bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell‐based selection provides novel molecular probes for cancer stem cells
Authors: Sefah Kwame , Bae Kyung‐Mi , Phillips Joseph A. , Siemann Dietmar W. , Su Zhen , McClellan Steve , Vieweg Johannes , Tan Weihong
Published: November 2012

Cancer stem cells (CSC) represent a malignant subpopulation of cells in hierarchically organized tumors. They constitute a subpopulation of malignant cells within a tumor mass and possess the ability to self‐renew giving rise to heterogeneous tumor cell populations with a complex set of differentiated tumor cells. CSC may be the cause of metastasis and therapeutic refractory disease. Because few markers exist to identify and isolate pure CSC, we used cell‐based Systematic Evolution of Ligands by EXponential enrichment (cell‐SELEX) to create DNA aptamers that can identify novel molecular targets on the surfaces of live CSC. Out of 22 putative DNA sequences, 3 bound to ∼90% and 5 bound to ∼15% of DU145 prostate cancer cells. The 15% of cells that were positive for the second panel of aptamers expressed high levels of E‐cadherin and CD44, had high aldehyde dehydrogenase 1 activity, grew as spheroids under nonadherent culture conditions, and initiated tumors in immune‐compromised mice. The discovery of the molecular targets of these aptamers could reveal novel CSC biomarkers.
Clinical and immunologic responses in melanoma patients vaccinated with MAGE‐A3‐genetically modified lymphocytes
Authors: Russo Vincenzo , Pilla Lorenzo , Lunghi Francesca , Crocchiolo Roberto , Greco Raffaella , Ciceri Fabio , Maggioni Daniela , Fontana Raffaella , Mukenge Sylvain , Rivoltini Licia , Rigamonti Gianluigi , Mercuri Santo Raffaele , Nicoletti Roberto , Maschio Alessandro Del , Gianolli Luigi , Fazio Ferruccio , Marchianò Alfonso , Florio Annabella Di , Maio Michele , Salomoni Monica , Gallo‐Stampino Corrado , Fiacco Matteo Del , Lambiase Antonio , Coulie Pierre G. , Patuzzo Roberto , Parmiani Giorgio , Traversari Catia , Bordignon Claudio , Santinami Mario , Bregni Marco
Published: November 2012

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti‐vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine‐specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE‐A3+ melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE‐A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV‐TK). HSV‐TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti‐TK and anti‐MAGE‐A3 T‐cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE‐A3‐specific immune responses showed a clinical benefit. Additionally, we report that responder and non‐responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.
The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model
Authors: ten Hagen Timo L.M. , Seynhaeve Ann L.B. , de Wiel‐Ambagtsheer Gisela aan , de Bruijn Ernst A. , van Tiel Sandra T. , Ruegg Curzio , Meyring Michael , Grell Matthias , Goodman Simon L. , Eggermont Alexander M.M.
Published: November 2012

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)‐α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better‐tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha‐V integrins, has both anti‐angiogenic and direct anti‐tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra‐peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.
A novel non‐invasive digital imaging method for continuous biomass monitoring and cell distribution mapping in photobioreactors
Authors: Uyar Basar
Published: November 2012

Background

In this study, a simple, non‐invasive, non‐destructive digital imaging method was developed to determine the cell biomass concentration and distribution in photobioreactors. For this purpose, images of a panel type photobioreactor containing Rhodobacter capsulatus as a model photosynthetic microorganism were captured with a digital camera and processed to obtain RGB color information.

Results

Acquired photobioreactor images were processed to quantify cell concentration, blue color component was shown to be suitable for estimating the cell concentration accurately. In a batch reactor, the biomass change over time was tracked efficiently by the proposed method as verified by mass and spectrophotometric analysis. Cell distribution profile in the photobioreactor was revealed by further analyses of the selected captured images. It was shown that cells were denser at the bottom part of the photobioreactor, and the concentration gradient increased over time during the batch runs.

Conclusion

This research suggests that image analysis technique may be used as a simple method for continuous and online monitoring of cell concentration in photobioreactors. The research also demonstrated that a cell distribution map in the photobioreactor can be constructed to reveal non‐homogeneity. © 2012 Society of Chemical Industry
Degradation of short chain polychlorinated paraffins by a new isolate: tests in pure culture and sewage sludge
Authors: Lu Mang
Published: November 2012

BACKGROUND

Short chain chlorinated paraffins SCCPs are priority hazardous substances classified by the European Water Framework Directive and have been detected in sewage sludge of wastewater treatment plants worldwide. However, studies on the biodegradation of SCCPs presented in sewage sludge are very scarce.

RESULTS

In this study, a bacterial strain that can utilize SCCPs as a sole source of carbon and energy was isolated from soil. This strain was identified as Pseudomonas sp. N35. The efficacy of SCCP degradation by strain N35 was tested in pure culture and sewage sludge microcosms containing 66.1 mg kg–1 SCCPs. The results showed that 57.5% of chloride was released into the medium as chloride ions in pure culture within 20 days. Mesophilic temperature and near‐neutral pH were most favorable for SCCP degradation. The addition of low concentrations of glucose, Tween‐80 and acetone (20 mg L–1) enhanced SCCP degradation. Bioaugmentation resulted in 73.4% removal of SCCPs in the sludge microcosm after 30 days of treatment.

CONCLUSION

Bioaugmentation with specific strains may be of great significance in bioremediation of SCCP‐containing sewage sludge.© 2012 Society of Chemical Industry
Multiphasic contrast‐enhanced MRI: Single‐slice versus volumetric quantification of tumor enhancement for the assessment of renal clear‐cell carcinoma fuhrman grade
Authors: Vargas Hebert Alberto , Delaney Holly G. , Delappe Eithne M. , Wang Ya , Zheng Junting , Moskowitz Chaya S. , Tan Yongqiang , Zhao Binsheng , Schwartz Lawrence H. , Hricak Hedvig , Russo Paul , Akin Oguz
Published: November 2012

Purpose:

To assess the association between clear‐cell carcinoma pathology grade at nephrectomy and magnetic resonance imaging (MRI) tumor enhancement.

Materials and Methods:

The Institutional Review Board approved this retrospective study and waived the informed consent requirement. In all, 32 patients underwent multiphase contrast‐enhanced MRI prior to nephrectomy. MRI tumor enhancement was measured using two approaches: 1) the most enhancing portion of the tumor on a single slice and 2) volumetric analysis of enhancement in the entire tumor. Associations between pathological grade, tumor size, and enhancement were evaluated using the Kruskal–Wallis test and generalized logistic regression models.

Results:

No significant association between pathology grade and enhancement was found when measurements were made on a single slice. When measured in the entire tumor, significant associations were found between higher pathology grades and lower mean, median, top 10%, top 25%, and top 50% tumor enhancement (P < 0.001–0.002). On multivariate analysis the association between grade and enhancement remained significant (P = 0.041–0.043), but tumor size did not make an additional contribution beyond tumor enhancement alone in differentiating between tumor grades.

Conclusion:

There is significant association between tumor grade and enhancement, but only when measured in the entire tumor and not on the most enhancing portion on a single slice. J. Magn. Reson. Imaging 2013;37:1160–1167. © 2012 Wiley Periodicals, Inc.
Neoadjuvant chemotherapy evaluation by MRI volumetry in rectal cancer followed by chemoradiation and total mesorectal excision: Initial experience
Authors: Nougaret Stephanie , Fujii Shinya , Addley Helen C. , Bibeau Frederic , Pandey Himanshu , Mikhael Hisham , Reinhold Caroline , Azria David , Rouanet Philippe , Gallix Benoit
Published: November 2012

Purpose:

To evaluate rectal cancer volumetry in predicting initial neoadjuvant chemotherapy response.

Materials and Methods:

Sixteen consecutive patients who underwent neoadjuvant chemotherapy (CX) before chemoradiotherapy (CRT) and surgery were enrolled in this retrospective study. Tumor volume was evaluated at the first magnetic resonance imaging (MRI), after CX and after CRT. Tumor volume regression (TVR) and downstaging were compared with histological results according to Tumor Regression Grade (TRG) to assess CX and CRT response, respectively.

Results:

The mean tumor volume was 132 cm3 ± 166 before and 56 cm3 ± 71 after CX. TVR after CX was significantly different between patients with poor histologic response (TRG1/2) and those with good histologic response (TRG3/4) (P = 0.001). An optimal cutoff of TVR >68% (area under the curve [AUC]: 0.9, 95% confidence interval [CI]: 0.65–0.98, P = 0.0001) to predict good histology response after CX was assessed by receiver operating characteristic curve. According to previous data and this study, we defined 70% as the best cutoff values according to sensitivity (86%), specificity (100%) of TVR for predicting good histology response. In contradistinction, MRI downstaging was associated with TRG only after CRT (P = 0.04).

Conclusion:

Our pilot study showed that MRI volumetry can predict early histological response after CX and before CRT. MRI volumetry could help the clinician to distinguish early responders in order to aid appropriate individually tailored therapies. J. Magn. Reson. Imaging 2013;38:726–732. © 2012 Wiley Periodicals, Inc.
Effects of age and gender on neuroanatomical volumes
Authors: Inano Sachiko , Takao Hidemasa , Hayashi Naoto , Yoshioka Naoki , Mori Harushi , Kunimatsu Akira , Abe Osamu , Ohtomo Kuni
Published: November 2012

Purpose:

To investigate age‐related differences, gender differences, and age‐by‐gender interactions on the volumes of 18 neuroanatomical structures, with a large sample at a single institution.

Materials and Methods:

A total of 861 normal subjects (mean age = 56.1 ± 9.8 years, age range = 24.0–84.8 years) were included in this study. All subjects were scanned at 3.0 T. Measurement of the 18 neuroanatomical volumes was performed with FreeSurfer v. 4.5. Differences in volumes of neuroanatomical structures were tested using analysis of covariance with intracranial volume‐normalized volume as the dependent variable, and independent variables of age, sex, age × sex, age × age, age × age × sex, and scanner. Nonsignificant higher‐order terms were removed sequentially from the model. A P value of < 0.0028 (=0.5/18) was considered to indicate a statistically significant difference.

Results:

All neuroanatomical volumes, except for the caudate nucleus, pallidum, and 4th ventricle, were significantly related to age (linearly or quadratically). Significant gender differences were found in all neuroanatomical volumes, except for cerebral white matter, cerebellar cortex, caudate nucleus, and amygdala. No neuroanatomical volume showed a significant interaction between age (age × age) and gender.

Conclusion:

Our results showed age and gender effects on neuroanatomical volumes, and indicate no gender difference in the aging process of neuroanatomical volumes. J. Magn. Reson. Imaging 2013;37:1072–1076. © 2012 Wiley Periodicals, Inc.
Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease
Authors: Ubhi Kiren , Rockenstein Edward , Vazquez‐Roque Ruben , Mante Michael , Inglis Chandra , Patrick Christina , Adame Anthony , Fahnestock Margaret , Doppler Edith , Novak Philip , Moessler Herbert , Masliah Eliezer
Published: November 2012

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid‐β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic‐like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro‐nerve growth factor (NGF), NGF, brain‐derived neurotrophic factor (BDNF), neurotropin (NT)‐3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro‐NGF were increased in saline‐treated hAPP tg mice. In contrast, CBL‐treated hAPP tg mice showed levels of pro‐NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL‐treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75NTR immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline‐treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro‐NGF/NGF balance and a concomitant protection of cholinergic neurons. © 2012 Wiley Periodicals, Inc.
Self‐evolving oxidative stress with identifiable pre‐ and postmitochondrial phases in PC12 cells
Authors: Zhang Ganlin , Morin Christophe , Zhu Xiaoxin , Bao Huynh Minh , Ouidir Ouidja Mohand , Sepulveda‐Diaz Julia Elisa , Raisman‐Vozari Rita , Li Ping , Papy‐Garcia Dulce
Published: November 2012

During the neurodegenerative process in several brain diseases, oxidative stress is known to play important roles in disease severity and evolution. Although early events of stress, such as increased lipid peroxidation and decreased superoxide dismutase, are known to characterize early onsets of these diseases, little is known about the events that participate in maintaining the chronic evolving phase influencing the disease progression in neurons. Here, we used differentiated PC12 cells to identify premitochondrial and postmitochondrial events occurring during the oxidative stress cascade leading to apoptosis. Our data indicate that an acute and strong oxidative impulse (500 μM H2O2, 30 min) can induce, in this model, a 24‐hr self‐evolving stress, which advances from a premitochondrial phase characterized by lysosomes and cathepsin B and D translocations to cytosol and early mitochondrial membrane hyperpolarization. This phase lasts for about 5 hr and is followed by a postmitochondrial phase distinguished by mitochondrial membrane depolarization, reactive oxygen species increase, caspase‐9 and caspase‐3 activations, and apoptosis. Inhibition of cathepsins B and D suggests that cells can be protected at the premitochondrial phase of stress evolution and that new cathepsins regulators, such as glycosaminoglycans mimetics, can be considered as new therapeutic prototypes for neurodegeneration. Insofar as early oxidative stress markers have been related to the early onset of neurodegeneration, strategies protecting cells at the premitochondrial phase of oxidative stress may have important therapeutic applications. © 2012 Wiley Periodicals, Inc.
Delayed leptin administration after stroke induces neurogenesis and angiogenesis
Authors: Avraham Y. , Dayan M. , Lassri V. , Vorobiev L. , Davidi N. , Chernoguz D. , Berry E. , Leker R.R.
Published: November 2012

Leptin is a potent AMP kinase (AMPK) inhibitor that induces neuroprotection, neurogenesis, and angiogenesis when administered immediately after stroke. To dissociate these effects, we explored the effects of delayed administration of leptin, at 10 days after stroke onset, on neurogenesis and angiogenesis after stroke. Sabra mice underwent photothrombotic stroke and were treated with vehicle or leptin given either as a single dose or in triple dosing, 10 days later. Newborn cells were labeled with bromodeoxyuridine. Functional outcome was studied with the neurological severity score for 90 days poststroke, and the brains were then evaluated via immunohistochemistry. Final infarct volumes did not differ between the groups. Exogenous leptin led to significant increments in the number of proliferating BrdU+ cells in the subventricular zone and in the cortex abutting the lesion (2.5‐fold and 1.4‐fold, respectively). There were significant increments in the number of newborn neurons and glia (4‐ and 3.4‐fold, respectively) in leptin‐treated animals. Leptin also significantly increased the number of blood vessels in the perilesioned cortex. However, animals treated with leptin failed to demonstrate significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis even when given late after stroke but does not lead to better functional outcome in this delayed‐treatment paradigm. These results suggest that the main beneficial effects of leptin after stroke are associated with its early neuroprotective role rather than with its proneurogenic or proangiogenic effects. © 2012 Wiley Periodicals, Inc.
Experimental epidural hematoma causes cerebral infarction and activates neocortical glial and neuronal genesis in adult guinea pigs
Authors: Pan Aihua , Li Ming , Gao Jun‐Yan , Xue Zhi‐Qin , Li Zhiyuan , Yuan Xian‐Yui , Luo Duan‐Wu , Luo Xue‐Gang , Yan Xiao‐Xin
Published: November 2012

Epidural hematoma (EDH) is a type of life‐threatening traumatic brain injury. Little is known about the extent to which EDH may cause neural damage and regenerative response in the cerebral cortex. Here we attempted to explore these issues by using guinea pigs as an experimental model. Unilateral EDH was induced by injection of 0.1 ml autologous blood into the extradural space, with experimental effects examined at 7, 14, 30, and 60 days postlesion. An infarct developed in the cortex deep to the EDH largely after 7 days postlesion, with neuronal death occurred from layers I to V in the central infarct region, as evidenced by loss of immunoreactivity (IR) for neuron‐specific nuclear antigen (NeuN). Glial fibrillary acidic protein (GFAP) IR appeared as a cellular band surrounding the infarct and extending into the periinfarct cortex along the pia. Doublecortin (DCX) IR emerged in these same areas, with labeled cells appearing as astrocytic and neuronal profiles. DCX/GFAP colocalization was found in these regions commonly at 7 and 14 days postlesion, whereas DCX/NeuN‐colabeled neurons were detectable at 30 and 60 days postlesion. Subpopulations of GFAP‐, DCX‐, or NeuN‐immunoreactive cells colocalized with the endogenous proliferative marker Ki‐67 or bromodeoxyuridine (BrdU) after pulse‐chase with this birth‐dating marker. The results suggest that experimental EDH can cause severe neuronal loss, induce significant glial activation, and promote a certain degree of local neuronal genesis in adult guinea pig neocortex. These findings point to potential therapeutic targets for improving neuronal recovery in clinical management of EDH. © 2012 Wiley Periodicals, Inc.
Synucleins: Are they two‐edged swords?
Authors: Surguchov Andrei
Published: November 2012

The synuclein family consists of three distinct highly homologous genes, α‐synuclein, β‐synuclein, and γ‐synuclein, which have so far been found only in vertebrates. Proteins encoded by these genes are characterized by an acidic C‐terminal region and five or six imperfect repeat motifs (KTKEGV) distributed throughout the highly conserved N‐terminal region. Numerous data demonstrate that synucleins are implicated in two groups of the most devastating human disorders, i.e., neurodegenerative diseases (NDDs) and cancer. Mutations in the α‐synuclein gene are associated with familial forms of Parkinson's disease (PD), and accumulation of α‐synuclein inclusions is a hallmark of this disorder. In breast cancer, increased expression of γ‐synuclein correlates with disease progression. Conversely, some results indicate that the members of the synuclein family may have a protective effect. How might these small proteins combine such controversial properties? We present evidence that synuclein's features are basically regulated by two mechanisms, i.e., posttranslational modifications (PTMs) and the level of their expression. We also discuss a new, emerging area of investigation of synucleins, namely, their role in the cell‐to‐cell propagation of pathology. © 2012 Wiley Periodicals, Inc.
Guanosine protects against reperfusion injury in rat brains after ischemic stroke
Authors: Connell Barry J. , Di Iorio Patrizia , Sayeed Iqbal , Ballerini Patrizia , Saleh Monique C. , Giuliani Patricia , Saleh Tarek M. , Rathbone Michel P. , Su Caixin , Jiang Shucui
Published: November 2012

After ischemic stroke, early thrombolytic therapy to reestablish tissue perfusion improves outcome but triggers a cascade of deleterious cellular and molecular events. Using a collaborative approach, our groups examined the effects of guanosine (Guo) in response to ischemic reperfusion injury in vitro and in vivo. In a transient middle cerebral artery occlusion (MCAO) in rats, Guo significantly reduced infarct volume in a dose‐dependent manner when given systemically either immediately before or 30 min, but not 60 min, after the onset of the 5.5‐hr reperfusion period. In a separate experiment, Guo significantly reduced infarct volume after 24 hr of reperfusion when administered 5 min before reperfusion. Western blot analysis did not reveal any significant changes either in endoplasmic reticulum (ER) stress proteins (GRP 78 and 94) or HSP 70 or in levels of m‐calpain. In vitro oxygen and glucose deprivation (OGD) significantly increased production of both reactive oxygen species (ROS) and interleukin‐8 (IL‐8) in the primary astrocytes. Guo did not alter ROS or IL‐8 production when given to the astrocytes before OGD. However, Guo when added to the cells prior to or 30 min after reperfusion significantly reduced IL‐8 release but not ROS formation. Our study revealed a dose‐ and time‐dependent protective effect of Guo on reperfusion injury in vitro and vivo. The mechanisms by which Guo exerts its effect are independent of unfolded proteins in ER or the level of intracellular calcium or ROS formation. However, the effect may be induced, at least partially, by inhibiting IL‐8, a marker of reperfusion‐triggered proinflammatory events. © 2012 Wiley Periodicals, Inc.
The use of ovarian vessels for microvascular tissue transfer in lower extremity limb salvage
Authors: Senchenkov Alex , Sim Franklin H.
Published: November 2012

Limb salvage procedures in previously operated, radiated, and vessel‐depleted fields rely heavily on the use of microvascular tissue transfer. This report illustrates the feasibility of the use of ovarian vessels for the revascularization of a free flap. We have achieved success with the use of rectus abdominis muscle free flap for coverage of exposed vascular reconstruction in the 75‐year‐old soft tissue sarcoma patient with twice chemoradiated femoral and hypogastric defect, preventing external hemipelvectomy. © 2012 Wiley Periodicals, Inc. Microsurgery, 2013.
Quantitative Evaluation and Prediction of Drug Effects and Toxicological Risk Using Mechanistic Multiscale Models
Authors: Niklas Jens , Diaz Ochoa Juan G , Bucher Joachim , Mauch Klaus
Published: November 2012

Integrating in vitro and in silico approaches has great potential for reducing experimental effort and delivering know‐how and intellectual property in drug development. Here, we focus on a possible framework for multiscale modeling in pharmaceutical drug development. Looking at the modeling frameworks at different scales, it is obvious that choosing the proper level of complexity and abstraction is not a trivial task. At cellular level, we consider that the application of validated kinetic models of cellular toxicity mechanisms of drugs is particularly important for deriving valid predictions. These kinetic models can be applied for integrating inter‐individual differences, e.g. obtained from data measured in surgical liver samples, into predictions of drug effects. Challenges identified include (i) the development of sufficiently detailed, structured organ models, (ii) definition of multiscale models that can be efficiently handled by available super‐computing facilities, and (iii) availability of validated cell‐type and organ‐specific kinetic metabolic models. Multiscale models can streamline drug development by facilitating the design of experiments and trials, by providing and testing hypotheses, and by reducing time and costs due to less experiments and improved decision‐making. In this review, we discuss the required pieces, possibilities, and challenges in multiscale modeling for the prediction of drug effects.
Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps
Authors: Méndez‐Lucio Oscar , Pérez‐Villanueva Jaime , Castillo Rafael , Medina‐Franco José L.
Published: November 2012

Structure‐activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay. To illustrate this concept, we discuss a case study where Structure‐Activity Similarity maps were used to systematically identify and analyze activity cliff generators present in a dataset of 168 compounds tested against three peroxisome‐proliferator‐activated receptor (PPAR) subtypes. Single‐target and dual‐target activity cliff generators for PPARα and δ were identified. In addition, docking calculations of compounds that were classified as cliff generators helped to suggest a hot spot in the target protein responsible of activity cliffs and to analyze its implication in ligand‐enzyme interaction.
Early hematopoietic stem cell transplant is associated with favorable outcomes in children with MDS
Authors: Smith Angela R. , Christiansen Ellen C. , Wagner John E. , Cao Qing , MacMillan Margaret L. , Stefanski Heather E. , Trotz Barbara A. , Burke Michael J. , Verneris Michael R.
Published: November 2012

Background

Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for childhood myelodysplastic syndrome (MDS), there is no consensus regarding patient or disease characteristics that predict outcomes.

Procedure

We reviewed 37 consecutive pediatric MDS patients who received myeloablative HSCT between 1990 and 2010 at a single center.

Results

Twenty had primary MDS and 17 had secondary MDS. Diagnostic cytogenetics included monosomy 7 (n = 21), trisomy 8 (n = 7) or normal/other (n = 8). According to the modified WHO MDS classification, thirty had refractory cytopenia and seven had refractory anemia with excess blasts. IPSS scores were: low risk (n = 1), intermediate‐1 (n = 15), and intermediate‐2 (n = 21). OS and DFS at 10 years in the entire cohort was 53% and 45%. Relapse at 10 years was 26% and 1 year TRM was 25%. In multivariate analysis, factors associated with improved 3 years DFS were not receiving pre‐HSCT chemotherapy (RR = 0.30, 95% CI 0.10–0.88; P = 0.03) and a shorter interval (<140 days) from time of diagnosis to transplant (RR = 0.27, 95% CI 0.09–0.80; P = 0.02). Three years DFS in patients who did not receive pre‐HSCT chemotherapy and those who had a shorter interval to transplant (n = 16) was 80%.

Conclusion

These results suggest that children with MDS should be referred for allogeneic HSCT soon after diagnosis and that pre‐HSCT chemotherapy does not appear to improve outcomes. Pediatr Blood Cancer 2013; 60: 705–710. © 2012 Wiley Periodicals, Inc.
Successful liver transplantation in an infant with stage 4S(M) neuroblastoma
Authors: Steele Melanie , Jones Nicola L. , Ng Vicky , Kamath Binita , Avitzur Yaron , Chami Rose , Cutz Ernest , Fecteau Annie , Baruchel Sylvain
Published: November 2012

We report a 2.5‐month‐old infant with bilateral adrenal neuroblastoma, stage 4S(M), with liver metastases and chemotherapy‐induced veno‐occlusive disease leading to cirrhosis requiring liver transplantation. Despite unknown tumour histology and MYCN‐amplification status, we proceeded with liver transplant. This decision was based on clinical suspicion that our patient was MYCN‐negative due to significant tumour regression, and was supported by evidence indicating that MYCN‐amplification is rare in infants with favourable‐stage neuroblastoma. This is the second case report of neuroblastoma requiring liver transplantation; however, in the previously reported case, the diagnosis of neuroblastoma was not established until after transplantation. We discuss this unique case to justify the potential use of life‐saving liver transplants in infants with neuroblastoma. Pediatr Blood Cancer 2013; 60: 515–517. © 2012 Wiley Periodicals, Inc.
Pharmacokinetic interaction between methotrexate and chloral hydrate
Authors: Dao Kim , Ivanyuk Anton , Buclin Thierry , Beck‐Popovic Maja , Diezi Manuel
Published: November 2012

We report the case of a drug interaction between methotrexate (MTX) and chloral hydrate (CH) observed in a child treated for acute leukemia. Significantly slower MTX clearance and increased MTX exposure occurred on the first three courses of a high‐dose chemotherapy when co‐administered with CH despite normal renal function, adequate hydration, and alkalinization. Mean MTX area under the curve associated with CH administration was 1,134 µmol hours/L, compared to 608 µmol hours/L after discontinuation of CH. This interaction possibly resulted from a competition between anionic CH metabolites and MTX for renal tubular excretion. Pediatr Blood Cancer 2013; 60: 518–520. © 2012 Wiley Periodicals, Inc.
Mental health disorders influence admission rates for pain in children with sickle cell disease
Authors: Myrvik Matthew P. , Burks Lisa M. , Hoffman Raymond G. , Dasgupta Mahua , Panepinto Julie A.
Published: November 2012

Background

Patients with sickle cell disease (SCD) experience a broad range of mental health disorders placing them at risk for more complicated hospitalizations for pain. The current study examined the impact of mental health disorders on admission rates and hospital length of stay (LOS) for vaso‐occlusive pain events (VOE) in pediatric patients with SCD.

Procedure

Patients (5–18 years old) with a primary discharge diagnosis of SCD with crisis were acquired through the Pediatric Health Information System and categorized by history of mental health disorders (mood disorder, anxiety disorder, disruptive behavior disorder, and substance use disorder). Using a retrospective cohort design, hospital admission rates for VOE were examined as the primary outcome and LOS as a secondary outcome.

Results

A total of 5,825 patients accounted for 23,561 admissions for SCD with crisis with approximately 8% of the patients having a mental health diagnosis. Longer LOS was found among patients with a history of any mental health diagnosis (P < 0.0001) and within the mood disorder (P < 0.0001), anxiety disorder (P < 0.0001), and substance use disorder (P = 0.01) subtypes. Hospital admissions rates for VOE were higher among patients with a history of any mental health diagnosis (P < 0.0001) and within the mood disorder (P < 0.0001), anxiety disorder (P < 0.0001), disruptive behavior disorder (P = 0.002), and substance use disorder (P < 0.0001) subtypes.

Conclusions

Pediatric patients with SCD and a history of a mental health diagnosis have longer LOS and higher admission rates for management of VOE. Ultimately, these findings suggest that mental health pose a challenge to the management of sickle cell pain. Pediatr Blood Cancer 2013; 60: 1211–1214. © 2012 Wiley Periodicals, Inc.
Cationic polymerization of isoprene using zinc halides as co‐initiators: towards well‐defined oligo(isoprene)s under mild conditions
Authors: Rozentsvet Victor A , Kozlov Valery G , Ziganshina Elza F , Boreiko Natalya P , Kostjuk Sergei V
Published: November 2012

The activity of ZnX2‐based initiating systems (X = Cl, Br, I) in the cationic polymerization of isoprene was studied. The highest activity was achieved when co‐initiator (ZnX2) was solubilized in a minimal amount of strongly coordinating solvent such as diethyl ether or acetone and when trichloroacetic acid was used as an initiator. It is shown that the polymerization rate increased in the series ZnI2 < ZnCl2 < ZnBr2. An increase of initiator concentration and temperature also led to an increase of the polymerization rate. The obtained polyisoprenes did not contain high‐molecular‐weight and insoluble fractions and were characterized by low number‐average molecular weight and relatively narrow molecular weight distribution. Unsaturation of polyisoprene decreased with an increase of monomer conversion and reaction temperature. The unsaturated part of the polyisoprene chain possessed predominantly 1,4‐trans microstructure with regular and inverse addition, whereas the 1,2‐ and 3,4‐isomers were present as minor components. It is shown that the synthesized low‐molecular‐weight polyisoprenes are effective plasticizers for rubber compounds in the manufacture of tyres. © 2012 Society of Chemical Industry
Antibacterial and biocompatible surfaces based on dopamine autooxidized silver nanoparticles
Authors: Sureshkumar Manthiriyappan , Siswanto Dessy Yovita , Chen Yong‐Cin , Lee Cheng‐Kang , Wang Meng‐Jiy
Published: November 2012

A facile and green method is proposed to immobilize silver nanoparticles (AgNPs) showing antibacterial and biocompatible properties on surfaces of substrates. The adhesive and reductive polydopamine (Pdop) coating was applied on the substrates such as polyethylene, glass, poly(methyl methacrylate), and poly(lactic‐co‐glycolic acid) by simply dipping into dopamine solutions. AgNPs of 50–70 nm formed uniformly on the Pdop‐coated surfaces after immersing in silver nitrate solution where the density of AgNPs was modulated by Pdop immobilization time. Antibacterial efficacy, lactate dehydrogenase assay, and cell morphology observed by microscopy indicated that the as‐prepared AgNPs deposited on Pdop/substrates possessed effective biocidal properties and did not inhibit the growth of L‐929 cells mouse fibroblasts. The proposed method can be easily applied on different substrates and revealed good biocompatibility, which could be further developed for applications in biomaterials. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013
Ethylmalonic acid modulates Na+, K+‐ATPase activity and mRNA levels in rat cerebral cortex
Authors: Schuck Patrícia Fernanda , De Assis Dênis Reis , Viegas Carolina Maso , Brandão Pereira Talita Carneiro , Machado Jéssica Luca , Furlanetto Camila Brulezi , Bogo Mauricio Reis , Streck Emilio Luiz , Ferreira Gustavo Costa
Published: November 2012

Ethylmalonic acid (EMA) accumulates in tissues of patients affected by short‐chain acyl‐CoA dehydrogenase deficiency and ethylmalonic encephalopathy, illnesses characterized by variable neurological symptoms. In this work, we investigated the in vitro and in vivo EMA effects on Na+,K+‐ATPase (NAK) activity and mRNA levels in cerebral cortex from 30‐day‐old rats. For in vitro studies, cerebral cortex homogenates were incubated in the presence of EMA at 0.5, 1, or 2.5 mM concentrations for 1 h. For in vivo experiments, animals received three subcutaneous EMA injections (6 μmol g−1; 90‐min interval) and were killed 60 min after the last injection. After that, NAK activity and its mRNA expression were measured. We observed that EMA did not affect this enzyme activity in vitro. In contrast, EMA administration significantly increased NAK activity and decreased mRNA NAK expression as assessed by semiquantitative reverse transcriptase polymerase chain reaction when compared with control group. Considering the high score of residues prone to phosphorylation on NAK, this profile can be associated with a possible regulation by specific phosphorylation sites of the enzyme. Altogether, the present results suggest that NAK alterations may be involved in the pathophysiology of brain damage found in patients in which EMA accumulates. Synapse, 2013. © 2012 Wiley Periodicals, Inc.
Baclofen did not modify sexually dimorphic c‐Fos expression during morphine withdrawal syndrome
Authors: Pedrón Valeria T. , Taravini Irene R.E. , Induni Andrea S. , Balerio Graciela N.
Published: November 2012

In previous studies, we have reported sex‐related differences during morphine withdrawal. We have also shown that the GABAB agonist baclofen (BAC) was able to prevent the morphine withdrawal syndrome in male as well as in female mice. Considering that early gene expression is induced by drugs of abuse, we evaluated the expression of c‐Fos in several brain areas, in mice of either sex during naloxone (NAL)‐precipitated withdrawal, and after pretreatment with BAC. Swiss‐Webster prepubertal mice were rendered dependent by i.p. injection of morphine (2 mg/kg), twice daily for 9 days. On the 10th day, dependent mice were divided into two groups: the withdrawal group received NAL (6 mg/kg, i.p.) after the last dose of morphine, while the prevention group received BAC (2 mg/kg, i.p.) before NAL. Thirty minutes after NAL, animals were sacrificed by transcardial perfusion. Brains were removed and slices were obtained to perform immunohistochemical studies. Our results show a significant decrease in c‐Fos expression in hippocampal dentate gyrus, CA3, and CA1 areas of morphine withdrawn males, vs. their control group. Conversely, in females, the number of c‐Fos positive nuclei was not modified in any of the areas studied. BAC pretreatment had no effect on the decreased c‐Fos expression in morphine withdrawn males. The sexual dimorphism observed here confirms the greater sensitivity of males over females in their response to morphine. The preventive action of BAC on the expression of morphine withdrawal would not be related to an effect on c‐Fos expression. Synapse, 2013. © 2012 Wiley Periodicals, Inc.
Mitochondrial plasticity of the hippocampus in a genetic rat model of depression after antidepressant treatment
Authors: Chen Fenghua , Wegener Gregers , Madsen Torsten M. , Nyengaard Jens R.
Published: November 2012

Depressive disorders and the treatment thereof have been associated with a number of neuroplastic events, such as neurogenesis and synaptic remodeling in discrete areas of the brain. The associations of these events in changes regarding the energy supply have not been investigated. Here, we investigated the changes in mitochondrial plasticity and its correlation to morphological alterations of neuroplasticity in the hippocampus, both associated with a depressive phenotype, and after treatment, with antidepressant imipramine. Design‐based stereological methods were used to estimate the number and volume of mitochondria in CA1 of the hippocampus in two different strains of rats, the Sprague–Dawley (SD) and Flinders rats, which display a genetic susceptibility to depressive behavior, the Flinders‐sensitive line (FSL) and their corresponding controls, the Flinders‐resistant line (FRL). Results showed a significantly reduced number of mitochondria in CA1, which was significantly smaller in the untreated FSL saline group compared to the FRL group. However, the mean volume of mitochondria was significantly larger in the FSL saline group compared to the FRL saline group. Following treatment, the FSL imipramine group showed a significant increase in the number of mitochondria compared to the FSL saline group. Treatment with imipramine in the SD rats did not induce significant differences in the number of mitochondria. Our results indicate that depression may be related to impairments of mitochondrial plasticity in the hippocampus and antidepressant treatment may counteract with the structural impairments. Moreover, the changes in mitochondrial morphology and number are a consistent feature of neuroplasticity. Synapse, 2013. © 2012 Wiley Periodicals, Inc.
The greenhouse development rights framework for global burden sharing: reflection on principles and prospects
Authors: Baer Paul
Published: November 2012

The Greenhouse Development Rights (GDRs) Framework is a proposal for a global climate agreement in which the obligations assigned to nations are based on a combination of responsibility (contribution to the problem) and capacity (ability to pay). A key feature of the GDRs framework is that it is modeled on the assignment of a ‘right to development’ to individuals, such that individuals with incomes below a ‘development threshold’ are nominally exempted from obligations to pay for mitigation and adaptation. Obligations for those ‘over the threshold’ are calculated in the same way for rich persons in poor countries and rich persons in rich countries. As income distribution within countries is taken into account and all countries have some wealthy people, all countries have a positive obligation to contribute to global mitigation and adaptation requirements, eliminating the sharp distinction between Annex I and non‐Annex I countries. In the last few years, GDRs has become one of the most widely known of the many so‐called burden‐sharing frameworks that have been proposed. In this essay, one of the co‐authors of the GDRs framework presents the framework's fundamental principles, describes its place in the larger discussion of burden‐sharing and climate justice, and reflects on its prospects in the next phase of the global climate negotiations. Hopefully it will be helpful both to readers new to GDRs and to our existing supporters and critics. WIREs Clim Change 2013, 4:61–71. doi: 10.1002/wcc.201

This article is categorized under:

Climate, Nature, and Ethics > Climate Change and Human Rights
Mechanisms of memory enhancement
Authors: Stern Sarah A. , Alberini Cristina M.
Published: November 2012

The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long‐term memories are formed has provided insight into how memories might also be enhanced. Capitalizing on this knowledge, it has been postulated that targeting many of the same mechanisms, including CREB activation, AMPA/NMDA receptor trafficking, neuromodulation (e.g., via dopamine, adrenaline, cortisol, or acetylcholine) and metabolic processes (e.g., via glucose and insulin) may all lead to the enhancement of memory. These and other mechanisms and/or approaches have been tested via genetic or pharmacological methods in animal models, and several have been investigated in humans as well. In addition, a number of behavioral methods, including exercise and reconsolidation, may also serve to strengthen and enhance memories. By utilizing this information and continuing to investigate these promising avenues, memory enhancement may indeed be achieved in the future. WIREs Syst Biol Med 2013, 5:37–53. doi: 10.1002/wsbm.1196

This article is categorized under:

Translational, Genomic, and Systems Medicine > Therapeutic Methods

Translational, Genomic, and Systems Medicine > Translational Medicine
Physics reach of CERN-based SuperBeam neutrino oscillation experiments
Authors: Coloma Pilar , Fernández-Martínez Enrique , Labarga Luis
Published: November 2012

Abstract

We compare the physics potential of two representative options for a Super-Beam in Europe, studying the achievable precision at 1σ with which the CP violation phase (δ) could be measured, as well as the mass hierarchy and CP violation discovery potentials. The first setup corresponds to a high energy beam aiming from CERN to a 100 kt liquid argon detector placed at the Pyhäsalmi mine (2300 km), one of the LAGUNA candidate sites. The second setup corresponds to a much lower energy beam, aiming from CERN to a 500 kt water Čerenkov detector placed at the Gran Sasso underground laboratory (730 km). This second option is also studied for a baseline of 650 km, corresponding to the LAGUNA candidate sites of Umbria and the Canfranc underground laboratory. All results are presented also for scenarios with statistics lowered by factors of 2, 4, 8 and 16 to study the possible reductions of flux, detector mass or running time allowed by the large value of θ
13 recently measured.
QCD threshold corrections for gluino pair production at hadron colliders
Authors: Langenfeld Ulrich , Moch Sven-Olaf , Pfoh Torsten
Published: November 2012

Abstract

We present the complete threshold enhanced predictions in QCD for the total cross section of gluino pair production at hadron colliders at next-to-next-to-leading order. Thanks to the computation of the required one-loop hard matching coefficients our results are accurate to the next-to-next-to-leading logarithm. In a brief phenomenological study we provide predictions for the total hadronic cross sections at the LHC and we discuss the uncertainties arising from scale variations and the parton distribution functions.