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BackgroundSQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC™) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492) demonstrating SQ3370’s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity.MethodsTreatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors.ResultsSQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370’s safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3+and CD8+T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment.ConclusionsSQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development.Trial registrationNCT04106492; 7 September 2019

This dataset is supplemental to "Ultraviolet Photooxidation of Smectite-Bound Fe(II) and Implications for the Origin of Martian Nontronites". SI_H2_June2017 contains the hydrogen abundances measured during UV irradiation experiments for all of the clay samples. SI_VNIR_Sept2017 includes measured visible near-infrared (VNIR) spectra for all of the clay samples. SI_XANES_July2017 includes the XANES (X-ray absorption near-edge structure) dataset collected at the National Synchrotron Light Source II (NSLS-II) at Brookhaven National Laboratory. SI_XRD_20162018 includes the X-ray Diffraction (XRD) patterns for all of the clay samples.

BACKGROUND: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease. RESEARCH QUESTION: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV(3)/FEV(6)) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? STUDY DESIGN AND METHODS: The study included 832 current and former smokers with post-bronchodilator FEV(1)/FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV(3)/FEV(6) based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV(3) and FEV(6). Regression modeling was used to evaluate the relationship between baseline FEV(3)/FEV(6) and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD. RESULTS: FEV(3)/FEV(6) less than the LLN at baseline, defined as reduced compared with FEV(3)/FEV(6) at or above the LLN, was associated with lower FEV(1), poorer health status (St. George’s Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV(3) and FEV(6) showed excellent agreement between repeat measurements. A reduced FEV(3)/FEV(6) was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV(3)/FEV(6) was also associated with development of COPD according to spirometry results (post-bronchodilator FEV(1)/FVC < 0.7) during study follow-up. INTERPRETATION: FEV(3)/FEV(6) is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV(3)/FEV(6) can identify those at risk for future development of COPD and respiratory exacerbations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov: ClinicalTrials.gov.

This work presents kinetic modeling efforts to evaluate the anti-knock tendency of several substituted phenols if used as gasoline additives. They are p-cresol, m-cresol, o-cresol, 2,4-xylenol, 2-ethylphenol, and guaiacol. A detailed kinetic model was constructed to predict the ignition of blends of the phenols in n-butane with the help of reaction mechanism generator (RMG), an open-source software package. The resulting model, which has 1465 species and 27 428 reactions, was validated against literature n-butane ignition data in the low-to-intermediate temperature range. To rank the anti-knock tendency of the additives, engine-like simulations were performed in a closed adiabatic homogenous batch reactor with a volume history derived from the pressure profile of a real research octane number (RON) engine test. The ignition timings of the additive blends were compared to that of primary reference fuels (PRFs) to quantitatively predict the anti-knock ability. The model predictions agree well with experimental determinations of the changes in RON induced by the additives. This study explains the chemical mechanism by which methyl-substituted phenols increase RON, and demonstrates how fundamental chemical kinetics can be used to evaluate practical fuel additive performance.

This work presents shock tube experiments and kinetic modeling efforts on the pyrolysis and combustion of JP-10. The experiments were performed at 6–8 atm using 2000 ppm of JP-10 over a temperature range of 1000–1600 K for pyrolysis and oxidation equivalence ratios from 0.14 to 1.0. This work distinguishes itself from previous studies as GC/MS was used to identify and quantify the products within the shocked samples, enabling the tracking of product yield dependence on equivalence ratio as well as identifying several new intermediates that form during JP-10’s decomposition. A detailed, comprehensive model of JP-10’s combustion and pyrolysis kinetics was constructed with the help of RMG, an open-source reaction mechanism generation software package. The resulting model, which includes 691 species reacting in 15,518 reactions, was extensively validated against the shock tube experimental dataset as well as newly published flow tube pyrolysis data from Ghent. Most of the important rate coefficients were computed using quantum chemistry. The model succeeds in identifying all major pyrolysis and combustion products and captures key trends in the product distribution. Simulated ignition delays agree within a factor of 4 with most experimental ignition delay data gathered from literature. The presented experimental work and modeling efforts yield new insights on JP-10’s complex decomposition and oxidation chemistry and identify key pathways towards aromatics formation., Naval Air Warfare Center (U.S.) (Contract N68335-09-C-0367), Naval Air Warfare Center (U.S.) (Contract N68335-10-C-0534), United States. Department of Energy. Office of Basic Energy Sciences (Grant DE-FG02-98ER14914), National Science Foundation (U.S.) (Grant 0535604), National Science Foundation (U.S.) (Grant 0312359), United States. Department of Energy. Office of Basic Energy Sciences (DE-SC0001198), Richard Burnes

Sedimenticola selenatireducens strain AK4OH1(T) (= DSM 17993(T) = ATCC BAA-1233(T)) is a microaerophilic bacterium isolated from sediment from the Arthur Kill intertidal strait between New Jersey and Staten Island, NY. S. selenatireducens is Gram-negative and belongs to the Gammaproteobacteria. Strain AK4OH1(T) was the first representative of its genus to be isolated for its unique coupling of the oxidation of aromatic acids to the respiration of selenate. It is a versatile heterotroph and can use a variety of carbon compounds, but can also grow lithoautotrophically under hypoxic and anaerobic conditions. The draft genome comprises 4,588,530 bp and 4276 predicted protein-coding genes including genes for the anaerobic degradation of 4-hydroxybenzoate and benzoate. Here we report the main features of the genome of S. selenatireducens strain AK4OH1(T).