High Gastric Cancer Mortality and Years of Life Lost in Nicaragua: A Population-Based Study 1997 - 2012.

BACKGROUND: Gastric adenocarcinoma (GC) is the fourth leading cause of cancer-related mortality, and leading infection-associated cancer. GC has striking geographic variability, with high incidence in East Asia and mountainous Latin America. Reliable cancer data and population-based cancer registries (PBCRs) are lacking for the majority of LMICs, including the Central American Four region (CA-4, Nicaragua, El Salvador, Honduras, and Guatemala). METHODS: Mortality data for Nicaragua were obtained from the highly-rated Ministry of Health death registry. All the patients were diagnosed with gastric cancer between 1997 and 2012 (ICD-10 codes C16.0-C16.9) and death due to any cause were included in the study. Data on variables such as sex, age (stratified by 5-year age groups), municipality, urban/rural, altitude, and year of death were analyzed. RESULTS: A total of 3,886 stomach cancer deaths were reported in Nicaragua between 1997 and 2012, of which 2,214 (56.9%) were male. The ASMR were 13.1 and 8.7 per 100,000 habitants for males and females, respectively, and without significant change during the study period (APC= -0.7, P=0.2). An average of 17.9 years were lost per death (AYLL), accounting for 67,964 years of life lost (YYL). CONCLUSIONS: The burden of gastric cancer mortality is high in Nicaragua with significantly elevated ASMR, YYL, and AYLL. IMPACT: The projected increase in mortality portends the double cancer burden in northern Central America, with persistent infection-associated cancers and growing transition cancers (e.g., breast and colon cancers), which has implications for cancer control in Mesoamerica and U.S. Latino populations.

Fine particulate matter (PM2.5) promotes chemoresistance and aggressive phenotype of A549 lung cancer cells.

Lung cancer is one of the most aggressive malignancies with a high mortality rate. In large cities, particulate matter (PM) is a common air pollutant. High PM levels with aerodynamic size ≤2.5 µm (PM2.5) associates with lung cancer incidence and mortality. In this work, we explored PM2.5 effects on the behavior of lung cancer cells. To this, we chronically exposed A549 cells to increasing PM2.5 concentrations collected in México City, then evaluating cell proliferation, chemoresponse, migration, invasion, spheroid formation, and P-glycoprotein and N-cadherin expression. Chronic PM2.5 exposure from 1 µg/cm2 stimulated A549 cell proliferation, migration, and chemoresistance and upregulated P-glycoprotein and N-cadherin expression. PM2.5 also induced larger multicellular tumor spheroids (MCTS) and less disintegration compared with control cells. Therefore, these results indicate lung cancer patients exposed to airborne PM2.5 as urban pollutant could develop more aggressive tumor phenotypes, with increased cell proliferation, migration, and chemoresistance.

Use of red mud activated at different temperatures as a low cost adsorbent of reactive dye / Uso de lama vermelha ativada em diferentes temperaturas como um adsorvente de baixo custo de corante reativo

ABSTRACT Red mud, a waste product generated during alumina extraction from bauxite, could be used as a low-cost adsorbent. Here, the effect of thermal treatment on the adsorption of Reactive Blue 19 (RB19) dye by red mud was compared with the adsorption capacity of untreated red mud. Thermal treatment of red mud at 500°C results in an increase in adsorption capacity from 357 mg g-1 (untreated red mud) to 416 mg g-1, under acidic conditions. Red mud samples thermally treated at 600°C and 800°C show a reduction in adsorption capacity, however, falling to 337 mg g-1, in acid medium. The change in the maximum adsorption capacity of red mud to RB19 following thermal treatment is associated with specific surface area. Red mud subjected to 500°C can be used for the treatment of water and wastewaters with a higher efficiency than untreated red mud, thus finding possible application in the textile industry.

RESUMO O resíduo de refino de bauxita (lama vermelha) é um resíduo importante gerado na produção de alumínio, podendo ser utilizado como adsorvente de baixo custo. Este estudo teve como objetivo investigar a influência do tratamento térmico na adsorção do corante azul reativo (RB19) por lama vermelha, comparando com a capacidade de adsorção de lama vermelha não tratada termicamente. O tratamento térmico da lama vermelha até 500°C resultou em aumento da capacidade de adsorção, variando seu valor de 357 mg g-1 (lama vermelha não tratada) a 416 mg g-1, em condições ácidas. No entanto, amostras de lama vermelha tratadas termicamente a 600 e 800°C mostraram uma redução na capacidade de adsorção, chegando a 337 mg g-1 em meio ácido. A mudança na capacidade máxima de adsorção de RB 19 na lama vermelha tratada termicamente está associada a valores de área superficial específica. Assim, é possível concluir que a lama vermelha tratada termicamente em 500°C pode ser utilizada para o tratamento de água e águas residuárias com maior eficiência do que a lama vermelha natural nas indústrias têxteis, contribuindo para novos insights sobre possíveis aplicações na indústria têxtil.

Virtual Reality-Based Framework to Simulate Control Algorithms for Robotic Assistance and Rehabilitation Tasks through a Standing Wheelchair.

The implementation of control algorithms oriented to robotic assistance and rehabilitation tasks for people with motor disabilities has been of increasing interest in recent years. However, practical implementation cannot be carried out unless one has the real robotic system availability. To overcome this drawback, this article presents the development of an interactive virtual reality (VR)-based framework that allows one to simulate the execution of rehabilitation tasks and robotic assistance through a robotic standing wheelchair. The virtual environment developed considers the kinematic and dynamic model of the standing human-wheelchair system with a displaced center of mass, since it can be displaced for different reasons, e.g.,: bad posture, limb amputations, obesity, etc. The standing wheelchair autonomous control scheme has been implemented through the Full Simulation (FS) and Hardware in the Loop (HIL) techniques. Finally, the performance of the virtual control schemes has been shown by means of several experiments based on robotic assistance and rehabilitation for people with motor disabilities.

Three-Dimensional Unified Motion Control of a Robotic Standing Wheelchair for Rehabilitation Purposes.

Technological advances in recent years have shown interest in the development of robots in the medical field. The integration of robotic systems in areas of assistance and rehabilitation improves the user's quality of life. In this context, this article presents a proposal for the unified control of a robotic standing wheelchair. Considering primary and secondary tasks as control objectives, the system performs tasks autonomously and the change of position and orientation can be performed at any time. The development of the control scheme was divided in two parts: (i) kinematic controller to solve the desired motion problem; and (ii) dynamic compensation of the standing wheelchair-human system. The design of the two controllers considers the theory of linear algebra, proposing a low computational cost and an asymptotically stable algorithm, without disturbances. The stability and robustness analysis of the system is performed by analyzing the evolution of the control errors in each sampling period. Finally, real experiments of the performance of the developed controller are performed using a built and instrumented standing wheelchair.

El ayuno intermitente: ¿la panacea de la alimentación? / Intermittent fasting: the panacea of food?

Introducción: el ayuno intermitente es un modelo nutricional en el cual se establecen ciclos regulares de ayuno y alimentación. Objetivos: explicar en qué consiste el ayuno intermitente e identificar la evidencia científica actual sobre su beneficio en la diabetes, obesidad y cáncer. Materiales y métodos: revisión bibliográfica sistemática de los artículos recuperados de la literatura científica sobre el ayuno intermitente. Se realizó una búsqueda exhaustiva en las siguien- tes bases de datos: Scielo, PubMed, Biblioteca Virtual en Salud en España (BSV), Dialnet, National Center for Biotechnology In- formation (NCBI) y Science Direct. Los criterios de inclusión em- pleados fueron aquellos artículos a texto completo disponibles gratuitamente que se publicaron en los últimos 10 años, aplican- do restricciones de lenguaje al español e inglés. Los criterios de exclusión se aplicaron a artículos de páginas web o revistas de divulgación, no académicas. La búsqueda y selección de artículos se realizó durante el mes de octubre de 2019. Resultados: luego de la búsqueda se seleccionaron 24 artículos. Conclusiones: el ayuno intermitente muestra un efecto bene - ficioso en relación con la diabetes y la obesidad, aunque se ne- cesitan más estudios científicos que lo avalen. En la actualidad, no existe consenso en la comunidad científica en relación con el cáncer.

In silico design and molecular basis for the selectivity of Olinone toward the first over the second bromodomain of BRD4.

Bromodomains (BrDs), a conserved structural module in chromatin-associated proteins, are well known for recognizing ε-N-acetyl lysine residues on histones. One of the most relevant BrDs is BRD4, a tandem BrD containing protein (BrD1 and BrD2) that plays a critical role in numerous diseases including cancer. Growing evidence shows that the two BrDs of BRD4 have different biological functions; hence selective ligands that can be used to study their functions are of great interest. Here, as a follow-up of our previous work, we first provide a detailed characterization study of the in silico rational design of Olinone as part of a series of five tetrahydropyrido indole-based compounds as BRD4 BrD1 inhibitors. Additionally, we investigated the molecular basis for Olinone's selective recognition by BrD1 over BrD2. Molecular dynamics simulations, free energy calculations, and conformational analyses of the apo-BRD4-BrD1|2 and BRD4-BrD1|2/Olinone complexes showed that Olinone's selectivity is facilitated by five key residues: Leu92 in BrD1|385 in BrD2 of ZA loop, Asn140|433, Asp144|His437 and Asp145|Glu438 of BC loop, and Ile146|Val49 of helix C. Furthermore, the difference in hydrogen bonds number and in mobility of the ZA and BC loops of the acetyl-lysine binding site between BRD4 BrD1/Olinone and BrD2/Olinone complexes also contribute to the difference in Olinone's binding affinity and selectivity toward BrD1 over BrD2. Altogether, our computer-aided molecular design techniques can effectively guide the development of small-molecule BRD4 BrD1 inhibitors, explain their selectivity origin, and further open doors to the design of new therapeutically improved derivatives.

Analysis of the postoperative hemostatic profile of colorectal cancer patients subjected to liver metastasis resection surgery.

BACKGROUND: Liver resection surgery has advanced greatly in recent years, and the adoption of fasttrack programs has yielded good results. Combination anesthesia (general anesthesia associated to epidural analgesia) is an anesthetic-analgesic strategy commonly used for the perioperative management of patients undergoing surgery of this kind, though there is controversy regarding the coagulation alterations it may cause and which can favor the development of spinal hematomas. AIM: To study the postoperative course of liver resection surgery, an analysis was made of the outcomes of liver resection surgery due to colorectal cancer metastases in our centre in terms of morbiditymortality and hospital stay according to the anesthetic technique used (general vs combination anesthesia). METHODS: A prospective study was made of 61 colorectal cancer patients undergoing surgery due to liver metastases under general and combination anesthesia between January 2014 and October 2015. The patient characteristics, intraoperative variables, postoperative complications, evolution of hemostatic parameters, and stay in intensive care and in hospital were analyzed. RESULTS: A total of 61 patients were included in two homogeneous groups: general anesthesia (n = 30) and combination anesthesia (general anesthesia associated to epidural analgesia) (n = 31). All patients had normal coagulation values before surgery. The international normalized ratio (INR) in both the general and combination anesthesia groups reached maximum values at 2448 h (mean 1.37 and 1.45 vs 1.39 and 1.41, respectively), followed by a gradual decrease. There was less intraoperative bleeding in the combination anesthesia group (769 mL) than in the general anesthesia group (1200 mL) (P < 0.05). Of the 61 patients, 38.8% in the general anesthesia group experienced some respiratory complication vs 6.6% in the combination anesthesia group (P < 0.001). The time to gastrointestinal tolerance was significantly correlated to the type of anesthesia, though not so the stay in critical care or the time to hospital discharge. CONCLUSION: Epidural analgesia in liver resection surgery was seen to be safe, with good results in terms of pain control and respiratory complications, and with no associated increase in complications secondary to altered hemostasis.

Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development.

BACKGROUND: Interactions between proteins play a key role in nearly all cellular process, and therefore, its dysregulation may lead to many different types of cellular dysfunctions. Hence, pathologic Protein-Protein Interactions (PPIs) constitute highly attractive drug targets and hold great potential for developing novel therapeutic agents for the treatment of incurable human diseases. Unfortunately, the identification of PPI inhibitors is an extremely challenging task, since traditionally used small molecules ligands are mostly unable to cover and anchor on the extensive and flat surfaces that define those binary protein complexes. In contrast, large biomolecules such as proteins or peptides are ideal fits for this so-called "undruggable" sites. However, their poor pharmacokinetic properties have also limited their applications as therapeutics. In this context, peptidomimetic molecules have emerged as an alternative and viable solution to this problem, since they conserve the architectural and structural features of peptides and also exhibit substantially improved pharmacokinetic profiles. CONCLUSION: In the last decades, a wide array of chemical approaches granting access to conformationally constrained peptides with substantially improved pharmacokinetic profiles have been described, with a special focus on those affording stapled peptides and allowing large-scale macrocyclizations. These peptidomimetic molecules have been successfully applied to target a plethora of biological hosts, which highlights their promising future as novel therapeutics for the treatment of incurable human diseases.

A Solid-Phase Approach to Accessing Bisthioether-Stapled Peptides Resulting in a Potent Inhibitor of PRC2 Catalytic Activity.

Stapled peptides have emerged as a new class of therapeutics to effectively target intractable protein-protein interactions. Thus, efficient and versatile methods granting easy access to this class of compounds and expanding the scope(s) of the currently available ones are of great interest. Now, a solid phase approach is described for the synthesis of bisthioether stapled peptides with multiple architectures, including single-turn, double-turn, and double-stapled macrocycles. This method allows for ligation with all-hydrocarbon linkers of various lengths, avoiding the use of unnatural amino acids and expensive catalysts, and affords cyclopeptides with remarkable resistance to proteolytic degradation. The potential of this procedure is demonstrated by applying it to generate a stapled peptide that shows potent in vitro inhibition of methyltransferase activity of the polycomb repressive complex 2 (PRC2) of proteins.

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

BACKGROUND: Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. PATIENTS AND METHODS: In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. RESULTS: Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. CONCLUSION: Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-Target Side Effects.

Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but they present challenging issues of complex chemical synthesis, undesirable physical properties, and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain of the MR and recruit different co-regulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension, or diabetic nephropathy. The main focus of this Perspective is to review the reported structure-activity relationships of the different series of compounds, as well as the structural studies that contribute to a better understanding of the receptor active site and are also helpful for optimization processes.

Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes.

Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-to-mesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma assays. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation.

Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression.

Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extraterminal domain) proteins has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our small-molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors toward differentiation, whereas inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target specific, as it was not detected in cells treated with inactive analogs and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors, may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration.

Caracterização química e mineralógica da incrustação em rede de ferro fundido e potencial de recuperação da capacidade hidráulica / Chemical and mineralogical incrustation characterization and potential of hydraulic performance recovery

O objetivo deste trabalho foi caracterizar química e mineralogicamente os depósitos em rede de ferro fundido e avaliado o potencial de recuperação da capacidade hidráulica em tubulação altamente comprometida pela incrustação. Para tal, foram feitas medidas do coeficiente de resistência (pitometria em trecho isolado de 71 m), análises química ( P-ES e ICP-MS), mineralógicas (laminação, difração de raios-X e microscopia eletrônica), dureza (escala de Mohs) e simulações em setor hipotético com cenários distintos (de C1 a C4) de troca e substituição da rede. Os resultados indicaram que a rede altamente comprometida tem potencial limitado de recuperação (de 3,9 a 14,0 m0,367.s-1). As caracterizações química e mineralógica indicaram Magnetita e Goethita, com dureza da ordem de 6 na escala Mohs. As simulações demonstraram potências relativas (razões Ci/C1) da ordem de 86,00, 1,00 e 0,02% em relação ao cenário atual.

The purpose of this work was to characterize chemical and mineralogical the water supply networks and to assess the hydraulic recovery on high-degraded pipe. Thus, the resistance (by pitometric essays), chemical analyses (ICP-MS and ICP-ES), mineralogical analysis (petrographic thin sections, X-ray difractometry and scanning electronic microscopy), hardness (Mohs scale) and simulations for pipe's change and rehabilitations scenarios were investigated (from Scenario 1 to 4). The results showed that the high-degraded pipe had a limited recovery (from 3,9 to 14,0 m0,367.s-1). The deposits were formed by oxide and hydroxide of iron (magnetite and goethite), which are materials of high hardness (6 on Mohs scale). The simulations indicated the required power ratio (Ci/C1) around 86.00, 1.00 and 0.02% in relation to present scenario.

Cyclic amino acid linkers stabilizing key loops of brain derived neurotrophic factor.

Based on ß-turn-like BDNF loops 2 and 4, involved in receptor interaction, cyclic peptide replicas were designed, synthesized and tested. In addition to the native turn residues, the cyclic peptides include a linker unit between the N- and C-termini, selected by molecular modeling among various non-proteinogenic cyclic amino acids. NMR conformational studies showed that most of the cyclic peptides were able to adopt turn-like structures. Several of the analogues displayed significant inhibition of the BDNF-induced TrkB receptor phosphorylation, and hence could be useful templates for developing improved antagonists for this receptor.

A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes.

As a master transcription factor in cellular responses to external stress, tumor suppressor p53 is tightly regulated. Excessive p53 activity during myocardial ischemia causes irreversible cellular injury and cardiomyocyte death. p53 activation is dependent on lysine acetylation by the lysine acetyltransferase and transcriptional coactivator CREB-binding protein (CBP) and on acetylation-directed CBP recruitment for p53 target gene expression. Here, we report a small molecule ischemin, developed with a structure-guided approach to inhibit the acetyl-lysine binding activity of the bromodomain of CBP. We show that ischemin alters post-translational modifications on p53 and histones, inhibits p53 interaction with CBP and transcriptional activity in cells, and prevents apoptosis in ischemic cardiomyocytes. Our study suggests small molecule modulation of acetylation-mediated interactions in gene transcription as a new approach to therapeutic interventions of human disorders such as myocardial ischemia.

Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors.

The CREB binding protein (CBP) is a human transcriptional coactivator consisting of several conserved functional modules, which interacts with distinct transcription factors including nuclear receptors, CREB, and STAT proteins. Despite the importance of CBP in transcriptional regulation, many questions regarding the role of its particular domains in CBP functions remain unanswered. Therefore, developing small molecules capable of selectively modulating a single domain of CBP is of invaluable aid at unraveling its prominent activities. Here we report the design, synthesis, and biological evaluation of conformationally restricted peptides as novel modulators for the acetyl-lysine binding bromodomain (BRD) of CBP. Utilizing a target structure-guided and computer-aided rational design approach, we developed a series of cyclic peptides with affinity for CBP BRD significantly greater than those of its biological ligands, including lysine-acetylated histones and tumor suppressor p53. The best cyclopeptide of the series exhibited a K(d) of 8.0 µM, representing a 24-fold improvement in affinity over that of the linear lysine 382-acetylated p53 peptide. This lead peptide is highly selective for CBP BRD over BRDs from other transcriptional proteins. Cell-based functional assays carried out in colorectal carcinoma HCT116 cells further demonstrated the efficacy of this compound to modulate p53 stability and function in response to DNA damage. Our results strongly argue that these CBP modulators can effectively inhibit p53 transcriptional activity by blocking p53K382ac binding to CBP BRD and promoting p53 instability by changes of its post-translational modification states, a different mechanism than that of the p53 inhibitors reported to date.

Assembling ligands in situ using bioorthogonal boronate ester synthesis.

Many molecules that could manipulate cellular function are not practical due to their large size and concomitant undesirable pharmocokinetic properties. Here, we describe a bioorthogonal, highly stable boronate ester (HiSBE) synthesis and use this reaction to synthesize a biologically active molecule from smaller precursors in a physiological context. The rapid rate of HiSBE synthesis suggests that it may be useful for assembling a wide variety of biologically active molecules in physiological solutions.

Specific mutation screening of TP53 gene by low-density DNA microarray.

TP53 is the most commonly mutated gene in human cancers. Approximately 90% of mutations in this gene are localized between domains encoding exons 5 to 8. The aim of this investigation was to examine the ability of the low density DNA microarray with the assistance of double tandem hybridization platform to characterize TP53 mutational hotspots in exons 5, 7, and 8 of the TP53. Nineteen capture probes specific to each potential mutation site were designed to hybridize to specific site. Virtual hybridization was used to predict the stability of hybridization of each capture probe with the target. Thirty-three DNA samples from different sources were analyzed for mutants in these exons. A total of 32 codon substitutions were found by DNA sequencing. 24 of them a showed a perfect correlation with the hybridization pattern system and DNA sequencing analysis of the regions scanned. Although in this work we directed our attention to some of the most representative mutations of the TP53 gene, the results suggest that this microarray system proved to be a rapid, reliable, and effective method for screening all the mutations in TP53 gene.