bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Fracture Reduction and Plate Position in the Aetiology of Flexor Pollicis Longus Tendon Rupture after Volar Plate Fixation of Distal Radius Fractures
Authors: Selvan David R. , Machin David G. , Perry Daniel , Simpson Claire , Thorpe Phillipa , Brown Daniel J. 
Published: January 2015

Background Flexor pollicis longus (FPL) rupture has been described as complication following volar plating for distal radius fractures. It has been hypothesised that this is due to plate prominence. The aim of the study was to investigate the relationship between sub-optimal plate position and fracture reduction on plate prominence. Methods Plate prominence was measured in two experimental models. In the first, the effect of plate position was investigated using 18 fresh frozen cadavers with prominence being measured using a micrometer. In the second study, the effect of fracture reduction on plate prominence was investigated using similar methodology with simulated mal-reductions on dry bone models. Results The results of the first study showed a significant increase in lift-off for three plates (DVR, Synthes Universal and Acu-Loc), if the plates were moved distally or proximally from the anatomical position. Similar increases in prominence were also seen with rotational mal-positions. The results of the second study showed a statistically significant effect on plate prominence for even a 5° mal-reduction ( p=0.001) with worsening lift-off with increasing mal-reduction. These changes are significantly different from baseline and also significantly different to the lift-off recorded with mal-reductions 5° better and worse. Mal-reductions also necessitate more proximal placement of the plate to avoid screw penetration of the articular surface, and each 5° increment is significantly different from baseline. Conclusions The results show a statistically and clinically significant effect of both plate position and fracture reduction on plate prominence and support the theory that both contribute to the aetiology of post-operative FPL rupture.
The sensitivity to change over time of the Amsterdam IADL Questionnaire©
Authors: Koster Naomi , Knol Dirk L. , Uitdehaag Bernard M.J. , Scheltens Philip , Sikkes Sietske A.M. 
Published: January 2015

AbstractIntroductionThis study aimed to investigate the sensitivity to change over time of a new informant‐based instrument to assess instrumental activities of daily living (IADL) during the course of dementia: the Amsterdam IADL Questionnaire© (A‐IADL‐Q).MethodsParticipants (n = 102) were patients and their informants who visited the Alzheimer Center of the VU University Medical Center. Linear mixed models with random effects were used to relate longitudinal change on the A‐IADL‐Q to diagnosis and to longitudinal change in cognitive measures.ResultsWe found longitudinal change on the A‐IADL‐Q to differ between diagnosis (P = .003), with dementia patients showing the fastest rate of decline (P < .001). In addition, we found longitudinal change on the A‐IADL‐Q to be related to longitudinal change in cognitive measures (global cognition: P < .001; memory: P = .024; executive functioning: P = .028).DiscussionFindings indicate the A‐IADL‐Q is sensitive to change over time in IADL functioning and can be used in evaluating treatment effects and assessing individual disease progress.
Spectral modelling of high Reynolds number unstably stratified homogeneous turbulence
Authors: Burlot A. , Gréa B.-J. , Godeferd F. S. , Cambon C. , Griffond J. 
Published: January 2015

AbstractWe study unconfined homogeneous turbulence with a destabilizing background density gradient in the Boussinesq approximation. Starting from initial isotropic turbulence, the buoyancy force induces a transient phase toward a self-similar regime accompanied by a rapid growth of kinetic energy and Reynolds number, along with the development of anisotropic structures in the flow in the direction of gravity. We model this with a two-point statistical approach using an axisymmetric eddy-damped quasi-normal Markovian (EDQNM) closure that includes buoyancy production. The model is able to match direct numerical simulations (DNS) in a parametric study showing the effect of initial Froude number and mixing intensity on the development of the flow. We further improve the model by including the stratification timescale in the characteristic relaxation time for triple correlations in the closure. It permits the computation of the long-term evolution of unstably stratified turbulence at high Reynolds number. This agrees with recent theoretical predictions concerning the self-similar dynamics and brings new insight into the spectral energy distribution and anisotropy of the flow.
MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies
Authors: Choudhary G S , Al-harbi S , Mazumder S , Hill B T , Smith M R , Bodo J , Hsi E D , Almasan A 
Published: January 2015

AbstractOverexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.
PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model
Authors: Mouton-Liger F , Rebillat A-S , Gourmaud S , Paquet C , Leguen A , Dumurgier J , Bernadelli P , Taupin V , Pradier L , Rooney T , Hugon J 
Published: January 2015

AbstractBrain thiamine homeostasis has an important role in energy metabolism and displays reduced activity in Alzheimer’s disease (AD). Thiamine deficiency (TD) induces regionally specific neuronal death in the animal and human brains associated with a mild chronic impairment of oxidative metabolism. These features make the TD model amenable to investigate the cellular mechanisms of neurodegeneration. Once activated by various cellular stresses, including oxidative stress, PKR acts as a pro-apoptotic kinase and negatively controls the protein translation leading to an increase of BACE1 translation. In this study, we used a mouse TD model to assess the involvement of PKR in neuronal death and the molecular mechanisms of AD. Our results showed that the TD model activates the PKR-eIF2α pathway, increases the BACE1 expression levels of Aβ in specific thalamus nuclei and induces motor deficits and neurodegeneration. These effects are reversed by PKR downregulation (using a specific inhibitor or in PKR knockout mice).
Phosphorylation of the translation initiation factor eIF2α at serine 51 determines the cell fate decisions of Akt in response to oxidative stress
Authors: Rajesh K , Krishnamoorthy J , Kazimierczak U , Tenkerian C , Papadakis A I , Wang S , Huang S , Koromilas A E 
Published: January 2015

AbstractPhosphorylation of the α subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP) is a master regulator of cell adaptation to various forms of stress with implications in antitumor treatments with chemotherapeutic drugs. Herein, we demonstrate that genetic loss of the eIF2α kinases PERK and GCN2 or impaired eIF2αP by genetic means renders immortalized mouse fibroblasts as well as human tumor cells increasingly susceptible to death by oxidative stress. We also show that eIF2αP facilitates Akt activation in cells subjected to oxidative insults. However, whereas Akt activation has a pro-survival role in eIF2αP-proficient cells, the lesser amount of activated Akt in eIF2αP-deficient cells promotes death. At the molecular level, we demonstrate that eIF2αP acts through an ATF4-independent mechanism to control Akt activity via the regulation of mTORC1. Specifically, eIF2αP downregulates mTORC1 activity, which in turn relieves the feedback inhibition of PI3K resulting in the upregulation of the mTORC2-Akt arm. Inhibition of mTORC1 by rapamycin restores Akt activity in eIF2αP-deficient cells but renders them highly susceptible to Akt-mediated death by oxidative stress. Our data demonstrate that eIF2αP acts as a molecular switch that dictates either cell survival or death by activated Akt in response to oxidative stress. Hence, we propose that inactivation of eIF2αP may be a suitable approach to unleash the killing power of Akt in tumor cells treated with pro-oxidant drugs.
Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling
Authors: Secq V , Leca J , Bressy C , Guillaumond F , Skrobuk P , Nigri J , Lac S , Lavaut M-N , Bui T-t , Thakur A K , Callizot N , Steinschneider R , Berthezene P , Dusetti N , Ouaissi M , Moutardier V , Calvo E , Bousquet C , Garcia S , Bidaut G , Vasseur S , Iovanna J L , Tomasini R 
Published: January 2015

AbstractPancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as ‘SLIT2’ (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that ‘CAF-secreted SLIT2’ increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.
Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)
Authors: Leverson J D , Zhang H , Chen J , Tahir S K , Phillips D C , Xue J , Nimmer P , Jin S , Smith M , Xiao Y , Kovar P , Tanaka A , Bruncko M , Sheppard G S , Wang L , Gierke S , Kategaya L , Anderson D J , Wong C , Eastham-Anderson J , Ludlam M J C , Sampath D , Fairbrother W J , Wertz I , Rosenberg S H , Tse C , Elmore S W , Souers A J 
Published: January 2015

AbstractThe anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone
Authors: Moore Z , Chakrabarti G , Luo X , Ali A , Hu Z , Fattah F J , Vemireddy R , DeBerardinis R J , Brekken R A , Boothman D A 
Published: January 2015

AbstractNicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD+ synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD+ pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD+ consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD+ synthesis while increasing NAD+ consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)+ depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD+-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD+ synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD+ pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors.
Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma
Authors: Singer E , Judkins J , Salomonis N , Matlaf L , Soteropoulos P , McAllister S , Soroceanu L 
Published: January 2015

AbstractGlioblastoma (GBM) resistance to therapy is the most common cause of tumor recurrence, which is ultimately fatal in 90% of the patients 5 years after initial diagnosis. A sub-population of tumor cells with stem-like properties, glioma stem cells (GSCs), is specifically endowed to resist or adapt to the standard therapies, leading to therapeutic resistance. Several anticancer agents, collectively termed redox therapeutics, act by increasing intracellular levels of reactive oxygen species (ROS). In this study, we investigated mechanisms underlying GSC response and resistance to cannabidiol (CBD), a non-toxic, non-psychoactive cannabinoid and redox modulator. Using primary GSCs, we showed that CBD induced a robust increase in ROS, which led to the inhibition of cell survival, phosphorylated (p)-AKT, self-renewal and a significant increase in the survival of GSC-bearing mice. Inhibition of self-renewal was mediated by the activation of the p-p38 pathway and downregulation of key stem cell regulators Sox2, Id1 and p-STAT3. Following CBD treatment, a subset of GSC successfully adapted, leading to tumor regrowth. Microarray, Taqman and functional assays revealed that therapeutic resistance was mediated by enhanced expression of the antioxidant response system Xc catalytic subunit xCT (SLC7A11 (solute carrier family 7 (anionic amino-acid transporter light chain), member 11)) and ROS-dependent upregulation of mesenchymal (MES) markers with concomitant downregulation of proneural (PN) markers, also known as PN–MES transition. This ‘reprogramming’ of GSCs occurred in culture and in vivo and was partially due to activation of the NFE2L2 (NRF2 (nuclear factor, erythroid 2-like)) transcriptional network. Using genetic knockdown and pharmacological inhibitors of SLC7A11, we demonstrated that combining CBD treatment with the inhibition of system Xc resulted in synergistic ROS increase leading to robust antitumor effects, that is, decreased GSC survival, self-renewal, and invasion. Our investigation provides novel mechanistic insights into the antitumor activity of redox therapeutics and suggests that combinatorial approaches using small molecule modulators of ROS offer therapeutic benefits in GBM.
Insulin-like growth factor-1 endues monocytes with immune suppressive ability to inhibit inflammation in the intestine
Authors: Ge Rong-Ti , Mo Li-Hua , Wu Ruijin , Liu Jiang-Qi , Zhang Huan-Ping , Liu Zhigang , Liu Zhanju , Yang Ping-Chang 
Published: January 2015

AbstractThe pathogenesis of some chronic inflammation such as inflammatory bowel disease is unclear. Insulin-like growth factor-1 (IGF1) has active immune regulatory capability. This study aims to investigate into the mechanism by which IGF1 modulates the monocyte (Mo) properties to inhibit immune inflammation in the intestine. In this study, the production of IGF1 by intestinal epithelial cells was evaluated by real time RT-PCR and Western blotting. Mos were analyzed by flow cytometry. A mouse colitis model was created with trinitrobenzene sulfonic acid. The results showed that mouse IECs produced IGF1, which could be up regulated by exposure to CpG-ODN (CpG-oligodeoxynueleotides) in the culture. Culture the CpG-ODN-primed IEC cells and Mos or exposure of Mos to IGF1 in the culture induced the Mos to express IL-10. The IGF1-primed Mos showed the immune suppressive effect on inhibiting the immune inflammation in the mouse colon. In conclusion, the IGF1-primed Mos are capable of suppressing immune inflammation in the intestine.
Superior radiation-resistant nanoengineered austenitic 304L stainless steel for applications in extreme radiation environments
Authors: Sun C. , Zheng S. , Wei C. C. , Wu Y. , Shao L. , Yang Y. , Hartwig K. T. , Maloy S. A. , Zinkle S. J. , Allen T. R. , Wang H. , Zhang X. 
Published: January 2015

AbstractNuclear energy provides more than 10% of electrical power internationally and the increasing engagement of nuclear energy is essential to meet the rapid worldwide increase in energy demand. A paramount challenge in the development of advanced nuclear reactors is the discovery of advanced structural materials that can endure extreme environments, such as severe neutron irradiation damage at high temperatures. It has been known for decades that high dose radiation can introduce significant void swelling accompanied by precipitation in austenitic stainless steel (SS). Here we report, however, that through nanoengineering, ultra-fine grained (UFG) 304L SS with an average grain size of ~100 nm, can withstand Fe ion irradiation at 500°C to 80 displacements-per-atom (dpa) with moderate grain coarsening. Compared to coarse grained (CG) counterparts, swelling resistance of UFG SS is improved by nearly an order of magnitude and swelling rate is reduced by a factor of 5. M23C6 precipitates, abundant in irradiated CG SS, are largely absent in UFG SS. This study provides a nanoengineering approach to design and discover radiation tolerant metallic materials for applications in extreme radiation environments.
Minimum jitter‐based adaptive decision feedback equaliser for giga‐bit‐per‐second serial links
Authors: Al‐Taee Alaa Rahman , Yuan Fei , Ye Andy 
Published: January 2015

This study presents a minimum jitter‐based adaptive decision feedback equaliser (DFE) for giga‐bit‐per‐second (Gbps) serial links. The adaptation in search for the optimal tap coefficients of DFE is carried out with the objective to minimise data jitter at the edge of data eyes. Jitter minimisation is achieved by adjusting the slope of the DFE that counteracts that of the channel. The effectiveness of the proposed adaptive DFE is evaluated by embedding the DFE in a 2 Gbps serial link. The data link is analysed using Spectre from Cadence Design Systems with BSIM4 device models. Simulation results demonstrate that the proposed adaptive DFE is capable of opening closed data eyes with 83% vertical opening, 68% horizontal opening and 16% data jitter over 1 m FR4 channel while consuming 15.45 mW.
Reversible catalytic dehydrogenation of alcohols for energy storage
Authors: Bonitatibus Peter J. , Chakraborty Sumit , Doherty Mark D. , Siclovan Oltea , Jones William D. , Soloveichik Grigorii L. 
Published: January 2015

Significance
Catalytic hydrogenation and dehydrogenation reactions are extremely important in organic chemistry and recently for energy storage in the form of chemical bonds. Although catalysts are known which catalyze both reactions, the rates and conditions required for the two are frequently very different due to the differences associated with the bonds to be activated (C–H/O–H/N–H and C = O/C = N/H–H). The use of a bifunctional catalyst would substantially simplify the design of processes related to energy storage. In this work, organometallic complexes of iron and iridium are shown to act as catalysts for reversible dehydrogenation of alcohols to carbonyl compounds. This finding opens a pathway to the development of catalysts for direct reversible electrochemical dehydrogenation of organic fuels in energy generation and storage reactions.
Concentric 360° domain wall nesting in magnetic tunnel junction films: a Lorentz TEM study
Authors: O’Shea K J , Rode K , Kurt H , McGrouther D , MacLaren D A 
Published: January 2015

Abstract
We describe the formation of an unusual concentric magnetic domain wall pattern in the free layer of a bottom pinned magnetic tunnel junction. Lorentz microscopy reveals that repeated switching of the free layer with a magnetic field applied perpendicular to the exchange bias direction can produce a series of concentric 360° domain wall loops, a phenomenon we refer to as domain wall nesting. We propose two necessary ingredients for the behaviour: (i) inhomogeneities in the grain-by-grain magnetic dispersion that break local symmetry to produce a preferential sense of magnetic rotation upon field switching; and (ii) structural defects that act to pin 360° domain walls. Further control of this behaviour may provide new functionality for future device applications.