab-based bioradiotherapy for p16-positive oropharyngeal squamous cell carcinoma in the context of revised HPV-based staging

Aim: To perform a comparison of Cisplatin vs. Cetuximab in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) in the context of the revised HPV-based staging.Background: Previous reports comparing these agents in head and neck cancer have included heterogenous disease and p16-status.Materials and methods: A retrospective review was conducted from 2006 to 2016 of patients with p16-positive OPSCC who underwent definitive radiotherapy concurrent with either triweekly Cisplatin (n?=?251) or Cetuximab (n?=?40). AJCC 8th Edition staging was adapted.Results: Median follow-up for surviving patients was 40 months. On multivariate analysis for all-comers, comparing Cisplatin and Cetuximab, 3-year locoregional recurrence (LRR): 6% vs. 16% (p?=?0.07), 3-year distant metastasis (DM): 8% vs. 21% (p?=?0.04), 3-year overall recurrence rate (ORR): 11% vs. 29% (p?=?0.01), and 3-year cause-specific survival (CSS): 94% vs. 79% (p?=?0.06), respectively. On stage-based subgroup analysis, for stage III disease, 3-year LRR: 5% vs. 10% (p?=?0.51), 3-year DM: 7% vs. 16% (p?=?0.32), 3-year ORR: 10% vs. 23% (p?=?0.15), and 3-year CSS: 95% vs. 82% (p?=?0.38). For stage III disease, 3-year LRR: 10% vs. 40% (p?=?0.07), 3-year DM: 9% vs. 43% (p?=?0.07), 3-year ORR: 15% vs. 55% (p?=?0.04), and 3-year CSS: 94% vs. 57% (p?=?0.048).Conclusions: When given concurrently with radiotherapy, Cetuximab and triweekly Cisplatin demonstrated comparable efficacy for AJCC 8th Edition stage I–II p16-positive OPSCC. However, Cetuximab appeared to be associated with higher rates of treatment failure and cancer-related deaths in stage III disease. Upon availability of the RTOG 1016 trial results, analysis based on the revised HPV-based staging should be performed to confirm these findings.     

Molecular analysis of the first avian influenza H5N1 isolates from fowl in Romania

Since the events of avian influenza (AI) caused by H5N1 subtype from Hong Kong (1997), the people worldwide have been confronted with new waves of epizootic influenza. In 2005 in Romania an unprecedent H5N1 epizootic occurred in domestic and wild birds. Therefore an immediate investigation by molecular approach of this highly pathogenic H5N1 strain was necessary. The virus isolation and the RNA extraction were performed in the Institute of Diagnosis and Animal Health while PCR and sequencing were carried out in Cantacuzino Institute. Herein we report the first evidence of H5N1 presence in Romanian fowls. The phylogenetic analysis of haemagglutinin and neuraminidase gene indicated a close relationship of Romanian strains to those from Siberia and China. The virological and molecular analysis of the first strains of avian virus from Romania confirmed the presence of H5N1 subtype, belonging to the genetic line Z. These results indicate that the avian virus from this genetic line is directly derived from the highly pathogenic viruses isolated in China and Russia in 2005.     

Ferritin protein nanocage ion channels: gating by N-terminal extensions

Ferritin protein nanocages, self-assembled from four-α-helix bundle subunits, use Fe²⁺ and oxygen to synthesize encapsulated, ferric oxide minerals. Ferritin minerals are iron concentrates stored for cell growth. Ferritins are also antioxidants, scavenging Fenton chemistry reactants. Channels for iron entry and exit consist of helical hairpin segments surrounding the 3-fold symmetry axes of the ferritin nanocages. We now report structural differences caused by amino acid substitutions in the Fe²⁺ ion entry and exit channels and at the cytoplasmic pores, from high resolution (1.3–1.8 Å) protein crystal structures of the eukaryotic model ferritin, frog M. Mutations that eliminate conserved ionic or hydrophobic interactions between Arg-72 and Asp-122 and between Leu-110 and Leu-134 increase flexibility in the ion channels, cytoplasmic pores, and/or the N-terminal extensions of the helix bundles. Decreased ion binding in the channels and changes in ordered water are also observed. Protein structural changes coincide with increased Fe²⁺ exit from dissolved, ferric minerals inside ferritin protein cages; Fe²⁺ exit from ferritin cages depends on a complex, surface-limited process to reduce and dissolve the ferric mineral. High concentrations of bovine serum albumin or lysozyme (protein crowders) to mimic the cytoplasm restored Fe²⁺ exit in the variants to wild type. The data suggest that fluctuations in pore structure control gating. The newly identified role of the ferritin subunit N-terminal extensions in gating Fe²⁺ exit from the cytoplasmic pores strengthens the structural and functional analogies between ferritin ion channels in the water-soluble protein assembly and membrane protein ion channels gated by cytoplasmic N-terminal peptides.