bluuebunny/crossref_metadata_2025 huggingface dataset:
Acupuncture for Vascular Mild Cognitive Impairment: A Systematic Review of Randomised Controlled Trials
Authors: Cao Huijuan , Wang Yuyi , Chang Dennis , Zhou Li , Liu Jianping
Published: October 2013

Background

Vascular mild cognitive impairment (VMCI) is the most common type of vascular cognitive impairment induced by cerebrovascular disease. No effective medicines are currently available for VMCI.

Objective

To assess the effectiveness and safety of acupuncture for VMCI.

Methods

Seven electronic databases were searched for randomised controlled trials which investigated the effects of acupuncture compared with no treatment, placebo or conventional therapies on cognitive function or other clinical outcomes in patients with VMCI. The quality of the trials selected was evaluated according to the ‘risk of bias’ assessment provided by the Cochrane Handbook for Systematic Reviews of Interventions. RevMan V.5.1 software was employed for data analysis.

Results

Twelve trials with 691 participants were included. The methodological quality of all included trials was unclear and/or they had a high risk of bias. Meta-analysis showed acupuncture in conjunction with other therapies could significantly improve Mini-Mental State Examination scores (mean difference 1.99, 95% CI 1.09 to 2.88, random model, p<0.0001, 6 trials). No included trials mentioned any adverse events of the treatment.

Conclusions

The current clinical evidence is not of sufficient quality for wider application of acupuncture to be recommended for the treatment of VMCI, and further large, rigorously designed trials are warranted.
Mechanical instability destabilises the ankle joint directly in the ankle-sprain mechanism
Authors: Gehring Dominic , Faschian Katrin , Lauber Benedikt , Lohrer Heinz , Nauck Tanja , Gollhofer Albert
Published: October 2013

Background

Despite massive research efforts, it remains unclear how mechanical ankle instability (MAI) and functional ankle instability (FAI) affect joint control in the situation of ankle sprain. Thus, the purpose of this study was to evaluate whether individuals with MAI have deficits in stabilising their ankle joint in a close-to-injury situation compared with those with FAI and healthy controls.

Methods

Ankle-joint control was assessed by means of three-dimensional motion analysis and electromyography in participants with FAI and MAI (n=19), in participants with pure FAI (n=9) and in healthy controls (n=18). Close-to-injury situations were simulated during standing, walking and jumping by means of a custom-made tilt platform.

Results

Individuals with FAI and MAI displayed significantly greater maximum ankle inversion angles (+5°) and inversion velocities (+50°/s) in the walking and jumping conditions compared to those with pure FAI and controls. Furthermore, individuals in the FAI and MAI group showed a significantly decreased pre-activation of the peroneus longus muscle during jumping compared to those with FAI. No differences between groups were found for plantar flexion and internal rotation, or for muscle activities following tilting of the platform.

Conclusions

The present study demonstrates that MAI is characterised by impairments of ankle-joint control in close-to-injury situations. This could make these individuals more prone to recurrent ankle sprains, and suggests the need for additional mechanical support such as braces or even surgery. In addition, the study highlights the fact that dynamic experimental test conditions in the acting participant are needed to further unravel the mystery of chronic ankle instability.
Outcomes from sudden cardiac arrest in US high schools: a 2-year prospective study from the National Registry for AED Use in Sports
Authors: Drezner Jonathan A , Toresdahl Brett G , Rao Ashwin L , Huszti Ella , Harmon Kimberly G
Published: October 2013

Background

Sudden cardiac arrest (SCA) is the leading cause of death in athletes during exercise. The effectiveness of school-based automated external defibrillator (AED) programmes has not been established through a prospective study.

Methods

A total of 2149 high schools participated in a prospective observational study beginning 1 August 2009, through 31 July 2011. Schools were contacted quarterly and reported all cases of SCA. Of these 95% of schools confirmed their participation for the entire 2-year study period. Cases of SCA were reviewed to confirm the details of the resuscitation. The primary outcome was survival to hospital discharge.

Results

School-based AED programmes were present in 87% of participating schools and in all but one of the schools reporting a case of SCA. Fifty nine cases of SCA were confirmed during the study period including 26 (44%) cases in students and 33 (56%) in adults; 39 (66%) cases occurred at an athletic facility during training or competition; 55 (93%) cases were witnessed and 54 (92%) received prompt cardiopulmonary resuscitation. A defibrillator was applied in 50 (85%) cases and a shock delivered onsite in 39 (66%). Overall, 42 of 59 (71%) SCA victims survived to hospital discharge, including 22 of 26 (85%) students and 20 of 33 (61%) adults. Of 18 student-athletes 16 (89%) and 8 of 9 (89%) adults who arrested during physical activity survived to hospital discharge.

Conclusions

High school AED programmes demonstrate a high survival rate for students and adults who suffer SCA on school campus. School-based AED programmes are strongly encouraged.
An injured climber
Authors: McQueen Carl , Bridle Philip , Bexon Karl , Wyse Matthew
Published: October 2013

Climbing incidents present a myriad of challenges to prehospital teams. Management decisions are often influenced by factors including difficulties in accessing patients, limited available resources and safe egress from scenes. This case illustrates the importance of an adaptable and innovative approach to scene management and clinical decision making in such cases.
Investigation and management of pancreatic tumours
Authors: Smith Lyn A , Jamieson Nigel B , McKay Colin J
Published: October 2013

Pancreatic cancer is the 10th most commonly diagnosed cancer in the UK and the fifth most common cause of cancer death. It remains one of the most aggressive cancers with over 95% of patients affected dying of their disease. Often presenting at an advanced stage of disease progression, there is currently no simple screening test available. Therefore a high clinical suspicion and prompt appropriate investigation is required from physicians when dealing with patients with symptoms in keeping with pancreatic cancer. The gastroenterology 2010 curriculum states that trainees should learn the presentation and multidisciplinary management of patients with pancreatic tumours. In this article we discuss the typical clinical presentations of common and less common pancreatic tumours followed by the investigation, staging and management required.
Admission neutrophil–lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy
Authors: Brooks Steven D , Spears Chauncey , Cummings Christopher , VanGilder Reyna L , Stinehart Kyle R , Gutmann Laurie , Domico Jennifer , Culp Stacey , Carpenter Jeffrey , Rai Ansaar , Barr Taura L
Published: October 2013

Objective

Immune dysregulation influences outcome following acute ischemic stroke (AIS). Admission white blood cell (WBC) counts are routinely obtained, making the neutrophil–lymphocyte ratio (NLR) a readily available biomarker of the immune response to stroke. This study sought to identify the relationship between NLR and 90 day AIS outcome.

Methods

A retrospective analysis was performed on patients who underwent endovascular therapy for AIS at West Virginia University Hospitals, Morgantown, West Virginia. Admission WBC differentials were analyzed as the NLR. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS) score and outcome by the modified Rankin Scale (mRS) score at 90 days. Univariate relationships between NLR, age, NIHSS, and mRS were established by correlation coefficients; the t test was used to compare NLR with recanalization and stroke location (anterior vs posterior). Logistic regression models were developed to identify the ability of NLR to predict mRS when controlling for age, recanalization, and treatment with IV tissue plasminogen activator (tPA).

Results

116 patients were reviewed from 2008 to 2011. Mean age of the sample was 67 years, and 54% were women. Mean baseline NIHSS score was 17 and 90 day mRS score was 4. There was a significant relationship between NLR and mRS (p=0.02) that remained when controlling for age, treatment with IV tPA, and recanalization. NLR ≥5.9 predicted poor outcome and death at 90 days.

Conclusions

This study shows that the NLR, a readily available biomarker, may be a clinically useful tool for risk stratification when evaluating AIS patients as candidates for endovascular therapies.
Cardiorespiratory fitness does not alter plasma pentraxin 3 and cortisol reactivity to acute psychological stress and exercise
Authors: Huang Chun-Jung , Webb Heather E. , Beasley Kathleen N. , McAlpine David A. , Tangsilsat Supatchara E. , Acevedo Edmund O.
Published: October 2013

Pentraxin 3 (PTX3) has been recently identified as a biomarker of vascular inflammation in predicting cardiovascular events. The purpose of this study was to examine the effect of cardiorespiratory fitness on plasma PTX3 and cortisol responses to stress, utilizing a dual-stress model. Fourteen male subjects were classified into high-fit (HF) and low-fit (LF) groups and completed 2 counterbalanced experimental conditions. The exercise-alone condition (EAC) consisted of cycling at 60% maximal oxygen uptake for 37 min, while the dual-stress condition (DSC) included 20 min of a mental stress while cycling for 37 min. Plasma PTX3 revealed significant increases over time with a significant elevation at 37 min in both HF and LF groups in response to EAC and DSC. No difference in plasma PTX3 levels was observed between EAC and DSC. In addition, plasma cortisol revealed a significant condition by time interaction with greater levels during DSC at 37 min, whereas cardiorespiratory fitness level did not reveal different plasma cortisol responses in either the EAC or DSC. Aerobic exercise induces plasma PTX3 release, while additional acute mental stress, in a dual-stress condition, does not exacerbate or further modulate the PTX3 response. Furthermore, cardiorespiratory fitness may not affect the stress reactivity of plasma PTX3 to physical and combined physical and psychological stressors. Finally, the exacerbated cortisol responses to combined stress may provide the potential link to biological pathways that explain changes in physiological homeostasis that may be associated with an increase in the risk of cardiovascular disease.
Does a physiological concentration of taurine increase acute muscle power output, time to fatigue, and recovery in isolated mouse soleus (slow) muscle with or without the presence of caffeine?
Authors: Tallis Jason , Higgins Matthew F. , Cox Val. M. , Duncan Michael J. , James Rob. S.
Published: October 2013

High concentrations of caffeine and taurine are key constituents of many ergogenic supplements ingested acutely to provide legal enhancements in athlete performance. Despite this, there is little evidence supporting the claims for the performance-enhancing effects of acute taurine supplementation. In-vitro models have demonstrated that a caffeine-induced muscle contracture can be further potentiated when combined with a high concentration of taurine. However, the high concentrations of caffeine used in previous research would be toxic for human consumption. Therefore, this study aimed to investigate whether a physiological dose of caffeine and taurine would directly potentiate skeletal muscle performance. Isolated mouse soleus muscle was used to examine the effects of physiological taurine (TAU), caffeine (CAF), and taurine–caffeine combined (TC) on (i) acute muscle power output; (ii) time to fatigue; and (iii) recovery from fatigue, compared with the untreated controls (CON). Treatment with TAU failed to elicit any significant difference in the measured parameters. Treatment with TC resulted in a significant increase in acute muscle power output and faster time to fatigue. The ergogenic benefit posed by TC was not different from the effects of caffeine alone, suggesting no acute ergogenic benefit of taurine.
Molecular and classical chromosomal techniques reveal diversity in bushcricket genera of Barbitistini (Orthoptera)
Authors: Warchałowska-Śliwa E. , Grzywacz B. , Maryańska-Nadachowska A. , Karamysheva T.V. , Heller K.-G. , Lehmann A.W. , Lehmann G.U.C. , Chobanov D.P.
Published: October 2013

The cytogenetic characteristics of 17 species of bushcricket belonging to eight genera of the tribe Barbitistini were examined by fluorescence in situ hybridization with 18S rDNA and (TTAGGn) telomeric as probes and by C-banding, silver, and fluorochrome staining. These markers were used to understand chromosomal organization and evolutionary relationships between genera or species within the same genus. The number of 18S rDNA clusters per haploid genome that co-localized with active nucleolus organizer regions (NORs) ranged from one to five, with the most common pattern being the presence of one NOR-bearing chromosome. This ribosomal cistron was preferentially located in the paracentromeric region of autosomes and very rarely in the sex chromosome. The results demonstrated coincidence between the localization of major ribosomal genes and active NORs and the position of C-band and GC-rich regions. The rDNA/NOR distribution and the composition of chromosome heterochromatin proved to be good cytogenetic markers for distinguishing species and phylogenetic lines and for understanding the genomic differentiation and evolution of Barbitistini. A comparison of cytogenetic and morphological or behavioral traits suggests that morphological and behavioral specialization in this group was not followed by major karyotype modification (except for Leptophyes). However, the occurrence and distribution of different repetitive DNA sites tends to vary among the taxa.
NaxCoO2 Cathode Material: Synthesized by Inverse Micro- Emulsion Method for Sodium Ion Batteries
Authors: Venkata Rami Reddy B. , Gopukumar Sukumaran
Published: October 2013

NaxCoO2 cathode material is synthesized by using inverse micro-emulsion method. The synthesized material has been characterized by using TG/DTA, XRD, SEM, and XPS, charge/discharge, cyclic voltammetry and EIS studies. XRD patterns reveal that the P2 phase formation of NaxCoO2. Electrochemical experiments have been performed by using CR-2032 type coin cells in which Na foil (Reference Electrode) and 1M NaClO4 in 1:1 PC/ EC (V/V) as an electrolyte. The synthesized NaxCoO2 material delivered the first cycle highest discharge capacity of 162 mAh /g when cycled at 0.1C rate between 2-4.2 V
Synthesis of Core-Shell Co@Pt/C Electrocatalyst and Effects of Stabilizer and pH on Its Performance
Authors: Cao Chunhui , Lin Rui , Zhao Tiantian , Huang Zhen , Ma Jianxin
Published: October 2013

Carbon-supported Co@Pt core shell catalysts have been synthesized by the two-step chemical reduction method. The effects of the catalyst preparation conditions including pH value of the initial solution and the stabilizers on the performance of the Co@Pt/C catalyst were investigated. Transmission Electron Microscope (TEM) and X-Ray Diffraction (XRD) techniques were used to characterize the nano-structured catalysts. The electrochemical performance of the as-prepared catalyst was characterized by cyclic voltammograms (CV) and liner sweep voltammogram (LSV) techniques. Additionally, the performance of the catalyst was evaluated by a test in single fuel cell. The results showed that the pH value and stabilizers not only significantly influenced the Co@Pt metal morphology property, but also the electrochemical and single cell performance. The proper pH value for preparation was 12, which might be due to that the pH condition would change the charge of the carbon black surface and higher pH value would be beneficial to the metal particles deposition on the surface of carbon support and form the highly dispersed catalyst. The different hydrophobic reaction, dimensional effect and particle interactions are caused by stabilizers. The evaluation of the fuel cell also proved that the optimization of the preparation was helpful to enhance the catalytic performance.
Impact of Cathode Fabrication on MEA Performance in PEFCs
Authors: Tanuma Toshihiro , Kinoshita Shinji
Published: October 2013

We reported that the membrane electrode assembly (MEA) using a hydrophilic micro porous layer (MPL) showed much better performance in a wide range of pressure and humidity conditions than that using a hydrophobic MPL. When operating an MEA, it usually needs to be humidified in order to maintain conductivity of the membrane. However, operation without humidification is critical to the commercialization of polymer electrolyte fuel cells (PEFCs) for backup power and automotive applications. We, therefore, evaluated MEAs at 60 ºC, at the H2/air stoichiometric ratio of 1.4/5.0, without humidification, in addition to the normal conditions of 80 ºC, 100 & 30 %RH. We found that the MEA employing a Gas Diffusion Electrode (GDE) method on the hydrophilic MPL showed the best performance under a very dry condition, suggesting the importance of the interface between the cathode and the MPL.
Optimization of the Titanium Oxysulfides (TiOySz) Performance Used as Positive Electrode in Lithium Microbatteries
Authors: Saoutieff Elise , Le Van-Jodin Lucie , Secouard Christophe , Proust Marina
Published: October 2013

An all solid-state-microbattery is defined as a stack of thin layers (5-20µm) including the active part, protective layers and current collectors. [1] In this work, the stack Li/LiPON/TiOS is studied. Titanium oxysulfide thin films (TiOySz) are used as positive electrode material. This material was selected because of their specific potential (reversibly insert of lithium below 3V vs. Li+/Li) well adapted for the considered application. Capacity of 100µA.h/cm2/µm can be reached. Correlation between microstructure, chemistry and performance of the active material is reported.
Investigation of H2, CO and Syngas Electrochemical Performance Using Ni/YSZ Pattern Anodes
Authors: Yao Weifang , Croiset Eric
Published: October 2013

In this work, Ni/YSZ pattern anodes with well-defined 2-D structure were employed to investigate the electrochemical oxidation of H2, CO and syngas. Electrochemical tests revealed that polarization resistance (Rp) depended on applied overpotenital and gas compositions. In H2/H2O environment, Rp decreases when increasing overpotential, H2 and H2O partial pressure. In CO/CO2 environment, Rp experiences a minimum value when increasing the overpotential from 0 to 0.3 V, and the minimum Rp appears when the overpotential is 0.1 V. Rp decreases with an increase in partial pressure of CO2, but increases when increasing partial pressure of CO. Charge transfer reactions contribute to the main electrode process in both H2/H2O and CO/CO2 environments.
Electrolyte Distribution and Discharge Time – A Combined Study of X-ray Tomography and Electrical Measurements of a Commercially Available Lithium-Ion Capacitor
Authors: Wieder Frank , Kallfaß Christoph , Manke Ingo , Hilger André , Tötzke C. , Hoch Constantin , Schier Herman , Graf Klaus , Banhart John
Published: October 2013

A lithium-ion capacitor (LIC) was studied during an extensive charge/discharge procedure. Changes in the interior three-dimensional structure were investigated by means of X-ray tomography during electrical cycling of the LIC. With increasing number of cycles we found electrolyte accumulating at the bottom of the capacitor. A clear correlation between electrolyte distribution at the bottom and performance of the LIC was determined.
Investigation of HNO3-Treated Carbon Xerogel Electrodes for Capacitive Deionization Applications
Authors: Gao Xin , Landon James , Neathery James K. , Liu Kunlei
Published: October 2013

Carbon xerogel (CX) materials were synthesized via poly-condensation reactions on a carbon cloth sheet, and the resulting sheets were used as electrodes in a capacitive deionization (CDI) cell. To study the effect of oxidation degree for the CX on the electrosorption performance, the electrodes were activated in concentrated HNO3 at various temperatures. Electrosorption examined in a flow cell shows that the electrosorption capacity significantly increases from 3.27 mg (NaCl) g-1 (Carbon) (corresponding to the untreated sample) to 5.46 mg (NaCl) g-1 (Carbon) (for the sample treated at 20°C). However, this value cannot be further improved by adding additional functional groups to the carbon surface by treating the sample at higher temperatures. These additional functional groups may interfere with the double layer used for ion adsorption. Finally, we conclude that the CX materials mildly treated in HNO3 could be a way of greatly improving the deionization capacity of CX for CDI applications.
The Effect of Hot-Pressing on Performance of MEA Using Acid-Doped Bacterial Cellulose as Proton Exchange Membranes
Authors: Jiang Gaopeng , Liu Lingling , Zhang Jing , Hong Feng , Qiao Jinli
Published: October 2013

This paper presents a novel optimization methodology to hot-pressing conditions of MEAs with acid-doped bacterial cellulose membranes sandwiched between catalyst layers of cathode and anode. It is convenient and economical to take the reserved ratio of proton conductivity of membrane as the measurement to optimize the hot-pressing condition instead of power density from single cell test. The optimum hot-pressing conditions for both H3PO4/BC and PA/BC selected by this method were verified by the real PEMFC tests, which demonstrated the feasibility of this method. In addition, this work also displayed the effect of supporting materials of hot-pressing on cell performance for the first time.
Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts
Authors: O-Uchi Jin , Jhun Bong Sook , Hurst Stephen , Bisetto Sara , Gross Polina , Chen Ming , Kettlewell Sarah , Park Jongsun , Oyamada Hideto , Smith Godfrey L. , Murayama Takashi , Sheu Shey-Shing
Published: October 2013

Ca+ influx to mitochondria is an important trigger for both mitochondrial dynamics and ATP generation in various cell types, including cardiac cells. Mitochondrial Ca2+ influx is mainly mediated by the mitochondrial Ca2+ uniporter (MCU). Growing evidence also indicates that mitochondrial Ca2+ influx mechanisms are regulated not solely by MCU but also by multiple channels/transporters. We have previously reported that skeletal muscle-type ryanodine receptor (RyR) type 1 (RyR1), which expressed at the mitochondrial inner membrane, serves as an additional Ca2+ uptake pathway in cardiomyocytes. However, it is still unclear which mitochondrial Ca2+ influx mechanism is the dominant regulator of mitochondrial morphology/dynamics and energetics in cardiomyocytes. To investigate the role of mitochondrial RyR1 in the regulation of mitochondrial morphology/function in cardiac cells, RyR1 was transiently or stably overexpressed in cardiac H9c2 myoblasts. We found that overexpressed RyR1 was partially localized in mitochondria as observed using both immunoblots of mitochondrial fractionation and confocal microscopy, whereas RyR2, the main RyR isoform in the cardiac sarcoplasmic reticulum, did not show any expression at mitochondria. Interestingly, overexpression of RyR1 but not MCU or RyR2 resulted in mitochondrial fragmentation. These fragmented mitochondria showed bigger and sustained mitochondrial Ca2+ transients compared with basal tubular mitochondria. In addition, RyR1-overexpressing cells had a higher mitochondrial ATP concentration under basal conditions and showed more ATP production in response to cytosolic Ca2+ elevation compared with nontransfected cells as observed by a matrix-targeted ATP biosensor. These results indicate that RyR1 possesses a mitochondrial targeting/retention signal and modulates mitochondrial morphology and Ca2+-induced ATP production in cardiac H9c2 myoblasts.
Parameter sensitivity analysis of a lumped-parameter model of a chain of lymphangions in series
Authors: Jamalian Samira , Bertram Christopher D. , Richardson William J. , Moore James E.
Published: October 2013

Any disruption of the lymphatic system due to trauma or injury can lead to edema. There is no effective cure for lymphedema, partly because predictive knowledge of lymphatic system reactions to interventions is lacking. A well-developed model of the system could greatly improve our understanding of its function. Lymphangions, defined as the vessel segment between two valves, are the individual pumping units. Based on our previous lumped-parameter model of a chain of lymphangions, this study aimed to identify the parameters that affect the system output the most using a sensitivity analysis. The system was highly sensitive to minimum valve resistance, such that variations in this parameter caused an order-of-magnitude change in time-average flow rate for certain values of imposed pressure difference. Average flow rate doubled when contraction frequency was increased within its physiological range. Optimum lymphangion length was found to be some 13–14.5 diameters. A peak of time-average flow rate occurred when transmural pressure was such that the pressure-diameter loop for active contractions was centered near maximum passive vessel compliance. Increasing the number of lymphangions in the chain improved the pumping in the presence of larger adverse pressure differences. For a given pressure difference, the optimal number of lymphangions increased with the total vessel length. These results indicate that further experiments to estimate valve resistance more accurately are necessary. The existence of an optimal value of transmural pressure may provide additional guidelines for increasing pumping in areas affected by edema.
Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures
Authors: Hobbs Carey A. , Blanchard Maxime G. , Alijevic Omar , Tan Chong Da , Kellenberger Stephan , Bencharit Sompop , Cao Rui , Kesimer Mehmet , Walton William G. , Henderson Ashley G. , Redinbo Matthew R. , Stutts M. Jackson , Tarran Robert
Published: October 2013

The epithelial sodium channel (ENaC) is responsible for Na+and fluid absorption across colon, kidney, and airway epithelia. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is a secreted, innate defense protein and an autocrine inhibitor of ENaC that is highly expressed in airway epithelia. While SPLUNC1 has a bactericidal permeability-increasing protein (BPI)-type structure, its NH2-terminal region lacks structure. Here we found that an 18 amino acid peptide, S18, which corresponded to residues G22-A39 of the SPLUNC1 NH2terminus inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.5 fold), while SPLUNC1 protein lacking this region was without effect. S18 did not inhibit the structurally related acid-sensing ion channels, indicating specificity for ENaC. However, S18 preferentially bound to the βENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Unlike control, CF human bronchial epithelial cultures (HBECs) where airway surface liquid (ASL) height was abnormally low (4.2 ± 0.6 μm), addition of S18 prevented ENaC-led ASL hyperabsorption and maintained CF ASL height at 7.9 ± 0.6 μm, even in the presence of neutrophil elastase, which is comparable to heights seen in normal HBECs. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, suggesting that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the S18 peptide suggests that this peptide may be suitable for treating CF lung disease.
In SilicoRisk Assessment of HLA-A*02:06-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Caused by Cold Medicine Ingredients
Authors: Isogai Hideto , Miyadera Hiroko , Ueta Mayumi , Sotozono Chie , Kinoshita Shigeru , Tokunaga Katsushi , Hirayama Noriaki
Published: October 2013

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug hypersensitivities with high mortality. Typical over-the-counter drugs of cold medicines are suggested to be causative. As multiple ingredients are generally contained in cold medicines, it is of particular interest to investigate which ingredients are responsible for SJS/TEN. However, experimental examination of causal relationships between SJS/TEN and a particular drug molecule is not straightforward. Significant association between HLA-A*02:06 and SJS/TEN with severe ocular surface complications has been observed in the Japanese. In the present study, we have undertakenin silicodocking simulations between various ingredients contained in cold medicines available in Japan and the HLA-A*02:06 molecule. We use the composite risk index (CRI) that is the absolute value of the binding affinity multiplied by the daily dose to assess the potential risk of the adverse reactions. The drugs which have been recognized as causative drugs of SJS/TEN in Japan have revealed relatively high CRI, and the association between SJS/TEN and HLA-A*02:06 has been qualitatively verified. The results have also shown that some drugs whose links to SJS/TEN have not been clinically recognized in Japan show the high CRI and suggested that attention should be paid to their adverse drug reactions.
Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status
Authors: Frye Richard E. , Melnyk Stepan , Fuchs George , Reid Tyra , Jernigan Stefanie , Pavliv Oleksandra , Hubanks Amanda , Gaylor David W. , Walters Laura , James S. Jill
Published: October 2013

Treatments targeting metabolic abnormalities in children with autism are limited. Previously we reported that a nutritional treatment significantly improved glutathione metabolism in children with autistic disorder. In this study we evaluated changes in adaptive behaviors in this cohort and determined whether such changes are related to changes in glutathione metabolism. Thirty-seven children diagnosed with autistic disorder and abnormal glutathione and methylation metabolism were treated with twice weekly 75 µg/Kg methylcobalamin and twice daily 400 µg folinic acid for 3 months in an open-label fashion. The Vineland Adaptive Behavior Scale (VABS) and glutathione redox metabolites were measured at baseline and at the end of the treatment period. Over the treatment period, all VABS subscales significantly improved with an average effect size of 0.59, and an average improvement in skills of 7.7 months. A greater improvement in glutathione redox status was associated with a greater improvement in expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills. Age, gender, and history of regression did not influence treatment response. The significant behavioral improvements observed and the relationship between these improvements to glutathione redox status suggest that nutritional interventions targeting redox metabolism may benefit some children with autism.
Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy
Authors: Pandey Ambarish , Kulkarni Ashish , Roy Bhaskar , Goldman Aaron , Sarangi Sasmit , Sengupta Poulomi , Phipps Colin , Kopparam Jawahar , Oh Michael , Basu Sudipta , Kohandel Mohammad , Sengupta Shiladitya
Published: October 2013

Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer. Cancer Res; 74(3); 675–85. ©2013 AACR.
Supramolecular Nanoparticles That Target Phosphoinositide-3-Kinase Overcome Insulin Resistance and Exert Pronounced Antitumor Efficacy
Authors: Kulkarni Ashish A. , Roy Bhaskar , Rao Poornima S. , Wyant Gregory A. , Mahmoud Ayaat , Ramachandran Madhumitha , Sengupta Poulomi , Goldman Aaron , Kotamraju Venkata Ramana , Basu Sudipta , Mashelkar Raghunath A. , Ruoslahti Erkki , Dinulescu Daniela M. , Sengupta Shiladitya
Published: October 2013

The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance “class effect.” This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-RasLSL/+/Ptenfl/fl ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody–drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment. Cancer Res; 73(23); 6987–97. ©2013 AACR.
Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma
Authors: Nakamura Akito , Arita Takeo , Tsuchiya Shuntarou , Donelan Jill , Chouitar Jouhara , Carideo Elizabeth , Galvin Katherine , Okaniwa Masanori , Ishikawa Tomoyasu , Yoshida Sei
Published: October 2013

The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells. Somatic mutations in BRAF and NRAS are frequently observed in melanoma. Recently, the BRAF inhibitors vemurafenib and dabrafenib have emerged as promising agents for the treatment of melanoma patients with BRAF-activating mutations. However, as BRAF inhibitors induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, rapid emergence of acquired resistance and secondary skin tumors as well as presence of few effective treatment options for melanoma bearing wild-type BRAF (including NRAS-mutant melanoma) are clinical concerns. Here, we demonstrate that the selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. Our analysis using RNAi and TAK-632 in preclinical models reveals that the MAPK pathway of NRAS-mutated melanoma cells is highly dependent on RAF. We also show that TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. As a result, TAK-632 demonstrates potent antiproliferative effects both on NRAS-mutated melanoma cells and BRAF-mutated melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation. Furthermore, we demonstrate that the combination of TAK-632 and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic antiproliferative effects on these cells. Our findings characterize the unique features of TAK-632 as a pan-RAF inhibitor and provide rationale for its further investigation in NRAS-mutated melanoma and a subset of BRAF-mutated melanomas refractory to BRAF inhibitors. Cancer Res; 73(23); 7043–55. ©2013 AACR.
Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells
Authors: Troiani Teresa , Martinelli Erika , Napolitano Stefania , Vitagliano Donata , Ciuffreda Loreta Pia , Costantino Sara , Morgillo Floriana , Capasso Anna , Sforza Vincenzo , Nappi Anna , De Palma Raffaele , D'Aiuto Elena , Berrino Liberato , Bianco Roberto , Ciardiello Fortunato
Published: October 2013

Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.

Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.

Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET–dependent pathways, which were upregulated in GEO-CR cells. Furthermore, activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenous activation of MET by HGF stimulation in cetuximab-sensitive GEO and SW48 cells induced resistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-α, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-α overexpression induced the EGFR–MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.

Conclusions: These results suggest that overexpression of TGF-α through induction of EGFR–MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer. Clin Cancer Res; 19(24); 6751–65. ©2013 AACR.
ECOG Phase II Trial of Graded-Dose Peginterferon α-2b in Patients with Metastatic Melanoma Overexpressing Basic Fibroblast Growth Factor (E2602)
Authors: Go Ronald S. , Lee Sandra J. , Shin Donghoon , Callister Steven M. , Jobe Dean A. , Conry Robert M. , Tarhini Ahmad A. , Kirkwood John M.
Published: October 2013

Purpose: We investigated the use of graded-dose peginterferon α-2b (Peg-IFN) in patients with stage IV melanoma overexpressing basic fibroblast growth factor (FGF-2). The primary objective was suppression of plasma FGF-2 to within reference range (≤7.5 pg/mL).

Experimental Design: Plasma FGF-2 was measured at baseline (step 1), and patients with concentrations of 15 pg/mL or more were eligible for study treatment (step 2). Peg-IFN was given weekly at a starting dose of 0.5 μg/kg/wk with increment every 3 weeks based on serial FGF-2 concentrations.

Results: Two hundred seven patients entered step 1; 45 (22%) overexpressed FGF-2 (median = 22 pg/dL). Twenty-nine eligible patients entered step 2 and received treatment. Patients' median age was 64 years (range, 29–84 years). Most had more than two prior therapies. FGF-2 decreased in 28 (97%) patients, with suppression to reference range in 10 (35%). Median time to FGF-2 suppression was 30 days. The best clinical responses were partial response (7%) and stable disease (17%). Median progression-free survival (PFS) and overall survival (OS) were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely than those who did not to have a response or stable disease (P = 0.03). VEGF concentrations decreased in 27 patients (93%) during treatment and paralleled those of FGF-2 over time. We found no compensatory increase in VEGF among those with FGF-2 suppression.

Conclusions: Graded-dose Peg-IFN suppresses FGF-2 in patients with metastatic melanoma who overexpress FGF-2. Over one third of patients had complete suppression of plasma FGF-2, which correlated with clinical response to this therapy. Clin Cancer Res; 19(23); 6597–604. ©2013 AACR.
Poor Concordance among Nine Immunohistochemistry Classifiers of Cell-of-Origin for Diffuse Large B-Cell Lymphoma: Implications for Therapeutic Strategies
Authors: Coutinho Rita , Clear Andrew James , Owen Andrew , Wilson Andrew , Matthews Janet , Lee Abigail , Alvarez Rute , da Silva Maria Gomes , Cabeçadas José , Calaminici Maria , Gribben John G.
Published: October 2013

Purpose: The opportunity to improve therapeutic choices on the basis of molecular features of the tumor cells is on the horizon in diffuse large B-cell lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type (ABC) DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. Although molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome. However, results are poorly reproducible by independent groups.

Experimental Design: We investigated nine IHC algorithms for molecular classification in a dataset of DLBCL diagnostic biopsies, incorporating immunostaining for CD10, BCL6, BCL2, MUM1, FOXP1, GCET1, and LMO2. IHC profiles were assessed and agreed among three expert observers. A consensus matrix based on all scoring combinations and the number of subjects for each combination allowed us to assess reliability. The survival impact of individual markers and classifiers was evaluated using Kaplan–Meier curves and the log-rank test.

Results: The concordance in patient's classification across the different algorithms was low. Only 4% of the tumors have been classified as germinal center B-cell type (GCB) and 21% as ABC/non-GCB by all methods. None of the algorithms provided prognostic information in the R-CHOP (rituximab plus cyclophosphamide–adriamycin–vincristine–prednisone)–treated cohort.

Conclusion: Further work is required to standardize IHC algorithms for DLBCL cell-of-origin classification for these to be considered reliable alternatives to molecular-based methods to be used for clinical decisions. Clin Cancer Res; 19(24); 6686–95. ©2013 AACR.
Inhibition of Wee1 Sensitizes Cancer Cells to Antimetabolite Chemotherapeutics In Vitro and In Vivo, Independent of p53 Functionality
Authors: Van Linden Annemie A. , Baturin Dmitry , Ford James B. , Fosmire Susan P. , Gardner Lori , Korch Christopher , Reigan Philip , Porter Christopher C.
Published: October 2013

Inhibition of Wee1 is emerging as a novel therapeutic strategy for cancer, and some data suggest that cells with dysfunctional p53 are more sensitive to Wee1 inhibition combined with conventional chemotherapy than those with functional p53. We and others found that Wee1 inhibition sensitizes leukemia cells to cytarabine. Thus, we sought to determine whether chemosensitization by Wee1 inhibition is dependent on p53 dysfunction and whether combining Wee1 inhibition is tolerable and effective in vivo. Synergistic inhibition of proliferation with a Wee1 inhibitor in clinical development, MK1775, and cytarabine was observed in all acute myelogenous leukemia (AML) cell lines tested, regardless of p53 functionality. Mechanistic studies indicate that inhibition of Wee1 abrogates the S-phase checkpoint and augments apoptosis induced by cytarabine. In AML and lung cancer cell lines, genetic disruption of p53 did not alter the cells' enhanced sensitivity to antimetabolites with Wee1 inhibition. Finally, mice with AML were treated with cytarabine and/or MK1775. The combination of MK1775 and cytarabine was well tolerated in mice and enhanced the antileukemia effects of cytarabine, including survival. Thus, inhibition of Wee1 sensitizes hematologic and solid tumor cell lines to antimetabolite chemotherapeutics, whether p53 is functional or not, suggesting that the use of p53 mutation as a predictive biomarker for response to Wee1 inhibition may be restricted to certain cancers and/or chemotherapeutics. These data provide preclinical justification for testing MK1775 and cytarabine in patients with leukemia. Mol Cancer Ther; 12(12); 2675–84. ©2013 AACR.