bluuebunny/crossref_metadata_2025 huggingface dataset:
GPCR Signaling Mediates Tumor Metastasis via PI3Kβ
Authors: Khalil Bassem D. , Hsueh Christine , Cao Yanyan , Abi Saab Widian F. , Wang Yarong , Condeelis John S. , Bresnick Anne R. , Backer Jonathan M.
Published: March 2016

Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kβ has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein–coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease. Cancer Res; 76(10); 2944–53. ©2016 AACR.
Hemolytic E. coli Promotes Colonic Tumorigenesis in Females
Authors: Jin Ye , Tang Senwei , Li Weilin , Ng Siew Chien , Chan Michael W.Y. , Sung Joseph J.Y. , Yu Jun
Published: March 2016

Bacterial infection is linked to colorectal carcinogenesis, but the species that contribute to a protumorigenic ecology are ill-defined. Here we report evidence that α-hemolysin–positive (hly+) type I Escherichia coli (E. coli) drives adenomagenesis and colorectal cancer in human females but not males. We classified E. coli into four types using a novel typing method to monitor fimH mutation patterns of fecal isolates from adenoma patients (n= 59), colorectal cancer patients (n= 83), and healthy subjects (n= 85). hly+ type I E. coli was found to be relatively more prevalent in stools from females with adenoma and colorectal cancer, correlating with poor survival in colorectal cancer patients. In mechanistic studies in female mice, we found that hly+ type 1 E. coli activated expression of the glucose transporter GLUT1 and repressed expression of the tumor suppressor BIM. hly-encoded alpha hemolysin partially accounted for these effects by elevating the levels of HIF1α. Notably, colon tumorigenesis in mice could be promoted by feeding hly+ type I E. coli to female but not male subjects. Collectively, our findings point to hemolytic type I E. coli as a candidate causative factor of colorectal cancer in human females, with additional potential as a biomarker of disease susceptibility. Cancer Res; 76(10); 2891–900. ©2016 AACR.
CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages
Authors: De Ishani , Steffen Megan D. , Clark Paul A. , Patros Clayton J. , Sokn Emily , Bishop Stephanie M. , Litscher Suzanne , Maklakova Vilena I. , Kuo John S. , Rodriguez Fausto J. , Collier Lara S.
Published: March 2016

Current therapies for high-grade gliomas extend survival only modestly. The glioma microenvironment, including glioma-associated microglia/macrophages (GAM), is a potential therapeutic target. The microglia/macrophage cytokine CSF1 and its receptor CSF1R are overexpressed in human high-grade gliomas. To determine whether the other known CSF1R ligand IL34 is expressed in gliomas, we examined expression array data of human high-grade gliomas and performed RT-PCR on glioblastoma sphere-forming cell lines (GSC). Expression microarray analyses indicated that CSF1, but not IL34, is frequently overexpressed in human tumors. We found that while GSCs did express CSF1, most GSC lines did not express detectable levels of IL34 mRNA. We therefore studied the impact of modulating CSF1 levels on gliomagenesis in the context of the GFAP-V12Ha-ras-IRESLacZ (Ras*) model. Csf1 deficiency deterred glioma formation in the Ras* model, whereas CSF1 transgenic overexpression decreased the survival of Ras* mice and promoted the formation of high-grade gliomas. Conversely, CSF1 overexpression increased GAM density, but did not impact GAM polarization state. Regardless of CSF1 expression status, most GAMs were negative for the M2 polarization markers ARG1 and CD206; when present, ARG1+ and CD206+ cells were found in regions of peripheral immune cell invasion. Therefore, our findings indicate that CSF1 signaling is oncogenic during gliomagenesis through a mechanism distinct from modulating GAM polarization status. Cancer Res; 76(9); 2552–60. ©2016 AACR.
NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis
Authors: Shoshan Einav , Braeuer Russell R. , Kamiya Takafumi , Mobley Aaron K. , Huang Li , Vasquez Mayra E. , Velazquez-Torres Guermarie , Chakravarti Nitin , Ivan Cristina , Prieto Victor , Villares Gabriel J. , Bar-Eli Menashe
Published: March 2016

Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates IL2 expression during T-cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL8, and MMP3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL8 and MMP3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL8 and MMP3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment. Cancer Res; 76(11); 3145–55. ©2016 AACR.
Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest
Authors: Schaaf Lea , Schwab Matthias , Ulmer Christoph , Heine Simon , Mürdter Thomas E. , Schmid Jens O. , Sauer Georg , Aulitzky Walter E. , van der Kuip Heiko
Published: March 2016

Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868–75. ©2016 AACR.
Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity
Authors: Ricklefs Franz , Mineo Marco , Rooj Arun K. , Nakano Ichiro , Charest Al , Weissleder Ralph , Breakefield Xandra O. , Chiocca E. Antonio , Godlewski Jakub , Bronisz Agnieszka
Published: March 2016

A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo. Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876–81. ©2016 AACR.
Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study
Authors: Haznadar Majda , Cai Qiuyin , Krausz Kristopher W. , Bowman Elise D. , Margono Ezra , Noro Rintaro , Thompson Matthew D. , Mathé Ewy A. , Munro Heather M. , Steinwandel Mark D. , Gonzalez Frank J. , Blot William J. , Harris Curtis C.
Published: March 2016

Background: Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United States and worldwide, respectively.

Methods: While seeking to identify stable and reproducible biomarkers in noninvasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and indeterminate metabolite 561+, were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 nondiseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case–control set, whereas two metabolites were associated with lung cancer risk in European-Americans.

Results: OR of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 [95% confidence interval (CI), 1.2–3.4; P= 0.01]. In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR = 5.3; 95% CI, 1.6–17.6; P= 0.006 and OR=3.5; 95% CI, 1.5–8.4; P= 0.004, respectively). However, race itself did not significantly modify the associations. ROC analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P= 0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism.

Conclusion and Impact: These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as noninvasive, clinical screening tools for early diagnosis of lung cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 978–86. ©2016 AACR.
Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy
Authors: Thielen Noortje , Richter Johan , Baldauf Matthias , Barbany Gisela , Fioretos Thoas , Giles Francis , Gjertsen Bjørn-Tore , Hochhaus Andreas , Schuurhuis Gerrit Jan , Sopper Sieghart , Stenke Leif , Thunberg Sarah , Wolf Dominik , Ossenkoppele Gert , Porkka Kimmo , Janssen Jeroen , Mustjoki Satu
Published: March 2016

Purpose: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)–positive CD34+CD38− bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177).

Experimental design: Two flow cytometry–based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.

Results: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38− cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.

Conclusions: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030–8. ©2016 AACR.
Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9
Authors: Fan Minghua , Xu Yongping , Hong Fanzhen , Gao Xiaolin , Xin Gang , Hong Haijie , Dong Lihua , Zhao Xingbo
Published: March 2016

Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs). Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down-regulated the expression of β-catenin in HTR-8/SVneo cells, demonstrating that β-catenin is a downstream effector of Rac1 in trophoblast invasion. Conclusion: Our data suggest that Rac1-mediated activation of β-catenin might regulate Snail and MMP9 expression subsequently promoting trophoblast invasion in pregnancy.
High Frequencies of Anti-Host Reactive CD8+ T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model
Authors: Gassa Asmae , Kalkavan Halime , Jian Fu , Duhan Vikas , Khairnar Vishal , Shaabani Namir , Honke Nadine , Carpinteiro Alexander , Botezatu Lacramioara , Crivello Pietro , Dolff Sebastian , Ferencik Stanislav , Häussinger Dieter , Khandanpour Cyrus , Fleischhauer Katharina , Witzke Oliver , Wahlers Thorsten , Hardt Cornelia , Lang Philipp A. , Lang Karl S.
Published: March 2016

Background: Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied. Methods: Here we used a CD8+ T cell transgenic mouse line (P14/CD45.1+) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8+ T cells after BMT. Results: We found that anti-host reactive CD8+ T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti-host reactive CD8+ T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccharides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8+ T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8+ T cells. Conclusion: We found that after BMT anti-host reactive CD8+ T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, LPS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8+ T cells after BMT.
Incidentally Raised Cardiac Troponin I Has a Worse Prognosis in Older Patients Compared to Those with Normal Cardiac Troponin I and Patients with Acute Coronary Syndrome: A Cohort Study
Authors: Mannu Gurdeep Singh , Honney Katie , Spooner Robert , Clark Allan B. , Bettencourt-Silva Joao H. , Zaman M. Justin S. , Loke Yoon K. , Myint Phyo K.
Published: March 2016

Background: Incidentally elevated cardiac troponin I (cTnI) levels are common in acutely unwell older patients. However, little is known about how this impacts on the prognosis of these patients. Objective: We aimed to investigate whether incidentally elevated cTnI levels (group 1) are associated with poorer outcome when compared to age- and sex-matched patients without an elevated cTnI level (group 2), and to patients diagnosed with acute coronary syndrome (group 3). Patients and Methods: This prospective, matched cohort study placed patients ≥75 years old who were admitted to a University teaching hospital into groups 1-3, based on the cTnI levels and underlying diagnosis. Outcomes were compared between the groups using mixed-effects regression models and adjusted for renal function and C-reactive protein. All-cause mortality at discharge, at 1 month and 3 months, alongside the length of hospital stay (LOS), were recorded. Results: In total, 315 patients were included, with 105 patients in each of the 3 groups. The mean age was 84.8 ± 5.5 years, with 41.9% males. All patients were followed up for 3 months. The percent all-cause mortality at discharge and the LOS for groups 1, 2 and 3 were 12.4, 3.8 and 8.6% and 11.2, 8.5 and 7.7 days, respectively. Group 1 had significantly increased mortality at 3 months [odds ratio (OR) 2.80, 95% confidence interval (CI) 1.12-6.96; p = 0.040] and LOS (OR 1.39, 95% CI 1.08-1.79; p = 0.008) compared to group 2 and did not differ significantly when compared to 3-month mortality (OR 2.39, 95% CI 0.91-6.29; p = 0.079) or LOS (OR 1.26, 95% CI 0.96-1.66; p = 0.097) in group 3. Conclusion: There is a significant association between an incidental rise in cTnI level with mortality and LOS in older patients. Further research is required to evaluate whether a more systematic management of these patients would improve the prognosis.
Hypomethylating Agents for Relapse after Allogeneic Hematopoietic Cell Transplantation in Myeloid Malignancies: A Case Series and Review of the Literature
Authors: Im Annie , Raptis Anastasios , Hou Jing-Zhou , Tompkins Cheryl , Winfield Melissa , Guay Mary , Boyiadzis Michael , Agha Mounzer
Published: March 2016

Background/Aims: Relapse is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT). Hypomethylating agents (HMAs) have immunomodulatory properties, including augmenting tumor antigen presentation that may enhance the graft-versus-leukemia effect. Moreover, inhibitory effects on T-cell activation and cytokine production may lead to a lower incidence of graft-versus-host disease (GVHD). Our aim was to describe outcomes in patients treated with HMAs for relapse after HCT. Methods: Subjects were retrospectively identified as patients with relapse or loss of donor chimerism after HCT for myeloid malignancies treated with HMAs at the University of Pittsburgh. Results: Thirteen patients were identified, with a median age of 57 years and a median time to relapse of 98 days. Nine of 12 (75%) evaluable patients had a complete remission (CR). Grade I-IV acute GVHD involving the liver occurred in 6 patients. Cases of acute liver GVHD were diagnosed clinically based on the elevation of liver function tests. The median survival was 14.3 months from the time of relapse. Conclusion: HMAs for relapse after HCT can be effective in inducing a CR. This may be due to epigenetic changes and immunomodulatory effects that enhance the graft-versus-leukemia effect. There may be a risk of GVHD, and further exploration into pathophysiology and predisposing factors are warranted.
Werner Forssmann - A Nobel Prize Winner and His Political Attitude before and after 1945
Authors: Packy Lisa-Maria , Krischel Matthis , Gross Dominik
Published: March 2016

Purpose: In 1956, the Nobel Prize in Physiology or Medicine was awarded jointly to Werner Forssmann, André Frédéric Cournand and Dickinson W. Richards for their development of cardiac catheterization. Forssmann performed a self-experiment in 1929 by inserting a urethral catheter into his right ventricular cavity via his antecubital vein. Despite his popularity as one of the first German Nobel Laureates after 1945, little is known about Forssmann personally. This contribution aims to close this gap regarding the Nazi period and early post-war Germany. Methods: Primary historical sources from Forssmann's private archive were examined, evaluated and interpreted for the first time. Additionally, a comparative analysis based on further archival and secondary sources was performed. Results: Werner Forssmann joined the Nazi Party, the Sturmabteilung (Stormtroopers, SA) and the Nationalsozialistischer Deutscher Ärztebund (Nazi Doctors' Association) in 1932, a year before Hitler's assumption of power. In his autobiography, Forssmann referred to the political situation in passing. However, he expressed his personal thoughts in private letters which he wrote as a medical officer during the war. After World War II, Forssmann underwent denazification and was banned from practicing medicine for 3 years. He did not seem to be averse to Hitler's politics and in some ways expressed his approval. However, correspondence from the 1960s with 2 Jewish colleagues reveals that Forssmann may have changed his attitude toward National Socialism later. Conclusion: Werner Forssmann's political attitudes during the Third Reich and in the post-war era can be characterized as early agreement that gradually changed to a more critical distance to Nazi ideology. In this respect, Forssmann appears to be quite a typical example of a larger proportion of German medical doctors during these eras.
Bronchoscopic Transparenchymal Nodule Access: Feasibility and Safety in an Endoscopic Unit
Authors: Harzheim Dominik , Sterman Daniel , Shah Pallav L. , Eberhardt Ralf , Herth Felix J.F.
Published: March 2016

Background: The minimal invasive investigation of solitary pulmonary nodules becomes increasingly important with the emergence of lung cancer screening. Objectives: We report the results of the first utilization of a recently developed procedure in a bronchoscopy suite, which approaches solitary pulmonary nodules via a transparenchymal path. Methods: This study was a prospective, single-arm interventional study. We investigated patients with a solitary pulmonary nodule detected on CT imaging, which was suspicious for malignancy. The subject's CT was employed to calculate an airway wall point of entry (POE) as well as an avascular path through lung tissue from the POE to the solitary pulmonary nodule. Using a set of catheter-based tools under fused fluoroscopy guidance, a tunnelled tract was created from the POE to the nodule. The patients were surveyed for at least 72 h in our hospital. The primary end point of the study was to evaluate the feasibility to access and biopsy solitary pulmonary nodules outside of an operation theatre. Results: Six patients were recruited, and a tunnel pathway was created in 5 patients. There were no adverse events during the procedures. Two pneumothoraces were diagnosed by chest X-ray 2 h after the procedure, with one pneumothorax requiring drainage. Adequate biopsies were obtained from all 5 patients in whom a tunnel path was created. Conclusions: This study demonstrates that bronchoscopic transparenchymal access of solitary pulmonary nodules is feasible outside an operation theatre.
Comparison of OFDM System in terms of BER using Different Transform and Channel Coding
Authors: Manhas Pratima , Soni M.K
Published: March 2016

Orthogonal frequency division multiplexing is a type of multicarrier modulation technique which is used in wireless communication. OFDM can be used in various wireless and wired application such Digital audio broadcasting, digital video broadcasting & wireless LAN. The Performance of OFDM system depends on various parameters such as using different transform, different modulation and by putting various channel coding. In this paper OFDM system is modeled by using different transform (DWT/FFT), different modulation (BPSK, QPSK, QAM) and different channel coding (Linear / Cyclic block codes) for AWGN channel. The performance parameter is calculated as Bit error rate (BER) for various transform/modulation/channel coding based OFDM systems. MATLAB Simulink tool is used to calculate the bit error rate (BER).
Development of Quran Reciter Identification System Using MFCC and Neural Network
Authors: Hasan Asda Tayseer Mohammed , Surya Gunawan Teddy
Published: March 2016

Currently, the Quran is recited by so many reciters with different ways and voices.  Some people like to listen to this reciter and others like to listen to other reciters. Sometimes we hear a very nice recitation of al-Quran and want to know who the reciter is. Therefore, this paper is about  the development of Quran reciter recognition and identification system based on Mel Frequency Cepstral Coefficient (MFCC) feature extraction and artificial neural network (ANN). From every speech, characteristics from the utterances will be extracted through neural network model. In this paper a database of five Quran reciters is created and used in training and testing. The feature vector will be fed into Neural Network back propagation learning algorithm for training and identification processes of different speakers. Consequently,  91.2%  of the successful match between targets and input occurred with certain number of hidden layers  which shows how efficient are Mel Frequency Cepstral Coefficient (MFCC) feature extraction  and artificial neural network (ANN) in identifying the reciter voice perfectly.
A Review on Machine Translation Approaches
Authors: Kituku Benson , Muchemi Lawrence , Nganga Wanjiku
Published: March 2016

There is need to fill the gap between two entities which use different languages  to communicate which can be done either via human translation or machine translation means. The world has over 7000 living natural languages, thus making it costly if human translation route is taken hence need for machine translation. There is need to know the available machine translation approaches and their requirement in order to decide which one suits for particular languages or not, hence the motivation for this survey. The survey provide overview and architectures of the three major techniques available namely: rule based translation, corpus based translation and hybrid based translation plus their subcategories available in each approach.
Online Prediction of Transient Instability by Wide Area Measurement System
Authors: Namdari Farhad , Nourizadeh Maryam , Shakarami Mahmoodreza
Published: March 2016

In this paper an online accurate prediction method is proposed to enhance the speed of Transactionient stability assessment. This method is the measurement basis technique resulted from wide area measurement systems (WAMS). In the proposed method, the generators with same dynamic behavior, referred as to coherent generators, are clustered as a same group and they can be considered as an equivalent bus. So the system will be reduced into a small scale system. The admittance matrix parameters of the reduced system can be identified with the least square algorithm. Then the trajectory prediction is performed by real-time simulations. Obtained results from simulations on New England test system show the high noticeable efficiency for performance of the proposed method, capable in predicting of the disturbed trajectory under existence of unknown parameters in grid structure.. 
Robust Fractional Order Proportional, Integral and Derivative Stabilizer for Power Systems
Authors: Aboelela Magdy A.S. , M. Soliman Hisham
Published: March 2016

This paper focuses on the application of a robust Fractional Order PID (FOPID) stabilizer tuned by Genetic Algorithm (GA). The system’s robustness is assured through the application of Kharitonov’s theorem to overcome the effect of system parameter’s changes within upper and lower limits. The FOPID stabilizer has been approximated during the optimization using the Oustaloup’s approximation for fractional calculus and using the “nipid” toolbox of Matlab during simulation. The objective is to keep robust stabilization with maximum achievable degree of stability against system's uncertainty. This optimization will be achieved with the proper choice of the FOPID stabilizer’s parameters (kp, ki, kd, l, and d) as discussed later in this article. The optimization has been done using the GA which limits the boundaries of the tuned parameters within the permissible region. The calculations have been applied to a single machine infinite bus (SMIB)power system using Matlab and Simulink. The results show superior behavior of the proposed stabilizer over the traditional PID.
Study on the Glass Silicon Anodic Direct Bonding Parameters
Authors: Jia Li , Hao Guo , Zhiping Guo , Shujing Miao , Jingxiang Wang
Published: March 2016

By MEMS packaging test platform for bonding process of bonding temperature and bonding time, and test silicon specifications experimental study. Experimental results indicate that when the bonding voltage of 1200V, bonding temperature of 4450C to 4550C, bonding time is 60s,the void fraction is less than 5%.Glass and silicon wafer bonding quality can achieve the best. The experimental results in order to improve the glass silicon bonding quality provide the basis.
Design and Fabrication of LC-Oscillator Tool Kits Based Op-Amp for Engineering Education Purpose
Authors: Fuada Syifaul , Elmunsyah Hakkun , Suwasono Suwasono
Published: March 2016

In this paper, a proposed design, fabrication and testing of sine wave oscillator “LC” type (Hartley and Colpitts oscillator) has been performed using five approaches. The first approach proposed design is done theoretically using the basic theorems used to generate oscillations, such as the condition of oscillation criteria and determine the values of capacitor (C) and inductor (L) component, Secondly it is done using simulation technique (LTSpice IV), Thirdly the simulated design is implemented practically using IC OP-AMP 741 with passive elements such as resistors, capacitors and inductors by oscilloscope and frequency generator. Fourthly design the Hartley and colpitts tool kit by 2-D and 3-D, layouting the circuit by Eagle PCB design software then package into tool box which integrated each other. Finaly, the LC-oscillator tool kit was tested such as resistor, capasitor and inductor module and write the result into tables (for jobsheet data).
A Overlapping Carrier Based SPWM for a 5-Level Cascaded H-bridge Multilevel Inverter
Authors: D. Teryima Kureve , Y. Nentawe Goshwe , O. David Agbo
Published: March 2016

This paper proposes a switching control for a cascaded H-bridge inverter structure with reduced switches which is used to improve the THD performance of a single phase five level CHB MLI. The multi level inverter is simulated for the conventional carrier overlapping APOD and the proposed carrier overlapping APOD Pulse Width Modulation (PWM) switching control technique. The total harmonic distortion (THD) of the output voltages are observed for both PWM control techniques. The performance of the symmetric CHB MLI is simulated using MATLAB-SIMULINK. It is observed that the proposed carrier overlapping APODPWM provides output with relatively low THD as compared to the conventional carrier overlapping APODPWM.
Loss of Excitation Faults Detection in Hydro-Generators Using an Adaptive Neuro Fuzzy Inference System
Authors: Abdel Aziz Mohamed Salah El-Din , Elsamahy Mohamed , Moustafa Mohamed , Bendary Fahmy
Published: March 2016

This paper presents a new approach for Loss of Excitation (LOE) faults detection in Hydro-generators using Adaptive Neuro Fuzzy Inference System. The proposed scheme was trained by data from simulation of a 345kV system under various faults conditions and tested for different loading conditions. Details of the design process and the results of performance using the proposed technique are discussed in the paper. Two different techniques are discussed in this article according to the type of inputs to the proposed ANFIS unit, the generator terminal impedance measurements (R & X) and the generator RMS Line to Line voltage and Phase current (Vtrms & Ia). The two proposed techniques results are compared with each other and are compared with the traditional distance relay response in addition to other technique. The results show that the proposed Artificial Intelligent based technique is efficient in the Loss of Excitation faults (LOE) detection process and the obtained results are very promising.
Galectin-1 and Galectin-3 Constitute Novel-Binding Partners for Factor VIII
Authors: O’Sullivan Jamie M. , Jenkins P. Vince , Rawley Orla , Gegenbauer Kristina , Chion Alain , Lavin Michelle , Byrne Barry , O’Kennedy Richard , Preston Roger J.S. , Brophy Teresa M. , O’Donnell James S.
Published: March 2016

Objective—

Recent studies have demonstrated that galectin-1 (Gal-1) and galectin-3 (Gal-3) can bind von Willebrand factor and directly modulate von Willebrand factor–dependent early thrombus formation in vivo. Because the glycans expressed on human factor VIII (FVIII) are similar to those of von Willebrand factor, we investigated whether galectins might also bind and modulate the activity of FVIII.

Approach and Results—

Immunosorbant assays and surface plasmon resonance analysis confirmed that Gal-1 and Gal-3 bound purified FVIII with high affinity. Exoglycosidase removal of FVIII N-linked glycans significantly reduced binding to both Gal-1 and Gal-3. Moreover, combined removal of both the N- and O-glycans of FVIII further attenuated Gal-3 binding. Notably, specific digestion of FVIII high-mannose glycans at N239 and N2118 significantly impaired FVIII affinity for Gal-1. Importantly Gal-1, but not Gal-3, bound to free FVIII in the plasma milieu, and significantly inhibited FVIII functional activity. Interestingly, commercial recombinant FVIII (rFVIII) concentrates are manufactured in different cell lines and differ in their glycosylation profiles. Although the biological mechanism has not been defined, recent studies in previously untreated patients with severe hemophilia A reported significant differences in inhibitor development associated with different rFVIII products. Interestingly, Gal-1 and Gal-3 both displayed enhanced affinity for BHK–rFVIII compared with CHO–rFVIII. Furthermore, binding of Gal-1 and Gal-3 to BDD–FVIII was markedly reduced compared with full-length rFVIII.

Conclusions—

We have identified Gal-1 and Gal-3 as novel-binding partners for human FVIII and demonstrated that Gal-1 binding can influence the procoagulant activity of FVIII.
Local Production of Fatty Acid–Binding Protein 4 in Epicardial/Perivascular Fat and Macrophages Is Linked to Coronary Atherosclerosis
Authors: Furuhashi Masato , Fuseya Takahiro , Murata Masaki , Hoshina Kyoko , Ishimura Shutaro , Mita Tomohiro , Watanabe Yuki , Omori Akina , Matsumoto Megumi , Sugaya Takeshi , Oikawa Tsuyoshi , Nishida Junichi , Kokubu Nobuaki , Tanaka Marenao , Moniwa Norihito , Yoshida Hideaki , Sawada Norimasa , Shimamoto Kazuaki , Miura Tetsuji
Published: March 2016

Objective—

Fatty acid–binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically investigated roles of FABP4 in the development of coronary artery atherosclerosis.

Approach and Results—

First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction. Second, we confirmed that FABP4 was secreted from macrophages and adipocytes cultured in vitro. Third, we investigated the effect of exogenous FABP4 on macrophages and human coronary artery–derived smooth muscle cells and endothelial cells in vitro. Treatment of the cells with recombinant FABP4 significantly increased gene expression of inflammatory markers in a dose-dependent manner. Finally, we measured serum FABP4 level in the aortic root (Ao-FABP4) and coronary sinus (CS-FABP4) of 34 patients with suspected or known coronary artery disease. Coronary stenosis score assessed by the modified Gensini score was weakly correlated with CS-FABP4 but was not correlated with Ao-FABP4. A stronger correlation (
r
=0.59,
P
<0.01) was observed for the relationship between coronary stenosis score and coronary veno-arterial difference in FABP4 level, (CS-Ao)-FABP4, indicating local production of FABP4 during coronary circulation in the heart. Multivariate analysis indicated that (CS-Ao)-FABP4 was an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors.

Conclusions—

FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.
LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and Proarteriogenic Reprogramming
Authors: Ren Bin , Best Brad , Ramakrishnan Devi Prasadh , Walcott Brian P. , Storz Peter , Silverstein Roy L.
Published: March 2016

Objective—

CD36 is a scavenger and antiangiogenic receptor that is important in atherothrombotic diseases, diabetes mellitus, cancer, and obesity. Lysophosphatidic acid, a phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by downregulating endothelial
CD36
transcription via protein kinase D1 (PKD-1) signaling. We aimed to understand mechanisms by which lysophosphatidic acid–mediated angiogenic signaling is integrated to regulate
CD36
transcription and endothelial cell function via a nuclear transcriptional complex.

Approach and Results—

Microvascular endothelial cells expressing
CD36
were used for studying angiogenic signaling and
CD36
transcription. Gene transfection and transduction, RT-qPCR, avidin–biotin-conjugated DNA-binding assay, chromatin immunoprecipitation assay, co-immunoprecipitation, proximal ligation assay, and immunofluorescence microscopy showed that lysophosphatidic acid–mediated
CD36
transcriptional repression involved PKD-1 signaling mediated formation of forkhead box protein O1–histone deacetylase 7 complex in the nucleus. Unexpectedly, turning off
CD36
transcription initiated reprogramming microvascular endothelial cells to express ephrin B2, a critical molecular signature involved in angiogenesis and arteriogenesis. Spheroid-based angiogenesis and in vivo Matrigel angiogenesis assays indicated that angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. A mouse tumor angiogenesis model revealed enhanced PKD-1 signaling and expression of ephrin B2 and smooth muscle actin in neovessels of Lewis Lung Carcinomas, along with low-CD36 expression or
CD36
deficiency.

Conclusions—

Lysophosphatidic acid/PKD-1 signaling leads to nuclear accumulation of histone deacetylase 7, where it interacts with forkhead box protein O1 to suppress endothelial
CD36
transcription and mediates silencing of antiangiogenic switch, resulting in proangiogenic and proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for ischemic cardiovascular disease and cancer.
Common and Rare Genetic Variation in
CCR2
,
CCR5
, or
CX3CR1
and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits
Authors: Golbus Jessica R. , Stitziel Nathan O. , Zhao Wei , Xue Chenyi , Farrall Martin , McPherson Ruth , Erdmann Jeanette , Deloukas Panos , Watkins Hugh , Schunkert Heribert , Samani Nilesh J. , Saleheen Danish , Kathiresan Sekar , Reilly Muredach P.
Published: March 2016

Background—

The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits.

Methods and Results—

We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in
CCR2
,
CCR5
, or
CX3CR1
with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including
CX3CR1
V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus.

Conclusions—

No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.
HIV Infection Itself May Not Be Associated With Subclinical Coronary Artery Disease Among African Americans Without Cardiovascular Symptoms
Authors: Lai Hong , Moore Richard , Celentano David D. , Gerstenblith Gary , Treisman Glenn , Keruly Jeanne C. , Kickler Thomas , Li Ji , Chen Shaoguang , Lai Shenghan , Fishman Elliot K.
Published: March 2016

Background

The key objectives of this study were to examine whether
HIV
infection itself is associated with subclinical coronary atherosclerosis and the potential contributions of cocaine use and antiretroviral therapies (
ART
s) to subclinical coronary artery disease (
CAD
) in
HIV
‐infected persons.

Methods and Results

Between June 2004 and February 2015, 1429 African American (
AA
) adults with/without
HIV
infection in Baltimore, Maryland, were enrolled in an observational study of the effects of
HIV
infection, exposure to
ART
, and cocaine use on subclinical
CAD
. The prevalence of subclinical coronary atherosclerosis was 30.0% in
HIV
‐uninfected and 33.7% in
HIV
‐infected (
P
=0.17). Stratified analyses revealed that compared to
HIV
‐uninfected,
HIV
‐infected
ART
naïve were at significantly lower risk for subclinical coronary atherosclerosis, whereas
HIV
‐infected long‐term
ART
users (≥36 months) were at significantly higher risk. Thus, an overall nonsignificant association between subclinical coronary atherosclerosis and
HIV
was found. Furthermore, compared to those who were
ART
naïve, long‐term
ART
users (≥36 months) were at significantly higher risk for subclinical coronary atherosclerosis in chronic cocaine users, but not in those who never used cocaine. Cocaine use was independently associated with subclinical coronary atherosclerosis.

Conclusions

Overall,
HIV
infection, per se, was not associated with subclinical coronary atherosclerosis in this population. Cocaine use was prevalent in both
HIV
‐infected and ‐uninfected individuals and itself was associated with subclinical disease. In addition, cocaine significantly elevated the risk for
ART
‐associated subclinical coronary atherosclerosis. Treating cocaine addiction must be a high priority for managing
HIV
disease and preventing
HIV
/
ART
‐associated subclinical and clinical
CAD
in individuals with
HIV
infection.