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Intraoperative hypothermia is a common event during laparoscopic operations. An external warming blanket has been shown to be effective in preventing hypothermia. It has now been proposed that using heated and humidified insufflation gas can prevent hypothermia and decrease postoperative pain. Therefore, we examined the extent of intraoperative hypothermia in patients undergoing laparoscopic Nissen fundoplication using an upper body warming blanket. We also attempted to determine whether using heated and humidified insufflation gas in addition to an external warming blanket would help to maintain intraoperative core temperature or decrease postoperative pain. Twenty patients were randomized to receive either standard carbon dioxide (CO2) gas (control, n = 10) or heated and humidified gas (heated and humidified, n = 10). After the induction of anesthesia, an external warming blanket was placed on all patients in both groups. Intraoperative core temperature and intraabdominal temperature were measured at 15-min intervals. Postoperative pain intensity was assessed using a visual analogue pain scale, and the amount of analgesic consumption was recorded. Volume of gas delivered, number of lens-fogging episodes, intraoperative urine output, and hemodynamic data were also recorded. There was no significant difference between the two groups in age, length of operation, or volume of CO2 gas delivered. Compared with baseline value, mean core temperature increased by 0.4 degrees C in the heated and humidified group and by 0.3 degrees C in the control group at 1.5 h after surgical incision. Intraabdominal temperature increased by 0.2 degrees C in the heated and humidified group but decreased by 0.5 degrees C in the control group at 1.5 h after abdominal insufflation. There was no significant difference between the two groups in visual analog pain scale (5.4 +/- 1.6 control vs 4.5 +/- 2.8 heated and humidified), morphine consumed (27 +/- 26 mg control vs 32 +/- 19 mg heated and humidified), urine output, lens-fogging episodes, or hemodynamic parameters. Heated and humidified gas, when used in addition to an external warming blanket, minimized the reduction of intraabdominal temperature but did not alter core temperature or reduce postoperative pain.

We evaluated the safety and feasibility of performing a laparoscopic intracorporeal end-to-side small bowel anastomosis using a stapling technique as part of a Roux-en-Y gastric bypass operation (RYGBP). 80 consecutive patients who underwent RYGBP with laparoscopic jejunojejunostomy were evaluated. Operative time and intraoperative and postoperative complications directly related to the jejunojejunostomy anastomosis were recorded. All 80 laparoscopic jejunojejunostomy procedures were successfully performed without conversion to laparotomy. Mean operative time was longer for the first 40 laparoscopic RYGBP than for the last 40 RYGBP (32+/-18 min vs 21+/-14 min, respectively, p<0.05). Intraoperative complications were staple-line bleeding (2 patients) and narrowing of the anastomosis (1 patient). Postoperative complications were four small bowel obstructions: technical narrowing at jejunojejunostomy site (2 patients), angulation of the afferent limb (1 patient), and food impaction at the jejunojejunostomy anastomosis (1 patient). These four patients underwent successful laparoscopic re-exploration and creation of another jejunojejunostomy proximal to the original anastomosis. There were no small bowel anastomotic leaks. The median time to resuming oral diet was 2 days. Laparoscopic jejunojejunostomy as part of the RYGBP operation is a safe and technically feasible procedure. Postoperative small bowel obstruction is a potential complication, which can be prevented by avoiding technical narrowing of the afferent limb.

Background: Intraoperative hypothermia is a common event during laparoscopic operations. An external warming blanket has been shown to be effective in preventing hypothermia. It has now been proposed that using heated and humidified insufflation gas can prevent hypothermia and decrease postoperative pain. Therefore, we examined the extent of intraoperative hypothermia in patients undergoing laparoscopic Nissen fundoplication using an upper body warming blanket. We also attempted to determine whether using heated and humidified insufflation gas in addition to an external warming blanket would help to maintain intraoperative core temperature or decrease postoperative pain. Methods: Twenty patients were randomized to receive either standard carbon dioxide (CO2) gas (control, n = 10) or heated and humidified gas (heated and humidified, n = 10). After the induction of anesthesia, an external warming blanket was placed on all patients in both groups. Intraoperative core temperature and intraabdominal temperature were measured at 15-min intervals. Postoperative pain intensity was assessed using a visual analogue pain scale, and the amount of analgesic consumption was recorded. Volume of gas delivered, number of lens-fogging episodes, intraoperative urine output, and hemodynamic data were also recorded. Results: There was no significant difference between the two groups in age, length of operation, or volume of CO2 gas delivered. Compared with baseline value, mean core temperature increased by 0.4°C in the heated and humidified group and by 0.3°C in the control group at 1.5 h after surgical incision. Intraabdominal temperature increased by 0.2°C in the heated and humidified group but decreased by 0.5°C in the control group at 1.5 h after abdominal insufflation. There was no significant difference between the two groups in visual analog pain scale (5.4 ± 1.6 control vs 4.5 ± 2.8 heated and humidified), morphine consumed (27 ± 26 mg control vs 32 ± 19 mg heated and humidified), urine output, lens-fogging episodes, or hemodynamic parameters. Conclusion: Heated and humidified gas, when used in addition to an external warming blanket, minimized the reduction of intraabdominal temperature but did not alter core temperature or reduce postoperative pain.

The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H₂O₂ as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.

Maintenance of memory and synaptic plasticity depends on de novo protein synthesis and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer’s disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation factor eukaryotic elongation factor 2 (eEF2) in the hippocampi of human AD patients as well as transgenic AD model mice. Phosphorylation of eEF2 (at the Thr 56 site) by its only known kinase, eEF2K, leads to inhibition of general protein synthesis. A recent study suggests that Aβ-induced neurotoxicity could be associated with an interaction between eEF2 phosphorylation and the transcription factor nuclear erythroid 2-related factor (NRF2)-mediated antioxidant response. In this brief communication, we report that global homozygous knockout of the eEF2K gene alleviates deficits of long-term recognition and spatial learning in a mouse model of AD (APP/PS1). Moreover, eEF2K knockout does not alter brain Aβ pathology in APP/PS1 mice. The hippocampal NRF2 antioxidant response in the APP/PS1 mice, measured by expression levels of NQO1 and HO-1, is ameliorated by suppression of eEF2K signaling. Together, the findings may contribute to our understanding of the molecular mechanisms underlying AD pathogenesis, indicating that suppression of eEF2K activity could be a beneficial therapeutic option for this devastating neurodegenerative disease.

Marine microorganisms are of considerable interest as a promising source of enzymes with unsuspected potentials as catalysts for chemical synthesis. We describe here an efficient method for one-pot indolizine synthesis that has been developed using lipase A and lipase B from Candida antarctica as biocatalysts. As showed by HPLC/MS analysis, the yield in indolizines was higher in the presence of the biocatalyst than in absence of enzyme. Lipase A, from Candida antarctica, showed high catalytic activity and selectivity for the cycloaddition reactions. When the reactions were performed under ultrasound irradiation, the Candida antarctica lipase catalyzed reactions yielded pure indolozines, in good yields and in very short time.

A series of yeast strains was tested in order to evaluate their catalytic potential in biocatalysis of one-pot indolizine’s synthesis. Yeast cultivation was performed in a submerged system at 28 °C for 72 h at 180 rpm. An assessment of the reagents’ toxicity on yeast viability and metabolic functionality concluded that the growth potential of three Yarrowia lipolytica strains were least affected by the reactants compared to the other yeast strains. Further, crude fermentation products (biomass and cell-free supernatant)—obtained by submerged cultivation of these yeasts—were used in multistep cascade reactions for the production of fluorescent indolizine compounds with important biologic activities. A whole–cell catalyzed multicomponent reaction of activated alkynes, α-bromo-carbonyl reagents and 4,4′-bipyridine, at room temperature in buffer solution led to the efficient synthesis of bis-indolizines 4a, 4b and 4c, in good-to-excellent yields (47%–77%). The metabolites of the selected Y. lipolytica strains can be considered effective biocatalysts in cycloaddition reactions and the high purity and bioconversion yields of the synthesized indolizines indicates a great potential of this type of “green” catalysts. Seeds of Triticum estivum L. were used to investigate the impact of the final products on the germination and seedling growth. The most sensitive physiological parameters suggest that indolizines, at the concentrations tested, have non-toxic effect on germination and seedling growth of wheat, fact also confirmed by confocal laser scanning microscopy images.

Transcription stability enforces cellular identity and function and is tightly controlled by restrictions imposed on both transcription factor function and target gene accessibility. Progression of cancer to metastasis and multi-drug resistance requires the flexibilization of transcriptional regulation so cells can explore different genomic landscapes that enable phenotypic plasticity underlying the emergence of aggressive and treatment-resistant clones. Here, we report a newly discovered nexus between changes in cancer metabolism and chromatin remodeling permissive to cell plasticity acquisition. Specifically, we show that increased levels of hydrogen peroxide produced in mitochondria but acting in the nucleus oxidize cysteine 96, a distinctive redox sensitive amino acid exclusive to the histone variant H3.1. The oxidation of H3.1 promotes its eviction from chromatin and exchange for H3.3 thereby opening silenced portions of the chromatin. Mutation of Cys96 by an oxidation-resistant serine residue or quenching of nuclear H2O2 reverses these phenotypes and suppresses chemotherapy resistance while inducing the remission of established metastatic disease in mice. Together, our results indicate that the increase in the production of mitochondrial H2O2 characteristic of metabolic dysfunction promotes transcriptional plasticity by removing restrictions imposed by the redox-sensitive histone variant H3.1.Competing Interest StatementThe authors have declared no competing interest.

The development of mutant-selective inhibitors for the KRAS G12C allele has generated considerable excitement. These KRAS G12C inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRAS G12C protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this thiol remain, motivating the present studies. Measurement of the C12 thiol pKa by NMR and an independent biochemical assay found a depressed pKa (relative to free cysteine) of 7.6 consistent with its susceptibility to chemical ligation. Using a novel and validated fluorescent KRAS Y137W variant amenable to stopped-flow spectroscopy, we characterized the kinetics of KRAS G12C fluorescence changes upon addition of ARS-853 or AMG 510, noting that ARS-853 addition at 5°C elicited both a rapid first phase (attributed to binding, yielding a Kd of 36.0 ± 0.7 μM), and a second, slower pH-dependent phase taken to represent covalent ligation. Consistent with the lower pKa of the C12 thiol, we found that reversible and irreversible oxidation of KRAS G12C occurred readily both in vitro and in the cellular environment, preventing the covalent binding of ARS-853. Moreover, we found that oxidation of the KRAS G12C thiol to sulfinic acid alters RAS conformation and dynamics to be more similar to KRAS G12D in comparison to the unmodified protein, as assessed by molecular dynamics simulations. Taken together, these findings provide insight for future KRAS G12C drug discovery efforts as well as identifying the occurrence of G12C oxidation with currently unknown biological ramifications. Competing Interest Statement The authors have declared no competing interest.

It is imperative to develop novel therapeutic strategies for Alzheimer's disease (AD) and related dementia syndromes based on solid mechanistic studies. Maintenance of memory and synaptic plasticity relies on de novo protein synthesis, which is partially regulated by phosphorylation of eukaryotic elongation factor 2 (eEF2) via its kinase eEF2K. Abnormally increased eEF2 phosphorylation and impaired mRNA translation have been linked to AD. We recently reported that prenatal genetic suppression of eEF2K is able to prevent aging-related cognitive deficits in AD model mice, suggesting the therapeutic potential of targeting eEF2K/eEF2 signaling in AD. Here, we tested two structurally-distinct small-molecule eEF2K inhibitors in two different lines of AD model mice after onset of cognitive impairments. Our data revealed that treatment with eEF2K inhibitors improved AD-associated synaptic plasticity impairments and cognitive dysfunction, without altering brain amyloid (Aβ) and tau pathology. Furthermore, eEF2K inhibition alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, protein synthesis, and dendritic polyribosome assembly. Our results may offer critical therapeutic implications for AD, and the proof-of-principle study indicates translational implication of inhibiting eEF2K for AD and related dementia syndromes. Competing Interest Statement The authors have declared no competing interest.