bluuebunny/crossref_metadata_2025 huggingface dataset:
Excitation-Contraction Coupling between Human Atrial Myocytes with Fibroblasts and Stretch Activated Channel Current: A Simulation Study
Authors: Zhan Heqing , Xia Ling
Published: August 2013

Myocytes have been regarded as the main objectives in most cardiac modeling studies and attracted a lot of attention. Connective tissue cells, such as fibroblasts (Fbs), also play crucial role in cardiac function. This study proposed an integrated myocyte-Isac-Fb electromechanical model to investigate the effect of Fbs and stretch activated ion channel current (Isac) on cardiac electrical excitation conduction and mechanical contraction. At the cellular level, an active Fb model was coupled with a human atrial myocyte electrophysiological model (includingIsac) and a mechanical model. At the tissue level, electrical excitation conduction was coupled with an elastic mechanical model, in which finite difference method (FDM) was used to solve the electrical excitation equations, while finite element method (FEM) was used for the mechanics equations. The simulation results showed that Fbs andIsaccoupling caused diverse effects on action potential morphology during repolarization, depolarized the resting membrane potential of the human atrial myocyte, slowed down wave propagation, and decreased strains in fibrotic tissue. This preliminary simulation study indicates that Fbs andIsachave important implications for modulating cardiac electromechanical behavior and should be considered in future cardiac modeling studies.
First Report of FVC and FEV1 Reference Values for Beninese Children Aged 11–16 Years
Authors: Messan Folly , Dansou Pierre , Marqueste Tanguy , Decherchi Patrick , Tossou Richard , Amoussou Toussaint , Sovi-Guidi Bénoîte
Published: August 2013

Background. The diagnosis of obstructive ventilatory disorders in children in Benin is not reliable despite the inclusion of ethnic correction factors for European standards (ERS-93) and the use of African-American standards (ITS-Black). Objectives. (1) Define standard values for forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) and (2) compare the FVC and FEV1 values observed in study subjects to those calculated by the ERS-93 and ITS-Black equations. Methods. FVC and FEV1 were measured using the MicroQuark Spirometer (Cosmed, Italy), and standing height was measured in 274 Beninese boys and 210 Beninese girls. The means and 95% confidence intervals for these values were calculated by univariate analysis. Results. FVC and FEV1 values calculated using the ERS-93 equations were significantly higher () than the measured values from our study. The percent change between the standard values in our study and the standards calculated using the ERS-93 and ITS-Black equations revealed differences between Beninese children and children of European or African-American descent. Conclusion. The differences observed between study samples and those derived from the ITS-Black and the ERS-93 equations should be used as ethnic correction factors.
Stridor in an Elderly Woman: An Unusual Presentation of a Giant Thyroglossal Cyst
Authors: Venkatesan Sithananda Kumar , Manoharan Kiruba Shankar , Parida Pradipta Kumar , Alexander Arun , Gopalakrishnan S.
Published: August 2013

Thyroglossal cysts are one of the most common midline neck masses. They usually present as midline painless cystic neck mass in the first three decades of life. These anomalies are very rare in elderly patients and may pose difficult diagnostic and therapeutic challenges. Here, we report a case of giant thyroglossal cyst in a 72-year-female patient who presented with stridor, hoarseness of voice, and vocal cord paresis with gross distortion of normal airway anatomy secondary to pressure effect of the mass. The gross distortion and displacement of airway along with respiratory distress in this patient posed a difficult situation in securing the airway. The airway was secured by a unique way of orotracheal intubation with the help of a ventilating airway exchange catheter. The cyst was excised in toto under general anaesthesia. The stridor completely resolved after surgery and tracheostomy was avoided.
Designing a Bioengine for Detection and Analysis of Base String on an Affected Sequence in High-Concentration Regions
Authors: Bhattacharyya Debnath , Mandal Bijoy Kumar , Kim Tai-hoon
Published: August 2013

We design an Algorithm for bioengine. As a program are enable optimal alignments searching between two sequences, the host sequence (normal plant) as well as query sequence (virus). Searching for homologues has become a routine operation of biological sequences in 4 × 4 combination with different subsequence (word size). This program takes the advantage of the high degree of homology between such sequences to construct an alignment of the matching regions. There is a main aim which is to detect the overlapping reading frames. This program also enables to find out the highly infected colones selection highest matching region with minimum gap or mismatch zones and unique virus colones matches. This is a small, portable, interactive, front-end program intended to be used to find out the regions of matching between host sequence and query subsequences. All the operations are carried out in fraction of seconds, depending on the required task and on the sequence length.
A Hybrid Estimation of Distribution Algorithm and Nelder-Mead Simplex Method for Solving a Class of Nonlinear Bilevel Programming Problems
Authors: Ren Aihong , Wang Yuping , Jia Fei
Published: August 2013

We propose a hybrid algorithm based on estimation of distribution algorithm (EDA) and Nelder-Mead simplex method (NM) to solve a class of nonlinear bilevel programming problems where the follower’s problem is linear with respect to the lower level variable. The bilevel programming is an NP-hard optimization problem, for which EDA-NM is applied as a new tool aiming at obtaining global optimal solutions of such a problem. In fact, EDA-NM is very easy to be implementedsince it does not require gradients information. Moreover, the hybrid algorithm intends to produce faster and more accurate convergence. In the proposed approach, for fixed upper level variable, we make use of the optimality conditions of linear programming to deal with the follower’s problem and obtain its optimal solution. Further, the leader’s objective function is taken as the fitness function. Based on these schemes, the hybrid algorithm is designed by combining EDA with NM. To verify the performance of EDA-NM, simulations on some test problems are made, and the results demonstrate that the proposed algorithm has a better performance than the compared algorithms. Finally, the proposed approach is used to solve a practical example about pollution charges problem.
New Criteria for Meromorphic Multivalent Alpha-Convex Functions
Authors: Arif Muhammad , Darus Maslina , Ghani Fazal , Islam Saeed
Published: August 2013

The aim of the present paper is to obtain sufficient condition for the class of meromorphicp-valent alpha convex functions of orderξand then to study mapping properties of the newly defined integral operators. Many known results appeared as special consequences of our work.
Method for Rapid Protein Identification in a Large Database
Authors: Zhang Wenli , Zhao Xiaofang
Published: August 2013

Protein identification is an integral part of proteomics research. The available tools to identify proteins in tandem mass spectrometry experiments are not optimized to face current challenges in terms of identification scale and speed owing to the exponential growth of the protein database and the accelerated generation of mass spectrometry data, as well as the demand for nonspecific digestion and post-modifications in complex-sample identification. As a result, a rapid method is required to mitigate such complexity and computation challenges. This paper thus aims to present an open method to prevent enzyme and modification specificity on a large database. This paper designed and developed a distributed program to facilitate application to computer resources. With this optimization, nearly linear speedup and real-time support are achieved on a large database with nonspecific digestion, thus enabling testing with two classical large protein databases in a 20-blade cluster. This work aids in the discovery of more significant biological results, such as modification sites, and enables the identification of more complex samples, such as metaproteomics samples.
Multistep Wind Speed Forecasting Based on Wavelet and Gaussian Processes
Authors: Chen Niya , Qian Zheng , Meng Xiaofeng
Published: August 2013

Accurate wind speed forecasts are necessary for the safety and economy of the renewable energy utilization. The wind speed forecasts can be obtained by statistical model based on historical data. In this paper, a novel W-GP model (wavelet decomposition based Gaussian process learning paradigm) is proposed for short-term wind speed forecasting. The nonstationary and nonlinear original wind speed series is first decomposed into a set of better-behaved constitutive subseries by wavelet decomposition. Then these sub-series are forecasted respectively by GP method, and the forecast results are summed to formulate an ensemble forecast for original wind speed series. Therefore, the previous process which obtains wind speed forecast result is named W-GP model. Finally, the proposed model is applied to short-term forecasting of the mean hourly and daily wind speed for a wind farm located in southern China. The prediction results indicate that the proposed W-GP model, which achieves a mean 13.34% improvement in RMSE (Root Mean Square Error) compared to persistence method for mean hourly data and a mean 7.71% improvement for mean daily wind speed data, shows the best forecasting accuracy among several forecasting models.
Distributional Patterns of Alien Plants in China: The Relative Importance of Phylogenetic History and Functional Attributes
Authors: Chen Youhua
Published: August 2013

Distribution patterns of alien species in nonnative ranges might be driven by a combination of various mechanisms, including phylogenetic history, competition for resource, environmental filtering, and so on. Both phylogenetic and functional limitations might work synergistically to determine the distribution of alien species. In this report, by utilizing the information of provincial distribution, functional attributes, and phylogeny for 95 alien species of China, the corresponding phylogenetic and functional community structures are evaluated. The results show that introduction pathway, life form, and flowering time of alien plants of China processed significant phylogenetic clustering patterns, while both the origin of distribution and reproduction mode of alien species showed phylogenetic overdispersion patterns, as revealed by NRI/NTI indices. The phylogenetic signal tests using Pagel’s statistic and Blomberg et al.’s statistic further verified the previous patterns, even though there are some inconsistencies. Through partial Mantel test, it is found that compositional patterns of alien plant community were mainly affected by phylogenetic limitation but not functional limitation. Conclusively, phylogeny plays a more important role in structuring provincial distribution of alien plants in China.
Dimensions of Hallucinations and Delusions in Affective and Nonaffective Illnesses
Authors: Kumari Ranju , Chaudhury Suprakash , Kumar Subodh
Published: August 2013

The aim of the study was to examine the dimensions of hallucinations and delusions in affective (manic episode, bipolar affective disorder, and depressive episode) and nonaffective disorders (schizophrenia, acute and transient psychotic disorders, and unspecified psychosis). Sixty outpatients divided equally into two groups comprising affective and nonaffective disorders were taken up for evaluation after screening, as per inclusion and exclusion criteria. Scores of 3 or above on delusion and hallucinatory behavior subscales of positive and negative syndrome scale were sufficient to warrant rating on the psychotic symptom rating scales with which auditory hallucination and delusion were assessed on various dimensions. Insight was assessed using the Beck cognitive insight scale (BCIS). There were no significant differences between the two groups on age, sex, marital status, education, and economic status. There were significant differences in total score and emotional characteristic subscale, cognitive interpretation subscale, and physical characteristic subscale of auditory hallucination scales in between the two groups. Correlation between BCIS-total and total auditory hallucinations score was negative (Spearman Rho −0.319;P<0.05). Hallucinating patients, more in nonaffective group, described a negative impact of hallucinating voices along with emotional consequences on their lives which lead to distress and disruption.
The Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells in Mice Premature Ovarian Failure
Authors: Wang Shufang , Yu Ling , Sun Min , Mu Sha , Wang Changyong , Wang Deqing , Yao Yuanqing
Published: August 2013

Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as promising cellular therapeutics for the treatment of several diseases. Mesenchymal-like cells derived from Wharton’s Jelly, called umbilical cord matrix stem cells (UCMSCs), reportedly secrete a variety of cytokines and growth factors, acting as trophic suppliers. Here, we used UCMSCs to treat premature ovarian failure (POF). Ovarian function was evaluated by ovulation and the number of follicles. Apoptosis of the granulosa cells (GC) was analyzed by TUNEL staining. We found that after transplantation of the UCMSCs, apoptosis of cumulus cells in the ovarian damage model was reduced and the function of the ovary had been recovered. The sex hormone level was significantly elevated in mice treated with UCMSCs. The number of follicles in the treated group was higher than in the control group. Our results demonstrate that UCMSCs can effectively restore ovary functionality and reduce apoptosis of granulosa cells. We compared the RNA expression of the UCMSCs treated group with the POF model and wild-type control group and found that the UCMSC group is most similar to the wild-type group. Our experiments provide new information regarding the treatment of ovarian function failure.
Inferior Flap Tympanoplasty: A Novel Technique for Anterior Perforation Closure
Authors: Gavriel Haim , Eviatar Ephraim
Published: August 2013

Objective. To report a novel tympanoplasty modification for anterior tympanic membrane perforation closure.Materials and Methods. A prospective study on 13 patients who underwent inferior tympanoplasty between December 2008 and May 2011 was carried out. In our technique, an inferior rather than a posterior flap is raised and the graft is laid from the inferior direction to obtain better access to the anterior part of the tympanic membrane perforation and provide better support.Results. A total of 13 patients underwent the novel inferior tympanoplasty technique with a mean age of 33 years. Six patients had undergone tympanoplasties and/or mastoidectomies in the past, 3 in the contralateral ear. A marginal perforation was observed in 3 cases, total perforation in 2 and subtotal in 1 case. The mean preoperative pure-tone average was 40.4 dB (10 to 90 dB), compared to 26.5 dB (10 to 55 dB) postoperatively. All perforations were found to be closed but one (92.3% success rate).Conclusions. The inferior tympanoplasty technique provides a favorable outcome in terms of tympanic membrane closure and hearing improvement for anterior perforations, even in difficult and complex cases. It is based on a well-known technique and is easy to implement.
Spontaneous Spinal Epidural Abscess Presenting in a Previously Healthy Young Adult Man
Authors: McDonald Andrew M. , Rollins Jason L.
Published: August 2013

We report a case of spontaneous spinal epidural abscess (SEA) with initial chief complaint of shoulder pain and no appreciable neurologic symptoms. Since outcomes of SEA appear to be related to the degree of neurologic deficit at the time of intervention, we explore opportunities for earlier diagnosis.
Detection of Gastric Cancer with Fourier Transform Infrared Spectroscopy and Support Vector Machine Classification
Authors: Li Qingbo , Wang Wei , Ling Xiaofeng , Wu Jin Guang
Published: August 2013

Early diagnosis and early medical treatments are the keys to save the patients' lives and improve the living quality. Fourier transform infrared (FT-IR) spectroscopy can distinguish malignant from normal tissues at the molecular level. In this paper, programs were made with pattern recognition method to classify unknown samples. Spectral data were pretreated by using smoothing and standard normal variate (SNV) methods. Leave-one-out cross validation was used to evaluate the discrimination result of support vector machine (SVM) method. A total of 54 gastric tissue samples were employed in this study, including 24 cases of normal tissue samples and 30 cases of cancerous tissue samples. The discrimination results of SVM method showed the sensitivity with 100%, specificity with 83.3%, and total discrimination accuracy with 92.2%.
Immunomodulatory Effect of Chinese Herbal Medicine Formula Sheng-Fei-Yu-Chuan-Tang in Lipopolysaccharide-Induced Acute Lung Injury Mice
Authors: Lin Chia-Hung , Yeh Ching-Hua , Lin Li-Jen , Wang Shulhn-Der , Wang Jen-Shu , Kao Shung-Te
Published: August 2013

Traditional Chinese medicine formula Sheng-Fei-Yu-Chuan-Tang (SFYCT), consisting of 13 medicinal plants, was used to treat patients with lung diseases. This study investigated the immunoregulatory effect of SFYCT on intratracheal lipopolysaccharides- (LPS-) challenged acute lung injury (ALI) mice. SFYCT attenuated pulmonary edema, macrophages, and neutrophils infiltration in the airways. SFYCT decreased inflammatory cytokines, including tumor necrosis factor-α(TNFα), interleukin-1β, and interleukin-6 and inhibited nitric oxide (NO) production but increased anti-inflammatory cytokines, interleukin-4, and interleukin-10, in the bronchoalveolar lavage fluid of LPS-challenged mice. TNFαand monocyte chemotactic protein-1 mRNA expression in the lung of LPS-challenged mice as well as LPS-stimulated lung epithelial cell and macrophage were decreased by SFYCT treatment. SFYCT treatment also decreased the inducible nitric oxide synthase expression and phosphorylation of nuclear factor-κB (NF-κB) in the lung of mice and macrophage with LPS stimulation. SFYCT treatment dose dependently decreased the LPS-induced NO and reactive oxygen species generation in LPS-stimulated macrophage. In conclusion, SFYCT attenuated lung inflammation during LPS-induced ALI through decreasing inflammatory cytokines production while increasing anti-inflammatory cytokines production. The immunoregulatory effect of SFYCT is related to inhibiting NF-κB phosphorylation.
In Vivo Imaging of Prostate Cancer Using [68Ga]-Labeled Bombesin Analog BAY86-7548
Authors: Kähkönen Esa , Jambor Ivan , Kemppainen Jukka , Lehtiö Kaisa , Grönroos Tove J. , Kuisma Anna , Luoto Pauliina , Sipilä Henri J. , Tolvanen Tuula , Alanen Kalle , Silén Jonna , Kallajoki Markku , Roivainen Anne , Schäfer Niklaus , Schibli Roger , Dragic Martina , Johayem Anass , Valencia Ray , Borkowski Sandra , Minn Heikki
Published: August 2013

Purpose: A novel [68Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer.

Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [11C]-acetate (n = 2) or [18F]-fluoromethylcholine (n = 1) PET/CT.

Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [11C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [18F]-fluoromethylcholine PET/CT.

Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer. Clin Cancer Res; 19(19); 5434–43. ©2013 AACR.
Ponatinib—A Step Forward in Overcoming Resistance in Chronic Myeloid Leukemia
Authors: Frankfurt Olga , Licht Jonathan D.
Published: August 2013

With the current therapy, the improvement in survival of patient with early chronic phase chronic myelogenous leukemia (CML) is unrivaled by that of any other leukemia. In fact, extrapolation of the survival curves may suggest that life expectancy of patients who achieve and maintain predetermined milestones may not differ from that of the age-matched healthy adults. The main reasons for such success are the presence of a well-defined molecular target, the BCR-ABL oncogene, necessary and sufficient for the initiation and propagation of CML, and the powerful and selective agents that inhibit it. Five U.S. Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKI), each with unique activities and toxicity profiles, allow for individualized patient care. Despite the remarkable responses of most patients, a small but significant fraction of patients develops clinical resistance to the TKIs, some of which is attributed to the BCR-ABL kinase domain mutations affecting TKI binding and activity. The recently approved third-generation TKI ponatinib showed remarkable activity in the patients with multi-TKI–resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. In lieu of the current emphasis on achieving earlier and more profound responses and excellent activity of ponatinib in the refractory setting, its optimal position among the available armamentarium of agents is being established. Clin Cancer Res; 19(21); 5828–34. ©2013 AACR.
Predicting Response to Bevacizumab in Ovarian Cancer: A Panel of Potential Biomarkers Informing Treatment Selection
Authors: Collinson Fiona , Hutchinson Michelle , Craven Rachel A. , Cairns David A. , Zougman Alexandre , Wind Tobias C. , Gahir Narinder , Messenger Michael P. , Jackson Sharon , Thompson Douglas , Adusei Cybil , Ledermann Jonathan A. , Hall Geoffrey , Jayson Gordon C. , Selby Peter J. , Banks Rosamonde E.
Published: August 2013

Purpose: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial.

Experimental Design: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).

Results: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm.

Conclusions: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts. Clin Cancer Res; 19(18); 5227–39. ©2013 AACR.
PI3K Stimulates DNA Synthesis and Cell-Cycle Progression via Its p55PIK Regulatory Subunit Interaction with PCNA
Authors: Wang Guihua , Cao Xiaonian , Lai Senyan , Luo Xuelai , Feng Yongdong , Xia Xianmin , Yen Paul M. , Gong Jianping , Hu Junbo
Published: August 2013

Previously, we have shown that p55PIK, an isoform of class IA phosphoinositide 3-kinase (PI3K), specifically interacts with important cell-cycle regulators, such as retinoblastoma (Rb), to promote cell-cycle progression. Here, we used the glutathione S-transferase pull-down assay to identify other p55PIK-interacting proteins besides Rb in a Rb-deficient cell line and found that p55PIK interacted with proliferation cell nuclear antigen (PCNA), which plays a key role in coordinating both initiation of the leading strand DNA replication and discontinuous lagging strand synthesis. Overexpression of p55PIK increased, and knockdown decreased, DNA synthesis and DNA replication by modulating the binding of DNA polymerase δ (Polδ) to PCNA. Moreover, a cell-permeable peptide containing the N-terminal–binding domain of p55PIK (TAT–N24) disrupted the p55PIK–PCNA interaction in cancer cells, and also inhibited the DNA synthesis and tumor growth in cell culture and in vivo. Altogether, our results show that the p55PIK–PCNA interaction is important in regulating DNA synthesis and contributes to tumorigenesis. Furthermore, the p55PIK–PCNA interaction provides a potential new target for anticancer drug development. Mol Cancer Ther; 12(10); 2100–9. ©2013 AACR.
Enhancement of Tumor-Reactive Cytotoxic CD4+ T-cell Responses after Ipilimumab Treatment in Four Advanced Melanoma Patients
Authors: Kitano Shigehisa , Tsuji Takemasa , Liu Caillian , Hirschhorn-Cymerman Daniel , Kyi Chrisann , Mu Zhenyu , Allison James P. , Gnjatic Sacha , Yuan Jianda D. , Wolchok Jedd D.
Published: August 2013

CD4+ T cells provide help to enhance and sustain cytotoxic CD8+ T-cell responses. A direct lytic role for this cell population in mouse models further supports the use of tumor-reactive CD4+ T cells for cancer immunotherapy. CTLA-4 blockade has been shown to expand antigen-specific cytotoxic CD4+ T cells in mouse models. We took advantage of spontaneous immunity to the NY-ESO-1 cancer-testis antigen to investigate quantitative and qualitative changes in antigen-specific CD4+ T-cell responses after ipilimumab (anti-CTLA-4 monoclonal antibody) treatment in patients with advanced melanoma. Four patients with NY-ESO-1 seropositive melanoma were chosen upon the availability of suitable blood specimens for characterizing the functions of NY-ESO-1 antigen-specific CD4+ T-cell response by enzyme-linked immunospot (ELISPOT), intracellular cytokine staining (ICS), and cytotoxicity assays. Multiple NY-ESO-1 antigen-specific CD4+ T-cell responses with TH1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen–specific CD4+ T-cell lines established from all four patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes), and secreted perforin and Granzyme B. Finally, we showed that these NY-ESO-1 antigen-specific CD4+ T-cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner. Our results show that antigen-specific cytotoxic CD4+ T-cell responses are induced after ipilimumab therapy in human cancer patients. Ipilimumab may induce the expression of lytic granules on antigen-specific cytotoxic CD4+ T cells via Eomes, revealing a novel consequence of immunologic checkpoint blockade. Cancer Immunol Res; 1(4); 235–44. ©2013 AACR.
FOXP3 Expression Is Related to High Ki-67 Index and Poor Prognosis in Lymph Node-Positive Breast Cancer Patients
Authors: Kim Min Hwan , Koo Ja Seung , Lee Soohyeon
Published: August 2013

Background: Recent preclinical studies have shown that Forkhead box protein 3 (FOXP3) is an important tumor suppressor gene. The clinical and prognostic implication of FOXP3 expression in breast cancer cells still remains controversial. Methods: We evaluated the FOXP3 expression status of 183 patients who underwent curative surgery for breast cancer using the immunohistochemical assay of tissue microarray. Results: We found FOXP3 expression in 51 out of 183 (27.9%) surgically resected breast cancer tumors, and 33 patients were scored as weak positive and 18 as strong positive. FOXP3-positive tumors were associated with significantly higher nuclear grade, higher histologic grade and a more negative estrogen receptor status. The FOXP3 expression level was independently associated with high Ki-67 index in a logistic regression model. In the node-positive subgroup, strong FOXP3 positivity was related to poor disease-free survival and disease-specific survival compared to FOXP3-negative patients, whereas there was no survival difference between FOXP3-negative and FOXP3-weak-positive patients. Multivariate analysis with adjustment for patient age and human epidermal growth factor receptor 2 status demonstrated significantly poor survival of FOXP3-strong-positive patients in node-positive patients. Conclusion: Our results suggest that strong FOXP3 expression in breast cancer cells is associated with poor prognosis and high Ki-67 index.
The Different Impact of BRCA Mutations on the Survival of Epithelial Ovarian Cancer Patients: A Retrospective Single-Center Experience
Authors: Lorusso D. , Cirillo F. , Mancini M. , Spatti G.B. , Grijuela B. , Ditto A. , Raspagliesi F.
Published: August 2013

Objectives: The objective of this study was to examine whether the oncologic outcomes of BRCA1-associated and BRCA2-associated ovarian cancers correlate differently. Methods: Genetic data and clinical characteristics were correlated with progression-free survival (PFS) and overall survival (OS). Results: Data from 147 BRCA-mutated patients (119 BRCA1-positive and 28 BRCA2-positive) were analyzed. At a median follow-up of 69 months, the median PFS was 27.2 and 45.46 months for BRCA1 and BRCA2 patients, respectively (p = 0.03). Median OS was 77.23 and 111.47 months for BRCA1 and BRCA2 patients, respectively (p = 0.08). Conclusion:BRCA2 mutations confer PFS and a trend to OS advantage compared with the BRCA1 mutation in BRCA-mutated epithelial ovarian cancer patients.
Preliminary Results of Cord Blood Mononuclear Cell Therapy for Multiple System Atrophy: A Report of Three Cases
Authors: Wu Shu-Hui , Yang Hai-Xin , Jiang Gui-Hua , Gong Dian-Rong , Wang Le-Xin
Published: August 2013

Objectives: This study was designed to evaluate the effects of cord blood mononuclear cell transplantation in multiple system atrophy (MSA). Clinical Presentation and Intervention: Cord blood mononuclear cells (1-2 × 108 cells/6 ml) were injected into the subarachnoid space using lumbar puncture in patients 1 and 2 and cisterna magna puncture in patient 3 in the 3 patients with MSA. The cord blood mononuclear cell transplantation was repeated 30 days after the first treatment in patients 1 and 2; it was repeated twice in patient 3. The clinical outcomes of treatment were used to assess the Unified Multiple System Atrophy Rating Scale (UMSARS) before, 90 and 180 days after the cell transplantation. There were no clinically noticeable side effects from the cord blood mononuclear cells. The UMSARS scores improved after 90 days of the cord blood mononuclear cell therapy in all 3 patients, the most significant improvement being that in urinary incontinence and ability to walk. Conclusions: Cord blood mononuclear cell transplantation was safe and potentially effective in the treatment of MSA in the 3 patients.
Long-Lasting Impact of Early Life Immune Stress on Neuroimmune Functions
Authors: Mouihate Abdeslam
Published: August 2013

Fever is one major cardinal sign of disease. It results from an intricate interplay between the immune system and the central nervous system. Bacterial or viral infections activate peripheral immune competent organs which send inflammatory signals to the brain and lead to an increase in body temperature. The increased body temperature creates a conducive environment to optimize the body's fight against the infection. A large body of experimental evidence suggests that early life bacterial or viral infections can lead to a long-lasting impact on this natural febrile response. The early life pathogenic encounter heightens the hypothalamic-pituitary-adrenal axis response, dampens the innate immune system, and consequently reduces the febrile response to a subsequent immune challenge during adulthood. This ‘programming' effect operates only when such early life immune challenges occur during a critical window of either prenatal or postnatal development. In this review, the mechanisms underlying the long-lasting impact of perinatal immune challenge on adult fever are addressed.
Is Greater Temperature Change Within a Day Associated With Increased Emergency Hospital Admissions for Heart Failure?
Authors: Qiu Hong , Tak-sun Yu Ignatius , Tse Lap Ah , Tian Linwei , Wang Xiaorong , Wong Tze Wai
Published: August 2013

Background—

Although the seasonal variation and the effect of cold temperature on heart failure (HF) morbidity have been well documented, it is unknown whether the temperature variation within a day, that is, diurnal temperature range (DTR), is an independent risk factor for HF. We hypothesized that large DTR might be a source of additional environmental stress and, therefore, a risk factor for HF exacerbation. We aimed to test the association between DTR and HF hospitalization and to examine the effect modifiers, such as age, sex, and season.

Methods and Results—

We collected daily meteorologic data and emergency HF hospital admissions from 2000 to 2007 in Hong Kong. We used Poisson regression models to fit the relationship between daily DTR and emergency HF hospitalizations, after adjusting for the time trend, seasonality, mean temperature, humidity, and levels of outdoor air pollution. We confirmed the seasonal variation of HF with peak hospital admissions in winter in Hong Kong. The adverse effects of DTR on emergency HF admissions were observed on the current day and lasted for the following several days. Every 1°C increase of DTR at lag
0
corresponded to 0.86% (95% confidence interval, 0.31%–1.43%) increment of emergency hospital admissions for HF. DTR exhibited significantly greater effect in the cool season, and on female and elderly patients.

Conclusions—

Greater temperature change within a day was associated with increased emergency hospital admissions for HF. Health policymakers and hospitals may want to take into account the increased demand of specific facilities for susceptive population in winter with greater daily temperature variations.
Global Proteomics and Pathway Analysis of Pressure-Overload–Induced Heart Failure and Its Attenuation by Mitochondrial-Targeted Peptides
Authors: Dai Dao-Fu , Hsieh Edward J. , Chen Tony , Menendez Lorena G. , Basisty Nathan B. , Tsai Lauren , Beyer Richard P. , Crispin David A. , Shulman Nicholas J. , Szeto Hazel H. , Tian Rong , MacCoss Michael J. , Rabinovitch Peter S.
Published: August 2013

Background—

We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, Szeto-Schiller (SS) 31 and SS20, on cardiac function, proteomic remodeling, and signaling pathways.

Methods and Results—

We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC)–induced heart failure and the associated signaling pathway changes using ingenuity pathway analysis. We found that 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis/gluconeogenesis, and citrate cycle. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of nonmitochondrial protein changes. This included significant amelioration of all the ingenuity pathway analysis noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, actin cytoskeleton pathways were significantly protected in SS20, whereas mitochondrial and metabolic pathways essentially were not.

Conclusions—

This study elucidates the signaling pathways significantly changed in pressure-overload–induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial-targeted peptide SS31 suggests that perturbed mitochondrial function may be an upstream signal to many of the pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.
Reactive Hyperemia Occurs Via Activation of Inwardly Rectifying Potassium Channels and Na
+
/K
+
-ATPase in Humans
Authors: Crecelius Anne R. , Richards Jennifer C. , Luckasen Gary J. , Larson Dennis G. , Dinenno Frank A.
Published: August 2013

Rationale:

Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health, yet the underlying vasodilator signaling pathways are controversial and thus remain unclear.

Objective:

We hypothesized that RH occurs via activation of inwardly rectifying potassium (K
IR
) channels and Na
+
/K
+
-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins in young healthy humans.

Methods and Results:

In 24 (23±1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) after 5 minutes of arterial occlusion. In protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions. For group 1, we studied control (saline), K
IR
channel inhibition (BaCl
2
), combined inhibition of K
IR
channels and Na
+
/K
+
-ATPase (BaCl
2
and ouabain, respectively), and combined inhibition of K
IR
channels, Na
+
/K
+
-ATPase, NO, and prostaglandins (BaCl
2
, ouabain,
l
-NMMA [
N

G

-monomethyl-
l
-arginine] and ketorolac, respectively). Group 2 received ouabain rather than BaCl
2
in the second trial. In protocol 2 (n=8), the following 3 RH trials were performed: control;
l
-NMMA plus ketorolac; and
l
-NMMA plus ketorolac plus BaCl
2
plus ouabain. All infusions were intra-arterial (brachial). Compared with control, BaCl
2
significantly reduced peak FBF (−50±6%;
P
<0.05), whereas ouabain and
l
-NMMA plus ketorolac did not. Total FBF (area under the curve) was attenuated by BaCl
2
(−61±3%) and ouabain (−44±12%) alone, and this effect was enhanced when combined (−87±4%), nearly abolishing RH.
l
-NMMA plus ketorolac did not impact total RH FBF before or after administration of BaCl
2
plus ouabain.

Conclusions:

Activation of K
IR
channels is the primary determinant of peak RH, whereas activation of both K
IR
channels and Na
+
/K
+
-ATPase explains nearly all of the total (AUC) RH in humans.
Long-Term Effects of Secondary Prevention on Cognitive Function in Stroke Patients
Authors: Douiri Abdel , McKevitt Christopher , Emmett Eva S. , Rudd Anthony G. , Wolfe Charles D.A.
Published: August 2013

Background—

Limited long-term follow-up data exist on the impact of appropriate secondary prevention therapies on cognitive function in patients after first-ever stroke. The aim of this study is to determine the effect of secondary prevention of vascular events on cognitive function after stroke.

Methods and Results—

Data were collected between 1995 and 2011 (n=4413) from the community-based South London Stroke Register covering an inner-city multiethnic source population of 271 817 inhabitants. Modified Poisson regression models were constructed to adjust for cognitive function status at 3 months, demographic and socioeconomic characteristics, case mix, stroke subtype, vascular risk factors, disability, and stroke recurrence. In patients with ischemic strokes without a history of atrial fibrillation (AF), there was a reduced risk of cognitive impairment associated with the use of different prevention treatments: (1) antihypertensives (relative risk, 0.7 [95% confidence interval, 0.57
–
0.82] for diuretics; relative risk, 0.8 [95% confidence interval, 0.64
–
0.98] for angiotensin-converting enzyme inhibitors; and relative risk, 0.7 [95% confidence interval, 0.55
–
0.81] for their combination), (2) a combination of aspirin and dipyridamole (relative risk, 0.8 [95% confidence interval, 0.68
–
1.01]), and (3) statin (relative risk, 0.9 [95% confidence interval, 0.76
–
1.06]) when clinically indicated. Protective effects against cognitive impairment were also observed in patients on the combination of antihypertensives, antithrombotic agents, and lipid-lowering drugs (relative risk, 0.55 [95% confidence interval, 0.40
–
0.77]). No significant associations were noted between poststroke cognitive impairment and antihypertensives among hemorrhagic stroke patients.

Conclusions—

Appropriate vascular risk management was associated with a long-term reduced risk of cognitive impairment. Focus on optimal preventive drug therapy of vascular risk factors and management should be supported.
Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding
Authors: Sarode Ravi , Milling Truman J. , Refaai Majed A. , Mangione Antoinette , Schneider Astrid , Durn Billie L. , Goldstein Joshua N.
Published: August 2013

Background—

Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal.

Methods and Results—

In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8–20.0) for the 4F-PCC group and 3.60 (1.9–38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, –5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (
P
<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event.

Conclusions—

4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00708435.
Hypertensive Retinopathy and Risk of Stroke
Authors: Ong Yi-Ting , Wong Tien Y. , Klein Ronald , Klein Barbara E.K. , Mitchell Paul , Sharrett A. Richey , Couper David J. , Ikram M. Kamran
Published: August 2013

Although assessment of hypertensive retinopathy signs has been recommended for determining end-organ damage and stratifying vascular risk in persons with hypertension, its value remains unclear. In this study, we examine whether hypertensive retinopathy predicts the long-term risk of stroke in those with hypertension. A total of 2907 participants with hypertension aged 50 to 73 years at the 1993 to 1995 examination, who had gradable retinal photographs, no history of diabetes mellitus, stroke, and coronary heart disease at baseline and data on incident stroke, were included from the Atherosclerosis Risk in Communities (ARIC) Study. Retinal photographs were assessed for hypertensive retinopathy signs and classified as none, mild, and moderate/severe. Incident events of any stroke, cerebral infarction, and hemorrhagic stroke were identified and validated. After a mean follow-up period of 13.0 years, 165 persons developed incident stroke (146 cerebral infarctions and 15 hemorrhagic strokes). After adjusting for age, sex, blood pressure, and other risk factors, persons with moderate hypertensive retinopathy were more likely to have stroke (moderate versus no retinopathy: multivariable hazard ratios, 2.37 [95% confidence interval, 1.39–4.02]). In participants with hypertension on medication with good control of blood pressure, hypertensive retinopathy was related to an increased risk of cerebral infarction (mild retinopathy: hazard ratio, 1.96 [95% confidence interval, 1.09–3.55]; and moderate retinopathy: hazard ratio, 2.98 [95% confidence interval, 1.01–8.83]). Hypertensive retinopathy predicts the long-term risk of stroke, independent of blood pressure, even in treated patients with hypertension with good hypertension control. Retinal photographic assessment of hypertensive retinopathy signs may be useful for assessment of stroke risk.