bluuebunny/crossref_metadata_2025 huggingface dataset:
Entire Blow‐Up Solutions of Semilinear Elliptic Systems with Quadratic Gradient Terms
Authors: Yang Yongju , Zhang Xinguang
Published: December 2012

We study the existence of entire positive solutions for the semilinear elliptic system with quadratic gradient terms, Δui+|∇ui|2 = pi(|x|)fi(u1, u2, …, ud) for i = 1,2, …, d on RN, N ≥ 3 and d ∈ {1,2, 3, …}. We establish the conditions on pi that ensure the existence of nonnegative radial solutions blowing up at infinity and also the conditions for bounded solutions on the entire space. The condition on fi is simple and different to the Keller‐Osserman condition.
Beyond Fifty Years of Millard’s Rotation-Advancement Technique in Cleft Lip Closure: Are There Many “Millards”?
Authors: da Silva Freitas Renato , Bertoco Alves Pedro , Shimizu Gisele Keiko Machado , Schuchovski Júlia Fortes , Lopes Marlon Augusto Câmara , Maluf Ivan , Forte Antonio Jorge V. , Alonso Nivaldo , Shin Joseph
Published: December 2012

In 1955, Millard developed the concept of rotation-advancement flap to treat cleft lip. Almost 6 decades later, it remains the most popular technique worldwide. Since the technique evolved and Millard published many technical variations, we decided to ask 10 experienced cleft surgeons how they would mark Millard’s 7 points in two unilateral cleft lip patient photos and compared the results. In both pictures, points 1 and 2 were marked identically among surgeons. Points 3 were located adjacent to each other, but not coincident, and the largest distances between points 3 were 4.95 mm and 4.03 mm on pictures 1 and 2, respectively. Similar patterns were obtained for points 4, eight of them were adjacent, and the greatest distance between the points was 4.39 mm. Points 5 had the most divergence between the points among evaluators, which were responsible for the different shapes of the C-flap. Points 6 also had dissimilar markings, and such difference accounts for varying resection areas among evaluators. The largest distances observed were 11.66 mm and 7 mm on pictures 1 and 2, respectively. In summary, much has changed since Millard’s initial procedure, but his basic principles have survived the inexorable test of time, proving that his idea has found place among the greatest concepts of modern plastic surgery.
An ℋ∞ Optimal Robust Pole Placement with Fixed Transparent Controller Structure on the Basis of Nonnegativity of Even Spectral Polynomials
Authors: Sarjaš Andrej , Svečko Rajko , Chowdhury Amor
Published: December 2012

This paper presents the synthesis of an optimal robust controller with the use of pole placement technique. The presented method includes solving a polynomial equation on the basis of the chosen fixed characteristic polynomial and introduced parametric solutions with a known parametric structure of the controller. Robustness criteria in an unstructured uncertainty description with metrics of norm  ℋ∞ are for a more reliable and effective formulation of objective functions for optimization presented in the form of a spectral polynomial with positivity conditions. The method enables robust low‐order controller design by using plant simplification with partial‐fraction decomposition, where the simplification remainder is added to the performance weight. The controller structure is assembled of well‐known parts such as disturbance rejection, and reference tracking. The approach also allows the possibility of multiobjective optimization of robust criteria, application of mixed sensitivity problem, and other closed‐loop limitation criteria, where the common criteria function can be composed from different unrelated criteria. Optimization and controller design are performed with iterative evolution algorithm.
Pityriasis Lichenoides Chronica Associated with Herpes Simplex Virus Type 2
Authors: González Rodríguez Antonio Javier , Montesinos Villaescusa Encarnación , Jordá Cuevas Esperanza
Published: December 2012

Introduction. Pityriasis lichenoides is a rare, acquired spectrum of skin conditions of an unknown etiology.Case Report. A 28-year-old man presented with recurrent outbreaks of herpes simplex virus associated with the onset of red-to-brown maculopapules located predominantly in trunk in each recurrence. Positive serologies to herpes simplex virus type 2 were detected. Histopathological examination of one of the lesions was consistent with a diagnosis of pityriasis lichenoides chronica.Discussion. Pityriasis lichenoides is a rare cutaneous entity of an unknown cause which includes different clinical presentations. A number of infectious agents have been implicated based on the clustering of multiple outbreaks and elevated serum titers to specific pathogens (human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus,Toxoplasma gondii, and herpes simplex virus). In our patient, resolution of cutaneous lesions coincided with the administration of antiviral drugs and clinical improvement in each genital herpes recurrence. In conclusion, we report a case in which cutaneous lesions of pityriasis lichenoides chronica and a herpes simplex virus-type 2-mediated disease have evolved concomitantly.
Immune Response to a Variable Pathogen: A Stochastic Model with Two Interlocked Darwinian Entities
Authors: Kuhn Christoph
Published: December 2012

This paper presents the modeling of a host immune system, more precisely the immune effector cell and immune memory cell population, and its interaction with an invading pathogen population. It will tackle two issues of interest; on the one hand, in defining a stochastic model accounting for the inherent nature of organisms in population dynamics, namely multiplication with mutation and selection; on the other hand, in providing a description of pathogens that may vary their antigens through mutations during infection of the host. Unlike most of the literature, which models the dynamics with first-order differential equations, this paper proposes a Galton-Watson type branching process to describe stochastically by whole distributions the population dynamics of pathogens and immune cells. In the first model case, the pathogen of a given type is either eradicated or shows oscillatory chronic response. In the second model case, the pathogen shows variational behavior changing its antigen resulting in a prolonged immune reaction.
Epithelioid Trophoblastic Tumor: A Case Report and Review of the Literature
Authors: Scott Eirwen M. , Smith Ashlee L. , Desouki Mohamed Mokhtar , Olawaiye Alexander B.
Published: December 2012

Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic tumor. Cases of ETT present as abnormal vaginal bleeding in women of reproductive age, with low human chorionic gonadotropin (hCG) levels. ETT can be a sequela of any gestational event and can present in both intrauterine and extrauterine sites. Metastasis and death have been reported. We present a case of a 44-year-old female incidentally diagnosed with ETT following laparoscopic-assisted vaginal hysterectomy. Postoperative evaluation for metastatic disease was negative. The patient has been closely followed and remains disease free 8 months postoperatively. ETT presents a diagnostic challenge due to its rarity and histologic resemblance to other pathologies. ETT is relatively chemoresistant and managed surgically. Misdiagnosis delays effective treatment and affects survival.
Effect of 2,4-Thiazolidinedione on Limousin Cattle Growth and on Muscle and Adipose Tissue Metabolism
Authors: Arévalo-Turrubiarte M. , González-Dávalos L. , Yabuta A. , Garza J. D. , Dávalos J. L. , Mora O. , Shimada A.
Published: December 2012

The main adipogenic transcription factor PPARγpossesses high affinity to 2,4-TZD, a member of the Thiazolidinedione family of insulin-sensitizing compounds used as adipogenic agents. We evaluated 2,4-TZD’s effect on bovine growth and PPAR tissue expression. Seventeen Limousin bulls (18 month-old; 350 kg body weight (BW)) were assigned into 2 treatments: control and 2,4-TZD (8 mg/70 kg BW) and were fed until bulls reached 500 kg BW. They were weighed and their blood was sampled. DNA, RNA, and protein were determined in liver; skeletal muscle; subcutaneous (SC), omental, perirenal adipose tissues (AT) to determine protein synthesis rate and cellular size. Expression of PPAR mRNA was measured in liver and muscle (PPARα, -δ, and -γ) and SC adipose tissue (γ) by real-time PCR. No significant differences were found (P>0.1) in weight gain, days on feed, and carcass quality. Muscle synthesis was greater in controls (P<0.05); cell size was larger with 2,4-TZD (P<0.05). PPARα, -δ, and -γexpressions with 2,4-TZD in liver were lower (P<0.01) than in muscle. No differences were found for PPARγmRNA expression in SCAT. The results suggest the potential use of 2,4-TZD in beef cattle diets, because it improves AT differentiation, liver, and muscle fatty acid oxidation that, therefore, might improve energy efficiency.
On Coupled Fixed Point Theorems for Nonlinear Contractions in Partially Ordered G‐Metric Spaces
Authors: Mohiuddine S. A. , Alotaibi Abdullah
Published: December 2012

Two concepts—one of the coupled fixed point and the other of the generalized metric space—play a very active role in recent research on the fixed point theory. The definition of coupled fixed point was introduced by Bhaskar and Lakshmikantham (2006) while the generalized metric space was introduced by Mustafa and Sims (2006). In this work, we determine some coupled fixed point theorems for mixed monotone mapping satisfying nonlinear contraction in the framework of generalized metric space endowed with partial order. We also prove the uniqueness of the coupled fixed point for such mappings in this setup.
Rational Biparameter Homotopy Perturbation Method and Laplace‐Padé Coupled Version
Authors: Vazquez-Leal Hector , Sarmiento-Reyes Arturo , Khan Yasir , Filobello-Nino Uriel , Diaz-Sanchez Alejandro
Published: December 2012

The fact that most of the physical phenomena are modelled by nonlinear differential equations
underlines the importance of having reliable methods for solving them. This work presents the rational
biparameter homotopy perturbation method (RBHPM) as a novel tool with the potential to find approximate
solutions for nonlinear differential equations. The method generates the solutions in the form of a quotient
of two power series of different homotopy parameters. Besides, in order to improve accuracy, we propose
the Laplace‐Padé rational biparameter homotopy perturbation method (LPRBHPM), when the solution is
expressed as the quotient of two truncated power series. The usage of the method is illustrated with two
case studies. On one side, a Ricatti nonlinear differential equation is solved and a comparison with the
homotopy perturbation method (HPM) is presented. On the other side, a nonforced Van der Pol Oscillator
is analysed and we compare results obtained with RBHPM, LPRBHPM, and HPM in order to conclude
that the LPRBHPM and RBHPM methods generate the most accurate approximated solutions.
PAPR Reduction of OFDM Signals by Novel Global Harmony Search in PTS Scheme
Authors: Salehinejad Hojjat , Talebi Siamak
Published: December 2012

The orthogonal frequency division multiplexing (OFDM) modulation technique is one of the key strategies for multiuser signal transmission especially in smart grids and wind farms. This paper introduces an approach for peak-to-average power ratio (PAPR) reduction of such signals based on novel global harmony search (NGHS) and partial transmit sequence (PTS) schemes. In PTS technique, the data block to be transmitted is partitioned into disjoint subblocks, which are combined using phase factors to minimize PAPR. The PTS requires an exhaustive search over all combinations of allowed phase factors. Therefore, with respect to the fast implementation and simplicity of NGHS technique, we could achieve significant reduction of PAPR.
FDG PET/CT in Initial Staging of Adult Soft-Tissue Sarcoma
Authors: Roberge David , Vakilian Siavosh , Alabed Yazan Z. , Turcotte Robert E. , Freeman Carolyn R. , Hickeson Marc
Published: December 2012

Soft-tissue sarcomas spread predominantly to the lung and it is unclear how often FDG-PET scans will detect metastases not already obvious by chest CT scan or clinical examination. Adult limb and body wall soft-tissue sarcoma cases were identified retrospectively. Ewing’s sarcoma, rhabdomyosarcoma, GIST, desmoid tumors, visceral tumors, bone tumors, and retroperitoneal sarcomas were excluded as were patients imaged for followup, response assessment, or recurrence. All patients had a diagnostic chest CT scan. 109 patients met these criteria, 87% of which had intermediate or high-grade tumors. The most common pathological diagnoses were leiomyosarcoma (17%), liposarcoma (17%), and undifferentiated or pleomorphic sarcoma (16%). 98% of previously unresected primary tumors were FDG avid. PET scans were negative for distant disease in 91/109 cases. The negative predictive value was 89%. Fourteen PET scans were positive. Of these, 6 patients were already known to have metastases, 3 were false positives, and 5 represented new findings of metastasis (positive predictive value 79%). In total, 5 patients were upstaged by FDG-PET (4.5%). Although PET scans may be of use in specific circumstances, routine use of FDG PET imaging as part of the initial staging of soft-tissue sarcomas was unlikely to alter management in our series.
FAME Storage Time in an Optimized Natural Antioxidant Mixture
Authors: Coppo Rodolfo Lopes , Borsato Dionísio , Pereira Jaqueline Laís , da Silva Hágata Cremasco
Published: December 2012

The study of B100 biodiesel oxidation stability, and its conservation, is extremely important to control its quality, especially regarding storage. Many spices have shown antioxidant effect and are the targets of study. Knowing the oxidation process in greater detail allows a reliable storage period to be stipulated for the biodiesel without its degradation until the time of use. Results have shown that according to the accelerated stove method, the optimal mixture, composed of 100% of oregano extract, can confer a 535-day shelf life to biodiesel without evident oxidation. According to the results obtained by the Rancimat method, the ideal mixture consists of 100% rosemary, resulting in 483 days of storage. The application of the process variable showed that the accelerated stove method was more suitable to determine oxidative stability of biodiesel.
Study of UV Transmission through a Few Edible Oils and Chicken Oil
Authors: Anil Kumar K. , Viswanathan K.
Published: December 2012

Effects of solar UV radiation on the biosphere are well known and a lot of studies are going on to reduce its dangerous effects on human beings. Atmospheric ozone layer is not uniform over the globe, so that less ozone over tropics makes it receive more UV insolation, than high latitude places. People in the tropics are continuously exposed to high UV dosage, leading to skin reddening and the dangerous “sun stroke.” In southern India people use some vegetable oils to protect the skin from sun heat. Studies of “sun stroke” show that people having skin of moderate colour are the main victims. In some parts of Southern Kerala like Kottayam, Ernakulam, and Alappuzha traditional people were using oil extracted from chicken, called “chicken oil,” for the treatment of “heat burns” and other types of burns. This motivated us to study the UV absorption characteristics of chicken oil, and compare them with that of other commonly used vegetable oils. It is found that the chicken oil shows maximum absorption of UV radiation of about 85%, and neem oil shows absorption of about 60%. Other oils show comparatively very low absorption of UV radiation. So this property of chicken oil may be the reason for using it as remedy for heat burns.
Moesin Is a Glioma Progression Marker That Induces Proliferation and Wnt/β-Catenin Pathway Activation via Interaction with CD44
Authors: Zhu Xiaoping , Morales Fabiana C. , Agarwal Nitin Kumar , Dogruluk Turgut , Gagea Mihai , Georgescu Maria-Magdalena
Published: December 2012

Moesin is an ERM family protein that connects the actin cytoskeleton to transmembrane receptors. With the identification of the ERM family protein NF2 as a tumor suppressor in glioblastoma, we investigated roles for other ERM proteins in this malignancy. Here, we report that overexpression of moesin occurs generally in high-grade glioblastoma in a pattern correlated with the stem cell marker CD44. Unlike NF2, moesin acts as an oncogene by increasing cell proliferation and stem cell neurosphere formation, with its ectopic overexpression sufficient to shorten survival in an orthotopic mouse model of glioblastoma. Moesin was the major ERM member activated by phosphorylation in glioblastoma cells, where it interacted and colocalized with CD44 in membrane protrusions. Increasing the levels of moesin competitively displaced NF2 from CD44, increasing CD44 expression in a positive feedback loop driven by the Wnt/β-catenin signaling pathway. Therapeutic targeting of the moesin–CD44 interaction with the small-molecule inhibitor 7-cyanoquinocarcinol (DX-52-1) or with a CD44-mimetic peptide specifically reduced the proliferation of glioblastoma cells overexpressing moesin, where the Wnt/β-catenin pathway was activated. Our findings establish moesin and CD44 as progression markers and drugable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/β-catenin pathway. Cancer Res; 73(3); 1142–55. ©2012 AACR.
DKK2 Mediates Osteolysis, Invasiveness, and Metastatic Spread in Ewing Sarcoma
Authors: Hauer Kristina , Calzada-Wack Julia , Steiger Katja , Grunewald Thomas G.P. , Baumhoer Daniel , Plehm Stephanie , Buch Thorsten , da Costa Olivia Prazeres , Esposito Irene , Burdach Stefan , Richter Günther H.S.
Published: December 2012

Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFβ1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells. Cancer Res; 73(2); 967–77. ©2012 AACR.
Novel Oncogene–Induced Metastatic Prostate Cancer Cell Lines Define Human Prostate Cancer Progression Signatures
Authors: Ju Xiaoming , Ertel Adam , Casimiro Mathew C. , Yu Zuoren , Meng Hui , McCue Peter A. , Walters Rhonda , Fortina Paolo , Lisanti Michael P. , Pestell Richard G.
Published: December 2012

Herein, murine prostate cancer cell lines, generated via selective transduction with a single oncogene (c-Myc, Ha-Ras, and v-Src), showed oncogene-specific prostate cancer molecular signatures that were recapitulated in human prostate cancer and developed lung metastasis in immune-competent mice. Interrogation of two independent retrospective cohorts of patient samples using the oncogene signature showed an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98% to 99%. In a blinded study, the signature algorithm showed independent substratification of reduced recurrence-free survival by Kaplan–Meier analysis. The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, which metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy, whereas the molecular signatures identified herein provides further value over current gene signature markers of prediction and outcome. Cancer Res; 73(2); 978–89. ©2012 AACR.
Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer
Authors: Chou Chun-Hung , Yang Neng-Kai , Liu Ting-Yun , Tai Shyh-Kuan , Hsu Dennis Shin-Shian , Chen Ya-Wei , Chen Yann-Jang , Chang Cheng-Chi , Tzeng Cheng-Hwai , Yang Muh-Hwa
Published: December 2012

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial–mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1–AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1. Cancer Res; 73(2); 953–66. ©2012 AACR.
Novel Mechanism of Apoptosis Resistance in Cancer Mediated by Extracellular PAR-4
Authors: Burikhanov Ravshan , Shrestha-Bhattarai Tripti , Qiu Shirley , Shukla Nidhi , Hebbar Nikhil , Lele Subodh M. , Horbinski Craig , Rangnekar Vivek M.
Published: December 2012

Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-κB, revealing that it can block PAR-4–mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. Cancer Res; 73(2); 1011–9. ©2012 AACR.
Hyperpolarized 13C-Pyruvate Magnetic Resonance Reveals Rapid Lactate Export in Metastatic Renal Cell Carcinomas
Authors: Keshari Kayvan R. , Sriram Renuka , Koelsch Bertram L. , Van Criekinge Mark , Wilson David M. , Kurhanewicz John , Wang Zhen J.
Published: December 2012

Renal cell carcinomas (RCC) are a heterogeneous group of tumors with a wide range of aggressiveness. Noninvasive methods to confidently predict the tumor biologic behavior and select appropriate treatment are lacking. Here, we investigate the dynamic metabolic flux in living RCC cells using hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) combined with a bioreactor platform and interrogated the biochemical basis of the MRS data with respect to cancer aggressiveness. RCC cells have significantly higher pyruvate-to-lactate flux than the normal renal tubule cells. Furthermore, a key feature distinguishing the localized from the metastatic RCC cells is the lactate efflux rate, mediated by the monocarboxylate transporter 4 (MCT4). The metastatic RCC cells have significantly higher MCT4 expression and corresponding higher lactate efflux, which is essential for maintaining a high rate of glycolysis. We show that such differential cellular transporter expression and associated metabolic phenotype can be noninvasively assessed via real-time monitoring of hyperpolarized 13C-pyruvate-to-lactate flux. Cancer Res; 73(2); 529–38. ©2012 AACR.
Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
Authors: Walsh Kyle M. , Gorlov Ivan P. , Hansen Helen M. , Wu Xifeng , Spitz Margaret R. , Zhang Huifeng , Lu Emily Y. , Wenzlaff Angela S. , Sison Jennette D. , Wei Chongjuan , Lloyd Stacy M. , Chen Wei , Frazier Marsha L. , Seldin Michael F. , Bierut Laura J. , Bracci Paige M. , Wrensch Margaret R. , Schwartz Ann G. , Wiencke John K. , Amos Christopher I.
Published: December 2012

Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.

Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.

Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5).

Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.

Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.
Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK
Authors: Kim Sae Won , Kim Su Jin , Park Sang Hoon , Yang Hyun Gul , Kang Moon Cheol , Choi Young Woo , Kim Seong Muk , Jeun Sin-Soo , Sung Young Chul
Published: December 2012

Purpose: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed.

Experimental Design: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated.

Results: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections.

Conclusion: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK. Clin Cancer Res; 19(2); 415–27. ©2012 AACR.
Integration of Cell Line and Clinical Trial Genome-Wide Analyses Supports a Polygenic Architecture of Paclitaxel-Induced Sensory Peripheral Neuropathy
Authors: Wheeler Heather E. , Gamazon Eric R. , Wing Claudia , Njiaju Uchenna O. , Njoku Chidiamara , Baldwin Robert Michael , Owzar Kouros , Jiang Chen , Watson Dorothy , Shterev Ivo , Kubo Michiaki , Zembutsu Hitoshi , Winer Eric P. , Hudis Clifford A. , Shulman Lawrence N. , Nakamura Yusuke , Ratain Mark J. , Kroetz Deanna L. , Cox Nancy J. , Dolan Mary Eileen
Published: December 2012

Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.

Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.

Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel.

Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients. Clin Cancer Res; 19(2); 491–9. ©2012 AACR.
Serum CD163 and TARC as Disease Response Biomarkers in Classical Hodgkin Lymphoma
Authors: Jones Kimberley , Vari Frank , Keane Colm , Crooks Pauline , Nourse Jamie P. , Seymour Louise A. , Gottlieb David , Ritchie David , Gill Devinder , Gandhi Maher K.
Published: December 2012

Purpose: Candidate circulating disease response biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin–Reed–Sternberg (HRS) cells or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, whereas benign CD163+ M2 tissue-associated macrophages (TAM) are prominent. CD163+ cells within the malignant node may be prognostic, but there is no data on serum CD163 (sCD163). The HRS-specific serum protein sTARC shows promise as a disease response biomarker. Tumor-specific and tumor-infiltrating circulating biomarkers have not been compared previously.

Experimental Design: We prospectively measured sCD163 and sTARC in 221 samples from 47 patients with Hodgkin lymphoma and 21 healthy participants. Blood was taken at five fixed time-points prior, during, and after first-line therapy. Results were compared with radiological assessment and plasma Epstein-Barr virus DNA (EBV-DNA). Potential sources of circulating CD163 were investigated, along with immunosuppressive properties of CD163.

Results: Pretherapy, both sCD163 and sTARC were markedly elevated compared with healthy and complete remission samples. sCD163 better reflected tumor burden during therapy, whereas sTARC had greater value upon completion of therapy. sCD163 correlated with plasma EBV-DNA, and associated with B symptoms, stage, and lymphopenia. Circulating CD163+ monocytes were elevated in patients, indicating that sCD163 are likely derived from circulating and intratumoral cells. Depletion of cHL CD163+ monocytes markedly enhanced T-cell proliferation, implicating monocytes and/or TAMs as potential novel targets for immunotherapeutic manipulation.

Conclusion: The combination of circulating tumor-infiltrate (sCD163) and tumor-specific (sTARC) proteins is more informative than either marker alone as disease response biomarkers in early and advanced disease during first-line therapy for cHL. Clin Cancer Res; 19(3); 731–42. ©2012 AACR.
PLK1 Inhibitors Synergistically Potentiate HDAC Inhibitor Lethality in Imatinib Mesylate–Sensitive or –Resistant BCR/ABL+ Leukemia Cells In Vitro and In Vivo
Authors: Dasmahapatra Girija , Patel Hiral , Nguyen Tri , Attkisson Elisa , Grant Steven
Published: December 2012

Purpose: To determine whether Polo-like kinase 1 (PLK1) inhibitors (e.g., BI2536) and histone deacetylase (HDAC) inhibitors (e.g., vorinostat) interact synergistically in the BCR/ABL+ leukemia cells sensitive or resistant to imatinib mesylate (IM) in vitro and in vivo.

Experimental Design: K562 and LAMA84 cells sensitive or resistant to imatinib mesylate and primary CML cells were exposed to BI2536 and vorinostat. Effects on cell viability and signaling pathways were determined using flow cytometry, Western blotting, and gene transfection. K562 and BV173/E255K animal models were used to test in vivo efficacy.

Results: Cotreatment with BI2536 and vorinostat synergistically induced cell death in parental or imatinib mesylate–resistant BCR/ABL+ cells and primary CD34+ bone marrow cells but was minimally toxic to normal cells. BI2536/vorinostat cotreatment triggered pronounced mitochondrial dysfunction, inhibition of p-BCR/ABL, caspase activation, PARP cleavage, reactive oxygen species (ROS) generation, and DNA damage (manifest by increased expression of γH2A.X, p-ATM, p-ATR), events attenuated by the antioxidant TBAP. PLK1 short hairpin RNA (shRNA) knockdown significantly increased HDACI lethality, whereas HDAC1–3 shRNA knockdown reciprocally increased BI2536-induced apoptosis. Genetic interruption of the DNA damage linker H1.2 partially but significantly reduced PLK1/HDAC inhibitor–mediated cell death, suggesting a functional role for DNA damage in lethality. Finally, BI2536/vorinostat cotreatment dramatically reduced tumor growth in both subcutaneous and systemic BCR/ABL+ leukemia xenograft models and significantly enhanced animal survival.

Conclusions: These findings suggest that concomitant PLK1 and HDAC inhibition is active against imatinib mesylate–sensitive or refractory CML and ALL cells both in vitro and in vivo and that this strategy warrants further evaluation in the setting of BCR/ABL+ leukemias. Clin Cancer Res; 19(2); 404–14. ©2012 AACR.
Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells
Authors: Sapra Puja , Damelin Marc , DiJoseph John , Marquette Kimberly , Geles Kenneth G. , Golas Jonathon , Dougher Maureen , Narayanan Bitha , Giannakou Andreas , Khandke Kiran , Dushin Russell , Ernstoff Elana , Lucas Judy , Leal Mauricio , Hu George , O'Donnell Christopher J. , Tchistiakova Lioudmila , Abraham Robert T. , Gerber Hans-Peter
Published: December 2012

Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non–small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/cycle × 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38–47. ©2012 AACR.
Gamma-amino Butyric Acid (GABA) Prevents the Induction of Nicotinic Receptor–Regulated Signaling by Chronic Ethanol in Pancreatic Cancer Cells and Normal Duct Epithelia
Authors: Al-Wadei Mohammed H. , Al-Wadei Hussein A.N. , Schuller Hildegard M.
Published: December 2012

Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChR) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through β-adrenergic receptors (β-AR). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA).

Using MTT assays, cell migration assays, Western blotting, immunoassays, and gene knockdown of individual nAChRs in two PDAC cell lines and in immortalized human pancreatic duct epithelial cells, our data show that treatment for seven days with ethanol induced the protein expression and sensitivity of nAChRs α3, α5, and α7 resulting in increased production of noradrenaline and adrenaline, which drive proliferation and migration via cyclic AMP (cAMP)-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells.

Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by upregulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitter production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption. Cancer Prev Res; 6(2); 139–48. ©2012 AACR.
Intraoperative Imprint Evaluation of Surgical Margins in Oral Squamous Cell Carcinoma
Authors: Yadav Gatha Singh , Donoghue Mandana , Tauro David P. , Yadav Ashutosh , Agarwal Sumit
Published: December 2012

Background: Oral squamous cell carcinoma (OSCC) is a multifactorial malignant epithelial neoplasm. Tumor clearance at the surgical margins in OSCC is a critical factor which strongly influences both the local recurrence and overall survival rate. A quick and accurate intraoperative diagnostic procedure can make a significant difference to the survival rate. Touch imprint cytology (TIC) has commonly been used in the past for the diagnosis of tumors and the detection of sentinel lymph node metastasis. It is routinely applied for intraoperative margin analysis of breast lumpectomy specimens, where it has been proven to have a good success rate. The effectiveness and reliability of TIC in the intraoperative margin evaluation of OSCC, however, has not been established so far. Objective: To investigate the diagnostic accuracy of the intraoperative TIC technique for assessing surgical margins in OSCC in comparison to paraffin-embedded hematoxylin and eosin-stained sections. Materials and Methods: Thirty previously untreated, biopsy-proven OSCC patients undergoing surgical treatment between December 2008 and September 2010 were included. Patients diagnosed with histological variants of squamous cell carcinoma (SCC) or recurrent tumor were excluded. Three hundred forty-eight touch imprint slides were prepared from 174 margins of 30 resected tumor specimens. Imprints from tumor proper were taken as positive controls. The slides were reported as positive, negative or suspicious for tumor. After all cytological interpretation was completed, the results were compared with the corresponding histological diagnosis. Results: This pioneer study showed that TIC has an overall accuracy of 83%, sensitivity of 91.1%, specificity of 74.4%, positive predictive value of 79.2% and a negative predictive value of 88.6%. The false-positive margins evaluated by TIC were 43 (12.3%) and the false-negative ones were 16 (4.6%). Conclusion: TIC is a quick, simple, inexpensive, highly accurate and reliable intraoperative technique to assess surgical margins in SCC of the oral cavity.
Well-Differentiated Villoglandular Adenocarcinoma of the Uterine Cervix: Assessment of Cytological Features by Histological Subtypes
Authors: Hagiwara Tomoko , Kaku Tsunehisa , Kobayashi Hiroaki , Wake Norio , Saito Toshiaki
Published: December 2012

Objective: Well-differentiated villoglandular adenocarcinoma (VGA) of the cervix involves papillae lined by different types of epithelial cells that are histologically subclassified into endocervical, endometrioid, or intestinal subtypes. The objective of the current study was to evaluate the definite cytological features of VGA by histological subtype. Study Design: We examined 8 cervical smears from patients confirmed to have pure VGA and classified them into the 3 histological subtypes. Results: The cervical smears were highly cellular and had a relatively clean background. The nuclei had minimal anisonucleosis and fine granular chromatin with almost inconspicuous nucleoli. The characteristic findings of the endocervical type were a palisading arrangement consisting of columnar or spindle-shaped cells with apical or elongated nuclei. Small but clear nucleoli were identified only in the endocervical type. In the endometrioid type, tumor cells consisted of cohesive sheets with smooth edges and very round nuclei. Cytoplasmic vacuolation was never observed in the endometrioid type. The tumor cells in the intestinal type were prominent with abundant cytoplasmic mucin. Conclusions: We demonstrated that the cytological features of this tumor can vary depending on the histological subtype and one should be aware of these features in order to improve diagnostic accuracy.
Feasibility of Fine-Needle Aspiration in the Diagnosis of Two Unusual Childhood Jaw Tumor Types: Prognoma and Cementifying Fibroma
Authors: Barroca Helena , Lopes José Manuel
Published: December 2012

Cytology features of childhood jaw tumors are infrequently reported in the literature. Fine-needle aspiration cytology (FNAC) has been used with good results in the differential diagnosis of bone lesions, being an excellent tool for the diagnosis of metastases and in the frontline approach to primary lesions. We report 3 cases of young children aged 3 years (case 1), 5 months (case 2), and 15 years (case 3) with jaw tumors diagnosed by FNAC. In the first two cases the diagnosis was prognoma, and in the third case cementifying fibroma. Despite the clinical and imaging similarity of the 3 cases – large maxillary/mandibular tumors – their characteristic cytological features allowed a confident diagnosis, excluding other differential alternatives. In both case 1 and case 2 a dual cell population of neuroepithelial and melanocytic cells was identified, consistent with a melanotic neuroectodermal tumor. In case 3 the presence of a bland spindle cell population as well as of several nodular dense eosinophilic, osteoid-like (cement) matrices, indicated a cementifying fibroma. All cases were resected and confirmed by histological examination. A review of the literature, including differential diagnosis, addresses the utility of FNAC in childhood jaw tumors.
Differential Immunohistochemical Expression of CD44s, E-Cadherin and β-Catenin among Hyperplastic and Neoplastic Lesions of the Prostate Gland
Authors: Lazari Paraskevi , Poulias Hercules , Gakiopoulou Hariklia , Thomopoulou Geogia-Heleni , Barbatis Calypso , Lazaris Andreas C.
Published: December 2012

Introduction: CD44s, E-cadherin and β-catenin are cell adhesion molecules (CAMs) and appear to influence organ development, inflammation, cancer invasion and metastasis. We studied the expression of these CAMs in prostate cancer (PCa), high-grade prostatic intraepithelial neoplasia (HGPIN) and nodular adenomatous hyperplasia (NH). Materials and Methods: 135 paraffin blocks of radical prostatectomy specimens were assessed. CAMs were determined by immunohistochemistry. All sections included PCa, HGPIN and NH. The expression was semiquantitatively evaluated in three scores (1+, 2+, 3+). The markers’ immunopositivity was statistically investigated with Gleason score and TNM stage. Results and Conclusions: CD44s had score 3+ in 41.5, 46.7 and 37.8% of areas with NH, HGPIN and PCa, respectively. E-cadherin immunostaining was highly detected in 71.1, 78.5 and 63.0% of NH, HGPIN and PCa areas while β-catenin score 3+ was exclusively membranous in 80.7% of NH and nuclear/cytoplasmic in 70.4 and 48.9% of HGPIN and PCa areas. No marker related to the Gleason score (p = 0.352). CD44s and E-cadherin expression was inversely associated with TNM stage (p = 0.021 and p = 0.042, respectively); no such association was observed for β-catenin (p = 0.556). The decreased expression of CD44s and E-cadherin is probably associated with the invasive potential of PCa. The β-catenin staining pattern in neoplastic lesions, either preinvasive or invasive, differs from that in non-neoplastic prostate lesions.