bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional 3‐D cardiac co‐culture model using bioactive chitosan nanofiber scaffolds
Authors: Hussain Ali , Collins George , Yip Derek , Cho Cheul H.
Published: September 2012

The in vitro generation of a three‐dimensional (3‐D) myocardial tissue‐like construct employing cells, biomaterials, and biomolecules is a promising strategy in cardiac tissue regeneration, drug testing, and tissue engineering applications. Despite significant progress in this field, current cardiac tissue models are not yet able to stably maintain functional characteristics of cardiomyocytes for long‐term culture and therapeutic purposes. The objective of this study was to fabricate bioactive 3‐D chitosan nanofiber scaffolds using an electrospinning technique and exploring its potential for long‐term cardiac function in the 3‐D co‐culture model. Chitosan is a natural polysaccharide biomaterial that is biocompatible, biodegradable, non‐toxic, and cost effective. Electrospun chitosan was utilized to provide structural scaffolding characterized by scale and architectural resemblance to the extracellular matrix (ECM) in vivo. The chitosan fibers were coated with fibronectin via adsorption in order to enhance cellular adhesion to the fibers and migration into the interfibrous milieu. Ventricular cardiomyocytes were harvested from neonatal rats and studied in various culture conditions (i.e., mono‐ and co‐cultures) for their viability and function. Cellular morphology and functionality were examined using immunofluorescent staining for alpha‐sarcomeric actin (SM‐actin) and gap junction protein, Connexin‐43 (Cx43). Scanning electron microscopy (SEM) and light microscopy were used to investigate cellular morphology, spatial organization, and contractions. Calcium indicator was used to monitor calcium ion flux of beating cardiomyocytes. The results demonstrate that the chitosan nanofibers retained their cylindrical morphology in long‐term cell cultures and exhibited good cellular attachment and spreading in the presence of adhesion molecule, fibronectin. Cardiomyocyte mono‐cultures resulted in loss of cardiomyocyte polarity and islands of non‐coherent contractions. However, the cardiomyocyte‐fibroblast co‐cultures resulted in polarized cardiomyocyte morphology and retained their morphology and function for long‐term culture. The Cx43 expression in the fibroblast co‐culture was higher than the cardiomyocytes mono‐culture and endothelial cells co‐culture. In addition, fibroblast co‐cultures demonstrated synchronized contractions involving large tissue‐like cellular networks. To our knowledge, this is the first attempt to test chitosan nanofiber scaffolds as a 3‐D cardiac co‐culture model. Our results demonstrate that chitosan nanofibers can serve as a potential scaffold that can retain cardiac structure and function. These studies will provide useful information to develop a strategy that allows us to generate engineered 3‐D cardiac tissue constructs using biocompatible and biodegradable chitosan nanofiber scaffolds for many tissue engineering applications. Biotechnol. Bioeng. 2013; 110: 637–647. © 2012 Wiley Periodicals, Inc.
Submission of scientifically sound and ethical manuscripts to peer‐reviewed journals – a reviewer's personal perspective on bioanalytical publications
Authors: Weng Naidong
Published: September 2012

In the pharmaceutical industry, bioanalysis is very dynamic and is probably one of the few fields of research covering the entire drug discovery, development and post‐marketing process. Important decisions on drug safety can partially rely on bioanalytical data, which therefore can be subject to regulatory scrutiny. Bioanalytical scientists have historically contributed significant numbers of scientific manuscripts in many peer‐reviewed analytical journals. All of these journals provide some high‐level instructions, but they also leave sufficient flexibility for reviewers to perform independent critique and offer recommendations for each submitted manuscript. Reviewers play a pivotal role in the process of bioanalytical publication to ensure the publication of high‐quality manuscripts in a timely fashion. Their efforts usually lead to improved manuscripts. However, it has to be a joint effort among authors, reviewers and editors to promote scientifically sound and ethically fair bioanalytical publications. Most of the submitted manuscripts were well written with only minor or moderate revisions required for further improvement. Nevertheless, there were small numbers of submitted manuscripts that did not meet the requirements for publications because of scientific or ethical deficiencies, which are discussed in this Letter to the Editor. Copyright © 2012 John Wiley & Sons, Ltd.
MicroRNA‐142 is mutated in about 20% of diffuse large B‐cell lymphoma
Authors: Kwanhian Wiyada , Lenze Dido , Alles Julia , Motsch Natalie , Barth Stephanie , Döll Celina , Imig Jochen , Hummel Michael , Tinguely Marianne , Trivedi Pankaj , Lulitanond Viraphong , Meister Gunter , Renner Christoph , Grässer Friedrich A.
Published: September 2012

MicroRNAs (miRNAs) are short 18–23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Our previous miRNA profiling of diffuse large B‐cell lymphoma (DLBCL) revealed a mutation in the seed sequence of miR‐142‐3p. Further analysis now showed that miR‐142 was mutated in 11 (19.64%) of the 56 DLBCL cases. Of these, one case had a mutation in both alleles, with the remainder being heterozygous. Four mutations were found in the mature miR‐142‐5p, four in the mature miR‐142‐3p, and three mutations affected the miR‐142 precursor. Two mutations in the seed sequence redirected miR‐142‐3p to the mRNA of the transcriptional repressor ZEB2 and one of them also targeted the ZEB1 mRNA. However, the other mutations in the mature miR‐142‐3p did not influence either the ZEB1 or ZEB2 3′ untranslated region (3′ UTR). On the other hand, the mutations affecting the seed sequence of miR‐142‐3p resulted in a loss of responsiveness in the 3′ UTR of the known miR‐142‐3p targets RAC1 and ADCY9. In contrast to the mouse p300 gene, the human p300 gene was not found to be a target for miR‐142‐5p. In one case with a mutation of the precursor, we observed aberrant processing of the miR‐142‐5p. Our data suggest that the mutations in miR‐142 probably lead to a loss rather than a gain of function. This is the first report describing mutations of a miRNA gene in a large percentage of a distinct lymphoma subtype.
18‐FDG PET/CT assessment of basal cell carcinoma with vismodegib
Authors: Thacker Curtis A. , Weiss Glen J. , Tibes Raoul , Blaydorn Lisa , Downhour Molly , White Erica , Baldwin Jason , Von Hoff Daniel D. , Korn Ronald L.
Published: September 2012

The use of 18‐fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) in subjects with advanced basal cell carcinoma (BCC) has not been fully explored due to the rarity of disease presentation. This study evaluated PET/CTs from subjects with advanced BCC participating in a phase I dose‐escalation clinical trial of vismodegib. Fourteen subjects with BCC were imaged with 18‐FDG PET/CT for lesion identification and response categorizing (European Organisation for Research and Treatment for Cancer [EORTC] and PET response criteria in solid tumors [PERCIST] 1.0). Several parameters including metabolic activity of target lesions, site of disease presentation and spread, treatment response, and prognostic significance of metabolic activity following therapy were evaluated. All subjects exhibited at least one hypermetabolic lesion. Most subjects had only four organ systems involved at study enrollment: skin–muscle (93%), lung (57%), lymph nodes (29%), and bone (21%). SUVmax measured across all lesions decreased (median 33%, SD ± 45%) following therapy with metabolic activity normalizing or disappearing in 42% of lesions. No significant difference was observed between EORTC and PERCIST 1.0. Subjects that demonstrated at least a 33% reduction in SUVmax from baseline had a significantly longer progression‐free survival (PFS) (median 17 months, 95% confidence interval [CI] ±4 months vs. 9 months, 95% CI ±5 months, P = 0.038) and overall survival (OS) (median 24 months, 95% CI ±4 months vs. 17 months, 95% CI ±13 months, P = 0.019). BCC lesions are hypermetabolic on 18‐FDG PET/CT. A decrease in SUVmax was associated with improved PFS and OS. These results further support the incorporation of 18‐FDG PET/CT scans in advanced BCC management.
Water‐immersion restraint stress disrupts nonenzymatic antioxidant defense systems through rapid and continuous ascorbic acid depletion in the adrenal gland of rats
Authors: Ohta Yoshiji , Yashiro Koji , Kaida Shingo , Imai Yoichiro , Ohashi Koji , Kitagawa Akira
Published: September 2012

We examined whether water‐immersion restraint stress (WIRS) disrupts nonenzymatic antioxidant defense systems through ascorbic acid depletion in the adrenal gland of rats. Rats were exposed to WIRS for 0.5, 1.5, 3 or 6 h. WIRS increased serum adrenocorticotropic hormone, corticosterone and glucose concentrations and adrenal corticosterone content at each time point. WIRS increased adrenal lipid peroxide content at 3 and 6 h, and the increase was twofold higher than the unstressed level at 6 h. WIRS decreased adrenal ascorbic acid content at each time point, and the decrease reached one‐third of the unstressed level at 6 h. WIRS increased adrenal reduced glutathione content at 0.5 and 6 h but reduced that content to half of the unstressed level at 6 h. WIRS increased adrenal α‐tocopherol content at 1.5 h but returned that content to the unstressed level thereafter. When rats with 6 h of WIRS was orally preadministered with l‐ascorbic acid (250 mg/kg), WIRS‐induced changes in adrenal lipid peroxide, ascorbic acid and reduced glutathione contents were attenuated without any change in stress response. These results indicate that WIRS disrupts nonenzymatic antioxidant defense systems through rapid and continuous ascorbic acid depletion in the adrenal gland of rats. Copyright © 2012 John Wiley & Sons, Ltd.
Metal Amidoboranes: Superior Double‐Hydrogen‐Transfer Agents in the Reduction of Ketones and Imines
Authors: Xu Weiliang , Wu Guotao , Yao Wei , Fan Hongjun , Wu Jishan , Chen Ping
Published: September 2012

Metal amidoboranes (MABs), such as lithium amidoborane (LiAB), show superior ability in reducing ketones and imines directly into their corresponding secondary alcohols and amines, respectively, at room temperature with high conversion and yields. A mechanistic study indicates that the reduction proceeds through a double‐hydrogen‐transfer process. Both protic H(N) and hydridic H(B) protons in the amidoborane participate in the reaction. Theoretical investigations show that the first (and rate‐determining) step of the reduction reaction is the elimination of LiH from LiAB, followed by the transfer of H(Li) to the C site of the unsaturated bond.
A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck
Authors: Adkins Douglas , Ley Jessica , Trinkaus Kathryn , Thorstad Wade , Lewis James , Wildes Tanya , Siegel Barry A. , Dehdashti Farrokh , Gay Hiram , Mehan Paul , Nussenbaum Brian
Published: September 2012

BACKGROUND:

Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5‐fluorouracil [5‐FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction nab‐paclitaxel and cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.

METHODS:

Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab‐paclitaxel 100 mg/m2/week; cetuximab 250 mg/m2/week; cisplatin 75 mg/m2 on day 1; 5‐FU 750 mg/m2/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.

RESULTS:

Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty‐nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2‐year overall and progression‐free survival rates were 84% and 65%, respectively.

CONCLUSIONS:

Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted. Cancer 2013. © 2012 American Cancer Society.
Whole‐genome microRNA expression profiling identifies a 5‐microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme
Authors: Zhang Wei , Zhang Jing , Yan Wei , You Gan , Bao Zhaoshi , Li Shouwei , Kang Chunsheng , Jiang Chuanlu , You Yongping , Zhang Yuxiang , Chen Clark C. , Song Sonya Wei , Jiang Tao
Published: September 2012

BACKGROUND:

More reliable clinical outcome prediction is required to better guide more personalized treatment for patients with primary glioblastoma multiforme (GBM). The objective of this study was to identify a microRNA expression signature to improve outcome prediction for patients with primary GBM.

METHODS:

A cohort of Chinese patients with primary GBM (n = 82) was analyzed using whole‐genome microRNA expression profiling with patients divided into a training set and a testing set. Cox regression and risk‐score analyses were used to develop a 5‐microRNA signature using 41 training samples. The signature was validated in 41 other test samples, in an independent cohort of 35 patients with GBM, and in the Cancer Genome Atlas data set.

RESULTS:

Patients who had high risk scores according to the 5‐microRNA signature had poor overall survival and progression‐free survival compared with patients who had low risk scores. Multivariate Cox analysis indicated that the 5‐microRNA signature was an independent prognostic biomarker after adjusting for other clinicopathologic and genetic factors, such as extent of resection, temozolomide chemotherapy, preoperative Karnofsky performance status score, isocitrate dehydrogenase 1 (IDH1) mutation, and O‐6‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation status.

CONCLUSIONS:

The 5‐microRNA signature was identified as an independent risk predictor that identified patients who had a high risk of unfavorable outcome, demonstrating its potential for personalizing cancer management. The authors concluded that this signature should be evaluated in further prospective studies. Cancer 2013. © 2012 American Cancer Society.
Antenna‐ and Metal‐Triggered Luminescence in Dense 1,3‐Benzodinitrile Metal–Organic Frameworks ∞3[LnCl3(1,3‐Ph(CN)2)], Ln = Eu, Tb
Authors: Höller Christoph J. , Matthes Philipp R. , Adlung Matthias , Wickleder Claudia , Müller‐Buschbaum Klaus
Published: September 2012

Luminescent homoleptic dense 1,3‐benzodinitrile MOFs (metal–organic frameworks) of Eu3+ and Tb3+ were prepared from the anhydrous chlorides LnCl3 (Ln = Eu, Tb) and a melt of the linker ligand 1,3‐benzodinitrile [1,3‐Ph(CN)2=C6H4(CN)2]. The 1,3‐benzodinitrile ligands act as chemical scissors and cut down the LnCl3 structure to 2D sheets of trigonal Cl ion prisms around the rare earth ions and interlinks these nets to form a 3D framework structure of the formula ∞3[LnCl3(1,3‐Ph(CN)2)]. Both compounds exhibit photoluminescence of the trivalent rare earth ions although they are fully concentrated (100 % luminescence centres), and are the sole examples in which a dinitrile linker is utilized as an antenna for rare earth luminescence subsequent to a transfer of the energy from an excited ligand state to an excited 4f state of the rare earth ion. The antenna effect is most efficient for the terbium‐containing framework, whereas the europium spectrum also exhibits metal 4f–4f excitation. The emission can be attributed to 4f–4f transitions of Eu3+ and Tb3+, which give a red emission for europium (intra 4f6 5D0→7F4–0) and a green emission for terbium (intra 4f8 5D4→7F0–6). For Eu3+ a rather uncommon case was observed, in which the 5D4→7F4 transition shows the highest intensity because of a strong ligand‐polarizability‐ and temperature‐dependent dynamic coupling (DC) effect. It is known that luminescence as an intrinsic property of the framework can be triggered in such MOFs by different excitation routes and that both the organic and the inorganic parts are essential for the functionality of these hybrid materials.
Single‐Piece Solid‐Contact Pb2+‐Selective Electrodes Based on Thiophene Oligomer
Authors: Xu Shuhua , Yuan Qun , Yu Shunyang , Wu Xuran
Published: September 2012

A single‐piece solid‐contact Pb2+‐selective electrode was prepared by adding a thiophene oligomer into the ion‐selective cocktail directly. The one‐step fabrication yielded an electrode with Nernstian response spanning a wide concentration range of 10−3–10−8 mol L−1, and detection limit as low as 5.6×10−9 mol L−1. The electrode had a quick response time of approximately 10–15 s and showed excellent selectivity over the most common univalent and divalent cations. The practical application of the proposed electrode has been tested by determining Pb2+ in real water samples.
Electrochemical Properties of Micro‐ and Regular Electrodes Modified with Environmentally Sensitive Poly(N‐Isopropylacrylamide) Gel via Electrochemically Induced Free‐Radical Polymerization
Authors: Karbarz Marcin , Łukaszek Aneta , Stojek Zbigniew
Published: September 2012

Thin layers of the thermo sensitive cross‐linked poly(N‐isopropylacrylamide) gel were anchored on the surface of platinum micro‐ and regular‐electrodes. No preliminary functionalization of the surface was used; just electroformation of radicals at the surface led to strong binding of the polymer net. The electroanalytical investigation was focused on how the volume phase transition affects the height of the voltammetric peak of a model compound, 1,1′‐ferrocenedimethanol. The changes in the oxidation peak current of the electroactive compound upon switching temperature were perfectly reversible. Additionally, it was found that these changes were very fast and the polymer film was very stable. Very good adhesion of poly(N‐isopropylacrylamide) gel to platinum surface and excellent reversibility of the shrinking/swelling process (volume phase transition) may produce new possibilities in electroanalysis.
Voltammetric Determination of Proguanil in Malarone and Spiked Urine with a Renewable Silver Amalgam Film Electrode
Authors: Smarzewska Sylwia , Skrzypek Slawomira , Ciesielski Witold
Published: September 2012

Electrochemical properties of proguanil were investigated by a voltammetric method (SWV) using a renewable silver amalgam film electrode. The influence of buffer pH as well as potential amplitude, frequency, and step potential was studied. The repeatability, precision and recovery of the developed method were examined. The reduction peak current was used for proguanil voltammetric determination in the range 1×10−7–6×10−6 mol L−1, LOD=2.9×10−8 mol L−1, LOQ=9.7×10−8 mol L−1. The standard addition method was used to determine proguanil in a commercial formulation (Malarone) and in spiked urine.
DNA polymerases in nonhomologous end joining: Are there any benefits to standing out from the crowd?
Authors: Ramsden Dale A. , Asagoshi Kenjiro
Published: September 2012

Chromosome breaks, often with damaged or missing DNA flanking the break site, are an important threat to genome stability. They are repaired in vertebrates primarily by nonhomologous end joining (NHEJ). NHEJ is unique among the major DNA repair pathways in that a continuous template cannot be used by DNA polymerases to instruct replacement of damaged or lost DNA. Nevertheless, at least 3 out of the 17 mammalian DNA polymerases are specifically employed by NHEJ. Biochemical and structural studies are further revealing how each of the polymerases employed by NHEJ possesses distinct and sophisticated means to overcome the barriers this pathway presents to polymerase activity. Still unclear, though, is how the resulting network of overlapping and nonoverlapping polymerase activities contributes to repair in cells. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.
Economic analysis of FDG‐PET–guided management of the neck after primary chemoradiotherapy for node‐positive head and neck squamous cell carcinoma
Authors: Pryor David I. , Porceddu Sandro V. , Scuffham Paul A. , Whitty Jennifer A. , Thomas Paul A. , Burmeister Bryan H.
Published: September 2012

Background

The aim of this economic analysis was to model different strategies using pre‐treatment nodal stage or nodal response assessment with CT or positron emission tomography (PET)/CT to determine the need for neck dissection.

Methods

A cost‐minimization analysis was developed on the basis of probability data from a prospective study of PET‐guided management of the neck in patients achieving a complete response at the primary site. Costs were derived from our institution's activity‐based clinical costing system. The effect of uncertainty was tested with sensitivity and scenario analyses including nationally representative cost data.

Results

Strategies incorporating PET had a 7% rate for neck dissection compared with 44% for CT‐guided and 90% for planned neck dissection. The cost per patient was A$16,502 for planned neck dissection, A$8014 for CT‐guided, and A$2573 for PET‐guided. A policy with PET used only for incomplete response on CT was the least‐cost strategy (A$2111). Policies incorporating PET remained the most efficient for all sensitivity/scenario analyses.

Conclusion

The incorporation of PET/CT into nodal response assessment significantly reduced the number of unnecessary neck dissections and generated considerable cost savings in our cohort. © 2012 Wiley Periodicals, Inc. Head Neck, 2013
Increased Apoptosis Induction in Hepatocellular Carcinoma by a Novel Tumor-Targeted TRAIL Fusion Protein Combined With Bortezomib
Authors: Wahl Kristin , Siegemund Martin , Lehner Frank , Vondran Florian , Nüssler Andreas , Länger Florian , Krech Till , Kontermann Roland , Manns Michael P. , Schulze-Osthoff Klaus , Pfizenmaier Klaus , Bantel Heike
Published: September 2012

As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients.

Conclusion:

EGFR-targeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment.
Histone Lysine Methyltransferase, Suppressor of Variegation 3-9 Homolog 1, Promotes Hepatocellular Carcinoma Progression and Is Negatively Regulated by MicroRNA-125b
Authors: Ngo-Yin Fan Dorothy , Tsang Felice Ho-Ching , Tam Aegean Hoi-Kam , Leung-Kuen Au Sandy , Wong Carmen Chak-Lui , Wei Lai , Man-Fong Lee Joyce , He Xianghuo , Oi-Lin Ng Irene , Wong Chun-Ming
Published: September 2012

Hepatocellular carcinoma (HCC) is a major liver malignancy. We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC. Suppressor of variegation 3-9 homolog 1 (SUV39H1), the prototype of histone methyltransferase, is the major enzyme responsible for histone H3 lysine 9 trimethylation, which, essentially, is involved in heterochromatin formation, chromosome segregation, and mitotic progression. However, the implication of SUV39H1 in hepatocarcinogenesis remains elusive. In this study, we found that SUV39H1 was frequently up-regulated in human HCCs and was significantly associated with increased Ki67 expression (

P

< 0.001) and the presence of venous invasion (

P

= 0.017). To investigate the role of SUV39H1 in HCC development, both gain- and loss-of-function models were established. SUV39H1 overexpression remarkably enhanced HCC cell clonogenicity, whereas knockdown of SUV39H1 substantially suppressed HCC cell proliferation and induced cell senescence. In addition, ectopic expression of SUV39H1 increased the migratory ability of HCC cells, whereas a reduced migration rate was observed in SUV39H1 knockdown cells. The significance of SUV39H1 in HCC was further demonstrated in a nude mice model; SUV39H1 knockdown drastically inhibited

in vivo

tumorigenicity and abolished pulmonary metastasis of HCC cells. We also identified microRNA-125b (miR-125b) as a post-transcriptional regulator of SUV39H1. Ectopic expression of miR-125b inhibited SUV39H1 3'-untranslated-region–coupled luciferase activity and suppressed endogenous SUV39H1 expression at both messenger RNA and protein levels. We have previously reported frequent down-regulation of miR-125b in HCC. Interestingly, miR-125b level was found to be inversely correlated with SUV39H1 expression (

P

= 0.001) in clinical specimens. Our observations suggested that miR-125b down-regulation may account for the aberrant SUV39H1 level in HCC.

Conclusion:

Our study demonstrated that SUV39H1 up-regulation contributed to HCC development and metastasis. The tumor-suppressive miR-125b served as a negative regulator of SUV39H1.
SEMIPARAMETRIC VECTOR MEM
Authors: Cipollini Fabrizio , Engle Robert F. , Gallo Giampiero M.
Published: September 2012

Financial time series are often non‐negative‐valued (volumes, trades, durations, realized volatility, daily range) and exhibit clustering. When joint dynamics is of interest, the vector multiplicative error model (vMEM; the element‐by‐element product of a vector of conditionally autoregressive scale factors and a multivariate i.i.d. innovation process) is a suitable strategy. Its parameters can be estimated by generalized method of moments, bypassing the problem of specifying a multivariate distribution for the errors. Simulated results show the gains in efficiency relative to an equation‐by‐equation approach. A vMEM on several measures of volatility justifies a joint approach revealing full interdependence. Copyright © 2012 John Wiley & Sons, Ltd.
An economic evaluation: Simulation of the cost-effectiveness and cost-utility of universal prevention strategies against osteoporosis-related fractures
Authors: Nshimyumukiza Léon , Durand Audrey , Gagnon Mathieu , Douville Xavier , Morin Suzanne , Lindsay Carmen , Duplantie Julie , Gagné Christian , Jean Sonia , Giguère Yves , Dodin Sylvie , Rousseau François , Reinharz Daniel
Published: September 2012

A patient-level Markov decision model was used to simulate a virtual cohort of 500,000 women 40 years old and over, in relation to osteoporosis-related hip, clinical vertebral, and wrist bone fractures events. Sixteen different screening options of three main scenario groups were compared: (1) the status quo (no specific national prevention program); (2) a universal primary prevention program; and (3) a universal screening and treatment program based on the 10-year absolute risk of fracture. The outcomes measured were total directs costs from the perspective of the public health care system, number of fractures, and quality-adjusted life-years (QALYs). Results show that an option consisting of a program promoting physical activity and treatment if a fracture occurs is the most cost-effective (CE) (cost/fracture averted) alternative and also the only cost saving one, especially for women 40 to 64 years old. In women who are 65 years and over, bone mineral density (BMD)-based screening and treatment based on the 10-year absolute fracture risk calculated using a Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool is the best next alternative. In terms of cost-utility (CU), results were similar. For women less than 65 years old, a program promoting physical activity emerged as cost-saving but BMD-based screening with pharmacological treatment also emerged as an interesting alternative. In conclusion, a program promoting physical activity is the most CE and CU option for women 40 to 64 years old. BMD screening and pharmacological treatment might be considered a reasonable alternative for women 65 years old and over because at a healthcare capacity of $50,000 Canadian dollars ($CAD) for each additional fracture averted or for one QALY gained its probabilities of cost-effectiveness compared to the program promoting physical activity are 63% and 75%, respectively, which could be considered socially acceptable. Consideration of the indirect costs could change these findings. © 2013 American Society for Bone and Mineral Research
Acute effect of calcium citrate on serum calcium and cardiovascular function
Authors: Burt Morton G , Mangelsdorf Brenda L , Srivastava Divya , Petersons Carolyn J
Published: September 2012

Calcium supplements have been associated with an increased risk of cardiovascular events. However, the validity of these findings has been questioned. A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated. Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid. We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function. In an open interventional study, we recruited 25 volunteers (16 female, age 60.3 ± 6.5 years, body mass index 25.7 ± 2.7 kg/m2) from the community who were not taking calcium supplements. Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate. We assessed well-validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry. Total and ionized serum calcium were acutely increased by 0.10 ± 0.07 and 0.06 ± 0.03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0.0001 for both comparisons). Following administration of calcium citrate there was a fall in AIx from a median of 29.7% (23.8% to 34.0%) to 26.4% (22.7% to 34.0%, p = 0.03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0.007). PWV and RHI were not significantly altered. The change in total calcium was negatively correlated with the change in AIx (r = –0.48, p = 0.02). In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion. If maintained long-term, these changes would be expected to reduce cardiovascular risk. Acute serum calcium–mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events. © 2013 American Society for Bone and Mineral Research
Vertebral fractures and trabecular microstructure in men with prostate cancer on androgen deprivation therapy
Authors: Greenspan Susan L , Wagner Julie , Nelson Joel B , Perera Subashan , Britton Cynthia , Resnick Neil M
Published: September 2012

Androgen deprivation therapy (ADT), a treatment for prostate cancer, is associated with bone loss and fractures. Dual-energy X-ray absorptiometry (DXA)–measured bone mineral density does not assess vertebral fractures (VF). High-resolution micro-magnetic resonance imaging (HR-MRI) assesses bone microarchitecture and provides structural information. To determine if VF identification increased the diagnosis of osteoporosis beyond DXA and if HR-MRI demonstrated skeletal deterioration in men with VF, we cross-sectionally studied 137 men aged ≥ 60 years with nonmetastatic prostate cancer on ADT for ≥ 6 months. Vertebral fracture assessment (VFA) by DXA was confirmed with X-rays. HR-MRI of the wrist included bone volume to total volume (BV/TV), surface density (trabecular plates), surface/curve ratio (plates/rods), and erosion index (higher depicts deterioration). VF were found in 37% of men; the majority were unknown. Seven percent of participants were classified as osteoporotic by hip or spine DXA. Thirty-seven percent of men without osteoporosis by DXA had VF identified, suggesting that 90% of patients with clinical osteoporosis would have been misclassified by DXA alone. By ANOVA comparison across VF grades, the BV/TV, surface density, and spine, hip, and wrist DXA were lower, and erosion index was higher in men with moderate-severe VF compared with lesser grades (all p < 0.05). By unadjusted ROC analysis, the addition of HR-MRI to DXA at the spine, hip, and femoral neck added substantially (AUC increased 0.831 to 0.902, p < 0.05) to prediction of moderate-severe vertebral fracture. HR-MRI indices were associated with spine, hip, and wrist DXA measures (p < 0.01). Longer duration of ADT was associated with lower BV/TV, surface density, and surface/curve ratio (p < 0.05). ADT for men with prostate cancer is associated with silent VF. DXA alone leads to misclassifications of osteoporosis, which can be avoided by VF assessment. HR-MRI provides a novel technique to assess deterioration of structural integrity in men with VF and adds micro-structural information. © 2013 American Society for Bone and Mineral Research
Dysregulated expression of secretogranin III is involved in neurotoxin‐induced dopaminergic neuron apoptosis
Authors: Li Fengrui , Tian Xiaofei , Zhou Yishu , Zhu Lanhui , Wang Baojie , Ding Mei , Pang Hao
Published: September 2012

The neurotoxins paraquat (PQ) and dopamine (DA or 6‐OHDA) cause apoptosis of dopaminergic neurons in the substantia nigra pars compacta (SNpc), reproducing an important pathological feature of Parkinson's disease (PD). Secretogranin III (SCG3), a member of the multifunctional granin family, plays a key role in neurotransmitter storage and transport and in secretory granule biogenesis, which involves the uptake of exogenous toxins and endogenous “toxins” in neuroendocrine cells. However, the molecular mechanisms of neurotoxin‐induced apoptosis in dopaminergic neurons and the role of SCG3‐associated signaling pathways in neuroendocrine regulation are unclear. To address this, we used PQ‐ and DA‐induced apoptosis in SH‐SY5Y human dopaminergic cells as an in vitro model to investigate the association between SCG3 expression level and apoptosis. SCG3 was highly expressed in SH‐SY5Y cells, and SCG3 mRNA and protein levels were dramatically decreased after PQ treatment. Apoptosis induced by PQ is associated with caspase activation and decreased SCG3 expression, and restoration of SCG3 expression is observed after treatment with caspase inhibitors. Overexpressed SCG3 in nonneuronal cells and endogenous SCG3 in SH‐SY5Y cells are cleaved into specific fragments by recombinant caspase‐3 and ‐7, but the fragments were not detected in PQ‐treated SH‐SY5Y cells. Therefore, SCG3 may be involved in apoptosis signal transduction as a caspase substrate, leading to loss of its original biological functions. In addition, SCG3 may be a pivotal component of the neuroendocrine pathway and play an important role in neuronal communication and neurotransmitter release, possibly representing a new potential target in the course of PD pathogenesis. © 2012 Wiley Periodicals, Inc.
Characterization of plasma β‐secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease
Authors: Wu Guoxin , Sankaranarayanan Sethu , Wong Jacky , Tugusheva Katherine , Michener Maria S. , Shi Xiaoping , Cook Jacquelynn J. , Simon Adam J. , Savage Mary J.
Published: September 2012

Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho‐thr181 tau consistently differentiate between Alzheimer's disease (AD) and age‐matched control subjects. In contrast, CSF β‐site APP‐cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age‐matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1‐specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ‐secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age‐matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies. © 2012 Wiley Periodicals, Inc.
Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of γ‐aminobutyric acid immunoreactivity and glutamate release in the retina
Authors: Guimarães‐Souza E.M. , Calaza K.C.
Published: September 2012

Glutamate, the major excitatory neurotransmitter in the retina, functions by activation of both ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors. Group III mGluRs, except for mGluR6, are mostly found in the inner plexiform layer (IPL), and their retinal functions are not well known. Therefore, we decided to investigate the effect of mGluRIII on glutamate release and GABAergic amacrine cells in the chick retina. The nonselective mGluRIII agonist L‐SOP promoted a decrease in the number of γ‐aminobutyric acid (GABA)‐positive cells and in the GABA immunoreactivity in all sublayers of the IPL. This effect was prevented by the antagonist MAP‐4, by GAT‐1 inhibitor, and by antagonists of iGluR. Under the conditions used, L‐SOP did not alter endogenous glutamate release. VU0155041, an mGluR4‐positive allosteric modulator, reduced GABA immunoreactivity in amacrine cells and in sublayers 2 and 4 of the IPL but evoked an increase in the glutamate released. VU0155041's effect was inhibited by the absence of calcium. AMN082, a selective mGluR7‐positive allosteric modulator, also decreased GABA immunoreactivity in amacrine cells and sublayers 1, 2, and 3 and increased glutamate release, and this effect was also inhibited by calcium absence. DCPG, an mGluR8‐selective agonist, did not significantly alter GABA immunoreactivity in amacrine cells or glutamate release. However, it did significantly increase GABA immunoreactivity in sublayers 4 and 5. The results suggest that mGluRIIIs are involved in the modulation of glutamate and GABA release in the retina, possibly participating in distinct visual pathways: mGluR4 might be involved with cholinergic circuitry, whereas mGluR7 and mGluR8 might participate, respectively, in the OFF and the ON pathways. © 2012 Wiley Periodicals, Inc.
Hyperbaric oxygen treatment prevents nitric oxide‐induced apoptosis in articular cartilage injury via enhancement of the expression of heat shock protein 70
Authors: Ueng Steve W. N. , Yuan Li‐Jen , Lin Song‐Shu , Niu Chi‐Chien , Chan Yi‐Sheng , Wang I‐Chun , Yang Chuen‐Yung , Chen Wen‐Jer
Published: September 2012

Heat shock proteins (HSPs), inflammatory cytokines, nitric oxide (NO), and localized hypoxia‐induced apoptosis are thought to be correlated to the degree of cartilage injury. We investigated the effect of hyperbaric oxygen (HBO) on (1) interleukin‐1β (IL‐1β)‐induced NO production and apoptosis of rabbit chondrocytes and (2) healing of articular cartilage defects. For the in vitro study, RT‐PCR and Western blotting were performed to detect mRNA and protein expressions of HSP70, inducible NO synthase (iNOS), and caspase 3 in IL‐1β‐treated chondrocytes. To clarify that the HSP70 was necessary for anti‐iNOS and anti‐apoptotic activity by HBO, we treated the cells with an HSP70 inhibitor, KNK437. For the in vivo study, cartilage defects were created in rabbits. The HBO group was exposed to 100% oxygen at 2.5 ATA for 1.5 h a day for 10 weeks. The control group was exposed to normal air. After sacrifice, specimen sections were sent for examination using a scoring system. Immunohistochemical analyses were performed to detect the expressions of iNOS, HSP70, and caspase 3. Our results suggested that HBO upregulated the mRNA and protein expressions of HSP70 and suppressed those of iNOS and caspase 3 in chondrocytes. KNK437 inhibited the HBO‐induced downregulation of iNOS and casapase 3 activities. The histological scores showed that HBO markedly enhanced cartilage repair. Immunohistostaining showed that HBO enhanced HSP70 expression and suppressed iNOS and caspase 3 expressions in chondrocytes. Accordingly, HBO treatment prevents NO‐induced apoptosis in articular cartilage injury via enhancement of the expression of heat shock protein 70. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 376–384, 2013
Laparoscopic pancreatectomy for malignancy
Authors: Fisher Sarah B. , Kooby David A.
Published: September 2012

Utilization of laparoscopic techniques for resection of the pancreas has slowly gained acceptance in specific situations and is now being applied to more challenging endeavors, such as pancreaticoduodenectomy for cancer. This review provides a summary of laparoscopic applications for pancreatic malignancy, with specific attention to the most common methods of pancreatic resection and their respective oncologic outcomes, including margin status, lymph node retrieval, and survival. J. Surg. Oncol. 2013;107:39–50. © 2012 Wiley Periodicals, Inc.
Abundance of rare and elusive species: Empirical investigation of closed versus spatially explicit capture–recapture models with lynx as a case study
Authors: Blanc Laetitia , Marboutin Eric , Gatti Sylvain , Gimenez Olivier
Published: September 2012

Effective conservation and management require reliable monitoring methods and estimates of abundance to prioritize human and financial investments. Camera trapping is a non‐invasive sampling method allowing the use of capture–recapture (CR) models to estimate abundance while accounting for the difficulty of detecting individuals in the wild. We investigated the relative performance of standard closed CR models and spatially explicit CR models (SECR) that incorporate spatial information in the data. Using simulations, we considered 4 scenarios comparing low versus high detection probability and small versus large populations and contrasted abundance estimates obtained from both approaches. Standard CR and SECR models both provided minimally biased abundance estimates, but precision was improved when using SECR models. The associated confidence intervals also provided better coverage than their non‐spatial counterpart. We concluded SECR models exhibit better statistical performance than standard closed CR models and allow for sound management strategies based on density maps of activity centers. To illustrate the comparison, we considered the Eurasian lynx (Lynx lynx) as a case study that provided the first abundance estimates of a local population in France. © 2012 The Wildlife Society.
Utility of cVEMPs in bilateral superior canal dehiscence syndrome
Authors: Niesten Marlien E.F. , McKenna Michael J. , Herrmann Barbara S. , Grolman Wilko , Lee Daniel J.
Published: September 2012

Objectives/Hypothesis:

To determine the utility of cervical vestibular evoked myogenic potential (cVEMP) thresholds in the surgical management of bilateral superior canal dehiscence syndrome (SCDS).

Study design:

Retrospective review.

Methods:

We identified patients who underwent surgical treatment for SCDS from our database of 147 patients diagnosed with superior canal dehiscence (SCD) between 2000 and 2011 at our institution. The diagnosis of SCDS was based on clinical signs and symptoms, audiometric and cVEMP testing, and high‐resolution computed tomography.

Results:

We identified 38 patients who underwent SCD surgery in 40 ears (2 bilateral). In seven patients with bilateral SCD, the more symptomatic ear had lower cVEMP thresholds, a larger air bone gap and a lateralizing tuning fork. In 13 patients with perioperative cVEMP testing, thresholds increased in 12 patients following primary repair, and no threshold shift was seen in one patient with persistence of symptoms after revision surgery. Audiometric data showed a significant mean decrease of the low‐frequency air‐bone gap and a mild (high‐frequency) bone conduction loss after surgical repair.

Conclusions:

We found that, 1) preoperative cVEMP thresholds, the magnitude of the air‐bone gap and tuning‐fork testing are important to confirm the worse ear in patients with bilateral SCD, 2) elevation of cVEMP thresholds following surgery correlates with improvement of symptoms and underscores the importance of postoperative testing in patients with bilateral disease or recurrence of symptoms and, 3) SCD plugging is associated with a partial closure of the air‐bone gap and a mild (high‐frequency) sensorineural hearing loss. Laryngoscope, 2013