Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
L-Arginine and chronic exercise reduce oxidative stress. However, it is unclear how they affect cardiomyocytes during cardiovascular disease (CVD) development. The aim of this research was to ...investigate the possible effects of L- arginine supplementation and aerobic training on systemic oxidative stress and their consequences on cardiomyocytes during cardiometabolic disease onset caused by excess fructose. Wistar rats were allocated into four groups: control (C), fructose (F, 10% fructose in water), fructose training (FT; moderate running, 50-70% of the maximal velocity), and fructose arginine (FA; 880 mg/kg/day). Fructose was given for two weeks and fructose plus treatments for the subsequent eight weeks. Body composition, blood glucose, insulin, lipid profile, lipid peroxidation, nitrite, metalloproteinase-2 (MMP-2) activity, left ventricle histological changes, microRNA-126, -195, and -146, eNOS, p-eNOS, and TNF-alpha expressions were analyzed. Higher abdominal fat mass, triacylglycerol level, and insulin level were observed in the F group, and both treatments reversed these alterations. Myocardial vascularization was impaired in fructose-fed groups, except in FT. Cardiomyocyte hypertrophy was observed in all fructose-fed groups. TNF-alpha levels were higher in fructose-fed groups than in the C group, and p-eNOS levels were higher in the FA than in the C and F groups. Lipid peroxidation was higher in the F group than in the FT and C groups. During CVD onset, moderate aerobic exercise reduced lipid peroxidation, and both training and L-arginine prevented metabolic changes caused by excessive fructose. Myocardial vascularization was impaired by fructose, and cardiomyocyte hypertrophy appeared to be influenced by pro-inflammatory and oxidative environments. Key words: Cardiovascular disease; Exercise; Arginine; Fructose; Oxidative stress
The aim of this work is to present preliminary results of the statistical and dynamical simulations carried out within the framework of the Flagship Pilot Study in southeastern South America ...(FPS-SESA) endorsed by the Coordinated Regional Climate Downscaling Experiments (CORDEX) program. The FPS-SESA initiative seeks to promote inter-institutional collaboration and further networking with focus on extreme rainfall events. The main scientific aim is to study multi-scale processes and interactions most conducive to extreme precipitation events through both statistical and dynamical downscaling techniques, including convection-permitting simulations. To this end, a targeted experiment was designed considering the season October 2009 to March 2010, a period with a record number of extreme precipitation events within SESA. Also, three individual extreme events within that season were chosen as case studies for analyzing specific regional processes and sensitivity to resolutions. Four dynamical and four statistical downscaling models (RCM and ESD respectively) from different institutions contributed to the experiment. In this work, an analysis of the capability of the set of the FPS-SESA downscaling methods in simulating daily precipitation during the selected warm season is presented together with an integrated assessment of multiple sources of observations and available CORDEX Regional Climate Model simulations. Comparisons among all simulations reveal that there is no single model that performs best in all aspects evaluated. The ability in reproducing the different features of daily precipitation depends on the model. However, the evaluation of the sequence of precipitation events, their intensity and timing suggests that FPS-SESA simulations based on both RCM and ESD yield promising results. Most models capture the extreme events selected, although with a considerable spread in accumulated values and the location of heavy precipitation.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•4MBC induced mortality, malformations and reduced growth in S. senegalensis larvae.•Swimming behaviour was affected by 4MBC at low concentrations.•4MBC caused alterations in AChE and LDH biochemical ...markers.•Assessment of behaviour is recommended in ecotoxicological studies with sole larvae.
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The inclusion of organic UV filters in personal care products (PCPs) has increased in recent years. 4-Methylbenzylidene camphor (4MBC) is one of the most used UV filters, and thus it is commonly found in aquatic ecosystems, with proved negative effects on aquatic organisms. Effects on early life stages of marine vertebrates are largely unknown. Therefore, the main goal of this work was to evaluate 4MBC effects on Senegalese sole (Solea Senegalensis Kaup, 1858) larvae at different levels of biological organization. S. senegalensis were exposed to increasing concentrations of 4MBC from egg stage until 96 h. Mortality, growth, malformations, behaviour and biochemical responses, including enzymatic biomarkers were studied. The exposure to 4MBC until 96 h post-fertilization (hpf) induced mortality and malformations in a dose-response manner. Besides, reduced growth with increasing concentrations was observed. The exposure to 4MBC also caused alterations on behaviour, including overall lower swimming time during light and dark periods. Biomarker alterations caused by 4MBC included imbalance of neurotransmission related endpoints (increased acetylcholinesterase activity) and decreased activity of enzymes related to anaerobic metabolism (lower cellular lactate dehydrogenase activity) at the lower concentrations tested. Furthermore, our results suggest that 4MBC do not induce oxidative stress in S. senegalensis larvae, since catalase and lipid peroxidation levels were not significantly altered by 4MBC.
S. senegalensis revealed to be a good model species for vertebrate animal testing in the marine environment. Sub-lethal concentrations of 4MBC induced toxic effects at all organizational levels. Swimming behaviour was a sensitive endpoint and showed that exposure to 4MBC causes impairment on response to light stimulus which is possibly linked with the observed imbalances on cholinesterase activity in larvae. Conservation concerns along distribution range of S. senegalensis should consider that increasing levels of UV filters in marine environment might have impact on the ecology of the species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is growing concern that modifications to the global environment such as ocean acidification and increased ultraviolet radiation may interact with anthropogenic pollutants to adversely affect ...the future marine environment. Despite this, little is known about the nature of the potential risks posed by such interactions. Here, we performed a multifactorial microcosm experiment to assess the impact of ocean acidification, ultraviolet B (UV‐B) radiation and oil hydrocarbon contamination on sediment chemistry, the microbial community (composition and function) and biochemical marker response of selected indicator species. We found that increased ocean acidification and oil contamination in the absence of UV‐B will significantly alter bacterial composition by, among other things, greatly reducing the relative abundance of Desulfobacterales, known to be important oil hydrocarbon degraders. Along with changes in bacterial composition, we identified concomitant shifts in the composition of oil hydrocarbons in the sediment and an increase in oxidative stress effects on our indicator species. Interestingly, our study identifies UV‐B as a critical component in the interaction between these factors, as its presence alleviates harmful effects caused by the combination of reduced pH and oil pollution. The model system used here shows that the interactive effect of reduced pH and oil contamination can adversely affect the structure and functioning of sediment benthic communities, with the potential to exacerbate the toxicity of oil hydrocarbons in marine ecosystems.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated ...significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥ 180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; -15.2 ± 23.5 vs. -8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
Post hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension. CLINICALTRIALS.GOV IDENTIFIER: NCT01418261.
The first 1000 days of life are a critical period when the foundations of child development and growth are established. Few studies in Latin America have examined the relationship of birth outcomes ...and neonatal care factors with development outcomes in young children. We aimed to assess the association between pregnancy and neonatal factors with children's developmental scores in a cross-sectional, population-based study of children in Ceará, Brazil.
Population-based, cross-sectional study of children aged 0-66 months (0-5.5 years) living in Ceará, Brazil. We examined the relationship of pregnancy (iron and folic acid supplementation, smoking and alcohol consumption) and neonatal (low birth weight (LBW) gestational age, neonatal care interventions, and breastfeeding in the first hour) factors with child development. Children's development was assessed with the Ages and Stages Questionnaire (ASQ-BR). We used multivariate generalized linear models that accounted for clustering sampling to evaluate the relationship of pregnancy and neonatal factors with development domain scores.
A total of 3566 children were enrolled. Among pregnancy factors, children whose mothers did not receive folic acid supplementation during pregnancy had lower fine motor and problem-solving scores (p-values< 0.05). As for neonatal factors, LBW was associated with 0.14 standard deviations (SD) lower (CI 95% -0.26, - 0.02) communication, 0.24 SD lower (95% CI: - 0.44, - 0.04) fine motor and 0.31 SD lower (CI 95% -0.45, - 0.16) problem-solving domain scores as compared to non-LBW children (p values < 0.05). In terms of care, newborns that required resuscitation, antibiotics for infection, or extended in-patient stay after birth had lower development scores in selected domains. Further, not initiating breastfeeding within the first hour after birth was associated with lower gross motor and person-social development scores (p-values < 0.05).
Pregnancy and neonatal care factors were associated with later child development outcomes. Infants at increased risk of suboptimal development, like LBW or newborns requiring extended in-patient care, may represent groups to target for supplemental intervention. Further, early integrated interventions to prevent adverse pregnancy and newborn outcomes may improve child development outcomes.
More than 200 million children fail to reach their full developmental potential in low- and middle-income countries. Adverse childhood experiences, maternal mental health, and intimate partner ...violence are negatively associated with child development outcomes. The relationship of these risk factors with child communication, gross motor, fine motor, problem-solving, and personal–social development scores in Brazil are assessed.
A population-based, cross-sectional study of preschool children living in the state of Ceará, Brazil, in 2017 was conducted. Child development was assessed with the Ages and Stages Questionnaire. Adverse childhood experiences for children were self-reported by the participants’ mothers using the Centers for Disease Control and Prevention Adverse Childhood Experiences Study‒adapted metric. Maternal mental health and intimate partner violence were evaluated using validated questionnaires. Sample-adjusted multivariable generalized linear models with interaction terms were used to determine the association of intimate partner violence, maternal mental health, and adverse childhood experiences with developmental outcomes and identify possible moderators. Data were analyzed between 2019 and 2020.
Children exposed to ≥3 adverse childhood experiences had −0.12 (95% CI= −0.24, 0) lower communication, −0.25 (95% CI= −0.46, −0.03) lower gross motor, −0.27 (95% CI= −0.47, −0.07) lower fine motor, and −0.17 (95% CI= −0.3, −0.03) lower personal–social domain scores than children with no adverse childhood experiences. Furthermore, the greater number of adverse childhood experiences was linearly associated with lower developmental scores. Maternal mental health and intimate partner violence were also associated with lower development scores.
Adverse childhood experiences were independently associated with developmental outcomes in Brazilian children. Community-based interventions to reduce the impact of adverse childhood experiences, intimate partner violence, and maternal mental health may benefits child development outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
N-doped carbon materials are promising metal-free catalysts for a number of applications. In this work, a cost effective and easy method to prepare N-doped carbon nanotubes by ball milling was ...developed, which avoids the use of solvents and production of wastes. Melamine and urea were used as nitrogen precursors. The textural and chemical properties of the N-doped materials were characterized by N2 adsorption at −196°C, temperature programmed desorption, elemental analysis, X-ray photoelectron spectroscopy and thermogravimetric analysis. The highest efficiency of N-doping was obtained with melamine. This method leads to the incorporation of large amounts of N-groups, namely quaternary nitrogen, pyridinic, and pyrrolic groups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
► Industrial steam explosion was applied to sugarcane straw. ► Use of grinded straw makes viable the large-scale pretreatment process. ► The process could be effective for pretreatment and ...delignication or delignification only. ► Hydrolysis conversion decreased after the alkaline treatment in high temperatures. ► Apparently the not removed lignin recovered the pulp decreasing the enzymatic access.
Steam explosion at 180, 190 and 200°C for 15min was applied to sugarcane straw in an industrial sugar/ethanol reactor (2.5m3). The pretreated straw was delignificated by sodium hydroxide and hydrolyzed with cellulases, or submitted directly to enzymatic hydrolysis after the pretreatment. The pretreatments led to remarkable hemicellulose solubilization, with the maximum (92.7%) for pretreatment performed at 200°C. Alkaline treatment of the pretreated materials led to lignin solubilization of 86.7% at 180°C, and only to 81.3% in the material pretreated at 200°C. All pretreatment conditions led to high hydrolysis conversion of cellulose, with the maximum (80.0%) achieved at 200°C. Delignification increase the enzymatic conversion (from 58.8% in the cellulignin to 85.1% in the delignificated pulp) of the material pretreated at 180°C, but for the material pretreated at 190°C, the improvement was less remarkable, while for the pretreated at 200°C the hydrolysis conversion decreased after the alkaline treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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