bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Adsorption of Orange II Using Cationic Surfactant Modified Biochar Pyrolyzed from Cornstalk
Authors: Mi Xiao , Li Guoting , Zhu Weiyong , Liu Lili
Published: June 2016

As dissolution of raw biomass is serious when used as an adsorbent, the cheap biochar pyrolyzed from biomass might be a good matrix. Raw cornstalk biochar was intentionally modified by cetyltrimethylammonium bromide (CTAB) to prepare the composite adsorbent designed for the removal of negatively charged pollutants. After modification, the removal efficiency for anionic dye Orange II (ORII) increased from 46.9% of the virgin cornstalk biochar to 99.7% of the CTAB-modified cornstalk biochar. The uptake of ORII proved to be favorable under acidic conditions but unfavorable under alkaline conditions. By nonlinear simulation, the Elovich model was the best to describe the adsorption kinetics. For linear simulation of the kinetic data, the pseudo-second-order kinetic model fitted the experimental points better than the pseudo-first-order model. Kinetic analysis indicated that the ORII adsorption process on the CTAB-modified cornstalk biochar might be chemical adsorption accompanied by ion exchange. At 298 K, the maximal adsorption capacity of the modified biochar is 26.9 mg/g by the Langmuir model. The adsorption of ORII increased with a rise in the reaction temperature. The enthalpy and entropy of the adsorption process are calculated to be 38.45 KJ mol−1and 185.0 J mol−1 K−1, respectively. The negative values ofΔG0at 288, 298, and 308 K were −14.92, −16.50, and −18.62 KJ mol−1, respectively. The above thermodynamic analysis demonstrates that the adsorption process was endothermic and spontaneous.
A Fault Diagnosis Scheme for Rolling Bearing Based on Particle Swarm Optimization in Variational Mode Decomposition
Authors: Yi Cancan , Lv Yong , Dang Zhang
Published: June 2016

Variational mode decomposition (VMD) is a new method of signal adaptive decomposition. In the VMD framework, the vibration signal is decomposed into multiple mode components by Wiener filtering in Fourier domain, and the center frequency of each mode component is updated as the center of gravity of the mode’s power spectrum. Therefore, each decomposed mode is compact around a center pulsation and has a limited bandwidth. In view of the situation that the penalty parameter and the number of components affect the decomposition effect in VMD algorithm, a novel method of fault feature extraction based on the combination of VMD and particle swarm optimization (PSO) algorithm is proposed. In this paper, the numerical simulation and the measured fault signals of the rolling bearing experiment system are analyzed by the proposed method. The results indicate that the proposed method is much more robust to sampling and noise. Additionally, the proposed method has an advantage over the EMD in complicated signal decomposition and can be utilized as a potential method in extracting the faint fault information of rolling bearings compared with the common method of envelope spectrum analysis.
Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer
Authors: Dou Qianhui , Chen Hai-Ning , Wang Kui , Yuan Kefei , Lei Yunlong , Li Kai , Lan Jiang , Chen Yan , Huang Zhao , Xie Na , Zhang Lu , Xiang Rong , Nice Edouard C. , Wei Yuquan , Huang Canhua
Published: June 2016

Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitination-mediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457–69. ©2016 AACR.
Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth
Authors: Cormerais Yann , Giuliano Sandy , LeFloch Renaud , Front Benoît , Durivault Jerome , Tambutté Eric , Massard Pierre-André , de la Ballina Laura Rodriguez , Endou Hitoshi , Wempe Michael F. , Palacin Manuel , Parks Scott K. , Pouyssegur Jacques
Published: June 2016

The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target. This complex promotes tumorigenesis with CD98 (4F2hc) engaging β-integrin signaling while LAT1 (SLC7A5) imports essential amino acids (EAA) and promotes mTORC1 activity. However, it is unclear as to which member of the heterodimer carries the most prevalent protumoral action. To answer this question, we explored the tumoral potential of each member by gene disruption of CD98, LAT1, or both and by inhibition of LAT1 with the selective inhibitor (JPH203) in six human cancer cell lines from colon, lung, and kidney. Each knockout respectively ablated 90% (CD98KO) and 100% (LAT1KO) of Na+-independent leucine transport activity. LAT1KO or JPH203-treated cells presented an amino acid stress response with ATF4, GCN2 activation, mTORC1 inhibition, and severe in vitro and in vivo tumor growth arrest. We show that this severe growth phenotype is independent of the level of expression of CD98 in the six tumor cell lines. Surprisingly, CD98KO cells with only 10% EAA transport activity displayed a normal growth phenotype, with mTORC1 activity and tumor growth rate undistinguishable from wild-type cells. However, CD98KO cells became extremely sensitive to inhibition or genetic disruption of LAT1 (CD98KO/LAT1KO). This finding demonstrates that the tumoral potential of CD98KO cells is due to residual LAT1 transport activity. Therefore, these findings clearly establish that LAT1 transport activity is the key growth-limiting step of the heterodimer and advocate the pharmacology development of LAT1 transporter inhibitors as a very promising anticancer target. Cancer Res; 76(15); 4481–92. ©2016 AACR.
Checkpoint Antibodies but not T Cell–Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation
Authors: Hettich Michael , Lahoti Jayashree , Prasad Shruthi , Niedermann Gabriele
Published: June 2016

T cell–recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell–recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis. This fast relapse was delayed by the further addition of anti-PD-1. Mechanistic investigations revealed restimulation-induced cell death mediated by BIM and FAS as an additional cause of bsAb-mediated TIL depletion. In contrast, the double combination of hRT and anti-PD-1 strongly increased TIL numbers, and even very large tumors were completely eradicated. Our study reveals the risk that CD3-engaging bsAbs can induce apoptotic TIL depletion followed by rapid tumor regrowth, reminiscent of tolerance induction by CD3 mAb-mediated T-cell depletion, warranting caution in their use for the treatment of solid tumors. Our findings also argue that combining radiotherapy and anti-PD-1 can be quite potent, including against very large tumors. Cancer Res; 76(16); 4673–83. ©2016 AACR.
HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells
Authors: Sadik Helen , Korangath Preethi , Nguyen Nguyen K. , Gyorffy Balazs , Kumar Rakesh , Hedayati Mohammad , Teo Wei Wen , Park Sunju , Panday Hardik , Munoz Teresa Gonzalez , Menyhart Otilia , Shah Nilay , Pandita Raj K. , Chang Jenny C. , DeWeese Theodore , Chang Howard Y. , Pandita Tej K. , Sukumar Saraswati
Published: June 2016

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor–negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB. Overexpressed HOXC10 increases S-phase–specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443–56. ©2016 AACR.
Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor–Positive Breast Cancer
Authors: Patel Hetal , Abduljabbar Rezvan , Lai Chun-Fui , Periyasamy Manikandan , Harrod Alison , Gemma Carolina , Steel Jennifer H. , Patel Naina , Busonero Claudia , Jerjees Dena , Remenyi Judit , Smith Sally , Gomm Jennifer J. , Magnani Luca , Győrffy Balázs , Jones Louise J. , Fuller-Pace Frances , Shousha Sami , Buluwela Laki , Rakha Emad A. , Ellis Ian O. , Coombes R. Charles , Ali Simak
Published: June 2016

Purpose: CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.

Experimental Design: mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathologic features and patient outcome.

Results: We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity.

Conclusions: Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929–38. ©2016 AACR.
Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells
Authors: Rabalski Adam J. , Gyenis Laszlo , Litchfield David W.
Published: June 2016

Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these inhibitors exhibit antitumor efficacy. Furthermore, in combinations with chemotherapeutics such as cisplatin or gemcitabine, either CX-4945 or CIGB-300 promote synergistic induction of apoptosis. While CSNK2 is a regulatory participant in many processes related to cancer, its potential to modulate caspase action may be particularly pertinent to its emergence as a therapeutic target. Because the substrate recognition motifs for CSNK2 and caspases are remarkably similar, CSNK2 can block the cleavage of many caspase substrates through the phosphorylation of sites adjacent to cleavage sites. Phosphoproteomic strategies have also revealed previously underappreciated roles for CSNK2 in the phosphorylation of several key constituents of DNA damage and DNA repair pathways. Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22(12); 2840–7. ©2016 AACR.
Serum Amyloid A Type 1 Gene Polymorphism in Egyptian Children with Familial Mediterranean Fever
Authors: Wilson Manal , Abou-Elalla Amany A. , Zakaria Mervat Talaat , Marzouk Huda , Fayed Hala Lotfy , Hanna Mariam Onsy F.
Published: June 2016

Background: Since spontaneous inflammation is an important contributor to familial Mediterranean fever (FMF), genetic variants mediating inflammation are of interest. We investigated gene variants in the acute-phase serum amyloid A type 1 (SAA1), a sensitive marker of inflammatory activity, and their association with susceptibility and severity of FMF. Methods: The genotypes of 2 single-nucleotide polymorphisms within exon 3 of SAA1 (2995C/T and 3010C/T) were determined in 105 Egyptian children with FMF and in 125 controls by polymerase chain reaction-restriction fragment length polymorphism. Genotyping of the causative MEFV mutations was performed by reverse hybridization. Results: The M694I mutation was the most frequent allele (42.8%), followed by V726A (18.6%), M680I (17.1%), E148Q (11.9%) and M694V (9.0%). The frequency of the SAA1 α, β and γ alleles was not significantly different between FMF patients and controls. The genotype frequency of SAA1 α/α was higher in patients than in healthy subjects (21.0 vs. 14.4%) although it did not reach statistical significance. The clinical manifestations including age at disease onset, number of FMF attacks, colchicine dose and severity score were not related to genotypes of SAA1. However, M694V mutation and female gender were significantly associated with severity. Conclusion: The genetic polymorphism of SAA1 is not associated with susceptibility and severity of FMF in Egyptian children.
An Inhibitory Role of Osthole in Rat MSCs Osteogenic Differentiation and Proliferation via Wnt/β-Catenin and Erk1/2-MAPK Pathways
Authors: Hu Hongyang , Chen Min , Dai Guangzu , Du Guoqing , Wang Xuezong , He Jie , Zhao Yongfang , Han Dapeng , Cao Yuelong , Zheng Yuxin , Ding Daofang
Published: June 2016

Background/Aims: Bone marrow-derived mesenchymal stem cells (MSCs) are responsible for new bone formation during adulthood. Accumulating evidences showed that Osthole promotes the osteogenic differentiation in primary osteoblasts. The aim of this study was to investigate whether Osthole exhibits a potential to stimulate the osteogenic differentiation of MSCs and the underlying mechanism. Methods: MSCs were treated with a gradient concentration of Osthole (6.25 µM, 12.5 µM, and 25 µM). Cell proliferation was assessed by western blotting with the proliferating cell nuclear antigen (PCNA) and Cyclin D1 antibodies, fluorescence activated cell sorting (FACS), and cell counting kit 8 (CCK8). MSCs were cultured in osteogenesis-induced medium for one or two weeks. The osteogenic differentiation of MSCs was estimated by Alkaline Phosphatase (ALP) staining, Alizarin red staining, Calcium influx, and quantitative PCR (qPCR). The underlying mechanism of Osthole-induced osteogenesis was further evaluated by western blotting with antibodies in Wnt/β-catenin, PI3K/Akt, BMPs/smad1/5/8, and MAPK signaling pathways. Results: Osthole inhibited proliferation of rat MSCs in a dose-dependent manner. Osthole suppressed osteogenic differentiation of rat MSCs by down-regulating the activities of Wnt/β-catenin and Erk1/2-MAPK signaling. Conclusions: Osthole inhibits the proliferation and osteogenic differentiation of rat MSCs, which might be mediated through blocking the Wnt/β-catenin and Erk1/2-MAPK signaling pathways.
Analysis of Long Non-Coding RNA Expression Profiles in Non-Small Cell Lung Cancer
Authors: Wang Li , Chen Zhenhong , An Li , Wang Yajuan , Zhang Zhijian , Guo Yinghua , Liu Changting
Published: June 2016

Background/Aims: Long non-coding RNAs (lncRNAs) play an important role in tumorigenesis. However, the role of lncRNA expression in human Non-small cell lung cancer (NSCLC) biology, prognosis and molecular classification remains unknown. Methods: We established the IncRNA profile in NSCLC by re-annotation of microarrays from the Gene expression omnibus database. Quantitative real-time PCR was used to determine expression of LINC00342. Results: 6066 differentially expressed IncRNAs were identified and we found a novel IncRNA, LINC00342 was significantly up-regulated in NSCLC tissues compared with normal tissues. We confirmed the over-expression of LINC00342 in a cohort of NSCLC patients and found LINC00342 expression level was positively correlated with lymph node metastasis and TNM stages. Furthermore, in a large online database of 1942 NSCLC patients, high expression of LINC00342 indicated poor Overall survival (HR = 1.28, 95% CI: 1.13-1.45) and post progression survival (HR = 1.43, 95% CI: 1.09-1.88). Bioinformatics analyses showed that LINC00342 was co-expressed with different protein-coding genes in NSCLC and normal tissues. Additionally, gene set enrichment analyses found that PTEN and P53 pathways genes were enriched in the groups with higher LINC00342 expression level. By small interfering RNAs mediated silence of LINC00342, proliferation ability was significantly inhibited in lung cancer cell line. Conclusion: To summary, our findings indicate that a set of IncRNAs are differentially expressed in NSCLC and we characterized a novel IncRNA, LINC00342 which is significantly up-regulated in NSCLC and could be a prognostic biomarker.
Fluid Intake and Vasopressin: Connecting the Dots
Authors: Guelinckx Isabelle , Vecchio Mariacristina , Perrier Erica T. , Lemetais Guillaume
Published: June 2016

In the last decade, cross-sectional and multiple cohort studies have associated total fluid intake or water intake with the risk for chronic kidney disease (CKD) and even the risk of developing hyperglycemia. Urine biomarkers have also been linked to the risk of CKD and lithiasis, and these biomarkers respond quickly to variations in fluid intake. High circulating copeptin levels, a surrogate marker of arginine vasopressin, have been associated with metabolic syndrome, renal dysfunction and increased risk for diabetes mellitus, cardiovascular disease and death. The aim of this paper was to explore how the various findings on water intake, hydration and health are interconnected, to highlight current gaps in our understanding and to propose a model that links water intake, homeostatic mechanisms to maintain water balance and health outcomes. Since plasma copeptin and vasopressin have been demonstrated to be sensitive to changes in water intake, inversely associated with 24-hour urine volume, and associated with urine biomarkers and fluid intake, vasopressin is proposed as the central player in this theoretical physiological model.
Vasopressin at Central Levels and Consequences of Dehydration
Authors: Bichet Daniel G.
Published: June 2016

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of central vasopressin release and perception of thirst is the key to diagnosis and management of these disorders. Mammals are osmoregulators; they have evolved mechanisms that maintain extracellular fluid osmolality near a stable value, and, in animal studies, osmoregulatory neurons express a truncated delta-N variant of the transient receptor potential vannilloid (TRPV1) channel involved in hypertonicity and thermal perception while systemic hypotonicity might be perceived by TRPV4 channels. Recent cellular and optogenetic animal experiments demonstrate that, in addition to the multifactorial process of excretion, circumventricular organ sensors reacting to osmotic pressure and angiotensin II, subserve genesis of thirst, volume regulation and behavioral effects of thirst avoidance.
Vasopressin, from Regulator to Disease Predictor for Diabetes and Cardiometabolic Risk
Authors: Melander Olle
Published: June 2016

Background: Type 2 diabetes and its cardiovascular disease complications are the major public health threats of our century. Although physical activity and dietary changes are the cornerstones in prevention of diabetes, their broad implementation is not elementary and other complementary lifestyle regimens are needed. Summary: Vasopressin (VP) is the main regulator of body water homeostasis, and at insufficient water intake, normal plasma osmolality can be maintained by increased pituitary VP secretion through VP-2 receptor mediated renal water reabsorption. During the last 6 years several independent studies have shown that high circulating VP, measured by the stable VP marker copeptin, predicts development of type 2 diabetes as well as the metabolic syndrome, cardiovascular disease and premature mortality. Interestingly, VP stimulates adrenocorticotrophic hormone, and as a consequence cortisol secretion, through pituitary VP-1B receptors, which could explain why the 25% of the middle-aged population with high circulating VP have a mild Cushing's syndrome-like phenotype. In rats, high VP results in deterioration of glucose tolerance whereas low VP, obtained by high water intake, ameliorates the VP associated dysmetabolic state, suggesting that the relationship between high VP and risk of diabetes and cardiometabolic disease in humans may be causal and reversible by increasing water intake. Key Messages: With the emerging evidence that high VP, which is present in 25% of the population, is an independent risk factor for diabetes and cardiometabolic disease, VP reduction through water supplementation appears as an attractive candidate intervention to prevent diabetes and its cardiovascular complications.
International Society of Nephrology-Hydration and Kidney Health Initiative - Expanding Research and Knowledge
Authors: Moist Louise M. , Clark William F. , Segantini Luca , Damster Sandrine , Le Bellego Laurent , Wong Germaine , Tonelli Marcello
Published: June 2016

The purpose of this manuscript is to describe a collaborative research initiative to explore the role of hydration in kidney health. Our understanding of the effects of hydration in health and disease is surprisingly limited, particularly when we consider the vital role of hydration in basic human physiology. Recent initiatives and research outcomes have challenged the global medical community to expand our knowledge about hydration, including the differences between water, sugared beverages and other consumables. Identification of the potential mechanisms contributing to the benefits of hydration has stimulated the global nephrology community to advance research regarding hydration for kidney health. Hydration and kidney health has been a focus of research for several research centers with a rapidly expanding world literature and knowledge. The International Society of Nephrology has collaborated with Danone Nutricia Research to promote development of kidney research initiatives, which focus on the role of hydration in kidney health and the global translation of this new information. This initiative supports the use of existing data in different regions and countries to expand dialogue among experts in the field of hydration and health, and to increase scientific interaction and productivity with the ultimate goal of improving kidney health.
Repetitive Transcranial Magnetic Stimulation Improved Symptoms of Obsessive-Compulsive Disorder, but Also Cognitive Performance: Results from a Randomized Clinical Trial with a Cross-Over Design and Sham Condition
Authors: Jahangard Leila , Haghighi Mohammad , Shyayganfard Mehran , Ahmadpanah Mohammad , Sadeghi Bahmani Dena , Bajoghli Hafez , Holsboer-Trachsler Edith , Brand Serge
Published: June 2016

Objective: There is some evidence that repetitive transcranial magnetic stimulation (rTMS) is an effective method of treating patients suffering from obsessive-compulsive disorder (OCD). Here, we tested the hypothesis that rTMS has a positive impact both on symptom severity and cognitive performance in such patients. Specifically, short-term verbal processing speed and flexibility were assessed. Method: Ten patients suffering from refractory OCD and treated with standard medication were randomly assigned either to a treatment-first or to a sham-first condition. At baseline and after 2 and 4 weeks, symptom severity (experts' ratings) and cognitive performance (auditory perception, visual perception, short-term memory, and processing speed) were assessed. After 2 weeks, the treatment condition switched to the sham condition, and the sham condition switched to the treatment condition. Results: Under treatment but not under sham conditions, symptom severity reduced. Moreover, cognitive performance improved in parallel. Conclusions: rTMS is a safe and efficient treatment for patients suffering from refractory OCD; symptoms and cognitive performance improved in parallel.
Recurrent Chronic Obstructive Pulmonary Disease Exacerbations after Endobronchial Valve Implantation Are Associated with the Presence of Pseudomonas aeruginosa
Authors: Tuleta Izabela , Pizarro Carmen , Molitor Ernst , Kristiansen Glen , Nickenig Georg , Skowasch Dirk
Published: June 2016

Background: Endoscopic lung volume reduction by means of endobronchial valve implantation is an established therapy in patients with severe emphysema. However, long-term complications such as chronic obstructive pulmonary disease (COPD) exacerbations are a limitation of this method. Objectives: As the mechanisms underlying increased rates of COPD exacerbations are unknown, the aim of our study was to determine whether infectious or inflammatory factors may contribute to these events and to investingate the consequent need for valve explantation. Methods: Tissue surrounding explanted endobronchial Zephyr valves was examined by microbiological, histological and cytological methods. Additionally, we performed a microbiological analysis of tracheal aspirates before both valve implantation and valve explantation. Moreover, blood samples were collected for the analysis of inflammatory markers. Results: Endobronchial valves were explanted from 16 patients. Reasons for explantation were frequent postprocedural COPD exacerbations (group 1: 8 patients) or loss of clinical benefit (group 2: 8 patients). Compared to group 2, the microbiological examinations of valve lavage and tracheal aspirates from patients in group 1 showed a higher detection of Gram-negative bacteria. In particular, infection with Pseudomonas aeruginosa was more predominant in group 1, while no presence could be detected in group 2. Blood inflammatory markers tended to be slightly higher in group 1 than in group 2; however, without reaching statistical significance. Conclusions: Increased rates of COPD exacerbations after endobronchial valve implantation are associated with the presence of P. aeruginosa. The finding warrants further investigation.
Successful Pregnancy after Improving Insulin Resistance with the Glucagon-Like Peptide-1 Analogue in a Woman with Polycystic Ovary Syndrome: A Case Report and Review of the Literature
Authors: Yang Qianying , Wang Fang
Published: June 2016

The polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. It is diagnosed by the presence of hyperandrogenemia, insulin resistance (IR), obesity and other endocrine or metabolic disorders. Exenatide (EX) is a kind of glucagon-like peptide, which is a new option for patients with diabetes mellitus. We present a patient with infertility for PCOS. She was overweight and her medical history included IR, right-sided ovarian mucinous cystadenomas, and left-sided teratoma. Although she had been treated with ovarian surgery, clomiphene citrate and gonadotropins, weight loss and metformin, which have been effective for dominant follicle development, she still failed to conceive. Then EX was initiated to intervene for 2 months. EX treatment was successful to improve IR; after that the infertile woman with PCOS became pregnant. EX improves IR and reproduction capacity in PCOS patients, reducing insulin level and ameliorating endocrine disorders, thereby improving ovarian function, promoting follicle development, and providing new avenues for the treatment of infertility with PCOS.
Time Course and Factors Correlating With Ventricular Tachyarrhythmias After Introduction of Steroid Therapy in Cardiac Sarcoidosis
Authors: Segawa Masato , Fukuda Koji , Nakano Makoto , Kondo Masateru , Satake Hiroyuki , Hirano Michinori , Shimokawa Hiroaki
Published: June 2016

Background—

The time course and factors correlating with ventricular tachyarrhythmias (VTs) after introduction of corticosteroid therapy in patients with cardiac sarcoidosis remain to be elucidated.

Methods and Results—

We examined 68 consecutive patients with cardiac sarcoidosis in the Tohoku University Hospital from October 1998 to September 2014 (age: 57±11 years old; male:female 18:50) and evaluated VTs after initiation of steroid therapy. VTs were defined as documented ventricular tachycardia or ventricular fibrillation lasting for more than 30 seconds or resulting in cardiovascular collapse, or appropriate implantable cardioverter defibrillator therapy. During a mean follow-up of 5.5 years, 20 out of 68 patients (29%) experienced VTs after initiation of corticosteroid therapy, especially in the first 12 months in 14 patients (70%). A multivariable analysis revealed that positive gallium scintigraphy had a significant correlation with VTs (hazard ratio, 11.33; 95% confidence interval, 3.22–39.92;
P
<0.001), in addition to reduced left ventricular ejection fraction (hazard ratio, 0.94; 95% confidence interval, 0.90–0.97;
P
=0.001). Furthermore, electrical storm was noted in 10 patients (14.7%), 8 within the first 12 months of treatment, whereas the recurrence of electric storm was relatively less.

Conclusions—

These results indicate that VTs and electric storm frequently occur in the first 12 months after initiation of corticosteroid therapy, presumably because of inflammatory conditions, and that the positive gallium scintigraphy is a significant and independent predictor of VTs. The present findings may be useful to further improve the management of VTs in patients with cardiac sarcoidosis.
Trends in 30-Day Readmission Rates for Patients Hospitalized With Heart Failure
Authors: Bergethon Kristin E. , Ju Christine , DeVore Adam D. , Hardy N. Chantelle , Fonarow Gregg C. , Yancy Clyde W. , Heidenreich Paul A. , Bhatt Deepak L. , Peterson Eric D. , Hernandez Adrian F.
Published: June 2016

Background—

Reducing hospital readmissions for patients with heart failure is a national priority, and quality improvement campaigns are targeting reductions of ≥20%. However, there are limited data on whether such targets have been met.

Methods and Results—

We analyzed data from the American Heart Association’s Get With The Guidelines-Heart Failure registry linked to Medicare claims between 2009 and 2012 to describe trends and relative reduction of rates of 30-day all-cause readmission among patients with heart failure. A total of 21,264 patients with heart failure were included from 70 US sites from January 2009 to October 2012. Overall hospital-level, risk-adjusted, 30-day all-cause readmission rates declined slightly, from 20.0% (SD, 1.3%) in 2009 to 19.0% (SD, 1.2%) in 2012 (
P
=0.001). Only 1 in 70 (1.4%) hospitals achieved the 20% relative reduction in 30-day risk-adjusted readmission rates. A multivariable linear regression model was used to determine hospital-level factors associated with relative improvements in 30-day risk-adjusted readmissions between 2009 and 2012. Teaching hospitals had higher relative readmission rates as compared with their peers, and hospitals that used postdischarge heart failure disease management programs had lower relative readmission rates.

Conclusions—

Although there has been slight improvement in 30-day all-cause readmission rates during the past 4 years in patients with heart failure, few hospitals have seen large success.
Pulmonary Vascular Distensibility Predicts Pulmonary Hypertension Severity, Exercise Capacity, and Survival in Heart Failure
Authors: Malhotra Rajeev , Dhakal Bishnu P. , Eisman Aaron S. , Pappagianopoulos Paul P. , Dress Ashley , Weiner Rory B. , Baggish Aaron L. , Semigran Marc J. , Lewis Gregory D.
Published: June 2016

Background—

Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity.

Methods and Results—

Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg,
P
<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, ρ=0.39,
P
<0.0001) with exercise and was an independent predictor of peak VO
2.
PV distensibility also predicted cardiovascular mortality independent of peak VO
2
in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10–0.93;
P
=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (
P
=0.015) in the sildenafil group only.

Conclusions—

PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00309790.
Transcription Factor 7-like 2 Mediates Canonical Wnt/β-Catenin Signaling and c-Myc Upregulation in Heart Failure
Authors: Hou Ning , Ye Bo , Li Xiang , Margulies Kenneth B. , Xu Haodong , Wang Xuejun , Li Faqian
Published: June 2016

Background—

How canonical Wnt/β-catenin signals in adult hearts, especially in different diseased states, remains unclear. The proto-oncogene, c-Myc, is a Wnt target and an early response gene during cardiac stress. It is not clear whether c-Myc is activated or how it is regulated during heart failure.

Methods and Results—

We investigated canonical Wnt/β-catenin signaling and how it regulated c-Myc expression in failing hearts of human ischemic heart disease, idiopathic dilated cardiomyopathy, and murine desmin–related cardiomyopathy. Our data demonstrated that canonical Wnt/β-catenin signaling was activated through nuclear accumulation of β-catenin in idiopathic dilated cardiomyopathy, ischemic heart disease, and murine desmin–related cardiomyopathy when compared with nonfailing controls and transcription factor 7-like 2 (TCF7L2) was the main β-catenin partner of the T-cell factor (TCF) family in adult hearts. We further revealed that c-Myc mRNA and protein levels were significantly elevated in failing hearts by real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemical staining. Immunoprecipitation and confocal microscopy further showed that β-catenin interacted and colocalized with TCF7L2. More importantly, chromatin immunoprecipitation confirmed that β-catenin and TCF7L2 were recruited to the regulatory elements of c-Myc. This recruitment was associated with increased histone H3 acetylation and transcriptional upregulation of c-Myc. With lentiviral infection, TCF7L2 overexpression increased c-Myc expression and cardiomyocyte size, whereas shRNA-mediated knockdown of TCF7L2 suppressed c-Myc expression and cardiomyocyte growth in cultured neonatal rat cardiomyocytes.

Conclusions—

This study indicates that TCF7L2 mediates canonic Wnt/β-catenin signaling and c-Myc upregulation during abnormal cardiac remodeling in heart failure and suppression of Wnt/β-catenin to c-Myc axis can be explored for preventing and treating heart failure.
Persistence of Severe Pulmonary Hypertension After Transcatheter Aortic Valve Replacement
Authors: Testa Luca , Latib Azeem , De Marco Federico , De Carlo Marco , Fiorina Claudia , Montone Rocco , Agnifili Mauro , Barbanti Marco , Petronio Anna Sonia , Biondi Zoccai Giuseppe , Ettori Federica , Klugmann Silvio , Tamburino Corrado , Brambilla Nedy , Colombo Antonio , Bedogni Francesco
Published: June 2016

Background—

Severe pulmonary hypertension (PH) is considered to negatively affect the outcome after transcatheter aortic valve replacement. However, a clear understanding of the pattern, evolution, and clinical impact of different grades of PH in this setting is lacking.

Methods and Results—

A total of 990 consecutive patients were enrolled in 6 high-volume centers and analyzed as follows: group 1, systolic pulmonary artery pressure (sPAP) <40 mm Hg (346 patients; 35%); group 2, sPAP 40 to 60 mm Hg (426 patients; 43%); and group 3, sPAP >60 mm Hg (218 patients; 22%). At 1 month, mortality rate did not differ across the groups. When compared with groups 1 and 2, patients in group 3 had a higher-rate of New York Heart Association 3 to 4 (26% versus 12% and 10%), and a higher-rate of hospitalization for heart failure (7% versus 3% and 3%). At 1 year, when compared with patients in group 1, patients in group 2 and 3 had both a higher overall mortality (hazard ratio [HR], 1.5 [1.3–3.2];
P
=0.01 and HR, 2.3 [1.8–2.8];
P
=0.001) and a higher cardiac mortality (HR, 1.3 [1.1–2.1];
P
=0.01 and HR, 1.7 [1.3–2.5];
P
=0.002). After 1 month, the sPAP decreased ≥15 mm Hg in 32% and 35% of the patients in groups 2 and 3. Baseline sPAP >60 mm Hg (HR, 1.6 [1.1–2.3];
P
=0.03) and, in a larger extent, a persistent severe PH after 1 month (HR, 2.4 [1.5–2.8];
P
=0.004), independently predicted 1-year mortality, whereas the 1-month reduction of the sPAP did not.

Conclusions—

The persistence of severe PH after transcatheter aortic valve replacement is a stronger predictor of 1-year mortality than baseline severe PH. The early reduction of sPAP is not associated with a reduced mortality. The benefit of transcatheter aortic valve replacement in terms of quality of life is substantial in patients with and without a reduction of sPAP at early follow-up.
Low Circulating Acute Brain-Derived Neurotrophic Factor Levels Are Associated With Poor Long-Term Functional Outcome After Ischemic Stroke
Authors: Stanne Tara M. , Åberg N. David , Nilsson Staffan , Jood Katarina , Blomstrand Christian , Andreasson Ulf , Blennow Kaj , Zetterberg Henrik , Isgaard Jörgen , Svensson Johan , Jern Christina
Published: June 2016

Background and Purpose—

Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair, and it influences stroke outcomes in animal models. Circulating BDNF concentrations are lowered in patients with traumatic brain injury, and low BDNF predicts poor recovery after this injury. We sought to investigate whether circulating concentrations of BDNF are altered in the acute phase of ischemic stroke and whether they are associated with short- or long-term functional outcome.

Methods—

Serum concentrations of BDNF were measured in the Sahlgrenska Academy Study on Ischemic Stroke. The main outcomes were modified Rankin Scale (mRS) good (mRS score of 0–2) versus poor (mRS score of 3–6) at 3 months and 2 years after stroke, and good (mRS score of 0–2) versus poor (mRS score of 3–5) at 7 years after stroke.

Results—

Acute concentrations of BDNF were significantly lower in ischemic stroke cases (n=491) compared with controls (n=513). BDNF concentrations were not significantly associated with 3-month outcome. However, patients with BDNF in the lowest tertile had an increased risk of experiencing a poor outcome both at 2-year and 7-year follow-up, and these associations were independent of vascular risk factors and stroke severity (odds ratio, 2.6; confidence intervals, 1.4–4.9;
P
=0.002 and odds ratio, 2.1; confidence intervals, 1.1–3.9;
P
=0.028, respectively).

Conclusions—

Circulating concentrations of BDNF protein are lowered in the acute phase of ischemic stroke, and low levels are associated with poor long-term functional outcome. Further studies are necessary to confirm these associations and to determine the predictive value of BDNF in stroke outcomes.
Intracranial Aneurysms in Sickle-Cell Disease Are Associated With the Hemoglobin SS Genotype But Not With Moyamoya Syndrome
Authors: Birkeland Peter , Gardner Kate , Kesse-Adu Rachel , Davies John , Lauritsen Jens , Rom Poulsen Frantz , Tolias Christos M. , Thein Swee Lay
Published: June 2016

Background and Purpose—

Intracranial aneurysms and aneurysmal subarachnoid hemorrhage may occur more frequently in sickle-cell disease (SCD), and this could be related to the sickle genotype and moyamoya syndrome seen in SCD.

Methods—

Records from a total of 1002 patients with SCD attending 2 specialized adult hematologic services were retrospectively reviewed. We analyzed data of a cohort of 767 patients attending 1 SCD clinic between 2002 and 2013 and of 235 patients from the other clinic who have had neurovascular imaging between 2007 and 2014.

Results—

We identified 4 patients in the cohort who had an aneurysmal subarachnoid hemorrhage during 9063 patient-years. The highest incidence rate was seen among women in the age group 30 to 39 years with the hemoglobin SS (HbSS) genotype (440 per 100 000 patient-years). Unruptured intracranial aneurysms were found in 20 of the 324 patients, who had imaging data; the prevalence was significantly higher in patients with HbSS genotype compared with other sickle genotypes with the highest prevalence (15%) observed in women in the age group 30 to 39 years. Fifty-one HbSS patients had a moyamoya vasculopathy, but only 3 of these had concomitant intracranial aneurysms.

Conclusions—

Intracranial aneurysms are common in HbSS SCD. There was also a trend toward more common occurrence of aneurysmal subarachnoid hemorrhage in HbSS; women in the age group 30 to 39 years were most at risk. There was no correlation between the occurrence of intracranial aneurysms and moyamoya syndrome.
Long-Term Risk of Stroke in Myocardial Infarction Survivors
Authors: Sundbøll Jens , Horváth-Puhó Erzsébet , Schmidt Morten , Pedersen Lars , Henderson Victor W. , Bøtker Hans Erik , Sørensen Henrik Toft
Published: June 2016

Background and Purpose—

Improved survival after myocardial infarction (MI) has increased the number of patients at risk of post-MI stroke. We examined risks of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in patients with MI compared with the general population.

Methods—

We conducted a nationwide population–based cohort study using Danish medical registries. During 1980 to 2009, we identified all patients with a first-time inpatient diagnosis of MI and formed a sex- and age-matched comparison cohort. We computed cumulative stroke risks and adjusted stroke rate ratios with 95% confidence intervals (CIs).

Results—

We identified 258 806 patients with an MI and 1 244 773 individuals from the general population. For patients with MI, the cumulative stroke risks after 1 to 30 years were 12.6% for ischemic stroke, 1.2% for ICH, and 0.24% for SAH. During the first 30 days after MI, the adjusted stroke rate ratio was 30-fold increased for ischemic stroke (31.9; 95% CI, 28.4–35.8), 20-fold for ICH (21.8; 95% CI, 16.6–28.5), and 15-fold for SAH (16.6; 95% CI, 8.7–32.0). The adjusted stroke rate ratio remained increased during 31 to 365 days (3-fold for ischemic stroke, 2-fold for ICH, and 1.5-fold for SAH). During the ensuing 1 to 30 years, the risks remained increased for ischemic stroke (1.6; 95% CI, 1.6–1.6) but decreased to near unity for ICH (1.1; 95% CI, 1.0–1.2) and SAH (1.1; 95% CI, 0.94–1.2).

Conclusions—

MI was a risk factor for all stroke subtypes during the first year of follow-up, but only for ischemic stroke thereafter.