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Σάββατο 11 Φεβρουαρίου 2017
Evaluation of the Biocontrol Potential of Purpureocillium lilacinum QLP12 against Verticillium dahliae in Eggplant
A fungus with broad spectrum antifungal activity was isolated from the soil in Qinling Mountain, Shaanxi Province, in China. The fungus was identified as Purpureocillium lilacinum based on ITS rDNA gene analysis. The strain, coded as QLP12, showed high inhibition activity on fungal mycelium growth in vitro, especially to Mucor piriformis, Trichothecium roseum, Rhizoctonia solani, and Verticillium dahliae, and its potential for biocontrol efficacy of eggplant. Verticillium wilt disease caused by Verticillium dahliae among 10 fungal species tested was explored. In greenhouse experiments, QLP12 showed an excellent growth-promoting effect on eggplant seed germination (76.7%), bud growth (79.4%), chlorophyll content (47.83%), root activity (182.02%), and so on. QLP12 can colonize the eggplant interior and also develop in rhizosphere soil. In greenhouse, the incidence of Verticillium wilt decreased by 83.82% with pretreated QLP12 fermentation broth in the soil. In the field, QLP12 showed prominent biocontrol effects on Verticillium wilt by reducing the disease index over the whole growth period, a decline of 40.1%. This study showed that the strain QLP12 is not only an effective biocontrol agent for controlling Verticillium wilt of eggplant, but also a plant growth-promoting fungus that deserves to be further developed.
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Molecular modeling, docking and dynamics simulations of the Dioclea lasiophylla Mart. Ex Benth seed lectin: An edematogenic and hypernociceptive protein
Publication date: Available online 11 February 2017
Source:Biochimie
Author(s): Vanir Reis Pinto-Junior, Vinicius Jose Silva Osterne, Mayara Queiroz Santiago, Claudia Figueiredo Lossio, Celso Shiniti Nagano, Cintia Renata Costa Rocha, Jessica Catarine Frutuoso Nascimento, Francisco Lucas Faustino Nascimento, Ivanice Bezerra Silva, Antonia Simoni Oliveira, Jorge Luis Almeida Correia, Rodrigo Bainy Leal, Ana Maria Sampaio Assreuy, Benildo Sousa Cavada, Kyria Santiago Nascimento
Lectins are proteins, or glycoproteins, capable of reversibly binding to specific mono- or oligosaccharides via a noncatalytic domain. The Diocleinae subtribe presents lectins with high structural similarity, but different effects based on biological activity assays. This variability results from small structural differences. Therefore, in this context, the present study aimed to perform a structural analysis of the lectin from Dioclea lasiophylla Mart. ex Benth seeds (DlyL) and evaluate its inflammatory effect. To accomplish this, DlyL was purified in a single step by affinity chromatography on Sephadex® G-50 matrix. DlyL primary structure was determined through a combination of tandem mass spectrometry and DNA sequencing. DlyL showed high similarity with other species from the same genus. Its theoretical three-dimensional structure was predicted by homology modelling, and the protein was subjected to ligand screening with monosaccharides, oligosaccharides and complex N-glycans by molecular docking. Stability and binding of the lectin with α-methyl-d-mannoside were assessed by molecular dynamics. DlyL showed acute inflammatory response with hypernociceptive effect in the paw edema model, possibly by interaction with glycans present at the cell surface.
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Source:Biochimie
Author(s): Vanir Reis Pinto-Junior, Vinicius Jose Silva Osterne, Mayara Queiroz Santiago, Claudia Figueiredo Lossio, Celso Shiniti Nagano, Cintia Renata Costa Rocha, Jessica Catarine Frutuoso Nascimento, Francisco Lucas Faustino Nascimento, Ivanice Bezerra Silva, Antonia Simoni Oliveira, Jorge Luis Almeida Correia, Rodrigo Bainy Leal, Ana Maria Sampaio Assreuy, Benildo Sousa Cavada, Kyria Santiago Nascimento
Lectins are proteins, or glycoproteins, capable of reversibly binding to specific mono- or oligosaccharides via a noncatalytic domain. The Diocleinae subtribe presents lectins with high structural similarity, but different effects based on biological activity assays. This variability results from small structural differences. Therefore, in this context, the present study aimed to perform a structural analysis of the lectin from Dioclea lasiophylla Mart. ex Benth seeds (DlyL) and evaluate its inflammatory effect. To accomplish this, DlyL was purified in a single step by affinity chromatography on Sephadex® G-50 matrix. DlyL primary structure was determined through a combination of tandem mass spectrometry and DNA sequencing. DlyL showed high similarity with other species from the same genus. Its theoretical three-dimensional structure was predicted by homology modelling, and the protein was subjected to ligand screening with monosaccharides, oligosaccharides and complex N-glycans by molecular docking. Stability and binding of the lectin with α-methyl-d-mannoside were assessed by molecular dynamics. DlyL showed acute inflammatory response with hypernociceptive effect in the paw edema model, possibly by interaction with glycans present at the cell surface.
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Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells
Publication date: Available online 11 February 2017
Source:Biochimie
Author(s): A.K. Mohamad Fairus, B. Choudhary, S. Hosahalli, N. Kavitha, O. Shatrah
Dihydroorotate dehydrogenase (DHODH) is the key enzyme in de novo biosynthesis of pyrimidine in both prokaryotes and eukaryotes. The de novo pathway of pyrimidine biosynthesis is essential in cancer cells proliferation. Leflunomide is an approved DHODH inhibitor that has been widely used for the treatment of arthritis. Similarly, brequinar sodium is another DHODH inhibitor that showed anti-tumour effect in MC38 colon carcinoma cells when used in combination with fluorouracil. Despite the potential role of DHODH inhibitors in cancer therapy, their mechanisms of action remain obscure and await further elucidation. Here, we evaluated the effect of DHODH inhibitors on the production of ATP and ROS in sensitive and non-sensitive breast cancer cells. Subsequently, the effects of DHODH inhibitors on cell cycle as well as on signalling molecules such as p53, p65 and STAT6 were evaluated in sensitive T-47D and non-sensitive MDAMB-436 cells. The correlations between DHODH protein expression, proliferation speed and sensitivity to DHODH inhibitors were also investigated in a panel of cancer cell lines. DHODH inhibitors-sensitive T-47D and MDAMB-231 cells appeared to preserve ROS production closely to endogenous ROS level whereas the opposite was observed in non-sensitive MDAMB-436 and W3.006 cells. In addition, we observed approximately 90% of intracellular ATP depletion in highly sensitive T-47D and MDAMB-231 cells compared to non-sensitive MDAMB-436 cells. There was significant over-expression of p53, p65 and STAT6 signalling molecules in sensitive cells which may be involved in mediating the S-phase arrest in cell cycle progression. The current study suggests that DHODH inhibitors are most effective in cells that express high levels of DHODH enzyme. The inhibition of cell proliferation by these inhibitors appears to be accompanied by ROS production as well as ATP depletion. The increase in expression of signalling molecules observed may be due to pyrimidine depletion which subsequently leads to cell cycle arrest at S-phase.
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Source:Biochimie
Author(s): A.K. Mohamad Fairus, B. Choudhary, S. Hosahalli, N. Kavitha, O. Shatrah
Dihydroorotate dehydrogenase (DHODH) is the key enzyme in de novo biosynthesis of pyrimidine in both prokaryotes and eukaryotes. The de novo pathway of pyrimidine biosynthesis is essential in cancer cells proliferation. Leflunomide is an approved DHODH inhibitor that has been widely used for the treatment of arthritis. Similarly, brequinar sodium is another DHODH inhibitor that showed anti-tumour effect in MC38 colon carcinoma cells when used in combination with fluorouracil. Despite the potential role of DHODH inhibitors in cancer therapy, their mechanisms of action remain obscure and await further elucidation. Here, we evaluated the effect of DHODH inhibitors on the production of ATP and ROS in sensitive and non-sensitive breast cancer cells. Subsequently, the effects of DHODH inhibitors on cell cycle as well as on signalling molecules such as p53, p65 and STAT6 were evaluated in sensitive T-47D and non-sensitive MDAMB-436 cells. The correlations between DHODH protein expression, proliferation speed and sensitivity to DHODH inhibitors were also investigated in a panel of cancer cell lines. DHODH inhibitors-sensitive T-47D and MDAMB-231 cells appeared to preserve ROS production closely to endogenous ROS level whereas the opposite was observed in non-sensitive MDAMB-436 and W3.006 cells. In addition, we observed approximately 90% of intracellular ATP depletion in highly sensitive T-47D and MDAMB-231 cells compared to non-sensitive MDAMB-436 cells. There was significant over-expression of p53, p65 and STAT6 signalling molecules in sensitive cells which may be involved in mediating the S-phase arrest in cell cycle progression. The current study suggests that DHODH inhibitors are most effective in cells that express high levels of DHODH enzyme. The inhibition of cell proliferation by these inhibitors appears to be accompanied by ROS production as well as ATP depletion. The increase in expression of signalling molecules observed may be due to pyrimidine depletion which subsequently leads to cell cycle arrest at S-phase.
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Gram (measure)
Gram (measure): A unit of measurement of weight and mass in the metric system. In weight, a gram is equal to a thousandth of a kilogram. In mass, a gram is equal to a thousandth of a liter (one cubic centimeter) of water at 4 degrees centigrade.
The word "gram" comes from the Late Latin "gramma" meaning a small weight via the French "gramme."
The abbreviation for gram is gm. Its symbol is g.
MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Characterization of a novel intrinsically radiopaque Drug-eluting Bead for image-guided therapy: DC Bead LUMI™
Publication date: 28 March 2017
Source:Journal of Controlled Release, Volume 250
Author(s): Koorosh Ashrafi, Yiqing Tang, Hugh Britton, Orianne Domenge, Delphine Blino, Andrew J. Bushby, Kseniya Shuturminska, Mark den Hartog, Alessandro Radaelli, Ayele H. Negussie, Andrew S. Mikhail, David L. Woods, Venkatesh Krishnasamy, Elliot B. Levy, Bradford J. Wood, Sean L. Willis, Matthew R. Dreher, Andrew L. Lewis
We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.
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Source:Journal of Controlled Release, Volume 250
Author(s): Koorosh Ashrafi, Yiqing Tang, Hugh Britton, Orianne Domenge, Delphine Blino, Andrew J. Bushby, Kseniya Shuturminska, Mark den Hartog, Alessandro Radaelli, Ayele H. Negussie, Andrew S. Mikhail, David L. Woods, Venkatesh Krishnasamy, Elliot B. Levy, Bradford J. Wood, Sean L. Willis, Matthew R. Dreher, Andrew L. Lewis
We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.
Graphical abstract
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Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum [Metabolism]
Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereo-specific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and cholestanol, the 5α-saturated analog of cholesterol. In Cyp27a1-/- mice, xanthomas are not formed, despite a significant cholestanol increase in the brain and cerebellum. The mechanism behind cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize cholestanol. It also is unclear why CYP27A1 deficiency results in preferential cholestanol accumulation in the cerebellum. We hypothesized that cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1-/-, Cyp46a1-/-, Cyp27a1-/- Cyp46a1-/-, and two wild type strains) and human brain specimens. In vitro experiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in cholestanol removal from the brain, and that several factors contribute to the preferential increase in cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include: (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, whose lack likely selectively increases the cerebellar cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/cholestanol-metabolizing P450s from a pool of metabolically available cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
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Dimeric but not monomeric α-lactalbumin potentiates apoptosis by up regulation of ATF3 and reduction of histone deacetylase activity in primary and immortalised cells
Publication date: Available online 11 February 2017
Source:Cellular Signalling
Author(s): Julie A. Sharp, Amelia J. Brennan, Galina Polekhina, David B. Ascher, Christophe Lefevre, Kevin R. Nicholas
α-lactalbumin is a protein of dual function found in milk of most mammals. α-lactalbumin binds β-1,4-galactosyltransferase to form the regulatory subunit for lactose synthesis and has also been shown to cause cell death. This study shows, for the first time, that α-lactalbumin isolated in a rare 28kDa dimeric form induces cell death, while 14kDa monomeric α-lactalbumin is inactive. In contrast to the casein derived and chemically induced α-lactalbumin variants, MAL and HAMLET/BAMLET, the effects of 28kDa α-lactalbumin are calcium independent and, unlike MAL and HAMLET, 28kDa α-lactalbumin dimer causes cell death of primary mammary cells and a variety of immortalised cell lines, which are committed to cell death pathways within 1–4h of exposure. Microarray analysis confirmed that cell death was the result of an apoptotic response. Functional assays determined that the mechanism by which 28kDa α-lactalbumin kills cells involved inhibition of histone deacetylase activity mediated by NF-kB. We also show that 28kDa α-lactalbumin occurs naturally in the milk of cows, goats and sheep, is low in concentration during mid-lactation, but accumulates during milk stasis, consistent with a role in involution.
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Source:Cellular Signalling
Author(s): Julie A. Sharp, Amelia J. Brennan, Galina Polekhina, David B. Ascher, Christophe Lefevre, Kevin R. Nicholas
α-lactalbumin is a protein of dual function found in milk of most mammals. α-lactalbumin binds β-1,4-galactosyltransferase to form the regulatory subunit for lactose synthesis and has also been shown to cause cell death. This study shows, for the first time, that α-lactalbumin isolated in a rare 28kDa dimeric form induces cell death, while 14kDa monomeric α-lactalbumin is inactive. In contrast to the casein derived and chemically induced α-lactalbumin variants, MAL and HAMLET/BAMLET, the effects of 28kDa α-lactalbumin are calcium independent and, unlike MAL and HAMLET, 28kDa α-lactalbumin dimer causes cell death of primary mammary cells and a variety of immortalised cell lines, which are committed to cell death pathways within 1–4h of exposure. Microarray analysis confirmed that cell death was the result of an apoptotic response. Functional assays determined that the mechanism by which 28kDa α-lactalbumin kills cells involved inhibition of histone deacetylase activity mediated by NF-kB. We also show that 28kDa α-lactalbumin occurs naturally in the milk of cows, goats and sheep, is low in concentration during mid-lactation, but accumulates during milk stasis, consistent with a role in involution.
Graphical abstract
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Suppressed Band Characteristics of an UWB Conical Monopole Antenna with Split Loops Based on the Equivalent Circuit
In this study, the principle of band suppressing an UWB antenna by attaching a small resonator is explained by developing its equivalent circuit. The realized UWB antenna is a conical monopole antenna that contains a split loop for band suppression. The conical monopole antenna corresponds to a transmission line terminated with load impedance, and the split loop is an LC resonator. The coupling between the conical monopole antenna and the split loop is represented as mutual inductance. Equivalent circuits for the UWB antenna suppressing single band [WLAN] and dual band [WLAN, WiMAX] have been suggested, and these equivalent circuits provide insight into the performance characteristics of the developed band suppressed UWB antenna to which a small sized resonator is installed. Simulation and measurement results on the input impedance and VSWR of the proposed equivalent circuit are closely matched. Thus, the validity of the equivalent circuit is confirmed. The measurement results demonstrate that the proposed antenna exhibits a gain of over 3 dBi in the working band and has an omnidirectional radiation pattern. Band rejection has been also implemented by split loops.
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Experimental Evaluation for the Microvibration Performance of a Segmented PC Method Based High Technology Industrial Facility Using 1/2 Scale Test Models
The precast concrete (PC) method used in the construction process of high technology industrial facilities is limited when applied to those with greater span lengths, due to the transport length restriction (maximum length of 15~16 m in Korea) set by traffic laws. In order to resolve this, this study introduces a structural system with a segmented PC system, and a 1/2 scale model with a width of 9000 mm (hereafter Segmented Model) is manufactured to evaluate vibration performance. Since a real vibrational environment cannot be reproduced for vibration testing using a scale model, a comparative analysis of their relative performances is conducted in this study. For this purpose, a 1/2 scale model with a width of 7200 mm (hereafter Nonsegmented Model) of a high technology industrial facility is additionally prepared using the conventional PC method. By applying the same experiment method for both scale models and comparing the results, the relative vibration performance of the Segmented Model is observed. Through impact testing, the natural frequencies of the two scale models are compared. Also, in order to analyze the estimated response induced by the equipment, the vibration responses due to the exciter are compared. The experimental results show that the Segmented Model exhibits similar or superior performances when compared to the Nonsegmented Model.
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Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Neurovegetative Dysregulation or Autonomic Failure?
Background. Joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), is a hereditary connective tissue disorder mainly characterized by generalized joint hypermobility, skin texture abnormalities, and visceral and vascular dysfunctions, also comprising symptoms of autonomic dysfunction. This study aims to further evaluate cardiovascular autonomic involvement in JHS/EDS-HT by a battery of functional tests. Methods. The response to cardiovascular reflex tests comprising deep breathing, Valsalva maneuver, 30/15 ratio, handgrip test, and head-up tilt test was studied in 35 JHS/EDS-HT adults. Heart rate and blood pressure variability was also investigated by spectral analysis in comparison to age and sex healthy matched group. Results. Valsalva ratio was normal in all patients, but 37.2% of them were not able to finish the test. At tilt, 48.6% patients showed postural orthostatic tachycardia, 31.4% orthostatic intolerance, 20% normal results. Only one patient had orthostatic hypotension. Spectral analysis showed significant higher baroreflex sensitivity values at rest compared to controls. Conclusions. This study confirms the abnormal cardiovascular autonomic profile in adults with JHS/EDS-HT and found the higher baroreflex sensitivity as a potential disease marker and clue for future research.
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Global Attractivity in a Discrete Mutualism Model with Infinite Deviating Arguments
A set of sufficient conditions is obtained for the global attractivity of the following two-species discrete mutualism model with infinite deviating arguments: and , where , , are all positive constants, , and . Our results generalize the main result of Yang et al. (2014).
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Effect of Vacancy Defects on the Electronic Structure and Optical Properties of GaN
The effect of gallium vacancy () and nitrogen vacancy () defects on the electronic structure and optical properties of GaN using the generalized gradient approximation method within the density functional theory were investigated. The results show that the band gap increases in GaN with vacancy defects. Crystal parameters decrease in GaN with nitrogen vacancy (GaN:) and increase in GaN with gallium vacancy (GaN:). The Ga vacancy introduces defect levels at the top of the valence band, and the defect levels are contributed by N2p electron states. In addition, the energy band shifts to lower energy in GaN: and moves to higher energy in GaN:. The level splitting is observed in the N2p states of GaN: and Ga3d states of GaN:. New peaks appear in lower energy region of imaginary dielectric function in GaN: and GaN:. The main peak moves to higher energy slightly and the intensity decreases.
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Prognostic Relevance and Function of MSX2 in Colorectal Cancer
Colorectal cancer patients with diabetes had the high risks of total mortality. High expression of MSX2 is related to development of diabetes. There are few reports about the clinical implications and function of MSX2 in colorectal cancer (CRC). The purpose of this study is to investigate the relationship between the expression of MSX2 and clinical relevance and discover the possible mechanism of MSX2 in the development of CRC. Compared with adjacent tissues, the expression of MSX2 was higher in tumor tissues in both mRNA and protein levels (). Kaplan-Meier survival analysis showed that high mRNA expression of MSX2 was associated with short survival time (). Chi-squared test analysis indicated that MSX2 expression was related to tumor size (), tumor locus (), clinical stage (), tumor invasion (), lymphatic metastasis (), and distant metastasis (). In vitro experiments demonstrated that knockdown of MSX2 expression attenuated cell proliferation and invasion, promoted cell cycle arrest and apoptosis, and inactivated Akt phosphorylation. In conclusion, MSX2 played a crucial role in the progression of CRC and may be a potential novel prognostic factor and therapeutic target for CRC therapy. Our work may provide certain enlightenment for investigating the mechanism of MSX2 in the process of diabetes.
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Pulling a Ligase out of a “HAT”: pCAF Mediates Ubiquitination of the Class II Transactivator
The Class II Transactivator (CIITA) is essential to the regulation of Major Histocompatibility Class II (MHC II) genes transcription. As the “master regulator” of MHC II transcription, CIITA regulation is imperative and requires various posttranslational modifications (PTMs) in order to facilitate its role. Previously we identified various ubiquitination events on CIITA. Monoubiquitination is important for CIITA transactivity, while K63 linked ubiquitination is involved in crosstalk with ERK1/2 phosphorylation, where together they mediate cellular movement from the cytoplasm to nuclear region. Further, CIITA is also modified by degradative K48 polyubiquitination. However, the E3 ligase responsible for these modifications was unknown. We show CIITA ubiquitination and transactivity are enhanced with the histone acetyltransferase (HAT), p300/CBP associated factor (pCAF), and the E3 ligase region within pCAF is necessary for both. Additionally, pCAF mediated ubiquitination is independent of pCAF’s HAT domain, and acetylation deficient CIITA is K48 polyubiquitinated and degraded in the presence of pCAF. Lastly, we identify the histone acetyltransferase, pCAF, as the E3 ligase responsible for CIITA’s ubiquitination.
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Role of Vitamin D in Uremic Vascular Calcification
The risk of cardiovascular death is 10 times higher in patients with CKD (chronic kidney disease) than in those without CKD. Vascular calcification, common in patients with CKD, is a predictor of cardiovascular mortality. Vitamin D deficiency, another complication of CKD, is associated with vascular calcification in patients with CKD. GFR decline, proteinuria, tubulointerstitial injury, and the therapeutic dose of active form vitamin D aggravate vitamin D deficiency and reduce its pleiotropic effect on the cardiovascular system. Vitamin D supplement for CKD patients provides a protective role in vascular calcification on the endothelium by (1) renin-angiotensin-aldosterone system inactivation, (2) alleviating insulin resistance, (3) reduction of cholesterol and inhibition of foam cell and cholesterol efflux in macrophages, and (4) modulating vascular regeneration. For the arterial calcification, vitamin D supplement provides adjunctive role in regressing proteinuria, reverse renal osteodystrophy, and restoring calcification inhibitors. Recently, adventitial progenitor cell has been linked to be involved in the vascular calcification. Vitamin D may provide a role in modulating adventitial progenitor cells. In summary, vitamin D supplement may provide an ancillary role for ameliorating uremic vascular calcification.
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Tumor Budding, uPA, and PAI-1 in Colorectal Cancer: Update of a Prospective Study
Aims. The prognostic role of the proteases uPA and PAI-1, as well as tumor budding, in colon cancer, has been investigated previously. Methods. We provide 6-year follow-up data and results of the validation set. The initial test set and validation set consisted of 55 colon cancers and 68 colorectal cancers, respectively. Tissue samples were analyzed for uPA and PAI-1 using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA). Tumor budding was analyzed on cytokeratin-stained slides. Survival analyses were performed using cut-offs that were determined previously. Results. uPA was not prognostic for outcome. PAI-1 showed a trend towards reduced cancer specific survival in PAI-1 high-grade cases (68 versus 83 months; ). The combination of high-grade PAI-1 and tumor budding was associated with significantly reduced cancer specific survival (60 versus 83 months; ). After pooling the data from both sets, multivariate analyses revealed that the factors pN-stage, V-stage, and a combination of tumor budding and PAI-1 were independently prognostic for the association with distant metastases. Conclusions. A synergistic adverse effect of PAI-1 and tumor budding in uni- and multivariable analyses was found. PAI-1 could serve as a target for anticancer therapy.
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The Correlation of Decreased Heart Rate Recovery and Chronotropic Incompetence with Exercise Capacity in Idiopathic Pulmonary Arterial Hypertension Patients
We show by this study that a decrease in HRR1 in IPAH patients is associated with severe limitation of exercise capacity. HRR1
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Interactive Palliative and End-of-Life Care Modules for Pediatric Residents
Background. There is a need for increased palliative care training during pediatric residency. Objective. In this pilot study, we created a comprehensive experiential model to teach palliative care skills to pediatric residents. Our Comfort Care Modules (CCMs) address pediatric palliative care (PPC) topics of breaking bad news, dyspnea, anxiety, pain management, and the dying child. We also evaluated a scoring system and gathered qualitative data. Methods. The CCMs are part of the University of California San Diego pediatric residency’s second-year curriculum. Comparisons were made for statistical trends between residents exposed to the modules and those not exposed . Results. Nineteen of 36 residents (52%) completed surveys to self-rate their preparedness, knowledge, and confidence about PPC before and after the intervention. Resident scores increased in all areas. All improvements reached statistical significance except confidence when breaking bad news. Overall, the resident feedback about the CCMs was positive. Conclusions. This study demonstrates that the CCMs can be performed effectively in an academic setting and can benefit residents’ self-perception of preparedness, confidence, and knowledge about pediatric palliative care. In the future, we plan to implement the modules on a larger scale. We encourage their use in interprofessional settings and across institutions.
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Parallel Algorithm for Wireless Data Compression and Encryption
As the wireless network has limited bandwidth and insecure shared media, the data compression and encryption are very useful for the broadcasting transportation of big data in IoT (Internet of Things). However, the traditional techniques of compression and encryption are neither competent nor efficient. In order to solve this problem, this paper presents a combined parallel algorithm named “CZ algorithm” which can compress and encrypt the big data efficiently. CZ algorithm uses a parallel pipeline, mixes the coding of compression and encryption, and supports the data window up to 1 TB (or larger). Moreover, CZ algorithm can encrypt the big data as a chaotic cryptosystem which will not decrease the compression speed. Meanwhile, a shareware named “ComZip” is developed based on CZ algorithm. The experiment results show that ComZip in 64 b system can get better compression ratio than WinRAR and 7-zip, and it can be faster than 7-zip in the big data compression. In addition, ComZip encrypts the big data without extra consumption of computing resources.
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Ultrasound as an Alternative to Conventional Marination: Acceptability and Mass Transfer
In this study, the effects of ultrasound- (US-) assisted beef marination on consumer perception and the homogeneity of the solute and mass transfer were evaluated. Marinated and US-treated meat samples (40 kHz, 11 W/cm2 for 20, 40, and 60 min, and storing at 4°C for 7 d) were evaluated by a group of consumers using a structured 9-point hedonic scale of satisfaction. The preferences were analyzed with XLSTAT-Sensory® software. The analysis was performed in conjunction with an energy-dispersive X-ray spectroscopic study to evaluate the sodium transference. The perception analysis indicated that the use of US-assisted marination did not increase the beef acceptability. The sonicated samples showed a more homogeneous distribution of sodium. However, traditional marination (TM) stored for 7 d resulted in greater mass transfer than the US-assisted marination without storage.
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IL-1β and IL-6 Are Highly Expressed in RF+IgE+ Systemic Lupus Erythematous Subtype
Background. Systemic lupus erythematosus (SLE) is an autoimmune disease with great heterogeneity in pathogenesis and clinical symptoms. Rheumatoid factor (RF) is one key indicator for rheumatoid arthritis (RA) while immunoglobulin E (IgE) is associated with type I hypersensitivity. To better categorize SLE subtypes, we determined the dominant cytokines based on familial SLE patients. Methods. RF, IgE, and multiple cytokines (i.e., IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ, IP-10, MCP-1, and MIP-1β) were measured in sera of familial SLE patients (), noninherited SLE patients (), and healthy controls (). Results. Three familial SLE patients and 5 noninherited SLE cases are with features of RF+IgE+. These RF+IgE+ SLE patients expressed significantly higher levels of IL-1β and IL-6 than the other SLE patients (). IL-6 correlated with both IgE and IL-1β levels in RF+IgE+ SLE patients (, ; , ), and IgE also correlated with IL-1β (, ). Conclusion. Both IL-1β and IL-6 are highly expressed cytokines in RF+IgE+ SLE subtype which may be related to the pathogenesis of this special SLE subtype and provide accurate treatment strategy by neutralizing IL-1β and IL-6.
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Numerical Method for the Design of Healing Chamber in Additive-Manufactured Dental Implants
The inclusion of a healing chamber in dental implants has been shown to promote biological healing. In this paper, a novel numerical approach to the design of the healing chamber for additive-manufactured dental implants is proposed. This study developed an algorithm for the modeling of bone growth and employed finite element method in ANSYS to facilitate the design of healing chambers with a highly complex configuration. The model was then applied to the design of dental implants for insertion into the posterior maxillary bones. Two types of ITI® solid cylindrical screwed implant with extra rectangular-shaped healing chamber as an initial design are adopted, with which to evaluate the proposed system. This resulted in several configurations for the healing chamber, which were then evaluated based on the corresponding volume fraction of healthy surrounding bone. The best of these implants resulted in a healing chamber surrounded by around 9.2% more healthy bone than that obtained from the original design. The optimal design increased the contact area between the bone and implant by around 52.9%, which is expected to have a significant effect on osseointegration. The proposed approach is highly efficient which typically completes the optimization of each implant within 3–5 days on an ordinary personal computer. It is also sufficiently general to permit extension to various loading conditions.
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Photodynamic Efficiency of Xanthene Dyes and Their Phototoxicity against a Carcinoma Cell Line: A Computational and Experimental Study
The aim of this study is to assess the insights of molecular properties of the xanthene dyes [fluorescein (FL), Rose Bengal (RB), erythrosin B (EB), and eosin Y (EY)] to correlate systematically their photodynamic efficiency as well as their phototoxicity against a carcinoma cell line. The phototoxicity was evaluated by comparing the values of the medium inhibitory concentration (IC50) upon HEp-2 cells with the xanthene corresponding photodynamic activity using the uric acid as a chemical dosimeter and their octanol-water partition coefficient (). RB was the more cytotoxic dye against HEp-2 cell line and the most efficient photosensitizer in causing photoxidation of uric acid; nevertheless it was the only one characterized as being hydrophobic among the xanthenes studied here. On the other hand, it was observed that the halogen substituents increased the hydrophilicity and photodynamic activity, consistent with the cytotoxic experiments. Furthermore, the reactivity index parameters, electric dipole moment, molecular volume, and the frontier orbitals were also obtained by the Density Functional Theory (DFT). The lowest dipole moment and highest molecular volume of RB corroborate with its highest hydrophobicity due to heavy atom substituents like halogens, while the halogen substituents did not affect expressively the electronic features at all.
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Efficacy of Juzentaihoto for Tumor Immunotherapy in B16 Melanoma Metastasis Model
Introduction. Medical care for Japanese cancer patients includes Western and Kampo medicines, and treatments with juzentaihoto (JTT) reportedly prevent cancer metastasis and recurrence. In this study, we examined the effects of JTT on natural killer (NK) cell activity and metastasis in combined treatments with anti-PD-1 antibody in a mouse model of melanoma metastasis. Methods. C57BL/6 male mice were intravenously injected with B16 melanoma cells (B16 cell) and were given chow containing 3% JTT. In subsequent in vivo experiments, we assessed serum cytokine levels and tumor colony formation in the lungs. Additionally, we assessed NK cell activity in ex vivo experiments. Results. JTT significantly suppressed B16 cell metastasis, whereas injection of anti-asialo-GM1 antibody into mice abrogated the inhibitory actions of JTT. JTT significantly increased interleukin- (IL-) 12 and interferon- (IFN-) γ levels in serum and induced NK cell activity. It increased the inhibitory actions of the anti-PD-1 antibody on B16 cell metastasis. Discussion. These data suggest that JTT inhibits B16 cell metastasis by inducing NK cell activity. Additionally, combination therapy with JTT and anti-PD-1 antibody increased treatment response rates for B16 melanoma.
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An Empirical Framework for Intersection Optimization Based on Uniform Design
Operational performance optimization of signalized intersections is one of the most important tasks for traffic engineers and researchers. To compensate for the limitations of practical implementation, simulation software packages have been widely used to evaluate different optimization strategies and thus to improve the efficiency of the intersections as well as the entire network. However, for the existing optimization studies on signalized intersections, the relationships among various optimization measures and the combination of strategies have not been fully investigated. In this paper, uniform design experimentation was introduced to combine different optimization measures into strategies and achieve the minimum time cost in model construction. VISSIM software package was then calibrated and used to evaluate various optimization strategies and identify the one with the best measurement of performance, namely, control delay at the signalized intersection. By taking a representative congested intersection in Shanghai as a case study, the optimal strategy was identified to reduce the overall control delay by 27.3%, which further verified the modeling capability of the proposed method.
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Two-Center Gaussian Potential Well for Studying Light Nucleus in Cluster Structure
The clustering phenomena are very important to determine structure of light nuclei and deformation of spherical shape is inevitable. Hence, we calculated the energy levels of two-center Gaussian potential well including spin-orbit coupling by solving the Schrödinger equation in the cylindrical coordinates. This model can predict the spin and parity of the light nuclei that have two identical cluster structures.
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Digital Lengthening to Treat Finger Deficiency: An Experience of 201 Digits in 104 Patients
Objectives. We evaluated the results of digital lengthening by distraction and second-stage bone graft. Methods. We treated finger deficiency of 201 digits in 104 patients (68 males, 36 females) by digital distraction and second-stage bone graft. The distraction was performed with a rate of 1 mm/day (for the first ten days) and 0.5 mm/day followed by using a self-designed bilateral tubal-helical external fixator. The mean follow-up period was 42 months (range 6 to 60 months). Results. The mean lengthening was 29.2 mm (range 25 to 40 mm) and 18.7 mm (range 12 to 32 mm) for metacarpal bones and phalanges, respectively. The mean elongation rate was 174.4% (range 145% to 202%) and 184.8% (range 115% to 283%) for metacarpal bones and phalanges, respectively. The static two-point discriminations and SpO2 showed no significant differences before and after distraction. Four complications were observed (two skin ruptures and two phalangeal splitting). No pin tract infection or tendon rupture showed. Digital lengthening improved functions of the hand. Conclusion. Digital distraction and second-stage bone graft is an effective method to compensate disabilities caused by lack of finger length. It could be an alternative plan for patients with thumb deficiency instead of toe-to-thumb transplant and patients with finger deficiency instead of ray resection.
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The First Evaluation of Workers’ General Health Examination in Korea
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The atypical Rho GTPase RhoD is a regulator of actin cytoskeleton dynamics and directed cell migration
Publication date: Available online 11 February 2017
Source:Experimental Cell Research
Author(s): Magdalena Blom, Katarina Reis, Johan Heldin, Johan Kreuger, Pontus Aspenström
RhoD belongs to the Rho GTPases, a protein family responsible for the regulation and organization of the actin cytoskeleton, and, consequently, many cellular processes like cell migration, cell division and vesicle trafficking. Here, we demonstrate that the actin cytoskeleton is dynamically regulated by increased or decreased protein levels of RhoD. Ectopic expression of RhoD has previously been shown to give an intertwined weave of actin filaments. We show that this RhoD-dependent effect is detected in several cell types and results in a less dynamic actin filament system. In contrast, RhoD depletion leads to increased actin filament-containing structures, such as cortical actin, stress fibers and edge ruffles. Moreover, vital cellular functions such as cell migration and proliferation are defective when RhoD is silenced. Taken together, we present data suggesting that RhoD is an important component in the control of actin dynamics and directed cell migration.
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Source:Experimental Cell Research
Author(s): Magdalena Blom, Katarina Reis, Johan Heldin, Johan Kreuger, Pontus Aspenström
RhoD belongs to the Rho GTPases, a protein family responsible for the regulation and organization of the actin cytoskeleton, and, consequently, many cellular processes like cell migration, cell division and vesicle trafficking. Here, we demonstrate that the actin cytoskeleton is dynamically regulated by increased or decreased protein levels of RhoD. Ectopic expression of RhoD has previously been shown to give an intertwined weave of actin filaments. We show that this RhoD-dependent effect is detected in several cell types and results in a less dynamic actin filament system. In contrast, RhoD depletion leads to increased actin filament-containing structures, such as cortical actin, stress fibers and edge ruffles. Moreover, vital cellular functions such as cell migration and proliferation are defective when RhoD is silenced. Taken together, we present data suggesting that RhoD is an important component in the control of actin dynamics and directed cell migration.
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Nrf2 mediates redox adaptation in NOX4-overexpressed non-small cell lung cancer cells
Publication date: Available online 11 February 2017
Source:Experimental Cell Research
Author(s): Qipeng Wu, Bei Yao, Ning Li, Lei Ma, Yanchao Deng, Yang Yang, Cheng Zeng, Zhicheng Yang, Bing Liu
The redox adaptation mechanisms in cancer cells are very complex and remain largely unclear. Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and confers apoptosis resistance on NSCLC cells. However, the comprehensive mechanisms for NOX4-mediated oxidative resistance of cancer cells remain still undentified. The present study found that NOX4-derived H2O2 enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) stability via disruption of redox-dependent proteasomal degradation and stimulated its activity through activation of PI3K signaling. Specifically, the results showed that ectopic NOX4 expression did not induce apoptosis of A549 cells; however, inhibition of Nrf2 resulted in obvious apoptotic death of NOX4-overexpressed A549 cells, accompanied by a significant increase in H2O2 level and decrease in GSH content. Besides, inhibition of Nrf2 could suppress cell growth and efficiently reverse the enhancement effect of NOX4 on cell growth. The in vivo data confirmed that inhibition of Nrf2 could interfere apoptosis resistance in NOX4-overexpressed A549 tumors and led to cell growth inhibition. In conclusion, these results reveal that Nrf2 is critically involved in redox adaptation regulation in NOX4-overexpressed NSCLC cells. Therefore, NOX4 and Nrf2 may be promising combination targets against malignant progression of NSCLC.
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Source:Experimental Cell Research
Author(s): Qipeng Wu, Bei Yao, Ning Li, Lei Ma, Yanchao Deng, Yang Yang, Cheng Zeng, Zhicheng Yang, Bing Liu
The redox adaptation mechanisms in cancer cells are very complex and remain largely unclear. Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and confers apoptosis resistance on NSCLC cells. However, the comprehensive mechanisms for NOX4-mediated oxidative resistance of cancer cells remain still undentified. The present study found that NOX4-derived H2O2 enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2) stability via disruption of redox-dependent proteasomal degradation and stimulated its activity through activation of PI3K signaling. Specifically, the results showed that ectopic NOX4 expression did not induce apoptosis of A549 cells; however, inhibition of Nrf2 resulted in obvious apoptotic death of NOX4-overexpressed A549 cells, accompanied by a significant increase in H2O2 level and decrease in GSH content. Besides, inhibition of Nrf2 could suppress cell growth and efficiently reverse the enhancement effect of NOX4 on cell growth. The in vivo data confirmed that inhibition of Nrf2 could interfere apoptosis resistance in NOX4-overexpressed A549 tumors and led to cell growth inhibition. In conclusion, these results reveal that Nrf2 is critically involved in redox adaptation regulation in NOX4-overexpressed NSCLC cells. Therefore, NOX4 and Nrf2 may be promising combination targets against malignant progression of NSCLC.
Graphical abstract
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Cervical cancer incidence in elderly women-biology or screening history?
Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Elsebeth Lynge, Stefan Lönnberg, Sven Törnberg
AimIn many countries, the age-specific pattern of cervical cancer incidence is currently bipolar with peaks at for instance 45 and 65 years of age. Consequently, a large proportion of cervical cancer cases are presently diagnosed in women above the screening age. The purpose of the study was to determine whether this bipolar pattern in age-specific incidence of cervical cancer reflects underlying biology or can be explained by the fact that the data come from birth cohorts with different screening histories.MethodsCombination of historical data on cervical screening and population-based cancer incidence data from Denmark 1943–2013, Finland and Norway 1953–2013, and Sweden 1958–2013.ResultsSince the implementation of screening, the incidence of cervical cancer has decreased for each successive birth cohort. All birth cohorts showed a unipolar age-specific pattern. In unscreened women in Denmark and Sweden, the incidence peaked around the age of 50; the peak was less marked in Finland; while peak age for unscreened women could not be determined for Norway due to widespread opportunistic screening. The current old-age peak in the incidence of cervical cancer represents residuals from unscreened or underscreened birth cohorts.ConclusionThe current bipolar pattern in age-specific incidence of cervical cancer can largely be explained by the different screening histories of successive birth cohorts. While it is reasonable to offer screening to elderly women today, birth cohort trends in disease burden should be carefully monitored to justify permanent changes in upper screening age.
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Source:European Journal of Cancer, Volume 74
Author(s): Elsebeth Lynge, Stefan Lönnberg, Sven Törnberg
AimIn many countries, the age-specific pattern of cervical cancer incidence is currently bipolar with peaks at for instance 45 and 65 years of age. Consequently, a large proportion of cervical cancer cases are presently diagnosed in women above the screening age. The purpose of the study was to determine whether this bipolar pattern in age-specific incidence of cervical cancer reflects underlying biology or can be explained by the fact that the data come from birth cohorts with different screening histories.MethodsCombination of historical data on cervical screening and population-based cancer incidence data from Denmark 1943–2013, Finland and Norway 1953–2013, and Sweden 1958–2013.ResultsSince the implementation of screening, the incidence of cervical cancer has decreased for each successive birth cohort. All birth cohorts showed a unipolar age-specific pattern. In unscreened women in Denmark and Sweden, the incidence peaked around the age of 50; the peak was less marked in Finland; while peak age for unscreened women could not be determined for Norway due to widespread opportunistic screening. The current old-age peak in the incidence of cervical cancer represents residuals from unscreened or underscreened birth cohorts.ConclusionThe current bipolar pattern in age-specific incidence of cervical cancer can largely be explained by the different screening histories of successive birth cohorts. While it is reasonable to offer screening to elderly women today, birth cohort trends in disease burden should be carefully monitored to justify permanent changes in upper screening age.
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Geriatric factors and outcomes in metastatic colorectal cancer
Publication date: Available online 10 February 2017
Source:European Journal of Cancer
Author(s): Demetris Papamichael, Matti Aapro
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Source:European Journal of Cancer
Author(s): Demetris Papamichael, Matti Aapro
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Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions
Publication date: Available online 11 February 2017
Source:Trends in Immunology
Author(s): Robin A. Aglietti, Erin C. Dueber
Pyroptosis is an inflammatory form of cell death that not only protects multicellular organisms from invading pathogenic bacteria and microbial infections, but can also lead to sepsis and lethal septic shock if overactivated. Here, we present an overview of recent developments within the pyroptosis field, beginning with the discovery of Gasdermin D (GSDMD) as a substrate of caspase-1 and caspase-11 upon detection of cytosolic lipopolysaccharide (LPS). Cleavage releases the N-terminal domain of GSDMD, causing it to form cytotoxic pores in the plasma membrane of cells. We further discuss the implications for the rest of the gasdermin (GSDM) family, which are emerging as mediators of programmed cell death in a variety of processes that regulate cellular differentiation and proliferation.
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Source:Trends in Immunology
Author(s): Robin A. Aglietti, Erin C. Dueber
Pyroptosis is an inflammatory form of cell death that not only protects multicellular organisms from invading pathogenic bacteria and microbial infections, but can also lead to sepsis and lethal septic shock if overactivated. Here, we present an overview of recent developments within the pyroptosis field, beginning with the discovery of Gasdermin D (GSDMD) as a substrate of caspase-1 and caspase-11 upon detection of cytosolic lipopolysaccharide (LPS). Cleavage releases the N-terminal domain of GSDMD, causing it to form cytotoxic pores in the plasma membrane of cells. We further discuss the implications for the rest of the gasdermin (GSDM) family, which are emerging as mediators of programmed cell death in a variety of processes that regulate cellular differentiation and proliferation.
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Adjuvant therapy in patients with Ductal Carcinoma in Situ of the breast: The Pandora’s box
Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Matteo Lazzeroni, Barbara K Dunn, Giancarlo Pruneri, Barbara Alicja Jereczek-Fossa, Roberto Orecchia, Bernardo Bonanni, Andrea DeCensi
Most patients with ductal carcinoma in situ of the breast (DCIS) are eligible for breast conservation treatment. The key management decision is whether to add radiotherapy and/or endocrine therapy to minimize the risk of a subsequent recurrence. Recent analyses indicating a lack of benefit in terms of breast cancer-associated mortality have suggested that more conservative approaches, omitting adjuvant therapy or even surgery, may be advisable. These mortality observations are directly influenced by widespread use of mammographic screening which has opened a Pandora’s box of subclinical DCIS and early invasive lesions. Confusion as to how aggressively such possibly indolent lesions should be treated has led to misunderstandings among patients and medical professionals. While awaiting further prospective evidence from clinical trials, we endorse an active treatment of DCIS as the standard of care. Our rationale is two-fold: invasive recurrences are associated with an increase in breast cancer mortality, which is not the only relevant endpoint for DCIS. The benefit of complete surgical excision, adjuvant radiotherapy and endocrine treatment in preventing recurrence and invasive progression has been demonstrated in DCIS. The challenge now is how to identify DCIS patients who will not progress to invasive carcinoma even without complete excision and, at the other extreme, those patients at the highest risk who require mastectomy for local control. The current controversies over whether and which adjuvant therapy should be implemented can at least in part be addressed by developing effective doctor-patient communications that enable mutual understanding about the management of this biologically heterogeneous disease.
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Source:Cancer Treatment Reviews
Author(s): Matteo Lazzeroni, Barbara K Dunn, Giancarlo Pruneri, Barbara Alicja Jereczek-Fossa, Roberto Orecchia, Bernardo Bonanni, Andrea DeCensi
Most patients with ductal carcinoma in situ of the breast (DCIS) are eligible for breast conservation treatment. The key management decision is whether to add radiotherapy and/or endocrine therapy to minimize the risk of a subsequent recurrence. Recent analyses indicating a lack of benefit in terms of breast cancer-associated mortality have suggested that more conservative approaches, omitting adjuvant therapy or even surgery, may be advisable. These mortality observations are directly influenced by widespread use of mammographic screening which has opened a Pandora’s box of subclinical DCIS and early invasive lesions. Confusion as to how aggressively such possibly indolent lesions should be treated has led to misunderstandings among patients and medical professionals. While awaiting further prospective evidence from clinical trials, we endorse an active treatment of DCIS as the standard of care. Our rationale is two-fold: invasive recurrences are associated with an increase in breast cancer mortality, which is not the only relevant endpoint for DCIS. The benefit of complete surgical excision, adjuvant radiotherapy and endocrine treatment in preventing recurrence and invasive progression has been demonstrated in DCIS. The challenge now is how to identify DCIS patients who will not progress to invasive carcinoma even without complete excision and, at the other extreme, those patients at the highest risk who require mastectomy for local control. The current controversies over whether and which adjuvant therapy should be implemented can at least in part be addressed by developing effective doctor-patient communications that enable mutual understanding about the management of this biologically heterogeneous disease.
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Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy
Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Chiara Ciccarese, Francesco Massari, Roberto Iacovelli, Michelangelo Fiorentino, Rodolfo Montironi, Vincenzo Di Nunno, Francesca Giunchi, Matteo Brunelli, Giampaolo Tortora
Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies.In the future, the identification of driver mutations present at a specific stage of the disease, the classification PCa based on specific molecular alterations, and the selection of the most appropriate therapy based on biomarkers predictors of response represent the foundations for an increasingly more accurate personalized medicine.
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Source:Cancer Treatment Reviews
Author(s): Chiara Ciccarese, Francesco Massari, Roberto Iacovelli, Michelangelo Fiorentino, Rodolfo Montironi, Vincenzo Di Nunno, Francesca Giunchi, Matteo Brunelli, Giampaolo Tortora
Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies.In the future, the identification of driver mutations present at a specific stage of the disease, the classification PCa based on specific molecular alterations, and the selection of the most appropriate therapy based on biomarkers predictors of response represent the foundations for an increasingly more accurate personalized medicine.
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Targeting the Programmed Death-1 Pathway in Lymphoid Neoplasms
Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Chi Young Ok, Ken H. Young
Programmed death-1 (PD-1) is a co-inhibitory molecule and is seen in CD4+ and CD8+ T cells. Upon binding to its ligands, programmed death ligand-1 (PD-L1) and -2 (PD-L2), PD-1 negatively regulates interleukin 2 (IL-2) production and T cell proliferation. Activated effector T-cells, which kill cancer cells, can be affected by PD-1 signaling in some lymphoid neoplasm that express PD-L1 or PD-L2. PD-L1 expression in tumor cells can be induced by extrinsic signal (i.e. interferon gamma) or intrinsic signals, such as genetic aberrations involving 9p24.1, latent Epstein-Barr virus infection, PD-L1 3’- untranslated region disruptions, and activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Anti-PD-1 therapy improves the overall response rate to treatment in patients with lymphoid neoplasms, particularly relapsed/refractory classical Hodgkin lymphoma. Inspired by their success in treating patients with classical Hodgkin lymphoma, medical practitioners have expanded PD-1 therapy, given as a single therapy or in combination with other drugs, to patients with other types of lymphoma. In this review, current clinical trials with anti-PD-1 or anti-PD-L1 drugs are summarized. The results of numerous clinical trials will broaden our understanding of PD-1 pathway and shall expand the list of patients who will get benefit from these agents including those who suffer from lymphoid neoplasms.
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Source:Cancer Treatment Reviews
Author(s): Chi Young Ok, Ken H. Young
Programmed death-1 (PD-1) is a co-inhibitory molecule and is seen in CD4+ and CD8+ T cells. Upon binding to its ligands, programmed death ligand-1 (PD-L1) and -2 (PD-L2), PD-1 negatively regulates interleukin 2 (IL-2) production and T cell proliferation. Activated effector T-cells, which kill cancer cells, can be affected by PD-1 signaling in some lymphoid neoplasm that express PD-L1 or PD-L2. PD-L1 expression in tumor cells can be induced by extrinsic signal (i.e. interferon gamma) or intrinsic signals, such as genetic aberrations involving 9p24.1, latent Epstein-Barr virus infection, PD-L1 3’- untranslated region disruptions, and activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Anti-PD-1 therapy improves the overall response rate to treatment in patients with lymphoid neoplasms, particularly relapsed/refractory classical Hodgkin lymphoma. Inspired by their success in treating patients with classical Hodgkin lymphoma, medical practitioners have expanded PD-1 therapy, given as a single therapy or in combination with other drugs, to patients with other types of lymphoma. In this review, current clinical trials with anti-PD-1 or anti-PD-L1 drugs are summarized. The results of numerous clinical trials will broaden our understanding of PD-1 pathway and shall expand the list of patients who will get benefit from these agents including those who suffer from lymphoid neoplasms.
Graphical abstract
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The Expanding Role of Immunotherapy
Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Juan Martin-Liberal, María Ochoa de Olza, Cinta Hierro, Alena Gros, Jordi Rodon, Josep Tabernero
The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.
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Source:Cancer Treatment Reviews
Author(s): Juan Martin-Liberal, María Ochoa de Olza, Cinta Hierro, Alena Gros, Jordi Rodon, Josep Tabernero
The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.
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Mycobacterium bovis in a European bison (Bison bonasus) raises concerns about tuberculosis in Brazilian captive wildlife populations: a case report
Tuberculosis caused by Mycobacterium bovis is an important worldwide zoonosis and has been reported to cause clinical disease in several animal species, including captive wildlife. This report describes a case of...
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IL-33 dysregulates regulatory T (Treg) cells and impairs established immunological tolerance in the lungs
Using mouse models, Chen et al. showed that IL-33 dysregulated Treg cells in the lungs of mice toward a “Th2 cell-like” phenotype and impaired established immunological tolerance in the lungs.
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Enteric helminth-induced type-I interferon signalling protects against pulmonary virus infection through interaction with the microbiota
Strictly enteric helminth infection protects against RSV-infection through microbiota-dependent induction of type I interferon in the lung, a novel mechanism which in the future may reveal new targets for the prevention and treatment of RSV infection.
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Contribution of Guanine Nucleotide Exchange Factor Vav2 to NLRP3 Inflammasome Activation in Mouse Podocytes During Hyperhomocysteinemia
Publication date: Available online 11 February 2017
Source:Free Radical Biology and Medicine
Author(s): Sabena M. Conley, Justine M. Abais-Battad, Xinxu Yuan, Qinghua Zhang, Krishna M. Boini, Pin-Lan Li
NADPH oxidase (NOX)-derived reactive oxygen species (ROS) have been demonstrated to mediate the activation of NOD-like receptor protein 3 (NLRP3) inflammasomes in podocytes in response to elevated levels of homocysteine (Hcys). However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The present study tested whether the guanine nucleotide exchange factor Vav2 mediates Rac1-mediated NOX activation in response to elevated Hcys leading to NLRP3 inflammasome activation in podocytes and consequent glomerular injury. In a mouse model of hyperhomocysteinemia (hHcys), we found that mice with hHcys (on the FF diet) or oncoVav2 (a constitutively active form of Vav2) transfection in the kidney exhibited increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1 and elevated IL-1β levels in glomeruli, indicating the formation and activation of the NLRP3 inflammasome. This glomerular NLRP3 inflammasome activation was accompanied by podocyte dysfunction and glomerular injury, even sclerosis. Local transfection of Vav2 shRNA plasmids significantly attenuated hHcys-induced NLRP3 inflammasome activation, podocyte injury, and glomerular sclerosis. In cultured podocytes, Hcys treatment and oncoVav2 transfection were also found to increase NLRP3 inflammasome formation and activation, which were all inhibited by Vav2 shRNA. Furthermore, Vav2 shRNA prevented Hcys-induced podocyte damage as shown by restoring Hcys-impaired VEGF secretion and podocin production. This inhibitory action of Vav2 shRNA on Hcys-induced podocyte injury was associated with reduction of Rac1 activity and ROS production. These results suggest that elevated Hcys levels activate Vav2 and thereby increase NOX activity leading to ROS production, which triggers NLRP3 inflammasome activation, podocyte dysfunction and glomerular injury.
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Source:Free Radical Biology and Medicine
Author(s): Sabena M. Conley, Justine M. Abais-Battad, Xinxu Yuan, Qinghua Zhang, Krishna M. Boini, Pin-Lan Li
NADPH oxidase (NOX)-derived reactive oxygen species (ROS) have been demonstrated to mediate the activation of NOD-like receptor protein 3 (NLRP3) inflammasomes in podocytes in response to elevated levels of homocysteine (Hcys). However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The present study tested whether the guanine nucleotide exchange factor Vav2 mediates Rac1-mediated NOX activation in response to elevated Hcys leading to NLRP3 inflammasome activation in podocytes and consequent glomerular injury. In a mouse model of hyperhomocysteinemia (hHcys), we found that mice with hHcys (on the FF diet) or oncoVav2 (a constitutively active form of Vav2) transfection in the kidney exhibited increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1 and elevated IL-1β levels in glomeruli, indicating the formation and activation of the NLRP3 inflammasome. This glomerular NLRP3 inflammasome activation was accompanied by podocyte dysfunction and glomerular injury, even sclerosis. Local transfection of Vav2 shRNA plasmids significantly attenuated hHcys-induced NLRP3 inflammasome activation, podocyte injury, and glomerular sclerosis. In cultured podocytes, Hcys treatment and oncoVav2 transfection were also found to increase NLRP3 inflammasome formation and activation, which were all inhibited by Vav2 shRNA. Furthermore, Vav2 shRNA prevented Hcys-induced podocyte damage as shown by restoring Hcys-impaired VEGF secretion and podocin production. This inhibitory action of Vav2 shRNA on Hcys-induced podocyte injury was associated with reduction of Rac1 activity and ROS production. These results suggest that elevated Hcys levels activate Vav2 and thereby increase NOX activity leading to ROS production, which triggers NLRP3 inflammasome activation, podocyte dysfunction and glomerular injury.
Graphical abstract
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Protective role of p53 in acetaminophen hepatotoxicity
Publication date: Available online 11 February 2017
Source:Free Radical Biology and Medicine
Author(s): Yazhen Huo, Shutao Yin, Mingzhu Yan, Sanda Win, Tin Aung Than, Mariam Aghajan, Hongbo Hu, Neil Kaplowitz
p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.
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Source:Free Radical Biology and Medicine
Author(s): Yazhen Huo, Shutao Yin, Mingzhu Yan, Sanda Win, Tin Aung Than, Mariam Aghajan, Hongbo Hu, Neil Kaplowitz
p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.
Graphical abstract
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Time-resolved phosphoproteome analysis of paradoxical RAF activation reveals novel targets of ERK [Research]
Small molecules targeting aberrant RAF activity, like Vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation, and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS-mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream paradoxical ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to Vemurafenib. Comprehensive data mining and filtering identified a total of 37910 phosphorylation sites, 660 of which were dynamically modulated upon treatment with Vemurafenib. We established that 83% of these dynamic phosphorylation sites were modulated in accordance with the phospho-ERK profile of the two cell lines. Accordingly, kinase-substrate prediction algorithms linked most of these dynamic sites to direct ERK1/2-mediated phosphorylation, supporting a low off-target rate for Vemurafenib. Functional classification of target proteins indicated the enrichment of known (nuclear pore, transcription factors, RAS-RTK signaling) and novel (Rho GTPases signaling, actin cytoskeleton) ERK-controlled functions. Our phosphoproteomic data combined with experimental validation established novel dynamic connections between ERK signaling and the transcriptional regulators TEAD3 (Hippo pathway), MKL1 and MKL2 (Rho-SRF pathway). We also confirm that an ERK docking site found in MKL1 is directly antagonized by overlapping actin binding, defining a novel mechanism of actin-modulated phosphorylation. Altogether, time-resolved phosphoproteomics further documented Vemurafenib selectivity and identified novel ERK downstream substrates.
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The HLA-B27 peptidome in vivo in spondyloarthritis-susceptible HLA-B27 transgenic rats and the effect of ERAP1 deletion [Research]
HLA-B27 is a class I major histocompatibility (MHC-I) allele that confers susceptibility to the rheumatic disease ankylosing spondylitis (AS) by an unknown mechanism. ERAP1 is an aminopeptidase that trims peptides in the endoplasmic reticulum for binding to MHC-I molecules. ERAP1 shows genetic epistasis with HLA-B27 in conferring susceptibility to AS. Male HLA-B27 transgenic rats develop arthritis and serve as an animal model of AS, whereas female B27 transgenic rats remain healthy. We used large-scale quantitative mass-spectrometry to identify over 15,000 unique HLA-B27 peptide ligands, isolated after immunoaffinity purification of the B27 molecules from the spleens of HLA-B27 transgenic rats. Heterozygous deletion of ERAP1, which reduced ERAP1 level to less than half, had no qualitative or quantitative effects on the B27 peptidome. Homozygous deletion of ERAP1 affected approximately one third of the B27 peptidome, but left most of the B27 peptidome unchanged, suggesting the possibility that some of the HLA-B27 immunopeptidome is not processed in the presence of ERAP1. Deletion on ERAP1 was permissive for the AS-like phenotype. Deletion of ERAP1 increased mean peptide length, and increased the frequency of C-terminal hydrophobic residues and of N-terminal Ala, Ser or Lys. The presence of ERAP1 increased the frequency of C-terminal Lys and Arg, of Glu and Asp at intermediate residues, and of N-terminal Gly. Several peptides of potential interest in AS pathogenesis, previously identified in human cell lines, were isolated. However, rats susceptible to arthritis had B27 peptidomes similar to those of non-susceptible rats, and no peptides were found to be uniquely associated with arthritis. Whether specific B27-bound peptides are required for AS pathogenesis remains to be determined. Data are available via ProteomeXchange with identifier PXD005502.
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Proteomic screen for cellular targets of the vaccinia virus F10 protein kinase reveals that phosphorylation of mDia regulates stress fiber formation [Research]
Vaccinia virus, a complex dsDNA virus, is unusual in replicating exclusively within the cytoplasm of infected cells. While this prototypic poxvirus encodes >200 proteins utilized during infection, a significant role for host proteins and cellular architecture is increasingly evident. The viral B1 kinase and H1 phosphatase are known to target cellular proteins as well as viral substrates, but little is known about the cellular substrates of the F10 kinase. F10 is essential for virion morphogenesis, beginning with the poorly understood process of diversion of membranes from the ER for the purpose of virion membrane biogenesis. To better understand the function of F10, we generated a cell line that carries a single, inducible F10 transgene. Using uninduced and induced cells, we performed stable isotope labeling of amino acids in cell culture (SILAC) coupled with phosphopeptide analysis to identify cellular targets of F10-mediated phosphorylation. We identified 27 proteins that showed statistically significant changes in phosphorylation upon the expression of the F10 kinase: 18 proteins showed an increase in phosphorylation while 9 proteins showed a decrease in phosphorylation. These proteins participate in several distinct cellular processes including cytoskeleton dynamics, membrane trafficking and cellular metabolism. One of the proteins with the greatest change in phosphorylation was mDia, a member of the formin family of cytoskeleton regulators; F10 induction led to increased phosphorylation on ser22. Induction of F10 induced a statistically significant decrease in the percentage of cells with actin stress fibers; however, this change was abrogated when an mDia ser22->ala variant was expressed. Moreover, expression of a ser22->asp variant leads to a reduction of stress fibers even in cells not expressing F10. In sum, we present the first unbiased screen for cellular targets of F10-mediated phosphorylation, and in so doing describe a heretofore unknown mechanism for regulating stress fiber formation through phosphorylation of mDia. Data are available via ProteomeXchange with identifier PXD005246.
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Comparative proteomics of purified pathogen vacuoles correlates intracellular replication of Legionella pneumophila with the small GTPase Rap1 [Research]
Legionella pneumophila is an opportunistic bacterial pathogen that causes a severe lung infection termed Legionnaires disease. The pathogen replicates in environmental protozoa as well as in macrophages within a unique membrane-bound compartment, the Legionella-containing-vacuole (LCV). LCV formation requires the bacterial Icm/Dot type IV secretion system, which translocates ca. 300 effector proteins into host cells, where they target distinct host factors. The L. pneumophila pentuple mutant (pentuple) lacks 5 gene clusters (31% of the effector proteins) and replicates in macrophages but not in Dictyostelium discoideum amoeba. To elucidate the host factors defining a replication-permissive compartment, we compare here the proteomes of intact LCVs isolated from D. discoideum or macrophages infected with Delta_pentuple or the parental strain Lp02. This analysis revealed that the majority of host proteins are shared in D. discoideum or macrophage LCVs containing the mutant or the parental strain, respectively, while some proteins preferentially localize to distinct LCVs. The small GTPase Rap1 was identified on D. discoideum LCVs containing strain Lp02 but not the pentuple mutant and on macrophage LCVs containing either strain. The localization pattern of active Rap1 on D. discoideum or macrophage LCVs was confirmed by fluorescence microscopy and imaging flow cytometry, and the depletion of Rap1 by RNA interference significantly reduced the intracellular growth of L. pneumophila. Thus, comparative proteomics identified Rap1 as a novel LCV host component implicated in intracellular replication of L. pneumophila.
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Targeted proteomics and absolute protein quantification for the construction of a stoichiometric host-pathogen surface density model [Research]
Sepsis is a systemic immune response responsible for considerable morbidity and mortality. Molecular modelling of host-pathogen interactions in the disease state represents a promising strategy to define molecular events of importance for the transition from superficial to invasive infectious diseases. Here we used the gram-positive bacterium Streptococcus pyogenes as a model system to establish a mass spectrometry based workflow for the construction of a stoichiometric surface density model between the S. pyogenes surface, the surface virulence factor M-protein, and adhered human blood plasma proteins. The workflow relies on stable isotope labelled reference peptides and selected reaction monitoring mass spectrometry analysis of a wild-type strain and an M-protein deficient mutant strain, to generate absolutely quantified protein stoichiometry ratios between S. pyogenes and interacting plasma proteins. The stoichiometry ratios in combination with a novel targeted mass spectrometry method to measure cell numbers enabled the construction of a stoichiometric surface density model using protein structures available from the protein data bank. The model outlines the topology and density of the host-pathogen protein interaction network on the S. pyogenes bacterial surface, revealing a dense and highly organized protein interaction network. Removal of the M-protein from S. pyogenes introduces a drastic change in the network topology, validated by electron microscopy. We propose that the stoichiometric surface density model of S. pyogenes in human blood plasma represents a scalable framework that can continuously be refined with the emergence of new results. Future integration of new results will improve the understanding of protein-protein interactions and their importance for bacterial virulence. Furthermore, we anticipate that the general properties of the developed workflow will facilitate the production of stoichiometric surface density models for other types of host-pathogen interactions.
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New Guidelines for Publication of Manuscripts Describing Development and Application of Targeted Mass Spectrometry Measurements of Peptides and Proteins [Editorial]
Molecular & Cellular Proteomics is pleased to announce new guidelines and requirements for papers describing the development and application of targeted mass spectrometry measurements of peptides, modified peptides and proteins. These guidelines will be implemented for papers submitted starting June, 2017.
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Asparagine-linked Glycans of Cryptosporidium parvum Contain a Single Long Arm, Are Barely Processed in the ER or Golgi, and Show a Strong Bias for Sites with Threonine [Research]
Cryptosporidium parvum causes severe diarrhea in infants in developing countries and in immunosuppressed persons, including those with AIDS. We are interested in the Asn-linked glycans (N-glycans) of C. parvum, because 1) the N-glycan precursor is predicted to contain five mannose and two glucose residues on a single long arm versus nine mannose and three glucose residues on the three-armed structure common in host N-glycans, 2) C. parvum is a rare eukaryote that lacks the machinery for N-glycan-dependent quality control of protein folding in the lumen of the Endoplasmic Reticulum (ER), and 3) ER and Golgi mannosidases, as well as glycosyltransferases that build complex N-glycans, are absent from the predicted proteome. The C. parvum N-glycans reported here, which were determined using a combination of collision-induced dissociation and electronic excitation dissociation, contain a single, unprocessed mannose arm +/- terminal glucose on the trimannosyl chitobiose core. Upon UPLC-MS separation and analysis of the C. parvum tryptic peptides, the total ion and extracted oxonium ion chromatograms delineated 32 peptides with occupied N-glycan sites; these were derived from 16 glycoproteins. While the number of potential N-glycan sites with Thr (NxT) is only about twice that with Ser (NxS), almost 90% of the occupied N-glycan sites contain NxT. The two most abundant C. parvum proteins modified with N-glycans were an immunodominant antigen on the surface of sporozoites (gp900) and the possible oocyst wall protein 1 (POWP1). Seven other glycoproteins with N-glycans were unique to C. parvum; five shared common ancestry with other apicomplexans; two glycoproteins shared common ancestry with many organisms. In summary, C. parvum N-glycans are remarkable for the absence of ER and Golgi modification and for the strong bias towards occupancy of N-glycan motifs containing Thr. Data are available via ProteomeXchange with identifier PXD005503.
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Sharpening host defenses during infection: Proteases cut to the chase [Perspective]
The human immune system consists of an intricate network of tightly controlled pathways, where proteases are essential regulators and executioners at multiple levels. Invading microbial pathogens also encode proteases that have evolved to manipulate and dysregulate host proteins including host proteases during the course of disease. The identification of pathogen proteases as well as their substrates and mechanisms of action have empowered significant developments in therapeutics for infectious diseases. Yet for many pathogens, there remains a great deal to be discovered. Recently, proteomic techniques have been developed that can identify proteolytically-processed proteins across the proteome. These 'degradomics' approaches can identify human substrates of microbial proteases during infection in vivo and expose the molecular-level changes that occur in the human proteome during infection as an operational network, to develop hypotheses for further research as well as new therapeutics. This Perspective Article reviews how proteases are utilized during infection by both the human host and invading bacterial pathogens, including archetypal virulence-associated microbial proteases, such as the Clostridia spp. botulinum and tetanus neurotoxins. We highlight the potential knowledge that degradomics studies of host-pathogen interactions would uncover, as well as how degradomics has been successfully applied in similar contexts, including use with a viral protease. We review how microbial proteases have been targeted in current therapeutic approaches, and how microbial proteases have shaped and even contributed to human therapeutics beyond infectious disease. Finally, we discuss how, moving forward, degradomics research would greatly contribute to our understanding of how microbial pathogens cause disease in vivo, the identification of novel substrates in vivo, and the development of improved therapeutics to counter these pathogens.
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The new issue is now available.Chikyukagaku
Vol.44 No.4
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The new issue is now available.Japanese Journal of Allergology
Vol.48 No.12
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Mathematical modelling unveils the essential role of cellular phosphatases in the inhibition of RAF-MEK-ERK signalling by sorafenib in hepatocellular carcinoma cells
Publication date: 28 April 2017
Source:Cancer Letters, Volume 392
Author(s): Zuzana Saidak, Anne-Sophie Giacobbi, Christophe Louandre, Chloé Sauzay, Youcef Mammeri, Antoine Galmiche
The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. We analysed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib. In silico predictions derived from our mathematical model suggested that the disappearance of phosphorylated MEK and ERK proteins catalysed by cellular phosphatases is an essential mechanism underlying the anti-ERK efficacy of sorafenib in HCC cells. This prediction was experimentally validated using specific inhibitors of the phosphatases PP2A (Protein Phosphatase 2A) and DUSP1/6 (Dual-specificity phosphatases 1/6). These findings highlight an unexpected mode of action of sorafenib on the kinome of HCC cells, and open new perspectives regarding the therapeutic targeting of the RAF-MEK-ERK cascade in this context.
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Source:Cancer Letters, Volume 392
Author(s): Zuzana Saidak, Anne-Sophie Giacobbi, Christophe Louandre, Chloé Sauzay, Youcef Mammeri, Antoine Galmiche
The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. We analysed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib. In silico predictions derived from our mathematical model suggested that the disappearance of phosphorylated MEK and ERK proteins catalysed by cellular phosphatases is an essential mechanism underlying the anti-ERK efficacy of sorafenib in HCC cells. This prediction was experimentally validated using specific inhibitors of the phosphatases PP2A (Protein Phosphatase 2A) and DUSP1/6 (Dual-specificity phosphatases 1/6). These findings highlight an unexpected mode of action of sorafenib on the kinome of HCC cells, and open new perspectives regarding the therapeutic targeting of the RAF-MEK-ERK cascade in this context.
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The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL)
Publication date: 28 April 2017
Source:Cancer Letters, Volume 392
Author(s): Mohiuddin Gazi, Sausan A. Moharram, Alissa Marhäll, Julhash U. Kazi
Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting.
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Source:Cancer Letters, Volume 392
Author(s): Mohiuddin Gazi, Sausan A. Moharram, Alissa Marhäll, Julhash U. Kazi
Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting.
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MHC class II restricted neoantigen: A promising target in tumor immunotherapy
Publication date: 28 April 2017
Source:Cancer Letters, Volume 392
Author(s): Zhichen Sun, Fangjun Chen, Fanyan Meng, Jia Wei, Baorui Liu
Neoantigen is a patient-specific tumor antigen resulted from mutations during oncogenesis. Emerging data suggested that immune responsiveness against neoantigens correlated with the success of clinical tumor immunotherapies. Nowadays, the majority of studies on neoantigens have focused on MHC class I restricted antigens recognized by CD8+ T cells. With improved understanding of the underlying principles of tumor biology and immunology, increasing emphasis has been put on CD4+ T cells and MHC class II restricted antigens. MHC class II restricted neoantigen has the potential to be a promising target of tumor immunotherapy, although the limited comprehension and technical difficulties need to be overcome before being applied into clinical practice. This review discussed the immunologic mechanism, screening technique, clinical application, limitations and prospectives of MHC class II restricted neoantigens in tumor immunotherapy.
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Source:Cancer Letters, Volume 392
Author(s): Zhichen Sun, Fangjun Chen, Fanyan Meng, Jia Wei, Baorui Liu
Neoantigen is a patient-specific tumor antigen resulted from mutations during oncogenesis. Emerging data suggested that immune responsiveness against neoantigens correlated with the success of clinical tumor immunotherapies. Nowadays, the majority of studies on neoantigens have focused on MHC class I restricted antigens recognized by CD8+ T cells. With improved understanding of the underlying principles of tumor biology and immunology, increasing emphasis has been put on CD4+ T cells and MHC class II restricted antigens. MHC class II restricted neoantigen has the potential to be a promising target of tumor immunotherapy, although the limited comprehension and technical difficulties need to be overcome before being applied into clinical practice. This review discussed the immunologic mechanism, screening technique, clinical application, limitations and prospectives of MHC class II restricted neoantigens in tumor immunotherapy.
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Clearance of cardiac troponin T with and without kidney function
Publication date: Available online 11 February 2017
Source:Clinical Biochemistry
Author(s): Vincent Fridén, Karin Starnberg, Aida Muslimovic, Sven-Erik Ricksten, Christian Bjurman, Niklas Forsgard, Anna Wickman, Ola Hammarsten
ObjectiveThe extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known.Methods and resultsWe examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8–19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort.ConclusionsAt high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.
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Source:Clinical Biochemistry
Author(s): Vincent Fridén, Karin Starnberg, Aida Muslimovic, Sven-Erik Ricksten, Christian Bjurman, Niklas Forsgard, Anna Wickman, Ola Hammarsten
ObjectiveThe extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known.Methods and resultsWe examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8–19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort.ConclusionsAt high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.
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Primary mediastinal large B cell lymphoma in a woman who is human immunodeficiency virus positive presenting with superior vena cava syndrome: a case report
The risk of non-Hodgkin lymphoma is increased 200-fold in individuals seropositive for human immunodeficiency virus compared to those free from human immunodeficiency virus. Human immunodeficiency virus-associ...
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Molecular landscape of arthrofibrosis: Microarray and bioinformatic analysis of the temporal expression of 380 genes during contracture genesis
Publication date: 30 April 2017
Source:Gene, Volume 610
Author(s): Mark E. Morrey, Matthew P. Abdel, Scott M. Riester, Amel Dudakovic, Andre J. van Wijnen, Bernard F. Morrey, Joaquin Sanchez-Sotelo
PurposeInflammatory changes are suspected in the pathophysiology of arthrofibrosis formation and require early molecular examination. Here, we assessed the hypothesis that early inflammatory genes are related to arthrofibrosis by ascertaining gene expression during the early stages of contracture genesis in an animal model.MethodsJoint trauma was incited surgically in a cohort of rabbits (n=36) knees followed by immobilization in a model of contracture. Six groups of 6 rabbits were sacrificed at multiple time points (0, 6, 12, 24, 72h and 2weeks). Microarray expression and RT-qPCR profiling were performed to determine genes that are significantly up or downregulated. Bioinformatic analysis was carried out to understand which biological programs and functional groups of genes are modulated in arthrofibrosis.ResultsGene expression profiling revealed a large number biologically relevant genes (>100) that are either upregulated or downregulated by at least a 1.5 fold (log2) during the first two weeks after joint injury during contracture development. Gene ontology analysis identified molecular pathways and programs that act during the course of fibrosis and joint contracture. Our main finding is that the development of contractures occur concomitant with modulation of genes mediating inflammatory responses, ECM remodeling and the epithelial-to-mesenchymal transition.ConclusionThe genesis of joint contracture reflects an imbalance between pro- and anti-fibrotic expression. Our study indicates that inflammatory genes may be involved in the process of contracture genesis and initiated at relatively early stages. Our findings also may inform clinical practice in the future by suggesting potential therapeutic targets in preventing the long-term development of arthrofibrosis.
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Source:Gene, Volume 610
Author(s): Mark E. Morrey, Matthew P. Abdel, Scott M. Riester, Amel Dudakovic, Andre J. van Wijnen, Bernard F. Morrey, Joaquin Sanchez-Sotelo
PurposeInflammatory changes are suspected in the pathophysiology of arthrofibrosis formation and require early molecular examination. Here, we assessed the hypothesis that early inflammatory genes are related to arthrofibrosis by ascertaining gene expression during the early stages of contracture genesis in an animal model.MethodsJoint trauma was incited surgically in a cohort of rabbits (n=36) knees followed by immobilization in a model of contracture. Six groups of 6 rabbits were sacrificed at multiple time points (0, 6, 12, 24, 72h and 2weeks). Microarray expression and RT-qPCR profiling were performed to determine genes that are significantly up or downregulated. Bioinformatic analysis was carried out to understand which biological programs and functional groups of genes are modulated in arthrofibrosis.ResultsGene expression profiling revealed a large number biologically relevant genes (>100) that are either upregulated or downregulated by at least a 1.5 fold (log2) during the first two weeks after joint injury during contracture development. Gene ontology analysis identified molecular pathways and programs that act during the course of fibrosis and joint contracture. Our main finding is that the development of contractures occur concomitant with modulation of genes mediating inflammatory responses, ECM remodeling and the epithelial-to-mesenchymal transition.ConclusionThe genesis of joint contracture reflects an imbalance between pro- and anti-fibrotic expression. Our study indicates that inflammatory genes may be involved in the process of contracture genesis and initiated at relatively early stages. Our findings also may inform clinical practice in the future by suggesting potential therapeutic targets in preventing the long-term development of arthrofibrosis.
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Knockdown of linc-OIP5 inhibits proliferation and migration of glioma cells through down-regulation of YAP-NOTCH signaling pathway
Publication date: 30 April 2017
Source:Gene, Volume 610
Author(s): Guo-wen Hu, Lei Wu, Wei Kuang, Yong Chen, Xin-gen Zhu, Hua Guo, Hai-li Lang
Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating the biological functions and underlying molecular mechanisms of glioma. Here, we investigated the expression level and biological function of linc-OIP5 in glioma. In the current study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to determine the expression of linc-OIP5 in glioma tissues and in adjacent normal tissues. Level of linc-OIP5 was up-regulated in glioma tissues and significantly correlated with the advanced tumor stage (III/IV). Subsequently, the efficacy of knockdown of linc-OIP5 by linc-OIP5-small interfering RNA (siRNA) was evaluated in vitro, and we found that knockdown of linc-OIP5 can inhibit glioma cells proliferation, migration in vitro and tumor formation in vivo. Further mechanistic studies revealed the effect of linc-OIP5 knockdown on glioma cell phenotype at least partially through down-regulation of YAP and inhibition of Notch signaling pathway activity. Thus, our study provides evidence that linc-OIP5 is a potential therapeutic target and novel molecular biomarker for glioma.
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Source:Gene, Volume 610
Author(s): Guo-wen Hu, Lei Wu, Wei Kuang, Yong Chen, Xin-gen Zhu, Hua Guo, Hai-li Lang
Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating the biological functions and underlying molecular mechanisms of glioma. Here, we investigated the expression level and biological function of linc-OIP5 in glioma. In the current study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to determine the expression of linc-OIP5 in glioma tissues and in adjacent normal tissues. Level of linc-OIP5 was up-regulated in glioma tissues and significantly correlated with the advanced tumor stage (III/IV). Subsequently, the efficacy of knockdown of linc-OIP5 by linc-OIP5-small interfering RNA (siRNA) was evaluated in vitro, and we found that knockdown of linc-OIP5 can inhibit glioma cells proliferation, migration in vitro and tumor formation in vivo. Further mechanistic studies revealed the effect of linc-OIP5 knockdown on glioma cell phenotype at least partially through down-regulation of YAP and inhibition of Notch signaling pathway activity. Thus, our study provides evidence that linc-OIP5 is a potential therapeutic target and novel molecular biomarker for glioma.
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Characterization of Bombyx mori mitochondrial transcription factor A, a conserved regulator of mitochondrial DNA
Publication date: 15 April 2017
Source:Gene, Volume 608
Author(s): Megumi Sumitani, Mari Kondo, Katsumi Kasashima, Hitoshi Endo, Kaoru Nakamura, Toshihiko Misawa, Hiromitsu Tanaka, Hideki Sezutsu
In the present study, we initially cloned and characterized a mitochondrial transcription factor A (Tfam) homologue in the silkworm, Bombyx mori. Bombyx mori TFAM (BmTFAM) localized to mitochondria in cultured silkworm and human cells, and co-localized with mtDNA nucleoids in human HeLa cells. In an immunoprecipitation analysis, BmTFAM was found to associate with human mtDNA in mitochondria, indicating its feature as a non-specific DNA-binding protein. In spite of the low identity between BmTFAM and human TFAM (26.5%), the expression of BmTFAM rescued mtDNA copy number reductions and enlarged mtDNA nucleoids in HeLa cells, which were induced by human Tfam knockdown. Thus, BmTFAM compensates for the function of human TFAM in HeLa cells, demonstrating that the mitochondrial function of TFAM is highly conserved between silkworms and humans. BmTfam mRNA was strongly expressed in early embryos. Through double-stranded RNA (dsRNA)-based RNA interference (RNAi) in silkworm embryos, we found that the knockdown of BmTFAM reduced the amount of mtDNA and induced growth retardation at the larval stage. Collectively, these results demonstrate that BmTFAM is a highly conserved mtDNA regulator and may be a good candidate for investigating and modulating mtDNA metabolism in this model organism.
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Source:Gene, Volume 608
Author(s): Megumi Sumitani, Mari Kondo, Katsumi Kasashima, Hitoshi Endo, Kaoru Nakamura, Toshihiko Misawa, Hiromitsu Tanaka, Hideki Sezutsu
In the present study, we initially cloned and characterized a mitochondrial transcription factor A (Tfam) homologue in the silkworm, Bombyx mori. Bombyx mori TFAM (BmTFAM) localized to mitochondria in cultured silkworm and human cells, and co-localized with mtDNA nucleoids in human HeLa cells. In an immunoprecipitation analysis, BmTFAM was found to associate with human mtDNA in mitochondria, indicating its feature as a non-specific DNA-binding protein. In spite of the low identity between BmTFAM and human TFAM (26.5%), the expression of BmTFAM rescued mtDNA copy number reductions and enlarged mtDNA nucleoids in HeLa cells, which were induced by human Tfam knockdown. Thus, BmTFAM compensates for the function of human TFAM in HeLa cells, demonstrating that the mitochondrial function of TFAM is highly conserved between silkworms and humans. BmTfam mRNA was strongly expressed in early embryos. Through double-stranded RNA (dsRNA)-based RNA interference (RNAi) in silkworm embryos, we found that the knockdown of BmTFAM reduced the amount of mtDNA and induced growth retardation at the larval stage. Collectively, these results demonstrate that BmTFAM is a highly conserved mtDNA regulator and may be a good candidate for investigating and modulating mtDNA metabolism in this model organism.
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Editorial Board
Publication date: 15 April 2017
Source:Gene, Volume 608
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Source:Gene, Volume 608
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Identification and characterization of Orf virus 050 protein proteolysis
Abstract
The Orf virus 050 (ORFV050) gene is located in the core region of the ORFV genome. It is similar to Vaccinia virus (VV) Copenhagen L4R, and encodes the DNA-binding virion core protein VP8, which has structures similar to the VV P25K core protein and may undergo similar proteolytic processing during virus assembly. Three conserved Ala–Gly–X motifs at putative cleavage sites were identified in ORFV050. To investigate the proteolysis of ORFV050 and its participation in viral assembly, full-length and site-directed mutant ORFV050 recombinant proteins were constructed and expressed. Two distinct protein bands of 28.5 and 25 kDa were detected in the infected cells using anti-ORFV050 polyclonal antiserum. A potential cleavage site was identified at amino acids 30–32 of ORFV050. Mutation of AG/A to (R) in ORFV050 abolished the process of proteolysis. ORFV050 is a late gene synthesized during viral replication in the host cytoplasm. According to these results, we conclude that ORFV050 undergoes proteolysis and plays an important role in viral assembly.
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Refractory sleep apnea caused by tubal tonsillar hypertrophy
Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Seok Chan Hong, Hyun Jin Min, Kyung Soo Kim
Snoring/sleep apnea are usual symptoms of adenotonsillar hypertrophy, and adenotonsillectomy is usually recommended. In rare cases, symptoms remain after surgery, and tubal tonsil hypertrophy could be the cause. We experienced a pediatric patient whose symptoms were refratory snoring/sleep apnea although he previously underwent three times of adenotonsillectomy. We diagnosed tubal tonsil hypertrophy which was the cause of refractory symptoms, and decided to perform volume reduction with radiofrequency ablation. We suggest that tubal tonsil hypertrophy should be taken into account of the cause of refractory sleep apnea after adenotonsillectomy, and volume reduction with radiofrequency may be an effective method.
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Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Seok Chan Hong, Hyun Jin Min, Kyung Soo Kim
Snoring/sleep apnea are usual symptoms of adenotonsillar hypertrophy, and adenotonsillectomy is usually recommended. In rare cases, symptoms remain after surgery, and tubal tonsil hypertrophy could be the cause. We experienced a pediatric patient whose symptoms were refratory snoring/sleep apnea although he previously underwent three times of adenotonsillectomy. We diagnosed tubal tonsil hypertrophy which was the cause of refractory symptoms, and decided to perform volume reduction with radiofrequency ablation. We suggest that tubal tonsil hypertrophy should be taken into account of the cause of refractory sleep apnea after adenotonsillectomy, and volume reduction with radiofrequency may be an effective method.
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A case of acute clival osteomyelitis in a 7-year-old boy secondary to infection of a Thornwaldt cyst
Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Yasmine Benadjaoud, Nathalie Klopp-Dutote, Morgane Choquet, Elodie Brunel, Raphaël Guiheneuf, Cyril Page
Clival osteomyelitis is a potentially life-threatening infection that can occur in healthy children. It can be related to congenital anomalies. We report the case of a 7-year-old boy with Streptococcus intermedius and Fusobacterium clival osteomyelitis arising from a Thornwaldt cyst situated in a fossa navicularis magna of the occipital bone. Multidisciplinary management is necessary to ensure rapid improvement and complete healing.
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Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Yasmine Benadjaoud, Nathalie Klopp-Dutote, Morgane Choquet, Elodie Brunel, Raphaël Guiheneuf, Cyril Page
Clival osteomyelitis is a potentially life-threatening infection that can occur in healthy children. It can be related to congenital anomalies. We report the case of a 7-year-old boy with Streptococcus intermedius and Fusobacterium clival osteomyelitis arising from a Thornwaldt cyst situated in a fossa navicularis magna of the occipital bone. Multidisciplinary management is necessary to ensure rapid improvement and complete healing.
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Pycnodysostosis at Otorhinolaryngology
Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Muhammet Fatih Topuz, Adem Binnetoglu, Murat Sarı, Tekin Baglam, Serap Turan
AimPycnodysostosis is a rare autosomal, recessive, skeletal dysplasia caused by a mutation in the cathepsin k gene. Pycnodysostosis is characterized by short stature, characteristic facial appearance (delayed closure of fontanelles and cranial sutures, mandibular hypoplasia and angle disorder, blue sclera), and acroosteolysis of the distal phalanges. Our aim was to describe the otorhinolaryngologic findings, differential diagnoses, various treatment options, and followup in eight cases of pycnodysostosis.MethodThis retrospective clinical study used data from eight patients diagnosed with pycnodysostosis by a single pediatric endocrinologist primarily based on clinical and radiographic findings. All patients were referred to the otorhinolaryngology outpatient clinic by the pediatric endocrinology unit of the Marmara University between February 2013 and March 2015. Detailed medical histories were obtained in all cases and otorhinolaryngologic physical examination, blood assays, electrocardiogram, lateral skull X-rays, chest radiograph, cephalometric investigations, tympanograms, and audiograms were also carried out. Sleep videos of patients were recorded and those with upper airway problems were evaluated for sleep apnea by polysomnography. Informed consent form was obtained from the parents of all patients.ResultsEight patients (7 females and 1 male) displaying proportionate dwarfism were included in the study. They had a mean age of 14.7 years (range: 13-16 y), the mean height of 141.3 cm (range 132-155 cm), and mean weight of 44.4 kg (range: 39.6-49.3 kg). All patients had facial dysmorphism with frontal bossing and the hands and feet had short digits with overlying cutaneous wrinkles that tapered off with large overriding nails. Midfacial hypoplasia and malocclusion were observed in seven of the eight patients (87.5%), four (50%) had micrognathia, and five (62.5%) had proptosis. Tympanograms and audiograms of all patients were type A and normal, and the mean of the pure tone audiogram was 13.3 dB (range: 10-16 dB). All patients had a narrow and grooved palate with disturbed dentition; two of them (25%) had mild markedness of the tongue base, five (62.5%) had grade 3 and three (37.5%) had grade 2 tonsillar hypertrophy, and five (62.5%) had adenoid hypertrophy. One patient (12.5%) had grade 3 Mallampati, four (50%) showed grade 2 Mallampati while three (37.5%) patients displayed grade 1 Mallampati score. Further, while six (75%) patients had no uvular pathology, one (12.5%) patient presented with uvular elongation and another patient had a bifid uvula. Cephalometric measurements such as PAS-UP (mean 5.67 mm; range: 5.0-7.6 mm) and PAS-TP (mean 9.61 mm; range: 8.5 - 12.2 mm) were lower than that of normal subjects. Video recordings showed that six of the eight patients (75%) had respiratory distress and four (50%) had sleep apnea. Polysomnography in these patients with sleep apnea showed that two had mild OSA (AHI: 18.2 and 20.1 events/hour) and two had severe OSA (AHI: 53.4 and 62.8 events/hour). For upper airway problems, an adenotonsillectomy was performed in two (25%) patients while two others required an adenoidectomy. Positive pressure ventilation was recommended in two patients with persistent sleep apnea after adeno/adenotonsillectomy. However, because of the parental objections, the follow-up polysomnographs could not be obtained.ConclusionPycnodysostosis is a very rare form of bone dysplasia. Otorhinolaryngologically, proper follow-up of these patients and appropriate treatment of upper airway problems are important to achieve an acceptable quality of life. Adeno/adenotonsillectomy and positive pressure ventilation, used as conservative approaches in treating upper airway problems, are effective and could be used instead of an aggressive surgery such as tracheotomy or maxillomandibular advancement. This study, to the best of our knowledge, is the largest case series on pycnodysostosis.
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Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Muhammet Fatih Topuz, Adem Binnetoglu, Murat Sarı, Tekin Baglam, Serap Turan
AimPycnodysostosis is a rare autosomal, recessive, skeletal dysplasia caused by a mutation in the cathepsin k gene. Pycnodysostosis is characterized by short stature, characteristic facial appearance (delayed closure of fontanelles and cranial sutures, mandibular hypoplasia and angle disorder, blue sclera), and acroosteolysis of the distal phalanges. Our aim was to describe the otorhinolaryngologic findings, differential diagnoses, various treatment options, and followup in eight cases of pycnodysostosis.MethodThis retrospective clinical study used data from eight patients diagnosed with pycnodysostosis by a single pediatric endocrinologist primarily based on clinical and radiographic findings. All patients were referred to the otorhinolaryngology outpatient clinic by the pediatric endocrinology unit of the Marmara University between February 2013 and March 2015. Detailed medical histories were obtained in all cases and otorhinolaryngologic physical examination, blood assays, electrocardiogram, lateral skull X-rays, chest radiograph, cephalometric investigations, tympanograms, and audiograms were also carried out. Sleep videos of patients were recorded and those with upper airway problems were evaluated for sleep apnea by polysomnography. Informed consent form was obtained from the parents of all patients.ResultsEight patients (7 females and 1 male) displaying proportionate dwarfism were included in the study. They had a mean age of 14.7 years (range: 13-16 y), the mean height of 141.3 cm (range 132-155 cm), and mean weight of 44.4 kg (range: 39.6-49.3 kg). All patients had facial dysmorphism with frontal bossing and the hands and feet had short digits with overlying cutaneous wrinkles that tapered off with large overriding nails. Midfacial hypoplasia and malocclusion were observed in seven of the eight patients (87.5%), four (50%) had micrognathia, and five (62.5%) had proptosis. Tympanograms and audiograms of all patients were type A and normal, and the mean of the pure tone audiogram was 13.3 dB (range: 10-16 dB). All patients had a narrow and grooved palate with disturbed dentition; two of them (25%) had mild markedness of the tongue base, five (62.5%) had grade 3 and three (37.5%) had grade 2 tonsillar hypertrophy, and five (62.5%) had adenoid hypertrophy. One patient (12.5%) had grade 3 Mallampati, four (50%) showed grade 2 Mallampati while three (37.5%) patients displayed grade 1 Mallampati score. Further, while six (75%) patients had no uvular pathology, one (12.5%) patient presented with uvular elongation and another patient had a bifid uvula. Cephalometric measurements such as PAS-UP (mean 5.67 mm; range: 5.0-7.6 mm) and PAS-TP (mean 9.61 mm; range: 8.5 - 12.2 mm) were lower than that of normal subjects. Video recordings showed that six of the eight patients (75%) had respiratory distress and four (50%) had sleep apnea. Polysomnography in these patients with sleep apnea showed that two had mild OSA (AHI: 18.2 and 20.1 events/hour) and two had severe OSA (AHI: 53.4 and 62.8 events/hour). For upper airway problems, an adenotonsillectomy was performed in two (25%) patients while two others required an adenoidectomy. Positive pressure ventilation was recommended in two patients with persistent sleep apnea after adeno/adenotonsillectomy. However, because of the parental objections, the follow-up polysomnographs could not be obtained.ConclusionPycnodysostosis is a very rare form of bone dysplasia. Otorhinolaryngologically, proper follow-up of these patients and appropriate treatment of upper airway problems are important to achieve an acceptable quality of life. Adeno/adenotonsillectomy and positive pressure ventilation, used as conservative approaches in treating upper airway problems, are effective and could be used instead of an aggressive surgery such as tracheotomy or maxillomandibular advancement. This study, to the best of our knowledge, is the largest case series on pycnodysostosis.
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Calcium, oxidative stress and connexin channels, a harmonious orchestra directing the response to radiotherapy treatment?
Publication date: Available online 11 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Elke Decrock, Delphine Hoorelbeke, Raghda Ramadan, Tinneke Delvaeye, Marijke De Bock, Nan Wang, Dmitri V Krysko, Sarah Baatout, Geert Bultynck, An Aerts, Mathieu Vinken, Luc Leybaert
Although radiotherapy is commonly used to treat cancer, its beneficial outcome is frequently hampered by the radiation resistance of tumor cells and adverse reactions in normal tissues. Mechanisms of cell-to-cell communication and how intercellular signals are translated into cellular responses, have become topics of intense investigation, particularly within the field of radiobiology. A substantial amount of evidence is available demonstrating that both gap junctional and paracrine communication pathways can propagate radiation-induced biological effects at the intercellular level, commonly referred to as radiation-induced bystander effects (RIBE). Multiple molecular signaling mechanisms involving oxidative stress, kinases, inflammatory molecules, and Ca2+ are postulated to contribute to RIBE. Ca2+ is a highly versatile and ubiquitous second messenger that regulates diverse cellular processes via the interaction with various signaling cascades. It furthermore provides a fast system for the dissemination of information at the intercellular level. Channels formed by transmembrane connexin (Cx) proteins, i.e. hemichannels and gap junction channels, can mediate the cell-to-cell propagation of increases in intracellular Ca2+ by ministering paracrine and direct cell-cell communication, respectively. We here review current knowledge on radiation-induced signaling mechanisms in irradiated and bystander cells, particularly focusing on the contribution of oxidative stress, Ca2+ and Cx channels. By illustrating the tight interplay between these different partners, we provide a conceptual framework for intercellular Ca2+ signaling as a key player in modulating the RIBE and the overall response to radiation.
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Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Elke Decrock, Delphine Hoorelbeke, Raghda Ramadan, Tinneke Delvaeye, Marijke De Bock, Nan Wang, Dmitri V Krysko, Sarah Baatout, Geert Bultynck, An Aerts, Mathieu Vinken, Luc Leybaert
Although radiotherapy is commonly used to treat cancer, its beneficial outcome is frequently hampered by the radiation resistance of tumor cells and adverse reactions in normal tissues. Mechanisms of cell-to-cell communication and how intercellular signals are translated into cellular responses, have become topics of intense investigation, particularly within the field of radiobiology. A substantial amount of evidence is available demonstrating that both gap junctional and paracrine communication pathways can propagate radiation-induced biological effects at the intercellular level, commonly referred to as radiation-induced bystander effects (RIBE). Multiple molecular signaling mechanisms involving oxidative stress, kinases, inflammatory molecules, and Ca2+ are postulated to contribute to RIBE. Ca2+ is a highly versatile and ubiquitous second messenger that regulates diverse cellular processes via the interaction with various signaling cascades. It furthermore provides a fast system for the dissemination of information at the intercellular level. Channels formed by transmembrane connexin (Cx) proteins, i.e. hemichannels and gap junction channels, can mediate the cell-to-cell propagation of increases in intracellular Ca2+ by ministering paracrine and direct cell-cell communication, respectively. We here review current knowledge on radiation-induced signaling mechanisms in irradiated and bystander cells, particularly focusing on the contribution of oxidative stress, Ca2+ and Cx channels. By illustrating the tight interplay between these different partners, we provide a conceptual framework for intercellular Ca2+ signaling as a key player in modulating the RIBE and the overall response to radiation.
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Contralateral Occlusion Test: The effect of external ear canal occlusion on hearing thresholds
Publication date: Available online 10 February 2017
Source:Acta Otorrinolaringológica Española
Author(s): Luis Roque Reis, Paulo Fernandes, Pedro Escada
Introduction and goalsBedside testing with tuning forks may decrease turnaround time and improve decision making for a quick qualitative assessment of hearing loss. The purpose of this study was to quantify the effects of ear canal occlusion on hearing, in order to decide which tuning fork frequency is more appropriate to use for quantifying hearing loss with the Contralateral Occlusion Test.MethodsTwenty normal-hearing adults (forty ears) underwent sound field pure tone audiometry with and without ear canal occlusion. Each ear was tested with the standard frequencies. The contralateral ear was suppressed with by masking. Ear occlusion was performed by two examiners.ResultsParticipants aged between 21 and 30 years (25.6±3.03 years) showed an increase in hearing thresholds with increasing frequencies from 19.94dB (250Hz) to 39.25dB (2000Hz). The threshold difference between occluded and unoccluded conditions was statistically significant and increased from 10.69dB (250Hz) to 32.12dB (2000Hz). There were no statistically significant differences according to gender or between the examiners.ConclusionThe occlusion effect increased the hearing thresholds and became more evident with higher frequencies. The occlusion method as performed demonstrated reproducibility. In the Contralateral Occlusion Test, 256Hz or 512Hz tuning forks should be used for diagnosis of mild hearing loss, and a 2048Hz tuning fork should be used for moderate hearing loss.
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Source:Acta Otorrinolaringológica Española
Author(s): Luis Roque Reis, Paulo Fernandes, Pedro Escada
Introduction and goalsBedside testing with tuning forks may decrease turnaround time and improve decision making for a quick qualitative assessment of hearing loss. The purpose of this study was to quantify the effects of ear canal occlusion on hearing, in order to decide which tuning fork frequency is more appropriate to use for quantifying hearing loss with the Contralateral Occlusion Test.MethodsTwenty normal-hearing adults (forty ears) underwent sound field pure tone audiometry with and without ear canal occlusion. Each ear was tested with the standard frequencies. The contralateral ear was suppressed with by masking. Ear occlusion was performed by two examiners.ResultsParticipants aged between 21 and 30 years (25.6±3.03 years) showed an increase in hearing thresholds with increasing frequencies from 19.94dB (250Hz) to 39.25dB (2000Hz). The threshold difference between occluded and unoccluded conditions was statistically significant and increased from 10.69dB (250Hz) to 32.12dB (2000Hz). There were no statistically significant differences according to gender or between the examiners.ConclusionThe occlusion effect increased the hearing thresholds and became more evident with higher frequencies. The occlusion method as performed demonstrated reproducibility. In the Contralateral Occlusion Test, 256Hz or 512Hz tuning forks should be used for diagnosis of mild hearing loss, and a 2048Hz tuning fork should be used for moderate hearing loss.
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Analysis of Plant UDP- Arabinopyranose Mutase (UAM): Role of Divalent Metals and Structure Prediction
Publication date: Available online 10 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Jijin R.A. Kuttiyatveetil, David A.R. Sanders
UDP-arabinopyranose mutase (UAM) is a plant enzyme which interconverts UDP-arabinopyranose (UDP-Arap; a six-membered sugar) to UDP-arabinofuranose (UDP-Araf; a five-membered sugar). Plant mutases belong to a small gene family called Reversibly Glycosylated Proteins (RGPs). So far, UAM has been identified in Oryza sativa (Rice), Arabidopsis thaliana and Hordeum vulgare (Barley). The enzyme requires divalent metal ions for catalytic activity. Here, the divalent metal ion dependency of UAMs from O. sativa (rice) and A. thaliana have been studied using HPLC-based kinetic assays. It was determined that UAM from these species had the highest relative activity in a range of 40–80μM Mn2+. Excess Mn2+ ion concentration decreased the enzyme activity. This trend was observed when other divalent metal ions were used to test activity. To gain a perspective of the role played by the metal ion in activity, an abinitio structural model was generated based on the UAM amino acid sequence and a potential metal binding region was identified. Based on our results, we propose that the probable role of metal in the UAM is stabilizing the diphosphate of the substrate, UDP-Arap.
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Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Jijin R.A. Kuttiyatveetil, David A.R. Sanders
UDP-arabinopyranose mutase (UAM) is a plant enzyme which interconverts UDP-arabinopyranose (UDP-Arap; a six-membered sugar) to UDP-arabinofuranose (UDP-Araf; a five-membered sugar). Plant mutases belong to a small gene family called Reversibly Glycosylated Proteins (RGPs). So far, UAM has been identified in Oryza sativa (Rice), Arabidopsis thaliana and Hordeum vulgare (Barley). The enzyme requires divalent metal ions for catalytic activity. Here, the divalent metal ion dependency of UAMs from O. sativa (rice) and A. thaliana have been studied using HPLC-based kinetic assays. It was determined that UAM from these species had the highest relative activity in a range of 40–80μM Mn2+. Excess Mn2+ ion concentration decreased the enzyme activity. This trend was observed when other divalent metal ions were used to test activity. To gain a perspective of the role played by the metal ion in activity, an abinitio structural model was generated based on the UAM amino acid sequence and a potential metal binding region was identified. Based on our results, we propose that the probable role of metal in the UAM is stabilizing the diphosphate of the substrate, UDP-Arap.
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Developing a methodology for estimating the drag in front-crawl swimming at various velocities
Publication date: Available online 10 February 2017
Source:Journal of Biomechanics
Author(s): Kenzo Narita, Motomu Nakashima, Hideki Takagi
We aimed to develop a new method for evaluating the drag in front-crawl swimming at various velocities and at full stroke. In this study, we introduce the basic principle and apparatus for the new method, which estimates the drag in swimming using measured values of residual thrust (MRT). Furthermore, we applied the MRT to evaluate the active drag (Da) and compared it with the passive drag (Dp) measured for the same swimmers. Da was estimated in five-stages for velocities ranging from 1.0 to 1.4 m s−1; Dp was measured at flow velocities ranging from 0.9 to 1.5 m s−1 at intervals of 0.1 m s−1. The variability in the values of Da at MRT was also investigated for two swimmers. According to the results, Da (Da = 32.3 v3.3, N = 30, R2 = 0.90) was larger than Dp (Dp = 23.5 v2.0, N = 42, R2 = 0.89) and the variability in Da for the two swimmers was 6.5% and 3.0%. MRT can be used to evaluate Da at various velocities and is special in that it can be applied to various swimming styles. Therefore, the evaluation of drag in swimming using MRT is expected to play a role in establishing the fundamental data for swimming.
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Source:Journal of Biomechanics
Author(s): Kenzo Narita, Motomu Nakashima, Hideki Takagi
We aimed to develop a new method for evaluating the drag in front-crawl swimming at various velocities and at full stroke. In this study, we introduce the basic principle and apparatus for the new method, which estimates the drag in swimming using measured values of residual thrust (MRT). Furthermore, we applied the MRT to evaluate the active drag (Da) and compared it with the passive drag (Dp) measured for the same swimmers. Da was estimated in five-stages for velocities ranging from 1.0 to 1.4 m s−1; Dp was measured at flow velocities ranging from 0.9 to 1.5 m s−1 at intervals of 0.1 m s−1. The variability in the values of Da at MRT was also investigated for two swimmers. According to the results, Da (Da = 32.3 v3.3, N = 30, R2 = 0.90) was larger than Dp (Dp = 23.5 v2.0, N = 42, R2 = 0.89) and the variability in Da for the two swimmers was 6.5% and 3.0%. MRT can be used to evaluate Da at various velocities and is special in that it can be applied to various swimming styles. Therefore, the evaluation of drag in swimming using MRT is expected to play a role in establishing the fundamental data for swimming.
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New Tools for Content Innovation and Data Sharing: Enhancing Reproducibility and Rigor in Biomechanics Research
Publication date: Available online 10 February 2017
Source:Journal of Biomechanics
Author(s): Farshid Guilak
We are currently in one of the most exciting times for science and engineering as we witness unprecedented growth computational and experimental capabilities to generate new data and models. To facilitate data and model sharing, and to enhance reproducibility and rigor in biomechanics research, the Journal of Biomechanics has introduced a number of tools for Content Innovation to allow presentation, sharing, and archiving of methods, models, and data in our articles. The tools include an Interactive Plot Viewer, 3D Geometric Shape and Model Viewer, Virtual Microscope, Interactive MATLAB Figure Viewer, and Audioslides. Authors are highly encouraged to make use of these in upcoming journal submissions.
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Source:Journal of Biomechanics
Author(s): Farshid Guilak
We are currently in one of the most exciting times for science and engineering as we witness unprecedented growth computational and experimental capabilities to generate new data and models. To facilitate data and model sharing, and to enhance reproducibility and rigor in biomechanics research, the Journal of Biomechanics has introduced a number of tools for Content Innovation to allow presentation, sharing, and archiving of methods, models, and data in our articles. The tools include an Interactive Plot Viewer, 3D Geometric Shape and Model Viewer, Virtual Microscope, Interactive MATLAB Figure Viewer, and Audioslides. Authors are highly encouraged to make use of these in upcoming journal submissions.
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