We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.

The aim of the present study was to assess the caries experience of children aged 6 to 7 years old in a socially deprived suburban area of Brazil’s Federal District, using the ICDAS II system and to investigate determinants of dental caries. The survey was carried out in six public schools by three calibrated examiners, on a sample of 835 children. ICDAS II codes had to be converted into dmf/DMF components at surface and tooth levels, resulting in unfamiliar caries variables, to enable some meaningful reporting of the findings. The prevalence of dental caries, including enamel and dentinal carious lesions, in primary teeth was 95.6% and in permanent teeth it was 63.7%. Mean values of d2mf2-t (enamel and dentinal lesions), d3mf3-t (dentine lesions), D2MF2-T and D3MF3-T indices were 6.9 ± 3.8, 3.2 ± 3.4, 1.7 ± 1.6 and 0.2 ± 0.5, respectively. Enamel carious lesions predominated in the dmf-t/s and DMF-T/S indices. Seven-year-old children had statistically significantly more enamel and dentine carious lesions in permanent teeth than 6-year-old children had. Using ICDAS II, the prevalence of dental caries in both dentitions was very high. In both dentitions, the decay component predominated, with hardly any restorations or extractions observed. The new ICDAS II system leads to overvaluation of the seriousness of dental caries experience and made reporting of outcomes cumbersome. Guidelines on analysing data and reporting results should be agreed upon before this system can be used in epidemiological surveys globally.

Disadvantaged children suffer because tooth cavities are not being treated and their clinical consequences not being surveyed. The present study aimed to assess the prevalence and severity of clinical consequences of untreated dentine carious lesions in schoolchildren from a deprived area of Brazil and to investigate the determinants of the pufa index. A sample of 835 children aged 6–7 years, from six public schools, was examined by 3 calibrated examiners. Clinical consequences of untreated dentine carious lesions in primary teeth were diagnosed using the four codes of the pufa index: ‘p’ (pulpal involvement), ‘u’ (ulceration), ‘f’ (fistulae), ‘a’ (abscess). Effects of gender, age, school, history of extraction, and toothache on the prevalence of pufa codes were tested. The prevalence of pufa codes was 23.7%. The mean pufa score was 0.4 ± 0.9. Code ‘p’ was the most prevalent (19.5%), whereas code ‘u’ was least prevalent (0.1%). Children with a history of extracted primary teeth due to caries had a 2.7 times higher chance to have a pufa code than children with no previous extraction. Children with toothache had a 5.6 times higher chance to have a pufa code than children without toothache. The prevalence of clinical consequences of untreated dentine carious lesions was moderate and the severity was low. The pufa index is an epidemiological tool complementary to existing caries indices aimed to assess dental caries. However, there appears to be no need to include code ‘u’ nor to score codes ‘f’ and ‘a’ separately.

Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of [Ca2+]i and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors.

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