bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic endocrine‐like cells differentiated from human umbilical cords Wharton’s jelly mesenchymal stem cells using small molecules
Authors: Belame Shivakumar Sharath , Bharti Dinesh , Baregundi Subbarao Raghavendra , Park Ju‐Mi , Son Young‐Bum , Ullah Imran , Choe Yong‐Ho , Lee Hyeong‐Jeong , Park Bong‐Wook , Lee Sung‐Lim , Rho Gyu‐Jin
Published: October 2018

Following success of pancreatic islet transplantation in the treatment of Type I diabetes mellitus, there is a growing interest in using cell‐based treatment approaches. However, severe shortage of donor islets–pancreas impeded the growth, and made researchers to search for an alternative treatment approaches. In this context, recently, stem cell–based therapy has gained more attention. The current study demonstrated that epigenetic modification improves the in vitro differentiation of Wharton’s jelly mesenchymal stem cells (WJMSCs) into pancreatic endocrine‐like cells. Here we used two histone deacetylase (HDAC) inhibitors namely trichostatin A (TSA) and TMP269. TSA inhibits both class I and II HDACs whereas TMP269 inhibits only class IIa HDACs. WJMSCs were differentiated using a multistep protocol in a serum‐free condition with or without TSA pretreatment. A marginal improvement in differentiation was observed after TSA pretreatment though it was not significant. However, exposing endocrine precursor‐like cells derived from WJMSCs to TMP269 alone has significantly improved the differentiation toward insulin‐producing cells. Further, increase in the expression of paired box 4 (PAX4), insulin, somatostatin, glucose transporter 2 (GLUT2), MAF bZIP transcription factor A (MAFA), pancreatic duodenal homeobox 1 (PDX‐1), and NKX6.1 was observed both at messenger RNA and protein levels. Nevertheless, TMP269‐treated cells secreted higher insulin upon glucose challenge, and demonstrated increased dithizone staining. These findings suggest that TMP269 may improve the in vitro differentiation of WJMSCs into insulin‐producing cells.
Zic1 mRNA is transiently upregulated in subcutaneous fat of acutely cold‐exposed mice
Authors: Perugini Jessica , Bordoni Laura , Venema Wiebe , Acciarini Samantha , Cinti Saverio , Gabbianelli Rosita , Giordano Antonio
Published: October 2018

In the mammalian adipose organ cold exposure not only activates typical brown adipose tissue, but also induces browning, that is the formation of thermogenic multilocular adipocytes in white, or predominantly white, adipose depots such as subcutaneous fat. Unlike typical brown adipocytes, newly formed thermogenic adipocytes have been reported not to express the gene zinc finger of the cerebellum 1 (Zic1). Here, a time course approach enabled us to document a significant increase in
Zic1 messenger RNA in inguinal subcutaneous fat from acutely (24 hr) cold‐exposed mice, which was paralleled by an increase in multilocular and paucilocular uncoupling protein 1‐positive adipocytes and in parenchymal noradrenergic innervation. This transient, depot‐specific molecular signature was associated not to
Zic1 promoter demethylation, but to chromatin remodeling through an H3K9me3 histone modification. These findings challenge the notion that
Zic1 is exclusively expressed by typical brown adipocytes and suggest its involvement in brown adipocyte precursor differentiation and/or white‐to‐brown adipocyte transdifferentiation.
TRPM4 channel is involved in regulating epithelial to mesenchymal transition, migration, and invasion of prostate cancer cell lines
Authors: Sagredo Alfredo I. , Sagredo Eduardo A. , Pola Victor , Echeverría César , Andaur Rodrigo , Michea Luis , Stutzin Andrés , Simon Felipe , Marcelain Katherine , Armisén Ricardo
Published: October 2018

Transient Receptor Potential Melastatin 4 (TRPM4) is a Ca2+‐activated and voltage‐dependent monovalent cation channel, which depolarizes the plasma cell membrane, thereby modulating Ca2+ influx across Ca2+‐permeable pathways. TRPM4 is involved in different physiological processes such as T cell activation and the migration of endothelial and certain immune cells. Overexpression of this channel has been reported in various types of tumors including prostate cancer. In this study, a significant overexpression of TRPM4 was found only in samples from cancer with a Gleason score higher than 7, which are more likely to spread. To evaluate whether TRPM4 overexpression was related to the spreading capability of tumors, TRPM4 was knockdown by using shRNAs in PC3 prostate cancer cells and the effect on cellular migration and invasion was analyzed. PC3 cells with reduced levels of TRPM4 (shTRPM4) display a decrease of the migration/invasion capability. A reduction in the expression of Snail1, a canonical epithelial to mesenchymal transition (EMT) transcription factor, was also observed. Consistently, these cells showed a significant change in the expression of key EMT markers such as MMP9, E‐cadherin/N‐cadherin, and vimentin, indicating a partial reversion of the EMT process. Whereas, the overexpression of TRPM4 in LnCaP cells resulted in increased levels of Snail1, reduction in the expression of E‐cadherin and increase in their migration potential. This study suggests a new and indirect mechanism of regulation of migration/invasion process by TRPM4 in prostate cancer cells, by inducing the expression of Snail1 gene and consequently, increasing the EMT.
Review of management strategies for orthostatic hypotension in older people
Authors: Godbole Gauri P. , Aggarwal Bhavna
Published: October 2018

Orthostatic hypotension (OH) is common in older people and is associated with a range of adverse outcomes. Although age‐related changes like decreased baroreflex sensitivity make older people prone to OH, medications are often a contributor. Diagnosis of OH can be challenging in older people, because the condition may present with atypical or non‐specific symptoms, such as visual disturbances, shortness of breath, mental fluctuation. Non‐pharmacological management is often a starting point for OH treatment. Fludrocortisone and midodrine remain the most studied drugs for pharmacological management, but newer agents are being tested. In this review we present the current evidence for existing and emerging treatments for OH and address the management of supine hypertension associated with the treatment of OH in patients with autonomic failure. In the management of OH, it is imperative that treatment is tailored to the individual, rather than focusing on attaining an arbitrary blood pressure target.
Prosuming tourist information:Asking questions onTripAdvisor
Authors: Oriade Ade , Robinson Peter
Published: October 2018

This paper aims to improve our knowledge regarding types of queries raised by travellers on digital platforms by developing a model that helps in identifying and classifying such queries. Qualitative data collection and analysis of questions and answer postings of visitors on TripAdvisor forum of 10 U.K. destinations were used. Extracted data were analysed using NVivo11. Preliminary analysis identified basic themes in tourist information search. Further analysis indicated that two principal factors help in classifying online travel queries facilitating the development of the WOLF model. Findings in this study also indicate some practical implications and areas of further study.
In vitro metabolism of magnolol and honokiol in rat liver microsomes and their interactions with seven cytochrome P substrates
Authors: Huang Yu , Liu Chunming , Liu Shu , Liu Zhiqiang , Li Sainan , Wang Yueqi
Published: October 2018

Rationale

Magnolol and honokiol are the main active components of Magnolia officinalis Rehd. et Wils. The study of their interactions with liver microsomes is very important for the clinical safety of M. officinalis Rehd. et Wils.

Methods

The main metabolites of magnolol and honokiol in rat liver microsomes were investigated using ultrahigh‐performance liquid chromatography/mass spectrometry and their possible structures were identified. In addition, cytochrome P450 (CYP450) isoenzymes of the major rat metabolites of magnolol and honokiol were identified using a specific inhibitor.

Results

This study suggests that the CYP2E1 subtype is responsible for the oxidation of magnolol and honokiol terminal double bonds to epoxy metabolites. CYP3A4 appears to be the major subtype responsible for further hydrolytic metabolism, while CYP1A2 may promote decarboxylation of the metabolites. CYP2A6 may be the main subtype responsible for the hydrogenation of magnolol (p < 0.05).

Conclusions

This study demonstrated that different CYP450 enzyme isoforms showed different activities in the in vitro metabolism of magnolol and honokiol in rat liver microsomes. It has certain practical applications in that we should pay attention to drug–drug interactions in clinical medications and also to drug–enzyme interactions.
A modified Ant Colony Optimization algorithm to solve a dynamic traveling salesman problem: A case study with drones for wildlife surveillance
Authors: Chowdhury Sudipta , Marufuzzaman Mohammad , Tunc Huseyin , Bian Linkan , Bullington William
Published: October 2018

This study presents a novel Ant Colony Optimization (ACO) framework to solve a dynamic traveling salesman problem. To maintain diversity via transferring knowledge to the pheromone trails from previous environments, Adaptive Large Neighborhood Search (ALNS) based immigrant schemes have been developed and compared with existing ACO-based immigrant schemes available in the literature. Numerical results indicate that the proposed immigrant schemes can handle dynamic environments efficiently compared to other immigrant-based ACOs. Finally, a real life case study for wildlife surveillance (specifically, deer) by drones has been developed and solved using the proposed algorithm. Results indicate that the drone service capabilities can be significantly impacted when the dynamicity of deer are taken into consideration.

Highlights Proposed a novel ACO-ALNS based metaheuristic. Four variants of the proposed metaheuristic is developed to investigate the efficiency of each of them. A real life case study mirroring the behavior of DTSP is developed.
Properties of vapor-deposited and solution-processed targets for laser-driven inertial confinement fusion experiments
Authors: Harding D.R. , Bonino M.J. , Sweet W. , Schoff M. , Greenwood A. , Satoh N. , Takagi M. , Nikroo A.
Published: October 2018

Targets for low-adiabat direct-drive-implosion experiments on OMEGA must meet rigorous specifications and tight tolerances on the diameter, wall thickness, wall-thickness uniformity, and presence of surface features. Of these, restrictions on the size and number of defects (bumps and depressions) on the surface are the most challenging. The properties of targets that are made using vapor-deposition and solution-based microencapsulation techniques are reviewed.

Targets were characterized using confocal microscopy, bright- and dark-field microscopy, atomic force microscopy, electron microscopy, and interferometry. Each technique has merits and limitations, and a combination of these techniques is necessary to adequately characterize a target.

The main limitation with the glow-discharge polymerization (GDP) method for making targets is that it produces hundreds of domes with a lateral dimension of 0.7–2 μm. Polishing these targets reduces the size of some but not all domes, but it adds scratches and grooves to the surface. Solution-made polystyrene shells lack the dome features of GDP targets but have hundreds of submicrometer-size voids throughout the wall of the target; a few of these voids can be as large as ∼12 μm at the surface.
Sliding instability of draining fluid films
Authors: Dietze Georg F. , Picardo Jason R. , Narayanan R.
Published: October 2018

The aim of this paper is to show that the spontaneous sliding of drops forming from an interfacial instability on the surface of a wall-bounded fluid film is caused by a symmetry-breaking secondary instability. As an example, we consider a water film suspended from a ceiling that drains into drops due to the Rayleigh–Taylor instability. Loss of symmetry is observed after the film has attained a quasi-steady state, following the buckling of the thin residual film separating two drops, whereby two extremely thin secondary troughs are generated. Instability emanates from these secondary troughs, which are very sensitive to surface curvature perturbations because drainage there is dominated by capillary pressure gradients. We have performed two types of linear stability analysis. Firstly, applying the frozen-time approximation to the quasi-steady base state and assuming exponential temporal growth, we have identified a single, asymmetric, unstable eigenmode, constituting a concerted sliding motion of the large drops and secondary troughs. Secondly, applying transient stability analysis to the time-dependent base state, we have found that the latter is unstable at all times after the residual film has buckled, and that localized pulses at the secondary troughs are most effective in triggering the aforementioned sliding eigenmode. The onset of sliding is controlled by the level of ambient noise, but, in the range studied, always occurs in the quasi-steady regime of the base state. The sliding instability is also observed in a very thin gas film underneath a liquid layer, which we have checked for physical properties encountered underneath Leidenfrost drops. In contrast, adding Marangoni stresses to the problem substantially modifies the draining mechanism and can suppress the sliding instability.
Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction
Authors: Cheng Chun-Ting , Qi Yue , Wang Yi-Chang , Chi Kevin K. , Chung Yiyin , Ouyang Ching , Chen Yun-Ru , Oh Myung Eun , Sheng Xiangpeng , Tang Yulong , Liu Yun-Ru , Lin H. Helen , Kuo Ching-Ying , Schones Dustin , Vidal Christina M. , Chu Jenny C.-Y. , Wang Hung-Jung , Chen Yu-Han , Miller Kyle M. , Chu Peiguo , Yen Yun , Jiang Lei , Kung Hsing-Jien , Ann David K.
Published: October 2018

Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies.
High polarization degree of the continuum of comet 2P/Encke based on spectropolarimetric signals during its 2017 apparition
Authors: Kwon Y. G. , Ishiguro M. , Shinnaka Y. , Nakaoka T. , Kuroda D. , Hanayama H. , Takahashi J. , Baar S. , Saito T. , Kawabata M. , Uemura M. , Morokuma T. , Murata K. L. , Takagi S. , Morihana K. , Nagayama T. , Sekiguchi K. , Kawabata K. S. , Akitaya H.
Published: October 2018

Context.Spectropolarimetry is a powerful technique for investigating the physical properties of gas and solid materials in cometary comae without mutual contamination, but only a few spectropolarimetric studies have been conducted to extract each component.

Aims.We attempt to derive the continuum (i.e., scattered light from dust coma) polarization degree of comet 2P/Encke, free of the influence of molecular emissions. The target is unique in that its orbit is dynamically decoupled from Jupiter, like the main-belt asteroids, but it ejects gas and dust like ordinary comets.

Methods.We observed the comet using the Hiroshima Optical and Near-Infrared Camera attached to the Cassegrain focus of the 150 cm Kanata telescope on UT 2017 February 21 when the comet was at the solar phase angle ofα= 75°.7.

Results.We find that the continuum polarization degree with respect to the scattering plane isPcont, r= 33.8 ± 2.7% at the effective wavelength of 0.82μm, which is significantly higher than those of cometary dust in a high-Pmaxgroup at similar phase angles. Assuming that an ensemble polarimetric response of the dust of 2P/Encke as a function of phase angle is morphologically similar with those of other comets, its maximum polarization degree is estimated toPmax≳ 40% atαmax≈ 100°. In addition, we obtain the polarization degrees of the C2swan bands (0.51–0.56μm), the NH2αbands (0.62–0.69μm), and the CN-red system (0.78–0.94μm) in a range of 3–19%, which depend on the molecular species and rotational quantum numbers of each branch. The polarization vector is aligned nearly perpendicularly to the scattering plane with an average of 0°.4 over a wavelength range of 0.50–0.97μm.

Conclusions.From the observational evidence, we conjecture that the high polarization degree of 2P/Encke might be attributable to a dominance of large dust particles around the nucleus, which have remained after frequent perihelion passages near the Sun.
Eating for Taste and Eating for Change: Ethical Consumption as a High-Status Practice
Authors: Huddart Kennedy Emily , Baumann Shyon , Johnston Josée
Published: October 2018

Under what conditions is ethical consumption a high-status practice? Using unique food consumption survey data on aesthetic and ethical preferences, we investigate how these orientations to food are related. Existing research on high-status food consumption points to the “foodie,” who defines good taste through aesthetic standards. And emergent evidence suggests the “ethical consumer,” whose consumption is driven by moral principles, may also be a high-status food identity. However, ethical consumption can be practiced in inexpensive and subcultural ways that do not conform to dominant status hierarchies (e.g., freeganism). In order to understand the complex cultural terrain of high-status consumption, we investigate how socioeconomic status (SES) is related to foodie and ethical consumer preferences and practices. Using a k-means cluster analysis of intercept survey data from food shoppers in Toronto, we identify four distinct clusters representing foodies, ethical consumers, ethical foodies, and those whose preferences involve neither aesthetic nor ethical ideals. Through multinomial logistic regression, we find that while high-status consumers can be foodies or ethical consumers, the highest status consumers prioritize ethical and foodie preferences. Respondents’ reported shopping locations corroborate the results of the regression analyses. The taste preferences of the highest status consumers are associated with culinary sophistication and moral considerations, suggesting that high cultural capital tastes incorporate aesthetic and ethical dimensions. These results contribute to literature examining how food consumption repertoires can produce and reinforce classed boundaries and to literature on tastes that has focused on aesthetics to the neglect of ethical ideals.
Multicenter Analysis of Transport Destinations for Pediatric Prehospital Patients
Authors: Lerner E. Brooke , Studnek Jonathan R. , Fumo Nicole , Banerjee Anjishnu , Arapi Igli , Browne Lorin R. , Ostermayer Daniel G. , Reynolds Stacy , Shah Manish I.
Published: October 2018

Background

Although all emergency departments (EDs) should be ready to treat children, some may have illnesses or injuries that require higher‐level pediatric resources that are not available at all hospitals. There are no national guidelines for emergency medical services (EMS) providers about when to directly transport children to hospitals with higher‐level pediatric resources, with the exception of severe trauma. Variability exists in EMS protocols about when children warrant transport to hospitals with higher‐level pediatric care.

Objective

The objective was to determine how frequently pediatric patients are transported by EMS to hospitals with higher‐level pediatric resources and to evaluate distribution patterns based on illness and injury severity.

Methods

We conducted a retrospective analysis of all pediatric (age 0–18 years) transports in three large EMS systems between November 2014 and November 2016. Each community had a hospital with higher‐level pediatric resources that was within a 30‐minute transport time from any location. Patients were included if they were transported by ground ambulance and the request originated in the 9‐1‐1 system. We assessed the frequency of transports to a hospital with higher‐level pediatric resources. Data were stratified by chief complaint of illness or injury and severity. Potential risk for severe injury was defined as meeting the physiologic step of the field triage guidelines and potential risk for severe illness was defined as having an abnormal vital sign after adjusting for patient age.

Results

A total of 41,345 pediatric patients were transported by a participating EMS agency to an ED and had complete destination data. A total of 55% of all EMS‐transported pediatric patients were transported to a hospital with higher‐level pediatric resources. There was variation by site (range = 45%–71%) in the percentage of children who went to a hospital with higher‐level pediatric resources. Patients over 15 years of age went to general EDs (57%) more often than younger patients. When stratified by severity, 60% of those with potentially severe illness and 74% of those with potentially severe trauma were transported to a hospital with higher‐level pediatric resources.

Conclusions

EMS providers commonly transport children to hospitals with higher‐level pediatric resources. However, more than one‐quarter of children with potentially severe injuries and illnesses are transported to general EDs.
Long noncoding RNA MAPKAPK5‐AS1 promotes colorectal cancer proliferation by partly silencing p21 expression
Authors: Ji Hao , Hui Bingqing , Wang Jirong , Zhu Ya , Tang Lingyu , Peng Peng , Wang Tianjun , Wang Lijuan , Xu Shufeng , Li Juan , Wang Keming
Published: October 2018

Colorectal cancer (CRC) is the third most common malignancy in the world, and long noncoding RNA (lncRNA) plays a critical role in carcinogenesis. Here, we report a novel lncRNA, MAPKAPK5‐AS1, that acts as a critical oncogene in CRC. In addition, we attempted to explore the functions of MAPKAPK5‐AS1 on tumor progression in vitro and in vivo. Quantitative RT‐PCR was used to examine the expression of MAPKAPK5‐AS1 in CRC tissues and cells. Expression of MAPKAPK5‐AS1 was significantly upregulated in 50 CRC tissues, and increased expression of MAPKAPK5‐AS1 was found to be associated with greater tumor size and advanced pathological stage in CRC patients. Knockdown of MAPKAPK5‐AS1 significantly inhibited proliferation and caused apoptosis in CRC cells. We also found that p21 is a target of MAPKAPK5‐AS1. In addition, we are the first to report that MAPKAPK5‐AS1 plays a carcinogenic role in CRC. MAPKAPK5‐AS1 is a novel prognostic biomarker and a potential therapeutic candidate for CRC cancer.
Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma
Authors: Nakagawa Makoto , Fujita Shuhei , Katsumoto Takuo , Yamagata Kazutsune , Ogawara Yoko , Hattori Ayuna , Kagiyama Yuki , Honma Daisuke , Araki Kazushi , Inoue Tatsuya , Kato Ayako , Inaki Koichiro , Wada Chisa , Ono Yoshimasa , Yamamoto Masahide , Miura Osamu , Nakashima Yasuharu , Kitabayashi Issay
Published: October 2018

Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM.
Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
Authors: Harada Mayumi , Morikawa Masato , Ozawa Takayuki , Kobayashi Mai , Tamura Yusuke , Takahashi Kei , Tanabe Masahiko , Tada Keiichiro , Seto Yasuyuki , Miyazono Kohei , Koinuma Daizo
Published: October 2018

Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.
Vitamin D deficiency is associated with inferior survival of patients with extranodal natural killer/T‐cell lymphoma
Authors: Kim Seok Jin , Shu Cheng , Ryu Kyung Ju , Kang Danbee , Cho Juhee , Ko Young Hyeh , Lee Soo‐Youn , Guallar Eliseo , Zhao Weili , Kim Won Seog
Published: October 2018

Vitamin D deficiency is a common health issue; however, the effect of vitamin D deficiency on the survival of T‐cell lymphoma is still not clear. We evaluated the impact of serum vitamin D level of patients with peripheral T‐cell lymphoma (PTCL) and extranodal natural killer/T‐cell lymphoma (ENKTL) on survival outcome. Pretreatment levels of 25‐hydroxyvitamin D [25(OH)D] and inflammatory cytokines were measured in serum samples that were archived at diagnosis, and we evaluated their association with survival in newly diagnosed patients with PTCL (n = 137) and ENKTL (n = 114) at a university‐based hospital in Korea. An independent cohort from Rui Jin Hospital (Shanghai, China) was used for validation. The median 25(OH)D serum level was 12.0 ng/mL (1.3‐60.0 ng/mL), and 40% had less than 10 ng/mL, which was defined as vitamin D deficiency. Median serum 25(OH)D levels were similar between PTCL (11.5 ng/mL) and ENKTL (12.9 ng/mL); however, vitamin D deficiency was associated with inferior survival in ENKTL but not with PTCL. The independent validation cohort (n = 115) also showed a significant association of vitamin D deficiency with poor survival in ENKTL. The 25(OH)D level had an inverse relation with inflammatory cytokines; this association had a negative effect only on survival of ENKTL, and not on PTCL. In conclusion, vitamin D deficiency was associated with inferior survival outcome of patients with ENKTL.
WHO PAYS NO TAX? THE DECLINING FRACTION PAYING INCOME TAXES AND INCREASING TAX PROGRESSIVITY
Authors: Splinter David
Published: October 2018

Using federal individual income tax data, this paper presents the first long‐run estimates of the fraction paying no income tax. Between 1985 and 2015, the fraction of working age adults paying no tax increased from 20% to 36%. A decomposition shows that almost all of this increase resulted from changes in tax policy, especially from more generous tax credits. Increasing tax progressivity over the last three decades also resulted from more generous tax credits. The substantial federal tax changes enacted in 2017 are forecasted to temporarily increase both the fraction paying no tax and individual income tax progressivity. (JEL H22, H24, H31)
Long‐term comparative safety analysis of the risks associated with adding or switching to a sulfonylurea as second‐line Type 2 diabetes mellitus treatment in a US veteran population
Authors: Powell W. R. , Christiansen C. L. , Miller D. R.
Published: October 2018

Aim

To examine the risks of all‐cause mortality and cardiovascular events associated with adding vs switching to second‐line therapies in a comparative safety study of people with Type 2 diabetes mellitus.

Methods

We conducted a retrospective cohort study using an as‐treated analysis of people served by the Veterans Health Administration who were on metformin and subsequently augmented this treatment or switched to other oral glucose‐lowering treatments between 1998 and 2012. This study included 145 250 people with long follow‐up. Confounding was addressed through several strategies, involving weighted propensity score models with rich confounder adjustment and strict inclusion criteria, coupled with an incident‐user design.

Results

Second‐line use of sulfonylureas was related to higher mortality (hazard ratio 1.39, 95% CI 1.14, 1.70) and cardiovascular risks (hazard ratio 1.19, 95% CI 1.09, 1.30) compared with thiazolidinedione therapy. Differential hazards were associated with discontinuing or not discontinuing metformin; switching to sulfonylurea therapy was associated with a higher risk of all‐cause mortality and cardiovascular events compared with all other therapies. Furthermore, add‐on sulfonylurea therapy was associated with an elevated risk for both outcomes when compared with thiazolidinedione add‐on therapy.

Conclusions

The results of the present study may inform decisions on whether to augment or discontinue metformin; when considering the long‐term risks, switching to a sulfonylurea appears unfavourable compared with other therapies. Instead, adding a thiazolidinedione to existing metformin therapy appears to be superior to adding or switching to a sulfonylurea.
Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for youth with Type 2 diabetes: reliability and validity
Authors: Varni J. W. , Delamater A. M. , Hood K. K. , Raymond J. K. , Chang N. T. , Driscoll K. A. , Wong J. C. , Yi‐Frazier J. P. , Grishman E. K. , Faith M. A. , Corathers S. D. , Kichler J. C. , Miller J. L. , Doskey E. M. , Aguirre V. P. , Heffer R. W. , Wilson D. P. ,   the Pediatric Quality of Life Inventory 3.2 Diabetes Module Testing Study Consortium
Published: October 2018

Aim

To test the measurement properties of the revised and updated Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module originally developed in Type 1 diabetes in youth with Type 2 diabetes.

Methods

The PedsQL 3.2 Diabetes Module and PedsQL Generic Core Scales were administered in a field test study to 100 young people aged 9–25 years with Type 2 diabetes. Factor analysis was conducted to determine the factor structure of the items.

Results

The 15‐item Diabetes Symptoms Summary Score and 12‐item Type 2‐specific Diabetes Management Summary Score were empirically derived through factor analysis. The Diabetes Symptoms and Type 2‐specific Diabetes Management Summary Scores showed acceptable to excellent reliability across the age groups tested (α = 0.85–0.94). The Diabetes Symptoms and Type 2‐specific Diabetes Management Summary Scores evidenced construct validity through large effect size correlations with the Generic Core Scales Total Scale Score (r = 0.67 and 0.57, respectively). HbA1c was correlated with the Diabetes Symptoms and Type 2‐specific Diabetes Management Summary Scores (r = −0.13 and −0.22). Minimal clinically important difference (MCID) scores were 5.91 and 7.39 for the Diabetes Symptoms and Type 2‐specific Diabetes Management Summary Scores.

Conclusions

The PedsQL 3.2 Diabetes Module Diabetes Symptoms Summary Score and Type 2‐specific Diabetes Management Summary Score exhibited satisfactory measurement properties for use as youth self‐reported diabetes symptoms and diabetes management outcomes for clinical research and clinical practice for young people with Type 2 diabetes.
Long‐term evaluation of fitness and demographic effects of a Chinook Salmon supplementation program
Authors: Janowitz‐Koch Ilana , Rabe Craig , Kinzer Ryan , Nelson Doug , Hess Maureen A. , Narum Shawn R.
Published: October 2018

While the goal of supplementation programs is to provide positive, population‐level effects for species of conservation concern, these programs can also present an inherent fitness risk when captive‐born individuals are fully integrated into the natural population. In order to evaluate the long‐term effects of a supplementation program and estimate the demographic and phenotypic factors influencing the fitness of a threatened population of Chinook Salmon (Oncorhynchus tshawytscha), we genotyped tissue samples spanning a 19‐year period (1998–2016) to generate pedigrees from adult fish returning to Johnson Creek, Idaho, USA. We expanded upon previous estimates of relative reproductive success (RRS) to include grandparentage analyses and used generalized linear models to determine whether origin (hatchery or natural) or phenotypic traits (timing of arrival to spawning grounds, body length, and age) significantly predicted reproductive success (RS) across multiple years. Our results provide evidence that this supplementation program with 100% natural‐origin broodstock provided a long‐term demographic boost to the population (mean of 4.56 times in the first generation and mean of 2.52 times in the second generation). Overall, when spawning in nature, hatchery‐origin fish demonstrated a trend toward lower RS compared to natural‐origin fish (p < 0.05). However, when hatchery‐origin fish successfully spawned with natural‐origin fish, they had similar RS compared to natural by natural crosses (first‐generation mean hatchery by natural cross RRS = 1.11 females, 1.13 males; second‐generation mean hatchery by natural cross RRS = 1.03 females, 1.08 males). While origin, return year, and body length were significant predictors of fitness for both males and females (p < 0.05), return day was significant for males but not females (p > 0.05). These results indicate that supplementation programs that reduce the potential for genetic adaptation to captivity can be effective at increasing population abundance while limiting long‐term fitness effects on wild populations.
DCL‐suppressed Nicotiana benthamiana plants: valuable tools in research and biotechnology
Authors: Katsarou Konstantina , Mitta Eleni , Bardani Eirini , Oulas Anastasis , Dadami Elena , Kalantidis Kriton
Published: October 2018

Summary

RNA silencing is a universal mechanism involved in development, epigenetic modifications and responses to biotic and abiotic stresses. The major components of this mechanism are Dicer‐like (DCL), Argonaute (AGO) and RNA‐dependent RNA polymerase (RDR) proteins. Understanding the role of each component is of great scientific and agronomic importance. Plants, including Nicotiana benthamiana, an important plant model, usually possess four DCL proteins, each of which has a specific role, namely being responsible for the production of an exclusive small RNA population. Here, we used RNA interference (RNAi) technology to target DCL proteins and produced single and combinatorial mutants for DCL. We analysed the phenotype for each DCL knockdown plant, together with the small RNA profile, by next‐generation sequencing (NGS). We also investigated transgene expression, as well as viral infections, and were able to show that DCL suppression results in distinct developmental defects, changes in small RNA populations, increases in transgene expression and, finally, higher susceptibility in certain RNA viruses. Therefore, these plants are excellent tools for the following: (i) to study the role of DCL enzymes; (ii) to overexpress proteins of interest; and (iii) to understand the complex relationship between the plant silencing mechanism and biotic or abiotic stresses.
PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survival
Authors: Micevic Goran , Thakral Durga , McGeary Meaghan , Bosenberg Marcus W.
Published: October 2018

The aim of this study is to determine the significance of programmed death ligand 1 (PD‐L1 or CD274) methylation in relation to PD‐L1 expression and survival in melanoma. Despite the clinical importance of therapies targeting the PD‐1/PD‐L1 immune checkpoint in melanoma, factors regulating PD‐L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD‐L1 promoter methylation in relation to PD‐L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD‐L1 expression in melanoma, and we identify the key methylated CpG loci in the PD‐L1 promoter, establish PD‐L1 methylation as an independent survival prognostic factor, provide proof of concept for altering PD‐L1 expression by hypomethylating agents, and uncover that PD‐L1 methylation is associated with an interferon signaling transcriptional phenotype. Based on our findings, measuring and altering PD‐L1 promoter DNA methylation may have potential prognostic and therapeutic applications in melanoma.
Dialysate sodium concentration: The forgotten salt shaker
Authors: Hanafusa Norio , Tsuchiya Ken , Nitta Kosaku
Published: October 2018

The concentration of sodium in dialysis fluid, a major determinant of extracellular fluid volume and blood pressure, plays a major role in the sodium balance in end‐stage renal disease patients. A low dialysate sodium concentration (DNa) reduces interdialytic weight gain (IDWG) and blood pressure and might help ameliorate endothelial dysfunction and inflammation. However, low DNa can also increase the incidence of hypotensive episodes and muscle cramps. Sodium profiling, as typically prescribed in which the DNa is ramped up from above 140 mEq/L to nonphysiological levels, might reduce hypotension in patients with hemodynamic instability but at the cost of the consequences of hypernatremia. Serum sodium concentrations of individual patients fall within a narrow range around a “sodium setpoint.” The sodium gradient, the difference between the sodium set point and the DNa, is associated more robustly with clinical outcomes than DNa itself. Sodium concentration presents several issues: the influence of the net negative charge of plasma proteins on sodium flux across the dialysis membrane (Donnan equilibrium); and the clinically important problems in measuring sodium levels. This article presents a review of the clinical effects of DNa and of basic aspects of sodium balance in hemodialysis patients.
Hemostatic profile under fluid resuscitation during rivaroxaban anticoagulation: an in vitro survey
Authors: Helin Tuukka A. , Zuurveld Marleen , Manninen Mikko , Meijers Joost C. M. , Lassila Riitta , Brinkman Herm Jan M.
Published: October 2018

BACKGROUND

Uncontrollable bleeding is the leading cause of death in traumatically injured patients. The extent to which direct factor Xa inhibitors interfere with the applied resuscitation measures is presently unknown.

STUDY DESIGN AND METHODS

In this study, we investigated the effect of the resuscitation fluids saline, albumin, fresh frozen plasma (FFP) and solvent/detergent (S/D)‐treated plasma, fibrinogen concentrate, prothrombin complex concentrate (PCC), and combinations thereof on the hemostatic profile of rivaroxaban‐anticoagulated whole blood and plasma. We used rivaroxaban‐spiked whole blood and plasma from healthy donors, as well as plasma from patients on rivaroxaban, and mimicked a resuscitation approach in a 50% plasma dilution setting. Thromboelastography, thrombin generation, and fibrin generation clot lysis test were assessed using tissue factor to initiate coagulation and tissue plasminogen activator to induce clot lysis.

RESULTS

Rivaroxaban resulted in a hypocoagulant state that remained largely unaltered upon subsequent 50% dilution with S/D‐treated plasma or FFP. Using S/D‐treated plasma as a diluent, clot stability decreased due to its low α2‐antiplasmin. Dilution with saline and albumin induced a profibrinolytic state and further deteriorated the impaired hemostatic potential of rivaroxaban‐anticoagulated blood, even after PCC and fibrinogen support. Combined use of plasma (either FFP or S/D treated) and PCC, however, considerably improved both coagulation and clot stability.

CONCLUSION

In the setting of rivaroxaban anticoagulation and major blood loss, transfusing plasma together with PCC may provide the most effective resuscitation approach with the notion that additional antifibrinolytic drug support (e.g., tranexamic acid) is likely required.
Spontaneous renal artery dissection masquerading as urinary tract infection
Authors: Chamarthi Gajapathiraju , Koratala Abhilash , Ruchi Rupam
Published: October 2018

Spontaneous renal artery dissection is a rare clinical entity, and symptoms vary from non-specific abdominal pain to life-threatening hypertension. A 44-year-old woman with no significant medical history initially presented with symptoms suggestive of urinary tract infection which did not respond to antibiotic therapy. Imaging revealed right renal infarction resulting from focal spontaneous renal artery dissection, which was managed conservatively. CT angiography is the preferred imaging modality for the diagnosis of this condition. Treatment options include medical management of hypertension with or without anticoagulation, endovascular intervention and surgical revascularisation depending on the presentation and the extent of the vascular and renal parenchymal involvement. This case emphasises the need to have high index of suspicion for uncommon diagnoses in patients who present with common symptoms but do not respond to empiric therapy.
Coronary artery ectasia in Crohn’s disease
Authors: Korovesis Theofanis , Katritsis George , Koudounis Panagiotis , Zografos Theodoros
Published: October 2018

Coronary artery ectasia (CAE) can be ascribed, in the majority of cases, to coronary atherosclerosis. Nevertheless, the presence of isolated ectatic lesions without obstructive coronary artery disease and the association of CAE with several autoimmune diseases characterised by systemic vascular involvement suggest that the pathogenesis of CAE may extend beyond coronary atherosclerosis. We herein report the case of a 56-year-old male patient with Crohn’s disease and isolated CAE, who has been found positive for IgM and IgA antiendothelial cell antibodies, and discuss a potential pathogenic mechanism.
Baerveldt-XEN persistent proximal occlusion: solving new problems with old answers
Authors: Teixeira Filipa , Caiado Filipa , Sens Paula , Abegão Pinto Luis
Published: October 2018

A 51-year-old woman was referred with uncontrolled intraocular pressure (IOP) despite maximal medical IOP-lowering therapy. Her background included several failed glaucoma filtering surgeries, including aqueous drainage devices. Considering the need to perform surgery in a patient with both scarred conjunctiva and corneal endothelial deficiency, a surgical technique combining cornea-friendly XEN stent connected to a large-plate Baerveldt glaucoma implant was undertaken. Unfortunately, XEN implants obstructed twice during the early postoperative period. As further XEN replacements were unfeasible, there was the need to bridge the gap between the Baerveldt tube and the anterior chamber. An easy accessible, cheap 22G angiocatheter segment was used for this purpose. With a follow-up of 6 months, there were no postoperative complications nor loss of efficiency, with IOP of 7 mmHg. Tube extension using angiocatheter is a viable, cost-effective option in these difficult cases, saving the surgeon from having to explant and replace the entire implant.
Appraising the quality standard underpinning international clinical practice guidelines for the selection and care of vascular access devices: a systematic review of reviews
Authors: Blanco-Mavillard Ian , Rodríguez-Calero Miguel Angel , Castro-Sánchez Enrique , Bennasar-Veny Miquel , De Pedro-Gómez Joan
Published: October 2018

Objective

Catheter-related bloodstream infections are one of the most important adverse events for patients. Evidence-based practice embraces interventions to prevent and reduce catheter-related bloodstream infections in patients. At present, a growing number of guidelines exist worldwide. The purpose of the study was to assess clinical practice guidelines for peripheral and central venous access device care and prevention of related complications.

Design

Systematic review of clinical practice guidelines: We conducted a search of the literature published from 2005 to 2018 using Medline/PubMed, Embase, CINAHL, Ovid, ScienceDirect, Scopus and Web of Science. We also evaluated grey literature sources and websites of organisations that compiled or produced guidelines. Guideline quality was assessed with the Appraisal of Guidelines for Research and Evaluation, Second Edition tool by three independent reviewers. Cohen’s kappa coefficient was used to evaluate the concordance between reviewers.

Results

We included seven guidelines in the evaluation. The concordance between observers was substantial, K=0.6364 (95% CI 0.0247 to 1.2259). We identified seven international guidelines, which scored poorly on crucial domains such as applicability (medium 39%), stakeholder involvement (medium 65%) and methodological rigour (medium 67%). Guidelines by Spanish Health Ministry and UK National Institute for Health and Care Excellence presented the highest quality.

Conclusions

It is crucial to critically evaluate the validity and reliability of clinical practice guidelines so the best, most context-specific document is selected. Such choice is a necessary prior step to encourage and support health organisations to transfer research results to clinical practice. The gaps identified in our study may explain the suboptimal clinical impact of guidelines. Such low adoption may be mitigated with the use of implementation guides accompanying clinical documents.