bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of “Deqi” during the Study of Needling “Wang’s Jiaji” Acupoints Treating Spasticity after Stroke
Authors: Li Huanqin , Liu Huilin , Liu Cunzhi , Shi Guangxia , Zhou Wei , Zhao Chengmei , Zhang Tao , Wang Xuefei , Wang Guiling , Zhao Yin , Sun Jingqing , Wang Jing , Wang Linpeng
Published: November 2014

Background. Acupuncture has been shown to reduce spasticity and prevent the onset of spasticity after stroke. The purpose of this study is to assess the effect of “Deqi” during needling “Wang’s Jiaji” acupoints treating spasticity in the early stage of stroke. Methods. This study is a multicenter, prospective, randomized, controlled trial. 238 patients with stroke (<21 days) participated and were randomly allocated to the verum‐acupuncture (n = 121) group or sham‐acupuncture group (n = 117). The verum‐acupuncture group received verum acupuncture required to produce the sense of “Deqi” while the sham‐acupuncture group received sham acupuncture without “Deqi.” Patients in both groups followed the same 30 min acupuncture regimen 5 times per week for a period of 4 weeks. Scales of MAS, FMA, ADL, MBI, NIHSS, SS‐QOL, and MRS were measured at baseline and at 2, 4, and 12 weeks after intervention. Results. Significant differences were observed between two groups. The MRS rating composition has the statistical difference after 4 weeks (P = 0.017). The score of MAS, FMA, Barthel, and SSQOL in verum‐acupuncture group has increased significantly compared with the sham‐acupuncture group after 12 weeks. There was 14% reduction of higher muscle tension in the verum‐acupuncture group. Conclusion. Acupuncture “Wang’s Jiaji” points with sensation of “Deqi” in the early stage may reduce the occurrence and decrease the severity of spasticity after stroke.
Analysis of QTLs Associated with the Rice Quality Related Gene by Double Haploid Populations
Authors: Lee Gyu-Ho , Yun Byung-Wook , Kim Kyung-Min
Published: November 2014

We investigated the growth characteristics and analyzed the physicochemical properties of a doubled haploid population derived from a cross between “Cheongcheong” and “Nagdong” to breed a rice variety that tastes good after cooking and to detect quantitative trait loci (QTLs) associated with the taste of cooked rice. The results showed that these compounds also represent a normal distribution. Correlation analysis of the amylose, protein, and lipid contents indicated that each compound is related to the taste of cooked rice. The QTLs related to amylose content were 4 QTLs, protein content was 2 QTLs, and lipid content was 2 QTLs. Four of the QTLs associated with amylose content were detected on chromosomes 7 and 11. The index of coincidence for the QTLs related to amylose, protein, and lipid content was 70%, respectively. These markers showing high percentage of coincidence can be useful to select desirable lines for rice breeding.
Distribution and Conservation ofDavilla(Dilleniaceae) in Brazilian Atlantic Forest Using Ecological Niche Modeling
Authors: Martins Pereira Ismael , Gomes-Klein Vera Lúcia , Groppo Milton
Published: November 2014

We have modeled the ecological niche for 12 plant species belonging to the genusDavilla(Dilleniaceae) which occur in the Atlantic Forest of Brazil. This group includes endemic species lianas threatened by extinction and is therefore a useful indicator for forest areas requiring conservation. The aims are to compare the distribution and richness of species within the protected areas, assessing the degree of protection and gap analysis of reserves for this group. We used the Maxent algorithm with environmental and occurrence data, and produced geographic distribution maps. The results show that high species richness occurs in forest and coastal forest of Espírito Santo to Bahia states. The endemic species compriseD. flexuosa, D. macrocarpa, D. flexuosa, D. grandifolia, andD. sessilifolia. In the Atlantic Forest of southeastern Brazil, the following endemic species occur:D. tintinnabulataandD. glaziovii, with this latter species being included in the “red list” due habitat loss and predatory extractivism. The indicators of species richness in the coastal region of Bahia correspond with floristic inventories that point to this area having a high biodiversity. Although this region has several protected areas, there are gaps in reserves, which, combined with anthropogenic threats and fragmentation, have caused several problems for biodiversity.
Phytochemical Analysis, Antioxidant Activity, Fatty Acids Composition, and Functional Group Analysis ofHeliotropium bacciferum
Authors: Ahmad Sohail , Ahmad Shabir , Bibi Ahtaram , Ishaq Muhammad Saqib , Afridi Muhammad Siddique , Kanwal Farina , Zakir Muhammad , Fatima Farid
Published: November 2014

Heliotropium bacciferumis paramount in medicinal perspective and belongs to Boraginaceae family. The crude and numerous fractions of leaves, stem, and roots of the plant were investigated for phytochemical analysis and DPPH radical scavenging activity. Phytochemical analysis of crude and fractions of the plant revealed the presence of alkaloids, saponins, tannins, steroids, terpenoids, flavonoids, glycosides, and phenols. The antioxidant (free radical scavenging) activity of various extracts of theHeliotropium bacciferumwas resolute against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical with the avail of UV spectrophotometer at 517 nm. The stock solution (1000 mg/mL) and then several dilutions (50, 100, 150, 200, and 250 mg/mL) of the crude and fractions were prepared. Ascorbic acid was used as a standard. The plant leaves (52.59 ± 0.84 to 90.74 ± 1.00), stem (50.19 ± 0.92 to 89.42 ± 1.10), and roots extracts (49.19 ± 0.52 to 90.01 ± 1.02) divulged magnificent antioxidant activities. For the ascertainment of the fatty acid constituents a gas chromatograph hyphenated to mass spectrometer was used. The essential fatty acids for growth maintenance such as linoleic acid (65.70%), eicosadienoic acid (15.12%), oleic acid (8.72%), and palmitic acid (8.14%) were found in high percentage. The infrared spectra of all extracts of the plant were recorded by IR Prestige-21 FTIR model.
Protective Effect of Selected Medicinal Plants against Hydrogen Peroxide Induced Oxidative Damage on Biological Substrates
Authors: Pai Kotebagilu Namratha , Reddy Palvai Vanitha , Urooj Asna
Published: November 2014

Oxidative stress is developed due to susceptibility of biological substrates to oxidation by generation of free radicals. In degenerative diseases, oxidative stress level can be reduced by antioxidants which neutralize free radicals. Primary objective of this work was to screen four medicinal plants, namely,Andrographis paniculata,Costus speciosus,Canthium parviflorum, andAbrus precatorius, for their antioxidant property using two biological substrates—RBC and microsomes. The antioxidative ability of three solvent extracts, methanol (100% and 80%) and aqueous leaf extracts, was studied at different concentrations by thiobarbituric acid reactive substances method using Fenton’s reagent to induce oxidation in the substrates. The polyphenol and flavonoid content were analyzed to relate with the observed antioxidant effect of the extracts. The phytochemical screening indicated the presence of flavonoids, polyphenols, tannins, andβ-carotene in the samples. In microsomes, 80% methanol extract ofCanthiumandCostusand, in RBC, 80% methanol extract ofCostusshowed highest inhibition of oxidation and correlated well with the polyphenol and flavonoid content. From the results it can be concluded that antioxidants from medicinal plants are capable of inhibiting oxidation in biological systems, suggesting scope for their use as nutraceuticals.
Can Meditation Influence Quality of Life, Depression, and Disease Outcome in Multiple Sclerosis? Findings from a Large International Web-Based Study
Authors: Levin Adam B. , Hadgkiss Emily J. , Weiland Tracey J. , Marck Claudia H. , van der Meer Dania M. , Pereira Naresh G. , Jelinek George A.
Published: November 2014

Objectives. To explore the association between meditation and health related quality of life (HRQOL), depression, fatigue, disability level, relapse rates, and disease activity in a large international sample of people with multiple sclerosis (MS).Methods. Participants were invited to take part in an online survey and answer questions relating to HRQOL, depression, fatigue, disability, relapse rates, and their involvement in meditation practices.Results. Statistically and potentially clinically significant differences between those who meditated once a week or more and participants who never meditated were present for mean mental health composite (MHC) scores, cognitive function scale, and health perception scale. The MHC results remained statistically significant on multivariate regression modelling when covariates were accounted for. Physical health composite (PHC) scores were higher in those that meditated; however, the differences were probably not clinically significant. Among those who meditated, fewer screened positive for depression, but there was no relationship with fatigue or relapse rate. Those with worsened disability levels were more likely to meditate.Discussion. The study reveals a significant association between meditation, lower risk of depression, and improved HRQOL in people with MS.
Tissue Taurine Depletion Alters Metabolic Response to Exercise and Reduces Running Capacity in Mice
Authors: Ito Takashi , Yoshikawa Natsumi , Schaffer Stephen W. , Azuma Junichi
Published: November 2014

Taurine is a sulfur-containing amino acid found in very high concentration in skeletal muscle. Taurine deficient mice engineered by knocking out the taurine transporter gene exhibit skeletal muscle wasting, structural defects, and exercise intolerance. In the present study, we investigated the mechanism underlying the development of metabolic abnormalities and exercise intolerance in muscle of the TauTKO phenotype. Running speed and endurance time of TauTKO mice were lower than those of control mice. Blood lactate level was elevated by >3-fold during treadmill running in TauTKO mice but remained largely unaltered by exercise in WT mice. Blood glucose was cleared faster during treadmill running in TauTKO mice than WT mice. AMP-activated kinase (AMPK)β-2 subunit was reduced in TauTKO muscle concomitant with a reduction inα1 andα2 subunits of AMPK. The level of PPARαand its targets, Gpx3, Cpt2, and Echs1, were also decreased in TauTKO muscle. Collectively, taurine depletion impairs metabolic adaptation to exercise in skeletal muscle, a phenomenon associated with a downregulation of AMPK and diminished NADH utilization by the mitochondrial respiratory chain. These findings suggest a crucial role of taurine in regulating energy metabolism in skeletal muscle of exercising TauTKO mice, changes that contribute to impaired exercise endurance.
B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells
Authors: Herr Ricarda , Köhler Martin , Andrlová Hana , Weinberg Florian , Möller Yvonne , Halbach Sebastian , Lutz Lisa , Mastroianni Justin , Klose Martin , Bittermann Nicola , Kowar Silke , Zeiser Robert , Olayioye Monilola A. , Lassmann Silke , Busch Hauke , Boerries Melanie , Brummer Tilman
Published: November 2014

BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-RafV600E oncoprotein. Doxycyclin-inducible knockdown of endogenous B-RafV600E decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell–cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-RafV600E in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells. Cancer Res; 75(1); 216–29. ©2014 AACR.
Loss of Estrogen-Regulated microRNA Expression Increases HER2 Signaling and Is Prognostic of Poor Outcome in Luminal Breast Cancer
Authors: Bailey Shannon T. , Westerling Thomas , Brown Myles
Published: November 2014

Among the genes regulated by estrogen receptor (ER) are miRNAs that play a role in breast cancer signaling pathways. To determine whether miRNAs are involved in ER-positive breast cancer progression to hormone independence, we profiled the expression of 800 miRNAs in the estrogen-dependent human breast cancer cell line MCF7 and its estrogen-independent derivative MCF7:2A (MCF7:2A) using NanoString. We found 78 miRNAs differentially expressed between the two cell lines, including a cluster comprising let-7c, miR99a, and miR125b, which is encoded in an intron of the long noncoding RNA LINC00478. These miRNAs are ER targets in MCF7 cells, and nearby ER binding and their expression are significantly decreased in MCF7:2A cells. The expression of these miRNAs was interrogated in patient samples profiled in The Cancer Genome Atlas (TCGA). Among luminal tumors, these miRNAs are expressed at higher levels in luminal A versus B tumors. Although their expression is uniformly low in luminal B tumors, they are lost only in a subset of luminal A patients. Interestingly, this subset with low expression of these miRNAs had worse overall survival compared with luminal A patients with high expression. We confirmed that miR125b directly targets HER2 and that let-7c also regulates HER2 protein expression. In addition, HER2 protein expression and activity are negatively correlated with let-7c expression in TCGA. In summary, we identified an ER-regulated miRNA cluster that regulates HER2, is lost with progression to estrogen independence, and may serve as a biomarker of poor outcome in ER+ luminal A breast cancer patients. Cancer Res; 75(2); 436–45. ©2014 AACR.
Changing Inequalities in Cervical Cancer: Modeling the Impact of Vaccine Uptake, Vaccine Herd Effects, and Cervical Cancer Screening in the Post-Vaccination Era
Authors: Malagón Talía , Drolet Mélanie , Boily Marie-Claude , Laprise Jean-François , Brisson Marc
Published: November 2014

Background: Inequalities in cervical cancer may be increased following mass vaccination against the human papillomavirus (HPV) if girls with low vaccine uptake also have low future participation in cervical cancer screening. We evaluated how vaccine uptake distribution affects inequalities in squamous cell carcinoma (SCC) incidence between groups with different screening participation.

Methods: We used an individual-based transmission dynamic model of HPV infection and disease (HPV-ADVISE). Females were stratified by routine screening frequency. We modeled the impact of vaccination on SCC incidence rate differences (absolute inequality) and incidence rate ratios (relative inequality) between women who have routine screening intervals of <5 years (frequently screened), ≥5 years (underscreened), and who are never screened. We compared simulations with uniform vaccine uptake with scenarios with unequal vaccine uptake, in which never and underscreened women have lower vaccine uptake than frequently screened women.

Results: Absolute SCC inequalities between groups with different screening rates were predicted to decrease after vaccination, even when women with the lowest screening participation had the lowest vaccine uptake. Herd effects helped reduce absolute inequalities when vaccine uptake was unequal. Conversely, relative SCC inequalities remained unchanged or increased after vaccination. Results were robust to different overall vaccination coverages and sexual mixing scenarios.

Conclusion: Though mass HPV vaccination is predicted to substantially decrease SCC incidence rates, never screened women will still have the highest disease burden after vaccination.

Impact: To reduce both absolute and relative SCC inequalities, public health initiatives will need to address inequalities in both vaccine uptake and in cervical cancer screening participation. Cancer Epidemiol Biomarkers Prev; 24(1); 276–85. ©2014 AACR.
Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer
Authors: Cristóbal Ion , Rincón Raúl , Manso Rebeca , Caramés Cristina , Zazo Sandra , Madoz-Gúrpide Juan , Rojo Federico , García-Foncillas Jesús
Published: November 2014

Purpose: SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC).

Experimental Design: We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC.

Results: SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P < 0.001) and progression-free survival (7.1 vs. 13.7 months; P < 0.001), and poor response to oxaliplatin-based chemotherapy (P = 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations.

Conclusions: SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720. Clin Cancer Res; 21(2); 347–56. ©2014 AACR.
Podoplanin-Positive Cancer-Associated Fibroblasts in the Tumor Microenvironment Induce Primary Resistance to EGFR-TKIs in Lung Adenocarcinoma with EGFR Mutation
Authors: Yoshida Tatsuya , Ishii Genichiro , Goto Koichi , Neri Shinya , Hashimoto Hiroko , Yoh Kiyotaka , Niho Seiji , Umemura Shigeki , Matsumoto Shingo , Ohmatsu Hironobu , Iida Shinsuke , Niimi Akio , Nagai Kanji , Ohe Yuichiro , Ochiai Atsushi
Published: November 2014

Purpose: The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs.

Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106).

Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P < 0.01).

Conclusions: Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs. Clin Cancer Res; 21(3); 642–51. ©2014 AACR.
A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers
Authors: Lassen Ulrik N. , Meulendijks Didier , Siu Lilian L. , Karanikas Vaios , Mau-Sorensen Morten , Schellens Jan H.M. , Jonker Derek J. , Hansen Aaron R. , Simcox Mary E. , Schostack Kathleen J. , Bottino Dean , Zhong Hua , Roessler Markus , Vega-Harring Suzana M. , Jarutat Tiantom , Geho David , Wang Ka , DeMario Mark , Goss Glenwood D.
Published: November 2014

Purpose: Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand–receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.

Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.

Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.

Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258–66. ©2014 AACR.
Significant Association of Oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients
Authors: Lee Keun-Wook , Lee Sung Sook , Kim Sang-Bae , Sohn Bo Hwa , Lee Hyun-Sung , Jang Hee-Jin , Park Yun-Yong , Kopetz Scott , Kim Sung Soo , Oh Sang Cheul , Lee Ju-Seog
Published: November 2014

Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer.

Experimental Design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment.

Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV colorectal cancer and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03).

Conclusions: Activation of YAP1 is highly associated with poor prognosis for colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab. Clin Cancer Res; 21(2); 357–64. ©2014 AACR.
The NEDD8-Activating Enzyme Inhibitor MLN4924 Disrupts Nucleotide Metabolism and Augments the Efficacy of Cytarabine
Authors: Nawrocki Steffan T. , Kelly Kevin R. , Smith Peter G. , Keaton Mignon , Carraway Hetty , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Carew Jennifer S.
Published: November 2014

Purpose: New therapies are urgently needed for patients with acute myelogenous leukemia (AML). The novel NEDDylation inhibitor MLN4924 (pevonedistat) has demonstrated significant preclinical antileukemic activity and preliminary efficacy in patients with AML in a phase I trial. On the basis of its antimyeloid and DNA-damaging properties, we investigated the ability of MLN4924 to augment conventional cytarabine (ara-C) therapy.

Experimental Design: The effects of MLN4924/ara-C on viability, clonogenic survival, apoptosis, DNA damage, and relevant pharmacodynamic targets were determined. The efficacy and pharmacodynamics of MLN4924/ara-C were assessed in an AML xenograft model.

Results: Cotreatment of AML cell lines and primary patient specimens with MLN4924 and ara-C led to diminished clonogenic survival, increased apoptosis, and synergistic levels of DNA damage. RNAi demonstrated that stabilization of CDT-1, an event previously shown to mediate the DNA-damaging effects of MLN4924, was not a key regulator of sensitivity to the MLN4924/ara-C combination. Global metabolic profiling revealed that MLN4924 disrupts nucleotide metabolism and depletes intracellular nucleotide pools in AML cells. Subsequent experiments showed that MLN4924 promoted increased incorporation of ara-C into the DNA of AML cells. This effect as well as the therapeutic benefit of the MLN4924/ara-C combination was antagonized by supplementation with the nucleotide building block ribose. Coadministration of MLN4924 and ara-C to mice bearing FLT3-ITD+ AML xenografts stably inhibited disease progression and increased DNA damage in vivo.

Conclusions: Our findings provide strong rationale for clinical investigation of the MLN4924/ara-C combination and establish a new link between therapeutic inhibition of NEDDylation and alterations in nucleotide metabolism. Clin Cancer Res; 21(2); 439–47. ©2014 AACR.
Darinaparsin Inhibits Prostate Tumor–Initiating Cells and Du145 Xenografts and Is an Inhibitor of Hedgehog Signaling
Authors: Bansal Nitu , Farley Nadine Johnson , Wu Lisa , Lewis Jonathan , Youssoufian Hagop , Bertino Joseph R.
Published: November 2014

Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumor-initiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G2–M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer. Mol Cancer Ther; 14(1); 23–30. ©2014 AACR.
A Multiplexable, Microfluidic Platform for the Rapid Quantitation of a Biomarker Panel for Early Ovarian Cancer Detection at the Point-of-Care
Authors: Shadfan Basil H. , Simmons Archana R. , Simmons Glennon W. , Ho Andy , Wong Jorge , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: November 2014

Point-of-care (POC) diagnostic platforms have the potential to enable low-cost, large-scale screening. As no single biomarker is shed by all ovarian cancers, multiplexed biomarker panels promise improved sensitivity and specificity to address the unmet need for early detection of ovarian cancer. We have configured the programmable bio-nano-chip (p-BNC)—a multiplexable, microfluidic, modular platform—to quantify a novel multi-marker panel comprising CA125, HE4, MMP-7, and CA72-4. The p-BNC is a bead-based immunoanalyzer system with a credit-card–sized footprint that integrates automated sample metering, bubble and debris removal, reagent storage and waste disposal, permitting POC analysis. Multiplexed p-BNC immunoassays demonstrated high specificity, low cross-reactivity, low limits of detection suitable for early detection, and a short analysis time of 43 minutes. Day-to-day variability, a critical factor for longitudinally monitoring biomarkers, ranged between 5.4% and 10.5%, well below the biologic variation for all four markers. Biomarker concentrations for 31 late-stage sera correlated well (R2 = 0.71 to 0.93 for various biomarkers) with values obtained on the Luminex platform. In a 31 patient cohort encompassing early- and late-stage ovarian cancers along with benign and healthy controls, the multiplexed p-BNC panel was able to distinguish cases from controls with 68.7% sensitivity at 80% specificity. Utility for longitudinal biomarker monitoring was demonstrated with prediagnostic plasma from 2 cases and 4 controls. Taken together, the p-BNC shows strong promise as a diagnostic tool for large-scale screening that takes advantage of faster results and lower costs while leveraging possible improvement in sensitivity and specificity from biomarker panels. Cancer Prev Res; 8(1); 37–48. ©2014 AACR.
Afucosylated Antibodies Increase Activation of FcγRIIIa-Dependent Signaling Components to Intensify Processes Promoting ADCC
Authors: Liu Scot D. , Chalouni Cecile , Young Judy C. , Junttila Teemu T. , Sliwkowski Mark X. , Lowe John B.
Published: November 2014

Antibody-dependent cellular cytotoxicity (ADCC) is a key mechanism by which therapeutic antibodies mediate their antitumor effects. The absence of fucose on the heavy chain of the antibody increases the affinity between the antibody and FcγRIIIa, which results in increased in vitro and in vivo ADCC compared with the fucosylated form. However, the cellular and molecular mechanisms responsible for increased ADCC are unknown. Through a series of biochemical and cellular studies, we find that human natural killer (NK) cells stimulated with afucosylated antibody exhibit enhanced activation of proximal FcγRIIIa signaling and downstream pathways, as well as enhanced cytoskeletal rearrangement and degranulation, relative to stimulation with fucosylated antibody. Furthermore, analysis of the interaction between human NK cells and targets using a high-throughput microscope-based antibody-dependent cytotoxicity assay shows that afucosylated antibodies increase the number of NK cells capable of killing multiple targets and the rate with which targets are killed. We conclude that the increase in affinity between afucosylated antibodies and FcγRIIIa enhances activation of signaling molecules, promoting cytoskeletal rearrangement and degranulation, which, in turn, potentiates the cytotoxic characteristics of NK cells to increase efficiency of ADCC. Cancer Immunol Res; 3(2); 173–83. ©2014 AACR.
Redundant and Cooperative Interactions between TLR5 and NLRC4 in Protective Lung Mucosal Immunity against Pseudomonas aeruginosa
Authors: Tolle Leslie , Yu Fu-shin , Kovach Melissa A. , Ballinger Megan N. , Newstead Michael W. , Zeng Xianying , Nunez Gabriel , Standiford Theodore J.
Published: November 2014

Flagellin is the major structural component of flagella expressed by Pseudomonas aeruginosa (PA) and other bacteria. This protein has been shown to activate the Toll-like receptor TLR5 and the Nod-like receptor Nlrc4/Ipaf, culminating in the expression of innate cytokines and antimicrobial molecules. In this study, we tested the hypothesis that TLR5 and Nlrc4 in combination are required for maximal protective lung innate mucosal immunity against PA. To test this hypothesis, we compared innate immune responses in wild-type (WT) C57B6 mice challenged with PA intratracheally to those observed in mice genetically deficient in TLR5 (TLR5-/-) or Nlrc4 (Nlrc4-/-) alone or in combination (TLR5/Nlrc4-/-). As compared to WT, TLR5-/- and Nlrc4-/- mice, we observed a significant increase in mortality in TLR5/Nlrc4-/- mice, which was associated with a >5,000-fold increase in lung PA colony-forming units and systemic bacterial dissemination. The increased mortality observed in double-deficient mice was not attributable to differences in lung leukocyte influx or lung injury responses. Levels of biologically active IL-1β and IL-18 were reduced in the bronchoalveolar lavage fluid from PA-infected Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, indicating the requirement for Nlrc4-dependent caspase-1 activation. Similarly, decreased production of biologically active IL-1β and activation of caspase-1 was observed in PA-stimulated pulmonary macrophages isolated from Nlrc4-/- and TLR5/Nlrc4-/- but not TLR5-/- mice, whereas the expression of iNOS and the production of NO were significantly reduced in cells from double-mutant but not single-mutant mice. Collectively, our findings indicate that TLR5 and Nlrc4 have both unique and redundant roles in lung antibacterial mucosal immunity, and the absence of both pathogen recognition receptors results in an increase in susceptibility to invasive lung infection.
Papillary Thyroid Cancer in Struma Testis with Malignant Transformation in the Lung Associated with Trisomy 17 Successfully Treated with Total Thyroidectomy and Radioiodine Ablation
Authors: Barakat Shadi , Odem Jamie , Batanian Jacqueline R. , Raza Shahzad , Khan Uzma Z.
Published: November 2014

Background: Struma testis is a rare entity, and there are only few reports on the malignant transformation of a testicular teratoma to papillary thyroid carcinoma in the literature. In this report, we describe the malignant transformation of struma testis with distant lung metastasis associated with trisomy 17 and a coexisting papillary microcarcinoma in the thyroid. Case Report: A 56-year-old man presented after a left orchiectomy for an undescended left testicle. Pathologic examination identified a monodermal teratoma composed of thyroid parenchyma and associated with a 1.7-cm papillary thyroid carcinoma. Further evaluation showed a pulmonary mass on a chest CT scan. Total thyroidectomy revealed a 0.5-mm focus of papillary thyroid cancer, and removal of the lung mass confirmed metastatic papillary thyroid cancer. Array-comparative genomic hybridization of both tumors showed trisomy 17 in the struma testes and the lung metastasis. The patient responded well to radioactive iodine ablation and has no evidence of cancer 3 years later. Conclusion: To our knowledge, this is the first case of papillary thyroid cancer in struma testes metastatic to the lung. It highlights the difficulties in treating these patients. Surgery to remove cancer foci, followed by radioactive iodine ablation, resulted in an excellent response in our patient. Interestingly, trisomy 17, which has so far been observed only in noninvasive thyroid nodules, was associated with pulmonary metastasis in our patient.
Access Site Complications After Peripheral Vascular Interventions
Authors: Ortiz Daniel , Jahangir Arshad , Singh Maharaj , Allaqaband Suhail , Bajwa Tanvir K. , Mewissen Mark W.
Published: November 2014

Background—

Access site hematomas and pseudoaneurysms are the most frequent complications of peripheral vascular intervention (PVI); however, their incidence and risk factors remain unclear.

Methods and Results—

We retrospectively analyzed data from the multicenter Vascular Quality Initiative on 22 226 patients who underwent 27 048 PVI from August 2007 to May 2013. Primary end points included incidence and predictors of access site complications (ASCs), length of postprocedural hospitalization, discharge status, and 30-day and 1-year mortality. ASC complicated 936 procedures (3.5%). Of these, 74.4% were minor complications, 9.7% were moderate requiring transfusion, 5.4% were moderate requiring thrombin injection, and 10.5% were severe requiring surgery. Predictors of ASC were age >75 years, female sex, white race, no prior PVI, nonfemoral arterial access site, >6-Fr sheath size, thrombolytics, arterial dissection, fluoroscopy time >30 minutes, nonuse of vascular closure device, bedridden preoperative ambulatory status, and urgent indication. Mean hospitalization was longer after procedures complicated by ASC (1.2±1.6 versus 1.9±1.9 days; range, 0–7 days;
P
=0.002). Severity of ASC correlated with higher rates of discharge to rehabilitation/nursing facilities compared with home discharge. Patients with severe ASC had higher 30-day mortality (6.1% versus 1.4%;
P
<0.001), and those with moderate ASC requiring transfusion had elevated 1-year mortality (12.1% versus 5.7%;
P
<0.001).

Conclusions—

Several factors independently predict ASC after PVI. Appropriate use of antithrombotic therapies and vascular closure device in patients at increased risk of ASC may improve post-PVI outcomes.
Hospital-Level Variation in Angina and Mortality at 1 Year After Myocardial Infarction
Authors: Vigen Rebecca , Spertus John A. , Maddox Thomas M. , Ho P. Michael , Jones Philip G. , Arnold Suzanne V. , Masoudi Frederick A. , Bradley Steven M.
Published: November 2014

Background—

Despite calls to expand measurement of acute myocardial infarction (AMI) outcomes to include symptom burden, little has been done to describe hospital-level variation in this patient-centered outcome, or its association with mortality. Understanding the relationship between symptoms and longer-term mortality could inform the importance of these outcomes for monitoring quality of care.

Methods and Results—

Among 4316 patients with AMI treated at 24 hospitals participating in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) study, we assessed risk-standardized 1-year symptom burden as measured by the Seattle Angina Questionnaire Angina Frequency Score and mortality attributed to the hospital that provided AMI care. Median odds ratios were used to assess outcome variation and reflect the relative odds of an outcome for 2 patients with identical covariates at different, randomly selected, hospitals. We then evaluated the correlation between hospital-level mortality and angina. Finally, we determined the extent to which variation in mortality and angina was explained by achievement of AMI performance measures. We observed hospital variation in risk-adjusted 1-year mortality (range, 4.9%–8.6%; median odds ratio, 1.30;
P
=0.01) and angina (range, 17.7%–29.4%; median odds ratio, 1.34;
P
<0.001). At the hospital level, mortality and angina at 1 year were weakly correlated (
r
=0.40; 95% confidence interval, 0.00–0.68;
P
=0.05). Accounting for the quality of AMI care did not attenuate variation in risk-adjusted 1-year mortality or angina.

Conclusions—

Symptom burden and mortality vary at the hospital level after AMI and are only weakly correlated. These findings suggest that symptom burden should be considered a separate quality domain that is not well captured by current quality metrics.
Health-Related Quality of Life in Patients With Atrial Fibrillation Treated With Rhythm Control Versus Rate Control
Authors: Ha Andrew C.T. , Breithardt Günter , Camm A. John , Crijns Harry J. , Fitzmaurice Garrett M. , Kowey Peter R. , Le Heuzey Jean-Yves , Naditch-Brûlé Lisa , Prystowsky Eric N. , Schwartz Peter J. , Torp-Pedersen Christian , Weintraub William S. , Dorian Paul
Published: November 2014

Background—

Improving health-related quality of life (HRQoL) is an important treatment goal in the management of patients with atrial fibrillation (AF). Uncertainty exists as to whether patients’ HRQoL differ when treated with medical rhythm control or rate control. We compared HRQoL between patients treated with rhythm control or rate control in a large observational registry of patients with recent-onset AF.

Methods and Results—

In the Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation (RECORD-AF), 2439 patients with recent onset (<1 year) AF completed an AF-specific HRQoL questionnaire, the University of Toronto Atrial Fibrillation Severity Scale. HRQoL was assessed by the AF symptom severity score (0–35, with higher scores reflecting more severe AF-related symptoms) at baseline and 1 year. The minimal clinically important difference was defined as a change of ≥3 points. The primary analysis was based on a propensity score-adjusted longitudinal regression analysis which compared the change in AF symptom severity scores between the 2 groups. Over an average follow-up of 1 year, the AF symptom severity scores improved in both groups (rhythm control: −2.82 point [95% confidence interval, −3.22 to −2.41]; rate control: −2.11 point [95% confidence interval, −2.54 to −1.67];
P
<0.01 for both groups). The magnitude of improvement was higher in the rhythm control group than the rate control group (unadjusted difference: −0.75 point; 95% confidence interval, −1.31 to −0.19;
P
=0.01; propensity score-adjusted difference: −0.71 point; 95% confidence interval, −1.31 to −0.11;
P
=0.02).

Conclusions—

In this observational cohort of recent-onset AF patients, treatment with medical rhythm- or rate control over 1 year was associated with an improvement in HRQoL. The magnitude of HRQoL improvement was minimally higher in patients treated with rhythm control than rate control. However, the overall degree of improvement was not large, and its clinical significance was uncertain.
Endothelin‐1 Induces Myofibrillar Disarray and Contractile Vector Variability in Hypertrophic Cardiomyopathy–Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Tanaka Atsushi , Yuasa Shinsuke , Mearini Giulia , Egashira Toru , Seki Tomohisa , Kodaira Masaki , Kusumoto Dai , Kuroda Yusuke , Okata Shinichiro , Suzuki Tomoyuki , Inohara Taku , Arimura Takuro , Makino Shinji , Kimura Kensuke , Kimura Akinori , Furukawa Tetsushi , Carrier Lucie , Node Koichi , Fukuda Keiichi
Published: November 2014

Background

Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic–environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient‐specific induced pluripotent stem cells (
iPSCs
) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM.

Methods and Results

We generated
iPSC
s from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high‐speed video imaging. The differences between control and HCM
iPSC
‐derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease‐promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy‐promoting factors. Interestingly, endothelin‐1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM
iPSC
‐derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous
Mybpc3
‐targeted knock in mice. High‐speed video imaging with motion vector prediction depicted physiological contractile dynamics in the
iPSC
‐derived cardiomyocytes, which revealed that self‐beating HCM
iPSC
‐derived single cardiomyocytes stimulated by endothelin‐1 showed variable contractile directions.

Conclusions

Interactions between the patient's genetic backgrounds and the environmental factor endothelin‐1 promote the HCM pathological phenotype and contractile variability in the HCM
iPSC
‐derived cardiomyocytes.
Hospital and Demographic Characteristics Associated With Advanced Primary Stroke Center Designation
Authors: McDonald Catherine M. , Cen Steven , Ramirez Lucas , Song Sarah , Saver Jeffrey L. , Mack William J. , Sanossian Nerses
Published: November 2014

Background and Purpose—

Despite evidence that primary stroke center (PSC) certification is associated with improvements in care and outcome, only a minority of hospitals have achieved this certification. We sought to determine hospital-based factors associated with achievement of PSC certification.

Methods—

We used the 2011 American Hospital Association survey and the 2010 national census for population and household data to identify potential hospital and demographic factors influencing certification as a PSC by the Joint Commission, Healthcare Facilities Accreditation Program, and DNV Healthcare.

Results—

Of the 3696 hospitals to complete the survey, 3069 fulfilling study criteria included 908 PSC (31%) and 2161 non-PSC. Independent hospital characteristics associated with PSC certification were Joint Commission accreditation (odds ratio [OR], 3.5; 95% confidence interval [CI], 2.4–5.0), increasing size (per quartile in number of beds; OR, 2.5; 95% CI, 2.1–3.1) and inpatient neurological services (OR, 3.2; 95% CI, 2.4–4.6), number of households per zip code (per 1000 households; OR, 1.1; 95% CI, 1.0–1.2), increasing Hispanic population (by 10% increase; OR, 1.1; 95% CI, 1.0–1.2), and income per household (per $10 000; OR, 1.2; 95% CI, 1.1–1.3). Designation as a sole community provider (OR, 0.22; 0.10–0.47) or governmental hospital control (0.61; 0.44–0.84) was associated with noncertification.

Conclusions—

Less than 1 in 3 hospitals has achieved certification as an PSC. Potential areas of improvement include increasing certification of governmental-controlled hospitals.