Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers doi: 10.3390/cancers10020041

Authors: Nidhi Gupta Keshav Gopal Chengsheng Wu Abdulraheem Alshareef Alexandra Chow Fang Wu Peng Wang Xiaoxia Ye Gilbert Bigras Raymond Lai

We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

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In This Issue

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TcR-α recombinations in renal cell carcinoma exome files correlate with an intermediate level of T-cell exhaustion biomarkers

Abstract

Renal cell carcinoma exome-derived, V(D)J recombination reads had an elevated presence and variability, for both TcR-α and -β, when compared to marginal tissue, reflecting an opportunity to assess tumor immunogenicity by comparison with marginal tissue T cells. PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads. Samples representing tumors with productive TcR-α recombination reads but no detectable, productive TcR-β recombination reads, reflected a 20% survival advantage, and RNASeq data indicated an intermediate level of immune checkpoint gene expression for those samples. These results raise the question of whether relatively high levels of detection of productive TcR-α recombination reads, in comparison with detection of reads representing the TcR-β gene, identify a microenvironment that has not yet entered a T-cell exhaustion phase and may thereby represent conditions for immune enhancements that do not require anti-immune checkpoint therapies.

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Rapid immunosurveillance by recirculating lymphocytes in the rat intestine: critical role of unsulfated sialyl-Lewis X on high endothelial venules of the Peyer’s patches

Abstract

Naive lymphocytes systemically recirculate for immunosurveillance inspecting foreign antigens and pathogens in the body. Trafficking behavior such as the migration pathway and transit time within the gastrointestinal tract, however, remains to be elucidated. Rat thoracic duct lymphocytes (TDLs) were transferred to a congeneic host that had undergone mesenteric lymphadenectomy. The migration pathway was investigated using newly developed four-color immunohistochemistry and immunofluorescence. Donor TDLs showed rapid transition in gut tissues from which they emerged in mesenteric lymph around 4 h after intravenous injection. Immunohistochemistry showed that donor TDLs predominantly transmigrated across high endothelial venules (HEVs) at the interfollicular area of the Peyer's patches (PPs), then exited into the LYVE-1⁺ efferent lymphatics, that were close to the venules. The rapid recirculation depended largely on the local expression of unsulfated sialyl-Lewis X on these venules where putative dendritic cells (DCs) were associated underneath. Recruited naive T cells briefly made contact with resident DCs before exiting to the lymphatics in the steady state. In some transplant settings, however, the T cells retained contact with DCs and were sensitized and differentiated into activated T cells. In conclusion, we directly demonstrated that lymphocyte recirculation within the gut is a very rapid process. The interfollicular area of PPs functions as a strategically central site for rapid immunosurveillance where HEVs, efferent lymphatics and resident DCs converge. PPs can, however, generate alloreactive T cells, leading to exacerbation of graft-versus-host disease or gut allograft rejection.

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Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma

Abstract

Cancer immunotherapy that blocks immune checkpoint molecules, such as PD-1/PD-L1, unleashes dysfunctional antitumor T-cell responses and has durable clinical benefits in various types of cancers. Yet its clinical efficacy is limited to a small proportion of patients, highlighting the need for identifying biomarkers that can predict the clinical response by exploring antitumor responses crucial for tumor regression. Here, we explored comprehensive immune-cell responses associated with clinical benefits using PBMCs from patients with malignant melanoma treated with anti-PD-1 monoclonal antibody. Pre- and post-treatment samples were collected from two different cohorts (discovery set and validation set) and subjected to mass cytometry assays that measured the expression levels of 35 proteins. Screening by high dimensional clustering in the discovery set identified increases in three micro-clusters of CD4⁺ T cells, a subset of central memory CD4⁺ T cells harboring the CD27⁺FAS⁻CD45RA⁻CCR7⁺ phenotype, after treatment in long-term survivors, but not in non-responders. The same increase was also observed in clinical responders in the validation set. We propose that increases in this subset of central memory CD4⁺ T cells in peripheral blood can be potentially used as a predictor of clinical response to PD-1 blockade therapy in patients with malignant melanoma.

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The immune checkpoint molecule VISTA regulates allergen-specific Th2-mediated immune responses

Abstract

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint receptor and ligand that regulates T-cell activation. We investigated the functional involvement of VISTA in T_h2 cell-mediated immune responses using an ovalbumin (OVA)-induced allergic asthma model. Treatment with an anti-VISTA monoclonal antibody (mAb) during allergen sensitization increased the production of antibodies, including total IgE, OVA-specific IgG1 and IgG2a and allergen-specific IL-5 and IL-13; it also increased the expression of IL-13 by splenic CD4⁺ T cells. However, treatment with the anti-VISTA mAb during sensitization did not accelerate asthmatic responses, including airway hyper-responsiveness (AHR) or the number of eosinophils in bronchoalveolar lavage (BAL) fluid. In contrast, treatment with the anti-VISTA mAb during allergen challenge significantly augmented AHR and BAL fluid eosinophilia. This treatment also increased the production of IL-5 and IL-13 in BAL fluid and the expression of IL-13 by CD4⁺ T cells in draining lymph nodes. These results suggest that VISTA is involved in the regulation of T_h2 cell generation and T_h2 cell-mediated antibody production and regulates asthmatic responses, especially in the effector phase.

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Improving socket design to prevent difficult removal of locking screws

Publication date: Available online 3 February 2018
Source:Injury
Author(s): Chen-Huei Lin, Ching-Kong Chao, Yi-Hsuan Tang, Jinn Lin
IntroductionReports of driver slippage leading to difficult locking screw removals have increased since the adoption of titanium for screw fabrication; the use of titanium is known to cause cross-threading and cold welding. Such problems occur most frequently in screws with hex sockets, and may cause serious surgical complications. This study aimed to improve screw socket design to prevent slippage and difficult screw removal.Materials and methodsThree types of small sockets (hex, Torx, and cruciate) and six types of large sockets (hex, Torx, Octatorx, Torx+ I, Torx+ II, and Torx+ III) with screw head diameters of 5.5 mm were manufactured from titanium, and corresponding screwdrivers were manufactured from stainless steel. The screw heads and drivers were mounted on a material testing machine, and torsional tests were conducted to simulate screw usage in clinical settings at two insertion depths: 1 and 2 mm. Ten specimens were tested from each design, and the maximum torque and failure patterns were recorded and compared.ResultsFor small sockets in 2 mm conditions, the hex with the largest driver core had the highest torque, followed by Torx and cruciate. In these tests, the drivers were twisted off in all specimens. However, under the 1 mm condition, the hex slipped and the torque decreased markedly. Overall, torque was higher for large sockets than for small sockets. The Octatorx, with a large core and simultaneous deformation of the driver and socket lobes, had the highest torque at almost twice that of the small hex. The hex had the lowest torque, a result of slippage in both the 1 and 2 mm conditions. Torx plus designs, with more designed degrees of freedom, were able to maintain a higher driving angle and larger core for higher torque.ConclusionsThe hex design showed slipping tendencies with a marked decrease in torque, especially under conditions with inadequate driver engagement. Large sockets allowed for substantial increases in torque. The Torx, Octatorx, and Torx plus designs displayed better performance than the hexes. Improvements to the socket design could effectively prevent slippage and solve difficult screw removal problems.



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The effect of tranexamic acid on hidden bleeding in older intertrochanteric fracture patients treated with PFNA

Publication date: Available online 2 February 2018
Source:Injury
Author(s): Shuwei Tian, Zheyuan Shen, Yang Liu, Yanlong Zhang, Aqin Peng
ObjectiveTo investigate the effect of tranexamic acid (TXA) on hidden bleeding in older intertrochanteric fracture patients treated with intramedullary nails.MethodBetween January 2016 and January 2017, 100 cases of intertrochanteric fractures eligible for the study were treated with proximal femoral nail antirotation (PFNA) in our hospital. All patients were divided into two groups of 50 patients each: the TXA group and a blank control group. In the TXA group, all patients received TXA at a dose of 10 mg/kg⁻¹ intravenously, 10 minutes preoperatively and 5 hours postoperatively. The control group did not receive TXA. We recorded the volume of intraoperative blood loss and postoperative drainage, and the need for postoperative blood transfusion and transfusion volume for all patients. Blood routine examination was performed on the day of surgery and 2 days postoperatively. We calculated the total blood loss and hidden blood loss in the two groups separately according to the Gross equation. All patients underwent deep vein ultrasound of the lower limbs preoperatively and 1 week postoperatively to detect thrombosis.ResultsCompared with controls, patients in the TXA group had lower: overt bleeding (50.59 ml; p = .012), total blood loss (181.58 ml; p = .005), hidden blood loss (130.64 ml; p = .037), volume of blood transfusion (110.0 ml; p = .019), and 20% lower transfusion rate compared with the control group. Patients receiving short-nail fixation had significantly lower hidden blood loss compared with patients receiving long-nail fixation (p < .05). However, we found no statistically significant difference in the incidence of deep vein thrombosis in the lower limbs between the two groups (p = .938).ConclusionTXA significantly reduced hidden blood loss in older intertrochanteric fracture patients treated with intramedullary nails without an increased risk of thrombosis in lower limb deep veins.



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Thoracic Injury Rule out Criteria and NEXUS Chest in Predicting the Risk of Traumatic Intra-thoracic Injuries; a Diagnostic Accuracy Study

Publication date: Available online 2 February 2018
Source:Injury
Author(s): Saeed Safari, Fatemeh Radfar, Alireza Baratloo
IntroductionThis study aimed to compare the diagnostic accuracy of NEXUS chest and Thoracic Injury Rule out criteria (TIRC) models in predicting the risk of intra-thoracic injuries following blunt multiple trauma.MethodsIn this diagnostic accuracy study, using the 2 mentioned models, blunt multiple trauma patients over the age of 15 years presenting to emergency department were screened regarding the presence of intra-thoracic injuries that are detectable via chest x-ray and screening performance characteristics of the models were compared.ResultsIn this study, 3118 patients with the mean (SD) age of 37.4 (16.9) years were studied (57.4% male). Based on TIRC and NEXUS chest, respectively, 1340 (43%) and 1417 (45.4%) patients were deemed in need of radiography performance. Sensitivity, specificity, and positive and negative predictive values of TIRC were 98.95%, 62.70%, 21.19% and 99.83%. These values were 98.61%, 59.94%, 19.97% and 99.76%, for NEXUS chest, respectively. Accuracy of TIRC and NEXUS chest models were 66.04 (95% CI: 64.34–67.70) and 63.50 (95% CI: 61.78–65.19), respectively.ConclusionTIRC and NEXUS chest models have proper and similar sensitivity in prediction of blunt traumatic intra-thoracic injuries that are detectable via chest x-ray. However, TIRC had a significantly higher specificity in this regard.



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Period prevalence and factors associated with road traffic crashes among young adults in Kuwait

Publication date: Available online 2 February 2018
Source:Injury
Author(s): Eisa Aldhafeeri, Farah Alshammari, Hana Jafar, Haya Malhas, Marina Botras, Noor Alnasrallah, Saeed Akhtar
ObjectivesThis cross-sectional study assessed one-year period prevalence of road traffic crashes (RTCs) and examined the factors associated with RTCs among young adults in Kuwait.Design and settingsDuring December 2016, 1500 students enrolled in 15 colleges of Kuwait University were invited to participate in the study. Students 18 years old or older and who drive by themselves were eligible. Data were collected using a structured self-administered questionnaire. One-year period prevalence of RTCs (≥1 vs. none) was computed. Multivariable log-binomial regression model was used to identify the risk factors associated with one-year period prevalence of RTCs.ResultsOf 1500 invited individuals, 1465 (97.7%) participated, of which 71.4% (1046/1465) were female, 56.4% (804/1426) were aged between 21 and 25 years, and 67.1% (980/1460) were Kuwaitis. One-year period prevalence of RTC was 38.9%. The final multivariable log-binomial regression model showed that after adjusting for the influences of other variables in the model, participants were more likely to have had at least one RTC during the past year, if they habitually sped over limit (adjusted PR = 1.19; 95% confidence interval (CI): 1.04–1.36), crossed a red light (adjusted PR = 1.33; 95% CI: 1.16–1.52), or if they have had three or more speeding tickets (adjusted PR = 1.40; 95% CI: 1.13–1.73) compared to those who reportedly had no RTC during the same period.ConclusionOne-year period prevalence of RTCs among university students in Kuwait, though relatively lower than the reported figures in similar populations elsewhere in the region, is yet high enough to warrant diligent attention. Habitual speeding, having had three or more speeding tickets, and the practice of crossing a red light were significantly and independently associated with at least one RTC during the past year. Targeted education and enforcement of existing traffic laws may reduce the RTCs frequency in this relatively young population. Future studies may look at impact of such interventions.



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Letter to the editor concerning “Intraoperative lateral wall fractures during Dynamic Hip Screw fixation for intertrochanteric fractures—Incidence, causative factors and clinical outcome”

Publication date: Available online 3 February 2018
Source:Injury
Author(s): Ahmet Imerci, Nevres Hurriyet Aydogan, Cagatay Gemci




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Prevalence and molecular characterization of oqxAB in clinical Escherichia coli isolates from companion animals and humans in Henan Province, China

The plasmid-encoded multidrug efflux pump oqxAB confers bacterial resistance primarily to olaquindox, quinolones, and chloramphenicol. The aims of this study were to investigate the prevalence of oqxAB among Esch...

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Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Abstract

Aim

Delta-like 1 homolog (DLK1) is a non-canonical ligand of Notch signaling, which plays a pivotal role in vascular development and tumor angiogenesis. This study aimed to elucidate the function and mechanism of DLK1 in angiogenesis.

Methods and results

By using in situ hybridization and immunohistochemical studies, expression analysis revealed a unique vascular tropism of DLK1 in vasculature of neuroblastoma and vascular tumors. Thus, it was hypothesized that DLK1 may be cleaved and then bound to endothelial cells, thereby regulating the endothelial function. To test such hypothesis, soluble DLK1 encompassing DLK1 extracellular domain (DLK1-EC) was generated and validated by its inhibitory function in adipogenesis assay. Recombinant DLK1-EC exhibited the preferential binding capability toward endothelial cells and stimulated the microvessels sprouting in aorta rings. Above all, implantation of DLK1-EC dose-dependently elicited the cornea neovascularization in rats. By using various angiogenesis assays, it was delineated that DLK1-EC stimulated the angiogenesis by promoting the proliferation, motility and tube formation of endothelial cells. By immunoblot and luciferase analysis, it was elucidated that DLK1-EC enhanced the expression and activities of Notch1/Akt/eNOS/Hes-1 signaling in dose- and time-dependent manners. Pharmaceutical blockage of Notch signaling using γ-secretase inhibitor DAPT abrogated the DLK1-EC-induced endothelial migration and Hes-1-driven luciferase activities. Furthermore, Notch1 inactivation by neutralizing antibodies or RNA interference reversed the DLK1-EC-induced angiogenesis.

Conclusions

The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells.

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miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

Abstract

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.

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To the Editor: Clinical Anatomy

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SAAMP 2.0: an algorithm to predict genotype-phenotype correlation of lysosomal storage diseases

ABSTRACT

Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAAMP 2.0 was developed by excluding 3 tools with worst performance, yielding a sensitivity of 94% and a specificity of 90%. To generalize the guideline to proteins without known structures, we built the 3D model of iduronate-2-sulfatase by homology modeling. Further, we investigated the phenotype severity of known disease-causing mutations of the GLB1 gene, which lead to two LSDs (GM1 gangliosidosis; Morquio disease type B). Based on previous literature and structural analysis, we associated these mutations with disease subtypes and proposed a theory to explain the complicated genotype-phenotype correlation. Collectively, an updated guideline for phenotype prediction with SAAMP 2.0 was proposed, which will provide essential information for early diagnosis and proper treatment allocation, and may be generalized to many monogenic diseases.

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Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling

Abstract

While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its roles in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from in vitro multiple ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional regulation via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help us to develop a new therapy to better suppress the ccRCC metastasis. This article is protected by copyright. All rights reserved.

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Arsenic Promotes the COX2/PGE2-SOX2 Axis to Increase the Malignant Stemness Properties of Urothelial Cells

Abstract

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion, and chemo-resistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features, and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. This article is protected by copyright. All rights reserved.

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Reply to “Is it significant? Is it relevant?”

We thank Drs. Manca and Deriu for their insightful comments (Manca and Deriu, 2018). We agree that the scientific and clinical relevance of a study is not necessarily reflected by the statistical significance of a specific test. A statistical cut-off, using a pre-defined significance threshold, should not be equated with the presence or absence of a scientifically or clinically relevant finding. Judging the scientific or clinical relevance requires more than simply referring to statistical significance.

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Freedom in Captivity: Managing Zoo Animals According to the ‘Five Freedoms’

Abstract

Animal welfare is a complex matter that includes scientific, ethical, economic and other dimensions. Despite the existence of more comprehensive approaches to animal welfare and the obvious shortcomings of the 'Five Freedoms', for zoological gardens the freedoms still constitute the general guidelines to be followed. These guidelines reflect both, an ethical view and a science based approach. Analysis reveals that the potential ineptitude of the 'Five Freedoms' lies in the manifold perceptions that people have of other animals. These perceptions are biased by our own (mammalian) umwelt, which is intertwined with different cultural attitudes towards other species (e.g. humanistic, moralistic, ecologistic). Perceptions of animals may be held simultaneously by different interest groups and may often be incompatible, thus often making it difficult to follow the 'Five Freedoms' in practice. We aim to recognise and consider the multiplicity of factors that, besides animal subjectivity, are relevant in understanding this hybrid environment. The moral value and practical applicability of the 'Five Freedoms' are sometimes undermined by prioritising some freedoms over others and by species bias. Both are characteristic phenomena of the zoo as a hybrid environment where other species are managed by humans. Given deficiencies are further amplified by humanistic and moralistic attitudes that people hold.

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Factors Affecting Palliative Care Development in Africa: In-Country Experts’ Perceptions in Seven Countries

Factors contributing to and impeding palliative care (PC) development in Africa can provide insights into current strategies for advancing PC.

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The Growing Demand for Hospice and Palliative Medicine Physicians: Will the Supply Keep Up?

The need for hospice and palliative care is growing rapidly as the population increases and ages and as both hospice and palliative care become more accepted. Hospice and palliative medicine (HPM) is a relatively new physician specialty, currently training 325 new fellows annually. Given the time needed to increase the supply of specialty trained physicians, it is important to assess future needs to guide planning for future training capacity.

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A rare presentation of cytomegalovirus infection in an immunocompetent patient

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Efficacy and safety of endoscopic submucosal dissection for gastric neoplasms in patients with compensated liver cirrhosis: a propensity score-matched case–control study

The clinical outcomes of endoscopic submucosal dissection (ESD) for gastric neoplasms in liver cirrhosis patients have not been adequately reported, leading to clinician concerns about adverse events, including bleeding and the deterioration of liver function. We compared the efficacy and safety of ESD between cirrhosis and non-cirrhosis patients.

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Life after Per-oral Endoscopic Myotomy (POEM): Long-term Outcomes of Quality of Life and Their Association with Eckardt Score

The clinical efficacy of POEM has been commonly established by the reduction in the Eckardt score (<3) after the procedure. However, achalasia can lead to significant impairment in the patient's quality of life that may go beyond the 4 classical achalasia symptoms as measured by the Eckardt score. The aims of our study were (1) to evaluate the effect of POEM on short and long-term health-related quality of life (HRQOL) and to (2) assess the association between HRQOL and Eckardt scores.

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Snap, crackle and pop: when sneezing leads to crackling in the neck

Wanding Yang<br />Jan 15, 2018; 2018:bcr-2016-218906-bcr-2016-218906<br />Rare disease

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Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment

Leonard B Weinstock<br />Jan 11, 2018; 2018:bcr-2017-221405-bcr-2017-221405<br />Novel treatment (new drug/intervention; established drug/procedure in new situation)

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Increased prevalence of rare sucrase-isomaltase (SI) pathogenic variants in irritable bowel syndrome patients

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Relationships Between Clinical Processes and Arteriovenous Fistula Cannulation and Maturation: A Multicenter Prospective Cohort Study

Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation.

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Update on Diabetic Nephropathy: Core Curriculum 2018

Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS).

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Comprehensive analysis of immune, extracellular matrices and pathogens profile in lung granulomatosis of unexplained etiology

This study analyzed the Type 1 and Type 2T helper (Th-1/Th-2) cytokines (including interleukins), immune cellular, matrix profile and pathogens in granulomas with unexplained etiology and compared to infectious and non-infectious etiology. Surgical lung biopsies from 108 patients were retrospectively reviewed. Histochemistry, immunohistochemistry, immunofluorescence, morphometry and polymerase chain reaction (PCR) were employed, respectively, to evaluate total collagen and elastin fibers, collagen I and III, immune cells, cytokines, metalloproteinase-9 (MMP-9), myofibroblasts and multiple usual and unusual pathogens.

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Medulloblastoma with myogenic and/or melanotic differentiation does not align immunohistochemically with the genetically defined molecular subgroups

The World Health Organization classification of central nervous system neoplasms (2016 update) recognizes four histological variants and genetically defined molecular subgroups within medulloblastoma (MB). MB with myogenic differentiation is one of the rare variant which is usually recognized as a pattern alongside the known histological variants. Due to its rarity, less is known about its molecular landscape and importantly about its placement in the current molecular schema. We aimed to analyze this rare variant for expression of three immunohistochemical markers conventionally used in molecular stratification of MB.

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Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals

Jacinta Perram<br />Nov 20, 2015; 2015:bcr2015211651-bcr2015211651<br />case-report

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Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation

Kai-Hsiang Chen<br />Feb 25, 2013; 2013:bcr2013008802-bcr2013008802<br />case-report

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Differential diagnosis of soft scalp lumps

Lawrence K Leung<br />Nov 15, 2011; 2011:bcr0720114492-bcr0720114492<br />case-report

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Projective complex matrix factorization for facial expression recognition

In this paper, a dimensionality reduction method applied on facial expression recognition is investigated. An unsupervised learning framework, projective complex matrix factorization (proCMF), is introduced to...

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The Wnt/β-catenin pathway determines the predisposition- and the efficiency of liver to pancreas reprogramming

Abstract

Transdifferentiation (TD) is the direct reprogramming of adult cells into cells of alternate fate and function. We were the first to show that liver cells can be transdifferentiated into beta-like, insulin producing cells, by ectopic expression of pancreatic transcription factors (pTFs). However, the efficiency of the process was consistently limited to <15% of the human liver cells treated in culture. The data in the current study suggest that liver to pancreas TD is restricted to a specific population of liver cells that is predisposed to undergo reprogramming.

We isolated TD-predisposed subpopulation of liver cells from >15 human donors using a lineage tracing system based on the wnt response element, part of the pericentral-specific promoter of Glutamine Synthetase (GLUL). The cells, that were propagated separately, consistently exhibited efficient fate switch and insulin production and secretion in >60% of the cells upon pTFs' expression. The rest of the cells, which originated from 85% of the culture, resisted TD. Both populations expressed the ectopic pTFs with similar efficiencies, followed by similar repression of hepatic genes.

Our data suggest that the TD-predisposed cells originate from a distinct population of liver cells that are enriched for wnt signaling, which is obligatory for efficient TD. In TD-resistant population, wnt induction is insufficient to induce TD. An additional step of chromatin opening enables TD of these cells.

Conclusion: Liver to pancreas TD occurs in defined predisposed cells. These cells' predisposition is maintained by WNT signaling that endows the cells with the plasticity needed to alter their transcriptional program and developmental fate, when triggered by ectopic pTFs. These results may have clinical implications by drastically increasing the efficacy of TD in future clinical uses. This article is protected by copyright. All rights reserved.

http://ift.tt/2BPH26d

Towards Personalized Medicine for Intrahepatic Cholangiocarcinoma: Pharmacogenomic Stratification of Patients

http://ift.tt/2nwKmi3

Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age

To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies.

http://ift.tt/2nDinwF

Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes

Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes.

http://ift.tt/2DYDYKQ

Severe Neurodevelopmental Impairment in Neonates Born Preterm: Impact of Varying Definitions in a Canadian Cohort

To assess the impact of variations in the definition of severe neurodevelopmental impairment (NDI) on the incidence of severe NDI and the association with risk factors using the Canadian Neonatal Follow-Up Network cohort.

http://ift.tt/2nE1stH

The Increasing Burden of Atopy and Allergy after Solid Organ Transplantation in Children

Solid organ transplantation in children for a variety of life-limiting illnesses and conditions will significantly impact quality of life. Advances in medical practice have included development of effective immunosuppressant and antimicrobial agents, improvements in intensive care management, and refinements in surgical practices. Consequently, survival of transplanted children is excellent, leading to a change in focus to mitigating the long-term effects of transplantation, many of which are attributable to lifelong immunosuppression and its consequences.

http://ift.tt/2DUcvKe

Risk of Death in Infants Who Have Experienced a Brief Resolved Unexplained Event: A Meta-Analysis

To estimate an upper bound on the risk of death after a brief resolved unexplained event (BRUE), a sudden alteration in an infant's breathing, color, tone, or responsiveness, previously labeled "apparent life-threatening event" (ALTE).

http://ift.tt/2nCr7mt

Worth a Try? Describing the Experiences of Families during the Course of Care in the Neonatal Intensive Care Unit When the Prognosis is Poor

To determine how parents of infants in the neonatal intensive care unit with a poor or uncertain prognosis view their experience, and whether they view their choices as "worth it," regardless of outcome.

http://ift.tt/2DWpdsa

Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy

To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy.

http://ift.tt/2nBHrUC

Cesarean Delivery and Childhood Malignancies: A Single-Center, Population-Based Cohort Study

Rising rates of cesarean deliveries worldwide prompt the evaluation of long-term morbidity to the offspring. In this retrospective cohort study, we evaluated whether cesarean delivery influences the development of childhood malignancies. We identified an association of cesarean delivery with acute lymphoblastic leukemia in children, suggesting prudence in the recommendation of cesarean delivery for nonmedically indicated cases.

http://ift.tt/2DVInyh

Routine Supplementation of Lactobacillus rhamnosus GG and Risk of Necrotizing Enterocolitis in Very Low Birth Weight Infants

To evaluate if routine supplementation of Lactobacillus rhamnosus GG ATCC 53103 (LGG) is associated with a decreased risk of necrotizing enterocolitis in very low birth weight (VLBW) infants.

http://ift.tt/2nDil81

The Maternal Nutritional Milieu and Neonatal Outcomes: Connecting the Dots

In this volume of The Journal, 2 seemingly unrelated articles1,2 shed new light on maternal nutritional influences on the health of offspring. The importance of the topic is magnified by current challenges faced by pregnant women who bear the burden of obesity, diabetes mellitus, hypertensive disorders, and proinflammatory diets.

http://ift.tt/2DWOtOH

Association of Health Insurance Status and Vaccination Coverage among Adolescents 13-17 Years of Age

To assess selected vaccination coverage among adolescents by health insurance status and other access-to-care characteristics.

http://ift.tt/2nErJrY

Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder

To study the utility of genetic evaluation and testing in patients with suspected fetal alcohol spectrum disorder (FASD).

http://ift.tt/2DVPXJ2

Risk Factors for Neonatal Venous and Arterial Thromboembolism in the Neonatal Intensive Care Unit—A Case Control Study

To identify risk factors associated with venous and arterial thrombosis in sick neonates admitted to the neonatal intensive care unit.

http://ift.tt/2nDpULV

Reply

We thank Lwin and Bragonier for their letter and for their interest in our study. We would like to address the 3 points that they raise.

http://ift.tt/2DWvfZD

Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria

To assess the prevalence of functional gastrointestinal (GI) disorders in children 0-18 years old according to the newly established Rome IV diagnostic criteria as reported by parents in a representative community sample.

http://ift.tt/2nG2eX0

Multiple Postnatal Infections in Newborns Born Preterm Predict Delayed Maturation of Motor Pathways at Term-Equivalent Age with Poorer Motor Outcomes at 3 Years

To evaluate whether the number of postnatal infections is associated with abnormal white matter maturation and poorer motor neurodevelopmental outcomes at 36 months of corrected age.

http://ift.tt/2DYDXqg

Postoperative Enteral Nutrition Guidelines Reduce the Risk of Intestinal Failure–Associated Liver Disease in Surgical Infants

To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure–associated liver disease (IFALD) among infants.

http://ift.tt/2nE1qlz

How Adolescents Search for and Appraise Online Health Information: A Systematic Review

To conduct a systematic review of the evidence concerning whether and how adolescents search for online health information and the extent to which they appraise the credibility of information they retrieve.

http://ift.tt/2DY9tVr

Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth

We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth.

http://ift.tt/2nGYnJF

Activation of pial and dural macrophages and dendritic cells by CSD (67 chrs)

Abstract

Objective:

Cortical spreading depression (CSD) has long been implicated in migraine attacks with aura. The process by which CSD, a cortical event that occurs within the blood brain barrier (BBB), results in nociceptor activation outside the BBB is likely mediated by multiple molecules and cells. The objective of this study was to determine whether CSD activates immune cells inside the BBB (pia), outside the BBB (dura), or in both, and if so, when.

Methods:

Investigating cellular events in the meninges shortly after CSD, we used in-vivo 2-photon imaging to identify changes in macrophages and dendritic cells (DC) that reside in the pia, arachnoid, and dura, and their anatomical relationship to TRPV1 axons.

Results:

We found that activated meningeal macrophages retract their processes and become circular, and that activated meningeal DC stop migrating. We found that CSD activates pial macrophages instantaneously, pial, subarachnoid and dural DC 6-12 minutes later, and dural macrophages 20 minutes later. Dural macrophages and DC can appear in close proximity to TRPV1-positive axons.

Interpretation:

The findings suggest that activation of pial macrophages may be more relevant to cases where aura and migraine begin simultaneously, that activation of dural macrophages may be more relevant to cases where headache begins 20-30 minutes after aura, and that activation of dural macrophages may be mediated by activation of migratory DC in the SAS and dura. The anatomical relationship between TRPV1-positive meningeal nociceptors, and dural macrophages and dendritic cells support a role for these immune cells in the modulation of head pain. This article is protected by copyright. All rights reserved.

http://ift.tt/2GGJake

Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage

Abstract

Objective:

Information about Rivaroxaban plasma levels (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.

Methods:

In a multicenter registry-based study (Novel-Oral-Anticoagulants-In-Stroke-Patients collaboration;NOACISP;ClinicalTrials.gov:NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS-patients had RivLev≤100ng/ml, indicating possible eligibility for thrombolysis and how many ICH-patients had RivLev≥75ng/ml, possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation; regression models) and studied the sensitivity and specificity of INR-thresholds to substitute RivLevs using cross tables and ROC curves.

Results:

Among 241 patients (median age 80 years[IQR73-84], median time-from-onset-to-admission 2 hours[IQR1-4.5hours], median RivLev 89ng/ml[31-194]), 190 had AIS and 51 had ICH. RivLev were similar in AIS-patients (82ng/ml[IQR30-202] and ICH-patients (102ng/ml[IQR 51-165]; p=0.24). Trough RivLev_{(≤137ng/ml)} occurred in 126/190 (66.3%) AIS- and 34/51 (66.7%) ICH-patients. Among AIS-patients, 108/190 (56.8%) had RivLev≤100ng/ml. In ICH-patients 33/51(64.7%) had RivLev≥75ng/ml. RivLev were associated with rivaroxaban dosage, inversely with renal function and time-since-last-intake (each p<.05). INR≤1.0 had a specificity of 98.9% and a sensitivity of 25.7% to predict RivLev≤100ng/ml. INR≥1.4 had a sensitivity of 59.3% and specificity of 90.1% to predict RivLev≥75ng/ml.

Interpretation:

RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under Rivaroxaban had RivLev low enough to consider thrombolysis. In ICH-patients, 2/3 had RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR-thresholds perform poor to inform treatment decisions in individual patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2s3JGpb

Sleep and Cognitive Decline: A Prospective Non-demented Elderly Cohort Study

Abstract

Objective: To investigate sleep disturbances that induce cognitive changes over four years in non-demented elderlies.

Methods: Data were acquired from a nationwide, population-based, prospective cohort of Korean elderlies (2,238 normal cognition [NC] and 655 mild cognitive impairment [MCI]). At baseline and 4-year follow up assessments, sleep-related parameters (mid-sleep time, sleep duration, latency, subjective quality, efficiency and daytime dysfunction) and cognitive status were measured using Pittsburgh Sleep Quality Index and Consortium to Establish a Registry for Alzheimer's Disease Assessment, respectively. We used logistic regression models adjusted for covariates including age, sex, education, apolipoprotein E genotype, Geriatric Depression Scale, Cumulative Illness Rating Scale, and physical activity.

Results: In participants with NC, long sleep latency (> 30 min), long sleep duration (≥ 7.95 hr), and late mid-sleep time (after 3:00AM) at baseline were related to the risk of cognitive decline at 4-year follow-up assessment; odds ratio (OR) was 1.40 for long sleep latency, 1.67 for long sleep duration, and 0.61 for late mid-sleep time. These relationships remained significant when these variables maintained their status throughout the follow-up period. Newly developed long sleep latency also doubled the risk of cognitive decline. In those with MCI, however, only long sleep latency reduced the chance of reversion to NC (OR = 0.69).

Interpretation: As early markers of cognitive decline, long sleep latency can be used for elderlies with NC or MCI, while long sleep duration and relatively early sleep time might be used for cognitively normal elderlies only. This article is protected by copyright. All rights reserved.

http://ift.tt/2GHaoHu

Mutations in MICAL-1 cause autosomal dominant lateral temporal epilepsy

Abstract

Objective: Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder.

Methods: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single nucleotide polymorphism-array linkage analysis.

Results: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain, and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics.

Interpretation: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. This article is protected by copyright. All rights reserved.

http://ift.tt/2rYS5Ky

Increase of HCN current in the aberrant excitability of spinal muscular atrophy

Abstract

Objective

The pathophysiology of spinal muscular atrophy (SMA) is still unclear.

Methods

The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, Western blotting and whole-cell patch-clamp recording were used for the identified hypothesis.

Results

The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold relationship was reproducible in a mouse model of mild SMA and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and Western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in the SMA mice, and voltage-clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA.

Interpretation

This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN-target for SMA therapy. This article is protected by copyright. All rights reserved.

http://ift.tt/2GGXQQp

When less is more (brain)—Comment on “Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage”

http://ift.tt/2s42lBm

Cortical Perception

http://ift.tt/2GHa7nW

Interpreting Alzheimer's disease polygenic scores

http://ift.tt/2s2f1bR

The neutral sphingomyelinase 2 in T cell receptor signaling and polarity

Journal Name: Biological Chemistry
Issue: Ahead of print


http://ift.tt/2EComcU

Neuroimaging Field Methods Using Functional Near Infrared Spectroscopy (NIRS) Neuroimaging to Study Global Child Development: Rural Sub-Saharan Africa

Portable neuroimaging approaches (functional Near Infrared Spectroscopy) provide advances to the study of the brain in previously inaccessible regions; here, rural Côte d'Ivoire. Innovation in methods and development of culturally-appropriate neuroimaging protocols permits novel study of the brain's development and children's learning outcomes in environments with significant poverty and adversity.

http://ift.tt/2s22YLJ

Multicolor Imaging Based on Interferometric Information in 4Pi Single-Molecule Switching Nanoscopy

By utilizing a dual-objective setup in single-molecule switching nanoscopy (SMSN; e.g. PALM, STORM or FPALM), it is possible to obtain three-dimensional (3D) images at 10 to 20 nm resolution. We have recently expanded this technology to the imaging of thick cells through the addition of deformable mirrors in each arm of the 4Pi-interferometric cavity and new image processing algorithms, significantly increasing the application range.

http://ift.tt/2GEnLbz

Nanoscopy with Multiple Off-States

Coordinate-targeted super-resolution techniques distinguish fluorophores within a diffraction-limited zone by differing molecular states (typically on vs. off) that are imprinted with light. In STED microscopy, state contrast is generated via stimulated emission. For strong spatial confinement, this requires high STED light intensities. Here we show that enhanced state contrast can be achieved by combining multiple off-state transitions, specifically by combining stimulated emission with reversible photoswitching in "protected STED".

http://ift.tt/2s3D6PC

Sub-Micron to Nanoscale Chemical Characterization of Biological Systems using Laser and AFM Based IR Spectroscopy

Infrared microspectroscopy is a powerful technique for obtaining unique chemical information from a variety of biological systems. In general, spatial resolutions are limited by the Abbe diffraction laws to ∼ λ/2 (3-10 µm). In recent years, the development of the AFM-IR technique has allowed for overcoming these diffraction limitations by using an AFM probe as the detector for IR absorption. Using a quantum cascade IR laser (QCL), the molecular vibrations in a sample are excited, leading to thermal expansion of the surface, which is monitored using an AFM cantilever.

http://ift.tt/2GGjfcv

Glial Channels and Transporters that Mediate Excretion of K+ in the Microenvironment between Glia and Neurons Shape Neuronal Output in C. elegans

Isolated microenvironments, such as the tripartite synapse, where the concentration of ions is regulated independently from the surrounding tissues, exist throughout the nervous system. While the regulation of ions in these microenvironments is known to be mainly mediated by glia, the molecular mechanisms of ion regulation and effects on neuronal output and animal behavior are poorly understood. Using the model system C. elegans, our lab published that Na+ channels of the DEG/ENaC family expressed in glia control neuronal Ca2+ transients and animal behavior in response to sensory stimuli.

http://ift.tt/2s5pXp0

Principles of Protein Structural Ensemble Determination

The biological functions of protein molecules are intimately dependent on their conformational dynamics. This aspect is particularly evident for disordered proteins, which constitute perhaps one-third of the human proteome. Therefore, structural ensembles often offer more useful representations of proteins than individual conformations. Here, we describe how the well-established principles of protein structure determination should be extended to the case of protein structural ensembles determination.

http://ift.tt/2GDRj93

Role of Cholesterol in Adenosine A2A Receptor Activity

G-protein coupled receptors (GPCRs) represent the largest family of membrane proteins in the living world, and serve key roles in cellular signaling to diverse stimuli. For this reason, GPCRs are the largest target of therapeutics on the market. Despite this importance, our understanding of the relationship between structure and function, including downstream signaling, is rather limited. Since the first human GPCR, β2-adrenergic receptor, was crystallized in 2007, a specific cholesterol binding site between helices I, II, III and IV - the cholesterol consensus motif (CCM) - was established, and as many as 25% of all class A GPCRs have been predicted to have a specific interaction with cholesterol.

http://ift.tt/2s0nmwT

Ornithine Decarboxylase Antizyme Pseudoknot RNA Binding to Spermine Regulates Gene Expression

Riboswitches are elements within messenger RNAs that directly bind to cellular metabolites and modulate gene expression through feedback regulation. Although riboswitches are widespread among bacteria, only one class further resides in fungi and plants, and no riboswitches have been found in animals. Here we propose the riboswitch function of a translational frame-shift stimulatory pseudoknot RNA (pkRNA) that is highly conserved among vertebrate ornithine decarboxylase antizyme (OAZ) genes involved in the regulation of polyamine biosynthesis.

http://ift.tt/2GItOvu

Light Sheet Spectroscopy for the Investigation of Biofilms

Biofilms are bacterial communities held together by a matrix composed of extracellular polymeric substances. They are complex organizations whose composition varies as they comprise multiple species of bacteria that secrete various polymeric compounds. Biofilms can exist over length scales from a few bacteria to dimensions of many micro- or millimeters. They have deleterious effects on human health due to their involvement in infections, food spoilage, and water fouling, and on many materials including, for instance, metal surfaces via corrosion.

http://ift.tt/2rYqXeU

Controlling Candidate Physical Inputs to the Spindle Assembly Checkpoint

To ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) prevents anaphase until chromosomes correctly attach to the spindle. The SAC detects some aspect of plus-end microtubule attachment to the kinetochore, and generation of tension is not sufficient to satisfy the SAC without it. However, we do not know whether tension is necessary to satisfy the SAC, and this is in part due to the difficulty of controlling tension in otherwise native end-on attachment scenarios. Here, we use laser ablation to change tension in real time, and we currently monitor SAC satisfaction.

http://ift.tt/2GGjeoX

Engineering-Based Approaches to Understanding, Diagnosing, and Treating Inherited Cardiomyopathies

Inherited cardiomyopathies (diseases of the heart muscle) affect roughly one million Americans and are the leading cause of sudden death in young athletes. Identifying and treating at-risk individuals is a complex undertaking that involves many challenges. These include a large proportion of patient families that lack a recognizable genetic marker and uncertainty surrounding the mechanisms that underlie these disorders. We have developed an array of engineering-based tools to address these obstacles in the clinical management of inherited cardiomyopathies.

http://ift.tt/2s0nn3V

Differential Association of Adenylyl Cyclase Isoforms with Membrane Microdomains Regulates cAMP Compartmentation in Human Airway Smooth Muscle Cells

Compartmentation of cAMP signaling is critical to explaining how different G-protein coupled receptors produce distinct responses within the same cell. Membrane microdomains have been suggested to play an important role by forming discrete receptor-specific signaling complexes. Key components include various isoforms of the cAMP producing enzyme adenylyl cyclase (AC). In human airway smooth muscle (HASM) cells, AC6 is preferentially found in caveolar/lipid raft membrane domains while AC2 is found in non-raft domains.

http://ift.tt/2GHpb4T

Microfluidic Tool for the Generation and Characterization of Lipid Gradients in Model Biomembranes

Many eukaryotic cells display distinct plasma membrane morphologies that depend on their life cycle and physiological conditions. These morphologies are often dynamic, show a high level of complexity and in some instances, give rise to polarized cells. We are interested in understanding how cells control micron scale polarization of membrane organization as seen during processes such as cytokinesis and chemotaxis or within statically polarized epithelial cells. Phosphoinositide gradients have been shown to be crucial for a range of important physiological events and it is our goal to explore how these gradients are created, maintained and reversed.

http://ift.tt/2s1bWIZ

Mechanistic Basis for Client Recognition and Amyloid Inhibition of NMNAT

Imbalance of proteostasis leads to abnormal protein aggregations as a common pathological hallmark in a variety of devastating human neurodegenerative diseases such as AD and PD. Chaperones play essential roles in maintaining proteostasis and preventing protein from abnormal aggregation. NMNAT, a NAD synthase firstly identified as a key protector in Wallerian axon degeneration, was recently found to possess chaperone activity and exhibits protective effects in cells and animal models of neurodegeneration.

http://ift.tt/2GGk6tN

Mitochondrial Effects on Anesthetic Sensitivity and Anesthetic Induced Neurodegeneration

Background. Anesthetic induced neurotoxicity (AIN) induced by early developmental exposure to volatile anesthetics (VAs) is a characteristic of organisms across a wide range of species. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. This is complicated by the fact that the mechanisms of action of VAs remain unknown. Mice lacking the mitochondrial complex I subunit, NDUFS4 (Ndufs4(KO)), are hypersensitive to VAs; loss of NDUFS4 in glutamatergic neurons conveys the entire VA hypersensitivity.

http://ift.tt/2rXzrCI

Biomimetic Membrane Design Principles for Angstrom Scale Separation

Functional biomimetic membranes are membrane protein-polymer based, or membrane protein-lipid based hybrid membranes. Biomimetic membranes can preserve membrane protein function and have been applied to areas such as DNA sequencing, drug delivery and water purification. Especially the discovery of Aquaporins has promoted studies into the development of biomimetic membranes as highly selective and permeable separation membranes. This presentation will describe our work on biomimetic membrane design principles, including both biomaterial selection for highly integrated biomimetic membranes with compatible protein-polymer combinations and robust membrane protein redesign targeting accurate small molecule separations.

http://ift.tt/2GGLvMc

Neurodegenerative Loss of Mitochondrial Quality via the 18kDa Protein TSPO

The 18kDa Translocator Protein (TSPO), is a nuclear-encoded protein residing on the outer mitochondrial membrane and linked to a variety of pathological conditions. Traditionally a target of pharmacological agents, its ability to efficiently signal cellular stress has been employed in diagnostic protocols of neuroinflammation1. Recently, breakthroughs on its role in mitochondrial physiology and metabolism, including the negative regulation of mitophagy, have provided evidences for its mechanistic role as stress-response adaptive element in pathophyioslogy.

http://ift.tt/2s1wTDX

Catastrophic Depolymerization of Microtubules Driven by Subunit Shape Change

Microtubules are key component of cells and understanding their behavior is key to cellular biophysics. While microtubules possess high mechanical strength (sufficient for driving, e.g., mitosis), they possess a distinctive dynamic instability between growth and catastrophically-fast depolymerization. GTP-tubulin (a tubulin dimer bound to GTP) self-assembles, but dephosphorylation of GTP- to GDP-tubulin within the tubule results in destabilization. The molecular origins of this instability have remained unclear despite their importance in cellular processes.

http://ift.tt/2GI5Xfu

Determining Nucleocapsid Protein Recognition of Non-canonical Substrate Hairpins

The nucleocapsid (NC) protein of HIV binds to and destabilizes the TAR hairpin in the HIV genome. Studies have shown that G-containing base pairs next to a distortion in the duplex are prime sites for NC induced destabilization. Indeed, the NMR structure of the NC protein bound at the G/C base pair at the stem-loop interface, and flipping out the bases in the loop. While the NC protein primarily binds to RNA, it can also recognize DNA hairpins. Here, we present basic characterization of NC protein binding to various DNA hairpins previously shown to form in the eukaryotic genome.

http://ift.tt/2s0nk8f

Functional Analysis of the Voltage Sensor Domain Present in the Mammalian Sperm-Specific NA+/H+ Exchanger by Patch-Clamp Fluorometry of Chimeric Fluorescent Voltage Sensor

Several enzymes, transporters and ion channels accurately regulate sperm motility. Some of these proteins are expressed only in spermatozoa, but the functional relationship among them is not fully understood. Sperm-specific Na+/H+ exchanger (sNHE) is an essential protein for mouse sperm motility regulation and is localized in the principal piece of mammalian spermatozoa. Differently from somatic NHEs, sNHE has two predicted regulatory domains, a voltage sensor domain (VSD) and a cyclic nucleotide binding domain (CNBD), although their functionality remains to be confirmed.

http://ift.tt/2GItGw0

G Protein-GPCR Interaction Studied by SANS

G protein-coupled membrane receptors (GPCR) transmit extracellular signals elicited by compounds like neural transmitters, hormones, odorants, or light to the cell interior, where they activate GTP-binding proteins (G proteins). It is desirable to study GPCR and G protein under functional conditions in their natural environment, namely a fluid lipid matrix. Experiments were conducted using the GPCR bovine rhodopsin and the G protein transducin. We have recently shown that SANS is capable of measuring the state of GPCR homo-oligomerization in a lipid matrix under functional conditions.

http://ift.tt/2s0njRJ

Analysis of Arabidopsis thaliana Growth Behavior in Different Light Qualities

Here, we present a protocol for studying plant growth behavior and especially phenotypes in a reproducible manner. We show how to provide variable and at the same time stable light conditions. Proper analyses depend on sufficient sample numbers and valid statistical evaluations.

http://ift.tt/2s6a4Pq

Determining if DNA Stained with a Cyanine Dye Can Be Digested with Restriction Enzymes

Staining DNA molecules for fluorescence microscopy allows a scientist to view them during an experiment. In the method presented here, DNA molecules are pre-stained with fluorescent dyes and digested with methylation and non-methylation sensitive restriction enzymes.

http://ift.tt/2EwoQBn

Constitutive and Inducible Systems for Genetic In Vivo Modification of Mouse Hepatocytes Using Hydrodynamic Tail Vein Injection

Hydrodynamic tail vein injection of transposon-based integration vectors enables stable transfection of murine hepatocytes in vivo. Here, we present a practical protocol for transfection systems that enables the long-term constitutive expression of a single transgene or combined constitutive and doxycycline-inducible expression of a transgene or miR-shRNA in the liver.

http://ift.tt/2DYZz1y

Gericare Eye Wash by Kareway Products: Recall - Potential Product Contamination

Audience: Consumer, Pharmacy, Risk Manager [Posted 02/02/2018] ISSUE: Kareway Products, Inc is voluntarily recalling 60,000 lots of Gericare Eye Wash, Sterile Eye Irrigation Solution, 4 fluid ounces to the hospital, retail or consumer level. The...

http://ift.tt/2EynfuP

People who survive an episode of severe alcoholic hepatitis should be advised to maintain total abstinence from alcohol

http://ift.tt/2DVE69U

Knockout of ULK1/2 protects against acetaminophen-induced acute liver injury independent of autophagy?

http://ift.tt/2ECkau0

MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

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http://ift.tt/2GEKHaq

Androgen receptor-independent prostate cancer: an emerging clinical entity

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http://ift.tt/2s1CLNl

Gericare Eye Wash by Kareway Products: Recall - Potential Product Contamination

Audience: Consumer, Pharmacy, Risk Manager [Posted 02/02/2018] ISSUE: Kareway Products, Inc is voluntarily recalling 60,000 lots of Gericare Eye Wash, Sterile Eye Irrigation Solution, 4 fluid ounces to the hospital, retail or consumer level. The...

http://ift.tt/2EynfuP

Mimicking and Measuring Occlusal Erosive Tooth Wear with the "Rub&Roll" and Non-contact Profilometry

The Rub&Roll can mimic the chewing cycle, allowing variation of chewing force, sliding distance, chewing velocity, number of cycles, and frequency, and with a combination of erosive and abrasive challenges can result in a complex simulation of oral ageing.

http://ift.tt/2GI8whK

Targeting ataxia telangiectasia-mutated- and Rad3-related kinase (ATR) in PTEN-deficient breast cancers for personalized therapy

Abstract

Purpose

Phosphate and tensin homolog (PTEN), a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN-deficient triple-negative breast cancer (TNBC).

Methods

PTEN, ATR and pCHK1^Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient- (MDA-MB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & γH2AX accumulation) and FITC-annexin V flow cytometry analysis.

Results

Low nuclear PTEN was associated with higher grade, pleomorphism, de-differentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values < 0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1^ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values < 0.05). VE-821 was selectively toxic in PTEN-deficient TNBC cells and resulted in accumulation of double-strand DNA breaks, cell cycle arrest, and increased apoptosis.

Conclusion

ATR signalling adversely impact survival in PTEN-deficient breast cancers. ATR inhibition is synthetically lethal in PTEN-deficient TNBC cells.

http://ift.tt/2GGpqxi

Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9

Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9

Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9, Published online: 02 February 2018; doi:10.1038/s41419-017-0240-z

Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9

http://ift.tt/2DZHaWz

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance, Published online: 02 February 2018; doi:10.1038/s41419-017-0233-y

The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

http://ift.tt/2nACWtF

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis, Published online: 02 February 2018; doi:10.1038/s41419-017-0147-8

Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis

http://ift.tt/2DXU2g2

Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination

Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination

Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination, Published online: 02 February 2018; doi:10.1038/s41419-017-0182-5

Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination

http://ift.tt/2nD3g67

Clinorotation-induced autophagy via HDM2-p53-mTOR pathway enhances cell migration in vascular endothelial cells

Clinorotation-induced autophagy via HDM2-p53-mTOR pathway enhances cell migration in vascular endothelial cells

Clinorotation-induced autophagy via HDM2-p53-mTOR pathway enhances cell migration in vascular endothelial cells, Published online: 02 February 2018; doi:10.1038/s41419-017-0185-2

Clinorotation-induced autophagy via HDM2-p53-mTOR pathway enhances cell migration in vascular endothelial cells

http://ift.tt/2DWZBLF

Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2–MRN–ATM axes

Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2–MRN–ATM axes

Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2–MRN–ATM axes, Published online: 02 February 2018; doi:10.1038/s41419-017-0192-3

Inactivation of ribosomal protein S27-like confers radiosensitivity via the Mdm2-p53 and Mdm2–MRN–ATM axes

http://ift.tt/2nD37zB

SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis

SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis

SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis, Published online: 02 February 2018; doi:10.1038/s41419-017-0205-2

SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis

http://ift.tt/2DTAOrI

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA, Published online: 02 February 2018; doi:10.1038/s41419-017-0224-z

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

http://ift.tt/2nAYypC

Economic Evaluation of Direct-Acting Antivirals for Hepatitis C in Norway

Abstract

Purpose

New direct-acting antiviral (DAA) drugs have revolutionized the treatment of hepatitis C in recent years.

Objective

Our objective was to analyse the cost effectiveness of combinations of different DAAs compared with ribavirin and peginterferon-α-2a, taking into account rebates from tender negotiations.

Methods

We used a compartmental model specifically developed for Norway to simulate hepatitis C and complications with and without different DAAs. All costs were based on Norwegian fees and estimates, estimating healthcare sector costs for the year 2016. We performed Monte Carlo simulations on uncertain input parameters to facilitate probabilistic sensitivity analyses.

Results

For patients diagnosed with genotype 1, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost effective compared with eight other available alternatives, given a cost-effectiveness threshold of €70,000 per quality-adjusted life-year. For genotype 2, the combination of sofosbuvir and ribavirin was the most effective and cost-effective alternative for all patients. Among available alternatives for patients with genotype 3, sofosbuvir in combination with peginterferon and ribavirin was the most cost-effective alternative, although the combination of daclatasvir and sofosbuvir was somewhat more effective.

Conclusions

For each of the hepatitis C genotypes 1, 2 and 3, there were combinations of DAAs that were cost effective in a Norwegian setting. As a result of recent tender negotiations in Norway, treating all diagnosed patients with hepatitis C with the most cost-effective DAAs will result in lower total expenditure on these medications compared with 2015.

http://ift.tt/2nBD2Bi

LncRNA SNHG5/miR-26a/SOX2 signal axis enhances proliferation of chondrocyte in osteoarthritis

Abstract

Chondrocyte is involved in the destruction of joints in osteoarthritis (OA) patients. The aim of this study was to explore the expression level of small nucleolar RNA host gene 5 (SNHG5) and evaluate its function in chondrocyte. In our current study, the expression levels of SNHG5, miR-26a, and SOX2 in 17 pairs of articular cartilage tissues and in the non-OA group were assessed by real-time quantitative reverse-transcription polymerase chain reaction. Results showed that the levels of SNHG5 and SOX2 were significantly downregulated in OA tissues, while the level of miR-26a was upregulated. MTT, colony formation and cell transwell assays were performed to assess the function of SNHG5 on the cell viability, growth ability, and migration capacity in CHON-001 cells. It was found that SNHG5 could promote chondrocyte cell proliferation and migration. The relationship between SNHG5 and miR-26a was confirmed by RIP and the luciferase reporter assays. SOX2 was identified as a target gene of miR-26a by the luciferase reporter assay. Rescue assay was applied to verify the relationship among SNHG5, miR-26a, and SOX2. Our current study demonstrated that SNHG5 is involved in the mechanism of OA through functioning as a ceRNA to competitively sponge miR-26a, therefore, regulating the expression of SOX2.

http://ift.tt/2E9GGwk

De novo variants in CDK13 associated with syndromic ID/DD; molecular and clinical delineation of 15 individuals and a further review

Abstract

De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of fifteen individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe two nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of two aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioural problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in two individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although two individuals harbouring a stop codons at the end of the kinase domain might have a milder phenotype. Overall there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview we provide suggestions for clinical work-up and management of this recently described ID syndrome.

http://ift.tt/2Ezc1Xd

Worldwide distribution of common IDUA pathogenic variants

Abstract

Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analysed on a worldwide scale. To address this, we analysed the genotypes of MPS I patients from thirty-five published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in northern and eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management.

http://ift.tt/2DWnOxq

Lack of clear and univocal genotype-phenotype correlation in Familial Mediterranean Fever patients: A systematic review

Abstract

Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype–phenotype correlation in FMF patients has been intensively investigated, however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyse the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the PRISMA guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF.

http://ift.tt/2EzyLGw

Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014

BACKGROUND

No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed.

METHODS

Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use.

RESULTS

This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival.

CONCLUSIONS

Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2GDD4RP

The pharmacodynamic and clinical trial evidence for statin dose

Abstract

Statin doses around estimated effective dose 50 (ED50) can reduce myocardial infarction by over 25% and mortality by around 10%. Being a competitive enzyme inhibitor, statin efficacy plateaus at doses that are multiples above the ED50, whilst on- and off-target adverse events increase in number and severity with increasing dose. For example, myopathy has been shown to increase by up to 29-fold and liver dysfunction by up to 9-fold as statin dose is increased. Doses of up to 40-fold ED50 have been promoted, but above 5-fold ED50, for example 10 mg of atorvastatin, there is no randomised controlled clinical trial evidence that coronary mortality is lowered, or that survival is increased.

http://ift.tt/2nBfbRX

Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations

Marijuana (Cannabis spp.) growing operations (MGO) in California have increased substantially since the mid-1990s. One environmental side-effect of MGOs is the extensive use of anticoagulant rodenticides (AR) to ...

http://ift.tt/2nFyBWb

Loop-mediated isothermal amplification (LAMP) shield for Arduino DNA detection

Loop-mediated isothermal amplification (LAMP) of DNA is gaining relevance as a method to detect nucleic acids, as it is easier, faster, and more powerful than conventional Polymerase Chain Reaction. However, L...

http://ift.tt/2DVmUFM

Effect of incorporation of soy flour on functional, nutritional, and sensory properties of mushroom–moringa-supplemented healthy soup

Abstract

The research study was conducted to evaluate the effect of soy flour on functional, nutritional, and sensory properties of mushroom–moringa-supplemented soup which could be used as a protein-supplemented ready-to-eat food. In this study, corn flour was supplemented with soy flour at different levels such as 20% (T4), 15% (T3), 10% (T2), and 5% (T1), and without soy flour was kept as control (T0). Fixed amount of mushroom and moringa leaf powder was added in all soup powders. Soup powders were analyzed for functional, nutritional, and sensory parameters. Bulk density (0.82–0.74 g/ml), dispersibility (82.1%–75.9%), pH (6.17–6.13), swelling capacity (3.98–3.65 ml/g), and viscosity were decreased, while water absorption capacity (70%–94%) was increased with increasing of soy flour percentages. Protein content of all the treatment groups increased from 10.66% to 19.97% along with a significant increased in fat (1.43%–6.97%), fiber (1.10%–2.30%), ash (15.77%–16.40%), and energy value (328.38–353.21 kcal/100 g) while decreased in moisture and carbohydrate content. On sensory evaluation, soup powders with 10% (T2) level of soy flour incorporation had highest scores for all the sensory attributes evaluated. Based on these results, it can be concluded that soy flour has effect on functional, nutritional, and sensory properties of soup powders and 10% supplementation of soy flour is suitable for ready-to-eat soup formulation. Besides these, use of mushroom and moringa leaf may also increase its nutritional value. Soup developed in this way may be sufficient to meet day-to-day nutritional requirements as a supplement.

Soy flour has effect on functional, nutritional, and sensory properties of soup powders, and 10% supplementation of soy flour is suitable for ready-to-eat soup formulation

http://ift.tt/2EwMRs5

Indigenous Ethiopian okra (Abelmoschus esculentus) mucilage: A novel ingredient with functional and antioxidant properties

Abstract

Functional and antioxidant properties of mucilage extracted from the pods of eight okra accessions grown in Benishangul-Gumuz region, Western Ethiopia, were evaluated. This study had shown that the mucilage contents of the pods of eight okra accessions ranged from 1.25 to 3.45 g/100 g. Functional properties of the mucilage of okra pods varied significantly (p < .05) and had respective ranges of bulk density of 0.58–0.64 g/ml; water absorption capacity of 2.45–4.60 ml/g; oil absorption capacity of 0.02–3.64 ml/g; emulsifying capacity of 42.22%–74.45%; emulsion stability of 42.22%–74.45%; foaming capacity of 50.51%–62.50%, and foam stability of 36.04%–54.35%. Total phenolic and flavonoid contents of the mucilage of the pods of okra accessions ranged from 4.66 to 49.93 mg GAE/g and 8.18–18.72 mg CE/g, respectively. The effective concentration (EC₅₀) values (mg/ml) of mucilage of okra pods varied from 3.15 to 6.60 and 1.10 to 1.85 for DPPH scavenging and metal-chelating activity, respectively. The study revealed that the mucilage of the pods of okra accessions was found to exhibit good functional properties and can offer a great potential in various food systems. Particularly, mucilage of the pods from OPA#5 and OPA#7 had desirable water and oil absorption capacities, whereas the mucilage of accession OPA#1 and OPA#6 had high emulsifying and foaming properties. The results also demonstrated that okra pod mucilage had potential sources of natural antioxidant.

Ethiopian okra mucilage: Functional and Antioxidant properties.

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Determination of geographical origin Turkish hazelnuts according to fatty acid composition

Abstract

This study focuses on detecting geographical origin of round type hazelnut (Corylus avellena L.) in Turkey using fatty acid (FA) composition. The samples were collected from Western, Central, and Eastern Black Sea regions between 2015 and 2016. FA profiles were determined by gas chromatography (GC), and most abundant fatty acid was oleic acid (C18:1) followed by linoleic acid (C18:2), palmitic acid (C16:0), and stearic acid (C18:1). The effect of geographical origin on the fatty acid profile of hazelnut oils was statistically analyzed by one-way ANOVA and linear discriminant analysis (LDA). The results showed that the Central Black Sea region had high content of total saturated fatty acids (%8.45), total monounsaturated fatty acids (%83.54), low content of total polyunsaturated fatty acids (%7.85), and Eastern Black Sea region had high content of linoleic (%9.10) and linolenic acid (%0.096). Six fatty acids (C16:1, C18:1, C18:2, C18:3, C20:0, and C20:1) identified by LDA provide 86.2% of correct predictions.

It has been investigated for the first time whether the fatty acid profile of Turkish hazelnut has changed according to the production regions and whether it is possible to determine the geographical origin by utilizing the profile of fatty acids.

http://ift.tt/2Ey1Jqf

Genotoxicity evaluation of So-ochim-tang-gamibang (SOCG), a herbal medicine

So-ochim-tang-gamibang (SOCG) is a traditional Korean medicine frequently used for depression in the clinical field. In this study, we evaluated the potential genotoxicity of SOCG using three standard batterie...

http://ift.tt/2DVvujI

Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2)

Betulinic acid (BA) is a natural triterpenoid compound and exhibits a wide range of biological and medicinal properties including anti-inflammatory activity. Therefore, this theoretical investigation is perfor...

http://ift.tt/2EzWma6

Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells

Most of herbal medicines are used without any standard safety and toxicological trials although common assumption is that these products are nontoxic. However, this assumption is incorrect and dangerous, so to...

http://ift.tt/2DVvkc6

Anti-inflammatory activities of Guang-Pheretima extract in lipopolysaccharide-stimulated RAW 264.7 murine macrophages

Guang-Pheretima, which is originated from Pheretima aspergillum, has been documented in academic Chinese herbal studies for nearly 2000 years for its prominent treating effects of various inflammatory diseases su...

http://ift.tt/2EAoHwW

Inpatient utilization and disparities: The last year of life of adolescent and young adult oncology patients in California

BACKGROUND

Studies of adolescent and young adult (AYA) oncology end-of-life care utilization are critical because cancer is the leading cause of nonaccidental AYA death and end-of-life care contributes significantly to health care expenditures. This study was designed to determine the quantity of and disparities in inpatient utilization in the last year of life of AYAs with cancer.

METHODS

The California Office of Statewide Health Planning and Development administrative discharge database, linked to death certificates, was used to perform a population-based analysis of cancer patients aged 15 to 39 years who died in 2000-2011. The number of hospital days and the inpatient costs were determined for each patient in the last year of his or her life, as were clinical and sociodemographic factors associated with high inpatient utilization. Admission patterns as death approached were also evaluated.

RESULTS

The 12,883 patients were admitted for 40 days on average in the last year of life, and this cost $151,072 per patient in inpatient costs. As death approached, the admission rates and the percentage of all admissions occurring at nonspecialty centers increased. Five percent of patients used 20% of bed days in the last year (high utilizers). Factors associated with high utilization included younger age (15-30 years), Hispanic ethnicity, non–health maintenance organization insurance, and hematologic malignancies.

CONCLUSIONS

AYA oncology decedents were admitted for 40 days in their last year of life. Subgroups with high utilization had distinct sociodemographic and clinical characteristics, and nonspecialty center admissions increased as death approached. This demonstrates the need for palliative care at nonspecialty centers. Future studies need to determine whether these patterns are goal-concurrent, include high utilizers, and monitor the effects of health care reform. Cancer 2018. © 2018 American Cancer Society.

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Mold infestation and aflatoxins production in traditionally processed spices and aromatic herbs powder mostly used in West Africa

Abstract

Mold infestation and occurrence of aflatoxins were investigated in 66 samples of dried spices and aromatic herbs powder (SAH) as commercialized in Benin and its neighboring countries. The samples were randomly collected from markets, supermarkets, and processing sites. Mold counts were enumerated according to standard method and aflatoxins levels were assessed using high-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD). The results revealed that mold counts of samples ranged between 2.62 and 4.34 LogCFU/g. Aflatoxin B₁ contents were between 0.46 μg/kg and 84.84 μg/kg with 40% of samples exceeding the recommended limit of 5 μg/kg. Aflatoxins G₁ and G₂ levels were low in general with means values varying from 0.24 to 8.56 μg/kg, and 0.11 to 3.68 μg/kg, respectively. Fifty-two percent (52%) of samples analyzed contained total aflatoxins levels lower than the stipulated limit of 10 μg/kg, whereas 92% of them were contaminated at various levels with one type aflatoxin, B₁ or B₂, G₁ or G₂. This study provides the first information about the occurrence of aflatoxins in the common spices used in West Africa.

The study documented the first information about the occurrence of aflatoxins in the common spices used in West Africa. Around of 50% of samples investigated were contaminated by total aflatoxins with values higher than 10 µg/kg. So, there is a potential for sporadic aflatoxin poisoning related to the consumption of SAH powder as commercialized in Benin and other countries of West Africa region.

http://ift.tt/2E7bzl8

Biokinetics, dosimetry, and radiation risk in infants after 99m Tc-MAG3 scans

Abstract

Background

Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing ^99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data.

Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing ^99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool.

Results

The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of ^99mTc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified).

Conclusion

In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with ^99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the ^99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.

http://ift.tt/2EAdmx1