bluuebunny/crossref_metadata_2025 huggingface dataset:
Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol
Authors: Tang Xiao-Yi , Sun Yao , Zhang Ang , Hu Guo-Liang , Cao Wei , Wang Dan-Hong , Zhang Bin , Chen Hu
Published: December 2016

Introduction

There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL.

Methods and analysis

This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively. Descriptive and analytical analyses will be performed.

Ethics and dissemination

Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.

Trial registration number

NCT02186860.
Ultrasonography of the prostate gland and testes in dogs
Authors: de Souza Mírley Barbosa , da Silva Lúcia Daniel Machado , Moxon Rachel , Russo Marco , England Gary C. W.
Published: December 2016

Ultrasonographic imaging is an important diagnostic tool because it allows assessment of the shape, size, position, margination and internal architecture of organs, as well as facilitating the study of vascular supply and vascularisation. Recently, there has been considerable development of B‐mode, Doppler and contrast‐enhanced ultrasonography for examination of the reproductive tract of dogs, both for studying normal physiology and in the clinical setting. This article describes the practical examination of the canine prostate gland and testes using a variety of ultrasound techniques, and details the normal appearance and blood flow of these organs as well as changes that may be observed with common reproductive disorders.
TAC-TIC use of tacrolimus-based regimens in lupus nephritis
Authors: Kraaij Tineke , Bredewold Obbo W , Trompet Stella , Huizinga Tom W J , Rabelink Ton J , de Craen Anton J M , Teng Y K Onno
Published: December 2016

Current guidelines do not mention tacrolimus (TAC) as a treatment option and no consensus has been reported on the role of TAC in lupus nephritis (LN). The present study aimed to guide clinical judgement on the use of TAC in patients with LN. A meta-analysis was performed for clinical studies investigating TAC regimens in LN on the basis of treatment target (induction or maintenance), concomitant immunosuppression and quality of the data. 23 clinical studies performed in patients with LN were identified: 6 case series, 9 cohort studies, 2 case-control studies and 6 randomised controlled trials (RCTs). Of the 6 RCTs, 5 RCTs investigated TAC regimens as induction treatment and 1 RCT as maintenance treatment. Five RCTs investigated TAC in combination with steroids and 2 TAC with mycophenolate plus steroids. All RCTs were performed in patients of Asian ethnicity. In a meta-analysis, TAC regimens achieved a significantly higher total response (relative risk (RR) 1.23, 95% CI 1.12 to 1.34, p<0.05) and significantly higher complete response (RR 1.48, 95% CI 1.23 to 1.77, p<0.05). The positive outcome was predominantly defined by the largest RCT investigating TAC with mycophenolate plus steroids. Regarding safety, the occurrence of leucopoenia was significantly lower, while the occurrence of increased creatine was higher. Clinical studies on TAC regimens for LN are limited to patients of Asian ethnicity and hampered by significant heterogeneity. The positive results on clinical efficacy of TAC as induction treatment in LN cannot be extrapolated beyond Asian patients with LN. Therefore, further confirmation in multiethnic, randomised trials is mandatory. Until then, TAC can be considered in selected patients with LN.
Influence of case definition on incidence and outcome of acute coronary syndromes
Authors: Torabi Azam , Cleland John G F , Sherwi Nasser , Atkin Paul , Panahi Hossein , Kilpatrick Eric , Thackray Simon , Hoye Angela , Alamgir Farqad , Goode Kevin , Rigby Alan , Clark Andrew L
Published: December 2016

Objective

Acute coronary syndromes (ACS) are common, but their incidence and outcome might depend greatly on how data are collected. We compared case ascertainment rates for ACS and myocardial infarction (MI) in a single institution using several different strategies.

Methods

The Hull and East Yorkshire Hospitals serve a population of ∼560 000. Patients admitted with ACS to cardiology or general medical wards were identified prospectively by trained nurses during 2005. Patients with a death or discharge code of MI were also identified by the hospital information department and, independently, from Myocardial Infarction National Audit Project (MINAP) records. The hospital laboratory identified all patients with an elevated serum troponin-T (TnT) by contemporary criteria (>0.03 µg/L in 2005).

Results

The prospective survey identified 1731 admissions (1439 patients) with ACS, including 764 admissions (704 patients) with MIs. The hospital information department reported only 552 admissions (544 patients) with MI and only 206 admissions (203 patients) were reported to the MINAP. Using all 3 strategies, 934 admissions (873 patients) for MI were identified, for which TnT was >1 µg/L in 443, 0.04–1.0 µg/L in 435, ≤0.03 µg/L in 19 and not recorded in 37. A further 823 patients had TnT >0.03 µg/L, but did not have ACS ascertained by any survey method. Of the 873 patients with MI, 146 (16.7%) died during admission and 218 (25.0%) by 1 year, but ranging from 9% for patients enrolled in the MINAP to 27% for those identified by the hospital information department.

Conclusions

MINAP and hospital statistics grossly underestimated the incidence of MI managed by our hospital. The 1-year mortality was highly dependent on the method of ascertainment.
Coexistence of abnormal systolic motion of mitral valve in a consecutive group of 324 adult Tetralogy of Fallot patients assessed with echocardiography
Authors: Agarwal Anushree , Harris Ian S , Mahadevan Vaikom S , Foster Elyse
Published: December 2016

Background

The presence of mitral valve prolapse (MVP) in congenital heart disease (CHD) patients is not well described. Tetralogy of Fallot (TOF) is the most common cyanotic CHD associated with overall good long-term survival after palliation. Since MVP is more often identified in adults and TOF patients are now surviving longer, we thus sought to perform this cohort study with a case–control design to (1) determine the prevalence of MVP and systolic displacement of mitral leaflets (SDML) in adult TOF patients, and (2) describe their clinical and imaging characteristics.

Methods

Retrospective interrogation of our echocardiography database identified 328 consecutive TOF patients ≥18 years from 1 January 2000 to 31 December 2014. All images were reviewed to identify patients with concomitant MVP (prolapse >2 mm beyond the long-axis annular plane) or SDML (<2 mm beyond the annular plane).

Results

26 (8%) TOF patients fulfilled criteria for systolic mitral valve abnormality (SMVA) (15 MVP; 11 SDML). 2 had moderate to severe mitral regurgitation requiring repair. When compared with 52 TOF patients without SMVA, those with SMVA were more likely to be females (60.7% vs 33.9%, p=0.03), less likely to have transannular patch (52% vs 97.4%, p<0.0001), had lower right ventricular ejection fraction (36.5% vs 43.8%, p=0.03) and a trend towards increased risk of atrial (44% vs 30.4%, p=0.5) and ventricular arrhythmias (32% vs 25.5%, p=0.6). On multivariate logistic regression, SMVA was independently associated with the absence of transannular patch (p=0.002) and atrial arrhythmias (p=0.04).

Conclusions

In this series of adult TOF patients, we describe a novel finding of a high prevalence of systolic mitral valve abnormalities.
MULTI-CHANNEL CONTAGION IN DYNAMIC INTERBANK MARKET NETWORK
Authors: XU TAO , HE JIANMIN , LI SHOUWEI
Published: December 2016

In this paper, a dynamic interbank market network model based on bank agent behaviors is developed to analyze financial contagion with counter-party and liquidity channels. Afterwards, we analyze the impact of dynamics on the stability of interbank market and find that dynamics of interbank market could enhance the resilience of the network, which suggests contagion might be overestimated in current studies. Moreover, we investigate the mechanism of contagion when counter-party and liquidity channels are both active in the dynamic interbank market network. Specifically, we analyze the effects of bank capitalization, interbank exposures, liquid assets, and bank credit lending preference on the stability of the banking system, respectively. First, we find that liquidity in interbank market and fluctuations of deposits could amplify the negative impact of each other on the resilience of interbank market network. Second, banks with higher capitalization level tend to be more resilient against financial contagion. Third, interbank exposures may have multiple effects on the resilience of interbank market network. Fourth, the resilience of interbank market network is a nonmonotonic function of percentage of liquid assets. Finally, we discover a complex relationship between bank credit lending preference and the resilience of interbank market.
Lyotropic liquid crystalline phthalocyanines containing 4-((S)-3,7-dimethyloctyloxy)phenoxy moieties
Authors: Korkut Sibel Eken , Ocak Hale , Bilgin-Eran Belkıs , Güzeller Dilek , Şener M. Kasım
Published: December 2016

The novel metal free phthalocyanine and its copper complex which are octa-substituted at the peripheral positions with 4-(([Formula: see text]-3,7-dimethlyoctyloxy)phenoxy moieties were synthesized and characterized by FT-IR, 1H NMR and mass spectroscopy. Their mesomorphic properties were studied by polarizing optical microscopy. The spectroscopic properties and aggregation behaviors of the novel phthalocyanines were also investigated by UV-vis spectroscopy in different solvents with same concentration as well as in a wide range of concentrations of chloroform. Both compounds with chloroform and [Formula: see text]-dodecane clearly show the lyotropic columnar mesophase in a wide temperature range whereas thermotropic liquid crystalline behavior for both compounds is not observed. Both of these novel compounds show no aggregation in toluene, tetrahydrofuran, dichloromethane and chloroform.
MOLECULAR EPIDEMIOLOGY OFCANINE PARVOVIRUS TYPE2A AND 2B AMONG SHELTER DOGS — THE NEW RECOMBINATION IN VIRUS
Authors: Sung Ming-Hua , Chen Tsung-Ming , Yang Yi-Chen , Lu Yuan-Ting , Hsu Man-Yu , Liang Michelle , Chen Kuan-Hua , Chao Day-Yu , Lan Yu-Ching
Published: December 2016

Canine parvovirus type 2 (CPV-2) is a severe enteric pathogen mainly affecting dogs. CPV-2 contains three antigenic variants (2a, 2b, and 2c) that are distributed internationally. Detection and characterization of the currently circulating CPV-2 strains are vital for the understanding of viral evolution, transmission, and the development of methods to control its spreading. Herein, we analyzed the strains in central Taiwan to provide information of local viral evolution, diversity, and epidemiology. Stool and blood samples from 24 dogs and 2 cats were genotyped by PCR amplification of strain-specific VP2 sequence collected during 2011–2013. 60% (16/26) of them were positive and 100% (16/16) of these positive samples were type 2b. Then, the full length VP2 gene was sequenced in 6 CPV-positive samples and a maximum-likelihood phylogenetic tree was constructed using both Taiwan and other strains worldwide. Surprisingly, all Taiwan CPVs showed high relatedness to type 2a. Recombination analysis revealed a recombination of VP2 gene between type 2a and 2b. This study demonstrates a recombination between CPV-2a and 2b in nature that contributes to the genetic diversity and evolution of CPV-2.
The Chess Player who Couldn’t Pass the Salt
Authors: Neville-Neil George
Published: December 2016

The problem inherent in almost all nonspecialist work in AI is that humans actually don’t understand intelligence very well in the first place. Now, computer scientists often think they understand intelligence because they have so often been the "smart" kid, but that’s got very little to do with understanding what intelligence actually is. In the absence of a clear understanding of how the human brain generates and evaluates ideas, which may or may not be a good basis for the concept of intelligence, we have introduced numerous proxies for intelligence, the first of which is game-playing behavior.
Endurance training attenuates the increase in peripheral chemoreflex sensitivity with intermittent hypoxia
Authors: Miller Amanda J. , Sauder Charity L. , Cauffman Aimee E. , Blaha Cheryl A. , Leuenberger Urs A.
Published: December 2016

Patients with heart failure and sleep apnea have greater chemoreflex sensitivity, presumably due to intermittent hypoxia (IH), and this is predictive of mortality. We hypothesized that endurance training would attenuate the effect of IH on peripheral chemoreflex sensitivity in healthy humans. Fifteen young healthy subjects (9 female, 26 ± 1 yr) participated. Between visits, 11 subjects underwent 8 wk of endurance training that included running four times/wk at 80% predicted maximum heart rate and interval training, and four control subjects did not change activity. Chemoreflex sensitivity (the slope of ventilation responses to serial oxygen desaturations), blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were assessed before and after 30 min of IH. Endurance training decreased resting systolic blood pressure (119 ± 3 to 113 ± 3 mmHg; P = 0.027) and heart rate (67 ± 3 to 61 ± 2 beats/min; P = 0.004) but did not alter respiratory parameters at rest ( P > 0.2). Endurance training attenuated the IH-induced increase in chemoreflex sensitivity (pretraining: Δ 0.045 ± 0.026 vs. posttraining: Δ −0.028 ± 0.040 l·min−1·% O2 desaturation−1; P = 0.045). Furthermore, IH increased mean blood pressure and MSNA burst rate before training ( P < 0.05), but IH did not alter these measures after training ( P > 0.2). All measurements were similar in the control subjects at both visits ( P > 0.05). Endurance training attenuates chemoreflex sensitization to IH, which may partially explain the beneficial effects of exercise training in patients with cardiovascular disease.
Seasonal expression of P450arom and estrogen receptors in scented glands of muskrats (Ondatra zibethicus)
Authors: Zhang Haolin , Lu Lu , Zhu Manyu , Zhang Fengwei , Sheng Xia , Yuan Zhengrong , Han Yingying , Watanabe Gen , Taya Kazuyoshi , Weng Qiang
Published: December 2016

Male muskrats have one pair of scented glands that grow and involute annually. To investigate the annual changes in the scented gland, we measured the expressions of aromatase cytochrome P-450 (P450arom) and estrogen receptors (ERs) in the scented glands. P450arom was expressed in glandular cells and epithelial cells in the scented glands during the breeding season, and only in glandular cells during the nonbreeding season. ERα and ERβ were also detected in different types of cells in the scented gland during the breeding and nonbreeding seasons. Both mRNA and protein levels of P450arom, ERα, and ERβ were higher in the scented glandular tissues during the breeding season than those during the nonbreeding season. In addition, small RNA sequencing showed that the predicted targets of the significantly changed microRNAs might be the genes encoding P450arom and ERs. In conclusion, the seasonal changes in the expression of P450arom and ERs may be involved in the regulation of scented gland functions.
Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype
Authors: Malgoyre Alexandra , Chabert Clovis , Tonini Julia , Koulmann Nathalie , Bigard Xavier , Sanchez Hervé
Published: December 2016

We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. Therefore, we used a group of pair-fed rats (reproducing the same caloric restriction, as observed in hypoxic animals), in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration supported by pyruvate and octanoate were unaffected. In contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on carnitine palmitoyltransferase 1 (CPT-1), decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise.

NEW & NOTEWORTHY Affinity for low concentrations of long-chain fatty acids (LCFA) in mitochondria skeletal muscles increases after chronic hypoxia. Combined with a lower respiratory exchange ratio, this suggests facility for fatty acid utilization at rest. This fuel preference is related to caloric restriction in oxidative muscle and to hypoxia in glycolytic one. In contrast, maximal oxidation for LCFA is decreased by chronic hypoxia in glycolytic muscle and can explain glucose dependence at exercise.
Esmolol infusion versus propranolol infusion: effects on heart rate and blood pressure in healthy volunteers
Authors: Muller Matthew D. , Ahmad Tariq Ali , Vargas Pelaez Alvaro F. , Proctor David N. , Bonavia Anthony S. , Luck J. Carter , Maman Stephan R. , Ross Amanda J. , Leuenberger Urs A. , McQuillan Patrick M.
Published: December 2016

Despite its widespread clinical use, the β1-adrenergic receptor antagonist esmolol hydrochloride is not commonly used in human physiology research, and the effective dose of esmolol (compared with the nonselective β-blocker propranolol) is unclear. In four separate studies we used cycle ergometry exercise and infusions of isoproterenol and epinephrine to test the heart rate (HR)-lowering effect of esmolol compared with propranolol and saline in healthy humans. In cohort 1, both esmolol (ΔHR 57 ± 6 beats/min) and propranolol (ΔHR 56 ± 7 beats/min) attenuated exercise tachycardia compared with saline (ΔHR 88 ± 17 beats/min). In cohort 2, we found that the HR response to exercise was similar at 5 min (ΔHR 57 ± 9 beats/min) and 60 min (ΔHR 55 ± 9 beats/min) after initiation of the esmolol maintenance infusion. In cohort 3, we confirmed that the HR-lowering effect of esmolol disappeared 45 min after termination of the maintenance infusion. In cohort 4, changes in femoral blood flow and hematological parameters in response to epinephrine infusion were not different between esmolol and saline infusion, indicating that our esmolol infusion paradigm does not block β2-receptors. Collectively, our data indicate that infusion of ~160 mg of esmolol (range 110-200 mg in the 5 min before exercise) acutely and selectively blocks β1-receptors in healthy humans. Additionally, β1-receptors remain blocked 60 min later if a maintenance infusion of ~0.2 mg·kg total body mass−1·min−1continues. The current data lay the foundation for future studies to evaluate β1- vs. β2-receptor control of the circulation in humans.

NEW & NOTEWORTHY We used cycle ergometry exercise and infusions of isoproterenol and epinephrine to test the heart rate-lowering effect of esmolol compared with propranolol and saline in healthy humans. Collectively, our data indicate that infusion of ~160 mg of esmolol (range 110-200 mg in the 5 min before exercise) acutely and selectively blocks β1-adrenergic receptors. These infusion parameters can be used in future experiments to evaluate β1- vs. β2-receptor control of the circulation in humans.
Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci
Authors: Reid Brett M. , Permuth Jennifer B. , Chen Y. Ann , Teer Jamie K. , Monteiro Alvaro N.A. , Chen Zhihua , Tyrer Jonathan , Berchuck Andrew , Chenevix-Trench Georgia , Doherty Jennifer A. , Goode Ellen L. , Iverson Edwin S. , Lawrenson Kate , Pearce Celeste L. , Pharoah Paul D. , Phelan Catherine M. , Ramus Susan J. , Rossing Mary Anne , Schildkraut Joellen M. , Cheng Jin Q. , Gayther Simon A. , Sellers Thomas A.
Published: December 2016

Background: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10−8). Most risk SNPs lie within non–protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets.

Methods: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10−5 > P > 5 × 10−8) overlapping lncRNAs.

Results: Of 5,294 EOC-associated SNPs (P < 1.0 × 10−5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10−4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression.

Conclusions: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC.

Impact: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116–25. ©2016 AACR.
RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer
Authors: Liu Yajing , Burness Monika L. , Martin-Trevino Rachel , Guy Joey , Bai Shoumin , Harouaka Ramdane , Brooks Michael D. , Shang Li , Fox Alex , Luther Tahra K. , Davis April , Baker Trenton L. , Colacino Justin , Clouthier Shawn G. , Shao Zhi-ming , Wicha Max S. , Liu Suling
Published: December 2016

Introduction: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)–deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display “cancer stem cell” properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown.

Experimental Design: We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models.

Results: We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1–wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment.

Conclusions: Our data suggest that in both BRCA1-mutant and BRCA1–wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514–22. ©2016 AACR.
Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells
Authors: Rajappa Prajwal , Cobb William S. , Vartanian Emma , Huang Yujie , Daly Laura , Hoffman Caitlin , Zhang Jane , Shen Beiyi , Yanowitch Rachel , Garg Kunal , Cisse Babacar , Haddock Sara , Huse Jason , Pisapia David J. , Chan Timothy A. , Lyden David C. , Bromberg Jacqueline F. , Greenfield Jeffrey P.
Published: December 2016

Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow–derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.

Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).

Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.

Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109–19. ©2016 AACR.
Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial
Authors: Chung Vincent , Mansfield Aaron S. , Braiteh Fadi , Richards Donald , Durivage Henry , Ungerleider Richard S. , Johnson Francis , Kovach John S.
Published: December 2016

Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.

Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design.

Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks.

Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.
Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
Authors: Wheeler Heather E. , Gamazon Eric R. , Frisina Robert D. , Perez-Cervantes Carlos , El Charif Omar , Mapes Brandon , Fossa Sophie D. , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Beard Clair J. , Fung Chunkit , Kollmannsberger Christian , Kim Jeri , Mushiroda Taisei , Kubo Michiaki , Ardeshir-Rouhani-Fard Shirin , Einhorn Lawrence H. , Cox Nancy J. , Dolan M. Eileen , Travis Lois B.
Published: December 2016

Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).

Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.

Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).

Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.
The Different T-cell Receptor Repertoires in Breast Cancer Tumors, Draining Lymph Nodes, and Adjacent Tissues
Authors: Wang Ting , Wang Changxi , Wu Jinghua , He Chenyang , Zhang Wei , Liu Jiayun , Zhang Ruifang , Lv Yonggang , Li Yongping , Zeng Xiaojing , Cao Hongzhi , Zhang Xiuqing , Xu Xun , Huang Chen , Wang Ling , Liu Xiao
Published: December 2016

T lymphocytes infiltrate the microenvironment of breast cancer tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCR) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here, we have analyzed the TCR repertoire of T cells using multiplex PCR and high-throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph nodes of breast cancer patients. T-cell repertoire diversity in tumors was lower than in lymph nodes, but higher than in nontumor tissue, with a preferential use of variable and joining genes. These data are consistent with the hypothesis that most of the T cells in tumors derive from the lymph node, followed by their expansion in tumor tissue. Positive nodes appeared to enhance T-cell infiltration into tumors and T-cell clonal expansion in lymph nodes. Additionally, the similarity in TCR repertoire between tumor and nontumor tissue was significantly higher in luminal-like, rather than basal-like, breast cancer. Our study elucidated the high heterogeneity of the TCR repertoire and provides potential for future improvements in immune-related diagnosis, therapy, and prognosis for breast cancer patients. Cancer Immunol Res; 5(2); 148–56. ©2016 AACR.
Infiltration of CD8 T Cells and Expression of PD-1 and PD-L1 in Synovial Sarcoma
Authors: Nowicki Theodore S. , Akiyama Ryan , Huang Rong Rong , Shintaku I. Peter , Wang Xiaoyan , Tumeh Paul C. , Singh Arun , Chmielowski Bartosz , Denny Christopher , Federman Noah , Ribas Antoni
Published: December 2016

Tumors expressing programmed death ligand 1 (PD-L1) interact with the corresponding negative-signal generating immune receptor on the surface of CD8 T cells, PD-1, thereby suppressing antitumor activity. Therapeutics blocking this interaction have shown promise in various cancers by restoring functional antitumor T-cell activity. We explored the degree of PD-L1, PD-1, and CD8 expression in a retrospective analysis of 29 clinical synovial sarcoma samples. Quantitative immunohistochemistry and multiplex immunofluorescence were used to determine relative quantification of CD8+ and PD-1+ T cells and PD-L1 expression within the intratumor area and the interface between the tumor and the surrounding nontumor tissue (i.e., invasive margin), and colocalization of these factors, respectively. PD-L1, PD-1, and CD8 cell densities in the tumor-invasive margins were significantly higher in the metastatic tumors than the primary tumors (P < 0.01), and PD-L1, PD-1, and CD8 cell densities were all significantly positively correlated with one other (P < 0.0001). PD-1 cell density in the tumor-invasive margin was significantly associated with worse progression-free survival. Multiplex immunofluorescence demonstrated coexpression of PD-1 and CD8 on lymphocytes within the invasive margin, as well as relative proximity between PD-1+ CD8 cells and PD-L1+ tumor cells. Our results provide a preclinical rationale for screening of patients with synovial sarcoma for the colocalization of CD8, PD-1, and PD-L1, which may be a marker for response to PD-1 blockade therapy. Cancer Immunol Res; 5(2); 118–26. ©2016 AACR.
Space Vector and Sinusoidal Pulse Width Modulation of Quasi Z-Source Inverter for Photovoltaic System
Authors: Prakash G. , Subramani C.
Published: December 2016

This paper compares the execution of Sinusoidal Pulse width Modulation (SPWM) and Space Vector Pulse Width Modulation (SVM) methods for a Quasi Z-source inverter (QZSI) is an another topology got from the standard Z-source inverter (ZSI).The QZSI gets each one of the upsides of the ZSI, which can comprehend buck/boost, inversion and power forming in a singular stage with upgraded trustworthiness. In like manner, the proposed QZSI has the novel purposes of enthusiasm of lower part evaluations and unfaltering dc current from the source. The QZSI highlights a broad assortment of voltage expansion which is reasonable for applications in photovoltaic (PV), as a result of the way that the PV cells yield contrasts comprehensively with temperature and daylight based enlightenment. The working qualities of the proposed course of action is analyzed in inconspicuous component and appeared differently in relation to that of the SPWM and SVM. Speculative examination of voltage help and direction methods for the QZSI in PV is explored in this paper. Amusement of the circuit setup for the previously stated equalization procedures have been taken a gander at in MATLAB/Simulation. Besides, the THD examination of both SPVM and SVM is compared.
T-S Fuzzy Observer and Controller of Doubly-Fed Induction Generator
Authors: Abdelmalki Fouad , Ouaaline Najat
Published: December 2016

This paper aims to ensure a stability and observability of doubly fed induction generator DFIG of a wind turbine based on the approach of fuzzy control type T-S PDC (Parallel Distributed Compensation) which determines the control laws by return state and fuzzy observers. First, the fuzzy TS model is used to precisely represent a nonlinear model of DFIG proposed and adopted in this work. Then, the stability analysis is based on the quadratic Lyapunov function to determine the gains that ensure the stability conditions. The fuzzy observer of DFIG is built to estimate non-measurable state vectors and the estimated states converging to the actual statements. The gains of observatory and of stability are obtained by solving a set of linear matrix inequality (LMI). Finally, numerical simulations are performed to verify the theoretical results and demonstrate satisfactory performance.
Backstepping Control of Wind and Photovoltaic Hybrid Renewable Energy System
Authors: El Azzaoui Marouane , Mahmoudi Hassane , Boudaraia Karima
Published: December 2016

This paper deals with the interconnected grid hybrid renewable energy system (HRES). The wind energy conversion system (WECS), is built around a wind turbine coupled to a doubly fed induction generator (DFIG). The stator of DFIG is directly related to the grid and the rotor is connected to the grid through back-to-back power converters. The proposed algorithm combines the nonlinear Backstepping approach and the eld orientation applied to control the DFIG. In a rst step, this technique is applied to the side converter rotor (RSC), to control the electromagnetic torque and reactive power, and secondly, it is applied to the grid side converter (GSC) to control the power exchanged with the grid and regulate the DC bus voltage. The PV energy system is composed by the PV array and the DC-DC boost converter which controlled by the MPPT method to extract the optimal power. Simulations results present the performances in terms of set point tracking, stability, and robustness with respect to the variation in wind speed and irradiation.
BPSK Modulation and Demodulation with Power Line Carrier Communication and GSM Communication for Smart Metering
Authors: Rajanna B V , Lalitha SVNL , Joga Rao Ganta , Shrivastava S K
Published: December 2016

GSM/GPRS and PLC communication are used for Automatic Meter Reading (AMR) applications. These AMR systems have made substantial progress over the recent years in terms of functionality, scalability, performance and openness such that they can perform remote metering applications for very demanding and complex systems. By using BPSK (Binary Phase Shift Keying) modulation with Power Line Carrier Communication, Smart Metering can be done in Rural Smart Micro-grids. The design and Simulation of BPSK Modulation and Demodulation are successfully done by using MATLAB/Simulink software. The advantages of using BPSK modulation over the QPSK modulation and the advantages of PLC Communication over the GSM Communication is identified in this paper.
Defining Control Strategies for Micro Grids Islanded Operation with Maximum Power Point Tracking using a Fuzzy Logic Control Scheme
Authors: Rajanna B V , Joga Rao Ganta , Shrivastava S.K
Published: December 2016

This paper explains about an intelligent control method for the maximum power point tracking (MPPT) of a photo voltaic system with different temperature and insolation conditions. This method uses a fuzzy logic controller applied to a DC-DC converter. The different steps of the design of this controller are presented together with its simulation and the feasibility of control methods to be adopted for the operation of a micro grid when it becomes isolated. Normally, the micro grid operates in interconnected mode with the medium voltage network; however, scheduled or forced isolation can take place. In such conditions, the micro grid must have the ability to operate stably and autonomously. An evaluation of the need of storage devices and load to take off strategies is included in this paper. The MPPT of a photovoltaic system for Micro Grid operaion using a Fuzzy logic control scheme is successfully designed and simulated by using MATLAB/Simulink Software.
Hardware Implementation of Single Phase Power Factor Correction System using Micro-controller
Authors: Kumar Jha Kartikesh , Mahato Bidyut , Prakash Prem , Chandra Jana Kartick
Published: December 2016

Rapid increase of consumers in electronics devices and the use of mains rectification circuits inside these electronic devices is the root cause of mains harmonic distortion. Automatic power factor correction techniques can be applied to the industries, power systems and households to make them stable inturns increases the efficiency of system as well as the apparatus. This paper deals with the hardware design of active power factor correction circuit employing boost converter which is used to boost the DC voltages with a controller based on PID control strategy. The pulses given to power switches by pulse width modulation techniques generated by utilizing micro-controller board, Arduino thus obviating the need of complex hardware circuitry. MATLAB/SIMULINK was used to design and tune the PID controller parameters. The simulation results are matching with the predictions and the same was implemented as hardware. The waveforms various test points and across capacitors were obtained, studied and compared with the theoretical waveforms and are found to be in precise proximity of theoretical waveforms.
Modelling, Impedance Design, and Efficiency Analysis of Battery Assists PV tied Quasi-Z source inverter
Authors: Sathayanarayanan T.K.S , Ramasamy M , Bharatiraja C , Munda JL
Published: December 2016

The photovoltaic (PV) power cohort becoming more and more attractive in modern power systems era to meet out the power demand in the globe. Consequently, the extraction of maximum power and reduced power electronics stuff for PV based power generation system research studies are growing continuously to meet out the large power-scale/high-voltage grid-tie demands. In this junction, to improve the efficiency of the existing PV tied Quasi-Z source inverter (QZSI), in this paper the new attempt has proposed here by connecting two batteries across to the QZ capacitors. When a battery connected across each capacitor, this system can deliver power to the load power when the PV panel outputs a variable power with fluctuations. The battery can be charged or discharged without any extra circuit, because of the unique impedance network of QZSI. New PWM techniques and principles are proposed to control the new energy stored QZSI when applied to the PV power system. They can control the inverter output power and manage the battery power simultaneously. The operating principle and power flow of this system are analysed. The Simulated and experimental results through using the planned 0.2-kW prototype validate the proposed analytic model and the design method. In addition, this paper analyzes all of the functioning states for a QZSI and calculates the power loss.
Development of a Novel Three Phase Grid-Tied Multilevel Inverter Topology
Authors: Shadab Mirza Mohammad , Mallick Mohammad Arifuddin , Tufail Mohammad , Asghar M. S. Jamil
Published: December 2016

The conventional line-commutated ac-to-dc converters/ inverters have square-shaped line current. It contains higher-order harmonics which generates EMI and it causes more heating of the core of distribution or power transformers. PWM based inverters using MOSFET/IGBT have higher switching losses, and the power handling capability and reliability are quite low in comparison to thyristors/ SCR. A thyristor based forced commutated inverters are not suitable for PWM applications due to the problems of commutation circuits. A pure sinusoidal voltage output or waveform with low harmonic contents is most desirable for ac load using dc to ac conversion. This paper presents a new multilevel inverter topology in which three phase ac- to-dc converter circuits are used in inversion mode by controlling the switching angle. Due to natural commutation, no separate circuit is required for synchronization. In this paper simulation and analysis are done for grid-tied three-phase 6-pulse, Two three-phase, 3-pulse and 12-pulse converter. These converters are analysed for different battery voltage and different switching angle combinations in order to reduce the total harmonic distortion (THD). Three-phase harmonic filters are further added to the grid side to reduce the harmonic content in the line current. A comparative study of these converters is also presented in this paper.