MiR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity in patients with head and neck cancer.

BACKGROUND: No biomarker is available for identifying cancer patients at risk of developing nephrotoxicity when treated with cisplatin. METHODS: We performed microRNA (miRNA) sequencing using plasma collected 5 days after cisplatin treatment (D5) from twelve patients with head and neck cancer with and without nephrotoxicity (grade ≥ 2 increased serum creatinine). The most differentially expressed miRNAs between the two groups were selected for quantification at baseline and D5 in a larger cohort of patients. The association between miRNAs and nephrotoxicity was evaluated by calculating the odds ratio (OR) from univariate logistic regression. Receiver operating characteristic curves (ROC) were used to estimate the area under the curve (AUC), sensitivity, and specificity. RESULTS: MiR-3168 (p = 1.98 × 10- 8), miR-4718 (p = 4.24 × 10- 5), and miR-6125 (p = 6.60 × 10- 5) were the most differentially expressed miRNAs and were further quantified in 43, 48, and 53 patients, respectively. The baseline expression of miR-3168 (p = 0.0456, OR = 1.03, 95% CI: 1.00-1.06) and miR-4718 (p = 0.0388, OR = 1.56, 95% CI: 1.03-2.46) were associated with an increased risk of nephrotoxicity, whereas miR-6125 showed a trend (p = 0.0618, OR = 1.73, 95% CI: 0.98-3.29). MiR-4718 showed the highest AUC (0.77, 95% CI: 0.61-0.93) with sensitivity of 66.76 and specificity of 79.49. CONCLUSIONS: We have provided evidence of baseline plasmatic expression of miR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity.

Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones and Study of Their In Vitro Metabolic Profile.

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.

Continuous flow reactor based with an immobilized biocatalyst for the continuous enzymatic transesterification of crude coconut oil.

Here, we have assessed the use of one packed bed or two packed bed reactors in series in which Burkholderia cepacia lipase (BCL) was immobilized on protic ionic liquid (PIL)-modified silica and used as a biocatalyst for the transesterification of crude coconut oil. Reaction parameters including volumetric flow, temperature, and molar ratio were evaluated. The conversion of transesterification reaction products (ethyl esters) was determined using gas chromatography and the quantities of intermediate products (diglyceride and monoglyceride [MG]) were assessed using high-performance liquid chromatography. Packed bed reactors in series produced ethyl esters with the greatest efficiency, achieving 65.27% conversion after 96 H at a volumetric flow rate of 0.50 mL Min-1 at 40 °C and a 1:9 molar ratio of oil to ethanol. Further, within the first 24 H of the reaction, increased MG (54.5%) production was observed. Molecular docking analyses were performed to evaluate the catalytic step of coconut oil transesterification in the presence of BCL. Molecular docking analysis showed that triglycerides have a higher affinity energy (-5.7 kcal mol-1 ) than the smallest MG (-6.0 kcal mol-1 ), therefore, BCL catalyzes the conversion of triglycerides rather than MG, which is consistent with experimental results.

Stereoselective synthesis of aryl cyclopentene scaffolds by Heck-Matsuda desymmetrization of 3-cyclopentenol.

A new enantioselective Heck-Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee's, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cis- arrangement in the formation of the 4-aryl-cyclopentenols.

Detection and sequencing of Zika virus in normocephalic newborns with congenital Zika infection.

Fourteen asymptomatic normocephalic newborns with confirmed congenital Zika infection were investigated. All newborns presented Zika virus (ZIKV) positivity on reverse transcriptase polymerase chain reaction. Following ZIKV-specific NS5 gene fragment sequencing in one child, phylogenetic analysis revealed that this isolate belonged to the Asian genotype, and clustered closely with other sequences previously isolated in north-east and northern regions of Brazil.

Urinary levels of TGF ß-1 and of cytokines in patients with prenatally detected nephrouropathies.

This study aimed to identify noninvasive biomarkers of clinically significant nephrouropathies in patients with antenatal renal and/or urinary tract alterations. Spot-urine levels of interleukin-6 (IL-6), transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α) were measured in 100 patients with antenatal detected nephrouropathies. Patients were divided in idiopathic hydronephrosis (n = 47), urinary tract malformations (n = 35), and dysplastic kidneys (n = 18). Urinary concentrations of TGF-ß1, IL-6, and TNF-α were compared between groups according to clinical and image findings. Receiver-operating characteristic (ROC) curves were analyzed for the overall diagnostic accuracy of TGF-ß1, IL-6, and TNF-α levels in discriminating infants with nephrouropathies. No significant differences in urinary TGF- ß1, IL-6, and TNF-α levels were found in the comparison between the groups. TGF-ß1 levels tended to be higher in patients with renal hypodysplasia compared to idiopathic hydronephrosis (p = 0.07). Twenty-nine patients had reduced DMSA uptake. In these cases, absolute urinary concentration of TGF-ß1 and levels standardized for creatinine were significantly higher than in patients with normal DMSA uptake, while IL6 and TNF-α did not differ between groups. Urinary cytokine measurements were not useful as a screening test for clinically significant nephrouropathies. Conversely, increased concentrations of TGF-ß1 pointed out to renal damage as indicated by reduced DMSA uptake.

Childhood obesity: evidence of an association between plasminogen activator inhibitor-1 levels and visceral adiposity.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been considered as a cardiovascular risk factor, mainly because of its strong association with insulin resistance. METHODS: To detect independent predictors of circulating PAI-1 levels in obese pediatric patients, we evaluated 86 subjects (mean age 10.7 +/- 2.8 years), 42 of whom were male (49%). Subjects were divided in two groups according to body mass index (BMI): obese subjects (n=61) and healthy non-obese controls (n=25). They were also divided by pubertal status. Besides anthropometric data, levels of PAI-1, leptin and biochemical markers of metabolic syndrome were measured. RESULTS: The obese group had higher levels of PAI-1, leptin and biochemical markers of metabolic syndrome than nonobese controls (p<0.05). However, multivariate regression analysis showed that only puberty progression (p=0.005) and abdominal circumference/height index (p=0.002) remained independent predictors of PAI-1 levels. CONCLUSION: In pediatric obesity, fat mass accumulation, mainly of visceral fat, and puberty progression were related to high PAI-1 levels, which might in turn contribute to cardiovascular risk.

Selective reductions of cyclic 1,3-diesters by using SmI(2) and H(2)O.

SmI(2)/H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.

Mixture design approach for the development of reduced fat lamb patties with carboxymethyl cellulose and inulin.

Fat replacement by carboxymethyl cellulose (CMC) and inulin (IN) for the manufacture of low-fat lamb patties was investigated utilizing mixture design. The effect of fat, CMC, and IN levels on texture, color, weight loss, patty diameter reduction, and sensory characteristics was investigated. The presence of CMC decreased hardness (p < 0.05). While CMC and IN also decreased springiness, cohesiveness, gumminess, and chewiness (p < 0.05), no effect on adhesiveness was observed (p > 0.05). CMC increased L* (lightness), a* (redness), and b* (yellowness) values in raw patties, whereas IN and fat contributed to a decrease on these parameters. Higher contents of CMC resulted in products with lower weight loss (p < 0.05) with no significative diameter reduction (p > 0.05). Nonetheless, higher levels of CMC affected the sensory acceptance resulting on products described as crumbly and with residual flavor by check-all-that-apply questions. CMC and IN can be used as fat replacers in lamb patties; however, the content of each ingredient must be carefully considered. In this study, it was observed that contents of CMC higher than 1% (w/w) negatively affected the product, whereas IN levels were not capable to decrease weight loss and diameter reduction in lamb patties.

Novel Virtual Environment for Alternative Treatment of Children with Cerebral Palsy.

Cerebral palsy is a severe condition usually caused by decreased brain oxygenation during pregnancy, at birth or soon after birth. Conventional treatments for cerebral palsy are often tiresome and expensive, leading patients to quit treatment. In this paper, we describe a virtual environment for patients to engage in a playful therapeutic game for neuropsychomotor rehabilitation, based on the experience of the occupational therapy program of the Nucleus for Integrated Medical Assistance (NAMI) at the University of Fortaleza, Brazil. Integration between patient and virtual environment occurs through the hand motion sensor "Leap Motion," plus the electroencephalographic sensor "MindWave," responsible for measuring attention levels during task execution. To evaluate the virtual environment, eight clinical experts on cerebral palsy were subjected to a questionnaire regarding the potential of the experimental virtual environment to promote cognitive and motor rehabilitation, as well as the potential of the treatment to enhance risks and/or negatively influence the patient's development. Based on the very positive appraisal of the experts, we propose that the experimental virtual environment is a promising alternative tool for the rehabilitation of children with cerebral palsy.

Synthesis and evaluation of (-)-Massoialactone and analogues as potential anticancer and anti-inflammatory agents.

(-)-Massoialactone, an α,ß-unsaturated δ-lactone isolated from Cryptocarya massoia, and five analogues were synthesized and their antiproliferative and anti-inflammatory activities were evaluated. The lactones were able to mimic the "core" functional group required for the biological activity of their parent natural compounds suggesting that substantially altered analogues may retain their properties.

Generation of long-lived plasma cells to serogroup B Neisseria meningitidis after murine immunisation with an outer membrane protein vaccine.

There is no universal vaccine against serogroup B meningococcus (Men B). We investigated the development of spleen and bone marrow-specific IgG-secreting plasma cells (ASC) in mice immunised with the Cuban outer membrane protein (OMP) vaccine (VA-MENGOC-BC). Bone marrow was the predominant anatomical site of specific ASC and showed constant ASC levels (approximately 4%) at each time point analysed, indicating the production of long-lived ASC. A mean of 2.36 and 0.35% of Men B ASC was detected in spleen after the third dose and 2 months later, respectively, indicating a short-lived population. The data suggest that a short-lived ASC population in spleen was responsible for serum IgG anti-OMP while ASC from bone marrow produced persistent bactericidal antibodies against the vaccine strain. The response to the booster dose was consistent with development of memory B cells by primary vaccination.