Search

Objective: To determine the circulating levels of insulin, Nε-carboxymethyllysine (CML), soluble receptor for advanced glycation end products (sRAGE), and markers of inflammation and oxidative stress (OS) in maternal and umbilical cord blood in a cohort of healthy women with normal pregnancy.Methods: We conducted an observational longitudinal study in a group of women (n = 31; age range 18-39 years) with healthy pregnancy starting at 30 weeks of gestation and finishing at the time of delivery. We collected weight and height in the participants and their neonates and calculated body mass index (BMI). Blood from each patient was collected at 30th week of pregnancy and at delivery when a sample of cord blood was also obtained. Glucose, lipid profile, CML, sRAGE, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), highly sensitivity C-reactive protein (hsPCR), and insulin were determined. The study was approved by the University of Guanajuato Institutional Ethics Committee.Results: All pregnancies reached term (mean gestational time 38.9 ± 0.83 weeks) and there were no maternal complications. Mean age was 27.6 years. Lipid profile values were higher in the group compared with our values in nonpregnant women. During pregnancy, levels of insulin increased (p < .0006), CML (p < .0001) and sRAGE (p < .01) decreased, levels of MDA did not change, while those of TNF-α and hsPCR tended to increase. In the neonates, we found lower levels of CML (p < .003), hsPCR (p < .004), and insulin (p < .004) and higher levels of sRAGE (p < .013) and TNF-α (p < .022) compared to their mothers at delivery. In the total group, we found association of CML of the mother at baseline with the CML (p < .0006) and MDA (p < .002) in neonates, while maternal sRAGE at the end of pregnancy was associated with CML (p < .004) of their neonates.Conclusions: Our study confirms that normal pregnancy is accompanied by insulin resistance (IR) and significant increase in lipid profile, and demonstrates that circulating levels of CML and sRAGE decreased significantly at the end of pregnancy. The lack of association between the course of insulin levels and those of CML probably results from the predominant role of placental factors in the pathogenesis of IR in pregnancy. sRAGE levels in the neonates are markedly increased compared to their mothers suggesting a placental origin of this compound which may have a protective effect on the fetus since sRAGE restricts Advanced glycation end product (AGE) effects and may exert anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Copyright of Acta Universitaria is the property of Universidad de Guanajuato/Acta Universitaria and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Acta Universitaria is the property of Universidad de Guanajuato/Acta Universitaria and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR + /HER2 - breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G 1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression., Competing Interests: Declaration of interests All authors listed on this manuscript are/were paid employees and/or owned stock of Pfizer, Inc. during data collection, analysis, and interpretation of their contributions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 ( 22 ) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3 S )-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate ( 1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1 .

Poly-ADP-ribosyltransferases play a critical role in DNA repair and cell death, and poly(ADP-ribosyl) polymerase 1 (PARP1) is a particularly important therapeutic target for the treatment of breast cancer because of its synthetic lethal relationship with breast cancer susceptibility proteins 1 and 2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA. Biochemically, talazoparib is also suspected to be a potent inhibitor of PARP5a/b (tankyrase1/2 [TNKS1/2]), which is an important regulator of Wnt/β-catenin pathway. Here we show using competition experiments in cell lysate that, at a clinically relevant concentration, talazoparib can potentially bind and engage TNKS1. Using surface plasmon resonance, we measured the dissociation constants of talazoparib, olaparib, niraparib, and veliparib for their interaction with PARP1 and TNKS1. The results show that talazoparib has strong affinity for PARP1 as well as uniquely strong affinity for TNKS1. Finally, we used crystallography and hydrogen deuterium exchange mass spectroscopy to dissect the molecular mechanism of differential selectivity of these PARP1 inhibitors. From these data, we conclude that subtle differences between the ligand-binding sites of PARP1 and TNKS1, differences in the electrostatic nature of the ligands, protein dynamics, and ligand conformational energetics contribute to the different pharmacology of these PARP1 inhibitors. These results will help in the design of drugs to treat Wnt/β-catenin pathway-related cancers, such as colorectal cancers., Competing Interests: Conflict of interest All authors are employees of Pfizer, Inc., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Treatment of children with CNS tumors (CNSTs) demands a complex, interdisciplinary approach that is rarely available in low- and middle-income countries. We established the Cross-Border Neuro-Oncology Program (CBNP) between Rady Children's Hospital, San Diego (RCHSD), and Hospital General, Tijuana (HGT), Mexico, to provide access to neuro-oncology care, including neurosurgic services, for children with CNSTs diagnosed at HGT. Our purpose was to assess the feasibility of the CBNP across the United States-Mexico border and improve survival for children with CNSTs at HGT by implementing the CBNP., Patients and Methods: We prospectively assessed clinicopathologic profiles, the extent of resection, progression-free survival, and overall survival (OS) in children with CNSTs at HGT from 2010 to 2017., Results: Sixty patients with CNSTs participated in the CBNP during the study period. The most common diagnoses were low-grade glioma (24.5%) and medulloblastoma (22.4%). Of patients who were eligible for surgery, 49 underwent resection at RCHSD and returned to HGT for collaborative management. Gross total resection was achieved in 78% of cases at RCHSD compared with 0% at HGT ( P < .001) and was a predictor of 5-year OS (hazard ratio, 0.250; 95% CI, 0.067 to 0.934; P = .024). Five-year OS improved from 0% before 2010 to 52% in 2017., Conclusion: The CBNP facilitated access to complex neuro-oncology care for underserved children in Mexico through binational exchanges of resources and expertise. Survival for patients in the CBNP dramatically improved. Gross total resection at RCHSD was associated with higher OS, highlighting the critical role of experienced neurosurgeons in the treatment of CNSTs. The CBNP model offers an attractive alternative for children with CNSTs in low- and middle-income countries who require complex neuro-oncology care, particularly those in close proximity to institutions in high-income countries with extensive neuro-oncology expertise.

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

Background: Canine heartworm infections were frequently diagnosed in Brazil before the new millennium. After the year 2000, the frequency of diagnosis showed a sharp decline; however, a few years later, new evidence indicated that the parasite was still present and that canine infection rates seemed to be increasing. Therefore, an updated survey of canine heartworm prevalence was conducted in several locations in south, southeast, and northeast Brazil., Methods: Dogs from 15 locations having previously reported a high prevalence of heartworm infection were included in the survey according to defined criteria, including the absence of treatment with a macrocyclic lactone for at least 1 year. Blood samples from 1531 dogs were evaluated by an in-clinic immunochromatography test kit (Witness® Heartworm, Zoetis, USA) for detection of Dirofilaria immitis antigen. At each location, epidemiologic data, including physical characteristics and clinical signs reported by owners or observed by veterinarians, were recorded on prepared forms for tabulation of results by location, clinical signs, and physical characteristics., Results: The overall prevalence of canine heartworm infection was 23.1%, with evidence of heartworm-infected dogs detected in all 15 locations studied. There was a tendency for higher prevalence rates in environmentally protected areas, despite some locations having less-than-ideal environmental temperatures for survival of vector mosquitoes. Among physical characteristics, it was noted that dogs with predominantly white hair coats and residing in areas with a high (≥20%) prevalence of heartworm were less likely to have heartworm infection detected by a commercial heartworm antigen test kit than were dogs with other coat colors. In general, dogs older than 2 years were more frequently positive for D. immitis antigen than were younger dogs. Clinical signs of heartworm infections were rare or owners were unable to detect them, and could not be used for reliable prediction of the presence of heartworm., Conclusions: These results indicate that the prevalence of D. immitis has increased in these areas of Brazil over the past few years. Small animal practitioners in these areas should include routine screening tests for heartworm infections in every dog's annual evaluation protocol and make sure to have uninfected dogs on prevention.

A practical C-H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature's methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical "litmus test" for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO.

The study evaluated the anthelmintic activity of aqueous extract of Zanthoxylum rhoifolium leaves in two experiments. In vitro test, cultures of goat fecal samples were treated with different concentrations of extract (134.5 to 335.0 mg.mL(-1)). In vivo test was composed of 20 sheep: G1: treated with 0.63 g.kg(-1), during four days; G2: same dose, for eight days; G3: ivermectin (200 microg.kg(-1)) and G4 untreated group. In vitro results showed a reduction of Haemonchus spp, Trichostrongylus spp. and Oesophagostomum spp. larvae greater than 95% in the concentrations between 335.0 and 193.7 mg.mL(-1). Faecal egg counting reduction was 51, 56 and 90% in G1, G2 and G3, respectively, while immature stages and adults ranged from 0 to 91% in G1 and from 26 to 94% in G2. Ivermectin effectiveness was 99% for L4 and L5 of H. contortus and 100% for other nematodes species. Clinical and biochemical parameters have remained in the normality and histophatologic analyses did not show alteration suggesting absence of toxicity. Although the great effectiveness of Z. rhoifolium leaves extract in vitro test, it displayed poor efficiency in vivo regarding gastrointestinal nematodes reduction.

The purpose of this study was to investigate whether sporulated Neospora caninum oocysts, which had been stored for 46 mo in a 2% sulfuric acid solution at 4 degrees C, remain morphologically viable and infective to gerbils (Meriones unguiculatus). Six gerbils were orally inoculated with doses of 400 or 1,200 oocysts. Two mo after inoculation, the animals did not show any clinical signs, had no histological lesions, and were seronegative for N. caninum at 1: 50 in an immunofluorescent antibody test. PCR using the brain from each gerbil did not reveal N. caninum specific DNA. We conclude that oocysts preserved for 46 mo are not infective, despite being morphologically intact.

The goal of this study is to describe and discuss the student selection process in the last three years by analyzing the formation and range of professional practice of the candidates through a descriptive exploratory study. The analysis of the curriculum of candidates reveals a high proportion without a previous degree and/or experience in the area. Based on the analysis of data obtained, we emphasize the importance of adjusting the program to the profile of students that enter the field without previous knowledge or restricting the program for professionals that are looking for an in-depth knowledge of mental health.

This paper aimed to consider about how the family is seen on the transformation process of the psychiatric care and how the family responds to this expectation. It was developed from literature review about the subject with emphasis given to the papers about the families of popular classes. It was noticed that the family is on focus of the Mental Health professionals, both to be helped as well as to help fulfill the changes expected on this care field. Nevertheless, not always enough support is given in a way that enable them to walk on this direction, so that a closer approach is necessary between those social actors.