bluuebunny/crossref_metadata_2025 huggingface dataset:
Rac1 modulates mammalian lung branching morphogenesis in part through canonical Wnt signaling
Authors: Danopoulos Soula , Krainock Michael , Toubat Omar , Thornton Matthew , Grubbs Brendan , Al Alam Denise
Published: October 2016

Lung branching morphogenesis relies on a number of factors, including proper epithelial cell proliferation and differentiation, cell polarity, and migration. Rac1, a small Rho GTPase, orchestrates a number of these cellular processes, including cell proliferation and differentiation, cellular alignment, and polarization. Furthermore, Rac1 modulates both noncanonical and canonical Wnt signaling, important pathways in lung branching morphogenesis. Culture of embryonic mouse lung explants in the presence of the Rac1 inhibitor (NSC23766) resulted in a dose-dependent decrease in branching. Increased cell death and BrdU uptake were notably seen in the mesenchyme, while no direct effect on the epithelium was observed. Moreover, vasculogenesis was impaired following Rac1 inhibition as shown by decreased Vegfa expression and impaired LacZ staining in Flk1-Lacz reporter mice. Rac1 inhibition decreased Fgf10 expression in conjunction with many of its associated factors. Moreover, using the reporter lines TOPGAL and Axin2-LacZ, there was an evident decrease in canonical Wnt signaling in the explants treated with the Rac1 inhibitor. Activation of canonical Wnt pathway using WNT3a or WNT7b only partially rescued the branching inhibition. Moreover, these results were validated on human explants, where Rac1 inhibition resulted in impaired branching and decreased AXIN2 and FGFR2b expression. We therefore conclude that Rac1 regulates lung branching morphogenesis, in part through canonical Wnt signaling. However, the exact mechanisms by which Rac1 interacts with canonical Wnt in human and mouse lung requires further investigation.
Effects of body position on exercise capacity and pulmonary vascular pressure-flow relationships
Authors: Forton Kevin , Motoji Yoshiki , Deboeck Gael , Faoro Vitalie , Naeije Robert
Published: October 2016

There has been revival of interest in exercise testing of the pulmonary circulation for the diagnosis of pulmonary vascular disease, but there still is uncertainty about body position and the most relevant measurements. Doppler echocardiography pulmonary hemodynamic measurements were performed at progressively increased workloads in 26 healthy adult volunteers in supine, semirecumbent, and upright positions that were randomly assigned at 24-h intervals. Mean pulmonary artery pressure (mPAP) was estimated from the maximum tricuspid regurgitation jet velocity. Cardiac output was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility α-index, the percent change of vessel diameter per millimeter mercury of mPAP, was calculated from multipoint mPAP-cardiac output plots. Body position did not affect maximum oxygen uptake (Vo2max), maximum respiratory exchange ratio, ventilatory equivalent for carbon dioxide, or slope of mPAP-cardiac output relationships, which was on average of 1.5 ± 0.4 mmHg·l−1·min−1. Maximum mPAP, cardiac output, and total pulmonary vascular resistance were, respectively, 34 ± 4 mmHg, 18 ± 3 l/min, and 1.9 ± 0.3 Wood units. However, the semirecumbent position was associated with a 10% decrease in maximum workload. Furthermore, cardiac output-workload or cardiac output-Vo2 relationships were nonlinear and variable. These results suggest that body position does not affect maximum exercise testing of the pulmonary circulation when results are expressed as mPAP-cardiac output or maximum total pulmonary vascular resistance. Maximum workload is decreased in semirecumbent compared with upright exercise. Workload or Vo2 cannot reliably be used as surrogates for cardiac output.
Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery
Authors: Martin Brian J. , McGlory Chris , MacInnis Martin J. , Allison Mary K. , Phillips Stuart M. , Gibala Martin J.
Published: October 2016

We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057–1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 ± 2 yr old; body mass index = 23 ± 4 kg/m2, peak O2 uptake = 38 ± 7 ml·kg−1·min−1; means ± SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U-13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 ± 0.34 vs. 1.48 ± 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 ± 133 vs. PLA = 1,052 ± 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 ± 2,153 vs. 7,039 ± 2,588 µIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 ± 0.16 vs. PLA = 0.43 ± 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 ± 0.14 vs. PLA = 0.44 ± 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans.
Transcriptomic differences in intra-abdominal adipose tissue in extremely obese adolescents with different stages of NAFLD
Authors: Sheldon Ryan D. , Kanosky Kayla M. , Wells Kevin D. , Miles Lili , Perfield James W. , Xanthakos Stavra , Inge Thomas H. , Rector R. Scott
Published: October 2016

Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [ Mage16.9 ± 0.4 yr, body mass index (BMI) z-score 2.7 ± 0.1] undergoing bariatric surgery and liver biopsy categorized into three groups: no steatosis (normal, n = 8), steatosis only ( n = 13), or NASH ( n = 10) by liver histology. Age, body weight, and BMI did not differ among groups, but subjects with NASH were more insulin resistant (increased homeostatic model assessment/insulin resistance, P < 0.05 vs. other groups). RNA-Seq revealed 175 up- and 492 downregulated mRNA transcripts (≥±1.5-fold, false discovery rate <0.10) in IAT between NASH vs. Normal, with “mitochondrial dysfunction, P = 4.19E-7” being the top regulated canonical pathway identified by Ingenuity Pathway Analysis; only 19 mRNA transcripts were up- and 148 downregulated when comparing Steatosis vs. Normal, with suppression of “EIF2 signaling, P = 1.79E-27” being the top regulated pathway indicating increased cellular stress. A comparison of IAT between NASH vs. Steatosis found 515 up- and 175 downregulated genes, with “antigen presentation, P = 6.03E-18” being the top regulated canonical pathway and “inflammatory response” the top diseases and disorders function. Unique transcriptomic differences exist in IAT from severely obese adolescents with distinct stages of NAFLD, providing an important resource for identifying potential novel therapeutic targets for childhood NASH.
Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy
Authors: Widrick Jeffrey J. , Alexander Matthew S. , Sanchez Benjamin , Gibbs Devin E. , Kawahara Genri , Beggs Alan H. , Kunkel Louis M.
Published: October 2016

Sapje zebrafish lack the protein dystrophin and are the smallest vertebrate model of Duchenne muscular dystrophy (DMD). Their small size makes them ideal for large-scale drug discovery screens. However, the extent that sapje mimic the muscle dysfunction of higher vertebrate models of DMD is unclear. We used an optical birefringence assay to differentiate affected dystrophic sapje larvae from their unaffected siblings and then studied trunk muscle contractility at 4–7 days postfertilization. Preparation cross-sectional area (CSA) was similar for affected and unaffected larvae, yet tetanic forces of affected preparations were only 30–60% of normal. ANCOVA indicated that the linear relationship observed between tetanic force and CSA for unaffected preparations was absent in the affected population. Consequently, the average force/CSA of affected larvae was depressed 30–70%. Disproportionate reductions in twitch vs. tetanic force, and a slowing of twitch tension development and relaxation, indicated that the myofibrillar disorganization evident in the birefringence assay could not explain the entire force loss. Single eccentric contractions, in which activated preparations were lengthened 5–10%, resulted in tetanic force deficits in both groups of larvae. However, deficits of affected preparations were three- to fivefold greater at all strains and ages, even after accounting for any recovery. Based on these functional assessments, we conclude that the sapje mutant zebrafish is a phenotypically severe model of DMD. The severe contractile deficits of sapje larvae represent novel physiological endpoints for therapeutic drug screening.
Establishing the involvement of the novel geneAGBL5in retinitis pigmentosa by whole genome sequencing
Authors: Branham Kari , Matsui Hiroko , Biswas Pooja , Guru Aditya A. , Hicks Michael , Suk John J. , Li He , Jakubosky David , Long Tao , Telenti Amalio , Nariai Naoki , Heckenlively John R. , Frazer Kelly A. , Sieving Paul A. , Ayyagari Radha
Published: October 2016

While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40–50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of IRD in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10. Sequence reads were aligned to hg19 using BWA-MEM and variant calling was performed with Genome Analysis Toolkit. The called variants were annotated with SnpEff v4.11, PolyPhen v2.2.2, and CADD v1.3. Copy number variations were called using Genome STRiP (svtoolkit 2.00.1611) and SpeedSeq software. Variants were filtered to detect rare potentially deleterious variants segregating with disease. Candidate variants were validated by dideoxy sequencing. Clinical evaluation revealed typical adolescent-onset recessive retinitis pigmentosa (arRP) in affected members. WGS identified about 4 million variants in each individual. Two rare and potentially deleterious compound heterozygous variants p.Arg281Cys and p.Arg487* were identified in the gene ATP/GTP binding protein like 5 ( AGBL5) as likely causal variants. No additional variants in IRD genes that segregated with disease were identified. Mutation analysis confirmed the segregation of these variants with the IRD in the pedigree. Homology models indicated destabilization of AGBL5 due to the p.Arg281Cys change. Our findings establish the involvement of mutations in AGBL5 in RP and validate the WGS variant filtering pipeline we designed.
Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity
Authors: Lin Sheng-Chieh , Chou Yu-Ting , Jiang Shih Sheng , Chang Junn-Liang , Chung Chih-Hung , Kao Yu-Rung , Chang I-Shou , Wu Cheng-Wen
Published: October 2016

Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM–p21Cip1–cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036–48. ©2016 AACR.
E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia
Authors: Duque-Afonso Jesús , Lin Chiou-Hong , Han Kyuho , Wei Michael C. , Feng Jue , Kurzer Jason H. , Schneidawind Corina , Wong Stephen Hon-Kit , Bassik Michael C. , Cleary Michael L.
Published: October 2016

There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%–7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCγ2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCγ2 and inhibited proliferation of human and mouse preBCR+/E2A-PBX1+ leukemias in vitro and in vivo. Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCγ2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937–49. ©2016 AACR.
Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer
Authors: Parada Humberto , Bradshaw Patrick T. , Engel Lawrence S. , Conway Kathleen , Steck Susan E. , Teitelbaum Susan L. , Neugut Alfred I. , Santella Regina M. , Gammon Marilie D.
Published: October 2016

Background: Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association.

Methods: A population-based cohort of women (N = 1,508) diagnosed with first primary invasive or in situ breast cancer in 1996 to 1997 was interviewed shortly after diagnosis and again approximately 5 years later to assess ETS exposure, and women were followed for more than 18 years using the National Death Index; 597 deaths (237 associated with breast cancer) were identified. Multivariable Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for mortality among women with breast cancer as related to at-diagnosis and at-/postdiagnosis changes in ETS exposure.

Results: There was little or no association between at-diagnosis ETS exposure and all-cause (HR = 1.04; 95% CI, 0.78–1.40) or breast cancer–specific (HR = 0.98; 95% CI, 0.63–1.52) mortality. Mortality was elevated among women who reported cessation in postdiagnosis ETS exposure up to 1 year before the follow-up assessment, for all-cause (HR = 1.81; 95% CI, 0.87–3.74) and breast cancer mortality (HR = 1.89; 95% CI, 0.68–5.24); however, estimates were imprecise.

Conclusions: We found little evidence of an association between at-diagnosis ETS exposure and mortality after breast cancer. Postdiagnosis cessation of ETS exposure was positively associated with mortality, although we could not rule out chance and reverse causation as possible explanations.

Impact: Exposure to ETS does not appear to influence mortality after breast cancer. Cancer Epidemiol Biomarkers Prev; 26(2); 278–80. ©2016 AACR.
Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model
Authors: Lee Gina , Auffinger Brenda , Guo Donna , Hasan Tanwir , Deheeger Marc , Tobias Alex L. , Kim Jeong Yeon , Atashi Fatemeh , Zhang Lingjiao , Lesniak Maciej S. , James C. David , Ahmed Atique U.
Published: October 2016

Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti-glioma chemotherapy, temozolomide. In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single-cell level, glioma stem cell (GSC)-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem-like state and that temozolomide therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy-induced hypoxia-inducible factors (HIF) 1α and HIF2α play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon temozolomide therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. On the basis of our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the glioblastoma multiforme cells that induces the formation of therapy-resistant GSCs responsible for recurrence. Mol Cancer Ther; 15(12); 3064–76. ©2016 AACR.
Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer
Authors: Boukalova Stepana , Stursa Jan , Werner Lukas , Ezrova Zuzana , Cerny Jiri , Bezawork-Geleta Ayenachew , Pecinova Alena , Dong Lanfeng , Drahota Zdenek , Neuzil Jiri
Published: October 2016

Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875–86. ©2016 AACR.
Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer
Authors: Lu Jianfeng , McEachern Donna , Li Shunqiang , Ellis Matthew J. , Wang Shaomeng
Published: October 2016

Endocrine therapy has been highly effective for the treatment of estrogen receptor–positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2–p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models. Both WHIM9 and WHIM18 PDX models exhibit estradiol-independent tumor growth and are resistant to fulvestrant, a highly effective and selective estrogen receptor degrader (SERD). MI-77301 activates wild-type p53 in WHIM9 and WHIM18 cells in vitro and in xenograft tumor tissues in vivo, and it effectively induces upregulation of p21 and cell-cycle arrest in vitro in both models. Although fulvestrant fails to inhibit tumor growth in either of the xenograft models, MI-77301 is highly effective in inhibition of tumor growth at a well-tolerated dose schedule. This study provides a preclinical rationale for evaluation of MI-77301 or other MDM2 inhibitors as a new therapeutic strategy for the treatment of endocrine-resistant breast cancer retaining wild-type p53. Mol Cancer Ther; 15(12); 2887–93. ©2016 AACR.
The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells
Authors: Delgado-Goni Teresa , Miniotis Maria Falck , Wantuch Slawomir , Parkes Harold G. , Marais Richard , Workman Paul , Leach Martin O. , Beloueche-Babari Mounia
Published: October 2016

Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers. 1H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266.4 and SKMEL28) but not BRAFWT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine, and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained. 13C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and anaplerotic pyruvate carboxylase mitochondrial metabolism and decreased lipid synthesis. This metabolic shift was associated with depletion of hexokinase 2, acyl-CoA dehydrogenase 9, 3-phosphoglycerate dehydrogenase, and monocarboxylate transporters (MCT) 1 and 4 in BRAF-mutant but not BRAFWT cells and, interestingly, decreased BRAF-mutant cell dependency on glucose and glutamine for growth. Further, the reduction in MCT1 expression observed led to inhibition of hyperpolarized 13C-pyruvate–lactate exchange, a parameter that is translatable to in vivo imaging studies, in live WM266.4 cells. In conclusion, our data provide new insights into the molecular and metabolic consequences of BRAF inhibition in BRAF-driven human melanoma cells that may have potential for combinatorial therapeutic targeting as well as noninvasive imaging of response. Mol Cancer Ther; 15(12); 2987–99. ©2016 AACR.
Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation
Authors: Lallous Nada , Leblanc Eric , Munuganti Ravi S.N. , Hassona Mohamed D.H. , Nakouzi Nader Al , Awrey Shannon , Morin Helene , Roshan-Moniri Mani , Singh Kriti , Lawn Sam , Yamazaki Takeshi , Adomat Hans H. , Andre Christophe , Daugaard Mads , Young Robert N. , Guns Emma S. Tomlinson , Rennie Paul S. , Cherkasov Artem
Published: October 2016

The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide-resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3–directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936–45. ©2016 AACR.
Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells
Authors: Mukhtar Eiman , Adhami Vaqar Mustafa , Siddiqui Imtiaz Ahmad , Verma Ajit Kumar , Mukhtar Hasan
Published: October 2016

Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration–resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863–74. ©2016 AACR.
Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube
Authors: Eckert Mark A. , Pan Shawn , Hernandez Kyle M. , Loth Rachel M. , Andrade Jorge , Volchenboum Samuel L. , Faber Pieter , Montag Anthony , Lastra Ricardo , Peter Marcus E. , Yamada S. Diane , Lengyel Ernst
Published: October 2016

Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers.

Significance: We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342–51. ©2016 AACR.

See related commentary by Swisher et al., p. 1309.

This article is highlighted in the In This Issue feature, p. 1293
Systolic Blood Pressure on Admission and Mortality in Patients Hospitalized With Acute Heart Failure: Observations From the Gulf Acute Heart Failure Registry
Authors: Al-Lawati Jawad A. , Sulaiman Kadhim J. , Al-Zakwani Ibrahim , Alsheikh-Ali Alawi A. , Panduranga Prashanth , Al-Habib Khalid F. , Al-Suwaidi Jassim , Al-Mahmeed Wael , Al-Faleh Hussam , El-Asfar Abdelfatah , Al-Motarreb Ahmed , Ridha Mustafa , Bulbanat Bassam , Al-Jarallah Mohammed , Bazargani Nooshin , Asaad Nidal , Amin Haitham
Published: October 2016

We investigated the role of systolic blood pressure (SBP) in relation to in-hospital and postdischarge mortality in patients admitted with acute heart failure (AHF). The SBP of 4848 patients aged ≥18 years admitted with AHF was categorized into 5 groups: ≤90, 91 to 119, 120 to 139, 140 to 161, and >161 mm Hg. After adjusting for several confounders, multivariate logistic regression models showed that admission SBP was a significant predictor of mortality among both patients with preserved left ventricular function (defined as left ventricular ejection fraction [LVEF] ≥40%) and patients with left ventricular dysfunction (LVEF <40%). The adjusted odds ratios of in-hospital, 3-month, and 1-year mortality in the lowest SBP groups were 7.06 (95% confidence interval [CI]: 3.28-15.20; P < .001), 2.59 (95% CI: 1.35-4.96; P = .004), and 3.10 (95% CI: 2.04-4.72; P < .001) times the odds in the highest admission group (SBP > 161 mm Hg), respectively. We conclude that low admission SBP is an independent predictor of mortality in patients with AHF. The higher the admission SBP, the better the prognosis, regardless of age or LVEF.
Mean Transaortic Gradient is an Emerging Predictor of Chronic Kidney Disease in Elderly Patients
Authors: Platania Ingrid , Terranova Valentina , Tomasello Salvatore Davide , Boukhris Marouane , Cilia Chiara , Di Marca Salvatore , Pisano Marcella , Mastrosimone Gianluca , Cataudella Emanuela , Stancanelli Benedetta , Malatino Lorenzo
Published: October 2016

Arterial hypertension (AH) is a major risk factor for chronic kidney disease (CKD). However, whether AH maintains this role in the development of CKD in elderly patients with aortic stenosis (AS) or whether transaortic gradient influences CKD remains unclear. Consecutive hospitalized patients were prospectively recruited to evaluate the relationship between AS and CKD. In all patients, transthoracic 2-dimensional echocardiography was performed to evaluate AS; renal function was evaluated using the Chronic Kidney Disease Epidemiology Collaboration formula. A total of 346 patients were included in the study (mean age: 79.5 ± 7.4 years): 104 had diabetes mellitus (DM), 298 had AH, and 59 (moderate: 52; severe: 7) showed AS. After multivariate analysis, age ( P <.01), DM ( P = .02), and mean transaortic gradient ( P = .03), but not AH, were independent predictors of CKD. Both in the presence (n = 59) or absence (n = 287) of AS, the estimated glomerular filtration rate did not differ in patients with (51 ± 24 mL/min/1.73 m2and 59 ± 25 mL/min/1.73 m2, respectively) and those without AH (50 ± 21 mL/min/1.73 m2and 65 ± 24 mL/min/1.73 m2, respectively). In the whole population, for each mm Hg of mean transaortic gradient, the risk of CKD increased by 2.5 times.
Tree-Based Global Model Tests for Polytomous Rasch Models
Authors: Komboz Basil , Strobl Carolin , Zeileis Achim
Published: October 2016

Psychometric measurement models are only valid if measurement invariance holds between test takers of different groups. Global model tests, such as the well-established likelihood ratio (LR) test, are sensitive to violations of measurement invariance, such as differential item functioning and differential step functioning. However, these traditional approaches are only applicable when comparing previously specified reference and focal groups, such as males and females. Here, we propose a new framework for global model tests for polytomous Rasch models based on a model-based recursive partitioning algorithm. With this approach, a priori specification of reference and focal groups is no longer necessary, because they are automatically detected in a data-driven way. The statistical background of the new framework is introduced along with an instructive example. A series of simulation studies illustrates and compares its statistical properties to the well-established LR test. While both the LR test and the new framework are sensitive to differential item functioning and differential step functioning and respect a given significance level regardless of true differences in the ability distributions, the new data-driven approach is more powerful when the group structure is not known a priori—as will usually be the case in practical applications. The usage and interpretation of the new method are illustrated in an empirical application example. A software implementation is freely available in the R system for statistical computing.
A Study of Reverse-Worded Matched Item Pairs Using the Generalized Partial Credit and Nominal Response Models
Authors: Matlock Ki Lynn , Turner Ronna C. , Gitchel W. Dent
Published: October 2016

The generalized partial credit model (GPCM) is often used for polytomous data; however, the nominal response model (NRM) allows for the investigation of how adjacent categories may discriminate differently when items are positively or negatively worded. Ten items from three different self-reported scales were used (anxiety, depression, and perceived stress), and authors wrote an additional item worded in the opposite direction to pair with each original item. Sets of the original and reverse-worded items were administered, and responses were analyzed using the two models. The NRM fit significantly better than the GPCM, and it was able to detect category responses that may not function well. Positively worded items tended to be more discriminating than negatively worded items. For the depression scale, category boundary locations tended to have a larger range for the positively worded items than for the negatively worded items from both models. Some pairs of items functioned comparably when reverse-worded, but others did not. If an examinee responds in an extreme category to an item, the same examinee is not necessarily likely to respond in an extreme category at the opposite end of the rating scale to a similar item worded in the opposite direction. Results of this study may support the use of scales composed of items worded in the same direction, and particularly in the positive direction.
Is the Factor Observed in Investigations on the Item-Position Effect Actually the Difficulty Factor?
Authors: Schweizer Karl , Troche Stefan
Published: October 2016

In confirmatory factor analysis quite similar models of measurement serve the detection of the difficulty factor and the factor due to the item-position effect. The item-position effect refers to the increasing dependency among the responses to successively presented items of a test whereas the difficulty factor is ascribed to the wide range of item difficulties. The similarity of the models of measurement hampers the dissociation of these factors. Since the item-position effect should theoretically be independent of the item difficulties, the statistical ex post manipulation of the difficulties should enable the discrimination of the two types of factors. This method was investigated in two studies. In the first study, Advanced Progressive Matrices (APM) data of 300 participants were investigated. As expected, the factor thought to be due to the item-position effect was observed. In the second study, using data simulated to show the major characteristics of the APM data, the wide range of items with various difficulties was set to zero to reduce the likelihood of detecting the difficulty factor. Despite this reduction, however, the factor now identified as item-position factor, was observed in virtually all simulated datasets.
The Impact of Validity Screening on Associations Between Self-Reports of Bullying Victimization and Student Outcomes
Authors: Jia Yuane , Konold Timothy R. , Cornell Dewey , Huang Francis
Published: October 2016

Self-report surveys are widely used to measure adolescent risk behavior and academic adjustment, with results having an impact on national policy, assessment of school quality, and evaluation of school interventions. However, data obtained from self-reports can be distorted when adolescents intentionally provide inaccurate or careless responses. The current study illustrates the problem of invalid respondents in a sample ( N = 52,012) from 323 high schools that responded to a statewide assessment of school climate. Two approaches for identifying invalid respondents were applied, and contrasts between the valid and invalid responses revealed differences in means, prevalence rates of student adjustment, and associations among reports of bullying victimization and student adjustment outcomes. The results lend additional support for the need to screen for invalid responders in adolescent samples.
New current-feedback operational amplifier-based bandpass shadow filter
Authors: Abuelma’atti Muhammad Taher , Almutairi Naif
Published: October 2016

This article presents a new topology for implementing an electronically tunable bandpass filter using the current-feedback operational amplifier. The electronic tuning of the center frequency of the proposed circuit is achieved using an externally connected voltage amplifier in the feedback path without disturbing the constituents of the filter itself, that is a shadow filter. The proposed circuit can be used for developing an undergraduate experiment which illustrates the operation of bandpass filter and the electronic control of its center frequency using the concept of shadow filter. Experimental results obtained using the AD844 current-feedback operational amplifier are included.
Nanofibrillated cellulose as nanoreinforcement in Portland cement: Thermal, mechanical and microstructural properties
Authors: Mejdoub Roukaya , Hammi Halim , Suñol Joan Josep , Khitouni Mohamed , M‘nif Adel , Boufi Sami
Published: October 2016

Nanofibrillated cellulose from eucalyptus pulp, produced by high-pressure homogenization, was used as cement partial replacement for cement paste at a content ranging from 0% to 0.5% by weight of cement. The effect of the content of nanofibrillated cellulose on porosity, thermal properties, compressive strength and degree of cement hydration was investigated. Results have shown an improvement in the compressive strength by more than 50% with 0.3 wt% of added nanofibrillated cellulose. The porosity was reduced by nanofibrillated cellulose addition, and the greatest result was achieved with mixture incorporating 0.3 wt% nanofibrillated cellulose. The coefficient of thermal expansion and the thermal conductivity measurements, relative to nanofibrillated cellulose-reinforced cement pastes, have pointed out the reinforcement effectiveness of nanofibrillated cellulose. The degree of cement hydration has increased with nanofibrillated cellulose content. This trend was confirmed by X-ray diffraction and Fourier Transform Infrared spectroscopy. These analyses have revealed that the presence of nanofibrillated cellulose promoted the hydration of cement, by producing more portlandite and calcium silicate gel, which is likely the main reason accounting for the strong enhancement in the compressive strength.
Embedded resistive heating in composite scarf repairs
Authors: Ashrafi Mahdi , Smith Brandon P , Devasia Santosh , Tuttle Mark E
Published: October 2016

Composite scarf repairs were cured using heat generated by passing an electrical current through a woven graphite-epoxy prepreg embedded in the bondline. Resistance heating using the embedded prepreg resulted in a more uniform temperature distribution in the bondline while preventing any potential thermal damage to the surface of the scarf repairs. In contrast, conventional surface heating methods such as heat blankets or heat lamps lead to large through thickness thermal gradient that causes non-uniform temperature in the bondline and overheating the outer surface adjacent to the heater. Composite scarf repair specimens were created using the proposed embedded heating approach and through the use of a heat blanket for circular and rectangular scarf configurations. Tensile tests were performed for rectangular scarf specimens, and it was shown that the bond strengths of all specimens were found to be comparable. The proposed embedded curing technique results in bond strengths that equal or exceed those achieved with external heating and avoids overheating the surface of the scarf repairs.
Polymer composite reinforced with nanoparticles produced from graphitic carbon-rich fly ash
Authors: Algarni Abdullah , Salah Numan , Bourchak Mostefa , Jilani Asim , Alshahrie Ahmed , Nahas Mahmoud Nadim
Published: October 2016

Carbon nanotubes and graphene are considered effective reinforcement materials for various polymers because of their superior properties. However, they are expensive and difficult to separate and incorporate individually into matrix systems because of their tendency to exist in clustered form. In this work, carbon nanoparticles produced from graphitic carbon-rich fly ash by high-energy ball milling are evaluated as a reinforcement in a high-performance epoxy matrix system. They were used in various weight fractions ranging from 0.1 to 2 wt.%. The obtained carbon nanoparticles have an average particle size of around 20 nm, while XPS spectrum shows active carbonyl groups on their surfaces. The mechanical tensile properties of the carbon nanoparticles/epoxy nanocomposite, including their Young's modulus, stiffness, and load at fracture, were investigated. Moreover, the effect of ethanol as a dispersion medium was studied. The obtained results indicate that the Young's modulus and load at fracture changed only slightly upon the addition of carbon nanoparticles to the epoxy matrix system. On the other hand, the stiffness was improved by 60% over that of the pure epoxy matrix system. This improvement was obtained at 0.6 wt.% carbon nanoparticle content. The test results indicate that ethanol is effective in modifying the nanocomposite mechanical properties. Additionally, results show that low-cost CNPs might be useful as a reinforcement material for high-stiffness products.
Enhanced interlaminar fracture toughness of carbon fiber/bismaleimide composites via microwave curing
Authors: Zhou Jing , Li Yingguang , Li Nanya , Hao Xiaozhong
Published: October 2016

Carbon fiber-reinforced polymer composites have been widely used in the aerospace industry. However, they are extremely sensitive to crack initiation, propagation and interlaminar delamination which severely reduce their service life. This paper demonstrated that the Mode-I interlaminar fracture toughness could be significantly improved in carbon fiber/bismaleimide composites using a microwave curing process. An increase of about 53.5% in critical load and an increase of approximately 133.5% and 61.2% in fracture toughness and fracture resistance have been achieved, respectively. The microwave manufacturing cycle for composites was cut to 44% of the thermal processing cycle. Dynamic mechanical thermal analysis was performed to investigate the enhanced interfacial strength in microwave-cured composites. The improvement in fracture toughness was attributed to a better interfacial adhesion between resin and fiber, which was investigated by the observation of fracture surfaces with optical microscopes.
Applying Multilevel Modeling to Understand Individual and Cross-Cultural Variations in Attitudes Toward Homosexual People Across 28 European Countries
Authors: Donaldson Candice D. , Handren Lindsay M. , Lac Andrew
Published: October 2016

Individual and cross-cultural factors associated with attitudes toward homosexual people were examined in this study. Using cross-sectional data from the sixth biennial European Social Survey, which represents 36,959 individuals nested within 28 European countries, successive nested models were tested using multilevel modeling (MLM). Results found that attitudes varied cross-culturally as a function of people’s country of residence—this clustering effect was controlled for in all subsequent models. Individual-level predictors (Level 1) of male gender, older age, less education, being an immigrant to one’s residing country, conservative political affiliation, high religiosity, perceptions that politics in one’s country were unfair, low openness to change values, low self-transcendence values, high conservation values, and high self-enhancement values were significantly linked with anti-homosexuality attitudes. At the country level (Level 2), a high emphasis on social conservatism and fewer civil rights for homosexuals was connected with more unfavorable attitudes. Findings indicate main effects of predictors at both levels; however, country-level variables tended to yield stronger coefficients than individual-level factors, highlighting the contributions of macro- and microfactors in simultaneously shaping attitudes toward homosexuality. Beyond these effects, interactions of country- and individual-level variables show political affiliation, religiosity, self-enhancement values as stronger predictors in liberal countries, but openness to change values, younger age, and higher education as stronger predictors in conservative countries. Implications are discussed for understanding the wide continuum of views toward homosexuality across people and countries.