Mosaicism in health and disease — clones picking up speed

Many genetic studies focus on germline-inherited genomic variation. However, there is increasing realization that mutations occurring during our lifetime are so frequent and pervasive that, in all likelihood, no two of our cells are truly genetically identical. In this Review, the authors describe the detection, molecular nature and dynamics of this under-appreciated post-zygotic variation, and discuss the implications for normal human physiology and disease.

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Le Carbone, a charcoal supplement, modulates DSS-induced acute colitis in mice through activation of AMPKα and downregulation of STAT3 and caspase 3 dependent apoptotic pathways

Publication date: February 2017
Source:International Immunopharmacology, Volume 43
Author(s): Mst. Rejina Afrin, Somasundaram Arumugam, Md. Azizur Rahman, Vengadeshprabhu Karuppagounder, Remya Sreedhar, Meilei Harima, Hiroshi Suzuki, Takashi Nakamura, Shizuka Miyashita, Kenji Suzuki, Kazuyuki Ueno, Kenichi Watanabe
Le Carbone (LC) is a charcoal supplement, which contains a large amount of dietary fibers. Several studies suggested that charcoal supplement may be beneficial for stomach disorders, diarrhea, gas and indigestion. But no studies address whether LC intake would suppress inflammation, cell proliferation or disease progression in colitis. In the present study, the effect of LC on experimental colitis induced by dextran sulfate sodium (DSS) in mice and its possible mechanism of action were examined. A study was designed for 8days, using C57BL/6 female mice that were administered with 3% DSS in drinking water for 7days followed by another 1day consumption of normal water with or without treatment. LC suspension was administered daily for 7days via oral gavage using 5mg/mouse in treatment group and normal group was supplied with drinking water. LC suspension significantly attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic changes were significantly reduced by LC treatment. The inflammatory mediators TNFα, IL-1β, p-STAT3 and p-NF-κB induced in the colon by DSS were markedly suppressed by LC. The increased activation of AMPKα in the colon was also detected in LC group. Furthermore, the apoptotic marker protein cleaved caspase 3 was down-regulated and anti-apoptotic proteins Bcl2 and Bcl-xL were significantly up-regulated by LC treatment. Taken together, our results demonstrate the ability of LC to inhibit inflammation, apoptosis and give some evidence for its potential use as adjuvant treatment of inflammatory bowel disease.



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Frontline treatment of acute myeloid leukemia in adults

Publication date: Available online 11 December 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Gevorg Tamamyan, Tapan Kadia, Farhad Ravandi, Gautam Borthakur, Jorge Cortes, Elias Jabbour, Naval Daver, Maro Ohanian, Hagop Kantarjian, Marina Konopleva
Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40–50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.



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Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors

Publication date: February 2017
Source:Biomaterials, Volume 118
Author(s): Yunfeng Yan, Kejin Zhou, Hu Xiong, Jason B. Miller, Edward A. Motea, David A. Boothman, Li Liu, Daniel J. Siegwart
Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) readily accumulate in the liver after intravenous (i.v.) administration. Delivering RNAs to other organs and tumor tissues remains an ongoing challenge. Here, we utilized a 540-member combinatorial functional polyester library to discover nanoparticles (NPs) that enable efficacious siRNA delivery to A549 lung cancer cells in vitro and in vivo. PE4K-A13–0.33C6 and PE4K-A13–0.33C10 NPs were efficiently internalized into A549-Luc cells within 4 h. The addition of PEG 2000 DMG lipid or Pluronic F-127 onto the surface of the polyplexes reduced the surface charge of NPs, resulting in an increase of serum stability. We then explored aerosol delivery of stabilized PE4K-A13–0.33C6 and PE4K-A13–0.33C10 NPs to implanted orthotopic lung tumors. We found that by altering the administration route from i.v. to aerosol, the NPs could avoid liver accumulation and instead be specifically localized only in the lungs. This resulted in significant gene silencing in the A549 orthotopic lung tumors. Due to the ability to deliver siRNA to non-liver targets, this approach provides a privileged route for gene silencing in the lungs.



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Visualized detection of single-base difference in multiplexed loop-mediated isothermal amplification amplicons by invasive reaction coupled with oligonucleotide probe-modified gold nanoparticles

Publication date: 15 April 2017
Source:Biosensors and Bioelectronics, Volume 90
Author(s): Yan Lu, Xueping Ma, Jianping Wang, Nan Sheng, Tianhui Dong, Qinxin Song, Jianzhong Rui, Bingjie Zou, Guohua Zhou
Loop-mediated isothermal amplification (LAMP) is a well-developed DNA amplification method with an ultra-high sensitivity, but it is difficult to recognize a single-base difference (like genotyping) in target-specific amplicons by conventional detection ways, such as the intercalation of dyes into dsDNA amplicons or the increase of solution turbidity along with the polymerization process. To allow genotyping based on LAMP suitable for POCT (point-of-care testing) or on-site testing, here we proposed a highly specific and cost-effective method for detecting a single-base difference in LAMP amplicons. The method includes three key steps, sequence amplifier to amplify multiple fragments containing the single nucleotide polymorphisms (SNPs) of interest, allele identifier to recognize a targeted base in the amplicons by invasive reaction, and signal generator to yield signals by hybridization-induced assembly of oligonucleotide probe-modified gold nanoparticles. Because the allele identifier is sensitive to one base difference, it is possible to use multiplexed LAMP (mLAMP) to generate amplicon mixtures for multiple SNP typing. Genotyping of 3 different SNPs (CYP2C19*2, CYP2C19*3 and MDR1-C3435T) for guiding the dosage of clopidogrel is successfully carried out in a 3-plex LAMP on real clinical samples. As our method relies on the naked-eye detection and constant-temperature reaction, no expensive instrument is required for both target amplification and sequence identification, thus much suitable for inexpensive gene-guided personalized medicine in source-limited regions.



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Effects of Overground Locomotor Training on Walking Performance in Chronic Cervical Motor-Incomplete Spinal Cord Injury: A Pilot Study

Publication date: Available online 11 December 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Jared M. Gollie, Andrew A. Guccione, Gino S. Panza, Peter Y. Jo, Jeffrey E. Herrick
ObjectiveTo determine the effects of a novel overground locomotor training (OLT) program on walking performance in people with chronic cervical motor-incomplete spinal cord injury (iSCI).DesignBefore-After Pilot Study.SettingHuman performance research laboratory.ParticipantsAdults (n=6; age>18 years) with chronic cervical iSCI C & D according to the American Spinal Injury Association Impairment Scale (AIS).InterventionOLT included two 90-minute sessions per week for 12-15 weeks. Training sessions alternated between uniplanar and multiplanar stepping patterns. Each session was comprised of five segments: joint mobility; volitional muscle activation; task-isolation; task-integration; activity rehearsal.Main Outcome MeasuresOverground walking speed, oxygen consumption (VO2), carbon dioxide production (VCO2).ResultsOLT increased overground walking speed (0.36±0.20 vs 0.51±0.24 m·s; P<0.001, d=0.68). Significant decreases in VO2 (6.6±1.3 vs 5.7±1.4 ml·kg·min; P=0.038, d=0.67) and VCO2 (753.1±125.5 vs 670.7±120.3 ml·min; P=0.036, d=0.67) during self-selected constant work-rate treadmill walking was also noted after training.ConclusionsOLT program used in this pilot study is feasible and improved both overground walking speed and walking economy in a small sample of people with chronic cervical iSCI. Future studies are necessary to establish the efficacy of this OLT program as well as to differentiate among potential mechanisms contributing to enhanced walking performance in people with iSCI following OLT.



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Large scale syntheses of colloidal nanomaterials

Publication date: Available online 10 December 2016
Source:Nano Today
Author(s): Pearl L. Saldanha, Vladimir Lesnyak, Liberato Manna
Nanoscale materials have long promised to revolutionize science and technology, with claims being sustained by both the advances in their fabrication and by the many fundamental studies that have been carried out to date, which have revealed fascinating properties when materials dimensions shrink all the way down to a few hundreds/thousands of atoms. In this ongoing hype, on one side we have the futuristic views and promises of ubiquitous devices in which the operating units will be eventually scaled down to individual atoms or molecules. On the other side, we have the more realistic (and already unfolding) scenario represented by nanoscale materials making their way in a wide variety of applications (not always and not necessarily flagged as "high-tech") where downsizing truly brings about new or improved features that can be immediately exploited for some practical use. These applications have encompassed fields as disparate as medicine, biology, energy conversion and storage, catalysis, sensing, nanocomposite engineering, cosmetics, to cite the most popular ones. For a new technology to be pervasive and disruptive, the costs associated to the fabrication, the characterization and the assemblage of its key components have to drop quickly over time, while at the same time the material quality and the reproducibility of the various processes must keep improving. In the case of nanomaterials, we have not yet witnessed such an ubiquitous revolution, and one of the reasons is probably the lack of straightforward and reproducible synthetic protocols providing large amounts of nanomaterials and thus capable of efficient up-scaling to fulfil industrial needs. Another reason likely resides in the growing concern that nanomaterials will pose new threats to the environment, but this aspect will not be investigated here.In this review, we will touch upon the critical feature of nanomaterials science and engineering dealing with the high throughput synthesis, with a focus on materials prepared in the liquid phase, where the expertise of the authors of this review lays. As a note of caution to the reader, we will not cover in depth all existing approaches to large scale syntheses. Our discussion will be instead a broad summary of the main types of synthetic approaches developed to date, and which we believe will be useful to scientists and engineers who are approaching the fabrication of nanomaterials with an eye on their use in large-scale, industrial applications. The review has been written according to the principle "from the simple to the complex": it begins with the simplest one-batch heat-up synthesis approach, followed by hot-injection methods and ends by discussing the more sophisticated continuous flow syntheses of nanoparticles. Similarly, in each section, wherever possible, the discussion will start from simpler compounds, (for example, one-component noble metal nanocrystals), and will then move on to more complex structures (from binary to ternary and even quaternary compounds, which will be mainly metal oxides and chalcogenides).

Graphical abstract

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Title page / Editorial Board

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45, Supplement 1





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Supplement title page

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45, Supplement 1





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Table of contents

Publication date: December 2016
Source:Cancer Epidemiology, Volume 45, Supplement 1





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Salmonella-induced inflammasome activation in humans

Publication date: Available online 11 December 2016
Source:Molecular Immunology
Author(s): Damien Bierschenk, Dave Boucher, Kate Schroder
Inflammasomes are macromolecular complexes that assemble upon recognition of pathogen- or danger-associated molecular patterns. Inflammasome assembly is nucleated by the oligomerisation of specific, activated pattern recognition receptors within the cytosol. Inflammasomes function as platforms for the activation of the caspase-1 protease, which in turn triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and initiates pyroptosis, a highly inflammatory form of lytic cell death. Recently, additional inflammatory caspases (murine caspase-11, and human caspase-4/5) were also reported to be activated upon a pyroptosis-inducing 'non-canonical inflammasome' by direct recognition of lipopolysaccharide (LPS), a pathogen-associated molecular pattern. Here we review and discuss recent advances in our understanding of inflammasome-mediated host defence against Salmonella particularly in human cells, and their implications for cellular survival and cytokine secretion.



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Salmonella-induced inflammasome activation in humans

Publication date: Available online 11 December 2016
Source:Molecular Immunology
Author(s): Damien Bierschenk, Dave Boucher, Kate Schroder
Inflammasomes are macromolecular complexes that assemble upon recognition of pathogen- or danger-associated molecular patterns. Inflammasome assembly is nucleated by the oligomerisation of specific, activated pattern recognition receptors within the cytosol. Inflammasomes function as platforms for the activation of the caspase-1 protease, which in turn triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and initiates pyroptosis, a highly inflammatory form of lytic cell death. Recently, additional inflammatory caspases (murine caspase-11, and human caspase-4/5) were also reported to be activated upon a pyroptosis-inducing 'non-canonical inflammasome' by direct recognition of lipopolysaccharide (LPS), a pathogen-associated molecular pattern. Here we review and discuss recent advances in our understanding of inflammasome-mediated host defence against Salmonella particularly in human cells, and their implications for cellular survival and cytokine secretion.



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Isotopic (C–O–S) geochemistry and Re–Os geochronology of the Haobugao Zn–Fe deposit in Inner Mongolia, NE China

Publication date: April 2017
Source:Ore Geology Reviews, Volume 82
Author(s): Yuan Liu, Si-Hong Jiang, Leon Bagas, Ning Han, Chun-Liang Chen, Huan Kang
The Haobugao Zn–Fe deposit is a typical skarn deposit located in the southern part of the Great Xing'an Range that hosts polymetallic mineralization over a large region. The main ore minerals at the deposit include sphalerite, magnetite, galena, chalcopyrite and pyrite, and the main gangue minerals include andradite, grossular garnet, hedenbergite, diopside, ilvaite, calcite and quartz. There are broadly two mineralizing periods represented by the relatively older skarn and younger quartz–sulfide veins. In detail, there are five metallogenic stages consisting of an early skarn, late skarn, oxide, early quartz–sulfide, and late quartz–sulfide–calcite stages. Electron microprobe analyses show that the garnet at the deposit varies in composition from And97.95Gro0.41Pyr1.64 to And30.69Gro66.69Pyr2.63, and pyroxene is compositionally in the diopside–hedenbergite range (i.e. Di90.63Hd8.00Jo1.37–Hd88.98Di4.53Jo6.49). Petrographic observations and electron microprobe analyses indicate that the sphalerite has three generations ([Zn0.93Fe0.08]S–[Zn0.75Fe0.24]S). The Zn associated with the first generation sphalerite replaced Cu and Fe of early xenomorphic granular chalcopyrite (i.e. [Cu1.01Fe1.03]S2–[Cu0.99Fe0.99]S2), and part of the first generation sphalerite is coeval with late chalcopyrite (i.e. [Cu0.96Fe0.99Zn0.03]S2–[Cu1.00Fe1.03Zn0.01]S2). Magnetite has a noticeable negative Ce anomaly (δCe=∼0.17 to 0.54), which might be a result of the oxidized ore-fluid. Thirty δ³⁴SV-PDB analyses of sulfides from the ore range from −2.3 to −0.1‰ in value, which are indicative of a magmatic source. The δ¹³C‰ and δ¹⁸O‰ values for calcite from the ore formed at quartz–sulfide–calcite stage vary from −9.9 to −5.5‰ and from −4.2 to 1.1‰, respectively, contrasting with δ¹³C‰ (2.9–4.8‰) and δ¹⁸O‰ (9.8–13.9‰) values for calcite from marble. It is suggested that the ore-forming fluid associated with late stage of mineralization was predominantly magmatic in origin with some input of local meteoric water.Molybdenite from the Haobugao deposit defines an isochron age of 142±1Ma, which is interpreted as the mineralization age being synchronous, within error, with the zircon U–Pb ages of 140±1, 141±2, and 141±1Ma for granite at the deposit. These data and characteristics of lithology and mineralization further show that the Zn–Fe mineralization is temporally and spatially related to the emplacement of granite in an extensional tectonic setting during the Mesozoic.

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