bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular insights into melanoma brain metastases
Authors: Westphal Dana , Glitza Oliva Isabella C. , Niessner Heike
Published: May 2017

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune‐checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain‐specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163‐75. © 2017 American Cancer Society.
After a treatment breakthrough—progress, plateaus, and raising the bar
Authors: Margolin Kim A.
Published: May 2017

Although coverage of the new science of melanoma and its therapy has been extensive in the medical and scientific literature, this special issue of Cancer assembles several important contributions from leaders in the field of melanoma biology and therapy to educate and update readers concerning recent advances and expert thinking, which should be both informative and thought‐provoking.
Study of retinal neurodegeneration and maculopathy in diabetic Meriones shawi: A particular animal model with human‐like macula
Authors: Hammoum Imane , Benlarbi Maha , Dellaa Ahmed , Szabó Klaudia , Dékány Bulcsú , Csaba Dávid , Almási Zsuzsanna , Hajdú Rozina I. , Azaiz Rached , Charfeddine Ridha , Lukáts Ákos , Ben Chaouacha‐Chekir Rafika
Published: May 2017

The purpose of this work was to evaluate a potentially useful animal model, Meriones shawi (M.sh)—developing metabolic X syndrome, diabetes and possessing a visual streak similar to human macula—in the study of diabetic retinopathy and diabetic macular edema (DME). Type 2 diabetes (T2D) was induced by high fat diet administration in M.sh. Body weights, blood glucose levels were monitored throughout the study. Diabetic retinal histopathology was evaluated 3 and 7 months after diabetes induction. Retinal thickness was measured, retinal cell types were labeled by immunohistochemistry and the number of stained elements were quantified. Apoptosis was determined with TUNEL assay. T2D induced progressive changes in retinal histology. A significant decrease of retinal thickness and glial reactivity was observed without an increase in apoptosis rate. Photoreceptor outer segment degeneration was evident, with a significant decrease in the number of all cones and M‐cone subtype, but—surprisingly—an increase in S‐cones. Damage of the pigment epithelium was also confirmed. A decrease in the number and labeling intensity of parvalbumin‐ and calretinin‐positive amacrine cells and a loss of ganglion cells was detected. Other cell types showed no evident alterations. No DME‐like condition was noticed even after 7 months. M.sh could be a useful model to study the evolution of diabetic retinal pathology and to identify the role of hypertension and dyslipidemia in the development of the reported alterations. Longer follow up would be needed to evaluate the potential use of the visual streak in modeling human macular diseases.
Modulation of Wetting Gradients by Tuning the Interplay between Surface Structuration and Anisotropic Molecular Layers with Bipolar Electrochemistry
Authors: Bouffier Laurent , Reculusa Stéphane , Ravaine Valérie , Kuhn Alexander
Published: May 2017

A new simple and versatile method for the preparation of surface‐wetting gradients is proposed. It is based on the combination of electrode surface structuration introduced by a sacrificial template approach and the formation of a tunable molecular gradient by bipolar electrochemistry. The gradient involves the formation of a self‐assembled monolayer on a gold surface by selecting an appropriate thiol molecule and subsequent reductive desorption by means of bipolar electrochemistry. Under these conditions, completion of the reductive desorption process evolves along the bipolar surface with a maximum strength localized at the cathodic edge and a decreasing driving force towards the middle of the surface. The remaining quantity of surface‐immobilized thiol, therefore, varies as a function of the axial position, resulting in the formation of a molecular gradient. The surface of the bipolar electrode is characterized at each step of the modification by recording heterogeneous electron transfer. Also, the evolution of static contact angles measured with a water droplet deposited on the surface directly reveals the presence of the wetting gradient, which can be modulated by changing the properties of the thiol. This is exemplified with a long, hydrophobic alkane–thiol and a short, hydrophilic mercaptan.
Phenotypic assays for Mycobacterium tuberculosis infection
Authors: Song Ok‐Ryul , Deboosere Nathalie , Delorme Vincent , Queval Christophe J. , Deloison Gaspard , Werkmeister Elisabeth , Lafont Frank , Baulard Alain , Iantomasi Raffaella , Brodin Priscille
Published: May 2017

Tuberculosis (TB) is still a major global threat, killing more than one million persons each year. With the constant increase of Mycobacterium tuberculosis strains resistant to first‐ and second‐line drugs, there is an urgent need for the development of new drugs to control the propagation of TB. Although screenings of small molecules on axenic M. tuberculosis cultures were successful for the identification of novel putative anti‐TB drugs, new drugs in the development pipeline remains scarce. Host‐directed therapy may represent an alternative for drug development against TB. Indeed, M. tuberculosis has multiple specific interactions within host phagocytes, which may be targeted by small molecules. In order to enable drug discovery strategies against microbes residing within host macrophages, we developed multiple fluorescence‐based HT/CS phenotypic assays monitoring the intracellular replication of M. tuberculosis as well as its intracellular trafficking. What we propose here is a population‐based, multi‐parametric analysis pipeline that can be used to monitor the intracellular fate of M. tuberculosis and the dynamics of cellular events such as phagosomal maturation (acidification and permeabilization), zinc poisoning system or lipid body accumulation. Such analysis allows the quantification of biological events considering the host‐pathogen interplay and may thus be derived to other intracellular pathogens. © 2017 International Society for Advancement of Cytometry
Atypical adenoma of the thyroid diagnosed as anaplastic cancer by cytopathology
Authors: Hatakeyama Hiromitsu , Hoshino Kimiko , Mizoguchi Kenji , Suzuki Takayoshi , Hatanaka Kanako C. , Yamaya Yukie , Kano Satoshi , Mizumachi Takatsugu , Homma Akihiro
Published: May 2017

Atypical adenoma of the thyroid is a rare form of tumor, and its accurate diagnosis prior to surgical resection is difficult as the histological and pathological morphologies are very similar to those of anaplastic thyroid carcinoma (ATC), and its anaplastic transformation remains to be elucidated. We reported a case of a 75‐year‐old female with a thyroid isthmus nodule diagnosed repeatedly by FNAC as anaplastic carcinoma. Both the first and second FNAC specimen slides showed a large number of scattered or aggregated atypical cells consisting of large, pleomorphic nuclei with irregular membranes, chromatin clumps and prominent nucleoli. The morphology of the surgical specimen was similar to that of an anaplastic carcinoma and although it showed signs of transition from a normal follicular epithelium, there was no invasive growth or mitosis. This lesion was diagnosed as an atypical adenoma, and a papillary carcinoma was also present in the right lobe of the thyroid. Here we evaluate the molecular features of atypical adenomas in comparison with 9 ATC samples, and discuss whether or not atypical adenomas represent a form of premalignant lesion. Ki‐67 expression was found to be very low in atypical adenomas whereas all ATC samples showed high levels of Ki‐67 expression. Epithelial–mesenchymal transition (EMT) marker expression suggested that atypical adenomas maintain their epithelial phenotype to a higher degree than do ATCs. Differential diagnosis between ATC and atypical adenoma is difficult by cytological and histological methods alone, and Ki‐67 and EMT marker expression may support the diagnosis.
Clinical heterogeneity of type 1 diabetes (T1D) found in Asia
Authors: Park Yongsoo , Wintergerst Kupper A. , Zhou Zhiguang
Published: May 2017

Diabetes mellitus among young patients in Asia is caused by a complex set of factors. Although type 1 diabetes (T1D) remains the most common form of diabetes in children, the recent unabated increase in obesity has resulted in the emergence of type 2 diabetes (T2D) as a new type of diabetes among adolescents and young adults. In addition to the typical autoimmune type 1 diabetes (T1aD) and T2D patients, there is a variable incidence of cases of non‐autoimmune types of T1D associated with insulin deficiency (T1bD). Additional forms have been described, including fulminant T1D (FT1D). Although most diagnoses of T1D are classified as T1aD, fulminant T1D exists as a hyper‐acute subtype of T1D that affects older children, without associated autoimmunity. Patient with this rare aetiology of diabetes showed a complete loss of β‐cell secretory capacity without evidence of recovery, necessitating long‐term treatment with insulin. In addition, latent autoimmune diabetes in adults is a form of autoimmune‐mediated diabetes, usually diagnosed during the insulin‐dependent stage that follows a non‐insulin requiring phase, which can be diagnosed earlier based on anti‐islet autoantibody positivity. Some reports discuss T1bD. Others are elaborating on the presence of “atypical T1b diabetes,” such as Flatbush diabetes. The prevalence of diabetes mellitus in young adults continues to rise in Asian populations as T2D increases. With improved characterization of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future. Distinguishing T1D, T2D, and other forms of diabetes in young patients is challenging in Asian populations, as the correct diagnosis is clinically important and has implications for prognosis and management. Despite aetiological heterogeneity in the usual clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds as well as measuring islet autoantibodies and fasting plasma C‐peptide could provide a possible viable method to minimize complications.
Fatal intoxication by 5F–ADB and diphenidine: Detection, quantification, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q‐TOFMS
Authors: Kusano Maiko , Zaitsu Kei , Taki Kentaro , Hisatsune Kazuaki , Nakajima Jun'ichi , Moriyasu Takako , Asano Tomomi , Hayashi Yumi , Tsuchihashi Hitoshi , Ishii Akira
Published: May 2017

Despite the implementation of a new blanket scheduling system in 2013, new psychoactive substance (NPS) abuse remains a serious social concern in Japan. We present a fatal intoxication case involving 5F–ADB (methyl 2‐[1‐(5‐fluoropentyl)‐1H–indazole‐3‐carboxamido]‐3,3‐dimethylbutanoate) and diphenidine. Postmortem blood screening by liquid chromatography/quadrupole time‐of‐flight mass spectrometry (LC/Q‐TOFMS) in the information‐dependent acquisition mode only detected diphenidine. Further urinary screening using an in‐house database containing NPS and metabolites detected not only diphenidine but also possible 5F–ADB metabolites; subsequent targeted screening by LC/tandem mass spectrometry (LC/MS/MS) allowed for the detection of a very low level of unchanged 5F–ADB in postmortem heart blood. Quantification by standard addition resulted in the postmortem blood concentrations being 0.19 ± 0.04 ng/mL for 5F–ADB and 12 ± 2.6 ng/mL for diphenidine. Investigation of the urinary metabolites revealed pathways involving ester hydrolysis (M1) and oxidative defluorination (M2), and further oxidation to the carboxylic acid (M3) for 5F–ADB. Mono‐ and di‐hydroxylated diphenidine metabolites were also found. The present case demonstrates the importance of urinary metabolite screening for drugs with low blood concentration. Synthetic cannabinoids (SCs) fluorinated at the terminal N‐alkyl position are known to show higher cannabinoid receptor affinity relative to their non‐fluorinated analogues; 5F–ADB is no exception with high CB1 receptor activity and much greater potency than Δ9‐THC and other earlier SCs, thus we suspect its acute toxicity to be high compared to other structurally related SC analogues. The low blood concentration of 5F–ADB may be attributed to enzymatic and/or non‐enzymatic degradation, and further investigation into these possibilities is underway.
The most common diet results in low reproduction in a generalist seabird
Authors: van Donk Susanne , Camphuysen Kees C. J. , Shamoun‐Baranes Judy , van der Meer Jaap
Published: May 2017

Dietary specialization has been described across a wide range of taxa in the animal kingdom. Fitness consequences are, however, not well documented. We examined the reproductive consequences of different dietary specializations in the herring gull Larus argentatus, an omnivorous seabird, using an extensive dataset which includes breeding and dietary data of 10 successive years. We hypothesized that pairs that focused on prey of higher energetic value would yield higher fledging rates. An alternative hypothesis is that pairs that relied on more resources simultaneously would reproduce better. The novelty of this study is that we used continuous measurements representing dietary composition and degree of specialization rather than restricting our analysis to predefined categories. By relating these two continuous measurements for diet to several proxies for reproductive success, we show clear consequences of dietary choice. Most pairs concentrated on bivalves, a prey type not particularly rich in energy. Pairs feeding on energy‐rich prey (e.g., “domestic refuse and fishery discards”) during chick rearing were found to have a higher reproductive success, supporting the first hypothesis. Pairs that used more resources did not clearly have a higher reproductive success. The majority of the pairs did not switch to energy‐rich prey during chick rearing, despite low breeding outcome. We discuss how trade‐offs between factors such as resource availability, predictability, and the time and energy needed to obtain certain prey species may influence resource selection.
Heart Failure Virtual Consultation: bridging the gap of heart failure care in the community ‐ A mixed‐methods evaluation
Authors: Gallagher Joseph , James Stephanie , Keane Ciara , Fitzgerald Annie , Travers Bronagh , Quigley Etain , Hecht Christina , Zhou Shuaiwei , Watson Chris , Ledwidge Mark , McDonald Kenneth
Published: May 2017

Aims

We undertook a mixed‐methods evaluation of a Web‐based conferencing service (virtual consult) between general practitioners (GPs) and cardiologists in managing patients with heart failure in the community to determine its effect on use of specialist heart failure services and acceptability to GPs.

Methods and results

All cases from June 2015 to October 2016 were recorded using a standardized recording template, which recorded patient demographics, medical history, medications, and outcome of the virtual consult for each case. Quantitative surveys and qualitative interviewing of 17 participating GPs were also undertaken. During this time, 142 cases were discussed—68 relating to a new diagnosis of heart failure, 53 relating to emerging deterioration in a known heart failure patient, and 21 relating to therapeutic issues. Only 17% required review in outpatient department following the virtual consultation. GPs reported increased confidence in heart failure management, a broadening of their knowledge base, and a perception of overall better patient outcomes.

Conclusions

These data from an initial experience with Heart Failure Virtual Consultation present a very positive impact of this strategy on the provision of heart failure care in the community and acceptability to users. Further research on the implementation and expansion of this strategy is warranted.
A Diamino Alcohol Catalyzed Enantioselective Crossed Aldol Reaction of Acetaldehyde with Isatins – A Concise Total Synthesis of Antitumor Agents
Authors: Subba Reddy Ummareddy Venkata , Chennapuram Madhu , Seki Kento , Seki Chigusa , Anusha Bheemreddy , Kwon Eunsang , Okuyama Yuko , Uwai Koji , Tokiwa Michio , Takeshita Mitsuhiro , Nakano Hiroto
Published: May 2017

Enantioselective crossed aldol reactions of isatin derivatives and acetaldehyde have been developed with a series of simple diamino alcohol catalysts to afford 3‐substituted 3‐hydroxyindolin‐2‐ones in high chemical yields (up to 95 %) and optical purities (up to 92 % ee). The synthetic potential of the present protocol has been demonstrated by concise, enantioselective, protecting‐group‐free, and transition metal‐free total syntheses of antitumor and antiviral agents with the tryptanthrin architecture, that is, phaitanthrin B and cephalanthrin A, along with the biologically active indolidine alkaloids chimonamidine and donaxaridine as well as the formal synthesis of CPC‐1. The highly enantioselective outcome of this catalytic crossed aldol reaction was evaluated by calculating the Gibbs free energies of the possible transition states.
The empowering effect of punishment on forgiveness
Authors: Strelan Peter , Di Fiore Carolyn , Prooijen Jan‐Willem Van
Published: May 2017

We examined the process by which punishment enables forgiveness, testing the proposition that punishment restores a sense of justice to victims, an experience that is empowering. In Study 1 (N = 69), university students received insulting feedback and were given the opportunity (or not) to sanction the offender. In Study 2 (N = 91), participants imagined having the opportunity (or not) to recommend punishment for a person who had vandalized their house. A two‐step mediation model (punishment justice restoration empowerment forgiveness) was supported in these two studies. In Study 3 (N = 227), punishment options were expanded to test the role of victim voice in the context of third‐party and personal retributive and restorative justice responses to workplace bullying, as well as taking into account revenge as an alternative to justice restoration. When victims had voice, empowerment again played a central indirect role in relations between punishment and forgiveness.
Ratiometric fluorescent l‐arginine and l‐asparagine biosensors based on the oxazine 170 perchlorate‐ethyl cellulose membrane
Authors: An Kido , Duong Hong Dinh , Rhee Jong Il
Published: May 2017

Ratiometric fluorescent l‐arginine (Arg) and l‐asparagine (Asn) biosensors were developed using an oxazine 170 perchlorate (O17) ethyl cellulose (EC) membrane and the enzymes entrapped into the matrix of EC and hydrogel polyurethane. The sensing principles were based on the hydrolysis reactions of urea and l‐Arg under the catalysis of the urease and arginase to produce ammonia in the case of an l‐Arg‐sensing membrane and also on the hydrolysis reaction of l‐Asn under the catalysis of asparaginase in the case of an l‐Asn‐sensing membrane. The O17‐EC membrane reacted with the ammonia produced from the hydrolysis reactions and changed the fluorescence intensities at λem = 565 and 625 nm. The ratio of the fluorescence intensities at λem = 565 and 625 nm was proportional to the concentrations of l‐Arg or l‐Asn in the range of 0.1–10 mM. The LOD of the l‐Arg‐ and l‐Asn‐sensing membranes was 0.082 ± 0.0014 and 0.074 ± 0.0023 mM, respectively. The sensing membranes also showed good quality in terms of response time, reversibility, and stability. The interference study demonstrated that some components such as amino acids had little negative effects on the performance of the sensing membranes for the detection of l‐Arg and l‐Asn. These simple and sensitive ratiometric fluorescent sensing membranes provide a basic or comprehensive method for detecting l‐Arg and l‐Asn in blood and urine samples as well as in the fermentation processes.
Creating accessible admissions portal improves experience for all
Authors: Sutton Halley
Published: May 2017

MINNEAPOLIS — In 2015, the University of Colorado at Boulder received a letter from the Department of Justice stating the institution was out of compliance with the Americans with Disabilities Act and citing a list of items to be adjusted, or the institution would face consequences. It was a huge wake‐up call for the university and forced some much‐needed change. In a session at the annual American Association of Collegiate Registrars and Admissions Officers conference, Dustin Moody, assistant director of communications and technology at CU Boulder, shared lessons learned from the experience of updating the institution's technology to achieve ADA compliance. Read on for ways to determine whether your admissions and recruiting webpages are in compliance with the ADA.
Define and reward valued behaviors
Authors: Edmonds S. Chris
Published: May 2017

The material on this page is adapted from the article “Building a Positive, Purposeful, Productive Culture,” published in the Spring 2017 issue of Leader to Leader.
Updated species sensitivity distribution evaluations for acute and chronic lead toxicity to saltwater aquatic life
Authors: Church Brian G. , Van Sprang Patrick A. , Chowdhury M. Jasim , DeForest David K.
Published: May 2017

The US Environmental Protection Agency's (USEPA's) ambient water quality criteria (AWQC) for lead (Pb) in salt water were developed in 1984. The acute and chronic criteria are 210 and 8.1 μg/L dissolved Pb, respectively. Because data were limited in 1984, the chronic criterion was derived using an acute-to-chronic ratio, but there are now sufficient toxicity data such that an acute-to-chronic ratio is no longer needed. Based on the data now available, the proposed updated acute and chronic salt water Pb AWQC (following USEPA methods) are 100 and 10 µg/L, respectively. In the European Union, a chronic salt water predicted no-effect concentration based on the median 5th percentile hazardous concentration (HC5–50) was developed in 2008 for the Registration, Evaluation, Authorisation, and Restriction of Chemicals program, which forms the basis for deriving chronic environmental quality standards for Pb in European marine waters. The salt water HC5–50 previously derived for Pb was 6.1 μg/L, whereas the proposed, updated chronic salt water HC5–50 derived following European Union methods is 11.0 µg/L. Thus, despite differences in derivation methodologies, the proposed AWQC and HC5–50 values are very consistent. Studies evaluating the effect of water quality factors on bioavailability and toxicity of Pb in salt water are limited; the effect of water quality on Pb toxicity in salt water should be considered in future studies. Environ Toxicol Chem 2017;36:2974–2980. © 2017 SETAC
Periphyton uptake and trophic transfer of coal fly-ash–derived trace elements
Authors: Scheibener Shane A. , Rivera Nelson A. , Hesterberg Dean , Duckworth Owen W. , Buchwalter David B.
Published: May 2017

To determine whether the bioavailability of trace elements derived from coal ash leachates varies with the geochemical conditions associated with their formation, we quantified periphyton bioaccumulation and subsequent trophic transfer to the mayfly Neocloeon triangulifer. Oxic ash incubations favored periphyton uptake of arsenic, selenium, strontium, and manganese, whereas anoxic incubations favored periphyton uptake of uranium. Mayfly enrichment was strongest for selenium, whereas biodilution was observed for strontium, uranium, and arsenic. Environ Toxicol Chem 2017;36:2991–2996. © 2017 SETAC
Mysterious Cost of Capital for Energy Utilities
Authors: Makholm Jeff D.
Published: May 2017

No modern energy utility in the world goes for long without a “rate case” or “formula review” designed to produce a set of approved charges for their regulated services.
Pharmacokinetics and pharmacodynamics modeling of lonafarnib in patients with chronic hepatitis delta virus infection
Authors: Canini Laetitia , Koh Christopher , Cotler Scott J. , Uprichard Susan L. , Winters Mark A. , Han Ma Ai Thanda , Kleiner David E. , Idilman Ramazan , Yurdaydin Cihan , Glenn Jeffrey S. , Heller Theo , Dahari Harel
Published: May 2017

The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF‐PK model predicted average steady‐state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate ka = 0.43/hour and elimination rate ke = 0.045/hour. The PK/PD model identified an average delay of 0.56 hours and an LNF concentration that decreases HDV production by 50%, EC50 = 227 ng/mL, with a Hill factor h = 1.48. The HDV half‐life in blood was 1.87 days, and the average steady‐state LNF efficacy in blocking HDV production was ɛ = 87.7% for group 1 and ɛ = 95.2% for group 2. A biphasic HDV decline with an average phase 1 decline (0.9 log10 IU/mL and 1.32 log10 IU/mL) was observed in groups 1 and 2, respectively. Phase 2 was not significantly (P = 0.94) different between the two groups, with an average slope of –0.06 log IU/mL/day. The model suggests an LNF dose of ∼610 mg bid would achieve ɛ = 99%. Conclusion: The first PK/PD modeling study in patients with chronic HDV indicates that a ∼3‐fold increase in LNF dose (∼610 mg bid) would achieve 99% antiviral efficacy. A ritonavir‐boosted LNF combination may provide a means to increase LNF efficacy with minimal side effects. The modeling findings provide an important advance in understanding HDV dynamics and the basis to optimize LNF therapy for hepatitis D. (Hepatology Communications 2017;1:288–292)
Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study
Authors: Duell Eric J. , Lujan‐Barroso Leila , Sala Núria , Deitz McElyea Samantha , Overvad Kim , Tjonneland Anne , Olsen Anja , Weiderpass Elisabete , Busund Lill‐Tove , Moi Line , Muller David , Vineis Paolo , Aune Dagfinn , Matullo Giuseppe , Naccarati Alessio , Panico Salvatore , Tagliabue Giovanna , Tumino Rosario , Palli Domenico , Kaaks Rudolf , Katzke Verena A. , Boeing Heiner , Bueno‐de‐Mesquita H. B(as) , Peeters Petra H. , Trichopoulou Antonia , Lagiou Pagona , Kotanidou Anastasia , Travis Ruth C. , Wareham Nick , Khaw Kay‐Tee , Ramon Quiros Jose , Rodríguez‐Barranco Miguel , Dorronsoro Miren , Chirlaque María‐Dolores , Ardanaz Eva , Severi Gianluca , Boutron‐Ruault Marie‐Christine , Rebours Vinciane , Brennan Paul , Gunter Marc , Scelo Ghislaine , Cote Greg , Sherman Stuart , Korc Murray
Published: May 2017

Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case‐control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR‐10a, ‐10b, ‐21‐3p, ‐21‐5p, ‐30c, ‐106b, ‐155 and ‐212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT‐PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR‐10b, ‐21‐5p, ‐30c and ‐106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p‐values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR‐10a, ‐10b, ‐21‐5p, ‐30c, ‐155 and ‐212) overall, and for four miRs (‐10a, ‐10b, ‐21‐5p and ‐30c) at shorter follow‐up time between blood collection and diagnosis (≤5 yr, ≤2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose‐response trend with risk (p‐value = 0.0006). For shorter follow‐up (≤5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR‐212) to 0.79 (miR‐21‐5p).
Benefits and harms of breast cancer screening with mammography in women aged 40–49 years: A systematic review
Authors: van den Ende Caroline , Oordt‐Speets Anouk M. , Vroling Hilde , van Agt Heleen M. E.
Published: May 2017

Early detection of breast cancer through screening can lower breast cancer mortality rates and reduce the burden of this disease in the population. In most western countries, mammography screening starting from age 50 is recommended. However, there is debate about whether breast cancer screening should be extended to younger women. This systematic review provides an overview of the evidence from RCTs on the benefits and harms of breast cancer screening with mammography in women aged 40–49 years. The quality of the evidence for each outcome was appraised using the GRADE approach. Four articles reporting on two different trials—the Age trial and the Canadian National Breast Screening Study‐I (CNBSS‐I)—were included. The results showed no significant effect on breast cancer mortality (Age trial: RR 0.93 (95% CI 0.80–1.09); CNBSS‐I: HR 1.10 (95% CI 0.86–1.40)) nor on all‐cause mortality (RR 0.98, 95% CI 0.93–1.03) in women aged 40–49 years offered screening. Among regularly attending women, the cumulative risk of experiencing a false‐positive recall was 20.5%. Over‐diagnosis of invasive breast cancer at 5 years post‐cessation of screening for women aged 40–49 years was estimated to be 32% and at 20 years post‐cessation of screening to be 48%. Including ductal carcinoma in situ, these numbers were 41% and 55%. Based on the current evidence from randomised trials, extending mammography screening to younger age groups cannot be recommended. However, there were limitations including relatively low sensitivity of screening and screening attendance, insufficient power, and contamination, which may explain the nonsignificant results.
The role of metabolic reprogramming in γ‐herpesvirus‐associated oncogenesis
Authors: Lo Angela Kwok‐Fung , Dawson Christopher W. , Young Lawrence S. , Lo Kwok‐Wai
Published: May 2017

The γ‐herpesviruses, EBV and KSHV, are closely associated with a number of human cancers. While the signal transduction pathways exploited by γ‐herpesviruses to promote cell growth, survival and transformation have been reported, recent studies have uncovered the impact of γ‐herpesvirus infection on host cell metabolism. Here, we review the mechanisms used by γ‐herpesviruses to induce metabolic reprogramming in host cells, focusing on their ability to modulate the activity of metabolic regulators and manipulate metabolic pathways. While γ‐herpesviruses alter metabolic phenotypes as a means to support viral infection and long‐term persistence, this modulation can inadvertently contribute to cancer development. Strategies that target deregulated metabolic phenotypes induced by γ‐herpesviruses provide new opportunities for therapeutic intervention.
Direct influence of titanium and zirconia particles on the morphology and functionality of mature human osteoclasts
Authors: Pasold Juliane , Markhoff Jana , Tillmann Jenny , Krogull Martin , Pisowocki Phillip , Bader Rainer
Published: May 2017

Within the last ten years of biomedical implants, the focus is increasingly on bioceramics, specifically on zirconia (ZrO2). Hence, we analyzed the impact of ZrO2 particles in comparison to titanium particles on mature human osteoclasts (OCs) as little is known about the direct effect of wear particles on mature OCs and their role in the osteolytic process during aseptic endoprosthesis loosening. Changes in cell morphology and functionality of OCs incubated with particles in different concentrations were investigated in vitro. OCs tend to be enlarged after three days of cultivation with both types of particles, especially with high concentrations of ZrO2, suggesting increased cell fusion. Further, we identified significantly increased expression of OC specific and bone matrix related genes: VNR, RANK, TRAP, and CTSK pointing on a direct stimulatory particle effect on the functionality of mature OCs. In completion, we quantified the bone resorption activity of particle treated mature OCs but could not detect a significant difference in bone resorption compared to OCs cultivated without particles. However, we could identify significantly higher gene expression of MMP‐1 in particle treated OCs compared to untreated control OCs after three days of incubation. We also detected an impaired production of the tissue inhibitor of metalloproteinase, especially for OCs treated with high ZrO2 concentrations. In conclusion, our in vitro data show that abrasion particles could have a direct influence on mature OCs and therefore could promote increased OC‐mediated bone resorption during aseptic loosening of total joint replacements. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2608–2615, 2017.
Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application
Authors: Bahrami Afsane , Joodi Marjan , Moetamani‐Ahmadi Mehrdad , Maftouh Mina , Hassanian Seyed Mahdi , Ferns Gordon A. , Avan Amir
Published: May 2017

Hirschsprung's disease (HSCR) is a congenital disorder, defined by partial or complete loss of the neuronal ganglion cells in the intestinal tract, which is caused by the failure of neural crest cells to migrate completely during intestinal development during fetal life. HSCR has a multifactorial etiology, and genetic factors play a key role in its pathogenesis; these include mutations within several gene loci. These have been identified by screening candidate genes, or by conducting genome wide association (GWAS) studies. However, only a small portion of them have been proposed as major genetic risk factors for the HSCR. In this review, we focus on those genes that have been identified as either low penetrant or high penetrant variants that determine the risk of Hirschsprung's disease. J. Cell. Biochem. 119: 28–33, 2018. © 2017 Wiley Periodicals, Inc.
Routine hematological parameters are associated with short‐ and long‐term prognosis of patients with ischemic stroke
Authors: Fan Luo , Gui Li , Chai Er‐Qing , Wei Chao‐Jun
Published: May 2017

Background

Previous studies indicated that some routine hematological parameters are associated with the prognosis of ischemic stroke (IS), but none of study has evaluated them simultaneously. The aim of this study was to investigate the prognostic value of routine hematological parameters in IS patients.

Methods

Using medical record database, we retrospectively reviewed the patients with IS admitted in Gansu Province Hospital between June 2014 and July 2015. The prognostic value of routine hematological parameters on admission was analyzed using logistic regression model, receiver operating characteristic (ROC) curve analysis and Cox proportional hazards model.

Results

Patients with hospital mortality had significantly higher white blood cell (WBC), neutrophil, neutrophil to lymphocyte ratio (NLR), red blood cell distribution width (RDW) and National Institutes of Health Stroke Scale (NIHSS), while their lymphocyte, monocyte, and eosinophil were significantly lower. The area under ROC curve (AUC) for eosinophil, neutrophil, WBC, RDW, NLR, monocyte, and lymphocyte were 0.74 (95% CI, 0.67‐0.82), 0.76 (95% CI, 0.67‐0.84), 0.72 (95% CI, 0.64‐0.81), 0.65 (95% CI, 0.56‐0.73), 0.76 (95% CI, 0.68‐0.84), 0.67 (95% CI, 0.59‐0.76), and 0.75 (95% CI, 0.67‐0.83), respectively. In a multivariable logistical regression model, only WBC, NLR, and NIHSS were independently associated with hospital mortality. In a multivariable model, age, NIHSS, RDW, NLR, and eosinophil were independent prognostic factors for all‐cause mortality.

Conclusion

Red blood cell distribution width, NLR and eosinophil are independent prognostic factors for IS.
Application of molecular, microbiological, and immunological tests for the diagnosis of bone and joint tuberculosis
Authors: Tang Yinghua , Yin Lianli , Tang Shifu , Zhang Hongyu , Lan Jihui
Published: May 2017

Background

To evaluate the application of interferon gamma release assay (IGRA), rifampicin resistant real‐time fluorescence quantitative PCR technique Xpert Mycobacterium tuberculosis/rifampicin (Xpert MTB/RIF), and the levels of TNF‐α and TGF‐β in the diagnosis of bone and joint tuberculosis.

Methods

Eighty‐six patients with bone and joint tuberculosis, diagnosed by pathology or microbiology, were examined by Xpert MTB/RIF and IGRA (T‐SPOT. TB) for Mycobacterium tuberculosis infection, and the TNF‐α and TGF‐β levels of the patients were measured.

Results

The sensitivity of IGRA in diagnosing bone and joint tuberculosis was 81.4%; Xpert MTB/RIF's sensitivity was 70.9%. The combined sensitivity of the two methods was 91.9%. The combined detection sensitivity of the two methods was higher than individual IGRA or Xpert MTB/RIF detection sensitivity. The TNF‐α and TGF‐β levels in bone and joint tuberculosis patients were higher than those in the control group.

Conclusion

Xpert MTB/RIF, IGRA, TNF‐α, and TGF‐βs expression have value in the rapid diagnosis of bone and joint tuberculosis, and the sensitivity and accuracy of bone and joint tuberculosis diagnosis by combining them can improve it.
Effects of mechanical loading on human mesenchymal stem cells for cartilage tissue engineering
Authors: Choi Jane Ru , Yong Kar Wey , Choi Jean Yu
Published: May 2017

Today, articular cartilage damage is a major health problem, affecting people of all ages. The existing conventional articular cartilage repair techniques, such as autologous chondrocyte implantation (ACI), microfracture, and mosaicplasty, have many shortcomings which negatively affect their clinical outcomes. Therefore, it is essential to develop an alternative and efficient articular repair technique that can address those shortcomings. Cartilage tissue engineering, which aims to create a tissue‐engineered cartilage derived from human mesenchymal stem cells (MSCs), shows great promise for improving articular cartilage defect therapy. However, the use of tissue‐engineered cartilage for the clinical therapy of articular cartilage defect still remains challenging. Despite the importance of mechanical loading to create a functional cartilage has been well demonstrated, the specific type of mechanical loading and its optimal loading regime is still under investigation. This review summarizes the most recent advances in the effects of mechanical loading on human MSCs. First, the existing conventional articular repair techniques and their shortcomings are highlighted. The important parameters for the evaluation of the tissue‐engineered cartilage, including chondrogenic and hypertrophic differentiation of human MSCs are briefly discussed. The influence of mechanical loading on human MSCs is subsequently reviewed and the possible mechanotransduction signaling is highlighted. The development of non‐hypertrophic chondrogenesis in response to the changing mechanical microenvironment will aid in the establishment of a tissue‐engineered cartilage for efficient articular cartilage repair.
Effect of Albiglutide on Cholecystokinin‐Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study
Authors: Shaddinger Bonnie C. , Young Malcolm A. , Billiard Julia , Collins David A. , Hussaini Azra , Nino Antonio
Published: May 2017

The glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)‐induced gallbladder emptying in healthy subjects. It is unknown if all GLP‐1 RAs share this effect; therefore, the effect of the GLP‐1 RA albiglutide on gallbladder function was assessed. In this randomized, double‐blind, 2‐way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK‐induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile‐duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume‐effect curve was significantly greater with albiglutide (P = .029). Starting at the 30‐minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile‐duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP‐1 RAs, albiglutide decreased CCK‐induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.
The physics of MRI safety
Authors: Panych Lawrence P. , Madore Bruno
Published: May 2017

The main risks associated with magnetic resonance imaging (MRI) have been extensively reported and studied; for example, everyday objects may turn into projectiles, energy deposition can cause burns, varying fields can induce nerve stimulation, and loud noises can lead to auditory loss. The present review article is geared toward providing intuition about the physical mechanisms that give rise to these risks. On the one hand, excellent literature already exists on the practical aspect of risk management, with clinical workflow and recommendations. On the other hand, excellent technical articles also exist that explain these risks from basic principles of electromagnetism. We felt that an underserved niche might be found between the two, ie, somewhere between basic science and practical advice, to help develop intuition about electromagnetism that might prove of practical value when working around MR scanners. Following a wide‐ranging introduction, risks originating from the main magnetic field, the excitation RF electromagnetic field, and switching of the imaging gradients will be presented in turn.

Level of Evidence: 5

Technical Efficacy: 1

J. Magn. Reson. Imaging 2018;47:28–43.
Forced degradation studies of lansoprazole using LC‐ESI HRMS and 1H‐NMR experiments: in vitro toxicity evaluation of major degradation products
Authors: Shankar G. , Borkar R. M. , Suresh U. , Guntuku L. , Naidu V. G. M. , Nagesh N. , Srinivas R.
Published: May 2017

Regulatory agencies from all over the world have set up stringent guidelines with regard to drug degradation products due to their toxic effects or carcinogenicity. Lansoprazole, a proton‐pump inhibitor, was subjected to forced degradation studies as per ICH guidelines Q1A (R2). The drug was found to degrade under acidic, basic, neutral hydrolysis and oxidative stress conditions, whereas it was found to be stable under thermal and photolytic conditions. The chromatographic separation of the drug and its degradation products were achieved on a Hiber Purospher, C18 (250 × 4.6 mm, 5 μ) column using 10 mM ammonium acetate and acetonitrile as a mobile phase in a gradient elution mode at a flow rate of 1.0 ml/min. The eight degradation products (DP1–8) were identified and characterized by UPLC/ESI/HRMS with in‐source CID experiments combined with accurate mass measurements. DP‐1, DP‐2 and DP‐3 were formed in acidic, DP‐4 in basic, DP‐5 in neutral and DP‐1, DP‐6, DP‐7 and DP‐8 were in oxidation stress condition Among eight degradation products, five were hitherto unknown degradation products. In addition, one of the major degradation products, DP‐2, was isolated by using semi preparative HPLC and other two, DP‐6 and DP‐7 were synthesized. The cytotoxic effect of these degradation products (DP‐2, DP‐6 and DP‐7) were tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE‐1(normal prostate epithelial cells) by MTT assay. From the results of cytotoxicity, it was found that lansoprazole as well as its degradation products (DP‐2, DP‐6 and DP‐7) were nontoxic up to 50‐μM concentrations, and the latter showed slightly higher cytotoxicity when compared with that of lansoprazole. DNA binding studies using spectroscopic techniques indicate that DP‐2, DP‐6 and DP‐7 molecules interact with ctDNA and may bind to its surface. Copyright © 2017 John Wiley & Sons, Ltd.
Lactate supplementation in severe traumatic brain injured adults by primed constant infusion of sodium L‐lactate
Authors: Wolahan Stephanie M. , Mao Howard C. , Real Courtney , Vespa Paul M. , Glenn Thomas C.
Published: May 2017

Carbohydrate fuel augmentation following traumatic brain injury may be a viable treatment to improve recovery when cerebral oxidative metabolism of glucose is depressed. We performed a primed constant sodium L‐lactate infusion in 11 moderate to severely brain injured adults. Blood was collected before and periodically during the infusion study. We quantified global cerebral uptake of glucose and lactate and other systemic metabolites associated with energy metabolism. Our hypothesis was that cerebral lactate uptake, as measured by the arteriovenous difference of lactate (AVDlac), would increase in severely injured TBI patients in the neurocritical care unit. Infusion of sodium L‐lactate changed net cerebral lactate release, where the arteriovenous difference of lactate is negative, to net cerebral lactate uptake. Results from a mixed effects model of AVDlac with the fixed effects of infusion time, arterial lactate concentration, arterial glucose concentration and arteriovenous difference of glucose shows that doubling arterial lactate concentration (from .92 to 1.84 mM) results in an increase in AVDlac from −.078 mM to .090 mM. We did not detect changes in systemic glucose during the course of the infusion study and observed significant changes in alanine (30% [20 39]), glutamine (34% [24 43]), acetate (87% [60 113]), valine (40% [28 51]), and leucine (24% [16 32]) from baseline levels. Further studies are required to establish the impact of lactate supplementation on cerebral and systemic flux of lactate, on gluconeogenesis, and on the impact on cerebral energetics following injury. © 2017 Wiley Periodicals, Inc.