bluuebunny/crossref_metadata_2025 huggingface dataset:
A Simple Sperm DNA Toroid Integrity Test and Risk of Miscarriage
Authors: Chan Philip J. , Orzylowska Eliza M. , Corselli Johannah U. , Jacobson John D. , Wei Albert K.
Published: January 2015

Current methods of analyzing sperm chromatin competency overlook the inner sperm compartment which is inaccessible to probes and reagents. By breaking the molecular protamine disulfide bridges, the DNA toroids are exposed to integrity analysis. The aim was to develop a simple nuclear toroid test and determine its association with fertilization, pregnancy, and miscarriage. The approach involved treating washed sperm remaining after ICSI procedures (N=35cases) with acidified Triton X-100 and dithiothreitol (DTT) before Diff-Quik staining. Percentages of sperm with normal chromatin indicated by light-colored nuclei were assessed. The toroid integrity test showed more sperm with normal chromatin in the pregnant group (73.6 ± 1.7%, mean ± SEM) when compared with the miscarriage (51.2 ± 6.6%) or nonpregnant groups (60.9 ± 4.8%). Furthermore, the toroid results were correlated with ICSI fertilization (R=0.32,P=0.04) and pregnancy outcome (pregnant cases 73.6 ± 1.7% versus nonpregnant 58.0 ± 3.9%,P=0.001). ROC calculated cut-off was >70.0% for normal toroid integrity (sensitivity 0.98, specificity 0.33, and diagnostic accuracy 78.3%). An association between normal sperm toroid integrity and miscarriage was evident when the staining procedure included acidified detergent DTT pretreatment.
Recurrent Syncope Attributed to Left Main Coronary Artery Severe Stenosis
Authors: Li Min , Zheng Xinyi , Liu Hua , Liu Yujie
Published: January 2015

Patients with acute coronary syndrome (ACS) rarely manifest as recurrent syncope due to malignant ventricular arrhythmia. We report a case of a 56-year-old Chinese male with complaints of paroxysmal chest burning sensation and distress for 2 weeks as well as loss of consciousness for 3 days. The electrocardiogram (ECG) revealed paroxysmal multimorphologic ventricular tachycardia during attack and normal heart rhythm during intervals. Coronary angiograph showed 90% stenosis in left main coronary artery and 80% stenosis in anterior descending artery. Two stents sized4.0*18 mm and2.75*18 mm were placed at left main coronary artery and anterior descending artery, respectively, during percutaneous coronary intervention (PCI). The patient was discharged and never had ventricular arrhythmia again during a 3-month follow-up since the PCI. This indicated that ventricular tachycardia was correlated with persistent severe myocardial ischemia. Coronary vasospasm was highly suspected to be the reason of the sudden attack and acute exacerbation. PCI is recommended in patients with both severe coronary artery stenosis and ventricular arrhythmia. Removing myocardial ischemia may stop or relieve ventricular arrhythmia and prevent cardiac arrest.
Projective Synchronization of Hyperchaotic Financial Systems
Authors: Zheng Jiming , Du Bingfang
Published: January 2015

Based on a special matrix structure, the projective synchronization control laws of the hyperchaotic financial systems are proposed in this paper. Put a hyperchaotic financial system as the drive system, via transformation of the system state variables, construct its response system, and then design the controller based on the special matrix structure. The given scheme is applied to achieve projective synchronization of the different hyperchaotic financial systems. Numerical experiments demonstrate the effectiveness of the method.
Vitamin D Receptor Gene Polymorphisms and Haplotypes in Hungarian Patients with Idiopathic Inflammatory Myopathy
Authors: Bodoki Levente , Chen Ji-Qing , Zeher Margit , Nagy-Vincze Melinda , Griger Zoltán , Zilahi Erika , Dankó Katalin
Published: January 2015

Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studiedVDR-BsmI,VDR-ApaI,VDR-TaqI, andVDR-FokIpolymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females) and 93 controls (52 females). We did not obtain any significant differences forVDR-FokI,BsmI,ApaI, andTaqIgenotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution ofBB,Bb, andbbgenotypes than female patients, control male individuals, and the entire control group. Distribution ofTT,Tt, andttgenotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were thefbAt,FBaT, andfbAT. Our findings may reveal that there is a significant association:BbandTtgenotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes.
Harmful Effects of Synthetic Surface-Active Detergents against Atopic Dermatitis
Authors: Deguchi Hajime , Aoyama Riho , Takahashi Hideaki , Isobe Yoshinari , Tsutsumi Yutaka
Published: January 2015

We report herein two cases of intractable atopic dermatitis successfully treated by simply avoiding the contact with surface-active detergents in the daily life and living. The detergents were closely related to the exacerbation and remission of the disease. Steroid ointment was no longer used. We discuss that the removal of horny layer lipids by surface-active detergents accelerates the transepidermal water loss and disturbs the barrier function of the epidermis and thus is intimately involved in the pathogenesis of atopic dermatitis.
Pharmacokinetics of Etravirine Combined with Atazanavir/Ritonavir and a Nucleoside Reverse Transcriptase Inhibitor in Antiretroviral Treatment-Experienced, HIV-1-Infected Patients
Authors: Orrell Catherine , Felizarta Franco , Nell André , Kakuda Thomas N. , Lavreys Ludo , Nijs Steven , Tambuyzer Lotke , Van Solingen-Ristea Rodica , Tomaka Frank L.
Published: January 2015

Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between etravirine and atazanavir/ritonavir and safety and efficacy in treatment-experienced, HIV-1-infected patients.Methods. After a two-week lead-in of two nucleoside reverse transcriptase inhibitors (NRTIs) and atazanavir/ritonavir 300/100 mg, 44 patients received etravirine 200 mg bid with one NRTI, plus atazanavir/ritonavir 300/100 mg or 400/100 mg qd (n=22each group) over 48 weeks.Results. At steady-state etravirine with atazanavir/ritonavir 300/100 mg qd or 400/100 mg qd decreased atazanavirCmin⁡by 18% and 9%, respectively, with no change inAUC24 horCmax⁡versus atazanavir/ritonavir 300/100 mg qd alone (Day −1). EtravirineAUC12 hwas 24% higher and 16% lower with atazanavir/ritonavir 300/100 or 400/100 mg qd, respectively, versus historical controls. At Week 48, no significant differences were seen between the atazanavir/ritonavir groups in discontinuations due to adverse events (9.1% each group) and other safety parameters, the proportion of patients with viral load <50 copies/mL (intent-to-treat population, noncompleter = failure) (50.0%, atazanavir/ritonavir 300/100 mg qd versus 45.5%, 400/100 mg qd), and virologic failures (31.8% versus 27.3%, resp.).Conclusions. Etravirine 200 mg bid can be combined with atazanavir/ritonavir 300/100 mg qd and an NRTI in HIV-1-infected, treatment-experienced patients without dose adjustment.
Cascading Failures in Weighted Complex Networks of Transit Systems Based on Coupled Map Lattices
Authors: Huang Ailing , Zhang H. Michael , Guan Wei , Yang Yang , Zong Gaoqin
Published: January 2015

Study on the vulnerability and robustness of urban public transit networks (PTNs) has great implications for PTNs planning and emergency management, particularly considering passengers’ dynamic behaviors. We made a complex weighted network analysis based on passenger flow for Beijing’s bus stop network and multimodal transit network coupled with bus and urban rail systems. The analysis shows that there are small-world or scale-free properties in these two networks, which make them display different robustness under link or node failures. With consideration of the dynamic flow redistribution, we propose a model based on coupled map lattices to analyze the cascading failures of these two weighted networks. We find that the dynamic flow redistribution can significantly improve the tolerance of small-world or scale-free PTN against random faults. Because of the coupling of bus and rail systems, the multimodal network with scale-free topology and flow distribution structures displays an increasing tolerance even against intentional attack; however, its cascade is also much more intense once the failure is triggered. We find some thresholds of topological and flow coupling strength in the spreading process, which can be exploited to develop strategies to control cascade failures.
Nanoscale Bonding between Human Bone and Titanium Surfaces: Osseohybridization
Authors: Kim Jun-Sik , Kang Seok-Man , Seo Kyung-Won , Nahm Kyung-Yen , Chung Kyu-Rhim , Kim Seong-Hun , Ahn Jae-Pyeong
Published: January 2015

Until now, the chemical bonding between titanium and bone has been examined only through a few mechanical detachment tests. Therefore, in this study, a sandblasted and acid-etched titanium mini-implant was removed from a human patient after 2 months of placement in order to identify the chemical integration mechanism for nanoscale osseointegration of titanium implants. To prepare a transmission electron microscopy (TEM) specimen, the natural state was preserved as much as possible by cryofixation and scanning electron microscope/focused ion beam (SEM-FIB) milling without any chemical treatment. High-resolution TEM (HRTEM), energy dispersive X-ray spectroscopy (EDS), and scanning TEM (STEM)/electron energy loss spectroscopic analysis (EELS) were used to investigate the chemical composition and structure at the interface between the titanium and bone tissue. HRTEM and EDS data showed evidence of crystalline hydroxyapatite and intermixing of bone with the oxide layer of the implant. The STEM/EELS experiment provided particularly interesting results: carbon existed in polysaccharides, calcium and phosphorus existed as tricalcium phosphate (TCP), and titanium existed as oxidized titanium. In addition, the oxygen energy loss near edge structures (ELNESs) showed a possibility of the presence of CaTiO3. These STEM/EELS results can be explained by structures either with or without a chemical reaction layer. The possible existence of the osseohybridization area and the form of the carbon suggest that reconsideration of the standard definition of osseointegration is necessary.
Active Vibration Control of an Axially Translating Robot Arm with Rotating-Prismatic Joint Using Self-Sensing Actuator
Authors: Zhao Liang , Hu Zhen-Dong
Published: January 2015

Active vibration control of an axially translating robot arm with rotating-prismatic joint using self-sensing actuator is investigated. The equations of the system are derived by Lagrange’s equation with the assumed mode method. The displacement and velocity control law is used to configure the self-sensing actuator, which provides the active damping and stiffness effect to the structure. The numerical simulations reveal that the tip deflection of the arm can be effectively reduced by the self-sensing actuator. The amplitude of sensor voltage is inversely proportional to the length of axially translating arm. And higher feedback control gain results in lower sensor voltages and vibration amplitudes.
Biofunctionalized Nanofibers UsingArthrospira(Spirulina) Biomass and Biopolymer
Authors: Morais Michele Greque de , Stillings Christopher , Dersch Roland , Rudisile Markus , Pranke Patrícia , Costa Jorge Alberto Vieira , Wendorff Joachim
Published: January 2015

Electrospun nanofibers composed of polymers have been extensively researched because of their scientific and technical applications. Commercially available polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co-valerate (PHB-HV) copolymers are good choices for such nanofibers. We used a highly integrated method, by adjusting the properties of the spinning solutions, where the cyanophyteArthrospira(formallySpirulina) was the single source for nanofiber biofunctionalization. We investigated nanofibers using PHB extracted fromSpirulinaand the bacteriaCupriavidus necatorand compared the nanofibers to those made from commercially available PHB and PHB-HV. Our study assessed nanofiber formation and their selected thermal, mechanical, and optical properties. We found that nanofibers produced fromSpirulinaPHB and biofunctionalized withSpirulinabiomass exhibited properties which were equal to or better than nanofibers made with commercially available PHB or PHB-HV. Our methodology is highly promising for nanofiber production and biofunctionalization and can be used in many industrial and life science applications.
Validation of the Malay Version of the Inventory of Functional Status after Childbirth Questionnaire
Authors: Noor Norhayati Mohd , Aziz Aniza Abd. , Mostapa Mohd Rosmizaki , Awang Zainudin
Published: January 2015

Objective. This study was designed to examine the psychometric properties of Malay version of the Inventory of Functional Status after Childbirth (IFSAC).Design. A cross-sectional study.Materials and Methods. A total of 108 postpartum mothers attending Obstetrics and Gynaecology Clinic, in a tertiary teaching hospital in Malaysia, were involved. Construct validity and internal consistency were performed after the translation, content validity, and face validity process. The data were analyzed using Analysis of Moment Structure version 18 and Statistical Packages for the Social Sciences version 20.Results. The final model consists of four constructs, namely, infant care, personal care, household activities, and social and community activities, with 18 items demonstrating acceptable factor loadings, domain to domain correlation, and best fit (Chi-squared/degree of freedom = 1.678; Tucker-Lewis index = 0.923; comparative fit index = 0.936; and root mean square error of approximation = 0.080). Composite reliability and average variance extracted of the domains ranged from 0.659 to 0.921 and from 0.499 to 0.628, respectively.Conclusion. The study suggested that the four-factor model with 18 items of the Malay version of IFSAC was acceptable to be used to measure functional status after childbirth because it is valid, reliable, and simple.
Ornamental Exterior versus Therapeutic Interior of Madagascar Periwinkle (Catharanthus roseus): The Two Faces of a Versatile Herb
Authors: Nejat Naghmeh , Valdiani Alireza , Cahill David , Tan Yee-How , Maziah Mahmood , Abiri Rambod
Published: January 2015

Catharanthus roseus (L.) known as Madagascar periwinkle (MP) is a legendary medicinal plant mostly because of possessing two invaluable antitumor terpenoid indole alkaloids (TIAs), vincristine and vinblastine. The plant has also high aesthetic value as an evergreen ornamental that yields prolific blooms of splendid colors. The plant possesses yet another unique characteristic as an amiable experimental host for the maintenance of the smallest bacteria found on earth, the phytoplasmas and spiroplasmas, and serves as a model for their study. Botanical information with respect to synonyms, vernacular names, cultivars, floral morphology, and reproduction adds to understanding of the plant while the geography and ecology of periwinkle illustrate the organism’s ubiquity. Good agronomic practices ensure generous propagation of healthy plants that serve as a source of bioactive compounds and multitudinous horticultural applications. The correlation between genetic diversity, variants, and TIA production exists. MP is afflicted with a whole range of diseases that have to be properly managed. The ethnobotanical significance of MP is exemplified by its international usage as a traditional remedy for abundant ailments and not only for cancer. TIAs are present only in micro quantities in the plant and are highly poisonous per se rendering a challenge for researchers to increase yield and reduce toxicity.
Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma
Authors: Mazzocca Antonio , Dituri Francesco , De Santis Flavia , Filannino Addolorata , Lopane Chiara , Betz Regina C. , Li Ying-Yi , Mukaida Naofumi , Winter Peter , Tortorella Cosimo , Giannelli Gianluigi , Sabbà Carlo
Published: January 2015

The aberrant processes driving hepatocellular carcinoma (HCC) are not fully understood. Lysophosphatidic acid receptors (LPAR) are commonly overexpressed in HCC, but their contributions to malignant development are not well established. In this report, we show that aberrant expression of LPAR6 sustains tumorigenesis and growth of HCC. Overexpression of LPAR6 in HCC specimens associated with poor survival in a cohort of 128 patients with HCC. We took a genetic approach to elucidate how LPAR6 sustains the HCC tumorigenic process, including through an expression profiling analysis to identify genes under the control of LPAR6. RNAi-mediated attenuation of LPAR6 impaired HCC tumorigenicity in tumor xenograft assays. Expression profiling and mechanistic analyses identified Pim-3 as a pathophysiologically relevant LPAR6 target gene. In nonmalignant cells where LPAR6 overexpression was sufficient to drive malignant character, Pim-3 was upregulated at the level of transcription initiation through a STAT3-dependent mechanism. A further analysis of HCC clinical specimens validated the connection between overexpression of LPAR6 and Pim-3, high proliferation rates, and poorer survival outcomes. Together, our findings establish LPAR6 as an important theranostic target in HCC tumorigenesis. Cancer Res; 75(3); 532–43. ©2014 AACR.
Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes
Authors: Linnekamp Janneke F. , Wang Xin , Medema Jan Paul , Vermeulen Louis
Published: January 2015

Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in patients. For EGFR-targeted therapy, many mechanisms of resistance have been uncovered, for example, mutations in KRAS and BRAF, and upregulation of alternative receptors. Currently, routine testing for all known modifiers of response is unpractical, and as a result, decision-making for anti-EGFR therapy is still largely based on assessing the mutation status of an individual gene (KRAS). Recently, comprehensive classifications of colorectal cancer have been presented that integrate many of the (epi-)genetic and microenvironmental factors that contribute to colorectal cancer heterogeneity. These classification systems are not only of prognostic value but also predict therapy efficacy, including the response to anti-EGFR agents. Therefore, molecular subtype–based stratification to guide therapeutic decisions is a promising new strategy that might overcome the shortcomings of single gene testing in colorectal cancer as well as in other malignancies. Furthermore, the development of new agents in a disease subtype–specific fashion has the potential to transform drug-discovery studies and generate novel, more effective therapies. Cancer Res; 75(2); 245–9. ©2014 AACR.
Single-Strand DNA-Binding Protein SSB1 Facilitates TERT Recruitment to Telomeres and Maintains Telomere G-Overhangs
Authors: Pandita Raj K. , Chow Tracy T. , Udayakumar Durga , Bain Amanda L. , Cubeddu Liza , Hunt Clayton R. , Shi Wei , Horikoshi Nobuo , Zhao Yong , Wright Woodring E. , Khanna Kum Kum , Shay Jerry W. , Pandita Tej K.
Published: January 2015

Proliferating mammalian stem and cancer cells express telomerase [telomerase reverse transcriptase (TERT)] in an effort to extend chromosomal G-overhangs and maintain telomere ends. Telomerase-expressing cells also have higher levels of the single-stranded DNA-binding protein SSB1, which has a critical role in DNA double-strand break (DSB) repair. Here, we report that SSB1 binds specifically to G-strand telomeric DNA in vitro and associates with telomeres in vivo. SSB1 interacts with the TERT catalytic subunit and regulates its interaction with telomeres. Deletion of SSB1 reduces TERT interaction with telomeres and leads to G-overhang loss. Although SSB1 is recruited to DSB sites, we found no corresponding change in TERT levels at these sites, implying that SSB1–TERT interaction relies upon a specific chromatin structure or context. Our findings offer an explanation for how telomerase is recruited to telomeres to facilitate G-strand DNA extension, a critical step in maintaining telomere ends and cell viability in all cancer cells. Cancer Res; 75(5); 858–69. ©2015 AACR.
Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells from Multiple Myeloma
Authors: Yang Ye , Shi Jumei , Gu Zhimin , Salama Mohamed E. , Das Satyabrata , Wendlandt Erik , Xu Hongwei , Huang Junwei , Tao Yi , Hao Mu , Franqui Reinaldo , Levasseur Dana , Janz Siegfried , Tricot Guido , Zhan Fenghuang
Published: January 2015

Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary samples as surrogate for the elusive multiple myeloma stem cell, we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin–dependent upregulation of key stemness genes (OCT4, SOX2, NANOG, and MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, overexpression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered side population–derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than side population–derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma. Cancer Res; 75(3); 594–604. ©2014 AACR.
Novel Insights into Head and Neck Cancer using Next-Generation “Omic” Technologies
Authors: Sepiashvili Lusia , Bruce Jeff P. , Huang Shao Hui , O'Sullivan Brian , Liu Fei-Fei , Kislinger Thomas
Published: January 2015

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that develops via one of the two primary carcinogenic routes: chemical carcinogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. Human papillomavirus (HPV)–positive (HPV+) and HPV-negative (HPV−) HNSCCs represent distinct clinical entities, with the latter associated with significantly inferior outcome. The biologic basis of these different outcomes is an area of intense investigation; their therapeutic regimens are currently also being reevaluated, which would be significantly facilitated by reliable biomarkers for stratification. With the advent of the omics era and accelerated development of targeted therapies, there are unprecedented opportunities to address the challenges in the management of HNSCC. As summarized herein, side-by-side molecular characterization of HPV+ versus HPV− HNSCC has revealed distinct molecular landscapes, novel prognostic signatures, and potentially targetable biologic pathways. In particular, we focus on the evidence acquired from genome-wide omics pertinent to our understanding of the clinical behavior of HNSCC and on insights into personalized treatment opportunities. Integrating, mining, and validating these data toward clinically meaningful outcomes for patients with HNSCC in conjunction with systematic verification of the functional relevance of these findings are critical steps toward the design of personalized therapies. Cancer Res; 75(3); 480–6. ©2014 AACR.
Antibody-Mediated Delivery of Anti–KRAS-siRNA In Vivo Overcomes Therapy Resistance in Colon Cancer
Authors: Bäumer Sebastian , Bäumer Nicole , Appel Neele , Terheyden Lisa , Fremerey Julia , Schelhaas Sonja , Wardelmann Eva , Buchholz Frank , Berdel Wolfgang E. , Müller-Tidow Carsten
Published: January 2015

Purpose: KRAS mutations are frequent driver mutations in multiple cancers. KRAS mutations also induce anti-EGFR antibody resistance in adenocarcinoma such as colon cancer. The aim of this study was to overcome anti-EGFR antibody resistance by coupling the antibody to KRAS-specific siRNA.

Experimental Design: The anti-EGFR antibody was chemically coupled to siRNA. The resulting complex was tested for antibody binding efficiency, serum stability and ability to deliver siRNA to EGFR-expressing cells. Western blotting, viability, apoptosis, and colony formation assays were performed for efficacy evaluation in vitro. Furthermore, therapeutic activity of the antibody–KRAS-siRNA complexes was examined in in vivo xenograft mouse tumor models.

Results: Antibody–siRNA complexes were targeted and internalized via the EGFR receptor. Upon internalization, target gene expression was strongly and specifically repressed, followed by a reduced proliferation and viability, and induced apoptosis of the cells in vitro. Clonogenic growth of mutant KRAS-bearing cells was suppressed by KRAS-siRNA–anti-EGFR antibody complexes. In xenograft mouse models, anti-EGFR antibody–KRAS-siRNA complexes significantly slowed tumor growth in anti-EGFR–resistant cells.

Conclusions: The coupling of siRNA against KRAS to anti-EGFR antibodies provides a novel therapy approach for KRAS-mutated EGFR-positive cancer cells in vitro and in vivo. These findings provide an innovative approach for cancer-specific siRNA application and for enhanced therapeutic potential of monoclonal antibody therapy and personalized treatment of cancer entities. Clin Cancer Res; 21(6); 1383–94. ©2015 AACR.
Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation
Authors: Bohanes Pierre , Rankin Cathryn J. , Blanke Charles D. , Winder Thomas , Ulrich Cornelia M. , Smalley Stephen R. , Rich Tyvin A. , Martensen James A. , Benson Al B. , Mayer Robert J. , Cripps Christine M. , Danenberg Kathleen , Makar Karen W. , Zhang Wu , Benedetti Jacqueline K. , Lenz Heinz-Josef
Published: January 2015

Purpose: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)–based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy.

Experimental Design: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3–5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004).

Conclusion: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule. Clin Cancer Res; 21(7); 1583–90. ©2015 AACR.
DUSP1 Expression Induced by HDAC1 Inhibition Mediates Gefitinib Sensitivity in Non–Small Cell Lung Cancers
Authors: Lin Yun-Chieh , Lin Yu-Chin , Shih Jin-Yuan , Huang Wei-Jan , Chao Shi-Wei , Chang Yih-Leong , Chen Ching-Chow
Published: January 2015

Purpose: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. Patients with NSCLC with EGFR-activating mutation benefit greatly by gefitinib, an EGFR tyrosine kinase inhibitor. However, acquired resistance limits its clinical use. Histone deacetylases (HDAC) are oncoproteins associated with cancer progression and drug resistance. Here, we disclosed that inhibition of HDAC1 induced protein phosphatase DUSP1 upregulation to overcome gefitinib-acquired resistance.

Experimental Design: The effect of HDAC1 inhibition restored gefitinib sensitivity was assessed by in vitro MTT and apoptotic assays, and in vivo xenograft and orthotopic lung cancer mouse models. Protein phosphatase array was used to detect DUSP1 expression. Immunohistochemical staining and quantitative PCR were used to analyze DUSP1 expression in clinical NSCLC specimens.

Results: Gefitinib-resistant NSCLC cells showed HDAC1 overexpression, and its knockdown sensitized resistant cells to gefitinib in vitro and in preclinical models through DUSP1 expression. Overexpression of DUSP1 in resistant cells restored gefitinib sensitivity by inhibiting EGFR signaling and inducing apoptosis, whereas its knockdown in sensitive cells conferred gefitinib resistance. A novel HDAC inhibitor, WJ-26210-2, in combination with gefitinib upregulated DUSP1 expression to exert in vitro and in vivo synergistic effect on inactivation of EGFR signaling, growth inhibition, and apoptosis. Clinically, high DUSP1 level was correlated with delayed emergence of gefitinib-acquired resistance.

Conclusions: Decreased DUSP1 might be a mechanism responsible for gefitinib resistance, and DUSP1 might be a biomarker for gefitinib efficacy. HDAC1 inhibition–induced DUSP1 upregulation could be a promising strategy to overcome gefitinib-acquired resistance. Clin Cancer Res; 21(2); 428–38. ©2015 AACR.
Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia's Genetic Diversity
Authors: Heidel Florian H. , Arreba-Tutusaus Patricia , Armstrong Scott A. , Fischer Thomas
Published: January 2015

Acute myelogenous leukemia stem cells (AML–LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML–LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML–LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML–LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML–LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease. Clin Cancer Res; 21(2); 240–8. ©2015 AACR.
Sputum microRNA Biomarkers for Identifying Lung Cancer in Indeterminate Solitary Pulmonary Nodules
Authors: Xing Lingxiao , Su Jian , Guarnera Maria A. , Zhang Howard , Cai Ling , Zhou Rixin , Stass Sanford A. , Jiang Feng
Published: January 2015

Purpose: The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPN) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here, we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs.

Experimental Design: Using quantitative RT-PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant (n = 60) or benign SPNs (n = 62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant (n = 67) or benign SPNs (n = 69), and an external testing cohort of 155 patients with either malignant (n = 76) or benign SPNs (n = 79).

Results: In the training set, a panel of three miRNA biomarkers (miRs21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value.

Conclusions: Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed. Clin Cancer Res; 21(2); 484–9. ©2015 AACR.
KEAP1 Genetic Polymorphisms Associate with Breast Cancer Risk and Survival Outcomes
Authors: Hartikainen Jaana M. , Tengström Maria , Winqvist Robert , Jukkola-Vuorinen Arja , Pylkäs Katri , Kosma Veli-Matti , Soini Ylermi , Mannermaa Arto
Published: January 2015

Purpose: Defective oxidative stress response may increase cancer susceptibility. In tumors, these rescue mechanisms may cause chemo- and radioresistance impacting patient outcome. We previously showed that genetic variation in the nuclear factor erythroid 2–related factor 2 (NFE2L2) is associated with breast cancer risk and prognosis. Here we further studied this pathway by investigating Kelch-like ECH-associated protein 1 (KEAP1).

Experimental Design: Five tagging SNPs in the KEAP1 gene were genotyped in 996 breast cancer cases and 880 controls from two Finnish case–control sets. KEAP1 protein expression was studied in 373 invasive breast cancer tumors.

Results: rs34197572 genotype TT was associated with increased risk of breast cancer in the KBCP samples [P = 1.8×10−4; OR, 7.314; confidence interval (CI), 2.185–24.478]. rs11085735 allele A was associated with lower KEAP1 protein expression (P = 0.040; OR,= 3.545) and high nuclear NRF2 expression (P = 0.009; OR, 2.445) and worse survival in all invasive cases (P = 0.023; HR, 1.634). When including treatment data, rs11085735 was associated with recurrence-free survival (RFS; P = 0.020; HR, 1.545) and breast cancer–specific survival (P = 0.016; HR, 1.683) and rs34197572 with overall survival (P = 0.045; HR, 1.304). rs11085735 associated with RFS also among tamoxifen-treated cases (P = 0.003; HR, 3.517). Among radiotherapy-treated cases, overall survival was associated with rs34197572 (P = 0.018; HR, 1.486) and rs8113472 (P = 0.025; HR, 1.455). RFS was associated with rs9676881 (P = 0.024; HR, 1.452) and rs1048290 (P = 0.020; HR, 1.468) among all invasive cases and among estrogen receptor (ER)-positive tamoxifen-treated cases (P = 0.018; HR, 2.407 and P = 0.015; HR, 2.476, respectively).

Conclusions: The present findings suggest that the investigated SNPs have effects related to oxidative stress induced by cancer treatment, supporting involvement of the NRF2/KEAP1 pathway in breast cancer susceptibility and patient outcome. Clin Cancer Res; 21(7); 1591–601. ©2015 AACR.
Interleukin-6 as a Therapeutic Target
Authors: Rossi Jean-François , Lu Zhao-Yang , Jourdan Michel , Klein Bernard
Published: January 2015

Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease. Clin Cancer Res; 21(6); 1248–57. ©2015 AACR.
Clinical and Biological Effects of an Agonist Anti-CD40 Antibody: A Cancer Research UK Phase I Study
Authors: Johnson Peter , Challis Ruth , Chowdhury Ferdousi , Gao Yifang , Harvey Melanie , Geldart Tom , Kerr Paul , Chan Claude , Smith Anna , Steven Neil , Edwards Ceri , Ashton-Key Margaret , Hodges Elisabeth , Tutt Alison , Ottensmeier Christian , Glennie Martin , Williams Anthony
Published: January 2015

Purpose: This phase I study aimed to establish the biologic effects and MTD of the agonistic IgG1 chimeric anti-CD40 antibody ChiLob7/4 in patients (pts) with a range of CD40-expressing solid tumors and diffuse large B-cell lymphoma, resistant to conventional therapy. Potential mechanisms of action for agonistic anti-CD40 include direct cytotoxic effects on tumor cells and conditioning of antigen-presenting cells.

Experimental Design: ChiLob7/4 was given by IV infusion weekly for 4 doses at a range from 0.5 to 240 mg/dose. Validated ELISAs were used to quantify ChiLob7/4 in serum and test for anti-chimeric MAb (HACA) responses. Pharmacodynamic assessments included quantitation of T-cell, natural killer–cell, and B-cell numbers and activation in blood by flow cytometry and a panel of cytokines in plasma by Luminex technology. Planned dose escalation was in cohorts of 3 patients until MTD or biologic effect, defined as reduction of peripheral blood CD19+ B cells to 10% or less of baseline.

Results: Twenty-nine courses of treatment were given to 28 subjects. The MTD was 200 mg × 4, with dose-limiting toxicity of liver transaminase elevations at 240 mg. At 200 mg (range between 2.1 mg/kg and 3.3 mg/kg based on patient body weight), the trough level pretreatment was above 25 μg/mL. Grade 1-2 infusion reactions were seen above the dose of 16 mg, but could be prevented with single-dose corticosteroid premedication. HACA responses were seen after doses between 1.6 mg and 50 mg, but not above this. There were dose-dependent falls in blood B-cell numbers accompanied by reduced expression of CD21, and transient reductions in NK cell numbers with increased CD54 expression from 50 mg upward. MIP-1β and IL12 plasma concentrations rose after doses above 16 mg. Fifteen of 29 treatments were accompanied by disease stabilization for a median 6 months, the longest for 37 months.

Conclusions: ChiLob7/4 can activate B and NK cells at doses that can be administered safely, and should be tested in combination with other antibodies and chemotherapy agents. Clin Cancer Res; 21(6); 1321–8. ©2015 AACR.
Potential Role of pNF-H, a Biomarker of Axonal Damage in the Central Nervous System, as a Predictive Marker of Chemotherapy-Induced Cognitive Impairment
Authors: Natori Akina , Ogata Toru , Sumitani Masahiko , Kogure Takamichi , Yamauchi Teruo , Yamauchi Hideko
Published: January 2015

Purpose: Chemotherapy-induced cognitive impairment (CICI) is a clinically significant problem. Previous studies using magnetic resonance imaging indicated structural changes in the cerebral white matter of patients with CICI. Phosphorylated neurofilament heavy subunit (pNF-H), a major structural protein in axons, was recently reported to be elevated in the serum of patients with some central nervous system disorders. We performed a cross-sectional analysis of neuropsychological test results and serum pNF-H levels in patients undergoing adjuvant chemotherapy for breast cancer. Our hypothesis was that CICI is accompanied by axonal damage that can be detected by elevated serum pNF-H levels.

Experimental Design: Seventy-six patients with early breast cancer in various phases of treatment (naïve to chemotherapy; after one, three, or seven cycles of chemotherapy; or with a history of chemotherapy) were assessed by self-administered neuropsychological tests and a single pNF-H measurement. The χ2 and Mann–Whitney tests were used for statistical analysis.

Results: Increased pNF-H levels were observed in 28.8% of the patients who underwent chemotherapy, but in none of the chemotherapy-naïve patients or patients with a history of chemotherapy. The pNF-H–positive rate increased significantly in proportion to the number of chemotherapy cycles (one cycle, 5.0%; three cycles, 31.6%; seven cycles, 55.0%; P < 0.05). No significant differences in neuropsychological test results were observed among the groups.

Conclusions: The serum pNF-H level in patients undergoing chemotherapy for breast cancer increased in a cumulative dose-dependent manner, suggesting its potential application as a biomarker of neural damage after chemotherapy. Clin Cancer Res; 21(6); 1348–52. ©2015 AACR.
Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78
Authors: Mo Lihong , Bachelder Robin E. , Kennedy Margaret , Chen Po-Han , Chi Jen-Tsan , Berchuck Andrew , Cianciolo George , Pizzo Salvatore V.
Published: January 2015

Patients with ovarian cancer are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane (memGRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied the effects of ascites on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased memGRP78 levels compared with ID8 cells from normal culture. We hypothesized that these ascites-associated memGRP78+ cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that memGRP78+ cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared with memGRP78− cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared with those cultured in medium alone. Moreover, compared with their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: (i) reduce self-renewing ability of murine and human ovarian cancer cells preincubated with ascites and (ii) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that memGRP78 is a logical therapeutic target for late-stage ovarian cancer. Mol Cancer Ther; 14(3); 747–56. ©2015 AACR.
A Combinatory Strategy for Detection of Live CTCs Using Microfiltration and a New Telomerase-Selective Adenovirus
Authors: Ma Yanchun , Hao Sijie , Wang Shuwen , Zhao Yuanjun , Lim Bora , Lei Ming , Spector David J. , El-Deiry Wafik S. , Zheng Si-yang , Zhu Jiyue
Published: January 2015

Circulating tumor cells (CTC) have become an important biomarker for early cancer diagnosis, prognosis, and treatment monitoring. Recently, a replication-competent recombinant adenovirus driven by a human telomerase gene (hTERT) promoter was shown to detect live CTCs in blood samples of patients with cancer. Here, we report a new class of adenoviruses containing regulatory elements that repress the hTERT gene in normal cells. Compared with the virus with only the hTERT core promoter, the new viruses showed better selectivity for replication in cancer cells than in normal cells. In particular, Ad5GTSe, containing three extra copies of a repressor element, displayed a superior tropism for cancer cells among leukocytes and was thus selected for CTC detection in blood samples. To further improve the efficiency and specificity of CTC identification, we tested a combinatory strategy of microfiltration enrichment using flexible micro spring arrays and Ad5GTSe imaging. Our experiments showed that this method efficiently detected both cancer cells spiked into healthy blood and potential CTCs in blood samples of patients with breast and pancreatic cancer, demonstrating its potential as a highly sensitive and reliable system for detection and capture of CTCs of different tumor types. Mol Cancer Ther; 14(3); 835–43. ©2015 AACR.
CD30 Is a Potential Therapeutic Target in Malignant Mesothelioma
Authors: Dabir Snehal , Kresak Adam , Yang Michael , Fu Pingfu , Wildey Gary , Dowlati Afshin
Published: January 2015

CD30 is a cytokine receptor belonging to the TNF superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in nonlymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody–drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by IHC. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with tumor grade, stage, or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment. Mol Cancer Ther; 14(3); 740–6. ©2015 AACR.