Παρασκευή, 28 Απριλίου 2017

Multiple pre- and post-analytical lean approaches to the improvement of the laboratory turnaround time in a large core laboratory

Publication date: Available online 28 April 2017
Source:Clinical Biochemistry
Author(s): Amy H. Lou, Manal O. Elnenaei, Irene Sadek, Shauna Thompson, Bryan D. Crocker, Bassam A. Nassar
BackgroundCore laboratory (CL), as a new business model, facilitates consolidation and integration of laboratory services to enhance efficiency and reduce costs. This study evaluates the impact of total laboratory automation system (TLA), electric track vehicle (ETV) system and auto-verification (AV) of results on overall turnaround time (TAT) (phlebotomy to reporting TAT: PR-TAT) within a CL setting.MethodsMean, median and percentage of outlier (OP) for PR-TAT were compared for pre- and post-CL eras using five representative tests based on different request priorities. Comparison studies were also carried out on the intra-laboratory TAT (in-lab to reporting TAT: IR-TAT) and the delivery TAT (phlebotomy to in-lab TAT: PI-TAT) to reflect the efficiency of the TLA (both before and after introducing result AV) and ETV systems respectively.ResultsMedian PR-TATs for the urgent samples were reduced on average by 16% across all representative analytes. Median PR-TATs for the routine samples were curtailed by 51%, 50%, 49%, 34% and 22% for urea, potassium, thyroid stimulating hormone (TSH), complete blood count (CBC) and prothrombin time (PT) respectively. The shorter PR-TAT was attributed to a significant reduction of IR-TAT through the TLA. However, the median PI-TAT was delayed when the ETV was used. Application of various AV rules shortened the median IR-TATs for potassium and urea. However, the OP of PR-TAT for the STAT requests exceeding 60min were all higher than those from the pre-CL era.ConclusionsTLA and auto-verification rules help to efficiently manage substantial volumes of urgent and routine samples. However, the ETV application as it stands shows a negative impact on the PR-TAT.



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Striatal dopaminergic modulation of reinforcement learning predicts reward—Oriented behavior in daily life

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Publication date: Available online 29 April 2017
Source:Biological Psychology
Author(s): Zuzana Kasanova, Jenny Ceccarini, Michael J Frank, Thérèse van Amelsvoort, Jan Booij, Alexander Heinzel, Felix Mottaghy, Inez Myin-Germeys
Much human behavior is driven by rewards. Preclinical neurophysiological and clinical positron emission tomography (PET) studies have implicated striatal phasic dopamine (DA) release as a primary modulator of reward processing. However, the relationship between experimental reward-induced striatal DA release and responsiveness to naturalistic rewards, and therefore functional relevance of these findings, has been elusive.We therefore combined, for the first time, a DA D2/3 receptor [18F]fallypride PET during a probabilistic reinforcement learning (RL) task with a six day ecological momentary assessments (EMA) of reward-related behavior in the everyday life of 16 healthy volunteers. We detected significant reward-induced DA release in the bilateral putamen, caudate nucleus and ventral striatum, the extent of which was associated with better behavioral performance on the RL task across all regions. Furthermore, individual variability in the extent of reward-induced DA release in the right caudate nucleus and ventral striatum modulated the tendency to be actively engaged in a behavior if the active engagement was previously deemed enjoyable. This study suggests a link between striatal reward-related DA release and ecologically relevant reward-oriented behavior, suggesting an avenue for the inquiry into the DAergic basis of optimal and impaired motivational drive.



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miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect

Lactate dehydrogenase A (LDHA), a key enzyme regulating aerobic glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including LDHA, are being developed. However, the mechanisms of LDHA inhibition and the physiological significance of the LDHA inhibitors in cancer cells are unclear. Here, we show that microRNA-30a-5p (miR-30a-5p) suppresses LDHA expression by directly targeting its 3’-UTR.

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The Hippo pathway in hepatocellular carcinoma: non-coding RNAs in action

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. However, the current strategies curing HCC are far from satisfaction. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway that plays crucial roles in organ size control and tissue homeostasis. Its dysregulation is commonly observed in various types of cancer including HCC. Recently, the prominent role of non-coding RNAs in the Hippo pathway during normal development and neoplastic progression is also emerging in liver.

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LFG-500, a novel synthetic flavonoid, suppresses epithelial–mesenchymal transition in human lung adenocarcinoma cells by inhibiting NLRP3 in inflammatory microenvironment

Increasing evidence indicates that inflammatory microenvironment facilitates tumor metastasis. Here, we found that LFG-500, a novel synthetic flavonoid, significantly inhibited epithelial–mesenchymal transition (EMT) in human lung adenocarcinoma A549 and H1299 cells co-cultured with LPS-challenged THP-1 cells or cultured in THP-1 cell-derived conditioned medium. Moreover, we found that TNF-α is a direct and decisive factor for promoting EMT and LFG-500 suppressed TNF-α-induced EMT and cell motility.

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Major and ancillary magnetic resonance features of LI-RADS to assess HCC: an overview and update

Liver Imaging Reporting and Data System (LI-RADS) is a system for interpreting and reporting of imaging features on multidetector computed tomography (MDCT) and magnetic resonance (MR) studies in patients at r...

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Effects of heavy metal pollution on pigmented macrophages in kidney of Vardar chub (Squalius vardarensis Karaman)

Abstract

Pollution with heavy metals may influence the immune system of fish, leading to impairment of their health or even increase their mortality. The fish kidney is one of the first fish organs to be affected by water contamination. Amounts of kidney macrophages (MACs), which are involved in fish immune response, as well as the qualitative and quantitative changes in the pigmented MACs in fish kidney, are used as biomarkers of pollution. Therefore, in this study, we have evaluated relative and total volumes of trunk kidney pigmented MACs, and analyzed the pigments accumulated within them. Fish were sampled from two mining impacted rivers, Kriva and Zletovska, highly contaminated with heavy metals, and from one reference river, Bregalnica, in spring and autumn of 2012. We have observed that main pigments found in kidney MACs of Vardar chub were melanin and lipofuscin/ceroid, as well as that relative volumes of MACs ranged from 0.56 to 1.68%. Moreover, the results showed that relative volumes of pigmented MACs were higher in metal contaminated rivers, especially in autumn season in the Zletovska River, concurrently with extremely high metal exposure. In addition, condition factors and kidney somatic indices were found significantly lower in the Zletovska River in both seasons, autumn and spring, possibly also as a consequence of high water pollution. Our data confirm that increase in relative volumes of pigmented MACs may serve as warning sign of potential heavy metal pollution in aquatic environment.

Thumbnail image of graphical abstract
  • Heavy metals increase macrophage amount in the kidney
  • Macrophage aggregates are good biomarker for metal pollution


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Valve interstitial cell culture: Production of mature type I collagen and precise detection

Abstract

Collagen often acts as an extracellular and intracellular marker for in vitro experiments, and its quality defines tissue constructs. To validate collagen detection techniques, cardiac valve interstitial cells were isolated from pigs and cultured under two different conditions; with and without ascorbic acid. The culture with ascorbic acid reached higher cell growth and collagen deposition, although the expression levels of collagen gene stayed similar to the culture without ascorbic acid. The fluorescent microscopy was positive for collagen fibers in both the cultures. Visualization of only extracellular collagen returned a higher correlation coefficient when comparing the immunolabeling and second harmonic generation microscopy images in the culture with ascorbic acid. Lastly, it was proved that the hydroxyproline strongly contributes to the second-order susceptibility tensor of collagen molecules, and therefore the second harmonic generation signal is impaired in the culture without ascorbic acid.

Thumbnail image of graphical abstract

The VICs markers were identified together with the impact of ascorbic acid deficiency on the quality of collagen fibers. The conventional techniques were positive about deposited collagen; however, no SHG signal was detected.



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Vitreous

Vitreous: A clear, jelly-like substance that fills the middle of the eye. Also called the vitreous humor, "humor" in medicine referring to a fluid (or semifluid) substance.



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Roles of cancer/testis antigens (CTAs) in breast cancer

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Yongfei Li, Jun Li, Yifan Wang, Yanhong Zhang, Jiahui Chu, Chunxiao Sun, Ziyi Fu, Yi Huang, Hansheng Zhang, Hongyan Yuan, Yongmei Yin
Breast cancer is the most common cancer diagnosed and is the second leading cause of cancer death among women in the US. For breast cancer, early diagnosis and efficient therapy remains a significant clinical challenge. Therefore, it is necessary to identify novel tumor associated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens (CTAs) have emerged as a potential clinical biomarker targeting immunotherapy for various malignancies due to the nature of its characteristics. CTAs are a group of tumor associated antigens (TAAs) that display normal expression in immune-privileged organs, but display aberrant expression in several types of cancers, particularly in advanced cancers. Investigation of CTAs for the clinical management of breast malignancies indicates that these TAAs have potential roles as novel biomarkers, with increased specificity and sensitivity compared to those currently used in the clinic. Moreover, TAAs could be therapeutic targets for cancer immunotherapy. This review is an attempt to address the promising CTAs in breast cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions.



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MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Chunlin Ou, Zhenqiang Sun, Xiayu Li, Xiaoling Li, Weiguo Ren, Zailong Qin, Xuemei Zhang, Weitang Yuan, Jia Wang, Wentao Yu, Shiwen Zhang, Qiu Peng, Qun Yan, Wei Xiong, Guiyuan Li, Jian Ma
YAP1, a transcription co-activator, mediates the biological functions of the Hippo pathway. YAP1 inactivation is involved in cell–cell contact inhibition. In various tumors, YAP1 is upregulated through multiple mechanisms, and it functions as an oncogene. Here, we provided evidence that YAP1 influenced multiple signaling pathways in colorectal cancer (CRC) cells. We reported that miR-590-5p directly targets YAP1 and inhibits tumorigenesis in CRC cells both in vitro and in vivo xenograft model. We analyzed different cell densities and found that increased density caused increased expression of miR-590-5p, and decreased expression of its precursors (pri- and pre-miR-590). Increasing cancer cell density upregulated the expression of a RNase III endonuclease, DICER1. DICER1 increased miR-590 biogenesis and inhibited YAP1. In DICER1-defective CRC cells, addition of pre-miR-590 did not inhibit YAP1 expression. Analyses of clinical data demonstrated that the DICER1-miR-590-5p-YAP1 axis was dysregulated in CRC specimens and affected patient survival. Cell–cell contact inhibition is crucial to prevent uncontrolled cell proliferation. Identification of this cell density-sensitive, DICER1-miR-590-5p-YAP1 axis may provide a basis for developing new biomarkers or targeted therapies for CRC.



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E1a is an exogenous in vivo tumour suppressor

Publication date: 28 July 2017
Source:Cancer Letters, Volume 399
Author(s): Francisco J. Cimas, Juan L. Callejas-Valera, Dolores C. García-Olmo, Javier Hernández-Losa, Pedro Melgar-Rojas, María J. Ruiz-Hidalgo, Raquel Pascual-Serra, Marta Ortega-Muelas, Olga Roche, Pilar Marcos, Elena Garcia-Gil, Diego M. Fernandez-Aroca, Santiago Ramón y Cajal, J. Silvio Gutkind, Ricardo Sanchez-Prieto
The E1a gene from adenovirus has become a major tool in cancer research. Since the discovery of E1a, it has been proposed to be an oncogene, becoming a key element in the model of cooperation between oncogenes. However, E1a's in vivo behaviour is consistent with a tumour suppressor gene, due to the block/delay observed in different xenograft models. To clarify this interesting controversy, we have evaluated the effect of the E1a 13s isoform from adenovirus 5 in vivo. Initially, a conventional xenograft approach was performed using previously unreported HCT116 and B16-F10 cells, showing a clear anti-tumour effect regardless of the mouse's immunological background (immunosuppressed/immunocompetent). Next, we engineered a transgenic mouse model in which inducible E1a 13s expression was under the control of cytokeratin 5 to avoid side effects during embryonic development. Our results show that E1a is able to block chemical skin carcinogenesis, showing an anti-tumour effect. The present report demonstrates the in vivo anti-tumour effect of E1a, showing that the in vitro oncogenic role of E1a cannot be extrapolated in vivo, supporting its future use in gene therapy approaches.



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Intravoxel incoherent motion DWI of the pancreatic adenocarcinomas: monoexponential and biexponential apparent diffusion parameters and histopathological correlations

Abstract

Background

To investigate the associations between the diffusion parameters obtained from multiple-b-values diffusion weighted imaging (DWI) of pancreatic ductal adenocarcinoma (PDAC) and the aggressiveness and local stage prediction, and assess the values of the quantitative parameters for the discrimination of tumors from healthy pancreas.

Methods

Fifty-one patients with surgical pathology-proven PDAC (size, 35 ± 12 mm) and fifty-seven healthy volunteers were enrolled. Diffusion parameters including monoexponential apparent diffusion coefficient (ADCb and ADCtotal) and biexponential intravoxel incoherent motion (IVIM) parameters (ADCslow, ADCfast and f) based on 9 b-values (0 to 1000s/mm2) DWI were calculated for the lesions and the healthy pancreas. These parameters were compared by grades of differentiation, lymph node status, tumor stage and location. The diagnostic performances were calculated and compared by using the receiver operating characteristic curves (ROC) analyses.

Results

There was no statistically significant difference in ADCb, ADCtotal, ADCslow, ADCfast or f between PDAC stage T1/T2 and stage T3/T4 or moderately differentiated versus poorly differentiated PDAC (p = 0.060-0.941). In addition, no significant differences were observed for the quantitative parameters between tumors located in the pancreatic head versus other pancreatic regions (p = 0.203-0.954) or between tumors with and without metastatic peri-pancreatic lymph nodes (p = 0.313-0.917). ADC25-600, ADC1000, ADCtotal and ADCfast were significantly lower for PDAC compared the healthy pancreas (all p < 0.05). ROC analyses showed the area under curve for ADC20 was the largest (0.911) to distinguish PDAC from normal pancreas (cut-off value, 5.58 × 10−3mm2/s) and had the highest combined sensitivity (89.5%) and specificity (82.4%).

Conclusions

Multiple-b-values DWI derived monoexponential and biexponential parameters of PDAC do not exhibit significance dependence on tumor grade or tumor characteristics. ADC20 provided the best accuracy for differentiating PDAC from healthy pancreas in the study.



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Absence of Gim proteins, but not GimC complex, alter stress-induced transcription

Publication date: Available online 28 April 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ana Fátima Amorim, Dora Pinto, Laurent Kuras, Lisete Fernandes
Saccharomyces cerevisiae GimC (mammalian Prefoldin) is a hexameric (Gim1–6) cytoplasmic complex involved in the folding pathway of actin/tubulin. In contrast to a shared role in GimC complex, we show that absence of individual Gim proteins results in distinct stress responses. No concomitant alteration in F-actin integrity was observed. Transcription of stress responsive genes is altered in gim2Δ, gim3Δ and gim6Δ mutants: TRX2 gene is induced in these mutants but with a profile diverging from type cells, whereas CTT1 and HSP26 fail to be induced. Remaining gimΔ mutants display stress transcript abundance comparable to wild type cells. No alteration in the nuclear localization of the transcriptional activators for TRX2 (Yap1) and CTT1/HSP26 (Msn2) was observed in gim2Δ. In accordance with TRX2 induction, RNA polymerase II occupancy at TRX2 discriminates the wild type from gim2Δ and gim6Δ. In contrast, RNA polymerase II occupancy at CTT1 is similar in wild type and gim2Δ, but higher in gim6Δ. The absence of active RNA polymerase II at CTT1 in gim2Δ, but not in wild type and gim1Δ, explains the respective CTT1 transcript outputs. Altogether our results put forward the need of Gim2, Gim3 and Gim6 in oxidative and osmotic stress activated transcription; others Gim proteins are dispensable. Consequently, the participation of Gim proteins in activated-transcription is independent from the GimC complex.

Graphical abstract

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Identification of a New SUMO-Interacting Motif in PIASy [Molecular Biophysics]

SUMO conjugation is a reversible post-translational modification process implicated in the regulation of gene transcription, DNA repair, and cell cycle. SUMOylation depends on the sequential activities of E1 activating, E2 conjugating, and E3 ligating enzymes. SUMO E3 ligases enhance transfer of SUMO from the charged E2 enzyme to the substrate. We have previously identified PIASy, a member of the Siz/PIAS RING family of SUMO E3 ligases, as essential for mitotic chromosomal SUMOylation in frog egg extracts and demonstrated that it can mediate effective SUMOylation. To address how PIASy catalyze SUMOylation, we examined various truncations of PIASy for their ability to mediate SUMOylation. Using NMR chemical shift mapping and mutagenesis, we identified a new SUMO-interacting motif (SIM) in PIASy. The new SIM and the currently known SIM are both located at the C-terminus of PIASy, and both are required for the full ligase activity of PIASy. Our results provide novel insights into the mechanism of PIASy-mediated SUMOylation. PIASy adds to the growing list of SUMO E3 ligases containing multiple SIMs that play important roles in the E3 ligase activity.

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Molecular Impact of Covalent Modifications on Nonribosomal Peptide Synthetase Carrier Protein Communication [Molecular Biophysics]

Nonribosomal peptide (NRP) synthesis involves the interplay between covalent protein modifications, conformational fluctuations, catalysis, and transient protein-protein interactions. Delineating the mechanisms involved in orchestrating these various processes will deepen our understanding of domain-domain communication in nonribosomal peptide synthetases (NRPSs) and lay the groundwork for the rational reengineering of NRPSs by swapping domains handling different substrates to generate novel natural products. While many structural and biochemical studies of NRPSs exist, few studies have focused on the energetics and dynamics governing the interactions in these systems. Here, we present detailed binding studies of an adenylation domain and its partner carrier protein in apo, holo, and substrate-loaded forms. Results from fluorescence anisotropy, isothermal titration calorimetry, and NMR titrations indicated that covalent modifications to a carrier protein modulate domain communication, suggesting that chemical modifications to carrier proteins during NRPS synthesis may impart directionality to sequential NRPS domain interactions. Comparison of the structure and dynamics of an apo aryl carrier protein with those of its modified forms revealed structural fluctuations induced by post-translational modifications and mediated by modulations of protein dynamics. The results provide a comprehensive molecular description of a carrier protein throughout its life cycle and demonstrate how a network of dynamic residues can propagate the molecular impact of chemical modifications throughout a protein and influence its affinity towards partner domains.

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The acceptability and tolerability of nasal douching in children with allergic rhinitis: a systematic review

Allergic rhinitis (AR) is a significant issue in children. Treatment options include allergen avoidance, pharmacotherapy and immunotherapy. The use of nasal saline douching (NSD) in children has recently gained acceptability. However, there is limited data regarding the acceptability and tolerability of NSD in children with AR.

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THERAPEUTIC RATIONALE TO TARGET HIGHLY EXPRESSED CDK7 CONFERRING POOR OUTCOMES IN TRIPLE-NEGATIVE BREAST CANCER

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors BS-181 and THZ1 each down-regulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.

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Widespread use of misidentified cell line KB (HeLa): Incorrect attribution and its impact revealed through mining the scientific literature

Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 Correct and 171 Incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between Correct and Incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication.

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CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a pre-metastatic niche that ultimately promoted liver metastases. Importantly, pre-metastatic liver-infiltrating MDSC induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSC to form a pre-metastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to pre-metastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSC are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.

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Colloidal Carbon-Based Nanoparticles as Heavy Metal Adsorbent in Aqueous Solution: Cadmium Removal as a Case Study

Abstract

Hydrophilic carbonaceous nanoparticles (HNPs) of uniform sizes with a good degree of dispersion in water were produced from a commercial carbon black by nitric acid treatment. The surface treatment, performed at different reaction times, generates a variable number of oxygen functional groups, mainly carboxylic, which enhance the nanoparticles hydrophilicity and heavy metal adsorption capability. The HNPs were characterized by a number of analytical techniques, including FTIR spectroscopy, thermal and elemental analysis, N2 adsorption, dynamic light scattering, and zeta-potential measurements. The acid–base properties of the functional groups on the HNPs surface were also investigated by coulometric–potentiometric titrations. Cadmium adsorption tests were carried out in stirred reactors containing colloidal aqueous suspensions of HNPs and HNPs supported over silica. The effects of several parameters, such as the cadmium concentration, the temperature, and the solution pH, were studied. Sorbents showed an appreciable cadmium adsorption capability at different temperatures and in a wide range of pH values comparable or superior to several carbon-based sorbents, indicating a feasible use in commercial units.



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Mitochondrial DNA mutations in Parkinson's disease brain



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Response to Simon et al. ,



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Expression and Characterization of Serotype 2 Streptococcus suis Arginine Deiminase

Background: Arginine deiminase (ArcA) has been speculated to facilitate the intracellular survival of Streptococcus suis under acidic conditions. However, the physical and biological properties and function of SS2-ArcA have not yet been elucidated. Methods: Recombinant SS2-ArcA (rSS2-ArcA) was expressed and purified using Ni-NTA affinity chromatography. Under various pH and temperature conditions, the enzymatic properties of purified rSS2-ArcA and crude native SS2-ArcA were determined. Results: The SS2-arcA-deduced amino acid sequence contained a conserved catalytic triad (Cys399-His273-Glu218). The optimum temperature and pH of 47-kDa rSS2-ArcA and crude native SS2-ArcA were 42°C and pH 7.2. The rSS2-ArcA and crude native SS2-ArcA were stable for 3 h at 4 and 25°C, respectively. The pH stability and dependency tests suggested that rSS2-ArcA and crude native SS2-ArcA were functionally active in acidic conditions. The L-arginine substrate binding affinity (Km) values of rSS2-ArcA (specific activity 16.00 U/mg) and crude native SS2-ArcA (specific activity 0.23 U/mg) were 0.058 and 0.157 mM, respectively. rSS2-ArcA exhibited a weak binding affinity with the common ArcA inhibitors L-canavanine and L-NIO. Furthermore, the partial inactivation of SS2-ArcA significantly impaired the viability and growth of SS2 at pH 4.0, 6.0, and 7.5. Conclusions: This study profoundly demonstrated the involvement of ArcA enzymatic activity in S. suis survival under acidic conditions.
J Mol Microbiol Biotechnol 2017;27:133-146

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The Implications of Primate Behavioral Flexibility for Sustainable Human–Primate Coexistence in Anthropogenic Habitats

Abstract

People are an inescapable aspect of most environments inhabited by nonhuman primates today. Consequently, interest has grown in how primates adjust their behavior to live in anthropogenic habitats. However, our understanding of primate behavioral flexibility and the degree to which it will enable primates to survive alongside people in the long term remains limited. This Special Issue brings together a collection of papers that extend our knowledge of this subject. In this introduction, we first review the literature to identify past and present trends in research and then introduce the contributions to this Special Issue. Our literature review confirms that publications on primate behavior in anthropogenic habitats, including interactions with people, increased markedly since the 2000s. Publications concern a diversity of primates but include only 17% of currently recognized species, with certain primates overrepresented in studies, e.g., chimpanzees and macaques. Primates exhibit behavioral flexibility in anthropogenic habitats in various ways, most commonly documented as dietary adjustments, i.e., incorporation of human foods including agricultural crops and provisioned items, and as differences in activity, ranging, grouping patterns, and social organization, associated with changing anthropogenic factors. Publications are more likely to include information on negative rather than positive or neutral interactions between humans and primates. The contributions to this Special Issue include both empirical research and reviews that examine various aspects of the human–primate interface. Collectively, they show that primate behavior in shared landscapes does not always conflict with human interests, and demonstrate the value of examining behavior from a cost–benefit perspective without making prior assumptions concerning the nature of interactions. Careful interdisciplinary research has the potential to greatly improve our understanding of the complexities of human–primate interactions, and is crucial for identifying appropriate mechanisms to enable sustainable human–primate coexistence in the 21st century and beyond.



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Metabolic Profiling of Hoodia, Chamomile, Terminalia Species and Evaluation of Commercial Preparations Using Ultrahigh-Performance Liquid Chromatography Quadrupole-Time-of-Flight Mass Spectrometry

10-1055-s-0043-109239_pma1041-1.jpg

Planta Med
DOI: 10.1055/s-0043-109239

Ultrahigh-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UHPLC-QToF-MS) profiling was used for the identification of marker compounds and generation of metabolic patterns that could be interrogated using chemometric modeling software. UHPLC-QToF-MS was used to generate comprehensive fingerprints of three botanicals (Hoodia, Terminalia, and chamomile), each having different classes of compounds. Detection of a broad range of ions was carried out in full scan mode in both positive and negative modes over the range m/z 100–1700 using high-resolution mass spectrometry. Multivariate statistical analysis was used to extract relevant chemical information from the data to easily differentiate between Terminalia species, chamomile varieties, and quality control of Hoodia products. Using nontargeted analysis, identification of 37 compounds contributed to the differences between Terminalia species, 26 flavonoids were identified to show the differences between German and Roman chamomile, and 43 pregnane glycosides were identified from Hoodia gordonii samples. The UHPLC-QToF-MS-based chemical fingerprinting with principal component analysis was able to correctly distinguish botanicals and their commercial products. This work can be used as a basis to assure the quality of botanicals and commercial products.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Assessment of the Authenticity of Herbal Dietary Supplements: Comparison of Chemical and DNA Barcoding Methods

10-1055-s-0043-107881_pma1044-1.jpg

Planta Med
DOI: 10.1055/s-0043-107881

About 7 % of the U. S. population reports using botanical dietary supplements. Increased use of such supplements has led to discussions related to their authenticity and quality. Reports of adulteration with substandard materials or pharmaceuticals are of concern because such substitutions, whether inadvertent or deliberate, may reduce the efficacy of specific botanicals or lead to adverse events. Methods for verifying the identity of botanicals include macroscopic and microscopic examinations, chemical analysis, and DNA-based methods including DNA barcoding. Macroscopic and microscopic examinations may fail when a supplement consists of botanicals that have been processed beyond the ability to provide morphological characterizations. Chemical analysis of specific marker compounds encounters problems when these compounds are not distinct to a given species or when purified reference standards are not available. Recent investigations describing DNA barcoding analysis of botanical dietary supplements have raised concerns about the authenticity of the supplements themselves as well as the appropriateness of using DNA barcoding techniques with finished botanical products. We collected 112 market samples of frequently consumed botanical dietary supplements of ginkgo, soy, valerian, yohimbe, and St. Johnʼs wort and analyzed each for specific chemical markers (i.e., flavonol glycosides, total isoflavones, total valerenic acids, yohimbine, and hypericins, respectively). We used traditional DNA barcoding techniques targeting the nuclear ITS2 gene and the chloroplast gene psbA-trnH on the same samples to determine the presence of DNA of the labelled ingredient. We compared the results obtained by both methods to assess the contribution of each in determining the identity of the samples.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Evaluation of the Effect of Epilobium angustifolium Aqueous Extract on LNCaP Cell Proliferation in In Vitro and In Vivo Models

10-1055-s-0043-109372_pmb0095-1.jpg

Planta Med
DOI: 10.1055/s-0043-109372

Epilobium sp. are commonly used in traditional medicine in the treatment of early stages of benign prostatic hyperplasia and inflammation. It is suggested that a dominating constituent, oenothein B, is responsible for the extracts therapeutic effects. Several bioactivities were established for extracts and oenothein B in various in vitro models, but due to the questionable bioavailability of this dimeric macrocyclic ellagitannin, their significance in the in vivo effects remains unresolved. We have thus focused our attention on a complex comparative investigation of the in vitro and in vivo activities of phytochemically characterized Epilobium angustifolium aqueous extract and oenothein B on prostate cancer cells proliferation.Incubation of different cell lines with E. angustifolium aqueous extract resulted in a significant reduction of proliferation of PZ-HPV-7 and LNCaP cells, which was partly associated with antiandrogenic activity. These effects were fully congruent with oenothein B, examined in parallel. Oral supplementation of rats implanted with LNCaP cells with E. angustifolium aqueous extract 50–200 mg/kg b. w. resulted in a reduction of the occurrence of prostatic adenoma up to 13 %. Oenothein B was not detected in the urine and feces of the E. angustifolium aqueous extract-treated group, however, conjugates of nasutins gut microbiota metabolites of ellagitannins were detected in the urine, while in human volunteers supplemented with Epilobium tea, only urolithin conjugates were present.Despite observing significant and consistent effects in vitro and in vivo, we were unable to point out unequivocally the factors contributing to the observed E. angustifolium aqueous extract activity, facing the problems of an unknown metabolic fate of oenothein B and interspecies differences in E. angustifolium aqueous extract gut microbiota metabolism.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Ziziphi spinosae lily powder suspension in the treatment of depression-like behaviors in rats

Depression is a chronic, recurring and potentially life-threatening illness. Current treatments for depression are characterized by a low success rate and associated with a wide variety of side effects. The ai...

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Transcriptomic and proteomic insight into the effects of a defined European mistletoe extract in Ewing sarcoma cells reveals cellular stress responses

The hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties. They do all occur in combination in European mistletoe (Viscum...

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The Effect of a Vocal Loading Test on Cough and Phonation in Patients With Chronic Cough

Talking is a significant trigger for cough in patients with chronic cough; however, the stimulus required to trigger cough has not been quantified. The aim of this study was to examine the effect of a vocal loading task on phonation and cough behavior in patients with chronic cough and identify change following therapy.

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Singing Lessons for Respiratory Health: A Literature Review

Several studies have explored the role of music and singing as a treatment for respiratory symptoms. The objective of this paper was to review the current body of literature in regard to the use of singing as both a physiological and a psychological therapy for respiratory disease and assess the role the singing teacher might play in this treatment.

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Applications of fusion-fluorescence imaging using indocyanine green in laparoscopic hepatectomy

Abstract

Background

Indocyanine green (ICG)-fluorescence imaging has been developed for real-time identification of hepatic tumors and segmental boundaries during hepatectomy. Fusion ICG-fluorescence imaging (real-time visualization of pseudocolor-fluorescence signals on white-light color images) may serve as a reliable navigation tool especially in laparoscopic hepatectomy, in which gross inspection and palpation are limited.

Methods

The study population consisted of 41 patients undergoing laparoscopic hepatectomy. Hepatic tumors were identified by fluorescence imaging following the preoperative intravenous administration of ICG (0.5 mg/kg body weight). To visualize hepatic perfusion and segmental boundaries, ICG (1.25 mg) was injected intravenously during surgery, following closure of the proximal portal pedicle. A laparoscopic imaging system, which enabled superimposition of the pseudocolor-fluorescence images on white color images, was used for the fusion ICG-fluorescence imaging.

Results

Among the 53 malignant tumors resected, fusion ICG-fluorescence imaging revealed 45 nodules (85%), including three nodules of colorectal liver metastasis unidentifiable by white-light color images or intraoperative ultrasonography. It also delineated the segmental boundaries on the hepatic raw surfaces as well as on the phrenic/visceral surfaces in all 12 patients evaluated using this technique.

Conclusions

Fusion imaging enhances the feasibility of intraoperative ICG-fluorescence imaging in the identification of hepatic tumors and segmental boundaries. It may therefore help surgeons in the safe and accurate completion of laparoscopic hepatectomies.



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Ergonomics perspective for identifying and reducing internal operative flow disruption for laparoscopic urological surgery

Abstract

Background

The aim of this study is to examine operative flow disruption that occurs inside the surgical field, (internal operative flow disruption (OFD)), during urological laparoscopies, and to relate those events to external ergonomics environment in terms of monitor location, level of instruments' handles, and location of surgical team members. According to the our best knowledge, this is the first study of its kind.

Methods

A combination of real and video-aided observational study was conducted in the operating rooms at hospitals in Australia and China. Brain storming sessions were first conducted to identify the main internal OFD events, and the observable reasons, potential external, and latent ergonomic factors were listed. A prospective observational study was then conducted. The observer's records and the related video records of internal surgical fields were analysed. Procedures were categorised into groups based on similarity in ergonomics environment.

Results

The mapping process revealed 39 types of internal OFD events resulted from six reasons. A total of 24 procedures were selected and arranged into two groups, each with twelve procedures. Group A was carried out under satisfactory ergonomics environment, while Group B was conducted under unsatisfactory ergonomics environment. A total of 1178 OFD events were detected delaying the total observed operative times (2966 min) by 220 min (7.43%). Average OFD/h in group A was less than 15, while in group B about 29 OFD/h.

Conclusion

There are two main latent ergonomics factors affecting the surgeon's performance; non-physiological posture and long-period static posture. The delays and number of internal OFD were nearly doubled where procedures were conducted under unsatisfactory external ergonomics environment. Some events such as stopping operation and irrelevant conversations during long procedures may have a positive influence on the surgeon's performance.



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Laparoscopy may decrease morbidity and length of stay after elective colon cancer resection, especially in frail patients: results from an observational real-life study

Abstract

Background

Advantages of laparoscopic approach in colon cancer surgery have been previously demonstrated in controlled, randomized trials and in retrospective analysis of large administrative databases. Nevertheless, evidence of these advantages in prospective, observational studies from real-life settings is scarce.

Methods

This is a prospective, observational study, including a consecutive series of patients that underwent elective colonic resection for cancer in 52 Spanish hospitals. Pre-/intraoperative data, related to patient, tumor, surgical procedure, and hospital, were recorded as well as 60-day post-operative outcomes, including wound infection, complications, anastomotic leak, length of stay, and mortality. A univariate and multivariate analysis was performed to determine the influence of laparoscopy on short-term post-operative outcome. A sub-analysis of the effect of laparoscopy according to patients' pre-operative risk (ASA Score I–II vs. III–IV) was also performed.

Results

2968 patients were included: 44.2% were initially operated by laparoscopy, with a 13.9% conversion rate to laparotomy. At univariate analysis, laparoscopy was associated with a decreased mortality (p = 0.015), morbidity (p < 0.0001), wound infection (p < 0.0001), and post-operative length of stay (p < 0.0001). At multivariate analysis, laparoscopy resulted as an independent protective factor for morbidity (OR 0.7; p = 0.004), wound infection (OR 0.6; p < 0.0001), and length of post-operative stay (Effect—2 days; p < 0.0001), compared to open approach. These advantages were more relevant in high-risk patients (ASA III–IV), even if the majority of them were operated by open approach (67.1%).

Conclusions

In a real-life setting, laparoscopy decreases wound infection rate, post-operative complications, and length of stay, especially in ASA III–IV patients.



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Photothermal Transport of DNA in Entropy-Landscape Plasmonic Waveguides

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b08563
ancac3?d=yIl2AUoC8zA


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Broadband Fluorescence Enhancement with Self-Assembled Silver Nanoparticle Optical Antennas

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01621
ancac3?d=yIl2AUoC8zA


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Reply

Truly, the described clinical scenario1 had its origins in 1999 with the discovery and ongoing characterization of IL-18 binding protein (IL-18BP) by Novick et al.2 We are grateful for their correspondence detailing the salient properties of this molecule.3 Regrettably, our original article was unable to include such details due to space limitations and the need to provide sufficient detail on the clinical scenario presented. We obviously agree that this molecule is well suited to the task of therapeutically blocking IL-18.

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IL-18 binding protein reverses the life-threatening hyperinflammation of a baby with the NLRC4 mutation

We read with excitement the article titled “Life-threatening NLRC4-associated hyperinflammation successfully treated with Interleukin-18 inhibition” by Canna et al.1 We congratulate the authors for this outstanding diagnostic and therapeutic triumph. This article also represents translation from the bench of a unique protein, the IL-18 binding protein (IL-18BP),2 into a targeted therapy drug that saved the life of this child. IL-18BP was an unexpected discovery and we believe that a short description of its unique features3,4 is useful to scientists and essential to clinicians and therefore should have been included in the publication of Canna et al.

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A study of the effects of citrate-coated silver nanoparticles on RAW 264.7 cells using a toolbox of cytotoxic endpoints

Abstract

Citrate-coated silver nanoparticles (citrate-AgNPs) are among the most commonly used nanomaterials, widely present in industrial and biomedical products. In this study, the cytotoxicity of 30-nm citrate-AgNPs on the macrophage cell line RAW 264.7 was evaluated, using a battery of cytotoxicity endpoints (viability, oxidative stress, and cytostaticity/clastogenicity), at 24 and 48 h of exposure. Citrate-AgNPs decreased cell proliferation and viability only at 75 μg/mL, suggesting a low sensitivity of RAW cells to lower doses of these AgNPs. After 24 h of exposure, ROS content decreased in cells exposed to 60 μg/mL AgNPs (IC20 value), corroborating the high tolerance of these cells to citrate-AgNPs. However, these cells suffered an impairment of the cell cycle, shown by an increase at the sub-G1 phase. This increase of the sub-G1 population was correlated with an increase of DNA fragmentation, suggesting an increase of apoptosis. Thus, our data are important to understand the effects of low concentrations (IC20) of citrate-AgNPs on in vitro vital macrophage functions.



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Large Marks-decahedral Pd nanoparticles synthesized by a modified hydrothermal method using a homogeneous reactor

Abstract

Fivefold symmetry appears only in small particles and quasicrystals because internal stress in the particles increases with the particle size. However, a typical Marks decahedron with five re-entrant grooves located at the ends of the twin boundaries can further reduce the strain energy. During hydrothermal synthesis, it is difficult to stir the reaction solution contained in a digestion high-pressure tank because of the relatively small size and high-temperature and high-pressure sealed environment. In this work, we optimized a hydrothermal reaction system by replacing the conventional drying oven with a homogeneous reactor to shift the original static reaction solution into a full mixing state. Large Marks-decahedral Pd nanoparticles (~90 nm) have been successfully synthesized in the optimized hydrothermal synthesis system. Additionally, in the products, round Marks-decahedral Pd particles were also found for the first time. While it remains a challenge to understand the growth mechanism of the fivefold twinned structure, we proposed a plausible growth-mediated mechanism for Marks-decahedral Pd nanoparticles based on observations of the synthesis process.

Graphical abstract

This is a stepwise growth mechanism for Marks-decahedral Pd nanoparticles. First, many truncated tetrahedrons are formed. Then, two adjacent {111} facets of a truncated single tetrahedron simultaneously grow epitaxially, forming a truncated tri-tetrahedron. A Marks decahedron is formed directly by epitaxial growth of both concave {111} facets of a truncated tri-tetrahedron.


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Marvel at the images from Cassini’s first Grand Finale orbit

The Cassini spacecraft is beginning its final set of daring orbits with breathtaking images of the Saturn system and rings

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Marvel at the images from Cassini’s first Grand Finale orbit

saturnnorth-e1493410671964.jpg

The Cassini spacecraft is beginning its final set of daring orbits with breathtaking images of the Saturn system and rings

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Expansion of CD11b + Ly6G high and CD11b + CD49d + myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption

Abstract

Objective

Myeloid-derived suppressor cells (MDSCs) are important negative regulators of immune processes in cancer and other pathological conditions. We suggested that MDSCs play a key role in pathogenesis of chronic inflammation, which precedes and, to a certain extent, induces carcinogenesis. The present study aimed at investigation of MDSCs arising during chronic inflammation and light-at-night (LN)-induced stress, which is shown to accelerate chronic diseases.

Subjects

67 CD-1 mice and in vitro MDSC cultures.

Treatment

Adjuvant arthritis was induced by a subdermal injection of complete Freund's adjuvant. LN was induced by illumination of 750 lx at night.

Methods

Flow cytometry for evaluation of cell phenotypes and MTT standard test for cell proliferation were used.

Results

Increased levels of splenic CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells possessing suppressive potential in mice with adjuvant arthritis are shown. LN amplifies the process of CD11b+Ly6Ghigh expansion in mice with adjuvant arthritis. Expression of CD62L and CD195 is elevated on the myeloid cells during exposure to LN.

Conclusions

Our study raises the possibility that CD11b+Ly6Ghigh and CD11b+CD49d+ MDSCs play an important role in the induction of immunosuppressive environment typical for chronic inflammation. Also, LN can affect immune responses during chronic inflammation through recruitment of MDSCs from the bone marrow.



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Does Scientific Progress Consist in Increasing Knowledge or Understanding?

Abstract

Bird (2007) argues that scientific progress consists in increasing knowledge. Dellsén (2016a) objects that increasing knowledge is neither necessary nor sufficient for scientific progress, and argues that scientific progress rather consists in increasing understanding. Dellsén also contends that unlike Bird's view, his view can account for the scientific practices of using idealizations and of choosing simple theories over complex ones. I argue that Dellsén's criticisms against Bird's view fail, and that increasing understanding cannot account for scientific progress, if acceptance, as opposed to belief, is required for scientific understanding.



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Vertically Aligned Graphene Sheets Membrane for Highly Efficient Solar Thermal Generation of Clean Water

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01965
ancac3?d=yIl2AUoC8zA


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A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function

Abstract

Purpose

The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations.

Methods

Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14–112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC0-τ, CLR, and CLNR/F.

Results

The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19–75%) over a dosage interval. When CLR increased due to improved renal function, AUC0-τ decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 × 100 to obtain median AUC0–12 of 18–26 mg/L/h for metformin IR and AUC0–24 of 38–51 mg/L/h for metformin XR, with Cmax < 5 mg/L.

Conclusions

The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.



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Rhomboid proteases in human disease: Mechanisms and future prospects

Publication date: Available online 28 April 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Stefan Düsterhöft, Ulrike Künzel, Matthew Freeman
Rhomboids are intramembrane serine proteases that cleave the transmembrane helices of substrate proteins, typically releasing luminal/extracellular domains from the membrane. They are conserved in all branches of life and there is a growing recognition of their association with a wide range of human diseases. Human rhomboids, for example, have been implicated in cancer, metabolic disease and neurodegeneration, while rhomboids in apicomplexan parasites appear to contribute to their invasion of host cells. Recent advances in our knowledge of the structure and the enzyme function of rhomboids, and increasing efforts to identify specific inhibitors, are beginning to provide important insight into the prospect of rhomboids becoming future therapeutic targets. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.



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Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences

Publication date: Available online 28 April 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Artur Cieślar-Pobuda, Viktoria Knoflach, Mikael V. Ringh, Joachim Stark, Wirginia Likus, Krzysztof Siemianowicz, Saeid Ghavami, Andrzej Hudecki, Jason L. Green, Marek J. Łos
Reprogramming, or generation of induced pluripotent stem (iPS) cells (functionally similar to embryonic stem cells or ES cells) by the use of transcription factors (typically: Oct3/4, Sox2, c-Myc, Klf4) called “Yamanaka factors” (OSKM), has revolutionized regenerative medicine. However, factors used to induce stemness are also overexpressed in cancer. Both, ES cells and iPS cells cause teratoma formation when injected to tissues. This raises a safety concern for therapies based on iPS derivates. Transdifferentiation (lineage reprogramming, or -conversion), is a process in which one mature, specialized cell type changes into another without entering a pluripotent state. This process involves an ectopic expression of transcription factors and/or other stimuli. Unlike in the case of reprogramming, tissues obtained by this method do not carry the risk of subsequent teratomagenesis.

Graphical abstract

image


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Unobtrusive acquisition of cardiorespiratory signals

Abstract

Over the past years, various systems and techniques enabling unobtrusive/minimally obtrusive acquisition of physiological signals have evolved. These systems and techniques open up novel opportunities for sleep medicine. This work provides an overview of unobtrusive systems and techniques to monitor cardiorespiratory function. We present basic principles of mechanical, radar-based, optical, and electrical measurements, and present concrete examples focused on how such systems and techniques can be used for sleep medicine. This work demonstrates the high potential of unobtrusive acquisition. Furthermore, it highlights the need for a standardized evaluation of the available techniques and demonstrates the demand for sleep-specific developments of available techniques in interdisciplinary collaborations.



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Management of Grass Pollen Allergy with 5-Grass Pollen Tablet: Results of a 2-Year Real-Life Study

Abstract

Introduction

Allergen immunotherapy is the only treatment option for allergic rhinitis with disease-altering potential. It was the objective of this study to assess the effectiveness and tolerability of a 5-grass pollen tablet in a large population of non-selected grass pollen allergic patients, i.e. patients with different clinical profiles in daily clinical practice.

Methods

In a 2-year, prospective, open-label, multicenter, non-controlled, observational study patients were included from 327 centers across Germany. Rhinoconjunctivitis symptoms, symptomatic medication intake and adverse events were recorded.

Results

A total of 1482 patients aged 4–75 years were included. During the 2-year period of 5-grass pollen tablet therapy, mean rhinoconjunctivitis score decreased significantly in the overall study population by 65.5% (P < 0.001). The percentage of patients taking symptomatic medication decreased from 83.8% to 42.7%. Mean 2-year improvements in rhinoconjunctivitis scores and decreases in the percentage of patients taking symptomatic medication were broadly similar in adults, adolescents and children, in patients with polyallergy versus monoallergy, and in patients with/without asthma. Among polyallergic patients, concomitant application of another specific immunotherapy did not impair treatment outcomes. Adverse drug reactions, predominantly affecting the local application area, occurred in 15.4% of the overall patient population (n = 229). No cases of anaphylaxis or epinephrine use were documented.

Conclusion

This study indicates that sublingual immunotherapy with the 5-grass pollen tablet is well tolerated and provides sustained effectiveness over 2 years in patients with different clinical profiles, producing a significant decrease in allergic symptoms and a reduction in the use of symptomatic medication.

Funding

Stallergenes GmbH.



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RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

Abstract

Introduction

A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.

Methods

Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.

Results

In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.

Conclusion

RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).

Funding

AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.



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Management of Grass Pollen Allergy with 5-Grass Pollen Tablet: Results of a 2-Year Real-Life Study

Abstract

Introduction

Allergen immunotherapy is the only treatment option for allergic rhinitis with disease-altering potential. It was the objective of this study to assess the effectiveness and tolerability of a 5-grass pollen tablet in a large population of non-selected grass pollen allergic patients, i.e. patients with different clinical profiles in daily clinical practice.

Methods

In a 2-year, prospective, open-label, multicenter, non-controlled, observational study patients were included from 327 centers across Germany. Rhinoconjunctivitis symptoms, symptomatic medication intake and adverse events were recorded.

Results

A total of 1482 patients aged 4–75 years were included. During the 2-year period of 5-grass pollen tablet therapy, mean rhinoconjunctivitis score decreased significantly in the overall study population by 65.5% (P < 0.001). The percentage of patients taking symptomatic medication decreased from 83.8% to 42.7%. Mean 2-year improvements in rhinoconjunctivitis scores and decreases in the percentage of patients taking symptomatic medication were broadly similar in adults, adolescents and children, in patients with polyallergy versus monoallergy, and in patients with/without asthma. Among polyallergic patients, concomitant application of another specific immunotherapy did not impair treatment outcomes. Adverse drug reactions, predominantly affecting the local application area, occurred in 15.4% of the overall patient population (n = 229). No cases of anaphylaxis or epinephrine use were documented.

Conclusion

This study indicates that sublingual immunotherapy with the 5-grass pollen tablet is well tolerated and provides sustained effectiveness over 2 years in patients with different clinical profiles, producing a significant decrease in allergic symptoms and a reduction in the use of symptomatic medication.

Funding

Stallergenes GmbH.



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RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

Abstract

Introduction

A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.

Methods

Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.

Results

In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.

Conclusion

RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).

Funding

AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.



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Acetylation of Lysine ε-amino Groups Regulates Aminoacyl-tRNA Synthetase Activity in Escherichia coli [RNA]

Previous proteomic analyses have shown that aminoacyl-tRNA synthetases (aaRSs) in many organisms can be modified by acetylation of lysine (Lys). In this present study, leucyl-tRNA synthetase and arginyl-tRNA synthetase from Escherichia coli (EcLeuRS and EcArgRS) were overexpressed and purified, and found to be acetylated on Lys residues by mass spectrometry (MS). Glutamine (Gln) scanning mutagenesis revealed that Lys619, Lys624 and Lys809 in EcLeuRS and Lys126 and Lys408 in EcArgRS might play important roles in enzyme activity. Furthermore, we utilized a novel protein expression system to obtain enzymes harboring acetylated-Lys (AcK) at specific sites, and investigated their catalytic activity. Acetylation of these Lys residues could affect their aminoacylation activity by influencing amino acid activation and/or the affinity for tRNA. In vitro assays showed that acetyl-phosphate (AcP) nonenzymatically acetylates EcLeuRS and EcArgRS, and suggested the sirtuin class deacetylase CobB might regulate acetylation of these two enzymes. These findings imply a potential regulatory role for Lys acetylation in controlling the activity of aaRSs and thus protein synthesis.

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Enterovirus 71 Suppresses Interferon Responses by Blocking JAK/STAT Signaling through Inducing Karyopherin-{alpha}1 Degradation [Immunology]

Enterovirus 71 (EV71) has emerged as one of the most important enteroviruses since the eradication of poliovirus, and causes severe neurological symptoms for which no effective antiviral drugs are available. Type I interferons (IFN-α/β) have been used clinically as antiviral therapy as the first line of defense against virus infections successfully for decades. However, treatment with Type I interferons has not been effective in patients with EV71 infection. In this study, we found that in cells pre-treated with IFN-β, EV71 infection could still lead to a cytopathic effect and the viral replication was not affected. The mechanism by which EV71 antagonizes interferon signaling, however, has been controversial. Our study indicated that EV71 infection did not inhibit phosphorylation of STAT1/2 induced by IFN-β stimulation, but p-STAT1/2 transport into the nucleus was significantly blocked. We showed that EV71 infection reduced the formation of STAT1/ karyopherin-α1 (KPNA1) complex upon interferon stimulation, and that the virus downregulated the expression of KPNA1, a nuclear localization signal receptor for p-STAT1. Using specific caspase inhibitors and siRNA for caspase-3, we demonstrated that EV71 infection induced degradation of cellular KPNA1 in a caspase-3 dependent manner, which led to decreased induction of ISGs and IFN response. Viral 2A and 3C proteases did not degrade KPNA1, inhibit the activity of ISRE, or suppress the transcription of ISGs induced by IFN-β. Our study demonstrates a novel mechanism by which antiviral signaling is suppressed through degradation of KPNA1 by activated caspase-3 induced in an enteroviral infection.

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Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection [Membrane Biology]

Endocytosis, and the subsequent trafficking of endosomes, requires dynamic physical alterations in membrane shape that are mediated in part by endophilin proteins. The endophilin B family of proteins contains an N-terminal Bin/Amphiphysin/Rvs (N-BAR) domain that induces membrane curvature to regulate intracellular membrane dynamics. While endophilin B1 (SH3GLB1/Bif-1) is known to be involved in a number of cellular processes, including apoptosis, autophagy and endocytosis, the cellular function of endophilin B2 (SH3GLB2) is not well understood. In this study, we used genetic approaches that revealed that endophilin B2 is not required for embryonic development in vivo, but that endophilin B2 deficiency impairs endosomal trafficking in vitro as evidenced by suppressed endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry and replication. Mechanistically, although the loss of endophilin B2 did not affect endocytic internalization and lysosomal function, endophilin B2 appeared to regulate the trafficking of endocytic vesicles and autophagosomes to late endosomes or lysosomes. Moreover, we also found that despite having an intracellular localization and tissue distribution similar to endophilin B1, endophilin B2 is dispensable for mitochondrial apoptosis. Taken together, our findings suggest that endophilin B2 positively regulates the endocytic pathway in response to growth factor signaling, autophagy induction, and viral entry.

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Metalloriboswitches: RNA-Based Inorganic Ion Sensors that Regulate Genes [Gene Regulation]

Divalent ions fulfill essential cellular roles and are required for virulence by certain bacteria. Free intracellular Mg2+ can approach 5 mM, but at this level, Mn2+, Ni2+, or Co2+ can be growth-inhibitory, and Mg2+-fluoride is toxic. To maintain ion homeostasis, many bacteria have evolved ion sensors embedded in the 5′-leader sequences of mRNAs encoding ion uptake or efflux channels. Here, we review current insights into these "metalloriboswitches," emphasizing ion-specific binding by structured RNA aptamers and associated conformational changes in downstream signal sequences. This riboswitch-effector interplay produces a layer of gene regulatory feedback that has elicited interest as an antibacterial target.

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The soluble protease ADAMDEC1 released from activated platelets hydrolyzes platelet membrane pro-EGF to active high molecular weight EGF [Enzymology]

Platelets are the sole source of EGF in the circulation, yet how EGF is stored or released from stimulated cells are undefined. In fact, we found platelets did not store EGF, synthesized as a single 6 kDa domain in pro-EGF, but rather expressed intact pro-EGF precursor on granular and plasma membranes. Activated platelets released high-molecular-weight (HMW)-EGF, produced by a single cleavage between the EGF and transmembrane domains of pro-EGF. We synthesized a fluorogenic peptide encompassing residues surrounding the putative sessile arginyl residue and found stimulated platelets released a soluble activity that cleaved this pro-EGF1020-1027 peptide. High throughput screening identified chymostatins, bacterial peptides with a central cyclic arginyl structure, as inhibitors of this activity. In contrast, the matrix metalloproteinase/TACE inhibitor GM6001 was ineffective. Stimulated platelets released the soluble protease ADAMDEC1, recombinant ADAMDEC1 hydrolyzed pro-EGF1020-1027, and this activity was inhibited by chymostatin and not GM6001. Biotinylating platelet surface proteins showed ADAMDEC1 hydrolyzed surface pro-EGF to HMW-EGF that stimulated HeLa EGF receptor (EGFR) reporter cells, and EGFR-dependent tumor cell migration. This proteolysis was inhibited by chymostatin and not GM6001. Metabolizing pro-EGF R1023 to citrulline with recombinant polypeptide arginine deiminase 4 (PAD4) abolished ADAMDEC1-catalyzed pro-EGF1020-1027 peptidolysis, while pretreating intact platelets with PAD4 suppressed ADAMDEC1-, thrombin-, or collagen-induced release of HMW-EGF. We conclude activated platelets release ADAMDEC1 that hydrolyzes pro-EGF to soluble HMW-EGF, HMW-EGF is active, proteolytic cleavage of pro-EGF first occurs at the carboxyl terminal arginyl residue of the EGF domain, and proteolysis is the regulated and rate-limiting step in generating soluble EGF bioactivity.

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Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group

Abstract

Background

The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis.

Methods

We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy.

Results

Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome.

Conclusions

CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.



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Shout in fury but smile at life: A portrait of an adolescent with cancer on the Youth Project in Milan



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Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant

Abstract

Cardiomyopathy is common in long-term survivors of pediatric hematopoietic stem cell transplant (HSCT). Events occurring before and after HSCT when combined with specific insults during HSCT likely contribute to long-term risk. Strategies for detecting subclinical cardiomyopathy prior to patients developing overt heart failure are under investigation. Changes in HSCT preparative regimens and cardioprotective medications administered during chemotherapy may alter the risk for cardiomyopathy. Interventions in long-term survivors such as lifestyle modification and cardioactive medications are of increasing importance. Herein we review the causes of cardiac injury, discuss strategies for detection of cardiomyopathy, and evaluate therapeutic options for long-term HSCT survivors.



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Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement

Abstract

Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B-cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.



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The clinical severity of hemoglobin S/Black (Aγδβ)0-thalassemia

Abstract

Hemoglobin S/Black (Aγδβ)0-thalassemia is a rare sickle cell disease (SCD) variant. On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course. We report the clinical and laboratory data of nine patients whose diagnoses were confirmed by DNA-based techniques. Despite having mild anemia and high fetal hemoglobin level postinfancy, these patients developed many of the classic complications of SCD, including vaso-occlusive crisis, acute chest syndrome, avascular necrosis, and cholelithiasis. On the basis of these findings, we recommend that patients with this rare disorder receive specialized hematology care according to SCD guidelines.



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Clinical outcome of childhood chronic immune thrombocytopenia: A 38-year experience from a single tertiary center in Thailand

Abstract

Background

There is limited information on long-term follow-up and prognostic factors for remission among children diagnosed with chronic immune thrombocytopenia (ITP). The aim of this study was to determine clinical outcomes and factors influencing remission in childhood chronic ITP.

Study Design

The hospital records of children aged 0–15 years diagnosed with chronic ITP were retrospectively reviewed. Kaplan–Meier curves were fit to estimate the median time to complete remission with 95% confidence intervals (CIs). Multivariate Cox proportional hazards regression models were used to identify independent factors for remission.

Results

A total of 113 patients were included in the analysis. The number of children achieving complete remission was 49 (46%) and the median time to remission was 7.1 years (95% CI: 4.8–11.0). The remission rates at 3, 5, 10, and 20 years were 25, 43, 60, and 75%, respectively. Factors influencing remission were platelets >60 × 109/L at the onset of chronic ITP (hazard ratio [HR]: 7.24, 95% CI: 3.0–17.5) and treatment with intravenous immunoglobulin (HR: 0.37, 95% CI: 0.16–0.84). Age, gender, and clinical factors at the time of newly diagnosed ITP including bleeding manifestations, onset of symptoms, and history of preceding infection and vaccination were not predictive of remission.

Conclusion

The spontaneous complete remission rates of chronic ITP were 43 and 60% at 5 and 10 years, respectively, and reached 75% at 20 years. A higher platelet level at diagnosis of chronic ITP and form of treatment were statistically significant indicators for achieving complete remission.



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Electrophysiological effects of anthracyclines in adult survivors of pediatric malignancy

Abstract

Background

Anthracycline use is limited by cardiotoxicity, including arrhythmias and left ventricular (LV) dysfunction. We aim to characterize the association between electrophysiological changes and LV dysfunction.

Methods

A retrospective chart review was conducted, including all 147 pediatric cancer survivors at our institution over 18 years of age and treated with an anthracycline. One hundred thirty-four patients who had at least one electrocardiogram (ECG) and echocardiogram were analyzed. The association between dysfunction and baseline characteristics, treatment history, and electrocardigraphic parameters were analyzed using multivariable logistic regression. Additionally, a longitudinal generalized estimating equation (GEE) model was used to examine the temporal association between repeated measure corrected QT (QTc) intervals and subsequent LV function.

Results

In our population, 24% of patients had LV dysfunction. The initial posttreatment QTc interval was longer in patients with LV dysfunction (438 ± 35 vs. 420 ± 20 msec, P = 0.002). In logistic regression analysis, QTc interval (P < 0.001) and cumulative radiation dose (P = 0.027) were associated with LV dysfunction. On ECGs performed prior to evidence of LV dysfunction, the QTc was longer than on ECGs preceding a normal echocardiogram (451 ± 32 msec vs. 423 ± 25 msec, P < 0.001). Mean time from QTc ≥ 450 msec to evidence of LV dysfunction was 1.8 ± 2.9 years. In the longitudinal GEE model, QTc prolongation was associated with subsequent decreased fractional shortening.

Conclusions

Among adult survivors of pediatric cancer treated with anthracyclines, prolongation of the QTc interval was associated with subsequent LV dysfunction.



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Authorship Correction: Scalable Passive Sleep Monitoring Using Mobile Phones: Opportunities and Obstacles

n/a

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Association of vertebral compression fractures with physical performance measures among community-dwelling Japanese women aged 40 years and older

Abstract

Background

Numerous reported studies have shown that vertebral compression fractures are associated with impaired function or disability; however, few examined their association with objective measures of physical performance or functioning.

Methods

We examined the association of vertebral compression fractures with physical performance measures in 556 Japanese women aged 40–89 years. Lateral spine radiographs were obtained and radiographic vertebral compression fractures were assessed by quantitative morphometry, defined as vertebral heights more than 3 SD below the normal mean. Measures of physical performance included walking speed, chair stand time and functional reach. Adjusted means of performance-based measures according to the number and severity of vertebral compression fractures were calculated using general linear modeling methods.

Results

After adjusting for age, body mass index, back pain, number of painful joints, number of comorbidities and regular physical activities, the walking speed of women with two or more compression fractures (1.17 m/s) was significantly slower than that of women without compression fracture (1.24 m/s) (p = 0.03). Compared with women without compression fracture, chair stand time was longer in women with two or more compression fractures (p = 0.01), and functional reach was shorter (p = 0.01). No significant differences were observed in walking speed, chair stand time, or functional reach between women with one compression fracture and those without compression fracture.

Conclusions

Having multiple vertebral compression fractures affects physical performance in community-dwelling Japanese women. Poor physical functioning may lead to functional dependence, accelerated bone loss, and increased risk for falls, injuries, and fractures. Preventing vertebral compression fracture is considered important for preserving the independence of older adults.



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Visual analogue scale (VAS) as a monitoring tool for daily changes in asthma symptoms in adolescents: a prospective study

Success in asthma management hinges on patients’ competency to detect and respond to ever-changing symptom severity. Thus, it is crucial to have reliable, simple, and sustainable methods of symptom monitoring ...

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04/28/17 PHD comic: 'Automatic Reply'

Piled Higher & Deeper by Jorge Cham
www.phdcomics.com
Click on the title below to read the comic
title: "Automatic Reply" - originally published 4/28/2017

For the latest news in PHD Comics, CLICK HERE!



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The Role of Neuroscience in Psychiatry Redux

My response to a critique of a recent post

-- Read more on ScientificAmerican.com
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WITHDRAWN: Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma [Research]

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.



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Hyper-phosphorylation of Sequestosome-1 distinguishes resistance to cisplatin in patient derived high grade serous ovarian cancer cells [Research]

Platinum-resistance is a major limitation to effective chemotherapy regimens in high-grade serous ovarian cancer (HGSOC). To better understand the mechanisms involved we characterized the proteome and phosphoproteome in cisplatin sensitive and resistant HGSOC primary cells using a mass spectrometry-based proteomic strategy. PCA analysis identified a distinctive phosphoproteomic signature between cisplatin sensitive and resistant cell lines. The most phosphorylated protein in cisplatin resistant cells was sequestosome-1 (p62/SQSTM1). Changes in expression of apoptosis and autophagy related proteins Caspase-3 and SQSTM1, respectively, were validated by western blot analysis. A significant increase in apoptosis in the presence of cisplatin was observed in only the sensitive cell line while SQSTM1 revealed increased expression in the resistant cell line relative to sensitive cell line. Furthermore, site-specific phosphorylation on 20 amino acid residues of SQSTM1 was detected indicating a hyper-phosphorylation phenotype. This elevated hyper-phosphorylation of SQSTM1 in resistant HGSOC cell lines was validated with western blot analysis. Immunofluoresence staining of s28-pSQSTM1 showed inducible localization to autophagosomes upon cisplatin treatment in the sensitive cell line while being constitutively expressed to autophagosomes in the resistant cell. Furthermore, SQSTM1 expression was localized in cancer cells of clinical high-grade serous tumors. Here, we propose hyper- phosphorylation of SQSTM1 as a marker and a key proteomic change in cisplatin resistance development in ovarian cancers by activating the autophagy pathway and influencing down- regulation of apoptosis.



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Validation, identification and biological consequences of the site-specific O-GlcNAcylation dynamics of ChREBP [Research]

O-GlcNAcylation of carbohydrate-responsive element-binding protein (ChREBP) is believed as an important modulator of ChREBP activities, however little direct evidence of O-GlcNAcylation on ChREBP and no exact O-GlcNAcylation sites have been reported so far. Here, we validate O-GlcNAcylation on ChREBP in cell-free coupled transcription/translation system and in cells by chemoenzymatic and metabolic labeling, respectively. Moreover, for the first time, we identify O-GlcNAcylation on Ser614 in the C-terminus of ChREBP by mass spectrometry and validate two important sites, Thr517 and Ser839 for O-GlcNAcylation and their function via molecular and chemical biological method. Under high glucose conditions, Ser514 phosphorylation enhances ChREBP O-GlcNAcylation, maintaining the transcriptional activity of ChREBP; Ser839 O-GlcNAcylation is essential for Mlx-heterodimerization and DNA-binding activity enhancement, consequently inducing transcriptional activity. Ser839 O-GlcNAcylation is also crucial for ChREBP nuclear export partially by strengthening interactions with CRM1 and 14-3-3. This work is a detailed study of ChREBP O-GlcNAcylation and highlights the biological consequences of the site-specific O-GlcNAcylation dynamics of ChREBP.



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Feature analysis for classification of trace fluorescent labeled protein crystallization images

Large number of features are extracted from protein crystallization trial images to improve the accuracy of classifiers for predicting the presence of crystals or phases of the crystallization process. The exc...

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More promising leukaemia news from @uniofleicester with phase I data for novel BTK inhibitor: https://t.co/nl2fRuV1Mh

More promising leukaemia news from @uniofleicester with phase I data for novel BTK inhibitor: https://t.co/nl2fRuV1Mh

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Prevalence and antimicrobial resistance profile of Staphylococcus in dairy farms, abattoir and humans in Addis Ababa, Ethiopia

Staphylococcus species cause mastitis and wound infection in livestock and food poisoning in humans through ingestion of contaminated foods, including meat and dairy products. They are...

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Occupational factors and low back pain: a cross-sectional study of Bangladeshi female nurses

The suffering from low back pain (LBP) is very common among nurses. The high prevalence rates of LBP are observed in many countries. Many back injuries are due to individual and work-related factors. Our aim i...

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How common is ponticulus posticus on lateral cephalograms?

Ponticulus posticus is an anomaly of first cervical vertebra visible on lateral cephalogram and has some serious medical and surgical implications. Unfortunately, it is often overlooked or undetected by orthod...

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Molecular and epidemiological characterization of HIV-1 subtypes among Libyan patients

The epidemiological and clinical aspects of human immunodeficiency virus subtypes are of great interest worldwide. These subtypes are rarely studied in North African countries. Libya is a large country with th...

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Unraveling the mystery of DNA attacks in cells' powerhouse could pave way for new cancer treatments

New research has unravelled the mystery of how mitochondria -- the energy generators within cells -- can withstand attacks on their DNA from rogue molecules. The findings could pave the way for new treatments to tackle neurodegenerative diseases and...

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