bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesoscale Model to Select the Ideal Location for New Vineyard Plantations in the Rioja Qualified Denomination of Origin
Authors: Martínez-Cámara E. , Blanco J. , Jiménez E. , Saenz-Díez J. C. , Rioja J.
Published: October 2014

La Rioja is the region where the top rated wines from Spain come from and also the origin of one of the most prestigious wines in the world. It is worldwide recognized, not only for the quality of the vine, but also for the many factors involved in the process that are controllable by the farmer, such as fertilizers, irrigation, etc. Likewise, there are other key factors, which cannot be controlled that play, however, a crucial role in the quality of the wine, such as temperature, radiation, humidity, and rainfall. This research is focused on two of these factors: temperature and irradiation. The objective of this paper is to be able to recognize these factors, so as to ensure a proper decision criterion when selecting the best location for new vineyard plantations. To achieve this objective, a mesoscale model MM5 is used, and its performance is assessed and compared using different parameters, from the grid resolution to the physical parameterization of the model. Finally, the study evaluates the impact of the different parameterizations and options for the simulation of meteorological variables particularly relevant when choosing new vineyard sites (rainfall frequency, temperature, and sun exposure).
A Unique Case of Relapsed B-Acute Lymphoblastic Leukemia/Lymphoma as an Isolated Omental Mass
Authors: Kantekure Kanchan , Cossor Furha , Miller Kenneth B. , Pilichowska Monika E.
Published: October 2014

B-acute lymphoblastic leukemia/lymphoma (B-ALL) is a neoplasm of precursor cells committed to the B-cell lineage. Extramedullary involvement is frequent, with particular predilection for the central nervous system, lymph nodes, spleen, liver, and testis. We report an unusual case of B-ALL relapsing as an isolated omental mass along with bone marrow involvement.
Pretransplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin
Authors: Tokodai Kazuaki , Amada Noritoshi , Haga Izumi , Nakamura Atsushi , Kashiwadate Toshiaki , Kawagishi Naoki , Ohuchi Noriaki
Published: October 2014

Aims. To evaluate the predictive power of pretransplant HbA1c for new-onset diabetes after transplantation (NODAT) in kidney transplant candidates, who had several predispositions for fluctuated HbA1c levels.Methods. We performed a retrospective study of 119 patients without diabetes who received kidney transplantation between March 2000 and January 2012. Univariate and multivariate logistic regression analyses were used to investigate the association of several parameters with NODAT. Predictive discrimination of HbA1c was assessed using a receiver-operating characteristic curve.Results. Seventeen patients (14.3%) developed NODAT within 1 year of transplantation. Univariate logistic regression analysis revealed that recipient age, gender, and HbA1c were predictors of NODAT. In the multivariate analysis, the association between pretransplant HbA1c and NODAT development did not reach statistical significance (P=0.07). To avoid the strong influence of high-dose erythropoietin on HbA1c levels, we performed subgroup analyses on 85 patients receiving no or low-dose (≤6000 IU/week) erythropoietin. HbA1c was again an independent predictor for NODAT. Receiver-operating characteristic analysis revealed a cut-off value of 5.2% with an optimal sensitivity of 64% and specificity of 78% for predicting NODAT.Conclusions. Our results reveal that the pretransplant HbA1c level is a useful predictor for NODAT in patients receiving no or low-dose erythropoietin.
Canine Oral Eosinophilic Granuloma Treated with Electrochemotherapy
Authors: Tellado Matías Nicolás , Michinski Sebastián Diego , Olaiz Nahuel , Maglietti Felipe , Marshall Guillermo
Published: October 2014

A case of a canine oral eosinophilic granuloma in a 14-year-old female crossbred is described. The dog was presented with a history of ptyalism, halitosis, local pain, decreased appetite, and blood staining noted on food and water bowls. Clinical, hematologic, and biochemical examinations, abdominal ultrasonography, and 3-view chest radiographs were performed, and no metastases were found. Histopathologic examination of two 6 mm punch biopsies from the oral lesion revealed the presence of eosinophilic granulomatous lesions in the submucosa. After treatment with corticosteroids and wide spectrum antibiotics no significant changes in clinical signs and lesion size were observed. Electrochemotherapy (ECT), a novel tumor treatment routinely used for cutaneous and subcutaneous tumors in human patients in the European Union since 2006, was used to treat the eosinophilic granuloma. The procedure was performed under general anesthesia, followed by intravenous administration of bleomycin. Six weeks after treatment a complete response with disappearance of the mass and improvement of clinical signs were observed.
Mycobacterium ulceransDisease with Unusual Sites Not to Be Ignored
Authors: Abdoulaye Sangaré , Hamdan Kourouma Sarah , Isidore Kouassi Yao , Joseph Ecra Elidjé , Mamadou Kaloga , Patrice Gbery Ildevert
Published: October 2014

Objective. The usual preferential site of BU is in the limbs. In our experience, we noticed atypical and often misleading sites which pose serious issues for the diagnosis and often for the treatment.Methods. This is a retrospective study conducted over a period of ten years of BU treatment at the Department of Dermatology of the University Teaching Hospital of Treichville (Abidjan, Côte d’Ivoire). We included in this study all BU cases with atypical site diagnosed clinically and confirmed either by the histology, by smear, or by PCR.Results. Epidemiologically, the age of patients ranged from 3 to 72 years with a median age of 14.2 years. Children aged less than 15 years were affected in almost 80% of case. The clinical table was dominated by ulcerated forms in 82.1% of cases. The unusual topography mostly observed was that of the torso (thorax, back, and abdomen) in 76.8% of cases.Conclusion. BU is an endemic disease in Côte d’Ivoire where it constitutes a serious public health issue. Several years following its first cases, BU still is little known. This dermatosis may present atypical misleading clinical aspects which must be ignored.
A Clinical Trial to Investigate the Effect of Cynatine HNS on Hair and Nail Parameters
Authors: Beer Christina , Wood Simon , Veghte Robert H.
Published: October 2014

Objective. A new, novel product, Cynatine HNS, was evaluated for its effects as a supplement for improving various aspects of hair and nails in a randomized, double-blind, placebo-controlled clinical trial.Methods. A total of 50 females were included and randomized into two groups. The active group (n=25) received 2 capsules containing Cynatine HNS, comprised of Cynatine brand keratin (500 mg) plus vitamins and minerals, per day, and the placebo group (n=25) received 2 identical capsules of maltodextrin per day for 90 days. End points for hair loss, hair growth, hair strength, amino acid composition, and hair luster were measured. End points were also measured for nail strength and the appearance of nails.Results. The results show that subjects taking Cynatine HNS showed statistically significant improvements in their hair and nails when compared to placebo.Conclusion. Cynatine HNS is an effective supplement for improving hair and nails in 90 days or less. EudraCT number is 2014-002645-22.
Prevalence and Specificity of RBC Alloantibodies in Indian Patients Attending a Tertiary Care Hospital
Authors: Zaman Shamsuz , Chaurasia Rahul , Chatterjee Kabita , Thapliyal Rakesh Mohan
Published: October 2014

Background.Red blood cell (RBC) alloimmunization results from genetic disparity of RBC antigens between donor and recipients. Data about alloimmunization rate in general patient population is scarce especially from resource limited countries. We undertook this study to determine prevalence and specificity of RBC alloantibodies in patients admitted in various clinical specialties at a tertiary care hospital in North India.Methods.Antibody screening was carried out in 11,235 patients on automated QWALYS 3 platform (Diagast, Loos, France). Antibody identification was carried out with an 11-cell identification panel (ID-Diapanel, Diamed GmbH, Switzerland).Results.The overall incidence of RBC alloimmunization in transfused patients was 1.4% (157/11235), with anti-E being the most common specificity (36.3%), followed by anti-D (16%), anti-c (6.4%), anti-c + E (6.4%), anti-C + D (5.1%), and anti-K (4.5%). The highest incidence of alloimmunization was observed in hematology/oncology patients (1.9%), whereas in other specialties the range was 0.7–1%.Conclusion.As alloimmunization complicates the transfusion outcomes, authors recommend pretransfusion antibody screening and issue of Rh and Kell matched blood to patients who warrant high transfusion requirements in future.
A Krukenberg Tumor from an Occult Intramucosal Gastric Carcinoma Identified during an Autopsy
Authors: Nakamura Yoshiaki , Hiramatsu Ayako , Koyama Takafumi , Oyama Yu , Tanaka Ayuko , Honma Koichi
Published: October 2014

A healthy 45-year-old Japanese female developed right pleural effusion, ascites, and a pelvic mass. Bilateral salpingo-oophorectomy resolved the pleural effusion and ascites. Histopathological examination of the ovaries showed bilateral Krukenberg tumors with signet-ring cell carcinoma (SRCC). Extensive testing including upper and lower gastrointestinal endoscopy and whole-body imaging did not detect the primary lesion. Six months after bilateral salpingo-oophorectomy, the patient developed multiple osteoblastic bone lesions in the spine, pelvis, and femurs. A biopsy of the bone marrow showed SRCC. We administered four cycles of S-1 and cisplatin, resulting in the shrinkage of osteoblastic lesions; she remained stable for a year. Then, she developed disseminated intravascular coagulation with disease progression in the bones. Although she was treated with paclitaxel, the disseminated intravascular coagulation progressed, and she died in a month. During the autopsy, microscopic examination revealed four foci of intramucosal gastric SRCC and healthy macroscopic gastric mucosa.
Strong andΔ-Convergence Theorems for Common Fixed Points of a Finite Family of Multivalued Demicontractive Mappings in CAT(0)Spaces
Authors: Chidume C. E. , Bello A. U. , Ndambomve P.
Published: October 2014

LetKbe a nonempty closed and convex subset of a complete CAT(0) space. LetTi:K→CBK,i=1,2,…,m, be a family of multivalued demicontractive mappings such thatF:=⋂i=1mF(Ti)≠∅. A Krasnoselskii-type iterative sequence is shown toΔ-converge to a common fixed point of the familyTi,i=1,2,…,m. Strong convergence theorems are also proved under some additional conditions. Our theorems complement and extend several recent important results on approximation of fixed points of certain nonlinear mappings in CAT(0)spaces. Furthermore, our method of the proof is of special interest.
Adaptive Fuzzy Containment Control for Uncertain Nonlinear Multiagent Systems
Authors: Yu Yang , Jo Kang-Hyun
Published: October 2014

This paper considers the containment control problem for uncertain nonlinear multiagent systems under directed graphs. The followers are governed by nonlinear systems with unknown dynamics while the multiple leaders are neighbors of a subset of the followers. Fuzzy logic systems (FLSs) are used to identify the unknown dynamics and a distributed state feedback containment control protocol is proposed. This result is extended to the output feedback case, where observers are designed to estimate the unmeasurable states. Then, an output feedback containment control scheme is presented. The developed state feedback and output feedback containment controllers guarantee that the states of all followers converge to the convex hull spanned by the dynamic leaders. Based on Lyapunov stability theory, it is proved that the containment control errors are uniformly ultimately bounded (UUB). An example is provided to show the effectiveness of the proposed control method.
Mathematical Analysis of HIV Models with Switching Nonlinear Incidence Functions and Pulse Control
Authors: Wang Xiying , Xu Wei , Cui Yujun , Wang Xiaomei
Published: October 2014

This paper aims to study the dynamics of new HIV (the human immunodeficiency virus) models with switching nonlinear incidence functions and pulse control. Nonlinear incidence functions are first assumed to be time-varying functions and switching functional forms in time, which have more realistic significance to model infectious disease models. New threshold conditions with the periodic switching term are obtained to guarantee eradication of the disease, by using the novel type of common Lyapunov function. Furthermore, pulse vaccination is applied to the above model, and new sufficient conditions for the eradication of the disease are presented in terms of the pulse effect and the switching effect. Finally, several numerical examples are given to show the effectiveness of the proposed results, and future directions are put forward.
Prevalence of Acute Symptoms among Workers in Printing Factories
Authors: Decharat Somsiri
Published: October 2014

Objective.To identify socioeconomic situation factors and behavioral factors associated with the prevalence of acute symptoms among 150 printing workers in 16 printing factories in Southern Thailand.Materials and Methods.A cross-sectional study was conducted by interviewing 150 printing workers in 16 printing factories in Southern Thailand.Results.Acute symptoms comprised dizziness, drowsiness, eye irritation, light-headedness, rhinitis, shortness of breath, cough, chest tightness, nausea/vomiting, exacerbation of asthma, allergic skin reaction, and visual disorder. The prevalence of symptoms was consistently higher among workers in the printing process than among other workers. Smoking cigarettes and drinking alcohol were not associated with an increased prevalence of acute symptoms among these printing-factory workers.Conclusion.The significant associations were found between personal protective equipment and personal hygiene and prevalence of acute symptoms in printing workers.
Nocardia mikamiia Novel Species Causing Disseminated Nocardiosis: A Literature Review of Disseminated Nocardiosis
Authors: Khan Muhammad , Adnan Mohammed Muqeet , Shahbaz Najmi , Hamza Muhammad , Mujeeb Sufyan Abdul
Published: October 2014

Nocardiais an uncommon Gram-positive organism. It typically appears as delicate filamentous Gram-positive branching rods. In the United States it was estimated to be approximately 500 to 1000 new cases per year. The organism causes disease in immunocompromised individuals with pulmonary infection representing the most common site of infection.Nocardia mikamiihas been a recently isolated pathogen and not many cases of disseminated infection with this organism has been reported in the literature; we present a case of disseminated nocardiosis (mikamii sp.) in an immunocompromised patient. We also present a literature review on nocardiosis.
Targeting the c-Met/FZD8 Signaling Axis Eliminates Patient-Derived Cancer Stem–like Cells in Head and Neck Squamous Carcinomas
Authors: Sun Shuyang , Liu Suling , Duan Sheng Zhong , Zhang Lei , Zhou Henghua , Hu Yongjie , Zhou Xianghui , Shi Chaoji , Zhou Rong , Zhang Zhiyuan
Published: October 2014

Cancer stem–like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment. Cancer Res; 74(24); 7546–59. ©2014 AACR.
Nuclear Factor of Activated T-cell Activity Is Associated with Metastatic Capacity in Colon Cancer
Authors: Tripathi Manish K. , Deane Natasha G. , Zhu Jing , An Hanbing , Mima Shinji , Wang Xiaojing , Padmanabhan Sekhar , Shi Zhiao , Prodduturi Naresh , Ciombor Kristen K. , Chen Xi , Washington M. Kay , Zhang Bing , Beauchamp R. Daniel
Published: October 2014

Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis-related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence. Cancer Res; 74(23); 6947–57. ©2014 AACR.
αvβ6 Expression in Myoepithelial Cells: A Novel Marker for Predicting DCIS Progression with Therapeutic Potential
Authors: Allen Michael D. , Marshall John F. , Jones J. Louise
Published: October 2014

The tumor microenvironment dynamically regulates the progression of cancer. In the breast, a unique component of the microenvironment is the myoepithelial cell. Normal myoepithelial cells act as “natural tumor suppressors”; however, more recent evidence suggests that these cells develop phenotypic changes, which may contribute to loss of tumor suppressor activity. We have shown that myoepithelial cells in a subset of preinvasive ductal carcinoma in situ (DCIS) upregulate expression of the integrin αvβ6, switching on tumor promoter activity through activation of TGFβ and MMP9. This makes the tumor microenvironment more permissive to invasion, seen both in vitro and in vivo. In human tissue samples, increased myoepithelial αvβ6 expression correlated with increased risk of disease progression and recurrence. Current estimates suggest that as many as 50% of DCIS cases will never progress in the patient's lifetime, but there are no markers to predict the outcome of individual cases. The identification of αvβ6 in a subset of DCIS presents a unique way to stratify patients with DCIS into those who may or may not progress to more serious disease. As αvβ6 is not expressed on most normal adult tissues, this finding may also provide novel targets for therapy in this high-risk group. Cancer Res; 74(21); 5942–7. ©2014 AACR.
Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer
Authors: Parikh Falguni , Duluc Dorothée , Imai Naoko , Clark Amelia , Misiukiewicz Krzys , Bonomi Marcello , Gupta Vishal , Patsias Alexis , Parides Michael , Demicco Elizabeth G. , Zhang David Y. , Kim-Schulze Seunghee , Kao Johnny , Gnjatic Sacha , Oh Sangkon , Posner Marshall R. , Sikora Andrew G.
Published: October 2014

While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III–IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1–blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1–blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC. Cancer Res; 74(24); 7205–16. ©2014 AACR.
RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer
Authors: Calvayrac Olivier , Pradines Anne , Raymond-Letron Isabelle , Rouquette Isabelle , Bousquet Emilie , Lauwers-Cances Valérie , Filleron Thomas , Cadranel Jacques , Beau-Faller Michèle , Casanova Anne , Milia Julie , Favre Gilles , Mazières Julien
Published: October 2014

Purpose: A crucial event in lung adenocarcinoma progression is the switch from an aerogenous spread toward an infiltrating tumor. Loss of RhoB expression has been suggested to be critical for lung cancer invasion. Here, we tested RhoB expression as a prognostic biomarker in non–small cell lung cancer (NSCLC) with a special focus on lepidic pattern.

Experimental Design: We analyzed RhoB expression using both IHC and RT-qPCR in two series of operated patients (n = 100 and 48, respectively) and in a series of advanced lepidic adenocarcinoma (n = 31) from different hospitals. Next, we examined the role of RhoB in lung cancer progression in transgenic mice that express inducible EGFRL858R crossed with Rhob null mice.

Results: We identified that loss of RhoB expression was strongly associated with worse survival (P = 0.0001) and progression-free survival (P < 0.001) in the first series. We then confirmed these results after multivariate analyses of the second series. In the series of adenocarcinoma with lepidic features issued from a clinical trial (IFCT-0401), we showed that loss of RhoB expression was associated with higher aggressiveness of stage IV. Finally, we showed that EGFRL858R/Rhob+/+ mice developed mainly diffuse lung tumors with a lepidic pattern, whereas EGFRL858R/Rhob+/− and EGFRL858R/Rhob−/− developed a greater number of tumors, and aggressive adenocarcinomas with invasive properties.

Conclusions: We showed that RhoB is not only a strong prognostic factor in NSCLC but it is also critical for the acquisition of an aggressive phenotype of adenocarcinoma. Clin Cancer Res; 20(24); 6541–50. ©2014 AACR.
Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
Authors: Di Cosimo Serena , Sathyanarayanan Sriram , Bendell Johanna C. , Cervantes Andrés , Stein Mark N. , Braña Irene , Roda Desamparados , Haines Brian B. , Zhang Theresa , Winter Christopher G. , Jha Sharda , Xu Youyuan , Frazier Jason , Klinghoffer Richard A. , Leighton-Swayze Ann , Song Yang , Ebbinghaus Scot , Baselga José
Published: October 2014

Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.

Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.

Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.

Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.
Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma
Authors: Gao Huiping , Li Kesang , Tu Hong , Pan Xiaorong , Jiang Hua , Shi Bizhi , Kong Juan , Wang Hongyang , Yang Shengli , Gu Jianren , Li Zonghai
Published: October 2014

Purpose: The aim of our study is to elucidate whether T cells expressing GPC3-targeted chimeric antigen receptor (CAR) can efficiently eliminate GPC3-positive HCC cells and their potential in the treatment of HCC.

Experimental Design: T cells expressing a first-generation and third-generation GPC3-targeted CAR were prepared using lentiviral vector transduction. The in vitro and in vivo cytotoxic activities of the genetically engineered CAR T cells were evaluated against various HCC cell lines.

Results: GPC3-targeted CAR T cells could efficiently kill GPC3-positive HCC cells but not GPC3-negative cells in vitro. These cytotoxic activities seemed to be positively correlated with GPC3 expression levels in the target cells. In addition, T cells expressing the third-generation GPC3-targeted CAR could eradicate HCC xenografts with high level of GPC3 expression and efficiently suppress the growth of HCC xenografts with low GPC3 expression level in vivo. The survival of the mice bearing established orthotopic Huh-7 xenografts was significantly prolonged by the treatment with the third-generation GPC3-targeted CAR T cells.

Conclusions: GPC3-targeted CAR T cells could potently eliminate GPC3-positive HCC cells, thereby providing a promising therapeutic intervention for GPC3-positive HCC. Clin Cancer Res; 20(24); 6418–28. ©2014 AACR.
Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors
Authors: Chen Eddy J. , Sowalsky Adam G. , Gao Shuai , Cai Changmeng , Voznesensky Olga , Schaefer Rachel , Loda Massimo , True Lawrence D. , Ye Huihui , Troncoso Patricia , Lis Rosina L. , Kantoff Philip W. , Montgomery Robert B. , Nelson Peter S. , Bubley Glenn J. , Balk Steven P. , Taplin Mary-Ellen
Published: October 2014

Purpose: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.

Experimental Design: AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.

Results: The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.

Conclusions: These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. Clin Cancer Res; 21(6); 1273–80. ©2014 AACR.

See related commentary by Sharifi, p. 1240
Clever-1/Stabilin-1 Controls Cancer Growth and Metastasis
Authors: Karikoski Marika , Marttila-Ichihara Fumiko , Elima Kati , Rantakari Pia , Hollmén Maija , Kelkka Tiina , Gerke Heidi , Huovinen Ville , Irjala Heikki , Holmdahl Rikard , Salmi Marko , Jalkanen Sirpa
Published: October 2014

Purpose: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.

Experimental Design: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.

Results: Clever-1–deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.

Conclusion: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. Clin Cancer Res; 20(24); 6452–64. ©2014 AACR.
Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Weed Donald T. , Vella Jennifer L. , Reis Isildinha M. , De la fuente Adriana C. , Gomez Carmen , Sargi Zoukaa , Nazarian Ronen , Califano Joseph , Borrello Ivan , Serafini Paolo
Published: October 2014

Purpose: Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC.

Experimental Design: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment.

Results: MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity.

Conclusions: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. Clin Cancer Res; 21(1); 39–48. ©2014 AACR.
Involvement of microRNA-24 and DNA Methylation in Resistance of Nasopharyngeal Carcinoma to Ionizing Radiation
Authors: Wang Sumei , Zhang Rong , Claret Francois X. , Yang Huiling
Published: October 2014

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the epithelium. Radiotherapy is the standard therapy, but tumor resistance to this treatment reduces the 5-year patient survival rate dramatically. Studies are urgently needed to elucidate the mechanism of NPC radioresistance. Epigenetics—particularly microRNAs (miRNA) and DNA methylation—plays an important role in carcinogenesis and oncotherapy. We used qRT-PCR analysis and identified an miRNA signature from differentially expressed miRNAs. Our objectives were to identify the role of miR24 in NPC tumorigenesis and radioresistance and to identify the mechanisms by which miR24 is regulated. We found that miR24 inhibited NPC cell growth, promoted cell apoptosis, and suppressed the growth of NPC xenografts. We showed that miR24 was significantly downregulated in recurrent NPC tissues. When combined with irradiation, miR24 acted as a radiosensitizer in NPC cells. One of the miR24 precursors was embedded in a CpG island. Aberrant DNA methylation was involved in NPC response to radiotherapy, which linked inactivation of miR24 through hypermethylation of its precursor promoter with NPC radioresistance. Treating NPC cells with the DNA-hypomethylating agent 5-aza-2′-deoxycytidine compensated for the reduced miR24 expression. Together, our findings showed that miR24 was negatively regulated by hypermethylation of its precursor promoter in NPC radioresistance. Our findings defined a central role for miR24 as a tumor-suppressive miRNA in NPC and suggested its use in novel strategies for treatment of this cancer. Mol Cancer Ther; 13(12); 3163–74. ©2014 AACR.
Marine Sponge Cribrochalina vasculum Compounds Activate Intrinsic Apoptotic Signaling and Inhibit Growth Factor Signaling Cascades in Non–Small Cell Lung Carcinoma
Authors: Zovko Ana , Viktorsson Kristina , Hååg Petra , Kovalerchick Dimitry , Färnegårdh Katarina , Alimonti Andrea , Ilan Micha , Carmeli Shmuel , Lewensohn Rolf
Published: October 2014

Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non–small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies. Mol Cancer Ther; 13(12); 2941–54. ©2014 AACR.
Vorinostat Downregulates CD30 and Decreases Brentuximab Vedotin Efficacy in Human Lymphocytes
Authors: Hasanali Zainul S. , Epner Elliot M. , Feith David J. , Loughran Thomas P. , Sample Clare E.
Published: October 2014

With an increasing number of clinical trials looking at combination therapies in cancer, potential drug–drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody–drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)–cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm. Mol Cancer Ther; 13(12); 2784–92. ©2014 AACR.
TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway
Authors: Kim Mi-Ra , Lee Jeeyong , An You Sun , Jin Yeung Bae , Park In-Chul , Chung Eunkyung , Shin Incheol , Barcellos-Hoff Mary Helen , Yi Jae Youn
Published: October 2014

Several groups have reported that TGFβ1 regulates cellular responses to γ-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFβ1 in cellular responses to γ-irradiation was investigated in detail. The data indicate that TGFβ1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFβ1 was examined. Studies reveal that TGFβ1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFβ1-induced protection against IR. Overall, these data indicate that TGFβ1 facilitates the NHEJ repair process upon γ-irradiation and thereby enhances long-term survival.

Implications: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFβ signaling pathway. Mol Cancer Res; 13(2); 319–29. ©2014 AACR.
Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1–Dependent Trafficking of Integrins
Authors: Kozyulina Polina Y. , Loskutov Yuriy V. , Kozyreva Varvara K. , Rajulapati Anuradha , Ice Ryan J. , Jones Brandon C. , Pugacheva Elena N.
Published: October 2014

The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of the prometastatic protein, NEDD9, in breast cancer cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae-dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and colocalizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand–integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Reexpression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9-depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity.

Implications: This study provides valuable new insight into the potential therapeutic benefit of NEDD9 depletion to reduce dissemination of tumor cells and discovers a new regulatory role of NEDD9 in promoting migration through modulation of CAV1-dependent trafficking of integrins. Mol Cancer Res; 13(3); 423–38. ©2014 AACR.
Benefit–risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism
Authors: Ageno Walter , Beyer-Westendorf Jan
Published: October 2014

The prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non- VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit–risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and “reallife” data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.
Role of Dietary Fats in Modulating Cardiometabolic Risk During Moderate Weight Gain: A Randomized Double‐Blind Overfeeding Trial (LIPOGAIN Study)
Authors: Iggman David , Rosqvist Fredrik , Larsson Anders , Ärnlöv Johan , Beckman Lena , Rudling Mats , Risérus Ulf
Published: October 2014

Background

Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study.

Methods and Results

In a 7‐week, double‐blind, parallel‐group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (
PUFA
diet) or palm oil rich in saturated fatty acids (
SFA
diet). Despite comparable weight gain in the 2 groups, total: high‐density lipoprotein (
HDL
) cholesterol, low‐density lipoprotein:
HDL
cholesterol, and apolipoprotein B:
AI
ratios decreased during the
PUFA
versus the
SFA
diet (−0.37±0.59 versus +0.07±0.29, −0.31±0.49 versus +0.05±0.28, and −0.07±0.11 versus +0.01±0.07,
P
=0.003,
P
=0.007, and
P
=0.01 for between‐group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%,
P
<0.001) together with increased plasma proinsulin (+21%,
P
=0.007), insulin (+17%,
P
=0.003), proprotein convertase subtilisin/kexin type 9, (+9%,
P
=0.008) fibroblast growth factor‐21 (+31%,
P
=0.04), endothelial markers vascular cell adhesion molecule–1, intercellular adhesion molecule–1, and E‐selectin (+9, +5, and +10%, respectively,
P
<0.01 for all), whereas nonesterified fatty acids decreased (−28%,
P
=0.001).

Conclusions

Excess energy from
PUFA
versus
SFA
reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid‐lowering effects of
PUFA
.

Clinical Trial Registration

URL
:
http://ClinicalTrials.gov
. Unique identifier:
NCT
01427140.
Comparison of Constraint-Handling Mechanisms for the (1,λ)-ES on a Simple Constrained Problem
Authors: Hellwig Michael , Arnold Dirk V.
Published: October 2014

This paper investigates constraint-handling techniques used in nonelitist single-parent evolution strategies for the problem of maximizing a linear function with a single linear constraint. Two repair mechanisms are considered, and the analytical results are compared to those of earlier repair approaches in the same fitness environment. The first algorithm variant applies reflection to initially infeasible candidate solutions, and the second repair method uses truncation to generate feasible solutions from infeasible ones. The distributions describing the strategies’ one-generation behavior are calculated and used in a zeroth-order model for the steady state attained when operating with fixed step size. Considering cumulative step size adaptation, the qualitative differences in the behavior of the algorithm variants can be explained. The approach extends the theoretical knowledge of constraint-handling methods in the field of evolutionary computation and has implications for the design of constraint-handling techniques in connection with cumulative step size adaptation.