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1
Festa, Giulia, Francesco Mallamace, Giulia Maria Sancesario, Carmelo Corsaro, Domenico Mallamace, Enza Fazio, Laura Arcidiacono, et al. "Aggregation States of Aβ1–40, Aβ1–42 and Aβp3–42 Amyloid Beta Peptides: A SANS Study." International Journal of Molecular Sciences 20, no. 17 (August 24, 2019): 4126. http://dx.doi.org/10.3390/ijms20174126.
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Aggregation states of amyloid beta peptides for amyloid beta A β 1 – 40 to A β 1 – 42 and A β p 3 – 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer’s disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A β p 3 – 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.
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Salazar, Jairo, Joana Poejo, Ana M. Mata, Alejandro K. Samhan-Arias, and Carlos Gutierrez-Merino. "Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1–42) Interactions with Calmodulin and Calbindin-D28k." International Journal of Molecular Sciences 23, no. 4 (February 18, 2022): 2289. http://dx.doi.org/10.3390/ijms23042289.
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Amyloid β1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1–42) oligomers and extensively binds internalized Aβ(1–42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1–42), using a combined strategy based on the experimental results obtained for Aβ(1–42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1–42) HiLyteTM-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1–42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1–42):CaM and of Aβ(1–42):calbindin-D28k complexes.
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Shi, Dai, Jaime K. Y. Wong, Kaichuan Zhu, Peter G. Noakes, and Gerhard Rammes. "The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aβ1–42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 912. http://dx.doi.org/10.3390/ijms24020912.
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It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer’s disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how β-amyloid peptide 1–42 (Aβ1–42), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aβ1–42, Iso or Xe and the combination of Aβ1–42 with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aβ1–42 elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aβ1–42 both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aβ1–42-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation.
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Hemmerová, Erika, Tomáš Špringer, Zdeňka Krištofiková, and Jiří Homola. "Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study." International Journal of Molecular Sciences 21, no. 24 (December 20, 2020): 9727. http://dx.doi.org/10.3390/ijms21249727.
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In early stages of Alzheimer’s disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ1–40, Aβ1–42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K+ and Mg2+ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ1–40 and Aβ1–42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ1–40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K+ and increased concentrations of Mg2+ promote the interaction of both mitochondrial proteins with Aβ1–42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions.
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Snezhkina, Anastasiya V., Dmitry V. Kalinin, Vladislav S. Pavlov, Elena N. Lukyanova, Alexander L. Golovyuk, Maria S. Fedorova, Elena A. Pudova, et al. "Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas." International Journal of Molecular Sciences 21, no. 18 (September 22, 2020): 6950. http://dx.doi.org/10.3390/ijms21186950.
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Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas. We compared the mutation status of SDHx genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16). In SDHA-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD. Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.
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Kosznik-Kwaśnicka, Katarzyna, Łukasz Grabowski, Michał Grabski, Mateusz Kaszubski, Marcin Górniak, Agata Jurczak-Kurek, Grzegorz Węgrzyn, and Alicja Węgrzyn. "Bacteriophages vB_Sen-TO17 and vB_Sen-E22, Newly Isolated Viruses from Chicken Feces, Specific for Several Salmonella enterica Strains." International Journal of Molecular Sciences 21, no. 22 (November 21, 2020): 8821. http://dx.doi.org/10.3390/ijms21228821.
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Two newly discovered bacteriophages, isolated from chicken feces and infecting Salmonella enterica strains, are described in this report. These phages have been named vB_Sen-TO17 and vB_Sen-E22, and we present their molecular and functional characterization. Both studied viruses are able to infect several S. enterica strains and develop lytically, but their specific host ranges differ significantly. Electron microscopic analyses of virions have been performed, and full genome sequences were determined and characterized, along with molecular phylogenetic studies. Genomes of vB_Sen-TO17 (ds DNA of 41,658 bp) and vB_Sen-E22 (dsDNA of 108,987 bp) are devoid of homologs of any known or putative gene coding for toxins or any other proteins potentially deleterious for eukaryotic cells. Both phages adsorbed efficiently (>95% adsorbed virions) within 10 min at 42 °C (resembling chicken body temperature) on cells of most tested host strains. Kinetics of lytic development of vB_Sen-TO17 and vB_Sen-E22, determined in one-step growth experiments, indicated that development is complete within 30–40 min at 42 °C, whereas burst sizes vary from 9 to 79 progeny phages per cell for vB_Sen-TO17 and from 18 to 64 for vB_Sen-E22, depending on the host strain. Virions of both phages were relatively stable (from several percent to almost 100% survivability) under various conditions, including acidic and alkaline pH values (from 3 to 12), temperatures from −80 °C to 60 °C, 70% ethanol, chloroform, and 10% DMSO. These characteristics of vB_Sen-TO17 and vB_Sen-E22 indicate that these phages might be considered in further studies on phage therapy, particularly in attempts to eliminate S. enterica from chicken intestine.
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Morroni, Fabiana, Giulia Sita, Agnese Graziosi, Eleonora Turrini, Carmela Fimognari, Andrea Tarozzi, and Patrizia Hrelia. "Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on Aβ1-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice." International Journal of Molecular Sciences 19, no. 7 (July 18, 2018): 2083. http://dx.doi.org/10.3390/ijms19072083.
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Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of β-amyloid oligomers (Aβ1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Aβ1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Aβ1-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy.
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Brückmann, Roberto, Margret Tuchscherer, Armin Tuchscherer, Ulrike Gimsa, and Ellen Kanitz. "Early-Life Maternal Deprivation Predicts Stronger Sickness Behaviour and Reduced Immune Responses to Acute Endotoxaemia in a Pig Model." International Journal of Molecular Sciences 21, no. 15 (July 23, 2020): 5212. http://dx.doi.org/10.3390/ijms21155212.
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Early-life adversity may have programming effects on neuroendocrine and immune adaptation mechanisms in humans and socially living animals. Using a pig model, we investigated the effect of daily 2-h maternal and littermate deprivation from postnatal days 2–15, either alone (DA) or in a group of littermates (DG) on the neuroendocrine, immunological and behavioural responses of piglets challenged with the bacterial endotoxin lipopolysaccharide (LPS) on day 42. LPS increased plasma concentrations of cortisol, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) and induced typical signs of sickness in all piglets. DA+DG piglets showed stronger signs of sickness compared to control (C) piglets. Plasma TNF-α concentrations were significantly lower in DA+DG males. In addition, the TNF-α/IL-10 ratio was significantly lower in DA than in DG and C males. Gene expression analyses showed lower hypothalamic TNF-α mRNA expression and diminished mRNA expression of the mineralocorticoid receptor (MR) and IL-10 in the amygdala of DA+DG piglets in response to LPS. Interestingly, males showed a higher MR- and a lower IL-10 mRNA expression in the amygdala than females. The present data suggest that repeated maternal deprivation during early life may alter neuroendocrine and immune responses to acute endotoxaemia in a sex-specific manner.
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Zięba, Sebastian, Anne-Floor W. Pouwer, Artur Kowalik, Kamil Zalewski, Natalia Rusetska, Elwira Bakuła-Zalewska, Janusz Kopczyński, Johanna M. A. Pijnenborg, Joanne A. de Hullu, and Magdalena Kowalewska. "Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma." International Journal of Molecular Sciences 21, no. 14 (July 10, 2020): 4880. http://dx.doi.org/10.3390/ijms21144880.
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Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.
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Fernández, Marta S., Ricardo Mejía, and Eunice Zavala. "The interfacial calcium ion concentration as modulator of the latency phase in the hydrolysis of dimyristoylphosphatidylcholine liposomes by phospholipase A2." Biochemistry and Cell Biology 69, no. 10-11 (October 1, 1991): 722–27. http://dx.doi.org/10.1139/o91-108.
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Analysis of the time course of hydrolysis of dimyristoylphosphatidylcholine liposomes catalyzed by porcine pancreatic phospholipase A2 at 18 °C shows that, in the presence of 10 mM NaCl, the length of the latency period in the presteady-state phase increases from 3 to 10.5 min when the CaCl2 concentration is reduced from 15 to 1 mM. This inverse dependence of the lag period on calcium ion concentration is seen more readily at 1 M NaCl, where the induction time changes from 13.5 to 42 min by decreasing the concentration of CaCl2 from 15 to 1 mM. To interpret these results, we took into account the small amount of fatty acid that is produced during the latency phases. The fatty acid generates a negative surface electrostatic potential and makes the interfacial concentration of calcium ions different from the concentration in the bulk solvent. Variations in the analytical concentrations of NaCl and CaCl2 affect both the interfacial calcium ion concentration and electrostatic potential, as estimated theoretically from Grahame and Boltzmann equations. According to these estimates, the length of the latency period diminishes with the increase of the interfacial calcium concentration, but does not show any logical dependence on the change in surface electrostatic potential.Key words: phospholipase A2, latency phase, interfacial calcium ion concentration, liposomes.
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Dionisie, Vlad, Adela Magdalena Ciobanu, Vlad Alexandru Toma, Mihnea Costin Manea, Ioana Baldea, Diana Olteanu, Alexandra Sevastre-Berghian, et al. "Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress." International Journal of Molecular Sciences 22, no. 14 (July 13, 2021): 7483. http://dx.doi.org/10.3390/ijms22147483.
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In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.
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Moreno, Carlos, Ellie Bybee, Claudia M. Tellez Freitas, Brett E. Pickett, and K. Scott Weber. "Meta-Analysis of Two Human RNA-seq Datasets to Determine Periodontitis Diagnostic Biomarkers and Drug Target Candidates." International Journal of Molecular Sciences 23, no. 10 (May 17, 2022): 5580. http://dx.doi.org/10.3390/ijms23105580.
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Periodontitis is a chronic inflammatory oral disease that affects approximately 42% of adults 30 years of age or older in the United States. In response to microbial dysbiosis within the periodontal pockets surrounding teeth, the host immune system generates an inflammatory environment in which soft tissue and alveolar bone destruction occur. The objective of this study was to identify diagnostic biomarkers and the mechanistic drivers of inflammation in periodontitis to identify drugs that may be repurposed to treat chronic inflammation. A meta-analysis comprised of two independent RNA-seq datasets was performed. RNA-seq analysis, signal pathway impact analysis, protein-protein interaction analysis, and drug target analysis were performed to identify the critical pathways and key players that initiate inflammation in periodontitis as well as to predict potential drug targets. Seventy-eight differentially expressed genes, 10 significantly impacted signaling pathways, and 10 hub proteins in periodontal gingival tissue were identified. The top 10 drugs that may be repurposed for treating periodontitis were then predicted from the gene expression and pathway data. The efficacy of these drugs in treating periodontitis has yet to be investigated. However, this analysis indicates that these drugs may serve as potential therapeutics to treat inflammation in gingival tissue affected by periodontitis.
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Sushko, Ekaterina S., Natalia G. Vnukova, Grigoriy N. Churilov, and Nadezhda S. Kudryasheva. "Endohedral Gd-Containing Fullerenol: Toxicity, Antioxidant Activity and Regulation of Reactive Oxygen Species in Cellular and Enzymatic Systems." International Journal of Molecular Sciences 23, no. 9 (May 5, 2022): 5152. http://dx.doi.org/10.3390/ijms23095152.
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The Gd-containing metallofullerene derivatives are perspective magnetic resonance imaging contrast agents. We studied the bioeffects of a water-soluble fullerene derivative, gadolinium-endohedral fullerenol, with 40–42 oxygen groups (Gd@Fln). Bioluminescent cellular and enzymatic assays were applied to monitor toxicity and antioxidant activity of Gd@Fln in model solutions; bioluminescence was applied as a signaling physiological parameter. The Gd@Fln inhibited bioluminescence at high concentrations (>2·10−1 gL−1), revealing lower toxicity as compared to the previously studied fullerenols. Efficient activation of bioluminescence (up to almost 100%) and consumption of reactive oxygen species (ROS) in bacterial suspension were observed under low-concentration exposure to Gd@Fln (10−3–2·10−1 gL−1). Antioxidant capability of Gd@Fln was studied under conditions of model oxidative stress (i.e., solutions of model organic and inorganic oxidizers); antioxidant coefficients of Gd@Fln were determined at different concentrations and times of exposure. Contents of ROS were evaluated and correlations with toxicity/antioxidant coefficients were determined. The bioeffects of Gd@Fln were explained by hydrophobic interactions, electron affinity, and disturbing of ROS balance in the bioluminescence systems. The results contribute to understanding the molecular mechanism of “hormetic” cellular responses. Advantages of the bioluminescence assays to compare bioeffects of fullerenols based on their structural characteristics were demonstrated.
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Pomini, Karina Torres, Daniela Vieira Buchaim, Jesus Carlos Andreo, Marcelie Priscila de Oliveira Rosso, Bruna Botteon Della Coletta, Íris Jasmin Santos German, Ana Carolina Cestari Biguetti, et al. "Fibrin Sealant Derived from Human Plasma as a Scaffold for Bone Grafts Associated with Photobiomodulation Therapy." International Journal of Molecular Sciences 20, no. 7 (April 10, 2019): 1761. http://dx.doi.org/10.3390/ijms20071761.
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Fibrin sealants derived from human blood can be used in tissue engineering to assist in the repair of bone defects. The objective of this study was to evaluate the support system formed by a xenograft fibrin sealant associated with photobiomodulation therapy of critical defects in rat calvaria. Thirty-six rats were divided into four groups: BC (n = 8), defect filled with blood clot; FSB (n = 10), filled with fibrin sealant and xenograft; BCPBMT (n = 8), blood clot and photobiomodulation; FSBPBMT (n = 10), fibrin sealant, xenograft, and photobiomodulation. The animals were killed after 14 and 42 days. In the histological and microtomographic analysis, new bone formation was observed in all groups, limited to the defect margins, and without complete wound closure. In the FSB group, bone formation increased between periods (4.3 ± 0.46 to 6.01 ± 0.32), yet with lower volume density when compared to the FSBPBMT (5.6 ± 0.45 to 10.64 ± 0.97) group. It was concluded that the support system formed by the xenograft fibrin sealant associated with the photobiomodulation therapy protocol had a positive effect on the bone repair process.
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Yue, Qian, Xinhua Zhou, Zaijun Zhang, and Maggie Pui Man Hoi. "Murine Beta-Amyloid (1–42) Oligomers Disrupt Endothelial Barrier Integrity and VEGFR Signaling via Activating Astrocytes to Release Deleterious Soluble Factors." International Journal of Molecular Sciences 23, no. 3 (February 7, 2022): 1878. http://dx.doi.org/10.3390/ijms23031878.
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Transgenic mouse models of Alzheimer’s disease (AD) overexpress mutations of the human amyloid protein precursor (APP) and presenilin-1 (PSEN1) genes, which are known causes of amyloid pathology in familial AD. However, animal models for studying AD in the context of aging and age-related co-morbidities, such as blood–brain barrier (BBB) disruptions, are lacking. More recently, aged and progeroid mouse models have been proposed as alternatives to study aging-related AD, but the toxicity of murine amyloid-beta protein (Aβ) is not well defined. In this study, we aimed to study the potential toxicity of murine Aβ on brain endothelial cells and astrocytes, which are important components of the BBB, using mouse brain endothelial cells (bEnd.3) and astrocytes (C8-D1A). Murine-soluble Aβ (1–42) oligomers (sAβO42) (10 µM) induced negligible injuries in an endothelial monolayer but induced significant barrier disruptions in a bEnd.3 and C8-D1A co-culture. Similar results of endothelial perturbation were observed in a bEnd.3 monolayer treated with astrocyte-conditioned medium (ACM) generated by astrocytes exposed to sAβO42 (ACM-sAβO42), while additional exogenous sAβO42 did not cause further damage. Western blot analysis showed that ACM-sAβO42 altered the basal activities of vascular endothelial growth factor receptor 2 (VEGFR2), eNOS, and the signaling of the MEK/ERK and Akt pathways in bEnd.3. Our results showed that murine sAβO42 was moderately toxic to an endothelial and astrocyte co-culture. These damaging effects on the endothelial barrier were induced by deleterious soluble factors released from astrocytes, which disrupted endothelial VEGFR2 signaling and perturbed cell survival and barrier stabilization.
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Zhang, Qian, Chao Xue, Xin Wang, Kang Lu, Xueling Ge, Xiao Lv, Lingyan Zhang, Hongzhi Xu, and Yujie Jiang. "Bioinformatics Analysis of Differently Expressed Mirnas in CD5 Positive Relapsed and Refractory Diffuse Large B-Cell Lymphoma and Their Potential Theoretical and Clinical Investigations." Blood 136, Supplement 1 (November 5, 2020): 2–3. http://dx.doi.org/10.1182/blood-2020-141919.
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Introduction: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by a poor prognosis, poorly respond to the regulatory treatment strategy, and a relatively high incidence of central nervous system (CNS) infiltration. In this study, we aim to identify key differentially expressed miRNAs (DE-miRNAs) and their target genes in the peripheral blood of CD5+ refractory and relapsed (CD5+ R/R DLBCL) patients. The relationship of the DE-miRNAs and the pathogenesis of CD5+ R/R DLBCL will also be analyzed by bioinformatics tools. Methods: Three female patients with confirmed CD5+ R/R DLBCL were enrolled in this study, their age were 38, 62 and 65 years old, respectively. Three healthy female adults aged 42, 55 and 61, respectively were selected as the control group. The peripheral venous blood of them was collected for RNA extraction and standard small RNA sequencing. Differentially expressed miRNAs analysis was performed with R package edgeR. The target genes of DE-miRNAs were predicted by miRNet. A protein protein interaction (PPI) network was established for these target genes through string database. Functional annotation and pathway enrichment analyses for the target genes were performed through DAVID database to identify their potential functions, target genes, and pathways they might be involved in. Results: 1. Scatter plots, Volcano plots and Heat-maps were used to visualize miRNAs of Differentially expressed genes. As shown in Fig.1, Fig. 2 and Fig. 3. 2. Fifty-five sequences were significantly upregulated and 23 were significantly downregulated in patients with CD5+ R/R DLBCL.Among the candidate miRNAs, 11 up-regulated genes and 4 down-regulated genes were selected according to the log2FC value. The target genes of 11 potential up-regulated and 4 down-regulated DE-miRNAs were successively predicted by As shown in Table 1, a total of 439 and 632 predicted targets of the up-regulated and down-regulated DE-miRNAs were identified, respectively. 3. PPI networks of predicted target genes of 11 upregulated DE-miRNAs (Fig.4a) and 4 downregulated DE-miRNAs (Fig. 4b) were separately constructed using the STRING database and Cytoscape software. According to a degree, the top 10 hub genes in the networks were screened out and were listed inTable 2. Six important hub genes were identified, including two target genes predicted by up-regulating DE-miRNAs, namely NRAS and PIK3R1, and four target genes predicted by down-regulating DE-miRNAs, namely EGFR, VEGFA, IGF1 and Grb2. 4. DAVID now provides a comprehensive set of functional annotation tools for investigators to understand biological meaning. GO analysis was divided into three functional groups, including molecular function (MF), biological processes (BP), and cell composition (CC). The top 10 GO terms of targets of up-regulated DE-miRNAs were presented in Fig.5a-c. The top 10 GO terms of targets of down-regulated DE-miRNAs were shown in Fig. 5d-f. 5. Based on the KEGG database, we analyzed the pathways in which the differentially expressed target genes were involved in. As shown in Fig. 6a-b. The targets of up-regulated DE-miRNAs were enriched in pathways in cancer, oxytocin signaling pathway, ErbB signaling pathway, Rap1 signaling pathway, and proteoglycans in cancer. Whereas the targets of down-regulated DE-miRNAs were enriched in pathways in cancer, Ras signaling pathway, and PI3K-Akt signaling pathway. Conclusions: In this study, we analyzed the differentially expressed miRNAs in CD5+ R/R DLBCL patients, identified their potential functions, target genes, and pathways they might be involved in. This study found that ErbB signaling pathway, Rap1 signaling pathway, Ras signaling pathway and PI3K Akt signaling pathway were the most frequently involved pathways of miRNAs related genes. Target genes including NRAS, PIK3R1, EGFR, VEGFA, IGF1, and Grb2 might have a close relationship in the pathogenesis of CD5+ R/R DLBCL. New targeted drugs related to these pathways and genes may be beneficial to the treatment of CD5+ DLBCL. Our preliminary informatic results might be helpful to deeply understand the pathogenesis and chemotherapy resistance mechanism of CD5+ R/R DLBCL. In the future, we will verify our preliminary informatic results in pathological tissues from patients with CD5+ DLBCL in larger samples. Disclosures No relevant conflicts of interest to declare.
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Szyszka, Marta, Lukasz Paschke, Marianna Tyczewska, Karol Jopek, Piotr Celichowski, Paulina Milecka, Gulnara Sultanova, et al. "Analysis of Transcriptome, Selected Intracellular Signaling Pathways, Proliferation and Apoptosis of LNCaP Cells Exposed to High Leptin Concentrations." International Journal of Molecular Sciences 20, no. 21 (October 30, 2019): 5412. http://dx.doi.org/10.3390/ijms20215412.
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Leptin, the first discovered adipokine, has been connected to various physiological and pathophysiological processes, including cancerogenesis. Increasing evidence confirms its influence on prostate cancer cells. However, studies on the effects of leptin on the proliferation and apoptosis of the androgen-sensitive LNCaP line of prostate cancer cells brought conflicting results. Therefore, we performed studies on the effects of high LEP concentration (1 × 10−6 M) on gene expression profile, change of selected signaling pathways, proliferation and apoptosis of LNCaP cells. RTCA (real-time cell analyzer) revealed inhibitory effect of LEP on cell proliferation, but lower LEP concentrations (10−8 and 10−10 M) did not affect cell division. Moreover, flow cytometry with a specific antibody for Cleaved PARP-1, an apoptosis marker, confirmed the activation of apoptosis in leptin-exposed LNCaP line of prostate cancer cells. Within 24 h LEP (10−6 M) increases expression of 297 genes and decreases expression of 119 genes. Differentially expressed genes (DEGs) were subjected to functional annotation and clusterization using the DAVID bioinformatics tools. Most ontological groups are associated with proliferation and apoptosis (seven groups), immune response (six) and extracellular matrix (two). These results were confirmed by the Gene Set Enrichment Analysis (GSEA). The leptin’s effect on apoptosis stimulation was also confirmed using Pathview library. These results were also confirmed by qPCR method. The results of Western Blot analysis (exposure to LEP 10 min, 1, 2, 4 and 24 h) suggest (after 24 h) decrease of p38 MAPK, p44-42 mitogen-activated protein kinase and Bcl-2 phosphorylated at threonine 56. Moreover, exposure of LNCaP cells to LEP significantly stimulates the secretion of matrix metallopeptidase 7 (MMP7). Obtained results suggest activation of apoptotic processes in LNCaP cells cultured at high LEP concentration. At the same time, this activation is accompanied by inhibition of proliferation of the tested cells.
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Kishore, Bhuvan, John Davis, Katayoun Rezvani, David Marin, Richard M. Szydlo, Loaiza Sandra, Giles Chrissy, et al. "Cryopreserved Allogeneic Peripheral Blood Stem Cells Result in Outcome Equivalent to Those of Fresh Infusions Enabling Rational Scheduling of Donations,." Blood 118, no. 21 (November 18, 2011): 4052. http://dx.doi.org/10.1182/blood.v118.21.4052.4052.
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Abstract Abstract 4052 Introduction: Donor stem cells are traditionally infused fresh into recipients in the setting of allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, we investigated outcomes of 133 sibling allografts using cryopreserved peripheral blood stem cells. We demonstrate that cryopreservation did not have a negative impact on engraftment when compared to data from the IBMTR/EBMT, Seattle and the Canadian registry studies. Non-relapse mortality (NRM) and overall survival (OS) were within acceptable limits. Patients and Methods: We identified all recipients of HLA-matched sibling peripheral stem cells cryopreserved for a minimum of 7 days, who underwent allo-SCT at Hammersmith Hospital from January 1998 until May 2011 (n = 133). The median age at allo-SCT of 78 (59 %) males and 55 (41 %) females was 48 (17 – 65) yrs. Thirty-five (26 %) were transplanted for CML (including accelerated and blast phase), 42 (31 %) for AML, 11 (8 %) for ALL, 14 (11 %) for myeloma and 13 (10%) for other causes. Fifty-six (42 %) had myeloablative and 77 (58 %) had reduced intensity conditioning, with 23 (17 %) having in vivo T-cell depletion with monoclonal anti-CD52 antibody (alemtuzumab). Using validated institutional protocols hematopoietic progenitor cell collections were cryopreserved on the day of collection or on following morning. Cells are were mixed with 10 % v/v dimethyl sulfoxide, frozen to -−00°C at a controlled rate and then transferred to vapor phase liquid nitrogen ≤ −150°C. Thawing and infusion of cells were performed in accordance with a standard protocol defining thawing temperature and the maximum time between thawing and infusion. Median CD-34+ cell dose infused was 9.83 × 106/kg (range 2.4 – 33 × 106/kg). All cryopreserved peripheral blood stem cell collections were infused into the recipients. Engraftment was defined as a peripheral absolute neutrophil count (ANC) of 0.5 × 109/L for 2 successive days and platelet count of > 50 × 109/L for 2 consecutive days, both without support. G-CSF was used only in delayed neutrophil engraftment (> 30 days). Results: Overall 125 (93 %) achieved neutrophil engraftment and median time to engraftment was 19 (range 10 – 42) days. Delayed neutrophil engraftment (>30 days) was present in 4 patients. Results are comparable to the registry data which showed neutrophil engraftment in a median of 14 – 19 days (Table 1). Cumulative probability of achieving ANC > of 0.5 × 109/L for the whole cohort was 94 % (88 – 95). Eight of the 133 patients who died early (< day 30) failed to achieve neutrophil engraftment prior to death. The causes of death were sepsis (n = 6), myocardial ischemia (n = 1) and renal failure (n = 1).Three recovered counts with G-CSF and one patient required stem cell rescue. One hundred and thirteen patients (84 %) recovered platelets to >50 × 109/L within a median time of 21 (range 0 – 240) days, which again is similar to registry data as shown in table 1. The cumulative probability of achieving platelets of 50 × 109/L was 84 % (77 – 88). Twenty patients (16 %) failed to achieve this threshold and causes were multiple. There was no association between CD34+ cell doses infused and delayed or non engraftment of platelets. The incidence of acute and chronic GvHD were 44 % (grade II-IV GvHD 31 %) and 30 % (50 % extensive) respectively. Day 100 NRM was 23 % and OS at 3 years was 50 %. Conclusion: This study provides evidence that cryopreservation and subsequent infusion of peripheral blood stem cell harvests is safe, ensures durable engraftment and is comparable to fresh stem cell infusions (Table 1). We do not routinely use growth factors to aid count recovery and as such the time to engraftment data is consistent. Cryopreservation importantly allows for flexibility in arranging admissions and scheduling regimens for both the donors and the transplant units. Although not observed in our cohort, there is a theoretical risk of not utilizing the cryopreserved cells, thus unnecessarily harvesting donors. One way to circumvent this possibility is by timing the collection close to the transplant. Disclosures: No relevant conflicts of interest to declare.
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Hwang, Sung-Hee, Hojin Yeom, Byeal-I. Han, Byung-Joo Ham, Yong-Moon Lee, Mi-Ryung Han, and Michael Lee. "Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation." International Journal of Molecular Sciences 21, no. 15 (July 29, 2020): 5387. http://dx.doi.org/10.3390/ijms21155387.
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An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated strategy comprising an in vitro Bhas 42 CTA and global DNA methylation analysis. For this purpose, 10 NGTXCs, which were also predicted to be negative through Derek/Sarah structure–activity relationship analysis, were first tested for transforming activity in Bhas 42 cells. Methylation profiles using reduced representation bisulfite sequencing were generated for seven NGTXCs that were positive in CTAs. In general, the differentially methylated regions (DMRs) within promoter regions showed slightly more bias toward hypermethylation than the DMRs across the whole genome. We also identified 13 genes associated with overlapping DMRs within the promoter regions in four NGTXCs, of which seven were hypermethylated and six were hypomethylated. Using ingenuity pathway analysis, the genes with DMRs at the CpG sites were found to be enriched in cancer-related categories, including “cell-to-cell signaling and interaction” as well as “cell death and survival”. Moreover, the networks related to “cell death and survival”, which were considered to be associated with carcinogenesis, were identified in six NGTXCs. These results suggest that epigenetic changes supporting cell transformation processes occur during non-genotoxic carcinogenesis. Taken together, our combined system can become an attractive component for an integrated approach for the testing and assessment of NGTXCs.
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Duarte, Ana I., Emanuel Candeias, Inês N. Alves, Débora Mena, Daniela F. Silva, Nuno J. Machado, Elisa J. Campos, Maria S. Santos, Catarina R. Oliveira, and Paula I. Moreira. "Liraglutide Protects Against Brain Amyloid-β1–42 Accumulation in Female Mice with Early Alzheimer’s Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation." International Journal of Molecular Sciences 21, no. 5 (March 4, 2020): 1746. http://dx.doi.org/10.3390/ijms21051746.
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Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aβ1–42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.
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Ghevaria, Harita, Sioban SenGupta, Roy Naja, Rabi Odia, Holly Exeter, Paul Serhal, Xavier Viñals Gonzalez, Xuhui Sun, and Joy Delhanty. "Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes." International Journal of Molecular Sciences 23, no. 2 (January 8, 2022): 665. http://dx.doi.org/10.3390/ijms23020665.
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Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence in situ hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10–20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.
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Souza-Monteiro, Deiweson, Maria Karolina Martins Ferreira, Leonardo Oliveira Bittencourt, Walessa Alana Bragança Aragão, Igor Gonçalves de Oliveira, Cristiane Socorro Ferraz Maia, Marco Aurelio M. Freire, Fatemeh Vida Zohoori, Marília Afonso Rabelo Buzalaf, and Rafael Rodrigues Lima. "Intrauterine and Postnatal Exposure to High Levels of Fluoride Is Associated with Motor Impairments, Oxidative Stress, and Morphological Damage in the Cerebellum of Offspring Rats." International Journal of Molecular Sciences 23, no. 15 (August 2, 2022): 8556. http://dx.doi.org/10.3390/ijms23158556.
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Fluoride (F) is abundantly present on Earth and plays a beneficial role in human health. However, exposure to high doses of F can be a risk, mainly in endemic fluorosis regions. In light of this, we investigated the effects of F exposure during the intrauterine and postnatal periods of rats, in doses similar to those recommended in drinking water and the levels of F in regions with endemic fluorosis, on the offspring rats’ cerebellum. Pregnant rats were divided into three groups: control (received ultrapure water only), 10 mg F/L, and 50 mg F/L for a period of 42 days (21 days gestation and 21 days lactation). At the end of the lactation period, the male pups were evaluated by behavioral tests, morphological markers, and biochemistry assays. The results pointed out that 50 mg F/L exposure during the intrauterine and lactational period of rats is capable of promoting oxidative stress in the cerebellum with a decrease in Purkinje cell density and myelin basic protein compromise, which could be associated with functional motor impairments. In addition, although 10 mg F/L exposure promoted redox alterations, it did not affect other parameters evaluated, highlighting the safe use of F in low doses.
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Cao, Liru, Xiaomin Lu, Pengyu Zhang, Guorui Wang, Li Wei, and Tongchao Wang. "Systematic Analysis of Differentially Expressed Maize ZmbZIP Genes between Drought and Rewatering Transcriptome Reveals bZIP Family Members Involved in Abiotic Stress Responses." International Journal of Molecular Sciences 20, no. 17 (August 22, 2019): 4103. http://dx.doi.org/10.3390/ijms20174103.
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The basic leucine zipper (bZIP) family of transcription factors (TFs) regulate diverse phenomena during plant growth and development and are involved in stress responses and hormone signaling. However, only a few bZIPs have been functionally characterized. In this paper, 54 maize bZIP genes were screened from previously published drought and rewatering transcriptomes. These genes were divided into nine groups in a phylogenetic analysis, supported by motif and intron/exon analyses. The 54 genes were unevenly distributed on 10 chromosomes and contained 18 segmental duplications, suggesting that segmental duplication events have contributed to the expansion of the maize bZIP family. Spatio-temporal expression analyses showed that bZIP genes are widely expressed during maize development. We identified 10 core ZmbZIPs involved in protein transport, transcriptional regulation, and cellular metabolism by principal component analysis, gene co-expression network analysis, and Gene Ontology enrichment analysis. In addition, 15 potential stress-responsive ZmbZIPs were identified by expression analyses. Localization analyses showed that ZmbZIP17, -33, -42, and -45 are nuclear proteins. These results provide the basis for future functional genomic studies on bZIP TFs in maize and identify candidate genes with potential applications in breeding/genetic engineering for increased stress resistance. These data represent a high-quality molecular resource for selecting resistant breeding materials.
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Lee, Chen, Lee, and Chang. "Suppressing Antibacterial Resistance: Chemical Binding of Monolayer Quaternary Ammonium Salts to Polymethyl Methacrylate in an Aqueous Solution and its Clinical Efficacy." International Journal of Molecular Sciences 20, no. 19 (September 20, 2019): 4668. http://dx.doi.org/10.3390/ijms20194668.
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Antibacterial resistance (ABR) poses an enormous threat to human health. ABR mainly develops due to bacteria being constantly exposed to diluted levels of disinfectants. Here, we propose a method for suppressing ABR through the chemical binding of disinfectants to polymethyl methacrylate (PMMA) device surfaces in solutions of 5%, 10%, and 20% disinfectant concentrations. PMMA discs were fabricated from a commercial orthodontic acrylic resin system (Ortho-Jet) and quaternary ammonium salts (QAS), 3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride (42% in methanol), were used as the disinfectant. The PMMA surfaces were activated in 3 M sulfuric acid at 80 °C for 5 h for the esterification of hydrolyzed QAS to PMMA. Fourier transform infrared difference spectra confirmed that the carboxy-terminated PMMA was chemically bound to the QAS. In vitro cell viability tests using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays revealed that 5%QAS-c-PMMA was more biocompatible than 10%QAS-c-PMMA and 20%QAS-c-PMMA. The results of antibacterial tests and clinical trials demonstrated the excellent antibacterial power of 5%QAS-c-PMMA. This method is the first solution-based approach to successfully avoid disinfectant leakage and subsequent ABR, as revealed by mass spectrometry studies of the solution obtained by agitating the disinfectant-bound PMMA for 28 days.
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Ibrahim, Nagwa. "Impact of dose rounding of cancer therapy on cost avoidance: a pilot study." Farmeconomia. Health economics and therapeutic pathways 14, no. 4 (December 18, 2013): 169–72. http://dx.doi.org/10.7175/fe.v14i4.658.
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BACKGROUND: A significant and progressive cost rising in medical oncology due to the incorporation of novel and highly expensive drugs into clinical practice have been seen in the past ten years. Dose rounding is an option might be used in oncology settings to avoid extra cost. The purpose of this project is to determine the theoretical cost saving related to a dose rounding process for biological and chemotherapy agents in adult oncology settings and to determine the opinion of oncologists about dose rounding.MATERIALS AND METHODS: Data was obtained prospectively during April 2011. All chemotherapy and targeted therapy orders prescribed in adult oncology outpatient clinics as well as in-patient wards have been collected. We considered rounding to an amount within 15% for targeted therapy and 10% for cytotoxic drugs. Chemotherapy dosing was calculated according to body surface area. Prescriptions that include cancer therapy in doses that might be rounded according to study criteria were identified.RESULTS: Two hundred and thirty three orders of chemotherapy and targeted therapy were processed by Adult Oncology Satellite Pharmacy during the period of data collection. Forty percent of the collected prescriptions fulfilled the criteria. The potential cost savings from dose rounding per year was $192,800. Data was extrapolated from the determined monthly cost savings. The highest cost saving was for breast cancer orders $80,820 (42%), followed by colorectal cancer $47,965 (25%), while in non-Hodgkin's lymphoma cost savings was $ 45,107 (23%) and for other types of cancer that include non small cell lung cancer, prostate and ovarian cancer, in addition to head and neck cost savings was $18,867 (10%).CONCLUSIONS: Our experience confirms the significant cost savings of cancer therapy by applying dose rounding to chemotherapy and biologic drugs prescriptions. While clinical impact of the suggested percentage needs to be evaluated.
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Khalkar, Prajakta, Nuria Díaz-Argelich, Juan Antonio Palop, Carmen Sanmartín, and Aristi Fernandes. "Novel Methylselenoesters Induce Programed Cell Death via Entosis in Pancreatic Cancer Cells." International Journal of Molecular Sciences 19, no. 10 (September 20, 2018): 2849. http://dx.doi.org/10.3390/ijms19102849.
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Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH3SeH) being one of the key executors. In search of novel CH3SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI50 < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH3SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds.
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Gamez, Carolina, Barbara Schneider-Wald, Karen Bieback, Andy Schuette, Sylvia Büttner, Mathias Hafner, Norbert Gretz, and Markus L. Schwarz. "Compression Bioreactor-Based Mechanical Loading Induces Mobilization of Human Bone Marrow-Derived Mesenchymal Stromal Cells into Collagen Scaffolds In Vitro." International Journal of Molecular Sciences 21, no. 21 (November 4, 2020): 8249. http://dx.doi.org/10.3390/ijms21218249.
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Articular cartilage (AC) is an avascular tissue composed of scattered chondrocytes embedded in a dense extracellular matrix, in which nourishment takes place via the synovial fluid at the surface. AC has a limited intrinsic healing capacity, and thus mainly surgical techniques have been used to relieve pain and improve function. Approaches to promote regeneration remain challenging. The microfracture (MF) approach targets the bone marrow (BM) as a source of factors and progenitor cells to heal chondral defects in situ by opening small holes in the subchondral bone. However, the original function of AC is not obtained yet. We hypothesize that mechanical stimulation can mobilize mesenchymal stromal cells (MSCs) from BM reservoirs upon MF of the subchondral bone. Thus, the aim of this study was to compare the counts of mobilized human BM-MSCs (hBM-MSCs) in alginate-laminin (alginate-Ln) or collagen-I (col-I) scaffolds upon intermittent mechanical loading. The mechanical set up within an established bioreactor consisted of 10% strain, 0.3 Hz, breaks of 10 s every 180 cycles for 24 h. Contrary to previous findings using porcine MSCs, no significant cell count was found for hBM-MSCs into alginate-Ln scaffolds upon mechanical stimulation (8 ± 5 viable cells/mm3 for loaded and 4 ± 2 viable cells/mm3 for unloaded alginate-Ln scaffolds). However, intermittent mechanical stimulation induced the mobilization of hBM-MSCs into col-I scaffolds 10-fold compared to the unloaded col-I controls (245 ± 42 viable cells/mm3 vs. 22 ± 6 viable cells/mm3, respectively; p-value < 0.0001). Cells that mobilized into the scaffolds by mechanical loading did not show morphological changes. This study confirmed that hBM-MSCs can be mobilized in vitro from a reservoir toward col-I but not alginate-Ln scaffolds upon intermittent mechanical loading, against gravity.
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Abbasi, Ali, Soraya Hosseini, Anongnat Somwangthanaroj, Ahmad Azmin Mohamad, and Soorathep Kheawhom. "Poly(2,6-Dimethyl-1,4-Phenylene Oxide)-Based Hydroxide Exchange Separator Membranes for Zinc–Air Battery." International Journal of Molecular Sciences 20, no. 15 (July 26, 2019): 3678. http://dx.doi.org/10.3390/ijms20153678.
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Rechargeable zinc–air batteries are deemed as the most feasible alternative to replace lithium–ion batteries in various applications. Among battery components, separators play a crucial role in the commercial realization of rechargeable zinc–air batteries, especially from the viewpoint of preventing zincate (Zn(OH)42−) ion crossover from the zinc anode to the air cathode. In this study, a new hydroxide exchange membrane for zinc–air batteries was synthesized using poly (2,6-dimethyl-1,4-phenylene oxide) (PPO) as the base polymer. PPO was quaternized using three tertiary amines, including trimethylamine (TMA), 1-methylpyrolidine (MPY), and 1-methylimidazole (MIM), and casted into separator films. The successful synthesis process was confirmed by proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy, while their thermal stability was examined using thermogravimetric analysis. Besides, their water/electrolyte absorption capacity and dimensional change, induced by the electrolyte uptake, were studied. Ionic conductivity of PPO–TMA, PPO–MPY, and PPO–MIM was determined using electrochemical impedance spectroscopy to be 0.17, 0.16, and 0.003 mS/cm, respectively. Zincate crossover evaluation tests revealed very low zincate diffusion coefficient of 1.13 × 10−8, and 0.28 × 10−8 cm2/min for PPO–TMA, and PPO–MPY, respectively. Moreover, galvanostatic discharge performance of the primary batteries assembled using PPO–TMA and PPO–MPY as initial battery tests showed a high specific discharge capacity and specific power of ~800 mAh/gZn and 1000 mWh/gZn, respectively. Low zincate crossover and high discharge capacity of these separator membranes makes them potential materials to be used in zinc–air batteries.
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Shimoni, Avichai, Izhar Hardan, Avital Rand, Noga Shem-Tov, Ronit Yerushalmi, and Arnon Nagler. "Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation (SCT) with Fludarabine and Intravenous Busulfan Is Associated with Improved Toxicity Profile and Longer Survival Than Conditioning with Fludarabine and Melphalan in Patients with Chemo-Sensitive Hematological Malignancies." Blood 110, no. 11 (November 16, 2007): 2002. http://dx.doi.org/10.1182/blood.v110.11.2002.2002.
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Abstract Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic SCT. They are more effective when the underlying malignancy is in remission at the time of SCT. Various RIC regimens have been designed, yet there is no defined data as to whether any of the regimens has an advantage over the others. To answer this question we retrospectively analyzed SCT outcomes in 100 consecutive patients (pts) given RIC for various hematological malignancies including AML/MDS (n=45), ALL (n=8), CML (n=6), multiple myeloma (MM, n=18), various lymphomas (n=19), others (n=4). All pts were considered not eligible for myeloablative conditioning and were required to have chemo-sensitive disease at SCT. The median age was 56 years (23–75). Donors were HLA-matched siblings (n=53) or matched unrelated (n=47). RIC consisted of fludarabine with intravenous busulfan (6.4 mg/kg; FB, n=62) or with melphalan (100–140 mg/m2; FM, n=38). The FB group included older pts; median age 59(23–75) compared with 51(27–66) years in the FM group (p<0.001). The FB group included more pts with acute leukemia (66% vs 32%) while the FM group included more pts with MM (42% vs 2%, p< 0.0001) and also more pts with a prior autologous SCT (42% vs. 21%, p=0.02). Donor type was not different between the regimens. 93 pts engrafted, 2 died early and 5 had primary graft failure, 3 after FB and 2 after FM (p=NS). The median time to engraftment was not different among groups. NCI grade III–IV organ toxicity occurred in 13 (21%) and 17 pts (45%) after FB and FM, resulting in 4 and 1 deaths, respectively (p=0.04). The cumulative incidence of acute GVHD grade II–IV were 20% and 43% (p=0.004) and the rates of grade III–IV were 6% and 19% (p=0.03), respectively. The cumulative incidence of chronic GVHD was 44%; not different between the regimens. The 1-year non-relapse mortality (NRM) rate was 10% after FB (6 pts; 1 graft failure, 1 organ toxicity, 2 GVHD, 2 infections) and 27% after FM (10 pts; 1 graft failure, 4 organ toxicity, 4 GVHD, 1 infection)(p=0.03). Relapse rate was not statistically different between the regimens; 38% and 50% after FB and FM, respectively (p=NS). With a median follow-up of 28 months (1–80), 58 pts are alive and 42 have died (18 NRM including 2 late events in the FB group, 24 of relapse). 43 FB and 15 FM recipients are alive with an estimated 3-yr survival rate of 59%(95CI, 43–75) and 26%(95CI, 8–44, p=0.007). Disease-free survival rates were 46%(95CI, 31–61) and 28%(95CI, 12–43, P=0.03), respectively. Multivariable analysis determined that FM conditioning was associated with shorter survival (HR, 2.9 (1.2–7.0), p=0.02) while SCT from an unrelated donor was of borderline significance (HR, 1.8 (1.0–3.3), p=0.06). Age, disease type and prior autologous SCT were not predictive of survival in this cohort. In conclusion, there are marked differences in SCT outcomes between RIC regimens that are theoretically equivalent in dose intensity. The FM regimen in the doses used is more toxic. It was associated with higher incidence of NRM due to increased risk of both organ toxicity and acute GVHD. FM offered no advantage in disease control in pts with chemo-sensitive disease, thus reduced toxicity with FB translated into improved survival. These observations merit further study in more homogeneous pt population and in prospective studies.
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Ansah, Iris Baffour, Soo Hyun Lee, ChaeWon Mun, Dong-Ho Kim, and Sung-Gyu Park. "Interior Hotspot Engineering in Ag–Au Bimetallic Nanocomposites by In Situ Galvanic Replacement Reaction for Rapid and Sensitive Surface-Enhanced Raman Spectroscopy Detection." International Journal of Molecular Sciences 23, no. 19 (October 3, 2022): 11741. http://dx.doi.org/10.3390/ijms231911741.
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Engineering of interior hotspots provides a paradigm shift from traditional surface-enhanced Raman spectroscopy (SERS), in which the detection sensitivity depends on the positioning of adsorbed molecules. In the present work, we developed an Ag–Au bimetallic nanocomposite (SGBMNC) SERS platform with interior hotspots through facile chemical syntheses. Ag nanoparticles replaced by Au via the galvanic replacement reaction (GRR) provided hotspot regions inside the SGBMNC that remarkably enhanced the plasmonic activity compared to the conventional SERS platforms without the internal hotspots. The diffusion of analytes into the proposed interior hotspots during the GRR process enabled sensitive detections within 10 s. The SERS behaviors of the SGBMNC platform were investigated using methylene blue (MB) as a Raman probe dye. A quantitative study revealed excellent detection performance, with a limit of detection (LOD) of 42 pM for MB dye and a highly linear correlation between peak intensity and concentration (R2 ≥ 0.91). The SGBMNC platform also enabled the detection of toxic benzyl butyl phthalate with a sufficient LOD of 0.09 ppb (i.e., 280 pM). Therefore, we believe that the proposed methodology can be used for SERS assays of hazardous materials in practical fields.
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Suzumoto, Yoko, Orly Dym, Giovanni N. Roviello, Franz Worek, Joel L. Sussman, and Giuseppe Manco. "Structural and Functional Characterization of New SsoPox Variant Points to the Dimer Interface as a Driver for the Increase in Promiscuous Paraoxonase Activity." International Journal of Molecular Sciences 21, no. 5 (March 1, 2020): 1683. http://dx.doi.org/10.3390/ijms21051683.
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Increasing attention is more and more directed toward the thermostable Phosphotriesterase-Like-Lactonase (PLL) family of enzymes, for the efficient and reliable decontamination of toxic nerve agents. In the present study, the DNA Staggered Extension Process (StEP) technique was utilized to obtain new variants of PLL enzymes. Divergent homologous genes encoding PLL enzymes were utilized as templates for gene recombination and yielded a new variant of SsoPox from Saccharolobus solfataricus. The new mutant, V82L/C258L/I261F/W263A (4Mut) exhibited catalytic efficiency of 1.6 × 105 M−1 s−1 against paraoxon hydrolysis at 70°C, which is more than 3.5-fold and 42-fold improved in comparison with C258L/I261F/W263A (3Mut) and wild type SsoPox, respectively. 4Mut was also tested with chemical warfare nerve agents including tabun, sarin, soman, cyclosarin and VX. In particular, 4Mut showed about 10-fold enhancement in the hydrolysis of tabun and soman with respect to 3Mut. The crystal structure of 4Mut has been solved at the resolution of 2.8 Å. We propose that, reorganization of dimer conformation that led to increased central groove volume and dimer flexibility could be the major determinant for the improvement in hydrolytic activity in the 4Mut.
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Kovel, Ekaterina S., Arina G. Kicheeva, Natalia G. Vnukova, Grigory N. Churilov, Evsei A. Stepin, and Nadezhda S. Kudryasheva. "Toxicity and Antioxidant Activity of Fullerenol C60,70 with Low Number of Oxygen Substituents." International Journal of Molecular Sciences 22, no. 12 (June 15, 2021): 6382. http://dx.doi.org/10.3390/ijms22126382.
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Fullerene is a nanosized carbon structure with potential drug delivery applications. We studied the bioeffects of a water-soluble fullerene derivative, fullerenol, with 10-12 oxygen groups (F10-12); its structure was characterized by IR and XPS spectroscopy. A bioluminescent enzyme system was used to study toxic and antioxidant effects of F10-12 at the enzymatic level. Antioxidant characteristics of F10-12 were revealed in model solutions of organic and inorganic oxidizers. Low-concentration activation of bioluminescence was validated statistically in oxidizer solutions. Toxic and antioxidant characteristics of F10-12 were compared to those of homologous fullerenols with a higher number of oxygen groups:F24-28 and F40-42. No simple dependency was found between the toxic/antioxidant characteristics and the number of oxygen groups on the fullerene’s carbon cage. Lower toxicity and higher antioxidant activity of F24-28 were identified and presumptively attributed to its higher solubility. An active role of reactive oxygen species (ROS) in the bioeffects of F10-12 was demonstrated. Correlations between toxic/antioxidant characteristics of F10-12 and ROS content were evaluated. Toxic and antioxidant effects were related to the decrease in ROS content in the enzyme solutions. Our results reveal a complexity of ROS effects in the enzymatic assay system.
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Guerra, Carlos, Sarvesh Kumar, Fernando Aguilar-Galindo, Sergio Díaz-Tendero, Ana I. Lozano, Mónica Mendes, Juan C. Oller, Paulo Limão-Vieira, and Gustavo García. "Total Electron Detachment and Induced Cationic Fragmentation Cross Sections for Superoxide Anion (O2−) Collisions with Benzene (C6H6) Molecules." International Journal of Molecular Sciences 23, no. 3 (January 23, 2022): 1266. http://dx.doi.org/10.3390/ijms23031266.
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In this study, novel experimental total electron detachment cross sections for O2− collisions with benzene molecules are reported for the impact energy range (10–1000 eV), as measured with a transmission beam apparatus. By analysing the positively charged species produced during the collision events, relative total ionisation cross sections were derived in the incident energy range of 160–900 eV. Relative partial ionisation cross sections for fragments with m/z ≤ 78 u were also given in this energy range. We also confirmed that heavier compounds (m/z > 78 u) formed for impact energies between 550 and 800 eV. In order to further our knowledge about the collision dynamics governing the fragmentation of such heavier molecular compounds, we performed molecular dynamics calculations within the framework of the Density Functional Theory (DFT). These results demonstrated that the fragmentation of these heavier compounds strongly supports the experimental evidence of m/z = 39–42, 50, 60 (u) cations formation, which contributed to the broad local maximum in the total ionisation observed from 550 to 800 eV. This work reveals the reactivity induced by molecular anions colliding with hydrocarbons at high energies, processes that can take place in the interstellar medium under various local conditions.
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Parmar, Rajni, Federica Cattonaro, Carrie Phillips, Serguei Vassiliev, Michele Morgante, and Om P. Rajora. "Assembly and Annotation of Red Spruce (Picea rubens) Chloroplast Genome, Identification of Simple Sequence Repeats, and Phylogenetic Analysis in Picea." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15243. http://dx.doi.org/10.3390/ijms232315243.
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We have sequenced the chloroplast genome of red spruce (Picea rubens) for the first time using the single-end, short-reads (44 bp) Illumina sequences, assembled and functionally annotated it, and identified simple sequence repeats (SSRs). The contigs were assembled using SOAPdenovo2 following the retrieval of chloroplast genome sequences using the black spruce (Picea mariana) chloroplast genome as the reference. The assembled genome length was 122,115 bp (gaps included). Comparatively, the P. rubens chloroplast genome reported here may be considered a near-complete draft. Global genome alignment and phylogenetic analysis based on the whole chloroplast genome sequences of Picea rubens and 10 other Picea species revealed high sequence synteny and conservation among 11 Picea species and phylogenetic relationships consistent with their known classical interrelationships and published molecular phylogeny. The P. rubens chloroplast genome sequence showed the highest similarity with that of P. mariana and the lowest with that of P. sitchensis. We have annotated 107 genes including 69 protein-coding genes, 28 tRNAs, 4 rRNAs, few pseudogenes, identified 42 SSRs, and successfully designed primers for 26 SSRs. Mononucleotide A/T repeats were the most common followed by dinucleotide AT repeats. A similar pattern of microsatellite repeats occurrence was found in the chloroplast genomes of 11 Picea species.
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Ullah, S., D. F. Shams, S. A. Ur Rehman, S. A. Khattak, M. Noman, G. Rukh, H. Bibi, et al. "Application of visible light activated thiolated cobalt doped ZnO nanoparticles towards arsenic removal from aqueous systems." Digest Journal of Nanomaterials and Biostructures 17, no. 2 (April 2022): 443–55. http://dx.doi.org/10.15251/djnb.2022.172.443.
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Populations at large are exposed towards Arsenic (As) contamination in water worldwide making it unfit for drinking and human consumption. This study was designed to assess As removal efficiency of newly developed thiolated chitosan cobalt-doped zinc oxide (CoZnO) nanoparticles (NP) under visible light spectrum. In this study the Co-ZnO NP of various sizes (40–60 nm) were prepared through the co-precipitation method. Removal of As with Co-ZnO NP was investigated in batch tests experiments alongside determining the optimal dose of NP, kinetic rates, effect of light, pH and ultra-sonication. This was followed by a continuous flow test with Co-ZnO layered on Whatman® grade 42 filter paper. Overall, the Co-ZnO NP effectively treated As i.e. in sunlight (100%), neutral pH (100%), ultra-sonication (100%) and in continuous-flow system (100%). The removal of As was maximum (88%) at NP:As ratio of < 1:5 and minimum (25%) at 1:100. Similarly, darkness (21.4%) and (11.1%) uptake at low and high pH respectively. It was found that Co-ZnO NP can efficiently reduce As to non-toxic state i.e. below the WHO permissible limit of (10 µg/L) in drinking water.
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Valiente-Soriano, Francisco J., Johnny Di Pierdomenico, Diego García-Ayuso, Arturo Ortín-Martínez, Juan A. Miralles de Imperial-Ollero, Alejandro Gallego-Ortega, Manuel Jiménez-López, M. Paz Villegas-Pérez, S. Patricia Becerra, and Manuel Vidal-Sanz. "Pigment Epithelium-Derived Factor (PEDF) Fragments Prevent Mouse Cone Photoreceptor Cell Loss Induced by Focal Phototoxicity In Vivo." International Journal of Molecular Sciences 21, no. 19 (September 30, 2020): 7242. http://dx.doi.org/10.3390/ijms21197242.
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Here, we evaluated the effects of PEDF (pigment epithelium-derived factor) and PEDF peptides on cone-photoreceptor cell damage in a mouse model of focal LED-induced phototoxicity (LIP) in vivo. Swiss mice were dark-adapted overnight, anesthetized, and their left eyes were exposed to a blue LED placed over the cornea. Immediately after, intravitreal injection of PEDF, PEDF-peptide fragments 17-mer, 17-mer[H105A] or 17-mer[R99A] (all at 10 pmol) were administered into the left eye of each animal. BDNF (92 pmol) and bFGF (27 pmol) injections were positive controls, and vehicle negative control. After 7 days, LIP resulted in a consistent circular lesion located in the supratemporal quadrant and the number of S-cones were counted within an area centered on the lesion. Retinas treated with effectors had significantly greater S-cone numbers (PEDF (60%), 17-mer (56%), 17-mer [H105A] (57%), BDNF (64%) or bFGF (60%)) relative to their corresponding vehicle groups (≈42%). The 17-mer[R99A] with no PEDF receptor binding and no neurotrophic activity, PEDF combined with a molar excess of the PEDF receptor blocker P1 peptide, or with a PEDF-R enzymatic inhibitor had undetectable effects in S-cone survival. The findings demonstrated that the cone survival effects were mediated via interactions between the 17-mer region of the PEDF molecule and its PEDF-R receptor.
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Supramaniam, Janarthanan, Darren Yi Sern Low, See Kiat Wong, Loh Teng Hern Tan, Bey Fen Leo, Bey Hing Goh, Dazylah Darji, et al. "Facile Synthesis and Characterization of Palm CNF-ZnO Nanocomposites with Antibacterial and Reinforcing Properties." International Journal of Molecular Sciences 22, no. 11 (May 28, 2021): 5781. http://dx.doi.org/10.3390/ijms22115781.
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Cellulose nanofibers (CNF) isolated from plant biomass have attracted considerable interests in polymer engineering. The limitations associated with CNF-based nanocomposites are often linked to the time-consuming preparation methods and lack of desired surface functionalities. Herein, we demonstrate the feasibility of preparing a multifunctional CNF-zinc oxide (CNF-ZnO) nanocomposite with dual antibacterial and reinforcing properties via a facile and efficient ultrasound route. We characterized and examined the antibacterial and mechanical reinforcement performances of our ultrasonically induced nanocomposite. Based on our electron microscopy analyses, the ZnO deposited onto the nanofibrous network had a flake-like morphology with particle sizes ranging between 21 to 34 nm. pH levels between 8–10 led to the formation of ultrafine ZnO particles with a uniform size distribution. The resultant CNF-ZnO composite showed improved thermal stability compared to pure CNF. The composite showed potent inhibitory activities against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative Salmonella typhi (S. typhi) bacteria. A CNF-ZnO-reinforced natural rubber (NR/CNF-ZnO) composite film, which was produced via latex mixing and casting methods, exhibited up to 42% improvement in tensile strength compared with the neat NR. The findings of this study suggest that ultrasonically-synthesized palm CNF-ZnO nanocomposites could find potential applications in the biomedical field and in the development of high strength rubber composites.
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Osae, Eugene A., Tiffany Bullock, Madhavi Chintapalati, Susanne Brodesser, Samuel Hanlon, Rachel Redfern, Philipp Steven, C. Wayne Smith, Rolando E. Rumbaut, and Alan R. Burns. "Obese Mice with Dyslipidemia Exhibit Meibomian Gland Hypertrophy and Alterations in Meibum Composition and Aqueous Tear Production." International Journal of Molecular Sciences 21, no. 22 (November 20, 2020): 8772. http://dx.doi.org/10.3390/ijms21228772.
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Background: Dyslipidemia may be linked to meibomian gland dysfunction (MGD) and altered meibum lipid composition. The purpose was to determine if plasma and meibum cholesteryl esters (CE), triglycerides (TG), ceramides (Cer) and sphingomyelins (SM) change in a mouse model of diet-induced obesity where mice develop dyslipidemia. Methods: Male C57/BL6 mice (8/group, age = 6 wks) were fed a normal (ND; 15% kcal fat) or an obesogenic high-fat diet (HFD; 42% kcal fat) for 10 wks. Tear production was measured and meibography was performed. Body and epididymal adipose tissue (eAT) weights were determined. Nano-ESI-MS/MS and LC-ESI-MS/MS were used to detect CE, TG, Cer and SM species. Data were analyzed by principal component analysis, Pearson’s correlation and unpaired t-tests adjusted for multiple comparisons; significance set at p ≤ 0.05. Results: Compared to ND mice, HFD mice gained more weight and showed heavier eAT and dyslipidemia with higher levels of plasma CE, TG, Cer and SM. HFD mice had hypertrophic meibomian glands, increased levels of lipid species acylated by saturated fatty acids in plasma and meibum and excessive tear production. Conclusions: The majority of meibum lipid species with saturated fatty acids increased with HFD feeding with evidence of meibomian gland hypertrophy and excessive tearing. The dyslipidemia is associated with altered meibum composition, a key feature of MGD.
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Myers, Meagan, Karen McKim, Malathi Banda, Nysia George, and Barbara Parsons. "Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology." International Journal of Molecular Sciences 20, no. 5 (February 26, 2019): 1011. http://dx.doi.org/10.3390/ijms20051011.
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Information regarding the role of low-frequency hotspot cancer-driver mutations (CDMs) in breast carcinogenesis and therapeutic response is limited. Using the sensitive and quantitative Allele-specific Competitor Blocker PCR (ACB-PCR) approach, mutant fractions (MFs) of six CDMs (PIK3CA H1047R and E545K, KRAS G12D and G12V, HRAS G12D, and BRAF V600E) were quantified in invasive ductal carcinomas (IDCs; including ~20 samples per subtype). Measurable levels (i.e., ≥ 1 × 10−5, the lowest ACB-PCR standard employed) of the PIK3CA H1047R, PIK3CA E545K, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E mutations were observed in 34/81 (42%), 29/81 (36%), 51/81 (63%), 9/81 (11%), 70/81 (86%), and 48/81 (59%) of IDCs, respectively. Correlation analysis using available clinicopathological information revealed that PIK3CA H1047R and BRAF V600E MFs correlate positively with maximum tumor dimension. Analysis of IDC subtypes revealed minor mutant subpopulations of critical genes in the MAP kinase pathway (KRAS, HRAS, and BRAF) were prevalent across IDC subtypes. Few triple-negative breast cancers (TNBCs) had appreciable levels of PIK3CA mutation, suggesting that individuals with TNBC may be less responsive to inhibitors of the PI3K/AKT/mTOR pathway. These results suggest that low-frequency hotspot CDMs contribute significantly to the intertumoral and intratumoral genetic heterogeneity of IDCs, which has the potential to impact precision oncology approaches.
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Malik, Afshan N., Hannah S. Rosa, Eliane S. de Menezes, Priyanka Tamang, Zaidi Hamid, Anita Naik, Chandani Kiran Parsade, and Sobha Sivaprasad. "The Detection and Partial Localisation of Heteroplasmic Mutations in the Mitochondrial Genome of Patients with Diabetic Retinopathy." International Journal of Molecular Sciences 20, no. 24 (December 11, 2019): 6259. http://dx.doi.org/10.3390/ijms20246259.
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Diabetic retinopathy (DR) is a common complication of diabetes and a major cause of acquired blindness in adults. Mitochondria are cellular organelles involved in energy production which contain mitochondrial DNA (mtDNA). We previously showed that levels of circulating mtDNA were dysregulated in DR patients, and there was some evidence of mtDNA damage. In the current project, our aim was to confirm the presence of, and determine the location and prevalence of, mtDNA mutation in DR. DNA isolated from peripheral blood from diabetes patients (n = 59) with and without DR was used to amplify specific mtDNA regions which were digested with surveyor nuclease S1 to determine the presence and location of heteroplasmic mtDNA mutations were present. An initial screen of the entire mtDNA genome of 6 DR patients detected a higher prevalence of mutations in amplicon P, covering nucleotides 14,443 to 1066 and spanning the control region. Further analysis of 42 subjects showed the presence of putative mutations in amplicon P in 36% (14/39) of DR subjects and in 10% (2/20) non-DR subjects. The prevalence of mutations in DR was not related to the severity of the disease. The detection of a high-prevalence of putative mtDNA mutations within a specific region of the mitochondrial genome supports the view that mtDNA damage contributes to DR. The exact location and functional impact of these mutations remains to be determined.
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Derenzini, Enrico, Cinzia Pellegrini, Roberto Maglie, Vittorio Stefoni, Alessandro Broccoli, Letizia Gandolfi, Beatrice Casadei, et al. "Collection of Hematopoietic Stem Cells After Previous Exposure to Ittrium-90 Ibritumumab Tiuxetan (Zevalin) Is Feasible and Does Not Impair Autologous Stem Cell Transplantation Outcome in Follicular Lymphoma." Blood 120, no. 21 (November 16, 2012): 3019. http://dx.doi.org/10.1182/blood.v120.21.3019.3019.
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Abstract Abstract 3019 Background: Radioimmunotherapy (RIT) is an effective and manageable treatment option for those patients (pts) affected by follicular B-cell lymphoma (FL) who experience disease relapse. The results of RIT in the setting of first line consolidation are also very promising in terms of progression free and overall survival. On the other hand autologous stem cell transplantation (ASCT) is a suitable treatment option for relapsed FL patients. Although major concerns about the widespread use of RIT early in the disease course are the long term hematologic toxicity and the theoretical possible irreparable damage to bone marrow function with impairment of peripheral stem cell harvest, very few data are available about mobilization rates after Zevalin exposure. Methods: The aim of this monocentric study was to analyze the impact of prior Zevalin administration on peripheral blood stem cells (PBSC) mobilization and on the outcome of subsequent ASCT. Moreover the impact of different prior treatment regimens [Cyclophosphamide, Doxorubicin, Vincristine, Prednisone plus Rituximab (R-CHOP) or CHOP-like regimens vs Fludarabine, Mitoxantrone plus Rituximab (FM-R) vs Zevalin] and number of previous lines of therapy given earlier in the disease course, was prospectively evaluated in all FL patients (n=100) who underwent stem cell mobilization from January 2005 to March 2012. Results: At the time of mobilization, 68 pts had received R-CHOP or CHOP-like regimens, 20 pts FM-R, 12 pts RIT with Zevalin earlier in the disease course. Characteristics of pts such as age, weight and number of prior therapies, were well balanced in the 3 groups. Sixty one pts had received one prior therapy, 31 pts 2 therapies, 8 pts ≥ 3 lines of therapy. All pts received chemotherapy plus granulocyte colony stimulating factor (G-CSF) 5 μg/kg (n=94) or G-CSF alone (10 μg/kg) (n=6) as mobilization regimen. Mean CD34+ cells yield was 8.9 × 106/kg in the CHOP group, vs 5.8 × 106 CD34 + cells/kg in the FM-R group, vs 2.7 × 106 CD34 + cells/kg in the Zevalin group (p=0.05 CHOP vs FM-R; p<0.001 CHOP vs Zevalin; p<0.01 FM-R vs Zevalin; t test). The collection yield of 2.0 × 106 CD34 + cells/kg was reached in 98% (n=67) of pts in the CHOP group, vs 80% (n=16) in the FM-R group, vs 42% (n=5) in the Zevalin group. The number of previous treatments did not significantly affect PBSC harvest (1 vs 2 lines: p=0.1; 1 vs 3 lines: p=0.1; 2 vs 3 lines: p=0.3). Regarding the engraftment no differences were noted between the 3 groups and the median time to neutrophils (> 1000/μL) and platelets recovery (>20000/μL) was 10 and 11 days in all groups respectively. Only one pt in the CHOP group and one in the FM-R group did not undergo ASCT because of insufficient CD34+ harvest. Considering the Zevalin group (n=12), median age was 51 years (range 36–66). Seven pts received Zevalin as first line consolidation, 5 patients at disease relapse. Median number of prior therapies was 2 (range 1–4). Ten pts received chemotherapy plus G-CSF as initial mobilization regimen, 2 pts received G-CSF alone. Median time from RIT to mobilization was 13 months (4–60 months). Five pts (42%) reached the collection yield of > 2.0 × 106 CD34 + cells/kg with the first mobilization attempt. Considering the remaining 7 pts who failed (CD34+ cells below 10/mL before apheresis, or cell harvest below 2.0 × 106 CD34 + cells/kg), a surgical procedure was attempted in 4 pts, G-CSF + Plerixafor (240 μg/kg) in 3 pts. Remarkably the second harvest allowed 5 additional pts (3 pts after surgery, 2 pts after G-CSF + Plerixafor) to undergo ASCT. Finally ASCT was succesfully performed in 9 pts (75%). Median number of reinfused CD34+ cells was 2.3 × 106 CD34 + cells/kg (0.4–4.2). Three pts did not undergo ASCT, one because of disease progression, 2 pts because of insufficient CD34+ harvest. Conclusions: The type of previous therapy may significantly influence the mobilization rate in FL pts. Although mobilization was significantly impaired in pts previously treated with Zevalin compared to other chemotherapy regimens, stem cell harvest after RIT was feasible and the vast majority of patients retained the possibility to undergo ASCT with a second stem cell harvest, with no significant impact on engraftment. The use of Plerixafor seems to be particularly promising for those patients previously exposed to RIT who failed the first mobilization. Disclosures: No relevant conflicts of interest to declare.
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DeZern, Amy E., Michelle Petri, Douglas Kerr, Daniel Drachman, Adam Kaplin, Charles Hesdorffer, Grant Anhalt, Fredrick Wigley, Richard J. Jones, and Robert Brodsky. "High Dose Cyclophosphamide (HD CY) without Hematopoietic Stem Cell Transplantation (HSCT) in Refractory Severe Autoimmune Diseases: 11 Year Experience in Over 100 Patients." Blood 114, no. 22 (November 20, 2009): 3412. http://dx.doi.org/10.1182/blood.v114.22.3412.3412.
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Abstract Abstract 3412 Poster Board III-300 Introduction High-dose cyclophosphamide (HD CY) is a potent immunosuppressive agent that is used as conditioning for HSCT in most patients with both hematologic malignancies and autoimmune diseases. HD CY is highly toxic to lymphocytes, but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase (the primary mechanism of CY inactivation). We and others have shown that HD CY without stem cell support can induce durable remissions in a variety of severe autoimmune diseases. Here, we report the long term follow-up of 124 patients with a variety of severe autoimmune diseases treated with HD CY. Methods From August 1996 through August 2008, 124 consecutive patients with severe, refractory autoimmune diseases (excluding acquired severe aplastic anemia) were treated with HD CY (50mg/kg/d) for 4 consecutive days without HSCT. Six days after the last dose of CY, all patients received granulocyte colony stimulating factor (5 μg/kg/day) until the neutrophil count exceeded 0.5 × 109/liter. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose or administration of a new immunosuppressive medication. Results The most common diseases treated with HD CY included lupus (n=42), multiple sclerosis (MS, n=32), myasthenia gravis (n=14) scleroderma (SSC, n=10), autoimmune hemolytic anemia (n=9) and pemphigus (n=9). The median follow up is 47 (range 1-127) months. All patients experienced rapid hematopoietic recovery: an absolute neutrophil count (ANC) > 500/μL was achieved at a median of 13 (range 8-22) days after the last dose CY and the median duration of an ANC < 500/μL was 9 (range 4-23) days. The median time to last platelet transfusion after completion of CY was 13 (range 0-33) days and the median time to last packed red blood cell transfusion was 12 (range 0-24) days. The median number of PRBC transfusions was 2 (range 0-27) and the median number of platelet transfusions was 2 (range 0-18.) The overall treatment related mortality was 0.8% with the lone death occurring in a non-neutropenic SSC patient on day 51 after HD CY. Median number of hospitalized days was 4 (range 0-55) days. The overall response rate was 94% with 42% of responders maintaining a durable response at the time of analysis. Durability of response seemed to vary according to the underlying disease and/or disease severity. The actuarial event-free survival (EFS) at 60 months is 10.6% for SLE, 31% for MS, 42.1% for MG, 50% for AIHA, 33% for pemphigus, and 25% for the other diseases. Interestingly, disease activity improved from pre-HD CY in virtually all patients even at the time of relapse, as many patients became responsive to immunosuppressive agents that were previously ineffective in controlling their disease. Discussion HD CY with or without HSCT has a potent disease modifying effect in wide variety of autoimmune disorders. These data suggest that eliminating HSCT after HD CY maintains both its efficacy and safety. The duration of cytopenias compares favorably with HSCT, especially when factoring in the mobilization phase of HSCT. Furthermore, eliminating mobilization and HSCT may have at least theoretical advantages in that the overall duration of the procedure is shortened, any toxicity associated with mobilization is avoided, and the potential of reinfusing autoreactive lymphocytes with the autograft is averted. Disclosures Jones: Accentia: Patents & Royalties. Brodsky:Accentia: Patents & Royalties.
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Xu, Xiaorong, Yufeng Xiao, Ximin Zhang, Ming Tang, and Jing Tang. "Identification and Characterization of Circular RNAs Involved in the Flower Development and Senescence of Rhododendron delavayi Franch." International Journal of Molecular Sciences 23, no. 19 (September 23, 2022): 11214. http://dx.doi.org/10.3390/ijms231911214.
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Floral development and senescence are a crucial determinant for economic and ornamental value. CircRNAs play an essential role in regulating plant growth and development; however, there is no systematic identification of circRNAs during the lifespan of flowers. This study aims to explore the expression profile and functional role of circRNAs in the full flowering stages of Rhododendron delavayi Franch. We carried out transcriptome sequencing of the six stages of Rhododendron delavayi Franch flowers to identify the circular RNA expression profile. In addition, using bioinformatics methods, we explored the functions of circRNAs, including analysis of the circRNA-miRNA-mRNA network, short time-series expression miner (STEM), and so on. We identified 146 circRNAs, of which 79 were differentially expressed from the budding to fading stages. Furthermore, using STEM analysis, one of the 42 circRNA expression model profiles was significantly upregulated during the senescence stage, including 16 circRNAs. Additionally, 7 circRNA-miRNA-mRNA networks were constructed with 10 differentially expressed circRNAs, in which some target mRNA may regulate the development and senescence of the Rhododendron flowers. Finally, by analyzing the correlation between circRNAs and mRNA, combined with existing reports, we proposed that circRNAs play a regulatory role during flower development and senescence by mediating the jasmonate signaling pathway. Overall, these results provide new clues to the potential mechanism of circRNAs acting as novel post-transcriptional regulators in the development and senescence process of flowers.
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Kovács, Terézia, Mohamed Ahres, Tamás Pálmai, László Kovács, Matsuo Uemura, Cristina Crosatti, and Gabor Galiba. "Decreased R:FR Ratio in Incident White Light Affects the Composition of Barley Leaf Lipidome and Freezing Tolerance in a Temperature-Dependent Manner." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7557. http://dx.doi.org/10.3390/ijms21207557.
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In cereals, C-repeat binding factor genes have been defined as key components of the light quality-dependent regulation of frost tolerance by integrating phytochrome-mediated light and temperature signals. This study elucidates the differences in the lipid composition of barley leaves illuminated with white light or white light supplemented with far-red light at 5 or 15 °C. According to LC-MS analysis, far-red light supplementation increased the amount of monogalactosyldiacylglycerol species 36:6, 36:5, and 36:4 after 1 day at 5 °C, and 10 days at 15 °C resulted in a perturbed content of 38:6 species. Changes were observed in the levels of phosphatidylethanolamine, and phosphatidylserine under white light supplemented with far-red light illumination at 15 °C, whereas robust changes were observed in the amount of several phosphatidylserine species at 5 °C. At 15 °C, the amount of some phosphatidylglycerol species increased as a result of white light supplemented with far-red light illumination after 1 day. The ceramide (42:2)-3 content increased regardless of the temperature. The double-bond index of phosphatidylglycerol, phosphatidylserine, phosphatidylcholine ceramide together with total double-bond index changed when the plant was grown at 15 °C as a function of white light supplemented with far-red light. white light supplemented with far-red light increased the monogalactosyldiacylglycerol/diacylglycerol ratio as well. The gene expression changes are well correlated with the alterations in the lipidome.
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Culenova, Martina, Andreas Nicodemou, Zuzana Varchulova Novakova, Michaela Debreova, Veronika Smolinská, Sona Bernatova, Dana Ivanisova, et al. "Isolation, Culture and Comprehensive Characterization of Biological Properties of Human Urine-Derived Stem Cells." International Journal of Molecular Sciences 22, no. 22 (November 19, 2021): 12503. http://dx.doi.org/10.3390/ijms222212503.
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Mesenchymal stem cells (MSCs) represent an attractive source within the field of tissue engineering. However, their harvesting often requires invasive medical procedures. Urine-derived stem cells (UDSCs) display similar properties to MSCs, and their obtention and further processing is non-invasive for the donors as well as low cost. Here, we offer a comprehensive analysis of their biological properties. The goal of this study was to analyze their morphology, stemness, differentiation potential and cytokine profile. We have successfully isolated UDSCs from 25 urine samples. First colonies emerged up to 9 days after the initial seeding. Cell doubling time was 45 ± 0.24 SD, and when seeded at the density of 100 cells/cm2, they formed 42 ± 6.5 SD colonies within 10 days. Morphological analyzes revealed that two different types of the cell populations have been present. The first type had a rice-grain shape and the second one was characterized by a polyhedral shape. In several cell cultures, dome-shaped cells were observed as well. All examined UDSCs expressed typical MSC-like surface markers, CD73, CD90 and CD105. Moreover, conditioned media from UDSCs were harvested, and cytokine profile has been evaluated showing a significantly higher secretory rate of IL-8, IL-6 and chemokines MCP-1 and GM-CSF. We have also successfully induced human UDSCs into chondrogenic, osteogenic and myogenic cell lineages. Our findings indicate that UDSCs might have immense potential in the regeneration of the damaged tissues.
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Cacabelos, Ramon. "Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia." International Journal of Molecular Sciences 21, no. 9 (April 26, 2020): 3059. http://dx.doi.org/10.3390/ijms21093059.
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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
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Osawa, Leona, Nobuharu Tamaki, Masayuki Kurosaki, Sakura Kirino, Keiya Watakabe, Wan Wang, Mao Okada, et al. "Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein but not α-fetoprotein as a Long-Term Hepatocellular Carcinoma Predictor." International Journal of Molecular Sciences 21, no. 10 (May 21, 2020): 3640. http://dx.doi.org/10.3390/ijms21103640.
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Identification of high-risk patients for hepatocellular carcinoma (HCC) after sustained virological responses (SVR) is necessary to define candidates for long-term surveillance. In this study, we examined whether serum markers after 1 year of SVR could predict subsequent HCC development. Total 734 chronic hepatitis C patients without a history of HCC who achieved SVR with direct-acting antivirals were included. The regular surveillance for HCC started from 24 weeks after the end of treatment (SVR24). Factors at SVR24 and 1 year after SVR24 were analyzed for predicting HCC development. During the mean observation period of 19.7 ± 10 months, 24 patients developed HCC. At SVR24, Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA±M2BP) ≥ 1.85 and α-fetoprotein (AFP) ≥ 6.0 ng/mL were independent factors of HCC development. However, at 1 year after SVR24, WFA±M2BP ≥ 1.85 was associated with subsequent HCC development (hazard ratio: 23.5, 95% confidence interval: 2.68–205) but not AFP. Among patients with WFA±M2BP ≥ 1.85 at SVR24, 42% had WFA±M2BP < 1.85 at 1 year after SVR24 (WFA±M2BP declined group). Subsequent HCC development was significantly lower in the declined group than in the non-declined group (1 year HCC rate: 0% vs. 9.4%, p = 0.04). In conclusion, WFA±M2BP but not AFP could identify high and no-risk cases of HCC at 1 year after SVR. Therefore, it was useful as a real-time monitoring tool to identify the candidates for continuous surveillance for HCC.
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Harman, David Brendan, and Peter R. Johnston. "Using the stochastic Galerkin method as a predictive tool during an epidemic." ANZIAM Journal 59 (July 25, 2019): C301—C317. http://dx.doi.org/10.21914/anziamj.v59i0.12654.
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The ability to accurately predict the course of an epidemic is extremely important. This article looks at an influenza outbreak that spread through a small boarding school. Predictions are made on multiple days throughout the epidemic using the stochastic Galerkin method to consider a range of plausible values for the parameters. These predictions are then compared to known data points. Predictions made before the peak of the epidemic had much larger variances compared to predictions made after the peak of the epidemic.
References B. M. Chen-Charpentier, J. C. Cortes, J. V. Romero, and M. D. Rosello. Some recommendations for applying gPC (generalized polynomial chaos) to modeling: An analysis through the Airy random differential equation. Applied Mathematics and Computation, 219(9):4208 4218, 2013. doi:10.1016/j.amc.2012.11.007 B. M. Chen-Charpentier and D. Stanescu. Epidemic models with random coefficients. Mathematical and Computer Modelling, 52:1004 1010, 2010. doi:10.1016/j.mcm.2010.01.014 D. B. Harman and P. R. Johnston. Applying the stochastic galerkin method to epidemic models with individualised parameter distributions. In Proceedings of the 12th Biennial Engineering Mathematics and Applications Conference, EMAC-2015, volume 57 of ANZIAM J., pages C160C176, August 2016. doi:10.21914/anziamj.v57i0.10394 D. B. Harman and P. R. Johnston. Applying the stochastic galerkin method to epidemic models with uncertainty in the parameters. Mathematical Biosciences, 277:25 37, 2016. doi:10.1016/j.mbs.2016.03.012 D. B. Harman and P. R. Johnston. Boarding house: find border. 2019. doi:10.6084/m9.figshare.7699844.v1 D. B. Harman and P. R. Johnston. SIR uniform equations. 2 2019. doi:10.6084/m9.figshare.7692392.v1 H. W. Hethcote. The mathematics of infectious diseases. SIAM Review, 42(4):599653, 2000. doi:10.1137/S0036144500371907 R.I. Hickson and M.G. Roberts. How population heterogeneity in susceptibility and infectivity influences epidemic dynamics. Journal of Theoretical Biology, 350(0):70 80, 2014. doi:10.1016/j.jtbi.2014.01.014 W. O. Kermack and A. G. McKendrick. A contribution to the mathematical theory of epidemics. Proceedings of the Royal Society of London. Series A, 115(772):700721, August 1927. doi:10.1098/rspa.1927.0118 M. G. Roberts. A two-strain epidemic model with uncertainty in the interaction. The ANZIAM Journal, 54:108115, 10 2012. doi:10.1017/S1446181112000326 M. G. Roberts. Epidemic models with uncertainty in the reproduction number. Journal of Mathematical Biology, 66(7):14631474, 2013. doi:10.1007/s00285-012-0540-y F. Santonja and B. Chen-Charpentier. Uncertainty quantification in simulations of epidemics using polynomial chaos. Computational and Mathematical Methods in Medicine, 2012:742086, 2012. doi:10.1155/2012/742086 Communicable Disease Surveillance Centre (Public Health Laboratory Service) and Communicable Diseases (Scotland) Unit. Influenza in a boarding school. BMJ, 1(6112):587, 1978. doi:10.1136/bmj.1.6112.586 G. Strang. Linear Algebra and Its Applications. Thomson, Brooks/Cole, 2006. D. Xiu. Numerical Methods for Stochastic Computations: A Spectral Method Approach. Princeton University Press, 2010.
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Bélanger, Sophie Savary, Shi Hann Su, Sylvie Bélanger, Brigitte Lefebvre, Valéry Lavergne, Sandra Cohen, and Annie-Claude Labbé. "Pneumococcal Bacteremia Among Patients with Hematological Malignancies: Clinical Impact, Serotype Distribution and Antibiotic Resistance Profile in Tertiary-Care Centers." Blood 120, no. 21 (November 16, 2012): 2067. http://dx.doi.org/10.1182/blood.v120.21.2067.2067.
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Abstract Abstract 2067 Background: Pneumococcal invasive infections are over 13 times more common among patients with hematological malignancies than in the general population. Hematopoietic stem cell transplant (HSCT) recipients, particularly those with chronic graft-versus-host disease (cGvHD), are especially vulnerable. Two types of vaccines are available for prevention: pneumococcal polysaccharide vaccine (PPSV) and pneumococcal conjugate vaccine (PCV). PPSV covers more serotypes, but concerns have been raised over immune response, particularly in immunocompromised patients. The primary goals of this study were to evaluate clinical impact of pneumococcal bacteremia, serotypes involved and resistance profile in our hematological population. Methods: We performed a retrospective study based at Hôpital Maisonneuve-Rosemont and Hôpital Notre-Dame du CHUM, both in Montreal, Canada. Among all positive blood cultures for Streptococcus pneumoniae between January 1st, 2003 and December 31st, 2011, we selected patients with hematological malignancies. We reviewed patients' charts and electronic files. Serotypes and antibiotic susceptibility testing were done by the Laboratoire de Santé Publique du Québec. The study was approved by the hospitals' ethics committee. Results: During the eight-year period, 54 episodes of pneumococcal bacteremia (in 52 patients) occurred among patients with hematological malignancies. Median age was 63.5 years (range 21 to 91); 44% were female. One patient was splenectomized. The main hematological malignancies were multiple myeloma (42%) and non-Hodgkin lymphoma (29%). There were 16 HSCT recipients: 10 allogeneic (8 with cGVHD) and 6 autologous. Twenty-nine patients (55%) were on chemotherapy, including 10 HSCT recipients. Among the patients with cGVHD, 3 were on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis and 1 on pentamidine. At the time of the bacteremia, 81% of patients had a diagnosis of pneumonia (mean Fine score 118. Eleven patients were treated in the emergency department or in the outpatient clinic. Among the 43 hospitalized patients (80%), median hospitalization duration was 10 days. Intensive care unit admission was required for 9 episodes (17%). Eight patients died less than 30 days after the diagnosis of bacteremia, leading to a mortality rate of 15% and 19% among HSCT recipients. Vaccine history was not available in most patients' charts. However, all HSCT recipients should have received PPSV, as recommended in our institution. Twenty-four different serotypes were found. Theoretical coverage of these serotypes by the available vaccines was 26% for PCV-7, 35% for PCV-10, 50% for PCV-13, and 61% by PPSV; 33% episodes were not covered by any vaccine. Among patients with HSCT, the percentage of episodes not covered by any vaccine increased to 44%. PPSV covered 56% of episodes. Resistance to TMP-SMX was found in 17% of isolates. However, since 2006, all were susceptible. A third of isolates were resistant to erythromycin; the proportion of resistant isolates was higher among HSCT patients (50%). Only one isolate was resistant to fluoroquinolones, but was sensitive to all other antibiotics tested. One strain was of intermediate sensitivity to ceftriaxone, and was resistant to erythromycin and TMP-SMX. This patient was on TMP-SMX prophylaxis, and did not require admission. All strains were sensitive to penicillin and vancomycin. Conclusion: Pneumococcal bacteremia carries significant morbidity and mortality in patients with hematologic malignancies. Our mortality rate is similar to that found in other studies. Vaccination remains the cornerstone of prevention, but is imperfect in terms of immune response and coverage. One third of episodes were not covered by any available vaccine, and this proportion increased among HSCT recipients. Antibacterial prophylaxis in patients with cGVHD is therefore important and penicillin remains a good choice. In terms of treatment options for respiratory infection, given the high erythromycin resistance rate (34% vs. 20–25% found in the general population), macrolides should not be used as single agents. Third generation cephalosporins and fluoroquinolone resistance is very low, making it an interesting choices for respiratory infections. Disclosures: Labbé: Pfizer: Research Funding.
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Lior, O., I. Sergeev, N. Ruhimovich, M. Openheim, F. Benjaminov, D. Feldman, Y. Ringel, and T. Naftali. "P525 Patients’ Perception of Risks of biologic therapy During Covid-19 Pandemic in Israel Orly Lior, Ilia Sergeev, Nahum Ruhimovich, Michal Openheim, Fabiana Benjaminov, Dan Feldman, Yehuda Ringel, Timna Naftali Division of Gastroenterology and Liver Diseases, Meir Medical Center, Kfar Saba, Israel." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S501. http://dx.doi.org/10.1093/ecco-jcc/jjab076.647.
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Abstract Background Current inflammatory bowel disease (IBD) therapies are highly effective. However, compliance with treatment is influenced by patients’ perception of benefits versus risks. Understanding these perceptions and their influence on patients’ treatment decision-making is crucial for achieving compliance, especially during Covid-19 pandemic. Aim: to assess patients’ perception of risks of IBD exacerbation and SARS-CoV-2 infection, and their influence on patients’ decisions regarding biologic and immunosuppressive treatments during Covid-19 pandemic in Israel. Methods A prospective internet-based survey among Meir Medical Center, IBD clinic patients. Results 116 patients have responded. Mean age 42 (18–84), 44 (38%) males, 75 (64%) Crohn’s disease, 38 (32%) ulcerative colitis, 34 (29%) with history of abdominal surgery, 47 (40%) were in remission and 9(7.5%) with severe disease. 18 (15%) patients were on Immunosuppressive and 76 (66%) on biologic treatments. Concerns of contracting SARS-CoV-2 infection: 56 (48%) patients considered their risk as equal to that of the general population whereas 53 (46%) considered it to be increased. 55% of the patients related the increase risk of COVID-19 infection to their IBD treatment, whereas 47% related it to having IBD. Patients treated with biologics were more concerned of becoming infected with SARS-CoV-2 then those who were not. There was also a significant association between depression and anxiety levels and the fear of becoming infected (r= 0.3 for depression and 0.4 for anxiety). Adherence to IBD treatment: Only 8 (7.5%) patients considered stopping their IBD treatment, and only 4 (3.7%) patients actually stopped their treatment. Patients with more severe disease were more inclined to stop their treatment compared to those with mild disease. Reasons for not stopping treatment were fear of disease exacerbation in 37 (32%) patients, and reassuring information received from medical providers, in 25 (21.5%) patients. When faced with a theoretical question of trading long-term remission versus risk of SARS-CoV-2infection, 34 (29%) patients were willing to accept a 10% infection risk for a 10-year remission Conclusion Significant portion of the patients with IBD believe that they are at increased risk of contracting SARS-CoV-2 infection, and more than half of them related the increase risk to their IBD treatment. However, despite their fear most patients felt safe enough to continue their treatment. Patients with more severe disease and treated with biologics experienced higher levels of anxiety, depression and fear of COVID-19 infection. Identifying and addressing these fears early might increase patient’s adherence to treatment and prevent the hazardous effects of discontinuation of treatment.