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Introduction: Given several reports of an increased neurologic risk with retrograde arterial perfusion in minimally invasive mitral valve surgery, we sought to identify and synthesize the best available evidence on the influence of perfusion strategy on post-operative clinical outcomes in this population. Methods: A systematic search of PubMed, EMBASE, MEDLINE, and Cochrane library databases was performed to identify publications comparing clinical outcomes associated with antegrade and retrograde arterial perfusion in minimally invasive mitral valve surgery. Pre-specified outcomes of interest were neurologic events, mortality, and renal failure. The search was performed by two independent reviewers, with data abstraction following. Results: Seven observational studies were included in this review, with a total patient population of 5,385. Six were retrospective cohort in design, with a single small prospective cohort study identified. When available, adjusted publication-specific risk estimates were abstracted and included preferentially over unadjusted or reviewer-derived risk estimates. Meta-analysis was felt to be heavily flawed in the context of few small studies identified and was not performed. In adjusted estimates, there appeared to be an increased risk of neurologic complications with retrograde arterial perfusion. There was a null pattern apparent between arterial perfusion strategy and each of 30-day mortality and renal failure. Conclusion: Retrograde arterial perfusion in minimally invasive mitral valve surgery may be associated with an increased risk of neurologic events, without affecting the risk of 30-day mortality or renal failure. Although these patterns were identified, an overall paucity of evidence justifies further study. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daniel, Mesquita, Da Silva, de Souza, Lima, de Oliveira, de Moraes, Moreira-Nunes, Burbano, Zanatta and Montenegro.)

Gastric cancer (GC) is among the deadliest cancers worldwide despite available therapies, highlighting the need for novel therapies and pharmacological agents. Metabolic deregulation is a potential study area for new anticancer targets, but the in vitro metabolic studies are controversial, as different ranges of glucose used in the culture media can influence results. In this study, we evaluated cellular viability, glucose uptake, and LDH activity in gastric cancer cell lines when exposed to different glucose concentrations: high (HG, 25mM), low (LG, 5.5mM), and free (FG, 0mM) glucose media. Moreover, we evaluated how glucose variations may influence cellular phenotype and the expression of genes related to epithelial-mesenchymal transition (EMT), metabolism, and cancer development in metastatic GC cells (AGP-01). Results showed that metastatic cells exposed to FG medium evidenced higher alterations when compared to other cell lines. Most phenotypic assays did not show difference when exposed to either HG or LG media. However, gene expression profile of cells exposed to LG revealed differences in mRNA levels of metabolism-related genes when compared to HG medium. According to our results, we recommend using LG medium for metabolic studies since the glucose concentration is closer to physiological levels. These findings point out new relevant targets in metabolic reprogramming that can be alternatives to current chemotherapies in patients with metastatic GC., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gastric cancer has been considering one of the worst cancer types since it is diagnosed in advanced stages, currently in the metastatic stage. Therefore, the challenge is to find out a biomarker and a pharmacology target that would help face this worldwide health issue. In this sense, the mitogen-activated protein kinase (MAPK) signaling pathway has become an important aim of the studies in several cancers. Therefore, we evaluated the role of MAPK14 (p38α) inhibitor SB-245392 in the cellular process, such as proliferation, cell death, and cell migration, and whether MAPK14 gene could be a potential biomarker in gastric cancer models. The results clearly suggest that p38α inhibition significantly impairs the cell proliferation, induces modest apoptosis and strongly inhibits cell migration of gastric cancer cell (AGP-01). Gene expression analysis showed that c-MYC level was decreased and TP53 was increased after SB-245392 treatment. Furthermore, MAPK14 was found in high levels in gastric cancer samples compared to normal samples in the TCGA database, especially in advanced stages (stage 3 and 4), which is significantly associated with low rate survival of the patients. In conclusion, the MAPK14 could be a potential biomarker for advanced gastric cancer as well as a pharmacological target, which could improve the survival rate of patients., Competing Interests: Declaration of Competing Interest The authors declare to have no conflict of interest related to this manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Teredinidae are a family of highly adapted wood-feeding and wood-boring bivalves, commonly known as shipworms, whose evolution is linked to the acquisition of cellulolytic gammaproteobacterial symbionts harbored in bacteriocytes within the gills. In the present work we applied metagenomics to characterize microbiomes of the gills and digestive tract of Neoteredo reynei, a mangrove-adapted shipworm species found over a large range of the Brazilian coast. Comparative metagenomics grouped the gill symbiont community of different N. reynei specimens, indicating closely related bacterial types are shared. Similarly, the intestine and digestive gland communities were related, yet were more diverse than and showed no overlap with the gill community. Annotation of assembled metagenomic contigs revealed that the gill symbiotic community of N. reynei encodes a plethora of plant cell wall polysaccharides degrading glycoside hydrolase encoding genes, and Biosynthetic Gene Clusters (BGCs). In contrast, the digestive tract microbiomes seem to play little role in wood digestion and secondary metabolites biosynthesis. Metagenome binning recovered the nearly complete genome sequences of two symbiotic Teredinibacter strains from the gills, a representative of Teredinibacter turnerae "clade I" strain, and a yet to be cultivated Teredinibacter sp. type. These Teredinibacter genomes, as well as un-binned gill-derived gammaproteobacteria contigs, also include an endo-β-1,4-xylanase/acetylxylan esterase multi-catalytic carbohydrate-active enzyme, and a trans-acyltransferase polyketide synthase (trans-AT PKS) gene cluster with the gene cassette for generating β-branching on complex polyketides. Finally, we use multivariate analyses to show that the secondary metabolome from the genomes of Teredinibacter representatives, including genomes binned from N. reynei gills' metagenomes presented herein, stands out within the Cellvibrionaceae family by size, and enrichments for polyketide, nonribosomal peptide and hybrid BGCs. Results presented here add to the growing characterization of shipworm symbiotic microbiomes and indicate that the N. reynei gill gammaproteobacterial community is a prolific source of biotechnologically relevant enzymes for wood-digestion and bioactive compounds production., Competing Interests: The authors have declared that no competing interests exist.

Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 "binding" to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.

With the availability of high resolution structural data, increasing attention has focused on the mechanisms by which drugs and endogenous compounds allosterically modulate nicotinic acetylcholine receptor (nAChR) function. Lipids are potent modulators of the nAChR from Torpedo. Membrane lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations, as well as influencing the transitions between these conformational states. Structural and functional data highlight a role for the lipid-exposed M4 transmembrane α-helix of each subunit in lipid sensing, and suggest that lipids influence gating by altering the binding of M4 to the adjacent transmembrane α-helices, M1 and M3. M4 has also been implicated in both the folding and trafficking of nAChRs to the cell surface, as well as in the potentiation of nAChR gating by neurosteroids. Here, we discuss the roles of M4 in the folding, trafficking, and allosteric modulation of nAChRs. We also consider the hypothesis that variable chemistry at the M4-M1/M3 transmembrane α-helical interface in different nAChR subunits governs the capacity for potentiation by activating lipids. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Membrane lipids are potent modulators of the nicotinic acetylcholine receptor (nAChR) from Torpedo. Lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of activatable versus non-activatable conformations, as well as influencing the transitions between these conformational states. Of note, some membranes stabilize an electrically silent uncoupled conformation that binds agonist but does not undergo agonist-induced conformational transitions. The uncoupled nAChR, however, does transition to activatable conformations in relatively thick lipid bilayers, such as those found in lipid rafts. In this review, we discuss current understanding of lipid-nAChR interactions in the context of increasingly available high resolution structural and functional data. These data highlight different sites of lipid action, including the lipid-exposed M4 transmembrane α-helix. Current evidence suggests that lipids alter nAChR function by modulating interactions between M4 and the adjacent transmembrane α-helices, M1 and M3. These interactions have also been implicated in both the folding and trafficking of nAChRs to the cell surface. We review current mechanistic understanding of lipid-nAChR interactions, and highlight potential biological roles for lipid-nAChR interactions in modulating the synaptic response. This article is part of a Special Issue entitled: Lipid-protein interactions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The ability of the nicotinic acetylcholine receptor (nAChR) to undergo conformational transitions is exquisitely sensitive to its surrounding lipid environment. Previous work has highlighted a conformational selection mechanism, whereby different lipids stabilize different proportions of activatable resting versus nonactivatable conformations. In the absence of anionic lipids and cholesterol, the nAChR adopts an uncoupled conformation, which binds agonist with resting state-like affinity but does not usually undergo agonist-induced conformational transitions. Very slow (minutes to hours) transitions from uncoupled to coupled (resting, open and/or desensitized) conformations, however, can occur in membranes with relatively thick hydrophobic cores. Increasing membrane hydrophobic thickness 'awakens' uncoupled nAChRs by reducing the large activation energy barrier (or barriers) leading to coupled states, thus allowing conformational transitions to occur on an experimentally tractable timescale. Lipids shape activity by modulating the relative proportions of activatable versus nonactivatable conformations and by controlling the transitions between uncoupled and coupled conformations.

Background and Objective: A high percentage of bronchoscopically extracted foreign bodies in Ho Chi Minh City were pits of the sapote fruit, a finding previously unreported. This paper presents a review of foreign body extractions, which identifies the substances found, documents the diagnostic pathway and draws attention to the specific aspiration risk of the sapote pit., Methods: The records of 100 consecutive adults who were found to have a bronchial foreign body during flexible bronchoscopy were reviewed., Results: In 83% of patients, the foreign body extraction was performed more than 2 weeks after the aspiration had occurred. In only 34% of patients was the diagnosis of an aspirated foreign body considered early in the patient's clinical course. The most frequent foreign bodies found were sapote pits (41%), followed by small bones (38%). Foreign bodies were lodged more frequently in the right bronchial tree (64%). In 98% of patients, the foreign bodies were successfully removed with the flexible scope. There was one postoperative death, which was not ascribed to the procedure., Conclusions: Physicians need to consider foreign body aspirations when evaluating patients with recurrent pneumonia, unexplained cough or atelectasis. Awareness of this problem might lead to public health measures that could reduce the incidence of these aspirations.

Fluoroquinolones present various pharmacokinetic properties. That's the way we carried out a bibliographic summary about the pharmacokinetics of pefloxacin, ofloxacin and ciprofloxacin in patients hit by chronic renal failure, under haemodialysis or under continuous ambulatory peritoneal dialysis. Then, we will describe how to adapt drug dose according to the degree of renal insufficiency and the used molécule.

Background: Serum cystatin C (Scyst) has been suggested as an alternative index of glomerular filtration rate (GFR) and could be useful in renal transplant patients., Methods: In a 60-subject cohort (40 +/- 12 years old), we compared the simultaneous measurements of Scyst, serum creatinine (Screat), creatinine clearance (Ccreat), Cockcroft and Gault's estimated clearance (Ccg) and GFR measured using inulin clearance (Cin). Receiver operating characteristic (ROC) analysis was performed using two Cin cut-off (60 and 90 mL/min/1.73 m2)., Results: A significant correlation was found among Cin on one hand and 1/Scyst, Ccreat, 1/Screat and Ccg on the other hand. Best fits (sensitivity/specificity) at 90 mL/min/1.73 m2 were 1.18 mg/L (0.72/0.80) for Scyst, 1.32 mg/dL (0.67/0.90) for Screat, 77 mL/min (0.80/0.70) for Ccg and 104 mL/min (0.88/0.80) for Ccreat. The areas under the ROC curves were not significantly different., Conclusions: This study provides cut-off values for Screat and Ccg for detection of renal failure in renal transplant patients. However, the results also suggest that Scyst is not a more sensitive marker than Screat or Ccg for detecting renal failure in renal transplant patients.

Background: Although their assessment could be of the utmost importance to determine the surgical treatment for patients with univentricular hearts, differences in ventricular performance between partial and complete right heart bypass remain to be defined., Methods: Three different degrees of right heart bypass were investigated in 5 mongrel dogs: (1) superior vena cava to both pulmonary arteries shunt (SCP); (2) inferior vena cava to both pulmonary arteries shunt (ICP); and (3) both venae cavae to both pulmonary arteries shunt (BCP). Hemodynamic studies included evaluation of the cardiac index and left atrial pressure as a function of the degree of right heart bypass., Results: By maintaining the mean left atrial pressure at 5 mm Hg, cardiac indexes were 1.98 +/- 0.25, 1.67 +/- 0.29, and 1.33 +/- 0.21 L.min-1.m-2 for SCP, ICP, and BCP shunts, respectively (p = 0.001). When keeping the cardiac index constant, mean left atrial pressures were 5.2 +/- 0.8, 5.5 +/- 0.9, and 7 +/- 0.7 mm Hg for SCP, ICP, and BCP shunts, respectively (p = 0.001)., Conclusions: Increasing degrees of right heart bypass are associated with a significant decrease in ventricular performance in this experimental model.

There is still controversy about the optimal method of venoarterial cardiopulmonary bypass (CPB) for correction of congenital heart disease in neonates and young infants. High rates of CPB-related morbidity and mortality are still reported. Since 1980, conventional CPB with double caval cannulation with right-angled cannulae has been used in the high majority of neonates at Marie-Lannelongue Hospital. The extracorporeal circuit was miniaturized to be primed with a volume as small as possible. Priming (500 ml) was done with packed red cells and fresh frozen plasma. CPB was conducted at 30% haematocrit and normal ranges of flow rate, arterial pressure, systemic vascular resistances and oxygen delivery. These normal physiological parameters were also maintained during hypothermia. During the last two years, 151 neonates below 15 days old who underwent open-heart surgery were reviewed. The overall hospital mortality was 7.24%. None of the survivors had postoperative complications related to CPB. All physiological and biological values remained within normal ranges during the postoperative course.

Immediate and long-term results of the Fontan procedure depend on the value of the pulmonary vascular resistance. This parameter cannot always be quantified accurately during preoperative evaluation. Cavo-pulmonary bypass using an extra corporeal circulation allowed simulation a Fontan procedure in 5 patients, and prediction of the pressure changes in the pulmonary artery and the systemic atrium according to the pulmonary to systemic resistances ratio. This technique could be valuable in border line cases for deciding on the optimal therapeutic solution.

1. Whole soluble venom from the snake Crotalus durissus terrificus was detoxified by controlled iodination. Doses equivalent to 100 LD50 of the native venom were administered to mice, without signs of intoxication. 2. The non-toxic iodinated derivatives were able to stimulate antibodies in rabbits and horses within a short period (6 months) of immunization. Horse antisera attained titers of 0.5 to 0.9 mg/ml for protection against native venom. 3. Horse antisera obtained in horses from native and iodinated venom were run against both native and iodinated venoms, as antigens, in gel immunodiffusion. The precipitation lines showed total identity of the two types of sera.

The iodination of the T2 fraction abolished its lethal capacity, and doses up to 30 times the LD50 were injected i.p. in mice without noticeable toxic effects. The modified fraction retained its immunological properties. Antibodies generated against the iodinated T2 fraction were also reactive toward the native T2 fraction, T1 fraction and the whole soluble venom.