bluuebunny/crossref_metadata_2025 huggingface dataset:
Mathematical modeling reveals modulation of both nuclear influx and efflux of Foxo1 by the IGF-I/PI3K/Akt pathway in skeletal muscle fibers
Authors: Wimmer Robert J. , Liu Yewei , Schachter Tova Neustadt , Stonko David P. , Peercy Bradford E. , Schneider Martin F.
Published: January 2014

Foxo family transcription factors contribute to muscle atrophy by promoting transcription of the ubiquitin ligases muscle-specific RING finger protein and muscle atrophy F-box/atrogin-1. Foxo transcriptional effectiveness is largely determined by its nuclear-cytoplasmic distribution, with unphosphorylated Foxo1 transported into nuclei and phosphorylated Foxo1 transported out of nuclei. We expressed the fluorescent fusion protein Foxo1-green fluorescent protein (GFP) in cultured adult mouse flexor digitorum brevis muscle fibers and tracked the time course of the nuclear-to-cytoplasmic Foxo1-GFP mean pixel fluorescence ratio (N/C) in living fibers by confocal imaging. We previously showed that IGF-I, which activates the Foxo kinase Akt/PKB, caused a rapid marked decline in N/C, whereas inhibition of Akt caused a modest increase in N/C. Here we develop a two-state mathematical model for Foxo1 nuclear-cytoplasmic redistribution, where Foxo phosphorylation/dephosphorylation is assumed to be fast compared with nuclear influx and efflux. Cytoplasmic Foxo1-GFP mean pixel fluorescence is constant due to the much larger cytoplasmic than nuclear volume. Analysis of N/C time courses reveals that IGF-I strongly increased unidirectional nuclear efflux, indicating similarly increased fractional phosphorylation of Foxo1 within nuclei, and decreased unidirectional nuclear influx, indicating increased cytoplasmic fractional phosphorylation of Foxo1. Inhibition of Akt increased Foxo1 unidirectional nuclear influx, consistent with block of Foxo1 cytoplasmic phosphorylation, but did not decrease Foxo1 unidirectional nuclear efflux, indicating that Akt may not be involved in Foxo1 nuclear efflux under control conditions. New media change experiments show that cultured fibers release IGF-I-like factors, which maintain low nuclear Foxo1 in the medium. This study demonstrates the power of quantitative modeling of observed nuclear fluxes.
Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling
Authors: Wadosky Kristine M. , Rodríguez Jessica E. , Hite Rebecca L. , Min Jin-na , Walton Bethany L. , Willis Monte S.
Published: January 2014

Recent studies implicate the muscle-specific ubiquitin ligase muscle RING finger-1 (MuRF1) in inhibiting pathological cardiomyocyte growth in vivo by inhibiting the transcription factor SRF. These studies led us to hypothesize that MuRF1 similarly inhibits insulin-like growth factor-I (IGF-I)-mediated physiological cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: IGF-I stimulation of cardiac-derived cells with MuRF1 knockdown 1) exhibited an exaggerated hypertrophy and, 2) conversely, increased MuRF1 expression-abolished IGF-I-dependent cardiomyocyte growth. Enhanced hypertrophy with MuRF1 knockdown was accompanied by increases in Akt-regulated gene expression. Unexpectedly, MuRF1 inhibition of this gene expression profile was not a result of differences in p-Akt. Instead, we found that MuRF1 inhibits total protein levels of Akt, GSK-3β (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-I signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia-reperfusion injury. Since IGF-I regulates exercise-mediated physiological cardiac growth, we challenged MuRF1−/− and MuRF1-Tg+ mice and their wild-type sibling controls to 5 wk of voluntary wheel running. MuRF1−/− cardiac growth was increased significantly over wild-type control; conversely, the enhanced exercise-induced cardiac growth was lost in MuRF1-Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-I signaling via c-Jun is applicable in vivo and establish that further understanding of this novel mechanism may be crucial in the development of therapies targeting IGF-I signaling.
Activation of alternative NF-κB signaling during recovery of disuse-induced loss of muscle oxidative phenotype
Authors: Remels A. H. V. , Pansters N. A. , Gosker H. R. , Schols A. M. W. J. , Langen R. C. J.
Published: January 2014

Physical inactivity-induced loss of skeletal muscle oxidative phenotype (OXPHEN), often observed in chronic disease, adversely affects physical functioning and quality of life. Potential therapeutic targets remain to be identified, since the molecular mechanisms involved in reloading-induced recovery of muscle OXPHEN remain incompletely understood. We hypothesized a role for alternative NF-κB, as a recently identified positive regulator of muscle OXPHEN, in reloading-induced alterations in muscle OXPHEN. Markers and regulators (including alternative NF-κB signaling) of muscle OXPHEN were investigated in gastrocnemius muscle of mice subjected to a hindlimb suspension/reloading (HLS/RL) protocol. Expression levels of oxidative phosphorylation subunits and slow myosin heavy chain isoforms I and IIA increased rapidly upon RL. After an initial decrease upon HLS, mRNA levels of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC) molecules PGC-1α and PGC-1β and mRNA levels of mitochondrial transcription factor A (Tfam) and estrogen-related receptor α increased upon RL. PPAR-δ, nuclear respiratory factor 1 (NRF-1), NRF-2α, and sirtuin 1 mRNA levels increased during RL although expression levels were unaltered upon HLS. In addition, both Tfam and NRF-1 protein levels increased significantly during the RL period. Moreover, upon RL, IKK-α mRNA and protein levels increased, and phosphorylation of P100 and subsequent processing to P52 were elevated, reflecting alternative NF-κB activation. We conclude that RL-induced recovery of muscle OXPHEN is associated with activation of alternative NF-κB signaling.
Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat
Authors: Warren Blair E. , Lou Phing-How , Lucchinetti Eliana , Zhang Liyan , Clanachan Alexander S. , Affolter Andreas , Hersberger Martin , Zaugg Michael , Lemieux Hélène
Published: January 2014

Although evidence that type 2 diabetes mellitus (T2DM) is accompanied by mitochondrial dysfunction in skeletal muscle has been accumulating, a causal link between mitochondrial dysfunction and the pathogenesis of the disease remains unclear. Our study focuses on an early stage of the disease to determine whether mitochondrial dysfunction contributes to the development of T2DM. The fructose-fed (FF) rat was used as an animal model of early T2DM. Mitochondrial respiration and acylcarnitine species were measured in oxidative (soleus) and glycolytic [extensor digitorum longus (EDL)] muscle. Although FF rats displayed characteristic signs of T2DM, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, mitochondrial content was preserved in both muscles from FF rats. The EDL muscle had reduced complex I and complex I and II respiration in the presence of pyruvate but not glutamate. The decrease in pyruvate-supported respiration was due to a decrease in pyruvate dehydrogenase activity. Accumulation of C14:1 and C14:2 acylcarnitine species and a decrease in respiration supported by long-chain acylcarnitines but not acetylcarnitine indicated dysfunctional β-oxidation in the EDL muscle. In contrast, the soleus muscle showed preserved mitochondrial respiration, pyruvate dehydrogenase activity, and increased fatty acid oxidation, as evidenced by overall reduced acylcarnitine levels. Aconitase activity, a sensitive index of reactive oxygen species production in mitochondria, was reduced exclusively in EDL muscle, which showed lower levels of the antioxidant enzymes thioredoxin reductase and glutathione peroxidase. Here, we show that the glycolytic EDL muscle is more prone to an imbalance between energy supply and oxidation caused by insulin resistance than the oxidative soleus muscle.
Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews
Authors: Horn Charles C. , Meyers Kelly , Lim Audrey , Dye Matthew , Pak Diana , Rinaman Linda , Yates Bill J.
Published: January 2014

Signals from the vestibular system, area postrema, and forebrain elicit nausea and vomiting, but gastrointestinal (GI) vagal afferent input arguably plays the most prominent role in defense against food poisoning. It is difficult to determine the contribution of GI vagal afferent input on emesis because various agents (e.g., chemotherapy) often act on multiple sensory pathways. Intragastric copper sulfate (CuSO4) potentially provides a specific vagal emetic stimulus, but its actions are not well defined in musk shrews ( Suncus murinus), a primary small animal model used to study emesis. The aims of the current study were 1) to investigate the effects of subdiaphragmatic vagotomy on CuSO4-induced emesis and 2) to conduct preliminary transneuronal tracing of the GI-brain pathways in musk shrews. Vagotomy failed to inhibit the number of emetic episodes produced by optimal emetic doses of CuSO4(60 and 120 mg/kg ig), but the effects of lower doses were dependent on an intact vagus (20 and 40 mg/kg). Vagotomy also failed to affect emesis produced by motion (1 Hz, 10 min) or nicotine administration (5 mg/kg sc). Anterograde transport of the H129 strain of herpes simplex virus-1 from the ventral stomach wall identified the following brain regions as receiving inputs from vagal afferents: the nucleus of the solitary tract, area postrema, and lateral parabrachial nucleus. These data indicate that the contribution of vagal pathways to intragastric CuSO4-induced emesis is dose dependent in musk shrews. Furthermore, the current neural tracing data suggest brain stem anatomical circuits that are activated by GI signaling in the musk shrew.
Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging
Authors: Gordish Kevin L. , Beierwaltes William H.
Published: January 2014

Resveratrol is suggested to have beneficial cardiovascular and renoprotective effects. Resveratrol increases endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. We hypothesized resveratrol acts as an acute renal vasodilator, mediated through increased NO production and scavenging of reactive oxygen species (ROS). In anesthetized rats, we found 5.0 mg/kg body weight (bw) of resveratrol increased renal blood flow (RBF) by 8% [from 6.98 ± 0.42 to 7.54 ± 0.17 ml·min−1·gram of kidney weight−1(gkw); n = 8; P < 0.002] and decreased renal vascular resistance (RVR) by 18% from 15.00 ± 1.65 to 12.32 ± 1.20 arbitrary resistance units (ARU; P < 0.002). To test the participation of NO, we administered 5.0 mg/kg bw resveratrol before and after 10 mg/kg bw of the NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME). l-NAME reduced the increase in RBF to resveratrol by 54% (from 0.59 ± 0.05 to 0.27 ± 0.06 ml·min−1·gkw−1; n = 10; P < 0.001). To test the participation of ROS, we gave 5.0 mg/kg bw resveratrol before and after 1 mg/kg bw tempol, a superoxide dismutase mimetic. Resveratrol increased RBF 7.6% (from 5.91 ± 0.32 to 6.36 ± 0.12 ml·min−1·gkw−1; n = 7; P < 0.001) and decreased RVR 19% (from 18.83 ± 1.37 to 15.27 ± 1.37 ARU). Tempol blocked resveratrol-induced increase in RBF (from 0.45 ± 0.12 to 0.10 ± 0.05 ml·min−1·gkw−1; n = 7; P < 0.03) and the decrease in RVR posttempol was 44% of the control response (3.56 ± 0.34 vs. 1.57 ± 0.21 ARU; n = 7; P < 0.006). We also tested the role of endothelium-derived prostanoids. Two days of 10 mg/kg bw indomethacin pretreatment did not alter basal blood pressure or RBF. Resveratrol-induced vasodilation remained unaffected. We conclude intravenous resveratrol acts as an acute renal vasodilator, partially mediated by increased NO production/NO bioavailability and superoxide scavenging but not by inducing vasodilatory cyclooxygenase products.
Savings in locomotor adaptation explained by changes in learning parameters following initial adaptation
Authors: Mawase Firas , Shmuelof Lior , Bar-Haim Simona , Karniel Amir
Published: January 2014

Faster relearning of an external perturbation, savings, offers a behavioral linkage between motor learning and memory. To explain savings effects in reaching adaptation experiments, recent models suggested the existence of multiple learning components, each shows different learning and forgetting properties that may change following initial learning. Nevertheless, the existence of these components in rhythmic movements with other effectors, such as during locomotor adaptation, has not yet been studied. Here, we study savings in locomotor adaptation in two experiments; in the first, subjects adapted to speed perturbations during walking on a split-belt treadmill, briefly adapted to a counter-perturbation and then readapted. In a second experiment, subjects readapted after a prolonged period of washout of initial adaptation. In both experiments we find clear evidence for increased learning rates (savings) during readaptation. We show that the basic error-based multiple timescales linear state space model is not sufficient to explain savings during locomotor adaptation. Instead, we show that locomotor adaptation leads to changes in learning parameters, so that learning rates are faster during readaptation. Interestingly, we find an intersubject correlation between the slow learning component in initial adaptation and the fast learning component in the readaptation phase, suggesting an underlying mechanism for savings. Together, these findings suggest that savings in locomotion and in reaching may share common computational and neuronal mechanisms; both are driven by the slow learning component and are likely to depend on cortical plasticity.
Prehospital Intubation in Patients with Isolated Severe Traumatic Brain Injury: A 4-Year Observational Study
Authors: Tuma Mazin , El-Menyar Ayman , Abdelrahman Husham , Al-Thani Hassan , Zarour Ahmad , Parchani Ashok , Khoshnaw Sherwan , Peralta Ruben , Latifi Rifat
Published: January 2014

Objectives. To study the effect of prehospital intubation (PHI) on survival of patients with isolated severe traumatic brain injury (ISTBI).Method. Retrospective analyses of all intubated patients with ISTBI between 2008 and 2011 were studied. Comparison was made between those who were intubated in the PHI versus in the trauma resuscitation unit (TRU).Results. Among 1665 TBI patients, 160 met the inclusion criteria (105 underwent PHI, and 55 patients were intubated in TRU). PHI group was younger in age and had lower median scene motor GCS (P=0.001). Ventilator days and hospital length of stay (P=0.01and 0.006, resp.) were higher in TRUI group. Mean ISS, length of stay, initial blood pressure, pneumonia, and ARDS were comparable among the two groups. Mortality rate was higher in the PHI group (54% versus 31%,P=0.005). On multivariate regression analysis, scene motor GCS (OR 0.55; 95% CI 0.41–0.73) was an independent predictor for mortality.Conclusion. PHI did not offer survival benefit in our group of patients with ISTBI based on the head AIS and the scene motor GCS. However, more studies are warranted to prove this finding and identify patients who may benefit from this intervention.
Colorectal Surgery in Cirrhotic Patients
Authors: Paolino Jacqueline , Steinhagen Randolph M.
Published: January 2014

Patients with cirrhosis have a greater risk of morbidity and mortality following colorectal surgery. Therefore, preoperative medical optimization and risk assessment using criteria such as the MELD score are vital in preventing complications. Some risk factors include age, urgency of surgery, and ASA score. Postoperative morbidity and mortality are related to portal hypertension, ascites, infection, and anastomotic and stomal complications. This review highlights the assessment of risk and perioperative management of cirrhotic patients undergoing colorectal surgery.
Prevalence of Oral Lesions in Hospitalized Patients with Infectious Diseases in Northern Brazil
Authors: Gemaque Karina , Giacomelli Nascimento Gustavo , Cintra Junqueira José Luiz , Cavalcanti de Araújo Vera , Furuse Cristiane
Published: January 2014

The aim of this study was to assess the prevalence of oral lesions in infectious-contagious diseases patients being treated in the University Hospital of the Federal University of Pará, northern Brazil. One hundred seven patients with infectious diseases were clinically investigated for oral lesions at the University Hospital of Pará, northern Brazil. From total sample, most patients were men (65.7%) with a mean age of 45.4 years. About prevalence of systemic diseases, tuberculosis was the most frequent illness, followed by AIDS, hepatitis types B and C, leishmaniasis, and meningitis. Analyzing oral manifestations, periodontal diseases and candidiasis were the most prevalent diseases in both genders, followed by recurrent aphthous ulcers, saburral tongue, simplex herpes, and squamous cell carcinoma. Of all 107 patients, only 10 males and 6 females did not present any oral manifestation. There was no statistical difference between genders with any systemic condition (P>0.05). The great prevalence of oral manifestations in hospitalized patients with systemic disorder emphasizes the need of integral dental care in this context, aiming at a multidisciplinary approach of patients. Therefore, presence of some oral conditions, such as candidiasis, should be an alert to different systemic conditions, once in assistance with physicians; dentists can influence the early diagnosis and treatment.
The Activity of [60]Fullerene Derivatives Bearing Amine and Carboxylic Solubilizing Groups against Escherichia coli: A Comparative Study
Authors: Deryabin Dmitry G. , Davydova Olga K. , Yankina Zulfiya ZH. , Vasilchenko Alexey S. , Miroshnikov Sergei A. , Kornev Alexey B. , Ivanchikhina Anastasiya V. , Troshin Pavel A.
Published: January 2014

We report a comparative investigation of the antibacterial activity of two water‐soluble fullerene derivatives bearing protonated amine (AF) and deprotonated carboxylic (CF) groups appended to the fullerene cage via organic linkers. The negatively charged fullerene derivative CF showed no tendency to bind to the bacterial cells and, consequently, no significant antibacterial activity. In contrast, the compound AF loaded with cationic groups showed strong and partially irreversible binding to the negatively charged Escherichia coli K12 TG1 cells and to human erythrocytes, also possessing negative zeta potential. Adsorption of AF on the bacterial surface was visualized by atomic force microscopy revealing the formation of specific clusters (AF aggregates) surrounding the bacterial cell. Incubation of E. coli K12 TG1 with AF led to a dose‐dependent bactericidal effect with LD50  =  79.1 µM. The presence of human erythrocytes in the test medium decreased the AF antibacterial activity. Thus we reveal that the water‐soluble cationic fullerene derivative AF possesses promising antibacterial activity, which might be utilized in the development of novel types of chemical disinfectants.
Synthesis of Copper Nanoparticles by Thermal Decomposition and Their Antimicrobial Properties
Authors: Betancourt-Galindo R. , Reyes-Rodriguez P. Y. , Puente-Urbina B. A. , Avila-Orta C. A. , Rodríguez-Fernández O. S. , Cadenas-Pliego G. , Lira-Saldivar R. H. , García-Cerda L. A.
Published: January 2014

Copper nanoparticles were synthesized by thermal decomposition using copper chloride, sodium oleate, and phenyl ether as solvent agents. The formation of nanoparticles was evidenced by the X‐ray diffraction and transmission electron microscopy. The peaks in the XRD pattern correspond to the standard values of the face centered cubic (fcc) structure of metallic copper and no peaks of other impurity crystalline phases were detected. TEM analysis showed spherical nanoparticles with sizes in the range of 4 to 18 nm. The antibacterial properties of copper nanoparticles were evaluated in vitro against strains of Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity of copper nanoparticles synthesized by thermal decomposition showed significant inhibitory effect against these highly multidrug‐resistant bacterial strains.
Risk of Prostate Cancer in Lynch Syndrome: A Systematic Review and Meta-analysis
Authors: Ryan Shae , Jenkins Mark A. , Win Aung Ko
Published: January 2014

It has been controversial that men carrying a DNA mismatch repair (MMR) gene mutation (Lynch syndrome) are at heightened risk of prostate cancer given that an increased risk is likely to be modest and the prevalence of prostate cancer is high. We used PubMed to search for “molecular studies” that reported MMR-deficiency status of prostate cancer tumors in men with an MMR gene mutation, and “risk studies” that reported prostate cancer risk for men known or suspected to have an MMR gene mutation relative to that for noncarriers or the general population. Of the six molecular studies, 32 of 44 [73%, 95% confidence intervals (CI), 57%–85%] prostate cancer tumors in carriers were MMR deficient, which equates to carriers having a 3.67-fold increased risk of prostate cancer (95% CI, 2.32–6.67). Of the 12 risk studies, we estimated a 2.13-fold increased risk of prostate cancer (95% CI, 1.45–2.80) for male carriers in clinic-based retrospective cohorts, 2.11 (95% CI, 1.27–2.95) for male carriers with a prior diagnosis of colorectal cancer, and 2.28 (95% CI, 1.37–3.19) for all men from mutation-carrying families. The combination of evidence from molecular and risk studies in the current literature supports consideration of prostate cancer as part of Lynch syndrome. Cancer Epidemiol Biomarkers Prev; 23(3); 437–49. ©2014 AACR.
Decitabine Induces Delayed Reactive Oxygen Species (ROS) Accumulation in Leukemia Cells and Induces the Expression of ROS Generating Enzymes
Authors: Fandy Tamer E. , Jiemjit Anchalee , Thakar Manjusha , Rhoden Paulette , Suarez Lauren , Gore Steven D.
Published: January 2014

Purpose: Azanucleoside DNA methyltransferase (DNMT) inhibitors are currently approved by the U.S. Food and Drug Administration for treatment of myelodysplastic syndrome. The relative contributions of DNMT inhibition and other off-target effects to their clinical efficacy remain unclear. Data correlating DNA methylation reversal and clinical response have been conflicting. Consequently, it is necessary to investigate so-called off-target effects and their impact on cell survival and differentiation.

Experimental Design: Flow cytometry was used for cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation analysis. Gene expression analysis was performed using real-time PCR. DNA methylation was detected by methylation-specific PCR. Mitochondrial membrane potential was analyzed using JC-1 dye staining. Western blotting was used for quantitative protein expression analysis.

Results: 5-Aza-2′-deoxycytidine (DAC) induced cell-cycle arrest and apoptosis in leukemia cells. p53 expression was dispensable for DAC-induced apoptosis. DAC induced delayed ROS accumulation in leukemia cells but not in solid tumor cells and p53 expression was dispensable for ROS increase. ROS increase was deoxycytidine kinase dependent, indicating that incorporation of DAC into nuclear DNA is required for ROS generation. ROS accumulation by DAC was caspase-independent and mediated the dissipation of the mitochondrial membrane potential. Concordantly, ROS scavengers diminished DAC-induced apoptosis. DAC induced the expression of different NADPH oxidase isoforms and upregulated Nox4 protein expression in an ATM-dependent manner, indicating the involvement of DNA damage signaling in Nox4 upregulation.

Conclusion: These data highlight the importance of mechanisms other than DNA cytosine demethylation in modulating gene expression and suggest investigating the relevance of ROS accumulation to the clinical activity of DAC. Clin Cancer Res; 20(5); 1249–58. ©2014 AACR.
Inflammatory Markers and Development of Symptom Burden in Patients with Multiple Myeloma during Autologous Stem Cell Transplantation
Authors: Wang Xin Shelley , Shi Qiuling , Shah Nina D. , Heijnen Cobi J. , Cohen Evan N. , Reuben James M. , Orlowski Robert Z. , Qazilbash Muzaffar H. , Johnson Valen E. , Williams Loretta A. , Mendoza Tito R. , Cleeland Charles S.
Published: January 2014

Purpose: Increasing research suggests that inflammation mediates symptom development. In this longitudinal study, we examined inflammatory factors related to the development of high symptom burden during autologous hematopoietic stem cell transplant (AuSCT) for multiple myeloma.

Experimental Design: Patients (n = 63) repeatedly reported symptom severity on the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM) and contributed blood samples periodically for up to 100 days after AuSCT for inflammatory marker assays. The temporal associations between serum inflammatory marker concentrations and symptom severity outcomes were examined by nonlinear mixed-effect modeling.

Results: Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were consistently the most severe MDASI-MM symptoms during the study. Peak symptom severity occurred on day 8 after AuSCT, during white blood cell count nadir. Patterns of serum interleukin (IL)-6 (peak on day 9) and soluble IL-6 receptor (sIL-6R; nadir on day 8) expression paralleled symptom development over time (both P < 0.0001). By univariate analysis, serum IL-6, sIL-6R, IL-10, C-reactive protein, macrophage inflammatory protein (MIP)-1α, sIL-1R2, sIL-1RA, and soluble tumor necrosis factor receptor 1 were significantly related to the most severe symptoms during the first 30 days after AuSCT (all P < 0.05). By multivariate analysis, IL-6 (estimate = 0.170; P = 0.004) and MIP-1α (estimate = −0.172; P = 0.006) were temporally associated with the severity of the component symptom score.

Conclusions: Systemic inflammatory response was associated with high symptom burden during the acute phase of AuSCT. Additional research is needed to understand how the inflammatory response is mechanistically associated with symptom expression and whether suppression of this response can reduce symptoms without compromising tumor control. Clin Cancer Res; 20(5); 1366–74. ©2014 AACR.
XPO1 (CRM1) Inhibition Represses STAT3 Activation to Drive a Survivin-Dependent Oncogenic Switch in Triple-Negative Breast Cancer
Authors: Cheng Yan , Holloway Michael P. , Nguyen Kevin , McCauley Dilara , Landesman Yosef , Kauffman Michael G. , Shacham Sharon , Altura Rachel A.
Published: January 2014

Inhibition of XPO1 (CRM1)-mediated nuclear export of multiple tumor suppressor proteins has been proposed as a novel cancer therapeutic strategy to turn off oncogenic signals and enhance tumor suppression. Survivin is a multifunctional protein with oncogenic properties when expressed in the cytoplasm that requires the XPO1–RanGTP complex for its nuclear export. We investigated the antitumor mechanisms of the drug-like selective inhibitors of nuclear export (SINE) XPO1 antagonists KPT-185, KPT-251 KPT-276, and KPT-330 in estrogen receptor–positive and triple-negative breast cancer (TNBC) cell lines and xenograft models of human breast tumors. KPT compounds significantly inhibited breast cancer cell growth and induced tumor cell death, both in vitro and in vivo. These drugs initially promoted survivin accumulation within tumor cell nuclei. However, their major in vitro effect was to decrease survivin cytoplasmic protein levels, correlating with the onset of apoptosis. XPO1 inhibition repressed Survivin transcription by inhibiting CREB-binding protein-mediated STAT3 acetylation, and blocking STAT3 binding to the Survivin promoter. In addition, caspase-3 was activated to cleave survivin, rendering it unavailable to bind X-linked inhibitor of apoptosis protein and block the caspase cascade. Collectively, these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in TNBC. Mol Cancer Ther; 13(3); 675–86. ©2014 AACR.
HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis
Authors: Zhang Changwen , Yin Chunyang , Wang Lei , Zhang Shuping , Qian Yi , Ma Juan , Zhang Zhihong , Xu Yong , Liu Sijin
Published: January 2014

Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, c-Myc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3′-phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.

Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583–94. ©2014 AACR.
Raloxifene and Antiestrogenic Gonadorelin Inhibits Intestinal Tumorigenesis by Modulating Immune Cells and Decreasing Stem-like Cells
Authors: Janakiram Naveena B. , Mohammed Altaf , Brewer Misty , Bryant Taylor , Biddick Laura , Lightfoot Stan , Pathuri Gopal , Gali Hariprasad , Rao Chinthalapally V.
Published: January 2014

Studies suggest that estrogen plays a contributing role in colorectal cancer. This project examined the preventive effects of raloxifene, a selective estrogen receptor modulator (SERM), and gonadorelin, an antiestrogenic drug, in female ApcMin/+ mouse intestinal tumorigenesis. Six-week-old ApcMin/+mice were fed diet containing 1 ppm raloxifene or control diet. Gonadorelin (150 ng/mouse) was injected subcutaneously into one treatment group. Intestinal tumors were evaluated for tumor multiplicity and size. Mice treated with raloxifene and gonadorelin showed colon tumor inhibition of 80% and 75%, respectively. Both drugs significantly inhibited small intestinal tumor multiplicity and size (75%–65%, P < 0.0001). Raloxifene and gonadorelin showed significant tumor inhibition with 98% and 94% inhibition of polyps >2 mm in size. In mice fed with raloxifene or injected with gonadorelin, tumors showed significantly reduced proliferating cell nuclear antigen expression (58%–65%, P < 0.0001). Raloxifene treatment decreased β-catenin, cyclin D1, laminin 1β, Ccl6, and stem-like cells (Lgr 5, EpCAM, CD44/CD24), as well as suppressed inflammatory genes (COX-2, mPGES-1, 5-LOX,). Gonadorelin showed significant decrease in COX-2, mPGES-1, iNOS, and stem-like cells or increased NK cells and chemokines required for NK cells. Both drugs were effective in suppressing tumor growth albeit with different mechanisms. These observations show that either suppression of estrogen levels or modulation of estrogen receptor dramatically suppresses small intestinal and colonic tumor formation in female ApcMin/+ mice. These results support the concept of chemoprevention by these agents in reducing endogenous levels of estrogen or modulating ER signaling. Cancer Prev Res; 7(3); 300–9. ©2014 AACR.
Hyperuricemia Is a Significant Risk Factor for the Onset of Chronic Kidney Disease
Authors: Toda Akiko , Ishizaka Yuko , Tani Mizuki , Yamakado Minoru
Published: January 2014

Background: Recent studies have shown that hyperuricemia is an independent risk factor for cardiovascular disease. However, few studies have examined whether hyperuricemia is a risk factor for chronic kidney disease (CKD), so to investigate the significance of hyperuricemia as a risk factor for CKD, we analyzed data collected in annual health check-ups. Methods: The data of 11,048 subjects who underwent an annual health check-up were analyzed in cross-sectional and longitudinal studies. Results: After adjustment for covariate factors, a multivariate logistic regression analysis showed that age, systolic blood pressure, diastolic blood pressure, LDL-cholesterol, triglyceride, HbA1c, and uric acid (hazard ratio: 1.66) were independently and significantly associated with CKD. We also analyzed the data of 1,652 subjects who underwent annual health check-ups for 5 consecutive years. Over that 5-year period, 93 subjects developed CKD. We compared the baseline data of the subjects who developed CKD with the data of those who did not, and we found significant between-group differences in gender, age, HDL-cholesterol, the estimated glomerular filtration rate, and uric acid. After adjustment for several covariate factors, a multivariate Cox regression analysis showed that only age and hyperuricemia (hazard ratio: 1.36) were independent risk factors for the development of CKD. Conclusions: We found that hyperuricemia is an independent risk factor for the development of CKD.
A Fas-Associated via Death Domain Promoter Polymorphism (rs10898853, -16C/T) as a Risk Factor for Papillary Thyroid Cancer
Authors: Eun Y.G. , Chung D.H. , Kim S.W. , Lee Y.C. , Kim S.K. , Kwon K.H.
Published: January 2014

Purpose: To determine whether a Fas-associated via death domain (FADD) promoter single-nucleotide polymorphism (SNP) is associated with susceptibility to papillary thyroid cancer (PTC) and clinicopathological features of PTC. Methods: To identify a possible association with PTC, 94 patients with PTC and 346 healthy controls were recruited. One promoter SNP (rs10898853, -16C/T) was analyzed by direct sequencing. Multiple logistic regression models (co-dominant, dominant, recessive, and log-additive models) were applied, and odds ratios (ORs), 95% confidence intervals (CIs), and p values were calculated. Results: The genotype of the promoter SNP (rs10898853) of FADD was found to be significantly associated with PTC in the co-dominant model 2 (T/T vs. C/C; p = 0.002, OR = 2.80, 95% CI = 1.39-5.65), the recessive model (p = 0.003, OR = 2.21, 95% CI = 1.31-3.71), and the log-additive model (p = 0.002, OR = 1.71, 95% CI = 1.20-2.44). Allele frequency analysis showed that the C allele of rs10898853 was significantly associated with an increased risk of PTC (p = 0.002, OR = 1.67, 95% CI = 1.21-2.32). Conclusions: Our results suggest that the FADD promoter polymorphism is associated with susceptibility to PTC.
A European Community Pharmacy-Based Survey to Investigate Patterns of Prescription Fraud through Identification of Falsified Prescriptions
Authors: Lapeyre-Mestre Maryse , Gony Mireille , Carvajal Alfonso , Macias Diego , Conforti Anita , D'Incau Paola , Heerdink Rob , Van der Stichele Robert , Bergman Ulf ,   The OSIAP Europe Study Group
Published: January 2014

Aim: To identify prescription drugs involved in falsified prescriptions in community pharmacies in 6 European countries. Methods: A cross-sectional survey among 2,105 community pharmacies in Belgium, France, Italy, the Netherlands, Spain and Sweden was carried out to collect all suspect prescription forms. For each reported drug, the number of reported falsified prescriptions per thousand inhabitants was estimated. A falsification ratio was calculated by dividing the number of reports by the number of defined daily doses per 1,000 inhabitants per day for this drug, computed from national sale or reimbursement data. Results: On 862 prescription forms, benzodiazepines (zolpidem, bromazepam, alprazolam), buprenorphine (as an opioid maintenance drug) and tramadol were the most frequently reported. Depending on their level of use in each country, methylphenidate, morphine and flunitrazepam presented the highest falsification ratios, particularly in Spain, Belgium and France. Conclusions: Stimulants, opioids and some benzodiazepines were the most frequently reported drugs in this survey on falsified prescriptions, but differences between countries were observed.
The Use of Lanreotide Autogel® in the Treatment of Intestinal Obstruction in a Patient with Adenocarcinoma
Authors: Lybaert Willem
Published: January 2014

Intestinal obstruction is a common complication in patients with advanced abdominal or pelvic cancer. The synthetic somatostatin analogue octreotide can help relieve nausea, vomiting and pain in patients with inoperable obstruction. Here, we report a case of recurrent intestinal obstruction in a patient with adenocarcinoma. Although the obstruction was resolved after 3 days of treatment with octreotide, new episodes of obstruction occurred, resulting in a delay of the chemotherapy treatment. After 3 episodes of obstruction, we initiated treatment with a longer-acting somatostatin analogue, lanreotide Autogel® 120 mg, administered once every 4 weeks. The treatment with lanreotide Autogel is being continued, allowing for continuation of the chemotherapy without further episodes of intestinal subocclusion or obstruction. Until November 2013, the patient received eighteen 4-weekly injections of lanreotide Autogel and did not report side effects. This case report demonstrates the successful treatment of intestinal obstruction with lanreotide Autogel in a patient with adenocarcinoma.
Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy
Authors: Ihle Peter , Harder Sebastian , Schubert Ingrid , Abbas Sascha
Published: January 2014

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenpro-coumon users ≥18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20–2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84–2.38 and OR 1.34, 95% CI 1.03–1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62–3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08–4.84) and fluorquinolones (OR 3.13, 95% CI 2.74–3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01–8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics – particularly quinolones and co-trimoxazole – should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.
Cyclophilin A is an important mediator of platelet function by regulating integrin αIIbβ3 bidirectional signalling
Authors: Wang Lian , Soe Nwe Nwe , Sowden Mark , Xu Yingqian , Modjeski Kristina , Baskaran Padmamalini , Kim Yeonghwan , Smolock Elaine M. , Morrell Craig N. , Berk Bradford C.
Published: January 2014

Cyclophilin A (CyPA) is an important mediator in cardiovascular diseases. It possesses peptidyl-prolyl cis-trans isomerase activity (PPIase) and chaperone functions, which regulate protein folding, intracellular trafficking and reactive oxygen species (ROS) production. Platelet glycoprotein receptor αIIbβ3 integrin activation is the common pathway for platelet activation. It was our objective to understand the mechanism by which CyPA-regulates αIIbβ3 activation in platelets. Mice deficient for CyPA (CyPA−/−) had prolonged tail bleeding time compared to wild-type (WT) controls despite equivalent platelet numbers. In vitro studies revealed that CyPA−/− platelets exhibited dramatically decreased thrombin-induced platelet aggregation. In vivo, formation of occlusive thrombi following FeCl3 injury was also significantly impaired in CyPA−/− mice compared with WT-controls. Furthermore, CyPA deficiency inhibited flow-induced thrombus formation in vitro. Flow cytometry demonstrated that thrombin-induced ROS production and αIIbβ3 activation were reduced in CyPA−/− platelets. Coimmunoprecipitation studies showed ROS-dependent increased association of CyPA and αIIbβ3. This association was dependent upon the PPIase activity of CyPA. Significantly, fibrinogen-platelet binding, platelet spreading and cytoskeleton reorganisation were also altered in CyPA−/− platelets. Moreover, CyPA deficiency prevented thrombin-induced αIIbβ3 and cytoskeleton association. In conclusion, CyPA is an important mediator in platelet function by regulation of αIIbβ3 bidirectional signalling through increased ROS production and facilitating interaction between αIIbβ3 and the cell cytoskeleton.
Cellular Mechanism Underlying Hypothermia-Induced Ventricular Tachycardia/Ventricular Fibrillation in the Setting of Early Repolarization and the Protective Effect of Quinidine, Cilostazol, and Milrinone
Authors: Gurabi Zsolt , Koncz István , Patocskai Bence , Nesterenko Vladislav V. , Antzelevitch Charles
Published: January 2014

Background—

Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome and examines the effectiveness of quinidine, cilostazol, and milrinone to prevent hypothermia-induced arrhythmias.

Methods and Results—

Transmembrane action potentials were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3–10 μmol/L) and verapamil (1 μmol/L) was used to pharmacologically model the genetic mutations responsible for ER syndrome. Acetylcholine (3 μmol/L) was used to simulate increased parasympathetic tone, which is known to promote ER. In controls, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C–34°C) resulted in increased J-wave area on the ECG and accentuated epicardial action potential notch but no arrhythmic activity. In the setting of ER, hypothermia caused further accentuation of the epicardial action potential notch, leading to loss of the action potential dome at some sites but not others, thus creating the substrate for development of phase 2 reentry and VT/VF. Addition of the transient outward current antagonist quinidine (5 μmol/L) or the phosphodiesterase III inhibitors cilostazol (10 μmol/L) or milrinone (5 μmol/L) diminished the ER manifestations and prevented the hypothermia-induced phase 2 reentry and VT/VF.

Conclusions—

Hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities, leading to development of phase 2 reentry. Quinidine, cilostazol, and milrinone suppress the hypothermia-induced VT/VF by reversing the repolarization abnormalities.
Factors Associated With Longer Time to Treatment for Patients With Suspected Acute Coronary Syndromes
Authors: Sullivan Alison L. , Beshansky Joni R. , Ruthazer Robin , Murman David H. , Mader Timothy J. , Selker Harry P.
Published: January 2014

Background—

Rapid treatment of acute coronary syndromes (ACS) is important; causes of delay in emergency medical services care of ACS are poorly understood.

Methods and Results—

We performed an analysis of data from IMMEDIATE (Immediate Myocardial Metabolic Enhancement during Initial Assessment and Treatment in Emergency Care), a randomized controlled trial of emergency medical services treatment of people with symptoms suggesting ACS, using hierarchical multiple regression of elapsed time. Out-of-hospital ECGs were performed on 54 230 adults calling 9-1-1; 871 had presumed ACS, 303 of whom had ST-segment elevation myocardial infarction and underwent percutaneous coronary intervention. Women, participants with diabetes mellitus, and participants without previous cardiovascular disease waited longer to call 9-1-1 (by 28 minutes,
P
<0.01; 10 minutes,
P
=0.03; and 6 minutes,
P
=0.02, respectively), compared with their counterparts. Time from emergency medical services arrival to ECG was longer for women (1.5 minutes;
P
<0.01), older individuals (1.3 minutes;
P
<0.01), and those without a primary complaint of chest pain (3.5 minutes;
P
<0.01). On-scene times were longer for women (2 minutes;
P
<0.01) and older individuals (2 minutes;
P
<0.01). Older individuals and participants presenting on weekends and nights had longer door-to-balloon times (by 10, 14, and 11 minutes, respectively;
P
<0.01). Women and older individuals had longer total times (medical contact to balloon inflation: 16 minutes,
P
=0.01, and 9 minutes,
P
<0.01, respectively; symptom onset to balloon inflation: 31.5 minutes for women;
P
=0.02).

Conclusions—

We found delays throughout ACS care, resulting in substantial differences in total times for women and older individuals. These delays may impact outcomes; a comprehensive approach to reduce delay is needed.
Exosomes
Authors: Yellon Derek M. , Davidson Sean M.
Published: January 2014

Exosomes are nanosized lipid vesicles released from cells. They are capable of transferring proteins, mRNA, and miRNA between cells and, therefore, represent a potential means of intercellular communication. Exosomes can be proangiogenic and may have cardioprotective properties. In contrast, their larger cousins, microvesicles, seem to have generally detrimental effects that are prothrombotic and proinflammatory. Exosomes are released from multivesicular bodies via an exocytic pathway and have the potential for cell-specific targeting. This normal process is hijacked during various pathological conditions, such as cancer, viral infection, and amyloidopathies. We assess the evidence for a role of exosomes and microvesicles in normal cardiovascular physiology, as well as during cardiovascular disease. In addition to offering a potential source of cardiovascular biomarkers, exosomes may offer a nonimmunogenic means of manipulating the heart.