bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixing dynamics in bubbling fluidized beds
Authors: Bakshi A. , Ghoniem A. F. , Altantzis C.
Published: May 2017

Solids mixing affects thermal and concentration gradients in fluidized bed reactors and is, therefore, critical to their performance. Despite substantial effort over the past decades, understanding of solids mixing continues to be lacking because of technical limitations of diagnostics in large pilot and commercial‐scale reactors. This study is focused on investigating mixing dynamics and their dependence on operating conditions using computational fluid dynamics simulations. Toward this end, fine‐grid 3D simulations are conducted for the bubbling fluidization of three distinct Geldart B particles (1.15 mm LLDPE, 0.50 mm glass, and 0.29 mm alumina) at superficial gas velocities U/Umf = 2–4 in a pilot‐scale 50 cm diameter bed. The Two‐Fluid Model (TFM) is employed to describe the solids motion efficiently while bubbles are detected and tracked using MS3DATA. Detailed statistics of the flow‐field in and around bubbles are computed and used to describe bubble‐induced solids micromixing: solids upflow driven in the nose and wake regions while downflow along the bubble walls. Further, within these regions, the hydrodynamics are dependent only on particle and bubble characteristics, and relatively independent of the global operating conditions. Based on this finding, a predictive mechanistic, analytical model is developed which integrates bubble‐induced micromixing contributions over their size and spatial distributions to describe the gross solids circulation within the fluidized bed. Finally, it is shown that solids mixing is affected adversely in the presence of gas bypass, or throughflow, particularly in the fluidization of heavier particles. This is because of inefficient gas solids contacting as 30–50% of the superficial gas flow escapes with 2–3× shorter residence time through the bed. This is one of the first large‐scale studies where both the gas (bubble) and solids motion, and their interaction, are investigated in detail and the developed framework is useful for predicting solids mixing in large‐scale reactors as well as for analyzing mixing dynamics in complex reactive particulate systems. © 2017 American Institute of Chemical Engineers AIChE J, 63: 4316–4328, 2017
Alpha male replacements in nonhuman primates: Variability in processes, outcomes, and terminology
Authors: Teichroeb Julie A. , Jack Katharine M.
Published: May 2017

Alpha male replacements occur in all primates displaying a dominance hierarchy but the process can be extremely variable. Here, we review the primate literature to document differences in patterns of alpha male replacements, showing that group composition and dispersal patterns account for a large proportion of this variability. We also examine the consequences of alpha male replacements in terms of sexual selection theory, infanticide, and group compositions. Though alpha male replacements are often called takeovers in the literature, this term masks much of the variation that is present in these processes. We argue for more concise terminology and provide a list of terms that we suggest more accurately define these events. Finally, we introduce the papers in this special issue on alpha male replacements in the American Journal of Primatology and discuss areas where data are still lacking.
Denatonium‐induced sinonasal bacterial killing may play a role in chronic rhinosinusitis outcomes
Authors: Carey Ryan M. , Workman Alan D. , Hatten Kyle M. , Siebert Adam P. , Brooks Steven G. , Chen Bei , Adappa Nithin D. , Palmer James N. , Kennedy David W. , Lee Robert J. , Cohen Noam A.
Published: May 2017

Background

Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium‐mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes.

Methods

Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium‐stimulated sinonasal air‐liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations.

Results

There is variability in the degree of denatonium‐induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) (p = 0.037) and have worse 6‐month post‐FESS 22‐item Sino‐Nasal Outcome Test (SNOT‐22) scores (p = 0.012).

Conclusion

Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT‐22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity.
Prognostic models and nomograms for predicting survival of patients with maxillary sinus carcinomas
Authors: Shen Weidong , Sakamoto Naoko , Yang Limin
Published: May 2017

Background

Maxillary sinus carcinoma is an uncommon malignancy. Most reports on prognosis of this disease are from single institutions and include few patients. We used data from the United States National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program to construct models and nomograms for predicting outcomes of patients with maxillary sinus carcinomas.

Methods

We used records from 668 patients with primary maxillary sinus carcinomas reported to the SEER program from 2004 to 2013 to build nomograms based on stratified multivariable Cox proportional hazard models for predicting 5‐year overall survival (OS) and cause‐specific survival (CSS). Model building was internally validated with the bootstrap approach.

Results

Five‐year survival was 39.7% (95% confidence interval [CI], 35.5% to 44.5%) and 46.8% (42.3% to 51.8%) for OS and CSS, respectively. The final Cox model included the variables of age at diagnosis, tumor size, histologic type, TNM stage, and surgery. Radiotherapy was a stratification factor in the models. The models demonstrated good accuracy for predicting survival with a bootstrap‐corrected Somers Dxy of 0.44 for both OS and CSS models. Calibration curves indicated acceptable model calibration.

Conclusion

We developed tools for predicting prognosis that incorporate TNM stage and other readily available variables for patients with maxillary sinus carcinomas. The model performance was validated as good. These models can help clinicians to offer improved patient counseling in terms of clinical outcomes and make optimal treatment plans.
Common Fibril Structures Imply Systemically Conserved Protein Misfolding Pathways In Vivo
Authors: Annamalai Karthikeyan , Liberta Falk , Vielberg Marie‐Theres , Close William , Lilie Hauke , Gührs Karl‐Heinz , Schierhorn Angelika , Koehler Rolf , Schmidt Andreas , Haupt Christian , Hegenbart Ute , Schönland Stefan , Schmidt Matthias , Groll Michael , Fändrich Marcus
Published: May 2017

Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post‐translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril. Our data imply for both analyzed forms of amyloidosis that the pathways of protein misfolding are systemically conserved; that is, they follow the same rules irrespective of where inside one body fibrils are formed or accumulated.
Surface Modification of Two‐Dimensional Metal–Organic Layers Creates Biomimetic Catalytic Microenvironments for Selective Oxidation
Authors: Shi Wenjie , Cao Lingyun , Zhang Hua , Zhou Xin , An Bing , Lin Zekai , Dai Ruihan , Li Jianfeng , Wang Cheng , Lin Wenbin
Published: May 2017

Microenvironments in enzymes play crucial roles in controlling the activities and selectivities of reaction centers. Herein we report the tuning of the catalytic microenvironments of metal–organic layers (MOLs), a two‐dimensional version of metal–organic frameworks (MOFs) with thickness down to a monolayer, to control product selectivities. By modifying the secondary building units (SBUs) of MOLs with monocarboxylic acids, such as gluconic acid, we changed the hydrophobicity/hydrophilicity around the active sites and fine‐tuned the selectivity in photocatalytic oxidation of tetrahydrofuran (THF) to exclusively afford butyrolactone (BTL), likely a result of prolonging the residence time of reaction intermediates in the hydrophilic microenvironment of catalytic centers. Our work highlights new opportunities in using functional MOLs as highly tunable and selective two‐dimensional catalytic materials.
A Tunable Ionic Diode Based on a Biomimetic Structure‐Tailorable Nanochannel
Authors: Xiao Kai , Chen Lu , Zhang Zhen , Xie Ganhua , Li Pei , Kong Xiang‐Yu , Wen Liping , Jiang Lei
Published: May 2017

A tunable ionic diode is presented that is based on biomimetic structure‐tailorable nanochannels, with precise ion‐transport characteristics from ohmic behavior to bidirectional rectification as well as gating properties. The forward/reverse directions of the ionic diode and the degree of rectification can be well‐regulated by combining the patterned surface charge and the sophisticated structure. This system creates an ideal platform for precise transportation of ions and molecules, and potential applications in analytical sciences are anticipated.
Unexpected Direct Synthesis of N‐Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition
Authors: Choi Hans , Shirley Harry J. , Hume Paul A. , Brimble Margaret A. , Furkert Daniel P.
Published: May 2017

The unexpected synthesis of industrially important N‐vinyl amides directly from aldehydes and α,β‐unsaturated N‐vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide–enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom‐efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.
Catalytic Electrophilic Alkylation of p‐Quinones through a Redox Chain Reaction
Authors: Xu Xiao‐Long , Li Zhi
Published: May 2017

Allylation and benzylation of p‐quinones was achieved through an unusual redox chain reaction. Mechanistic studies suggest that the existence of trace hydroquinone initiates a redox chain reaction that consists of a Lewis acid catalyzed Friedel–Crafts alkylation and a subsequent redox equilibrium that regenerates hydroquinone. The electrophiles could be various allylic and benzylic esters. The addition of Hantzsch ester as an initiator improves the efficiency of the reaction.
Carbon Monoxide Dehydrogenase Reduces Cyanate to Cyanide
Authors: Ciaccafava Alexandre , Tombolelli Daria , Domnik Lilith , Jeoung Jae‐Hun , Dobbek Holger , Mroginski Maria‐Andrea , Zebger Ingo , Hildebrandt Peter
Published: May 2017

The biocatalytic function of carbon monoxide dehydrogenase (CODH) has a high environmental relevance owing to its ability to reduce CO2. Despite numerous studies on CODH over the past decades, its catalytic mechanism is not yet fully understood. In the present combined spectroscopic and theoretical study, we report first evidences for a cyanate (NCO−) to cyanide (CN−) reduction at the C‐cluster. The adduct remains bound to the catalytic center to form the so‐called CN−‐inhibited state. Notably, this conversion does not occur in crystals of the Carboxydothermus hydrogenoformans CODH enzyme (CODHIICh), as indicated by the lack of the corresponding CN− stretching mode. The transformation of NCO−, which also acts as an inhibitor of the two‐electron‐reduced Cred2 state of CODH, could thus mimic CO2 turnover and open new perspectives for elucidation of the detailed catalytic mechanism of CODH.
Single‐Atom Electrocatalysts
Authors: Zhu Chengzhou , Fu Shaofang , Shi Qiurong , Du Dan , Lin Yuehe
Published: May 2017

Recent years have witnessed a dramatic increase in the production of sustainable and renewable energy. However, the electrochemical performances of the various systems are limited, and there is an intensive search for highly efficient electrocatalysts by more rational control over the size, shape, composition, and structure. Of particular interest are the studies on single‐atom catalysts (SACs), which have sparked new interests in electrocatalysis because of their high catalytic activity, stability, selectivity, and 100 % atom utilization. In this Review, we introduce innovative syntheses and characterization techniques for SACs, with a focus on their electrochemical applications in the oxygen reduction/evolution reaction, hydrogen evolution reaction, and hydrocarbon conversion reactions for fuel cells (electrooxidation of methanol, ethanol, and formic acid). The electrocatalytic performance is further considered at an atomic level and the underlying mechanisms are discussed. The ultimate goal is the tailoring of single atoms for electrochemical applications.
Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation
Authors: Tseng Wen‐Hsuan , Chang Chung‐ke , Wu Pei‐Ching , Hu Nien‐Jen , Lee Gene‐Hsiang , Tzeng Ching‐Cherng , Neidle Stephen , Hou Ming‐Hon
Published: May 2017

Small‐molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. NiII(Chro)2 (Chro=chromomycin A3) binds specifically to the minor groove of (CCG)n repeats in duplex DNA, with unique fluorescence features that may serve as a probe for disease detection. Crystallographic studies revealed that the specificity originates from the large‐scale spatial rearrangement of the DNA structure, including extrusion of consecutive bases and backbone distortions, with a sharp bending of the duplex accompanied by conformational changes in the NiII chelate itself. The DNA deformation of CCG repeats upon binding forms a GGCC tetranucleotide tract, which is recognized by NiII(Chro)2. The extruded cytosine and last guanine nucleotides form water‐mediated hydrogen bonds, which aid in ligand recognition. The recognition can be accounted for by the classic induced‐fit paradigm.
Effects of polymer properties on jetting performance of electrohydrodynamic printing
Authors: Bae Jaehyun , Lee Jaewoong , Hyun Kim Se
Published: May 2017

We perform systematic study on the jetting performance of electrohydrodynamic (EHD) with an insulating polymers such as polystyrene (PS) and poly(methyl methacrylate) (PMMA). EHD printing applies electrostatic field to ink droplet hang on nozzle tip, which causes the deformation of the meniscus to generate discrete droplets or continuous jet stream. Although EHD jetting mechanism has been frequently investigated with conducting or semiconducting materials, there still needs to elucidate EHD jetting of insulating polymer materials for producing controllable droplets. In the present study, we focused on how the physical/chemical properties (conductivity, dielectric constant, and molecular weight) of an insulating polymer affect jetting behavior of EHD printing (especially, the deformation of the meniscus and the corresponding morphology of the printed one). The relationship between the printing parameters and applied voltage is also investigated, thereby allowing the optimization of EHD printings for PS and PMMA. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45044.
Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis
Authors: Fu Rong , Guo Chaohuan , Wang Shuang , Huang Yuefang , Jin Ou , Hu Haoqiang , Chen Jingxian , Xu Bihua , Zhou Mianjing , Zhao Jijun , Sung Sun‐sang J. , Wang Hongyang , Gaskin Felicia , Yang Niansheng , Fu Shu Man
Published: May 2017

Objective

Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. The purpose of this study was to investigate whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN.

Methods

A fluorescence‐labeled caspase 1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes derived from lupus‐prone NZM2328 mice and from renal biopsy tissues obtained from patients with LN. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, podocyte ultrastructure, and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line, and the cells were analyzed by flow cytometry.

Results

NLRP3 inflammasomes were activated in podocytes from lupus‐prone mice and from patients with LN. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histologic lesions, and podocyte foot process effacement in lupus‐prone mice. In vitro, sera from diseased NZM2328 mice activated NLRP3 inflammasomes in the podocyte cell line through the production of reactive oxygen species.

Conclusion

NLRP3 inflammasomes were activated in podocytes from lupus‐prone mice and from LN patients. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.
Effects of Teriparatide on Joint Erosions in Rheumatoid Arthritis: A Randomized Controlled Trial
Authors: Solomon D. H. , Kay J. , Duryea J. , Lu B. , Bolster M. B. , Yood R. A. , Han R. , Ball S. , Coleman C. , Lo E. , Wohlfahrt A. , Sury M. , Yin M. , Yu Z. , Zak A. , Gravallese E. M.
Published: May 2017

Objective

Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi).

Methods

We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait‐list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2‐tailed test, with P values less than 0.05 considered significant.

Results

Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was −0.4 mm3 (interquartile range [IQR] −34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm3 [IQR −29.6, 26.4]) (P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group.

Conclusion

Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.
Exacerbation of Aging‐Associated and Instability‐Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D2 Receptor
Authors: Ouhaddi Yassine , Nebbaki Sarah‐Salwa , Habouri Lauris , Afif Hassan , Lussier Bertrand , Kapoor Mohit , Narumiya Shuh , Pelletier Jean‐Pierre , Martel‐Pelletier Johanne , Benderdour Mohamed , Fahmi Hassan
Published: May 2017

Objective

D prostanoid receptor 1 (DP1), a receptor for prostaglandin D2, plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown. This study was undertaken to explore the roles of DP1 in the development of OA in murine models and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA.

Methods

The development of aging‐associated OA and destabilization of the medial meniscus (DMM)–induced OA was compared between DP1‐deficient (DP1−/−) and wild‐type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and micro–computed tomography. Cartilage explants from DP1−/− and WT mice were treated with interleukin‐1α (IL‐1α) ex vivo, to evaluate proteoglycan degradation. The effect of intraperitoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice.

Results

Compared to WT mice, DP1−/− mice had exacerbated cartilage degradation in both models of OA, and this was associated with increased expression of matrix metalloproteinase 13 and ADAMTS‐5. In addition, DP1−/− mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1−/− mice showed enhanced proteoglycan degradation following treatment with IL‐1α. Intraperitoneal injection of BW245C attenuated the severity of DMM‐induced cartilage degradation and bony changes in WT mice.

Conclusion

These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of the functions of DP1 may constitute a potential therapeutic target for the development of novel OA treatments.
Hydrogen bond‐Driven Self–Assembly between Amidinium Cations and Carboxylate Anions: A Combined Molecular Dynamics, NMR Spectroscopy, and Single Crystal X‐ray Diffraction Study
Authors: Thomas Michael , Anglim Lagones Thomas , Judd Martyna , Morshedi Mahbod , O'Mara Megan L. , White Nicholas G.
Published: May 2017

A combination of molecular dynamics (MD), NMR spectroscopy, and single crystal X‐ray diffraction (SCXRD) techniques was used to probe the self–assembly of para‐ and meta‐bis(amidinium) compounds with para‐, meta‐, and ortho‐dicarboxylates. Good concordance was observed between the MD and experimental results. In DMSO solution, the systems form several rapidly exchanging assemblies, in part because a range of hydrogen bonding interactions is possible between the amidinium and carboxylate moieties. Upon crystallization, the majority of the systems form 1D supramolecular polymers, which are held together by short N−H⋅⋅⋅O hydrogen bonds.
Aziridine‐Mediated Ligation at Phenylalanine and Tryptophan Sites
Authors: Bajaj Kiran , Sakhuja Rajeev
Published: May 2017

An efficient approach towards peptide synthesis that allows easy access to variety of small peptides via one‐pot aziridine‐mediated ligation/desulfurization strategy has been described. The protocol afforded a library of phenylalanine‐ and tryptophan‐containing α‐peptides in good yields by regioselective ring‐opening of aziridine‐3‐aryl‐2‐carboxylates with peptide thioacids, followed by desulfurization.
Production of microbial biosurfactants: Status quo of rhamnolipid and surfactin towards large‐scale production
Authors: Henkel Marius , Geissler Mareen , Weggenmann Fabiola , Hausmann Rudolf
Published: May 2017

Surfactants are an important class of industrial chemicals. Nowadays oleochemical surfactants such as alkyl polyglycosides (APGs) become increasingly important. This trend towards the utilization of renewable resources continues and consumers increasingly demand for environmentally friendly products. Consequently, research in microbial surfactants has drastically increased in the last years. While for mannosylerythritol lipids and sophorolipids established industrial processes exist, an implementation of other microbially derived surfactants has not yet been achieved. Amongst these biosurfactants, rhamnolipids synthesized by Pseudomonas aeruginosa and surfactin produced by Bacillus subtilis are so far the most analyzed biosurfactants due to their exceptional properties and the concomitant possible applications. In this review, a general overview is given regarding the current status of biosurfactants and benefits attributed to these molecules. Furthermore, the most recent research approaches for both rhamnolipids and surfactin are presented with respect to possible methods for industrial processes and the occurring drawbacks and limitations researchers have to address and overcome.
Picture free recall performance linked to the brain's structural connectome
Authors: Coynel David , Gschwind Leo , Fastenrath Matthias , Freytag Virginie , Milnik Annette , Spalek Klara , Papassotiropoulos Andreas , de Quervain Dominique J.‐F.
Published: May 2017

Introduction

Memory functions are highly variable between healthy humans. The neural correlates of this variability remain largely unknown.

Methods

Here, we investigated how differences in free recall performance are associated with DTI‐based properties of the brain's structural connectome and with grey matter volumes in 664 healthy young individuals tested in the same MR scanner.

Results

Global structural connectivity, but not overall or regional grey matter volumes, positively correlated with recall performance. Moreover, a set of 22 inter‐regional connections, including some with no previously reported relation to human memory, such as the connection between the temporal pole and the nucleus accumbens, explained 7.8% of phenotypic variance.

Conclusions

In conclusion, this large‐scale study indicates that individual memory performance is associated with the level of structural brain connectivity.
Are there differences in brain morphology according to handedness?
Authors: Jang Han , Lee Jae Youn , Lee Kang Il , Park Kang Min
Published: May 2017

Objective

This study aimed to investigate the differences in brain morphology according to handedness.

Materials and Methods

Forty‐two healthy subjects were enrolled (21 right‐handers and 21 nonright‐handers). The two groups were classified according to the Edinburgh Handedness Inventory. Measures of cortical morphology, such as thickness, surface area, volume, and curvature, and the volumes of subcortical structures, such as the amygdala, caudate, hippocampus, globus pallidus, putamen, and thalamus, were compared between the groups according to handedness using whole‐brain 3D T1‐weighted MRI. In addition, we investigated the white matter differences between the groups using diffusion tensor imaging. Moreover, we quantified correlations between the handedness scales of the Edinburgh Handedness Inventory and each measure of different brain morphologies.

Results

The volumes of the right putamen and left globus pallidus in nonright‐handed participants were significantly larger than those who were right‐handed (0.3559 vs. 0.3155%, p = .0028; 0.1101 vs. 0.0975%, p = .0025; respectively). Moreover, the volumes of the right putamen and left globus pallidus were negatively correlated with the handedness scales of the Edinburgh Handedness Inventory (r = −.392, p = .0101; r = −.361, p = .0189; respectively). However, the cortex morphology and the other subcortical volumes were not significantly different between the two groups. In addition, we did not find any white matter differences between the groups.

Conclusions

We demonstrated that there were significant differences in brain morphology between right‐handers and nonright‐handers, especially in the basal ganglia, which could produce differences in motor control according to handedness.
Germline INDELs and CNVs in a cohort of colorectal cancer patients: their characteristics, associations with relapse‐free survival time, and potential time‐varying effects on the risk of relapse
Authors: Werdyani Salem , Yu Yajun , Skardasi Georgia , Xu Jingxiong , Shestopaloff Konstantin , Xu Wei , Dicks Elizabeth , Green Jane , Parfrey Patrick , Yilmaz Yildiz E. , Savas Sevtap
Published: May 2017

INDELs and CNVs are structural variations that may play roles in cancer susceptibility and patient outcomes. Our objectives were a) to computationally detect and examine the genome‐wide INDEL/CNV profiles in a cohort of colorectal cancer patients, and b) to examine the associations of frequent INDELs/CNVs with relapse‐free survival time. We also identified unique variants in 13 Familial Colorectal Cancer Type X (FCCX) cases. The study cohort consisted of 495 colorectal cancer patients. QuantiSNP and PennCNV algorithms were utilized to predict the INDELs/CNVs using genome‐wide signal intensity data. Duplex PCR was used to validate predictions for 10 variants. Multivariable Cox regression models were used to test the associations of 106 common variants with relapse‐free survival time. Score test and the multivariable Cox proportional hazards models with time‐varying coefficients were applied to identify the variants with time‐varying effects on the relapse‐free survival time. A total of 3486 distinct INDELs/CNVs were identified in the patient cohort. The majority of these variants were rare (83%) and deletion variants (81%). The results of the computational predictions and duplex PCR results were highly concordant (93–100%). We identified four promising variants significantly associated with relapse‐free survival time (P < 0.05) in the multivariable Cox proportional hazards regression models after adjustment for clinical factors. More importantly, two additional variants were identified to have time‐varying effects on the risk of relapse. Finally, 58 rare variants were identified unique to the FCCX cases; none of them were detected in more than one patient. This is one of the first genome‐wide analyses that identified the germline INDEL/CNV profiles in colorectal cancer patients. Our analyses identified novel variants and genes that can biologically affect the risk of relapse in colorectal cancer patients. Additionally, for the first time, we identified germline variants that can potentially be early‐relapse markers in colorectal cancer.
Optimization of liposomal topotecan for use in treating neuroblastoma
Authors: Chernov Lina , Deyell Rebecca J. , Anantha Malathi , Dos Santos Nancy , Gilabert‐Oriol Roger , Bally Marcel B.
Published: May 2017

The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK‐N‐SH, IMR‐32 and LAN‐1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2‐distearoyl‐sn‐glycero‐3‐phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper‐drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug‐to‐lipid ratio engendered significant increases in drug retention. Dose‐range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug‐to‐lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10‐fold increase in plasma half‐life and a 1000‐fold increase in AUC0–24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN‐1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high‐dose radiotherapy such as 131I‐metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy.
LncRNA‐TCONS_00026907 is involved in the progression and prognosis of cervical cancer through inhibiting miR‐143‐5p
Authors: Jin Xuejing , Chen Xiangjian , Hu Yan , Ying Furong , Zou Ruanmin , Lin Feng , Shi Zhengzheng , Zhu Xuejie , Yan Xiaojian , Li Shi , Zhu Hua
Published: May 2017

Our previous long noncoding RNA (lncRNA) microarray revealed that lncRNA‐TCONS_00026907 is aberrantly expressed between cervical cancer tissues and adjacent tissues. This study aims to explore the potential role of TCONS_00026907 in the development of cervical cancer. The expression levels of TCONS_00026907 in cervical cancer tissues and adjacent tissues from 83 patients of cervical cancer were detected by quantitative real‐time polymerase chain reaction and the survival rate was analyzed. In vitro, HeLa and SiHa cells were transfected with small hairpin RNA (shRNA)‐TCONS_00026907, then cell proliferation, cycle distribution, apoptosis, migration and invasion were measured. To confirm TCONS_00026907 regulates expression of ELK1 through inhibiting miR‐143‐5p, overexpression of miR‐143‐5p and silencing of ELK1 were, respectively, performed in HeLa and SiHa cells. Results showed that TCONS_00026907 level was significantly higher in cervical cancer tissues compared to noncancerous tissues and the survival rate was lower in the high expression group. Silencing of TCONS_00026907, overexpression of miR‐143‐5p and silencing of ELK1 inhibited cervical cell cycle, proliferation, migration, and invasion, but promoted apoptosis, respectively. Furthermore, silencing of TCONS_00026907 suppressed the growth of cervical tumors and altered the expression of ELK1, p‐ELK1, C‐fos, Cyclin D1 and Bcl‐2 in vivo. Our study identifies TCONS_00026907 as a potent proto‐oncogene and indicates that TCONS_00026907/miR143‐5p/ELK1 regulatory pathway plays an important role in cervical cancer.
Methionine tumor starvation by erythrocyte‐encapsulated methionine gamma‐lyase activity controlled with per os vitamin B6
Authors: Gay Fabien , Aguera Karine , Sénéchal Karine , Tainturier Angie , Berlier Willy , Maucort‐Boulch Delphine , Honnorat Jérôme , Horand Françoise , Godfrin Yann , Bourgeaux Vanessa
Published: May 2017

Erymet is a new therapy resulting from the encapsulation of a methionine gamma‐lyase (MGL; EC number 4.4.1.11) in red blood cells (RBC). The aim of this study was to evaluate erymet potential efficacy in methionine (Met)‐dependent cancers. We produced a highly purified MGL using a cGMP process, determined the pharmacokinetics/pharmacodynamics (PK/PD) properties of erymet in mice, and assessed its efficacy on tumor growth prevention. Cytotoxicity of purified MGL was tested in six cancer cell lines. CD1 mice were injected with single erymet product supplemented or not with vitamin B6 vitamer pyridoxine (PN; a precursor of PLP cofactor). NMRI nude mice were xenografted in the flank with U‐87 MG‐luc2 glioblastoma cells for tumor growth study following five intravenous (IV) injections of erymet with daily PN oral administration. Endpoints included efficacy and event‐free survival (EFS). Finally, a repeated dose toxicity study of erymet combined with PN cofactor was conducted in CD1 mice. Recombinant MGL was cytotoxic on 4/6 cell lines tested. MGL half‐life was increased from <24 h to 9–12 days when encapsulated in RBC. Conversion of PN into PLP by RBC was demonstrated. Combined erymet + PN treatment led to a sustained Met depletion in plasma for several days with a 85% reduction of tumor volume after 45 days following cells implantation, and a significant EFS prolongation for treated mice. Repeated injections in mice exhibited a very good tolerability with only minor impact on clinical state (piloerection, lean aspect) and a slight decrease in hemoglobin and triglyceride concentrations. This study demonstrated that encapsulation of methioninase inside erythrocyte greatly enhanced pharmacokinetics properties of the enzyme and is efficacy against tumor growth. The perspective on these results is the clinical evaluation of the erymet product in patients with Met starvation‐sensitive tumors.
Analysis of physical characteristics of Tumor Treating Fields for human glioblastoma
Authors: Lok Edwin , San Pyay , Hua Van , Phung Melissa , Wong Eric T.
Published: May 2017

Tumor Treating Fields (TTFields) therapy is an approved treatment that has known clinical efficacy against recurrent and newly diagnosed glioblastoma. However, the distribution of the electric fields and the corresponding pattern of energy deposition in the brain are poorly understood. To evaluate the physical parameters that may influence TTFields, postacquisition MP‐RAGE, T1 and T2 MRI sequences from a responder with a right parietal glioblastoma were anatomically segmented and then solved using finite‐element method to determine the distribution of the electric fields and rate of energy deposition at the gross tumor volume (GTV) and other intracranial structures. Electric field–volume histograms (EVH) and specific absorption rate–volume histograms (SARVH) were constructed to numerically evaluate the relative and/or absolute magnitude volumetric differences between models. The electric field parameters EAUC, VE150, E95%, E50%, and E20%, as well as the SAR parameters SARAUC, VSAR7.5, SAR95%, SAR50%, and SAR20%, facilitated comparisons between models derived from various conditions. Specifically, TTFields at the GTV were influenced by the dielectric characteristics of the adjacent tissues as well as the GTV itself, particularly the presence or absence of a necrotic core. The thickness of the cerebrospinal fluid on the convexity of the brain and the geometry of the tumor were also relevant factors. Finally, the position of the arrays also influenced the electric field distribution and rate of energy deposition in the GTV. Using EVH and SARVH, a personalized approach for TTFields treatment can be developed when various patient‐related and tumor‐related factors are incorporated into the planning procedure.
Detail‐preserving SPH fluid control with deformation constraints
Authors: Feng Gang , Liu Shiguang
Published: May 2017

It is challenging to drive particle‐based smoothed‐particle hydrodynamics fluid to match the target shape and the deforming fluid shape between different models smoothly, especially when the natural fluid motion must be preserved. To achieve the desired behavior, we first generate control particles by sampling the target shapes and then apply a deformation constraint to each control particle, with its neighboring fluid particles keeping details within its influence region. For the generation of control particles, we classify input models into source object and target object, then separately sample them by voxelization method, and generate source control particles and target control particles, respectively. Our deformation constraint includes two parts. In the first part, we deform the source control model to the target control model according to specific space point correspondence between source control particles and target control particles; then, fluid particles are attracted by control particles and complete deformation between different shapes. In the second part, to reduce the lacking of fluid details when fluid deforms, we introduce a new control energy transfer mechanism for control particles. This deformation constraint is solved under smoothed‐particle hydrodynamics‐based fluid simulation framework, which makes our simulation fast, robust, and well suitable for interactive applications. Various experiments demonstrated the effectiveness of our method.
Alternative prosthodontic‐based treatment of a patient with hypocalcified type Amelogenesis Imperfecta
Authors: Jivanescu Anca , Miglionico Antonio , Barua Souman , Hategan Simona Ioana
Published: May 2017

Key Clinical Message

The Amelogenesis Imperfecta is associated with malocclusion and usually requires an interdisciplinary treatment. Due to the patient's refusal of orthodontic treatment, prosthodontics‐based treatments alternative was considered and planned. The patient was treated with zirconia‐based fixed partial dentures, which resulted in improved occlusion, better oral health, and improved esthetic appearance.
Inhibition of the Aggregation and Toxicity of the Minimal Amyloidogenic Fragment of Tau by Its Pro‐Substituted Analogues
Authors: Chemerovski‐Glikman Marina , Frenkel‐Pinter Moran , Mdah Ragad , Abu‐Mokh Amjaad , Gazit Ehud , Segal Daniel
Published: May 2017

Inhibiting the toxic aggregation of amyloid‐β and the tau protein, the key pathological agents involved in Alzheimer's, is a leading approach in modulating disease progression. Using an aggregative tau‐derived model peptide, Ac‐PHF6‐NH2, the substitution of its amino acids with proline, a known efficient β‐breaker, is shown to reduce self‐assembly. This effect is attributed to the steric hindrance created by the proline substitution, which results in disruption of the β‐sheet formation process. Moreover, several of the proline‐substituted peptides inhibit the aggregation of Ac‐PHF6‐NH2 amyloidogenic peptide. Two of these modified inhibitors also disassemble pre‐formed Ac‐PHF6‐NH2 fibrils and one inhibits induced cytotoxicity of the fibrils. Taken together, these lead β‐breaker peptides may be developed into novel Alzheimer's disease therapeutics.
Estimation of a generalized linear mixed model for response‐adaptive designs in multi‐centre clinical trials
Authors: Selvaratnam Selvakkadunko , Oyet Alwell J. , Yi Yanqing , Gadag Veeresh
Published: May 2017

Response‐adaptive designs are important alternatives to equal allocation in clinical trials because equal treatment allocation has been found to have ethical issues. In this article we discuss the implementation of response‐adaptive designs in multi‐centre clinical trials. We develop a generalized linear mixed model (GLMM) for analyzing data obtained from multi‐centre clinical trials and use the maximum likelihood (ML) approach to estimate the model parameters. We apply influence function techniques to derive the asymptotic properties of our estimators. The advantage of using the influence function approach is that it leads to a closed form expression for the asymptotic covariance of the estimated parameters. To our knowledge such a closed form expression does not currently exist in the literature. The performance of the ML estimator under various response‐adaptive designs is examined through simulation studies. We use our simulation studies to compare the asymptotic covariance matrix, based on the influence function to that based on the inverse of the Hessian matrix obtained from the likelihood function of the observations. The techniques are applied to real data obtained from a multi‐centre clinical trial designed to compare two cream preparations (active drug/control) for treating an infection. The Canadian Journal of Statistics 45: 310–325; 2017 © 2017 Statistical Society of Canada
The Breast and Cervical Cancer Early Detection Program, Medicaid, and breast cancer outcomes among Ohio's underserved women
Authors: Koroukian Siran M. , Bakaki Paul M. , Htoo Phyo Than , Han Xiaozhen , Schluchter Mark , Owusu Cynthia , Cooper Gregory S. , Rose Johnie , Flocke Susan A.
Published: May 2017

BACKGROUND

As an organized screening program, the national Breast and Cervical Cancer Early Detection Program (BCCEDP) was launched in the early 1990s to improve breast cancer outcomes among underserved women. To analyze the impact of the BCCEDP on breast cancer outcomes in Ohio, this study compared cancer stages and mortality across BCCEDP participants, Medicaid beneficiaries, and “all others.”

METHODS

This study linked data across the Ohio Cancer Incidence Surveillance System, Medicaid, the BCCEDP database, death certificates, and the US Census and identified 26,426 women aged 40 to 64 years who had been diagnosed with incident invasive breast cancer during the years 2002‐2008 (deaths through 2010). The study groups were as follows: BCCEDP participants (1‐time or repeat users), Medicaid beneficiaries (women enrolled in Medicaid before their cancer diagnosis [Medicaid/prediagnosis] or around the time of their cancer diagnosis [Medicaid/peridiagnosis]), and all others (women identified as neither BCCEDP participants nor Medicaid beneficiaries). The outcomes included advanced‐stage cancer at diagnosis and mortality. A multivariable logistic and survival analysis was conducted to examine the independent association between the BCCEDP and Medicaid status and the outcomes.

RESULTS

The percentage of women presenting with advanced‐stage disease was highest among women in the Medicaid/peridiagnosis group (63.4%) and lowest among BCCEDP repeat users (38.6%). With adjustments for potential confounders and even in comparison with Medicaid/prediagnosis beneficiaries, those in the Medicaid/peridiagnosis group were twice as likely to be diagnosed with advanced‐stage disease (adjusted odds ratio, 2.20; 95% confidence interval, 1.83‐2.66).

CONCLUSIONS

Medicaid/peridiagnosis women are at particularly high risk to be diagnosed with advanced‐stage disease. Efforts to reduce breast cancer disparities must target this group of women before they present to Medicaid. Cancer 2017;123:3097–106. © 2017 American Cancer Society.
Understanding temporal trends in medical costs associated with progression to metastatic prostate cancer
Authors: Frendl Daniel M. , Olumi Aria F.
Published: May 2017

The cost of care associated with progression to metastatic prostate cancer is an important outcome. The economic burden of progression to metastatic disease should be considered in assessments of the value of early prostate cancer detection and treatment.

See also pages 3591‐601.
Impact of subsequent metastases on costs and medical resource use for prostate cancer patients initially diagnosed with localized disease
Authors: Li Tracy T. , Shore Neal D. , Mehra Maneesha , Todd Mary B. , Saadi Ryan , Leblay Gaetan , Aggarwal Jyoti , Griffiths Robert I.
Published: May 2017

BACKGROUND

The impact of subsequent metastases on costs and medical resource use (MRU) for prostate cancer (PC) patients initially diagnosed with localized disease was estimated.

METHODS

Surveillance, Epidemiology, and End Results data, linked to Medicare (1999‐2012), were used to identify 7482 patients diagnosed with subsequent metastases 12 months or more after the initial diagnosis of localized PC (cases), and they were matched to 25,709 localized PC patients without subsequent metastases (controls). Patients were followed for costs and MRU from 12 months before their index date (subsequent metastases or a matched date for controls) up to 12 months after it. Costs and MRU were stratified by the setting/type of care/service. Multivariate mixed effects regression analyses were used to construct and compare longitudinal trajectories of marginal predicted costs and predicted probabilities of MRU between cases and controls.

RESULTS

Among the controls, predicted monthly costs remained relatively stable throughout the entire observation period (weighted mean per patient per month, $2746; range during 24 months, $2603‐2858). In contrast, among the cases, costs increased from $2622 (95% confidence interval [CI], $2525‐2719) 12 months before the diagnosis of subsequent metastases to $4767 (95% CI, $4623‐4910) 1 month before the diagnosis of subsequent metastases, peaked during the month of metastases at $13,291 (95% CI, $13,148‐13,435), and remained significantly higher than costs for the controls thereafter (eg, $4677 at + 12 months; 95% CI, $4549‐4805). Costs and MRU increased across a wide range of settings/types, including inpatient, outpatient, home health, and hospice settings.

CONCLUSIONS

In PC patients initially diagnosed with localized disease, a diagnosis of subsequent metastases is associated with substantially increased costs and MRU. Cancer 2017;123:3591‐601. © 2017 American Cancer Society.