Evofosfamide for the Treatment of Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication

Tribological behaviour of sintered iron bearings self-lubricated with PFPE under severe operating conditions

The tribological properties of sintered iron bearings self-lubricated with perfluoropolyethers (PFPEs) were investigated under severe operating conditions. Tests were carried out at a temperature of 150°C for a range of constant PV values and at room temperature for PV values exceeding the limits laid down by Metal Powder Industry Federation (MPIF) specifications. The performance of the PFPE-lubricated bearings was found to be superior to that bearings lubricated with mineral oil. At 150°C and PV=0.4 MN/ms the life of the PFPE-lubricated bearings exceeded 150 hours without damage -five to six times longer than the life given for such conditions by MPIF specifications

Plasma deposition of thin films from a F-containing cyclo-siloxane

Thin films have been deposited from radio-frequency glow discharges fed with vapors of a silicon- and fluorine-containing organic compound, namely 2,4,6-tris[(3,3,3-trifluoropropyl)(methyl)] cyclotrisiloxane, in mixture with argon

ESR of intermediate radicals in thermolysis mechanisms: peroxidic perfluoro polyethers

The photothermolysis between 100 and 250 C of polymers with perfluorooxymethylene, oxyethylene and oxypropylene structures and containing peroxidic units as photoactive initiators has been studied by ESR and the INDO MO method. Following the initial homolysis of peroxidic bonds and the beta scission of resulting alkoxy radicals, alkoxyfluoroalkyl radicals are formed wich, above 100 C, undrgo thermal decomposition by beta scission, initiating a chain depolymerization with formation of carbonyl compounds and C2F4 and C3F6 monomers; the latter add to RCF2. species yielding Cn (n>=3) units. By extension of these results, it is inferred that this mechanism is of major importance in the high-temperature pyrolisis of this class of compounds. Among the intermediates of the C2P and C3P photothermolysis, of special interest are some novel prymary alkoxyfluoroalkyl radicals with strongly bent structures at the radical centers and showing unusually large long-range interactions with gamma and delta fluorine atoms, wich are actually being investigated by MO methods

Spintrapping of intermediateradicals in the solid state gamma radiolysis of perfluoropolyethers

Significant features of the mechanism of the solid state gamma radiolysis of perfluoropolyethers was elecidated by trapping of reactive radicalsintermediates as spin adducts with 2-Methylnitrosopropane (MNP) or in solid matrices at low temperature. Polyethers with repeating units -[(OCF2CF2)x(OCF2)-y]n (A), yield radicals of type ROCF2• and ROCF2CF2•, which are identified from their nitroxyls derivatives. Clear evidence for radical ROCF2• was also obtained from its polycrystalline spectrum. Polyethers of formula -[(OCF2CF(CF3))x-(OCF2)y−]n (B), yield radicals ROCF2Ċ(CF3)-, as major product, togheter with minor amount of ROCF2. The polycrystalline ESR spectrum of the pure compound show the presence of ROCF2• and ROĊF(CF3)- as major products whilst the tertiary radical is not observed. These observations suggest that prominent processes in the radiolysis of A are CC and CO bond homolysis followed by β scission of the resulting a alkoxy radicals. The same type of reaction may be invoqued to rationalize the formation of ROCF2• and ROĊCF(CF3) in the radiolysis of B; however the identification of the tertiary radical implies either the partecipation of a dissociative elctron capture during the irradiation or Fluorine abstraction by primay ROCF2• species during the warm up above 77 K. A slow thermal reaction of MNP with polyethers, yielding nitroxyls, has been observed and it is actually being investigated