Allergy symptoms, serum total immunoglobulin E, and risk of head and neck cancer.

Abstract:
PURPOSE
Allergy symptoms have been associated with a reduced head and neck cancer (HNC) risk, while elevated blood immunoglobulin E (IgE) levels have been associated with an increased HNC risk. According to the "prophylaxis hypothesis," allergic reaction is the body's way of expelling carcinogens. IgE level may be increased by exposure to environmental carcinogens, including alcohol and cigarette smoke. We hypothesized that individuals with elevated serum IgE without allergy symptoms (i.e., asymptomatic atopic) would have the highest HNC risk.

METHODS
A case-control study of HNC (576 cases and 740 controls) was conducted to evaluate the association between allergy symptoms or serum total IgE and HNC risk and the effect modification of allergy symptoms on the association between serum total IgE and HNC risk.

RESULTS
Elevated serum total IgE was associated with a significantly increased HNC risk [odds ratio (OR) 1.71, 95 % confidence interval (CI) 1.21-2.42]. Having allergy symptoms was associated with a significantly reduced HNC risk (OR 0.56, 95 % CI 0.43-0.73). Compared to subjects with normal serum total IgE and no allergy symptoms, asymptomatic atopic individuals had a significantly increased HNC risk (OR 2.12, 95 % CI 1.33-3.35).

CONCLUSIONS
Our results provided further evidence to support the "prophylaxis hypothesis." Further investigations regarding the immune profiles of asymptomatic atopic individuals may provide additional clues for the biological mechanisms underlying the association between allergy symptoms, IgE, and HNC risk.

Liao|Hsiao-Chen|HC|
Wu|Shang-Yin|SY|
Ou|Chun-Yen|CY|
Hsiao|Jenn-Ren|JR|
Huang|Jehn-Shyun|JS|
Tsai|Sen-Tien|ST|
Huang|Cheng-Chih|CC|
Wong|Tung-Yiu|TY|
Lee|Wei-Ting|WT|
Chen|Ken-Chung|KC|
Fang|Sheen-Yie|SY|
Wu|Jiunn-Liang|JL|
Huang|Tze-Ta|TT|
Wu|Yuan-Hua|YH|
Hsueh|Wei-Ting|WT|
Yen|Chia-Jui|CJ|
Yang|Ming-Wei|MW|
Lin|Forn-Chia|FC|
Lai|Yu-Hsuan|YH|
Chang|Jang-Yang|JY|
Lin|Chen-Lin|CL|
Wang|Yi-Hui|YH|
Weng|Ya-Ling|YL|
Yang|Han-Chien|HC|
Chen|Yu-Shan|YS|
Chang|Jeffrey S|JS|

Allergy
Immunoglobulin E
Head and neck cancer
Case–control


CytoMatrix for a reliable and simple characterization of lung cancer stem cells from malignant pleural effusions.

Abstract: Cancer stem cells (CSCs) are a subpopulation with the properties of extensive self-renewal, capability to generate differentiated cancer cells and resistance to therapies. We have previously shown that malignant pleural effusions (MPEs) from patients with non-small-cell lung cancer (NSCLC) represent a valuable source of cancer cells that can be grown as three-dimensional (3D) spheroids enriched for stem-like features, which depend on the activation of the Yes-associated protein-transcriptional coactivator with PDZ-binding motif (YAP-TAZ)/Wnt-βcatenin/stearoyl-CoA desaturase 1 (SCD1) axis. Here, we describe a novel support, called CytoMatrix, for the characterization of limited amounts of cancer cells isolated from MPEs of patients with NSCLC. Our results show that this synthetic matrix allows an easy and fast characterization of several epithelial cellular markers. The use of CytoMatrix to study CSCs subpopulation confirms that SCD1 protein expression is enhanced in 3D spheroids when compared with 2D adherent cell cultures. YAP/TAZ nuclear-cytoplasmic distribution analysed by CytoMatrix in 3D spheroids is highly heterogeneous and faithfully reproduces what is observed in tumour biopsies. Our results confirm and extend the robustness of our workflow for the isolation and phenotypic characterization of primary cancer cells derived from the lung MPEs and underscore the role of SCD1.

Bruschini|Sara|S|
di Martino|Simona|S|
Pisanu|Maria Elena|ME|
Fattore|Luigi|L|
De Vitis|Claudia|C|
Laquintana|Valentina|V|
Buglioni|Simonetta|S|
Tabbì|Eugenio|E|
Cerri|Andrea|A|
Visca|Paolo|P|
Alessandrini|Gabriele|G|
Facciolo|Francesco|F|
Napoli|Christian|C|
Trombetta|Marcella|M|
Santoro|Antonio|A|
Crescenzi|Anna|A|
Ciliberto|Gennaro|G|
Mancini|Rita|R|0000-0002-5491-2449

CytoMatrix
lung cancer
cancer stem cells
MPEs
SCD1


Chromosomal-level assembly of Juglans sigillata genome using Nanopore, BioNano, and Hi-C analysis.

Abstract:
BACKGROUND
Juglans sigillata, or iron walnut, belonging to the order Juglandales, is an economically important tree species in Asia, especially in the Yunnan province of China. However, little research has been conducted on J. sigillata at the molecular level, which hinders understanding of its evolution, speciation, and synthesis of secondary metabolites, as well as its wide adaptability to its plateau environment. To address these issues, a high-quality reference genome of J. sigillata would be useful.

FINDINGS
To construct a high-quality reference genome for J. sigillata, we first generated 38.0 Gb short reads and 66.31 Gb long reads using Illumina and Nanopore sequencing platforms, respectively. The sequencing data were assembled into a 536.50-Mb genome assembly with a contig N50 length of 4.31 Mb. Additionally, we applied BioNano technology to identify contacts among contigs, which were then used to assemble contigs into scaffolds, resulting in a genome assembly with scaffold N50 length of 16.43 Mb and contig N50 length of 4.34 Mb. To obtain a chromosome-level genome assembly, we constructed 1 Hi-C library and sequenced 79.97 Gb raw reads using the Illumina HiSeq platform. We anchored ∼93% of the scaffold sequences into 16 chromosomes and evaluated the quality of our assembly using the high contact frequency heat map. Repetitive elements account for 50.06% of the genome, and 30,387 protein-coding genes were predicted from the genome, of which 99.8% have been functionally annotated. The genome-wide phylogenetic tree indicated an estimated divergence time between J. sigillata and Juglans regia of 49 million years ago on the basis of single-copy orthologous genes.

CONCLUSIONS
We provide the first chromosome-level genome for J. sigillata. It will lay a valuable foundation for future research on the genetic improvement of J. sigillata.

Ning|De-Lu|DL| Wu|Tao|T| Xiao|Liang-Jun|LJ| Ma|Ting|T| Fang|Wen-Liang|WL| Dong|Run-Quan|RQ| Cao|Fu-Liang|FL|

Juglans sigillata
evolution
genome assembly
annotation


Inhibitory effect of icariin on osteosarcoma cell proliferation via the Wnt/β-catenin signaling pathway.

Abstract: Osteosarcoma, is a kind of malignant tumor derived from malignant interstitial cells. The pathogenesis of osteosarcoma remains unclear and despite use of chemotherapy drugs, resistance to these drugs affects the success of treatment. The present study was conducted to investigate the effects of icariin (ICA) on osteosarcoma cell proliferation and to investigate the role of the Wnt/β-catenin signaling pathway in the inhibition process of ICA on osteosarcoma cell proliferation. Different concentrations of ICA were selected to treat the osteosarcoma cell line 143B for 24 h, and then the onset concentration of ICA when it inhibited the growth of osteosarcoma cancer cell line 143B was detected via an MTT assay. The effect of ICA on the apoptosis of colon cancer cell line 143B under this concentration was detected using a flow cytometer. RNA in osteosarcoma cell line 143B was extracted, followed by reverse transcription. The expression levels of related and apoptotic proteins in the Wnt/β-catenin signaling pathway using ICA were detected by semi-quantitative PCR and western blot analysis, respectively. The expression quantities of vascular endothelial growth factor (VEGF) and MMP-9 were detected by ELISA. MTT assay showed that ICA inhibited the growth of 143B when its concentration was 5 µM (p<0.01). Flow cytometry showed that the number of apoptotic cells after ICA treatment was significantly higher than that in control group (p<0.01). RNA in osteosarcoma cell line 143B was extracted, followed by reverse transcription. Semi-quantitative PCR and western blot analysis revealed that the expression levels of p-GSK3β, β-catenin, c-Myc and cyclin D1 in cells after ICA treatment were significantly downregulated (p<0.01), while the expression level of caspase-3 was significantly increased (p<0.01). ELISA showed that the expression quantities of VEGF and MMP-9 were significantly decreased (p<0.01). Thus, ICA can significantly inhibit osteosarcoma cell proliferation and promote osteosarcoma cell apoptosis, which may be realized by affecting the expression of the Wnt/β-catenin signaling pathway and blocking the expression of related proteins.

icariin
osteosarcoma
proliferation
Wnt/β-catenin signaling pathway


Metabolic Engineering of Yeast for the Production of 3-Hydroxypropionic Acid.

Abstract: The beta-hydroxy acid 3-hydroxypropionic acid (3-HP) is an attractive platform compound that can be used as a precursor for many commercially interesting compounds. In order to reduce the dependence on petroleum and follow sustainable development, 3-HP has been produced biologically from glucose or glycerol. It is reported that 3-HP synthesis pathways can be constructed in microbes such as Escherichia coli, Klebsiella pneumoniae and the yeast Saccharomyces cerevisiae. Among these host strains, yeast is prominent because of its strong acid tolerance which can simplify the fermentation process. Currently, the malonyl-CoA reductase pathway and the β-alanine pathway have been successfully constructed in yeast. This review presents the current developments in 3-HP production using yeast as an industrial host. By combining genome-scale engineering tools, malonyl-CoA biosensors and optimization of downstream fermentation, the production of 3-HP in yeast has the potential to reach or even exceed the yield of chemical production in the future.

Ji|Rong-Yu|RY| Ding|Ying|Y| Shi|Tian-Qiong|TQ| Lin|Lu|L| Huang|He|H| Gao|Zhen|Z| Ji|Xiao-Jun|XJ|

metabolic engineering
yeast
3-Hydroxypropionic acid
malonyl-CoA reductase pathway
β-alanine pathway


Voice modulatory cues to structure across languages and species.

Abstract: Voice modulatory cues such as variations in fundamental frequency, duration and pauses are key factors for structuring vocal signals in human speech and vocal communication in other tetrapods. Voice modulation physiology is highly similar in humans and other tetrapods due to shared ancestry and shared functional pressures for efficient communication. This has led to similarly structured vocalizations across humans and other tetrapods. Nonetheless, in their details, structural characteristics may vary across species and languages. Because data concerning voice modulation in non-human tetrapod vocal production and especially perception are relatively scarce compared to human vocal production and perception, this review focuses on voice modulatory cues used for speech segmentation across human languages, highlighting comparative data where available. Cues that are used similarly across many languages may help indicate which cues may result from physiological or basic cognitive constraints, and which cues may be employed more flexibly and are shaped by cultural evolution. This suggests promising candidates for future investigation of cues to structure in non-human tetrapod vocalizations. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part I)'.

voice modulation
speech segmentation
cross-linguistic comparisons
cross-species comparisons
linguistic structure
prosody


Statement of the expert group on the current practice and prospects for the treatment of complex perirectal fistulas in the course of Crohn's disease.

Abstract: Perirectal fistulas in the course of Crohn's disease (CD) constitute an important problem in this group of patients. They are observed in a vast majority of patients with involvement through colorectal inflammation. Perirectal fistulas in CD present a great diagnostic and therapeutic challenge due to the intensified clinical symptoms and worse prognosis than in the case of crypt originating fistulas. The condition for implementation of effective treatment of perirectal fistulas in the course of CD is the correct diagnosis, defining the anatomy of fistulas, presence of potential stenoses and inflammation in the gastrointestinal tract. Treatment of these fistulas is difficult and requires close cooperation between the colorectal surgeon and the gastroenterologist. The combination of surgical and pharmacological treatment has higher efficacy compared to surgical treatment or pharmacotherapy alone. In conservative treatment, aminosalicylates and steroids are of minor importance, while chemotherapeutics, antibiotics, and thiopurines find application in daily clinical practice. TNF-α neutralizing antibodies such as infliximab (IFX), adalimumab (ADA) or certolizumab (CER) prove to be the most effective. Surgical treatment may be provided as ad hoc; in this case, drainage procedures are recommended, usually with leaving a loose seton. Planned procedures consist in the excision of fistulas (simple fistulas) or performing more complex procedures, such as advancement flaps or ligation of the intersphincteric fistula tract Surgical measures can be complemented by the use of video technology (video-assisted anal fistula treatment VAAFT) or vacuum therapy. In extreme cases, it may be necessary to create the stoma. Treatment of perirectal fistulas includes adhesives or so-called plugs. High hopes may be associated with the introduction of stem cells into clinical practice, which is the administration of non-hematopoietic multipotent cells to the fistulas to induce the phenomenon of immunomodulation and tissue healing.

Banasiewicz|Tomasz|T| Eder|Piotr|P| Rydzewska|Grażyna|G| Reguła|Jarosław|J| Dobrowolska|Agnieszka|A| Durlik|Marek|M| Wallner|Grzegorz|G|

D013505:Digestive System Surgical Procedures

Crohn's disease
stem cells
biological treatment
perianal fistula
surgical treatment of fistulas


Quality of randomized controlled trials of new generation antidepressants and antipsychotics identified in the China National Knowledge Infrastructure (CNKI): a literature and telephone interview study.

Abstract:
BACKGROUND
We are witnessing an exponential increase in the number of randomized controlled trials (RCTs) reported from mainland China. The increase is particularly notable in the field of new generation antidepressants and antipsychotics. Several previous studies have raised doubts regarding their quality. However, the quality of most recent RCTs published in China may have improved.

METHODS
We searched RCTs that examined new generation antidepressants and antipsychotics published between 2013 and 2016 in the China National Knowledge Infrastructure (CNKI), the largest database of scientific publications in China. We interviewed the authors of a random subset of the identified references. We assessed the methodological rigor of each study based on the published reports and telephone interviews with the authors using six methodological domains adapted from the Cochrane's risk of bias tool.

RESULTS
The final sample consisted of 138 studies, for which we interviewed 58 authors; the authors of 51 studies declined the interview, and the authors of 29 studies could not be contacted. The 51 studies with refused interviews were significantly less likely to be reported from university-affiliated hospitals and were less likely to be published in Chinese core journals. Based on the published reports, most of the 58 studies were assessed to be at unclear risk of bias in most methodological domains. After the interview, only 10 studies were assessed to be at low risk of bias for sequence generation and allocation concealment. Assuming that the studies for which the authors declined interviews had an unclear risk, the proportion of RCTs at low risk of bias in both sequence generation and allocation concealment was 9.2% (10/109, 95% confidence interval [CI]: 5.0 to 16.2). The interviews indicated that the studies were at high risk of bias for most of the other domains.

CONCLUSION
In general, RCTs that evaluate new generation antidepressants or antipsychotics and are indexed in the CNKI continue to be of low quality. When conducting systematic reviews and meta-analyses in this field, it would be wise to include a specialist from China as a coresearcher to help assess the risk of bias in the identified studies.

Tong|Zheng|Z|
Li|Fangzhou|F|
Ogawa|Yusuke|Y|
Watanabe|Norio|N|
Furukawa|Toshi A|TA|0000-0003-2159-3776

D016032:Randomized Controlled Trials as Topic

Randomized controlled trials
China
Risk of bias
Antidepressive agents
Antipsychotic agents
Research integrity


Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies.

Abstract: Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies.


The Role of Information and Communication Technology in End-of-Life Planning Among a Sample of Canadian LGBT Older Adults.

Abstract: To better understand the role of technology in later-life planning among older lesbian, gay, bisexual, and trans (LGBT) adults, we conducted focus groups to explore factors linked to diverse sexual orientations and gender identities. Twenty focus groups were facilitated across Canada with 93 participants aged 55 to 89. Constant comparative analysis yielded four categories: (a) fear, (b) individual benefits, (d) social elements, and (d) contextual elements. Fear related to technology and fear of end-of-life planning. Individual benefits referred to technology as a platform for developing LGBT identities and as a source of information for later-life planning. Social elements were establishment and maintenance of personal relationships and social support networks. Contextual elements referred to physical and situational barriers to technology use that limited access and usability. These findings can inform technological practice and services to enhance later-life planning.

Mock|Steven E|SE|0000-0002-3370-9919
Walker|Earl P|EP|
Humble|Áine M|ÁM|0000-0003-1429-5869
de Vries|Brian|B|
Gutman|Gloria|G|
Gahagan|Jacqueline|J|
Chamberland|Line|L|
Aubert|Patrick|P|
Fast|Janet|J|

later-life planning
lesbian
gay
bisexual
Internet and communication technology
transgender


Identification of a Ferroptosis Gene Set That Mediates the Prognosis of Squamous Cell Carcinoma of the Head and Neck.

Abstract: Squamous cell carcinoma of the head and neck (HNSCC) is one of the six most common malignancies. HNSCC has both a high incidence and poor prognosis, and its prognostic factors remain unclear. Ferroptosis is a newly discovered form of programmed cell death that is iron-dependent. Increasing evidence indicates that targeting ferroptosis may present a new form of anti-tumor treatment. However, the prognostic value of ferroptosis-related genes (FRGs) in HNSCC is unclear. This study was designed to identify molecular markers associated with ferroptosis that influence prognosis in patients with HNSCC. We used HNSCC tumor and normal data from The Cancer Genome Atlas (TCGA) to identify prognosis-related FRGs. An FRG-based prognostic risk score was constructed, and its prognostic value for patients with HNSCC was evaluated using receiver operating characteristic curve (ROC) and nomogram analyses. The model was validated using the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis in patients with HNSCC revealed 11 FRGs that were significantly associated with overall survival (OS). We constructed a ferroptosis risk score model based on five genes and divided the patients into different risk groups based on its median value. Kaplan-Meier curve analysis showed that patients with a higher ferroptosis risk score had shorter OS (TCGA training set: P < 0.001, TCGA validation set: P < 0.05,GEO validation set: P < 0.001), and Gene Expression Profiling Interactive Analysis (GEPIA) further verified the relationships between these five genes and prognosis in patients with HNSCC. Multivariate Cox regression analysis showed that the risk score remained an independent predictor of OS after the exclusion of clinical confounders (HR > 1, P < 0.01). Significant differences in gene function enrichment analysis and immune cell infiltration status were identified between the two groups. The prognostic model can be used to predict the prognosis of patients with HNSCC. Moreover, the five FRGs may affect ferroptosis in HNSCC and thereby represent potential treatment targets. These results provide new directions for HNSCC treatment.

Li|Chunyan|C| Wang|Xuemin|X| Qin|Rujia|R| Zhong|Zhaoming|Z| Sun|Chuanzheng|C|

HNSCC
ferroptosis-related genes
immune cell infiltration
DEGs
worse prognosis


The Great Mime: Three Cases of Melanoma with Carcinoid-Like and Paraganglioma-Like Pattern with Emphasis on Differential Diagnosis.

Abstract: Melanoma is among the most aggressive tumors, with different histological patterns of presentation ranging from the usual and easily diagnosable pictures to complex patterns of difficult diagnostic interpretation. Here, we present three cases of a very rare melanoma variant described as "carcinoid-like" and "paraganglioma-like" in the literature, and a brief review of the current literature of the very few cases described to date.

melanoma carcinoid-like paraganglioma-like pattern


Trend analysis of disability-adjusted life years following adult out-of-hospital cardiac arrest in the United States: A study from the CARES Surveillance Group.

Abstract:
AIM
To estimate and trend disability-adjusted life years (DALY) following adult out-of-hospital cardiac arrest (OHCA) over time, and to compare OHCA DALY to other leading causes of death and disability in the U.S.

METHODS
DALY were calculated as the sum of years of life lost (YLL) and years lived with disability (YLD). Adult non-traumatic emergency medical services-treated OHCA from the Cardiac Arrest Registry to Enhance Survival (CARES) database for 2013-2018 were used to estimate YLL. Cerebral performance category score disability weights were used to estimate YLD. The calculated DALY for the study population was extrapolated to a national level to estimate total U.S. DALY. Data were reported as DALY total and rate. Data were compared to the top 10 causes of DALY in the U.S.

RESULTS
337,991 OHCA met study inclusion criteria. Total U.S. OHCA DALY increased from 3,005,308 in 2013 to 4,326,745 in 2018. The DALY rate increased from 950.9 per 100,000 individuals to 1322.4 per 100,000 individuals. OHCA DALY ranked fifth in the U.S. behind ischemic heart disease (2470), drug use disorders (1703), chronic obstructive pulmonary disease (1449), and back pain (1336). OHCA represented the largest percent increase in DALY rate (40.3%) over the study period.

CONCLUSION
Adult non-traumatic OHCA is a leading cause of DALY in the U.S. and the burden of disease due to OHCA has increased rapidly over time. These findings are likely due to more precise national OHCA surveillance, and suggest that the public health impact of OHCA is larger than previously described.

Coute|Ryan A|RA|
Nathanson|Brian H|BH|
Mader|Timothy J|TJ|
McNally|Bryan|B|
Kurz|Michael C|MC|

Out-Of-hospital cardiac arrest
Cause of death
Disability
Life expectancy


Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release.

Abstract: The transcription factor Hes3 is a component of a signaling pathway that supports the growth of neural stem cells with profound consequences in neurodegenerative disease models. Here we explored whether Hes3 also regulates pancreatic islet cells. We showed that Hes3 is expressed in human and rodent pancreatic islets. In mouse islets it co-localizes with alpha and beta cell markers. We employed the mouse insulinoma cell line MIN6 to perform in vitro characterization and functional studies in conditions known to modulate Hes3 based upon our previous work using neural stem cell cultures. In these conditions, cells showed elevated Hes3 expression and nuclear localization, grew efficiently, and showed higher evoked insulin release responses, compared with serum-containing conditions. They also exhibited higher expression of the transcription factor Pdx1 and insulin. Furthermore, they were responsive to pharmacological treatments with the GLP-1 analog Exendin-4, which increased nuclear Hes3 localization. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed cell growth and affected gene expression as revealed by DNA microarrays. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Hes3 overexpression (using a Hes3-GFP fusion construct) confirmed a role of Hes3 in regulating Pdx1 expression. Hes3 RNA interference reduced evoked insulin release. Mice lacking Hes3 exhibited increased islet damage by streptozotocin. These data suggest roles of Hes3 in pancreatic islet function.

Masjkur|Jimmy|J|
Arps-Forker|Carina|C|
Poser|Steven W|SW|
Nikolakopoulou|Polyxeni|P|
Toutouna|Louiza|L|
Chenna|Ramu|R|
Chavakis|Triantafyllos|T|
Chatzigeorgiou|Antonios|A|
Chen|Lan-Sun|LS|
Dubrovska|Anna|A|
Choudhary|Pratik|P|
Uphues|Ingo|I|
Mark|Michael|M|
Bornstein|Stefan R|SR|
Androutsellis-Theotokis|Andreas|A|

D051792:Basic Helix-Loop-Helix Transcription Factors

D020133:Reverse Transcriptase Polymerase Chain Reaction

Islet
Neurodegenerative Disease
Cell Culture
Beta Cell (B-cell)
Neural Stem Cell (NSC)
Neuroprogenitor Cell
Notch Pathway
Pancreas
Parkinson Disease
Signal Transduction


HEV ORF3 downregulatesCD14 and CD64 to impair macrophages phagocytosis through inhibiting JAK/STAT pathway.

Abstract: Hepatitis E virus (HEV) could induce chronic hepatitis and liver failure with high mortality through unknown mechanisms. The previous study showed that the HEV open reading frames 3 (ORF3) could inhibit macrophages inflammatory response. Impaired macrophages phagocytosis was also found in patients infected with HEV and its nucleic acids could be detected in macrophages. To elucidate the role of HEV ORF3 on phagocytosis, the phagocytosis activation was measured by phagocytosis test, flow cytometry, and phalloidin staining. Meanwhile, the expression of key phagocytic receptors and the activation of transduction pathway were investigated by using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Results of phagocytosis test showed that the HEV ORF3 could significantly impair the absorption capacity of latex beads. Furthermore, results of RT-qPCR and Western blot analysis showed that the expression of CD14 and CD64 decreased. Afterward, the present study showed that the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway was inhibited by HEV ORF3 and downregulation of CD14 and CD64 could be reversed by interferon γ, one activator of the JAK1/STAT1 signaling pathway. In conclusion, HEV ORF3 could significantly impair the phagocytosis of macrophage by downregulating expression of CD14 and CD64, which may function by inhibiting the activation of the JAK1/STAT1 signaling pathway.

D015536:Down-Regulation
D016752:Hepatitis E virus
D006801:Humans
D053612:Janus Kinases
D018950:Lipopolysaccharide Receptors
D008264:Macrophages
D016366:Open Reading Frames
D010587:Phagocytosis
D017452:Receptors, IgG
D050794:STAT1 Transcription Factor
D015398:Signal Transduction
D000074084:THP-1 Cells


Virus Assembly Pathways: Straying Away but Not Too Far.

Abstract: Non-enveloped RNA viruses pervade all domains of life. In a cell, they co-assemble from viral RNA and capsid proteins. Virus-like particles can form in vitro where virtually any non-cognate polyanionic cargo can be packaged. How only viral RNA gets selected for packaging in vivo, in presence of myriad other polyanionic species, has been a puzzle. Through a combination of charge detection mass spectrometry and cryo-electron microscopy, it is determined that co-assembling brome mosaic virus (BMV) coat proteins and nucleic acid oligomers results in capsid structures and stoichiometries that differ from the icosahedral virion. These previously unknown shell structures are strained and less stable than the native one. However, they contain large native structure fragments that can be recycled to form BMV virions, should a viral genome become available. The existence of such structures suggest the possibility of a previously unknown regulatory pathway for the packaging process inside cells.

Bond|Kevin|K|
Tsvetkova|Irina B|IB|
Wang|Joseph Che-Yen|JC|
Jarrold|Martin F|MF|
Dragnea|Bogdan|B|0000-0003-0611-2006

virus assembly
charge detection mass spectrometry
brome mosaic virus
cryo-electron microcopy


Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors.

Abstract: A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.

Stanton|Richard A|RA|
Lu|Xiao|X|
Detorio|Mervi|M|
Montero|Catherine|C|
Hammond|Emily T|ET|
Ehteshami|Maryam|M|
Domaoal|Robert A|RA|
Nettles|James H|JH|
Feraud|Michel|M|
Schinazi|Raymond F|RF|


Epigenetics in osteoarthritis: Potential of HDAC inhibitors as therapeutics.

Abstract: Osteoarthritis (OA) is the most common joint disease and the leading cause of chronic disability in middle-aged and older populations worldwide. The development of disease modifying therapy for OA is in its infancy largely because the regulatory mechanisms for the molecular effectors of OA pathogenesis are poorly understood. Recent studies identified epigenetic events as a critical regulator of molecular players involved in the induction and development of OA. Epigenetic mechanisms include DNA methylation, non-coding RNA and histone modifications. The aim of this review is to briefly highlight the recent advances in the epigenetics of cartilage and potential of HDACs (Histone deacetylases) inhibitors in the therapeutic management of OA. We summarize the recent studies utilizing HDAC inhibitors as potential therapeutics for inhibiting disease progression and preventing the cartilage destruction in OA. HDACs control normal cartilage development and homeostasis and understanding the impact of HDACs inhibitors on the disease pathogenesis is of interest because of its importance in affecting overall cartilage health and homeostasis. These findings also shed new light on cartilage disease pathophysiology and provide substantial evidence that HDACs may be potential novel therapeutic targets in OA.

Epigenetics
Osteoarthritis
HDACs
DNA methylation
lncRNA
miRNA


Novel antimicrobial peptides with promising activity against multidrug resistant Salmonella enterica serovar Choleraesuis and its stress response mechanism.

Abstract:
AIMS
To evaluate the antibacterial efficacy of novel antimicrobial peptides (AMPs) against multidrug-resistant (MDR) Salmonella enterica serovar Choleraesuis (Salm. Choleraesuis) and to delineate the AMP-responsive mechanisms of wild-type (WT) and MDR strains.

METHODS AND RESULTS
Proteomic approaches were performed based on two-dimensional gel electrophoresis and liquid chromatography-electrospray ionization-quadrupole- time-of-flight tandem mass spectrometry to analyse the protein profiles of these two strains upon exposure to AMP GW-Q6. Quantitative real-time PCR was conducted to determine the mRNA expression level of the target genes. Furthermore, lipopolysaccharide (LPS) competition analysis was used to verify whether LPS may serve as the potential binding target when AMP approach and adhere to the bacterial surface.

CONCLUSIONS
The minimal inhibitory concentration assay revealed that our AMPs were even more effective against the MDR strains (4-32 μg ml(-1) ), compared with those for the WT (8-64 μg ml(-1) ). LPS dose-dependently suppressed the GW-Q6 antimicrobial activity. Clusters of orthologous groups analysis showed that the majority of the AMP-responsive proteins were involved in cell envelope biogenesis and outer membrane, translation and chaperones.

SIGNIFICANCE AND IMPACT OF THE STUDY
These results indicated that the novel AMP GW-Q6 serves as a potential candidate for antimicrobial drug development against MDR strains. These findings will also be helpful for expanding our knowledge on the molecular mechanisms of AMP-microbe interaction and the pathogenicity of salmonellosis caused by MDR strains of Salm. Choleraesuis.

Tsai|W-C|WC| Zhuang|Z-J|ZJ| Lin|C-Y|CY| Chen|W-J|WJ|

D024901:Drug Resistance, Multiple, Bacterial

D060888:Real-Time Polymerase Chain Reaction


Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast-Osteoblasts Communication in Bone Remodeling.

Abstract: Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, play an important role in cellular communication during skeletal growth and homeostasis. Bioactive molecules carried by EVs are transported to neighboring and distant cells to trigger a series of signaling cascades influencing bone homeostasis. The bioactive activities of osteoclast-derived EVs include regulation of osteoclastogenesis and osteoclast-osteoblast communication. As osteoclast-derived EVs have the potential to regulate osteoclasts and osteoblasts, their application in osteoporosis and other bone metabolic disorders is currently under investigation. However, very few reviews of osteoclast-derived EVs in bone remodeling regulation have yet been published. This article aims to review recent advances in this field, summarizing a new regulator of osteoclastogenesis and osteoclast-osteoblast communication mediated by osteoclast-derived EVs. We will analyze the major challenges in the field and potential for the therapeutic application of EVs.

Yuan|Feng-Lai|FL| Wu|Qian-Yuan|QY| Miao|Zong-Ning|ZN| Xu|Ming-Hui|MH| Xu|Rui-Sheng|RS| Jiang|Dong-Lin|DL| Ye|Jun-Xing|JX| Chen|Fei-Hu|FH| Zhao|Ming-Dong|MD| Wang|Hao-Jue|HJ| Li|Xia|X|

extracellular vesicles
osteoclastogenesis
communication
bone remodeling
osteoclasts


Electrochemical Oxidative C(sp3 )-H/N-H Cross-Coupling for N-Mannich Bases with Hydrogen Evolution.

Abstract: N-Mannich bases are an important structure in various functional molecules. A new protocol to synthesize N-Mannich bases was established through electrochemical external-oxidant-free C(sp3 )-H/N-H cross-coupling with hydrogen evolution. Various N-methylanilines were explored in this transformation. Moreover, simple amides, heteroatom-containing amides, and succinimides were well tolerated in moderate-to-good yields. In addition, the electrochemical dehydrogenative C(sp3 )-H/N-H cross-coupling could be scaled up to 5 mmol. By using triethyl phosphite as trapping agent, the phosphorylation product was detected. At the same time, kinetic isotope effect experiments showed that the cleavage of the C-H bond is the rate-limiting step.

cross-coupling
N-Mannich
hydrogen evolution
CH functionalization
electrochemistry


KRAS: Reasons for optimism in lung cancer.

Abstract: Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon. It now seems clear that mutational subtype (most commonly G12C) of individual mutations is of greater relevance than the categorical evaluation of KRAS mutation presence or otherwise. A number of direct small molecules targeted to these subtypes are in development and have shown promising biological activity, with some in the late stages of preclinical validation.

Lindsay|C R|CR|
Jamal-Hanjani|M|M|
Forster|M|M|
Blackhall|F|F|

D017326:Clinical Trials, Phase III as Topic

KRAS
Non-small cell lung cancer
NSCLC
G12C
RAS


Production and analysis of recombinant tree nut allergens.

Abstract: Allergic reactions to tree nuts are a growing global concern as the number of affected individuals continues to rise. Unlike some food allergies, tree nuts can cause severe reactions that persist throughout life. The tree nuts discussed in this review include those most commonly responsible for allergic reactions: cashew, almond, hazelnut, walnut, pecan, Brazil nut, pistachio, and chestnut. The native allergenic proteins derived from tree nuts are frequently difficult to isolate and purify and may not be adequately represented in aqueous nut protein extracts. Consequently, defined recombinant allergens have become useful reagents in a variety of immunoassays aimed at the diagnosis of tree nut allergy, assessing cross-reactivity between various nuts and other seeds, mapping of IgE binding epitopes, and analyzing the effects of the food matrix, food processing, and gastric digestion on allergenicity. This review describes the approaches that can be used for the production of recombinant tree nut allergens and addresses key issues associated with their production and downstream applications.

Willison|Leanna N|LN|
Sathe|Shridhar K|SK|
Roux|Kenneth H|KH|

Tree nut
Food allergy
Allergy
Recombinant allergen
Epitope


The effects of phosphorus limitation on carbon metabolism in diatoms.

Abstract: Phosphorus is an essential element for life, serving as an integral component of nucleic acids, lipids and a diverse range of other metabolites. Concentrations of bioavailable phosphorus are low in many aquatic environments. Microalgae, including diatoms, apply physiological and molecular strategies such as phosphorus scavenging or recycling as well as adjusting cell growth in order to adapt to limiting phosphorus concentrations. Such strategies also involve adjustments of the carbon metabolism. Here, we review the effect of phosphorus limitation on carbon metabolism in diatoms. Two transcriptome studies are analysed in detail, supplemented by other transcriptome, proteome and metabolite data, to gain an overview of different pathways and their responses. Phosphorus, nitrogen and silicon limitation responses are compared, and similarities and differences discussed. We use the current knowledge to propose a suggestive model for the carbon flow in phosphorus-replete and phosphorus-limited diatom cells.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.

phosphorus
carbon metabolism
diatom
transcriptome
proteome


Arterial Stiffness and Blood Pressure in Patients Newly Diagnosed with Graves' Disease Compared with Euthyroid Controls.

Abstract:
Introduction and Objective
The excess cardiovascular morbidity and mortality in hyperthyroidism and Graves' disease (GD) is inadequately understood. We aimed to elucidate whether well-established cardiovascular risk factors such as arterial stiffness in terms of pulse wave velocity (PWV) and blood pressure differ in GD and controls.

Methods
This was a cross-sectional study comparing 55 hyperthyroid patients with newly diagnosed GD and 55 euthyroid, population-based controls matched for age, sex and menopausal status. PWV and blood pressure were measured in office (SphygmoCor Xcel) and 24-h ambulatory settings (Arteriograph). Differences between groups were assessed using adjusted linear regression analysis.

Results
Compared to controls, GD patients showed higher PWV in the 24-h but not in the office setting with an adjusted 24-h PWV difference of 1.0 (95% CI: 0.6-1.5) m/s. PWV was higher in GD at both day and night, and nightly PWV dipping was lower (-5.5, 95% CI: -10.4 to -0.6%). Furthermore, central and brachial pulse pressure was significantly higher in both the office and 24-h setting, whereas nightly central pulse pressure dipping was significantly lower in GD (-5.4, 95% CI: -10.5 to -0.2%). Mean arterial pressure did not differ between the groups.

Conclusions
Despite comparable blood pressure, GD is associated with a higher 24-h PWV that was not detected in the office setting. Pulse pressure was higher in GD, whereas mean arterial pressure did not differ between the groups. Longitudinal studies should pursue whether higher PWV might be a piece to the puzzle of understanding the increased risk of cardiovascular disease in hyperthyroidism and GD.

Grove-Laugesen|Diana|D|
Malmstroem|Sofie|S|
Ebbehoj|Eva|E|
Riis|Anne Lene|AL|
Watt|Torquil|T|
Rejnmark|Lars|L|
Würgler Hansen|Klavs|K|

Arterial stiffness
Blood pressure
Graves' disease
Hyperthyroidism
Pulse wave analysis


Endothelial Function Is Impaired in Patients Receiving Antihypertensive Drug Treatment Regardless of Blood Pressure Level: FMD-J Study (Flow-Mediated Dilation Japan).

Abstract: Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of <120 mm Hg, 7.5±2.8% for 120-129 mm Hg, 7.1±2.8% for 130-139 mm Hg, and 6.7±2.6% for ≥140 mm Hg; P<0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6±3.1% in treated hypertensives with systolic blood pressure of <120 mm Hg, 4.8±2.7% for 120-129 mm Hg, 4.9±2.8% for 130-139 mm Hg, and 4.5±2.3% for ≥140 mm Hg; P=0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.

Maruhashi|Tatsuya|T|
Soga|Junko|J|
Fujimura|Noritaka|N|
Idei|Naomi|N|
Mikami|Shinsuke|S|
Iwamoto|Yumiko|Y|
Iwamoto|Akimichi|A|
Kajikawa|Masato|M|
Matsumoto|Takeshi|T|
Oda|Nozomu|N|
Kishimoto|Shinji|S|
Matsui|Shogo|S|
Hashimoto|Haruki|H|
Aibara|Yoshiki|Y|
Yusoff|Farina Binti Mohamad|FBM|
Hidaka|Takayuki|T|
Kihara|Yasuki|Y|
Chayama|Kazuaki|K|
Noma|Kensuke|K|
Nakashima|Ayumu|A|
Goto|Chikara|C|
Tomiyama|Hirofumi|H|
Takase|Bonpei|B|
Kohro|Takahide|T|
Suzuki|Toru|T|
Ishizu|Tomoko|T|
Ueda|Shinichiro|S|
Yamazaki|Tsutomu|T|
Furumoto|Tomoo|T|
Kario|Kazuomi|K|
Inoue|Teruo|T|
Koba|Shinji|S|
Watanabe|Kentaro|K|
Takemoto|Yasuhiko|Y|
Hano|Takuzo|T|
Sata|Masataka|M|
Ishibashi|Yutaka|Y|
Node|Koichi|K|
Maemura|Koji|K|
Ohya|Yusuke|Y|
Furukawa|Taiji|T|
Ito|Hiroshi|H|
Ikeda|Hisao|H|
Yamashina|Akira|A|
Higashi|Yukihito|Y|

blood pressure
hypertension
vasodilation
antihypertensive agents
blood pressure determination


Comparison of Common Analytical Methods for the Quantification of Total Polyphenols and Flavanols in Fruit Juices and Ciders.

Abstract: Multiple analytical methods are used for quantification of total polyphenols and total flavanols in fruit juices and beverages. Four methods were evaluated in this study: Folin-Ciocalteu (F-C), Lowenthal permanganate (L-P), 4-dimethylaminocinnamaldehyde (DMAC), and the bovine serum albumin (BSA) precipitation method. Method validation parameters, including working range, limit of detection, limit of quantitation, precision (repeatability), accuracy, and specificity, were assessed and compared. The F-C method was not specific to polyphenols, and the L-P method had the widest working range but lacked accuracy. The DMAC method was the most specific to flavanols, and the BSA method was not suitable for quantification of smaller flavanols, such as catechin and epicatechin. Quantitative performance was evaluated using commercial fruit juice samples (n = 14), apple juice samples of different cultivars (n = 22), and commercial ciders (n = 17). In general, the L-P titration method and DMAC method resulted in higher quantitative values than the F-C method and BSA precipitation method, respectively. However, ratios of results obtained by the L-P and F-C method ranged from 1 to 28, and ratios of results obtained by the DMAC and BSA precipitation method ranged from <1 to 280. This tremendous variation is likely due to variation in polyphenol composition and sample matrix. This information provides perspective for comparison of results obtained through these different methods, and a basis for choosing the most appropriate analytical method for quantification of polyphenols to address a specific research question when working with commercial fruit juice, apple juice from different apple cultivars, and commercial ciders. PRACTICAL APPLICATION: This study compared results obtained when four common polyphenol quantification methods were applied to a diverse selection of fruit juices and beverages with distinct polyphenol composition and sample matrix. The matrix and polyphenol composition of the samples significantly influenced the results. Our findings can help manufacturers of fruit-based products choose the most appropriate analytical method for polyphenol quantification as part of a quality assurance program or to convey information on dietary polyphenol content to consumers. An assessment of analytical method validation parameters is provided for each of the four methods, which will help users of these methods to understand their limitations.

flavanols
Folin-Ciocalteu
DMAC
BSA precipitation
Lowenthal permanganate titration


Haloperidol and aripiprazole impact on the BDNF and glucocorticoid receptor levels in the rat hippocampus and prefrontal cortex: effect of the chronic mild stress.

Abstract: Objective. Changes in the brain derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC) and hippocampus (HIP) are associated with psychiatric diseases and stress response. Chronic mild stress (CMS) may alter BDNF as well as GR levels in both the PFC and the HIP. The aim of the present study was to find out whether chronic treatment with a typical antipsychotic haloperidol (HAL) and an atypical antipsychotic aripiprazole (ARI) may modify the CMS effect on the BDNF and GR expression in the above-mentioned structures. Methods. The rats were exposed to CMS for 3 weeks and from the 7th day of CMS injected with vehicle (VEH), HAL (1 mg/kg) or ARI (10 mg/kg) for 4 weeks. BDNF and GR mRNA levels were established in the PFC and the HIP by Real Time PCR, whereas, PFC and HIP samples were obtained by punching them from 500 µm thick frozen sections. C-Fos immunoreactivity was analyzed in the PFC and the HIP on 30 µm thick paraformaldehyde fixed sections. Weight gain and corticosterone (CORT) levels were also measured. Results. The CMS and HAL suppressed the BDNF and GR mRNA levels in the PFC. In the HIP, CMS elevated BDNF mRNA levels that were suppressed by HAL and ARI treatments. The CMS decreased the c-Fos immunoreactivity in the PFC in both HAL- and ARI-treated animals. In the HIP, HAL increased the c-Fos immunoreactivity that was again diminished in animals exposed to CMS. Stressed animals gained markedly less weight until the 7th day of CMS, however, later their weight gain did not differ from the unstressed ones or was even higher in CMS+HAL group. Un-stressed HAL and ARI animals gained less weight than the VEH ones. Neither CMS nor HAL/ARI affected the plasma CORT levels. Conclusion. The present data indicate that HAL and ARI in the doses 1 mg/kg or 10 mg/kg, respectively, does not modify the effect of the CMS preconditioning on the BDNF and GR mRNA levels in the PFC or the HIP. However, HAL seems to modify the CMS effect on the HIP activation.

Osacka|Jana|J| Koprdova|Romana|R| Tillinger|Andrej|A| Pirnik|Zdenko|Z| Kiss|Alexander|A|

haloperidol
aripiprazole
glucocorticoid receptors
rat
hippocampus
prefrontal cortex
brain derived neurotrophic factor
c-Fos-immunohisto-chemistry


Coffee Consumption and Oxidative Stress: A Review of Human Intervention Studies.

Abstract: Research on the potential protective effects of coffee and its bioactives (caffeine, chlorogenic acids and diterpenes) against oxidative stress and related chronic disease risk has been increasing in the last years. The present review summarizes the main findings on the effect of coffee consumption on protection against lipid, protein and DNA damage, as well as on the modulation of antioxidant capacity and antioxidant enzymes in human studies. Twenty-six dietary intervention studies (involving acute and chronic coffee intake) have been considered. Overall, the results suggest that coffee consumption can increase glutathione levels and improve protection against DNA damage, especially following regular/repeated intake. On the contrary, the effects of coffee on plasma antioxidant capacity and antioxidant enzymes, as well as on protein and lipid damage, are unclear following both acute and chronic exposure. The high heterogeneity in terms of type of coffee, doses and duration of the studies, the lack of information on coffee and/or brew bioactive composition, as well as the choice of biomarkers and the methods used for their evaluation, may partially explain the variability observed among findings. More robust and well-controlled intervention studies are necessary for a thorough understanding of the effect of coffee on oxidative stress markers in humans.

Martini|Daniela|D|
Del Bo'|Cristian|C|
Tassotti|Michele|M|
Riso|Patrizia|P|
Del Rio|Daniele|D|
Brighenti|Furio|F|
Porrini|Marisa|M|

coffee
DNA damage
antioxidant capacity
antioxidant enzymes
lipid damage
phenols
protein damage


Group cognitive-behavioural programme to reduce the impact of rheumatoid arthritis fatigue: the RAFT RCT with economic and qualitative evaluations.

Abstract:
BACKGROUND
Fatigue is a major problem in rheumatoid arthritis (RA). There is evidence for the clinical effectiveness of cognitive-behavioural therapy (CBT) delivered by clinical psychologists, but few rheumatology units have psychologists.

OBJECTIVES
To compare the clinical effectiveness and cost-effectiveness of a group CBT programme for RA fatigue [named RAFT, i.e. Reducing Arthritis Fatigue by clinical Teams using cognitive-behavioural (CB) approaches], delivered by the rheumatology team in addition to usual care (intervention), with usual care alone (control); and to evaluate tutors' experiences of the RAFT programme.

DESIGN
A randomised controlled trial. Central trials unit computerised randomisation in four consecutive cohorts within each of the seven centres. A nested qualitative evaluation was undertaken.

SETTING
Seven hospital rheumatology units in England and Wales.

PARTICIPANTS
Adults with RA and fatigue severity of ≥ 6 [out of 10, as measured by the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale (BRAF-NRS)] who had no recent changes in major RA medication/glucocorticoids.

INTERVENTIONS
RAFT - group CBT programme delivered by rheumatology tutor pairs (nurses/occupational therapists). Usual care - brief discussion of a RA fatigue self-management booklet with the research nurse.

MAIN OUTCOME MEASURES
Primary - fatigue impact (as measured by the BRAF-NRS) at 26 weeks. Secondary - fatigue severity/coping (as measured by the BRAF-NRS); broader fatigue impact [as measured by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ)]; self-reported clinical status; quality of life; mood; self-efficacy; and satisfaction. All data were collected at weeks 0, 6, 26, 52, 78 and 104. In addition, fatigue data were collected at weeks 10 and 18. The intention-to-treat analysis conducted was blind to treatment allocation, and adjusted for baseline scores and centre. Cost-effectiveness was explored through the intervention and RA-related health and social care costs, allowing the calculation of quality-adjusted life-years (QALYs) with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Tutor and focus group interviews were analysed using inductive thematic analysis.

RESULTS
A total of 308 out of 333 patients completed 26 weeks (RAFT, n/N = 156/175; control, n/N = 152/158). At 26 weeks, the mean BRAF-NRS impact was reduced for the RAFT programme (-1.36 units; p < 0.001) and the control interventions (-0.88 units; p < 0.004). Regression analysis showed a difference between treatment arms in favour of the RAFT programme [adjusted mean difference -0.59 units, 95% confidence interval (CI) -1.11 to -0.06 units; p = 0.03, effect size 0.36], and this was sustained over 2 years (-0.49 units, 95% CI -0.83 to -0.14 units; p = 0.01). At 26 weeks, further fatigue differences favoured the RAFT programme (BRAF-MDQ fatigue impact: adjusted mean difference -3.42 units, 95% CI -6.44 to - 0.39 units, p = 0.03; living with fatigue: adjusted mean difference -1.19 units, 95% CI -2.17 to -0.21 units, p = 0.02; and emotional fatigue: adjusted mean difference -0.91 units, 95% CI -1.58 to -0.23 units, p = 0.01), and these fatigue differences were sustained over 2 years. Self-efficacy favoured the RAFT programme at 26 weeks (Rheumatoid Arthritis Self-Efficacy Scale: adjusted mean difference 3.05 units, 95% CI 0.43 to 5.6 units; p = 0.02), as did BRAF-NRS coping over 2 years (adjusted mean difference 0.42 units, 95% CI 0.08 to 0.77 units; p = 0.02). Fatigue severity and other clinical outcomes were not different between trial arms and no harms were reported. Satisfaction with the RAFT programme was high, with 89% of patients scoring ≥ 8 out of 10, compared with 54% of patients in the control arm rating the booklet (p < 0.0001); and 96% of patients and 68% of patients recommending the RAFT programme and the booklet, respectively, to others (p < 0.001). There was no significant difference between arms for total societal costs including the RAFT programme training and delivery (mean difference £434, 95% CI -£389 to £1258), nor QALYs gained (mean difference 0.008, 95% CI -0.008 to 0.023). The probability of the RAFT programme being cost-effective was 28-35% at the National Institute for Health and Care Excellence's thresholds of £20,000-30,000 per QALY. Tutors felt that the RAFT programme's CB approaches challenged their usual problem-solving style, helped patients make life changes and improved tutors' wider clinical practice.

LIMITATIONS
Primary outcome data were missing for 25 patients; the EQ-5D-5L might not capture fatigue change; and 30% of the 2-year economic data were missing.

CONCLUSIONS
The RAFT programme improves RA fatigue impact beyond usual care alone; this was sustained for 2 years with high patient satisfaction, enhanced team skills and no harms. The RAFT programme is < 50% likely to be cost-effective; however, NHS costs were similar between treatment arms.

FUTURE WORK
Given the paucity of RA fatigue interventions, rheumatology teams might investigate the pragmatic implementation of the RAFT programme, which is low cost.

TRIAL REGISTRATION
Current Controlled Trials ISRCTN52709998.

FUNDING
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 57. See the NIHR Journals Library website for further project information.

RHEUMATOID ARTHRITIS
FATIGUE
RANDOMISED CONTROLLED TRIAL
SELF-MANAGEMENT
COGNITIVE THERAPY
COST–BENEFIT ANALYSIS
QUALITATIVE RESEARCH


Characterization of an fungal l-fucokinase involved in Mortierella alpina GDP-l-fucose salvage pathway.

Abstract: GDP-l-fucose functions as a biological donor for fucosyltransferases, which are required for the catalysis of l-fucose to various acceptor molecules including oligosaccharides, glycoproteins and glycolipids. Mortierella alpina is one of the highest lipid-producing fungi and can biosynthesis GDP-l-fucose in the de novo pathway. Analysis of the M. alpina genome suggests that there is a gene encoding l-fucokinase (FUK) for the conversion of fucose to l-fucose-1-phosphate in the GDP-l-fucose salvage pathway, which has never been found in fungi before. This gene was characterized to explore its role in GDP-l-fucose synthesis. The yield of GDP-l-fucose is relatively higher in lipid accumulation phase (0.096 mg per g cell) than that in cell multiplication phase (0.074 mg per g cell) of M. alpina Additionally, the transcript level of FUK is up regulated by nitrogen exhaustion when M. alpina starts to accumulate lipid, highlights the functional significance of FUK in the GDP-l-fucose biosynthesis in M. alpina Gene encoding FUK was expressed heterologously in Escherichia coli and the resulting protein was purified to homogeneity. The product of FUK reaction was analyzed by liquid chromatography and mass spectrometry. Kinetic parameters and other properties of FUK were investigated. Comparative analyses between the FUK protein and other homologous proteins were performed. To our knowledge, this study is the first to report a comprehensive characterization of FUK in a fungus. Mortierella alpina could be used as an alternative source for the production of GDP-l-fucose.

Wang|Hongchao|H|
Zhang|Chen|C|
Chen|Haiqin|H|
Yang|Qin|Q|
Zhou|Xin|X|
Gu|Zhennan|Z|
Zhang|Hao|H|
Chen|Wei|W|
Chen|Yong Q|YQ|

D015966:Gene Expression Regulation, Fungal

D017853:Phosphotransferases (Alcohol Group Acceptor)

characterization
l-fucokinase
GDP-l-fucose synthesis
Mortierella alpina/salvage pathway


On the Validity of the Stochastic Quasi-Steady-State Approximation in Open Enzyme Catalyzed Reactions: Timescale Separation or Singular Perturbation?

Abstract: The quasi-steady-state approximation is widely used to develop simplified deterministic or stochastic models of enzyme catalyzed reactions. In deterministic models, the quasi-steady-state approximation can be mathematically justified from singular perturbation theory. For several closed enzymatic reactions, the homologous extension of the quasi-steady-state approximation to the stochastic regime, known as the stochastic quasi-steady-state approximation, has been shown to be accurate under the analogous conditions that permit the quasi-steady-state reduction in the deterministic counterpart. However, it was recently demonstrated that the extension of the stochastic quasi-steady-state approximation to an open Michaelis-Menten reaction mechanism is only valid under a condition that is far more restrictive than the qualifier that ensures the validity of its corresponding deterministic quasi-steady-state approximation. In this paper, we suggest a possible explanation for this discrepancy from the lens of geometric singular perturbation theory. In so doing, we illustrate a misconception in the application of the quasi-steady-state approximation: timescale separation does not imply singular perturbation.

Quasi-steady-state approximation
Singular perturbation
Fenichel theory
Langevin equation
Linear noise approximation
Michaelis–Menten reaction mechanism
Slow scale linear noise approximation
Stochastic process
Tikhonov’s theorem


PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer.

Abstract:
OBJECTIVE
PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes.

METHODS
After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated.

RESULTS
A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%).

CONCLUSION
PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN-mu, and PIK3R1-mu and PIK3CA CNV.

Gonzalez-Bosquet|Jesus|J|
Bakkum-Gamez|Jamie N|JN|
Weaver|Amy L|AL|
McGree|Michaela E|ME|
Dowdy|Sean C|SC|
Famuyide|Abimbola O|AO|
Kipp|Benjamin R|BR|
Halling|Kevin C|KC|
Couch|Fergus J|FJ|
Podratz|Karl C|KC|


Heterogeneity of NK Cells and Other Innate Lymphoid Cells in Human and Murine Decidua.

Abstract: Innate lymphoid cells (ILCs) represent a heterogeneous group of cells lacking genetically rearranged antigen receptors that derive from common lymphoid progenitors. Five major groups of ILCs have been defined based on their cytokine production pattern and developmental transcription factor requirements: namely, natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells. ILC1s, ILC2s, and ILC3s mirror the corresponding T helper subsets (Th1, Th2, and Th17, respectively) and produce cytokines involved in defense against pathogens, lymphoid organogenesis, and tissue remodeling. During the first trimester of pregnancy, decidual tissues contain high proportion of decidual NK (dNK) cells, representing up to 50% of decidual lymphocytes, and ILC3s. They release peculiar cytokines and chemokines that contribute to successful pregnancy. Recent studies revealed that ILCs display a high degree of plasticity allowing their prompt adaptation to environmental changes. Decidual NK cells may derive from peripheral blood NK cells migrated when pregnancy establishes or from in situ differentiation of hematopoietic precursors. Previous studies showed that human and murine decidua contain dNK cells, tissue resident NK cells, and ILC3s, all characterized by unique phenotypic and functional properties, most likely induced by decidual microenvironment to favor the establishment and the maintenance of pregnancy. Thus, during the early phase of pregnancy, the simultaneous presence of different ILC subsets further underscores the complexity of the cellular components of decidual tissues as well as the role of decidual microenvironment in shaping the plasticity and the function of ILCs.

Vacca|Paola|P|
Chiossone|Laura|L|
Mingari|Maria Cristina|MC|
Moretta|Lorenzo|L|

decidua
innate lymphoid cells (ILCs)
natural killer (NK) cells
human and murine pregnancy
tolerance


Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response.

Abstract: The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses.

Kouwaki|Takahisa|T| Okamoto|Masaaki|M| Tsukamoto|Hirotake|H| Fukushima|Yoshimi|Y| Oshiumi|Hiroyuki|H|

extracellular vesicles
virus
innate immunity
microRNA


Asunaprevir (BMS-650032) for the treatment of hepatitis C virus.

Abstract: Asunaprevir, a second-generation NS3 protease inhibitor of hepatitis C virus (HCV), exhibits strong antiviral activity against HCV genotypes 1 and 4, but relatively weak activity against genotypes 2 and 3. For chronic HCV infection, asunaprevir with daclatasvir as an interferon-free dual treatment achieves a sustained virologic response of nearly 90% in genotype 1b, and a triple regimen with beclabuvir achieves an sustained virologic response >90%. Asunaprevir and daclatasvir dual treatment can be safely and effectively administered to liver transplant recipients with recurrent HCV. The major drawback of asunaprevir is its low threshold to resistance, which can be overcome by combining it with other direct-acting antivirals. Further studies of asunaprevir in combination with other direct-acting antivirals for the treatment of patients with HCV genotypes 1 or 4 and renal impairment or end-stage renal disease under hemodialysis, HIV-coinfection and liver and/or kidney transplant recipients are warranted.

asunaprevir
hepatitis C virus
daclatasvir
sustained virologic response
liver transplantation
direct-acting antiviral
interferon-free treatment


Nature-Based Social Prescribing in Urban Settings to Improve Social Connectedness and Mental Well-being: a Review.

Abstract:
PURPOSE OF REVIEW
Recent reports of a "loneliness epidemic" in the USA are growing along with a robust evidence base that suggests that loneliness and social isolation can compromise physical and psychological health. Screening for social isolation among at-risk populations and referring them to nature-based community services, resources, and activities through a social prescribing (SP) program may provide a way to connect vulnerable populations with the broader community and increase their sense of connectedness and belonging. In this review, we explore opportunities for social prescribing to be used as a tool to address connectedness through nature-based interventions.

RECENT FINDINGS
Social prescribing can include a variety of activities linked with voluntary and community sector organizations (e.g., walking and park prescriptions, community gardening, farmers' market vouchers). These activities can promote nature contact, strengthen social structures, and improve longer term mental and physical health by activating intrapersonal, interpersonal, and environmental processes. The prescriptions are appropriate for reaching a range of high-risk populations including moms who are minors who are minors, recent immigrants, older adults, economically and linguistically isolated populations, and unlikely users of nature and outdoor spaces. More research is needed to understand the impact of SPs on high-risk populations and the supports needed to allow them to feel at ease in the outdoors. Additionally, opportunities exist to develop technologically and socially innovative strategies to track patient participation in social prescriptions, monitor impact over time, and integrate prescribing into standard health care practice.

Leavell|M A|MA|
Leiferman|J A|JA|
Gascon|M|M|
Braddick|F|F|
Gonzalez|J C|JC|
Litt|J S|JS|

Nature-based
Social connectedness
Loneliness
Social isolation
Social prescriptions
Psychosocial processes


Membranes for olefin-paraffin separation: An industrial perspective.

Abstract: In the next decade, separation science will be an important research topic in addressing complex challenges like reducing carbon footprint, lowering energy cost, and making industrial processes simpler. In industrial chemical processes, particularly in petrochemical operations, separation and product refining steps are responsible for up to 30% of energy use and 30% of the capital cost. Membranes and adsorption technologies are being actively studied as alternative and partial replacement opportunities for the state-of-the-art cryogenic distillation systems. This paper provides an industrial perspective on the application of membranes in industrial petrochemical cracker operations. A gas separation performance figure of merit for propylene/propane separation for different classes of materials ranging from inorganic, carbon, polymeric, and facilitated transport membranes is also reported. An in-house-developed model provided insights into the importance of operational parameters on the overall membrane design.

Roy|Abhishek|A|
Venna|Surendar R|SR|0000-0003-1094-4534
Rogers|Gerard|G|
Tang|Li|L|
Fitzgibbons|Thomas C|TC|
Liu|Junqiang|J|0000-0002-6723-5491
McCurry|Hali|H|
Vickery|David J|DJ|
Flick|Derrick|D|
Fish|Barry|B|

membranes
separation
petrochemicals
cryogenic distillation


Slide Tracheoplasty for Congenital Tracheal Stenosis Repair: A Systematic Review and Meta-Analysis.

Abstract:
OBJECTIVES
Congenital tracheal stenosis (CTS) is a rare but life-threatening condition in children. At present, slide tracheoplasty has been advocated as the preferred technique for most cases of CTS. However, the morbidity and mortality subsequent to slide tracheoplasty need further elaboration. Therefore, a meta-analysis was performed on the outcomes of slide tracheoplasty in children with CTS.

STUDY DESIGN
Systematic review and meta-analysis.

METHODS
Electronic databases, including PubMed, Embase, and Cochrane Library CENTRAL, were systematically searched for the period from January 1990 to March 2021 for literature that reported clinical outcomes of slide tracheoplasty for children with CTS. Meta-regression and subgroup analyses were performed to determine the risk factors for in-hospital mortality and airway reinterventions.

RESULTS
A total of 25 studies involving 577 patients were included. For children with CTS, in-hospital and overall mortality after slide tracheoplasty was 6.1% (95% CI = 4.2%-8.0%) and 9.7% (95% CI = 7.3%-12.1%), respectively. The incidence of airway reinterventions was 23.0% (95% CI = 15.6%-30.5%). The length of postoperative ventilation and hospital stay was 6.8 days (95% CI = 5.1-8.4 days) and 19.2 days (95% CI = 15.8-22.7 days), respectively. Postoperative complications occurred in 46.6% (95% CI = 35.8%-57.4%) of all patients. Meta-regression analysis showed that a higher proportion of the recently published studies reported significantly better in-hospital survival (coefficient -0.011, P = .021).

CONCLUSIONS
In conclusion, in-hospital mortality after slide tracheoplasty is 6.1%, and the incidence of airway reinterventions is 23.0%. In-hospital mortality after slide tracheoplasty has decreased chronologically.

LEVEL OF EVIDENCE
NA Laryngoscope, 2021.

slide tracheoplasty
Congenital tracheal stenosis
children


Hyperaccumulator straw improves the cadmium phytoextraction efficiency of emergent plant Nasturtium officinale.

Abstract: With the development of economy, the heavy metal contamination has become an increasingly serious problem, especially the cadmium (Cd) contamination. The emergent plant Nasturtium officinale R. Br. is a Cd-accumulator with low phytoremediation ability. To improve Cd phytoextraction efficiency of N. officinale, the straw from Cd-hyperaccumulator plants Youngia erythrocarpa, Galinsoga parviflora, Siegesbeckia orientalis, and Bidens pilosa was applied to Cd-contaminated soil and N. officinale was then planted; the study assessed the effect of hyperaccumulator straw on the growth and Cd accumulation of N. officinale. The results showed that application of hyperaccumulator species straws increased the biomass and photosynthetic pigment content and reduced the root/shoot ratio of N. officinale. All straw treatments significantly increased Cd content in roots, but significantly decreased Cd content in shoots of N. officinale. Applying hyperaccumulator straw significantly increased the total Cd accumulation in the roots, shoots, and whole plants of N. officinale. Therefore, application of straw from four hyperaccumulator species promoted the growth of N. officinale and improved the phytoextraction efficiency of N. officinale in Cd-contaminated paddy field soil; the straw of Y. erythrocarpa provided the most improvement.

Hyperaccumulator straw
Cadmium
Nasturtium officinale
Phytoremediation


Stroke Versus Seizure - Perfusion Computerized Tomography in a Patient with Aphasia.

Abstract: Both stroke and seizures have varied clinical presentations and their differentiation in the acute setting is not always straightforward. We present the case of a patient who presented at the emergency room with acute onset aphasia. Clinically acute ischemic stroke was suspected. Perfusion CT was performed and demonstrated cortical hypervascularity in the left partietotemporal region. Additional MRI and EEG were performed and a final diagnosis of postictal aphasia was made. This case illustrates that perfusion CT is not only a useful tool for acute stroke management, but can also aid in the detection of seizures in patients presenting with stroke-like symptoms.

Dekeyzer|S|S|
Vanden Bossche|S|S|
Keereman|V|V|
Hemelsoet|D|D|
Van Driessche|V|V|

Stroke
Seizure
Perfusion CT
Postical aphasia
Stroke mimicry


Electrospun drug loaded membranes for sublingual administration of sumatriptan and naproxen.

Abstract: Sublingual administration of active pharmaceutical substances is in principle favourable for rapid onset of drug action, ready accessibility and avoidance of first pass metabolism. This administration could prove very useful in the treatment of migraines, thus two frequently used drugs were selected for our study. Sumatriptan succinate, naproxen, and its salt as well as combinations of these were incorporated into nanofibrous membranes via the electrospinning process. DSC measurements proved that the resulted membranes contained non-crystalline drug forms. SEM imaging approved good homogeneity of diameter and shape of the membrane nanofibres. The nanofibrous membranes always showed the rapid and mutually independent release of the tested drugs. The drugs exhibited very high differences in sublingual permeation rates in vitro, but the rates of both substances were increased several times using nanofibrous membranes as the drug carrier in comparison to drug solutions. The released drugs subsequently permeated through sublingual mucosa preferentially as non-ionized moieties. The prepared nanofibrous membranes proved very flexible and mechanically resistant. With their drug load capacity of up to 40% of membrane mass, they could be very advantageous for the formulation of sublingual drug delivery systems.

Vrbata|Petr|P| Berka|Pavel|P| Stránská|Denisa|D| Doležal|Pavel|P| Musilová|Marie|M| Čižinská|Lucie|L|

Sublingual
Sumatriptan
Naproxen
Naproxen
Migraine
sumatriptan succinate
Nanofibre
Electrospinning
NAP
NAPS
SUS
naproxen
naproxen sodium


Nonexpanded Adipose Stromal Vascular Fraction Local Therapy on Peripheral Nerve Regeneration Using Allografts.

Abstract:
AIM OF THE STUDY
Adipose tissue possesses a population of multi-potent stem cells which can be differentiated to a Schwann cell phenotype and may be of benefit for treatment of peripheral nerve injuries. Effects of local therapy of nonexpanded adipose stromal vascular fraction (SVF) on peripheral nerve regeneration was studied using allografts in a rat sciatic nerve model.

MATERIALS AND METHODS
Thirty male white Wistar rats were divided into three experimental groups (n = 10), randomly: Sham-operated group (SHAM), allograft group (ALLO), SVF-treated group (ALLO/SVF). In SHAM group left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis muscle was sutured. In the ALLO group the left sciatic nerve was exposed through a gluteal muscle incision and transected proximal to the tibio-peroneal bifurcation where a 10 mm segment was excised. The same procedure was performed in the ALLO/SVF group. The harvested nerves of the rats of ALLO group were served as allograft for ALLO/SVF group and vice versa. The SHAM and ALLO groups received 100 μL phosphate buffered saline and the ALLO/SVF group received 100 μL SVF (2.25 ± 0.45 × 10(7) cells) locally where the grafting was performed.

RESULTS
Behavioral, functional, biomechanical, and gastrocnemius muscle mass showed earlier regeneration of axons in ALLO/SVF than in ALLO group (p < .05). Histomorphometic and immunohistochemical studies also showed earlier regeneration of axons in ALLO/SVF than in ALLO group (p < .05).

CONCLUSIONS
Administration of nonexpanded SVF could accelerate functional recovery after nerve allografting in sciatic nerve. It may have clinical implications for the surgical management of patients after nerve transection.

Mohammadi|Rahim|R| Mehrtash|Moein|M| Mehrtash|Moeid|M| Sajjadi|Seyedeh-Sepideh|SS|

D000273:Adipose Tissue
D064591:Allografts
D000818:Animals
D002454:Cell Differentiation
D004195:Disease Models, Animal
D006801:Humans
D008297:Male
D039902:Multipotent Stem Cells
D018482:Muscle, Skeletal
D009416:Nerve Regeneration
D059348:Peripheral Nerve Injuries
D011897:Random Allocation
D051381:Rats
D017208:Rats, Wistar
D020127:Recovery of Function
D012583:Schwann Cells
D012584:Sciatic Nerve
D017154:Stromal Cells
D014184:Transplantation, Homologous

local
allograft
SVF
rat
sciatic
Peripheral nerve repair


Introducing automated hand hygiene surveillance to an Australian hospital: Mirroring the HOW2 Benchmark Study.

Abstract:
BACKGROUND
Human auditing and collating hand hygiene compliance data take hundreds of hours. We report on 24/7 overt observations to establish adjusted average daily hand hygiene opportunities (HHOs) used as the denominator in an automated surveillance that reports daily compliance rates.

METHODS
Overt 24/7 automated surveillance collected HHOs in medical and surgical wards. Accredited auditors observed health care workers' interaction between patient and patient zones to collect the total number of HHOs, indications, and compliance and noncompliance. Automated surveillance captured compliance (ie, events) via low power radio connected to alcohol-based handrub (ABHR) dispensers. Events were divided by HHOs, adjusted for daily patient-to-nurse ratio, to establish daily rates.

RESULTS
Human auditors collected 21,450 HHOs during 24/7 with 1,532 average unadjusted HHOs per day. This was 4.4 times larger than the minimum ward sample required for accreditation. The average adjusted HHOs for ABHR alone on the medical ward was 63 HHOs per patient day and 40 HHOs per patient day on the surgical ward. From July 1, 2014-July 31, 2015 the automated surveillance system collected 889,968 events.

CONCLUSIONS
Automated surveillance collects 4 times the amount of data on each ward per day than a human auditor usually collects for a quarterly compliance report.

Azim|Syed|S| Juergens|Craig|C| Hines|John|J| McLaws|Mary-Louise|ML|

automated
audit
compliance
24/7 surveillance
Australia


Histological validation of the automated caries detection system (ACDS) in classifying occlusal caries with the ICDAS II system in vitro.

Abstract:
AIM
To compare the diagnostic performance of the automated caries detection system (ACDS) for the detection and diagnosis of occlusal caries with the histological appearance of the lesions.

METHODS
Eighteen posterior permanent teeth were used, out of which 40 sections were made and 53 areas were evaluated. Teeth with hypoplastic and/or hypomineralised areas or sealants on the occlusal surfaces were excluded from the study. The teeth that were used for this study were a subgroup of the teeth used in the study that introduced ACDS system. This subgroup consisted of teeth having in their occlusal surfaces early carious lesions classified as international caries detection and scoring system (ICDAS) 0, 1, 2 and 3 after clinical examination by the examiners. Histological preparations were classified by experienced examiners based on the Ekstrand, Ricketts and Kidd (ERK) system and for the respective occlusal surfaces by the ACDS system based on ICDAS II system. There were two threshold limits considered as carious in either system ICDAS ≥ 2 or ≥ 3 and ERK index ≥ 2 or ≥ 3 and all possible combinations were analysed. Statistical methods of weighted version of kappa coefficient, Kendall's tau-b correlation coefficient and p-values using the Fisher's exact method were used at the confidence level of 0.05.

RESULTS
Intra-examiner kappa coefficient agreement was 0.87 and 0.89 while the inter-examiner for the two trials were 0.87 and 0.92. The ICDAS3-ERK3 combination between the ACDS and histological sections presented the best agreement with kappa coefficient 0.76, agreement 92.5%, sensitivity 100% and specificity 91.1%. ICDAS3-ERK3 combination between the optical examination of the examiners compared to the histological preparations showed kappa coefficient 0.87, agreement 96.2%, sensitivity 100%, Specificity 95.6%.

CONCLUSION
The evidence supports the view that ACDS classification of occlusal surfaces based on the ICDAS system are comparable with classification to that of an examiner and with the histology of the lesion. The use of ACDS has the distinct advantage though of removing the subjectivity of the examiner since it performs the classification without any intervention by him.

Berdouses|E D|ED|
Oulis|C J|CJ|
Michalaki|M|M|
Tripoliti|E E|EE|
Fotiadis|D I|DI|

D003731:Dental Caries
D019229:Dentition, Permanent
D006801:Humans
D008963:Molar
D015203:Reproducibility of Results
D012680:Sensitivity and Specificity

Occlusal caries
Caries diagnosis
Digital imaging
ICDASII
Microscopy
Segmentation
Tooth histology


Self-Assembled FeSe2 Microspheres with High-Rate Capability and Long-Term Stability as Anode Material for Sodium- and Potassium-Ion Batteries.

Abstract: Sodium- and potassium-ion batteries have attracted intensive attention recently as low-cost alternatives to lithium-ion batteries with naturally abundant resources. However, the large ionic radii of Na+ and K+ render their slow mobility, leading to sluggish diffusion in host materials. Herein, hierarchical FeSe2 microspheres assembled by closely packed nano/microrods are rationally designed and synthesized through a facile solvothermal method. Without carbonaceous material incorporation, the electrode delivers a reversible Na+ storage capacity of 559 mA h g-1 at a current rate of 0.1 A g-1 and a remarkable rate performance with a capacity of 525 mA h g-1 at 20 A g-1 . As for K+ storage, the FeSe2 anode delivers a high reversible capacity of 393 mA h g-1 at 0.4 A g-1 . Even at a high current rate of 5 A g-1 , a discharge capacity of 322 mA h g-1 can be achieved, which is among the best high-rate anodes for K+ storage. The excellent electrochemical performance can be attributed to the favorable morphological structure and the use of an ether-based electrolyte during cycling. Moreover, quantitative study suggests a strong pseudocapacitive contribution, which boosts fast kinetics and interfacial storage.

high-rate capability
anode materials
batteries
electrochemistry
transition metal selenides


Mass spectrometry-based analysis of cerebrospinal fluid from arthritis patients-immune-related candidate proteins affected by TNF blocking treatment.

Abstract:
BACKGROUND
Signs of inflammation in cerebrospinal fluid (CSF) of rheumatoid arthritis patients correlate positively with fatigue, a central nervous system (CNS)-related symptom that can be partially suppressed by TNF blockade. This suggests a possible role for CNS inflammation in arthritis that may be affected by TNF blockade. We therefore investigated the effects of TNF blockade on the arthritis CSF proteome and how candidate proteins related to clinical measures of disease activity and inflammation.

METHODS
Mass spectrometry-based quantitative proteomic analysis was performed on CSF from seven polyarthritis patients before and during infliximab treatment. Treatment-associated proteins were identified using univariate (Wilcoxon signed rank test) and multivariate (partial least squares discriminant analysis (PLS-DA)) strategies. Relations between selected candidate proteins and clinical measures were investigated using the Spearman correlations. Additionally, selected proteins were cross-referenced to other studies investigating human CSF in a thorough literature search to ensure feasibility of our results.

RESULTS
Univariate analysis of arthritis CSF proteome revealed a decrease of 35 proteins, predominantly involved in inflammatory processes, following TNF blockade. Seven candidate proteins, Contactin-1 (CNTN1), fibrinogen gamma chain (FGG), hemopexin (HPX), cell adhesion molecule-3 (CADM3), alpha-1B-glycoprotein (A1BG), complement factor B (CFB), and beta-2-microglobulin (B2M), were selected for further studies based on identification by both univariate and multivariate analyses and reported detection in human CSF and known associations to arthritis. Decreased levels of FGG and CFB in CSF after treatment showed strong correlations with both erythrocyte sedimentation rate and disability scores, while CNTN1 and CADM3 were associated with pain.

CONCLUSION
Several immune-related proteins in the CSF of arthritis patients decreased during TNF blockade, including FGG and CFB that both correlated strongly with systemic inflammation. Our findings stress that also intrathecal inflammatory pathways are related to arthritis symptoms and may be affected by TNF blockade.

Estelius|Johanna|J|
Lengqvist|Johan|J|
Ossipova|Elena|E|
Idborg|Helena|H|
Le Maître|Erwan|E|
Andersson|Magnus L A|MLA|
Brundin|Lou|L|
Khademi|Mohsen|M|
Svenungsson|Elisabet|E|
Jakobsson|Per-Johan|PJ|
Lampa|Jon|J|

D000079424:Tumor Necrosis Factor Inhibitors

CSF
Rheumatoid arthritis
Proteomics
Ankylosing spondylitis
Anti-TNF
Chronic inflammation
Intrathecal inflammation
Juvenile chronic arthritis
Psoriatic arthritis


Breast cancer in pregnant patients: A review of the literature.

Abstract: Breast cancer diagnosed during pregnancy is a rare occurrence at present; however, in recent years a trend towards delayed childbirth is generating an increase in its incidence. This situation requires a multidisciplinary approach involving obstetricians, oncologists and surgeons. In this review we analyse diagnostic methods, different possible treatments and long-term patient prognosis. We conducted a search for articles published in PubMed, or in abstract form from the San Antonio Breast Cancer Symposium (SABCS), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) annual meeting, using the search terms: "Breast cancer and pregnancy". Breast cancer occurring during pregnancy requires extra effort to offer patients the best multidisciplinary management. There is no difference in the pathology-based classification, but breast cancer during pregnancy seems to be associated with different patterns of gene expression. Chemotherapy and surgery are generally safe and well-tolerated by patients during the second and third trimesters of pregnancy. The poorer prognosis could be attributed mainly to a delay in diagnosis and because breast cancer in young patients is a more aggressive disease. Finally, balancing the health of mother and child must be paramount.

Martínez|María Teresa|MT|
Bermejo|Begoña|B|
Hernando|Cristina|C|
Gambardella|Valentina|V|
Cejalvo|Juan Miguel|JM|
Lluch|Ana|A|

Breast cancer
Pregnancy
Treatment
Prognosis
Diagnosis


Root exudates drive interspecific facilitation by enhancing nodulation and N2 fixation.

Abstract: Plant diversity in experimental systems often enhances ecosystem productivity, but the mechanisms causing this overyielding are only partly understood. Intercropping faba beans (Vicia faba L.) and maize (Zea mays L.) result in overyielding and also, enhanced nodulation by faba beans. By using permeable and impermeable root barriers in a 2-y field experiment, we show that root-root interactions between faba bean and maize significantly increase both nodulation and symbiotic N2 fixation in intercropped faba bean. Furthermore, root exudates from maize promote faba bean nodulation, whereas root exudates from wheat and barley do not. Thus, a decline of soil nitrate concentrations caused by intercropped cereals is not the sole mechanism for maize promoting faba bean nodulation. Intercropped maize also caused a twofold increase in exudation of flavonoids (signaling compounds for rhizobia) in the systems. Roots of faba bean treated with maize root exudates exhibited an immediate 11-fold increase in the expression of chalcone-flavanone isomerase (involved in flavonoid synthesis) gene together with a significantly increased expression of genes mediating nodulation and auxin response. After 35 d, faba beans treated with maize root exudate continued to show up-regulation of key nodulation genes, such as early nodulin 93 (ENOD93), and promoted nitrogen fixation. Our results reveal a mechanism for how intercropped maize promotes nitrogen fixation of faba bean, where maize root exudates promote flavonoid synthesis in faba bean, increase nodulation, and stimulate nitrogen fixation after enhanced gene expression. These results indicate facilitative root-root interactions and provide a mechanism for a positive relationship between species diversity and ecosystem productivity.

Li|Bai|B| Li|Yu-Ying|YY| Wu|Hua-Mao|HM| Zhang|Fang-Fang|FF| Li|Chun-Jie|CJ| Li|Xue-Xian|XX| Lambers|Hans|H| Li|Long|L|

D000383:Agriculture
D015870:Gene Expression
D019833:Genistein
D007529:Isoflavones
D009586:Nitrogen Fixation
D010940:Plant Proteins
D018517:Plant Roots
D031307:Vicia faba
D003313:Zea mays

intercropping
signals
gene expression
flavanoids
root–root interactions


Dual role of superoxide dismutase 2 induced in activated microglia: oxidative stress tolerance and convergence of inflammatory responses.

Abstract: Microglia are activated quickly in response to external pathogens or cell debris and clear these substances via the inflammatory response. However, excessive activation of microglia can be harmful to host cells due to the increased production of reactive oxygen species and proinflammatory cytokines. Superoxide dismutase 2 (SOD2) is reportedly induced under various inflammatory conditions in the central nervous system. We herein demonstrated that activated microglia strongly express SOD2 and examined the role of SOD2, focusing on regulation of the microglial activity and the susceptibility of microglia to oxidative stress. When rat primary microglia were treated with LPS, poly(I:C), peptidoglycan, or CpG oligodeoxynucleotide, respectively, the mRNA and protein levels of SOD2 largely increased. However, an increased expression of SOD2 was not detected in the primary neurons or astrocytes, indicating that SOD2 is specifically induced in microglia under inflammatory conditions. The activated microglia showed high tolerance to oxidative stress, whereas SOD2 knockdown conferred vulnerability to oxidative stress. Interestingly, the production of proinflammatory cytokines was increased in the activated microglia treated with SOD2 siRNA compared with that observed in the control siRNA-treated cells. Pretreatment with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, decreased in not only reactive oxygen species generation but also the proinflammatory cytokine expression. Notably, SOD2 knockdown largely potentiated the nuclear factor κB activity in the activated microglia. Taken together, increased SOD2 conferred tolerance to oxidative stress in the microglia and decreased proinflammatory cytokine production by attenuating the nuclear factor κB activity. Therefore, SOD2 might regulate neuroinflammation by controlling the microglial activities.

Ishihara|Yasuhiro|Y| Takemoto|Takuya|T| Itoh|Kouichi|K| Ishida|Atsuhiko|A| Yamazaki|Takeshi|T|

D015971:Gene Expression Regulation, Enzymologic

microglia
oxidative stress
NF-kappaB
inflammation
superoxide dismutase (SOD)


Transcriptional regulation of SLURP2, a psoriasis-associated gene, is under control of IL-22 in the skin: A special reference to the nested gene LYNX1.

Abstract: A novel nicotinic acetylcholine (ACh) receptor (nAChR)-mediated transduction pathway, regulating keratinocyte function, has been elucidated in studies of secreted mammalian Ly6/urokinase plasminogen activator receptor-related protein (SLURP)-1 and -2. SLURPs are members of Ly6/neurotoxin superfamily (Ly6SF) of proteins containing the unique three-finger domain in their three-dimensional structure. Some endogenously expressed Ly6SF proteins (such as LYNX1, SLURP-1, and SLURP-2) modulate the function of nAChR, either as allosteric and/or orthosteric modulators, or as antagonists. Although the expression and functions of SLURP-1 and SLURP-2 in keratinocytes are well documented, the expression and the modes of action of LYNX1 in keratinocytes are unknown. Additionally, a particular hybrid transcript, LYNX1-SLURP2, which contains both LYNX1 and SLURP-2 sequences, with unknown function, has been reported. Furthermore, although SLURP2 is a gene strongly induced in psoriatic skin lesions, the mechanisms controlling SLURP2 expression are largely unknown. To better understand the function of nAChRs in keratinocytes, we investigated the expression profiles of LYNX1, LYNX1-SLURP-2, and SLURP-2 in keratinocytes under various inflammatory conditions. We found that keratinocytes express LYNX1 and SLURP2, but not LYNX1-SLURP2, at mRNA and protein levels. IL-22 treatment increased SLURP2 expression in keratinocytes, but this effect was completely abolished by IFN-γ. Furthermore, the IL-22-induced up-regulation of SLURP2 was completely suppressed by the inhibitor or siRNA for STAT3, a major transcriptional factor downstream of IL-22. These findings provide new insights into the nAChR-mediated regulatory mechanism of SLURP-2 expression in keratinocytes.

Moriwaki|Yasuhiro|Y| Takada|Kiyoko|K| Tsuji|Shoutaro|S| Kawashima|Koichiro|K| Misawa|Hidemi|H|

D048868:Adaptor Proteins, Signal Transducing


Superior Mesentric Artery Syndrome in a Patient with Subacute Intestinal Obstruction: A Case Report.

Abstract: Superior Mesenteric Artery (SMA) syndrome is one of the rare cause of proximal small bowel obstruction wherein, the third part of the duodenum is compressed between the SMA at its origin and abdominal aorta due to decreased angulations in these two vessels. This decreased angulation exerts a compression effect on third part of the duodenum, resulting in duodenal obstruction which may be complete or partial. There are number of causes which can lead to this entity and will be discussed briefly. Here we report imaging findings of such a rare cause of proximal small bowel obstruction in a young male patient who presented to the emergency surgical department with non specific symptoms of pain abdomen and abdominal fullness. Patient was evaluated under the standard protocol in management of abdominal pain. General physical examination, erect and supine radiograph were taken. On barium meal follow-through examination, there was paucity of contrast agent distal to the second part of duodenum with proximal dilation of stomach, first and second part of duodenum which raised us the possibility of SMA syndrome. Reconstructed CECT abdomen confirmed the decreased angulation between SMA and abdominal aorta and diagnosed it as SMA syndrome. Findings were correlated on duodenojejunostomy anastomotic surgical procedure. Diagnosing and reporting such a case of SMA syndrome is of utmost importance because the clinical presentation being non-specific pertaining to small bowel obstruction which may pose a diagnostic difficulty to the surgeon and with the further delay in diagnosis, patients may end up with chronic symptoms and complications of the disease, repeated hospital visits and electrolyte abnormalities.

Kaur|Amarjit|A|
Pawar|Naveen Chandrashekhar|NC|
Singla|Sonam|S|
Mohi|Jaswinder Kaur|JK|
Sharma|Shivani|S|

Barium studies
Decreased aortomesenteric angle
Wilkie’s syndrome