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Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER + ) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER + human epidermal growth factor receptor-negative (HER2 - ) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER + HER2 - mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 ., (© 2024. The Author(s).)

Tritium concentrations in oceans were compiled from the literature, online databases and original measurements in order to determine the global distribution of tritium concentrations according to latitude and depth in all oceans. The total inventory of tritium decay corrected in 2016 has been estimated using evaluation of the natural and artificial contributions in 23 spatial subdivisions of the total ocean. It is determined equal to 26.8 ± 14 kg including 3.8 kg of cosmogenic tritium. That is in agreement with the total atmospheric input of tritium from nuclear bomb tests and the natural inventory at steady-state estimated from natural production rates in the literature (27.8-29.3 kg in the Earth). We confirm the global increase in tritium according to latitude observed in the Northern hemisphere since 1967 with a maximum in the Arctic Ocean. The minimum tritium concentrations observed in the Southern Ocean were close to steady-state with known natural tritium deposition. We focused on the temporal evolution of surface (0 to 500 m) tritium concentrations in a selected area of the North Atlantic Ocean (30°N-60°N) where we found the 2016 concentration to be 0.60 ± 0.10 TU (1σ). Results showed that in that area, between 1988 and 2013, tritium concentrations: i) decreased faster than the sole radioactive decay, due to a mixing with lower and lateral less concentrated waters, and ii) decreased towards an apparent steady state concentration. The half-time mixing rate of surface waters and the steady state concentration were respectively calculated to be 23 ± 5 years (1σ) and 0.38 ± 0.07 TU (1σ). This apparent steady-state concentration in the North Atlantic Ocean implies a mean tritium deposition of 1870 ± 345 Bq·m -2 (1σ), five folds higher than the known inputs (natural, nuclear tests fallout and industrial releases, ~367 Bq·m -2 ) in this area., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We determined the resistance to quinolone of 309 Salmonella enterica subsp. enterica serotype Typhimurium strains isolated from humans and animals (cattle, pigs, or poultry) in 1995 or 1996. Nalidixic acid resistance increased from 8.5% in 1995 to 18.6% in 1996. The highest resistance levels correlated with a mutation at Ser-83 (or Asp-82). All strains remained ciprofloxacin susceptible. Human and animal isolates were compared by pulsed-field gel electrophoresis, and the banding patterns of the human isolates most closely matched those of the bovine isolates.

To determine the prevalence of quinolone resistance in Salmonella typhimurium strains from humans or animals (cattle, poultry, swine), the S. typhimurium strains isolated at a teaching hospital and at the central veterinary laboratory of the same district between January 1, 1995, and December 31, 1996 were studied. Susceptibility to nalidixic acid was determined using the disk diffusion method. Strains with decreased susceptibility to nalidixic acid were subjected to minimal inhibitory concentration (MIC) determination for pefloxacin, ofloxacin, ciprofloxacin, norfloxacin, levofloxacin, and grepafloxacin. Decreased susceptibility to nalidixic acid was demonstrated for 41 of the 309 strains studied and increased from 8.5% in 1995 to 18.6% in 1996. MIC90 values of fluoroquinolones for strains with decreased susceptibility to nalidixic acid were lower than 1 mg/L, which is the cutoff above which a strain is classified as susceptible, but were higher than for strains that were susceptible to nalidixic acid. These low levels of resistance may be the first step in selection of mutant strains with high levels of resistance to fluoroquinolones. This warrants continued monitoring of resistance of Salmonella to fluoroquinolones.

This paper describes the design of E3N, a prospective cohort study conducted in France on risk factors for female cancers. The cohort comprises 100,000 women, aged 40-65 years at baseline in 1990. Participants were asked to complete questionnaires every 18 months. The main hypotheses studied concern the relationship between diet and cancer and between hormonal treatments and cancer. All cancers diagnosed are registered, together with other diseases (cardiovascular diseases, diabetes, osteoporosis). The study population and the follow-up procedure are described.

The purpose of this study is to assess the impact of improvement measures for hygiene and water supply, installation of latrines and health education on the incidence of ascaridiasis and ankylostomiasis with 2 to 4 years old children in some villages of southern Côte d'Ivoire. The method used is the comparison of children carrying parasites before and after intervention. Initially in 1988, the stools of all children aged from 2 to 4 were collected and examined in order to look for the presence of parasites in the stools. Two identical inquiries were made in 1990 and 1992. The results show a reduction of the rate of incidence for ascaridiasis by 75% and ankylostomiasis by 82%. They demonstrate the importance of an appropriate evacuation of excreta, of an education of mothers and of domestic hygiene in the process of prevention of children parasitosis.

The purpose is to assess the impact of compliance with measures of hygiene and water supply and oral rehydration on the diarrhoea with under 5 years of age in four villages of southern Côte d'Ivoire. The method used is to compare morbidity and mortality of children, firstly between two groups of villages without such measures, secondly in two villages before and after implementing them. Initially, an exhaustive survey has determined the incidence rate of diarrhoea, the proportion of deaths resulting from such diarrhoea as well as the mortality rate 1988. Two similar survey were made in 1990 and 1992. The results show a 50% reduction of the incidence rate of diarrhoea and a 85% reduction of the proportion of deaths related to diarrhoea in the villages with intervention. The mortality rate to diarrhoea was likewise reduced by 85%. These results show the importance of the improvement and accessibility to drinkable water and hygiene in the prevention of diarrhoea in areas children.