bluuebunny/crossref_metadata_2025 huggingface dataset:
Alkene Cleavage Catalysed by Heme and Nonheme Enzymes: Reaction Mechanisms and Biocatalytic Applications
Authors: Mutti Francesco G.
Published: July 2012

The oxidative cleavage of alkenes is classically performed by chemical methods, although they display several drawbacks. Ozonolysis requires harsh conditions (−78°C, for a safe process) and reducing reagents in a molar amount, whereas the use of poisonous heavy metals such as Cr, Os, or Ru as catalysts is additionally plagued by low yield and selectivity. Conversely, heme and nonheme enzymes can catalyse the oxidative alkene cleavage at ambient temperature and atmospheric pressure in an aqueous buffer, showing excellent chemo- and regioselectivities in certain cases. This paper focuses on the alkene cleavage catalysed by iron cofactor-dependent enzymes encompassing the reaction mechanisms (in case where it is known) and the application of these enzymes in biocatalysis.
Atypical Celiac Disease: From Recognizing to Managing
Authors: Admou B. , Essaadouni L. , Krati K. , Zaher K. , Sbihi M. , Chabaa L. , Belaabidia B. , Alaoui-Yazidi A.
Published: July 2012

The nonclassic clinical presentation of celiac disease (CD) becomes increasingly common in physician’s daily practice, which requires an awareness of its many clinical faces with atypical, silent, and latent forms. Besides the common genetic background (HLA DQ2/DQ8) of the disease, other non-HLA genes are now notably reported with a probable association to atypical forms. The availability of high-sensitive and specific serologic tests such as antitissue transglutuminase, antiendomysium, and more recent antideamidated, gliadin peptide antibodies permits to efficiently uncover a large portion of the submerged CD iceberg, including individuals having conditions associated with a high risk of developing CD (type 1 diabetes, autoimmune diseases, Down syndrome, family history of CD, etc.), biologic abnormalities (iron deficiency anemia, abnormal transaminase levels, etc.), and extraintestinal symptoms (short stature, neuropsychiatric disorders, alopecia, dental enamel hypoplasia, recurrent aphtous stomatitis, etc.). Despite the therapeutic alternatives currently in developing, the strict adherence to a GFD remains the only effective and safe therapy for CD.
Boundary Layer Flow of Second Grade Fluid in a Cylinder with Heat Transfer
Authors: Nadeem S. , Rehman Abdul , Lee Changhoon , Lee Jinho
Published: July 2012

An analysis is carried out to obtain the similarity solution of the steady boundary layer flow and heat transfer of a second grade through a horizontal cylinder. The governing partial differential equations along with the boundary conditions are reduced to dimensionless form by using the boundary layer approximation and applying suitable similarity transformation. The resulting nonlinear coupled system of ordinary differential equations subject to the appropriate boundary conditions is solved by homotopy analysis method (HAM). The effects of the physical parameters on the flow and heat transfer characteristics of the model are presented. The behavior of skin friction coefficient and Nusselt numbers is studied for different parameters.
Closed Form Integration of Singular and Hypersingular Integrals in 3D BEM Formulations for Heat Conduction
Authors: Tadeu A. , Prata J. , Simões N.
Published: July 2012

The evaluation of the singular and hypersingular integrals that appear in three‐dimensional boundary element formulations for heat diffusion, in the frequency domain, is presented in analytical form. This improves computational efficiency and accuracy. Numerical integrations using existing techniques based on standard Gaussian integration schemes that incorporate an enormous amount of sampling points are used to verify the solutions of singular integrals. For the hypersingular integrals the comparison is evaluated by making use of an analytical solution that is valid for circular domains, combined with a standard Gaussian integration scheme for the remaining boundary element domain. Closed form solutions for cylindrical inclusions (with null temperatures and null heat fluxes prescribed on the boundary) are then derived and used to validate the three‐dimensional boundary element formulations.
Priapism: Comorbid Factors and Treatment Outcomes in a Contemporary Series
Authors: Gottsch Henry P. , Berger Richard E. , Yang Claire C.
Published: July 2012

Objective. The goal of this study is to describe comorbid characteristics in patients who have priapism, and their treatment outcomes.Methods. Chart review was undertaken on men who had a diagnosis of priapism from a tertiary medical center, from 2000–2010. Men with priapism due exclusively to the use of prescription erectile aids and medications were not included in the review.Results. We identified 79 patients with the priapism. The most common type of priapism was the low flow variant. High flow priapism was identified in 2 patients. The most common general comorbid condition associated with priapism was mental illness (including substance abuse), which was present in 56% of the patients. Neurogenic priapism accounted for 19% of the total priapism events. Psychopharmaceutical agents and recreational drugs were commonly associated with ischemic priapism. Acute complications of priapism treatment were not common, but long-term complications, especially erectile dysfunction, were frequent.Conclusions. We describe the characteristics and outcomes of a large group of patients with priapism. Our experience at a tertiary care center indicates that mental illness, including substance abuse disorders, is a highly prevalent comorbid condition in men who experience priapism. Consistent with previous reports, erectile dysfunction is the most common complication from priapism and its treatment, occurring in the majority of men.
Retroviral Env Glycoprotein Trafficking and Incorporation into Virions
Authors: Murakami Tsutomu
Published: July 2012

Together with the Gag protein, the Env glycoprotein is a major retroviral structural protein and is essential for forming infectious virus particles. Env is synthesized, processed, and transported to certain microdomains at the plasma membrane and takes advantage of the same host machinery for its trafficking as that used by cellular glycoproteins. Incorporation of Env into progeny virions is probably mediated by the interaction between Env and Gag, in some cases with the additional involvement of certain host factors. Although several general models have been proposed to explain the incorporation of retroviral Env glycoproteins into virions, the actual mechanism for this process is still unclear, partly because structural data on the Env protein cytoplasmic tail is lacking. This paper presents the current understanding of the synthesis, trafficking, and virion incorporation of retroviral Env proteins.
Propagation Behavior of Virus Codes in the Situation That Infected Computers Are Connected to the Internet with Positive Probability
Authors: Yang Lu-Xing , Yang Xiaofan
Published: July 2012

All the known models describing the propagation of virus codes were based on the assumption that a computer is uninfected at the time it is being connected to the Internet. In reality, however, it is much likely that infected computers are connected to the Internet. This paper is intended to investigate the propagation behavior of virus programs provided infected computers are connected to the Internet with positive probability. For that purpose, a new model characterizing the spread of computer virus is proposed. Theoretical analysis of this model indicates that (1) there is a unique (viral) equilibrium, and (2) this equilibrium is globally asymptotically stable. Further study shows that, by taking active measures, the percentage of infected computers can be made below an acceptable threshold value.
Laparoscopic Gastric Plication for the Treatment of Morbid Obesity: A Review
Authors: Kourkoulos Michael , Giorgakis Emmanouil , Kokkinos Charalampos , Mavromatis Theodoros , Griniatsos John , Nikiteas Nikolaos , Tsigris Christos
Published: July 2012

Introduction. Laparoscopic greater curvature plication is an operation that is gaining ground in the treatment of morbid obesity, as it appears to replicate the results of laparoscopic sleeve gastrectomy with fewer complications.Aim. Review of current literature, especially results on weight loss and complications.Method. 11 (eleven) published articles on laparoscopic gastric plication, of which 1 preclinical study, 8 prospective studies for a total of 521 patients and 2 case reports of unusual complications.Results. Reported Paracentage of EWL in all studies is comparable to Laparoscopic Sleeve Gastrectomy (around 50% in 6 months, 60–65% in 12 months, 60–65% in 24 months) and total complication rate is at 15,1% with minor complications in 10,7%, major complications in 4,4%. Reoperation rate was 3%, conversion rate was 0,2%, and mortality was zero.Conclusion. Current literature on gastric plication and its modifications is limited and sketchy at times. Low cost, short hospital stay, absence of prosthetic material, and reversibility make it an attractive option. Initial data show that LGCP is effective for short- and medium-term weight loss, complication and reoperation rates are low, and GERD symptoms are unaffected. More data is required, and randomized control trials must be completed in order to reach safe conclusions.
Efficient Variational Approaches for Deformable Registration of Images
Authors: Akinlar Mehmet Ali , Kurulay Muhammet , Secer Aydin , Bayram Mustafa
Published: July 2012

Dirichlet, anisotropic, and Huber regularization terms are presented for efficient registration of deformable images. Image registration, an ill‐posed optimization problem, is solved using a gradient‐descent‐based method and some fundamental theorems in calculus of variations. Euler‐Lagrange equations with homogeneous Neumann boundary conditions are obtained. These equations are discretized by multigrid and finite difference numerical techniques. The method is applied to the registration of brain MR images of size 65 × 65. Computational results indicate that the presented method is quite fast and efficient in the registration of deformable medical images.
The Janus Face of Lipids in Human Breast Cancer: How Polyunsaturated Fatty Acids Affect Tumor Cell Hallmarks
Authors: Chénais Benoît , Blanckaert Vincent
Published: July 2012

For several years, lipids and especially and polyunsaturated fatty acids (PUFAs) receive much attention in human health. Epidemiological studies tend to correlate a PUFA-rich diet with a reduced incidence of cancer, including breast cancer. However, the molecular and cellular mechanisms supporting the effect of PUFAs in breast cancer cells remain relatively unknown. Here, we review some recent progress in understanding the impact that PUFA may have on breast cancer cell proliferation, apoptosis, migration, and invasion. While most of the results obtained with docosahexaenoic acid and/or eicosapentaenoic acid show a decrease of tumor cell proliferation and/or aggressivity, there is some evidence that other lipids, which accumulate in breast cancer tissues, such as arachidonic acid may have opposite effects. Finally, lipids and especially PUFAs appear as potential adjuvants to conventional cancer therapy.
Wide Angular Aperture Circularly Polarized Low-Profile EBG Antenna
Authors: Salah Toubet Moustapha , Ahmad Ahmad Elsayed , Chantalat Regis , Hajj Mohamad , Arnaud Eric , Jecko Bernard , Monediere Thierry , Boustie Christelle , Palacin Baptiste
Published: July 2012

This paper describes the design of a compact and wide angular circularly polarized low-profile EBG antenna. Except at 3.7 GHz and forθlower than −25° in the plane equals to 0°, the modelized structure provides an axial ratio lower than 3 dB, over a wide angular aperture of 60° and over a bandwidth of 5.3% ([3.7 GHz–3.9 GHz]). It has a very low height of 11.9 mm (/7 at 3.8 GHz). A prototype has been manufactured, and the measured performances, considering the tolerance of the measurement base (±0.5 dB), are quite similar to the simulated ones.
CFD Modeling of Boiling Flow in PSBT 5×5 Bundle
Authors: Lo Simon , Osman Joseph
Published: July 2012

Three-dimensional computational fluid dynamics (CFD) method was used to model the boiling two-phase flow in one of the PSBT 5-by-5 rod bundle tests. The rod bundle with all the spacers was modeled explicitly using unstructured computational grids. The six-equation, two-fluid model with the wall boiling model was used to model the boiling two-phase flows in the bundle. The computed void fractions compare well with the measured data at the measuring plane. In addition to the averaged void data, the CFD results give a very detailed picture of the flow and void distributions in the bundle and how they are affected by solid structures in the flow paths such as the spacer grids and mixing vanes.
Transmetatarsal Amputation: A Case Series and Review of the Literature
Authors: McCallum Ryan , Tagoe Mark
Published: July 2012

Foot ulceration is a major cause of morbidity amongst patients with diabetes. In severe cases of ulceration, osteomyelitis and amputation can ensue. A distinct lack of agreement exists on the most appropriate level of amputation in cases of severe foot ulceration/infection to provide predictable healing rates. This paper provides an overview of the transmetatarsal amputation (TMA) as a limb salvage procedure and is written with the perspective and experiences of the Department of Podiatric Surgery at West Middlesex University Hospital (WMUH). We have reflected on the cases of 11 patients (12 feet) and have found the TMA to be an effective procedure in the management of cases of severe forefoot ulceration and infection.
Novel Genes from Formation to Function
Authors: Ponce Rita , Martinsen Lene , Vicente Luís M. , Hartl Daniel L.
Published: July 2012

The study of the evolution of novel genes generally focuses on the formation of new coding sequences. However, equally important in the evolution of novel functional genes are the formation of regulatory regions that allow the expression of the genes and the effects of the new genes in the organism as well. Herein, we discuss the current knowledge on the evolution of novel functional genes, and we examine in more detail the youngest genes discovered. We examine the existing data on a very recent and rapidly evolving cluster of duplicated genes, theSdicgene cluster. This cluster of genes is an excellent model for the evolution of novel genes, as it is very recent and may still be in the process of evolving.
Positive Periodic Solutions of Second‐Order Differential Equations with Delays
Authors: Li Yongxiang
Published: July 2012

The existence results of positive ω‐periodic solutions
are obtained for the second‐order differential equation with delays −u″ + a(t) = f(t, u(t − τ1), …, u(t − τn)), where a ∈ C(ℝ, (0, ∞)) is a ω‐periodic function, f : ℝ × [0, ∞) n → [0, ∞) is a continuous function, which is ω‐periodic in t, and τ1, τ2, …, τn are positive constants. Our discussion is based on the fixed point index theory in cones.
Appendiceal Mucocele Diagnosed in Patients with Inflammatory Bowel Disease Using Endoscopic Ultrasound
Authors: Wong Uni , Darwin Peter
Published: July 2012

When a bulging appendiceal orifice is observed during surveillance colonoscopy, the possibility of appendiceal mucocele must be considered. Appendiceal mucocele is a rare group of lesions characterized by mucinous distension of the appendiceal lumen with the dangerous potential to rupture, resulting in the development of pseudomyxoma peritonei. Early recognition and diagnosis of appendiceal mucocele can prevent the dreaded complication of pseudomyxoma peritonei but it requires a high index of suspicion. Patients with inflammatory bowel disease are at increased risk for colorectal neoplasm but neoplasm of the appendix is infrequently reported. We report two of the first cases of appendiceal mucoceles diagnosed in patients with inflammatory bowel disease using endoscopic ultrasound.
The Role of S100A12 as a Systemic Marker of Inflammation
Authors: Meijer B. , Gearry R. B. , Day A. S.
Published: July 2012

S100A12 is a member of the S100 family of calcium-binding proteins with important extracellular activities. In recent years, investigators across a number of fields have delineated the patterns of S100A12 expression in a variety of conditions. These data suggest that S100A12 can be used as a valuable serum inflammatory marker.
Recent Advances in Dermatitis Herpetiformis
Authors: Nakajima Kimiko
Published: July 2012

Dermatitis herpetiformis is an autoimmune bullous disease that is associated with gluten sensitivity which typically presents as celiac disease. As both conditions are multifactorial disorders, it is not clear how specific pathogenetic mechanisms may lead to the dysregulation of immune responses in the skin and small bowel, respectively. Recent studies have demonstrated that IgA and antibodies against epidermal transglutaminase 3 play an important role in the pathogenesis of dermatitis herpetiformis. Here, we review recent immunopathological progress in understanding the pathogenesis of dermatitis herpetiformis.
Quercetin and Sesamin Protect Dopaminergic Cells from MPP+-Induced Neuroinflammation in a Microglial (N9)-Neuronal (PC12) Coculture System
Authors: Bournival Julie , Plouffe Marilyn , Renaud Justine , Provencher Cindy , Martinoli Maria-Grazia
Published: July 2012

A growing body of evidence indicates that the majority of Parkinson’s disease (PD) cases are associated with microglia activation with resultant elevation of various inflammatory mediators and neuroinflammation. In this study, we investigated the effects of 2 natural molecules, quercetin and sesamin, on neuroinflammation induced by the Parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP+) in a glial-neuronal system. We first established that quercetin and sesamin defend microglial cells against MPP+-induced increases in the mRNA or protein levels of 3 pro-inflammatory cytokines (interleukin-6, IL-1βand tumor necrosis factor-alpha), as revealed by real time-quantitative polymerase chain reaction and enzyme-linked immunoabsorbent assay, respectively. Quercetin and sesamin also decrease MPP+-induced oxidative stress in microglial cells by reducing inducible nitric oxide synthase protein expression as well as mitochondrial superoxide radicals. We then measured neuronal cell death and apoptosis after MPP+activation of microglia, in a microglial (N9)-neuronal (PC12) coculture system. Our results revealed that quercetin and sesamin rescued neuronal PC12 cells from apoptotic death induced by MPP+activation of microglial cells. Altogether, our data demonstrate that the phytoestrogen quercetin and the lignan sesamin diminish MPP+-evoked microglial activation and suggest that both these molecules may be regarded as potent, natural, anti-inflammatory compounds.
The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination
Authors: Skelhorne-Gross Graham , Nicol Christopher J. B.
Published: July 2012

Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)γactivation protects against tumourigenesis, results from a few clinical trials using PPARγligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPARγligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)αagonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPARγligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPARγligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPARγligands in combination with other agents in the treatment and management of several cancers.
Doppler Parameters of Hepatic and Renal Hemodynamics in Patients with Liver Cirrhosis
Authors: Popov D. , Krasteva R. , Ivanova R. , Mateva L. , Krastev Z.
Published: July 2012

Introduction. There are limited studies on simultaneous evaluation of liver and renal blood flow using Doppler methods. We evaluated and compared the changes of liver and renal Doppler US parameters in patients with liver cirrhosis according to the degree of liver disease.Material and Methods. We assessed a large spectrum of liver and renal Doppler US parameters in 67 patients with liver cirrhosis.Results. Significant differences between Child’s classes or score, as well as MELD score, were observed in all investigated intrarenal blood flow Doppler US parameters, except renal artery peak systolic velocity, but only in some of the hepatic ones. The deviations of renal Doppler US parameters were also related with the complications of liver cirrhosis, as well as serum urea and creatinine levels. There was relationship between Doppler US parameters of hepatic artery and the corresponding renal artery Doppler US parameters. The changes of Doppler US parameters were age independent.Conclusion. Our results show, renal Doppler US parameters correlate with the severity and complications of liver cirrhosis. Because of dynamic deviations of renal Doppler US parameters with advance of liver cirrhosis, we recommend Doppler US of renal artery as a part of follow up of these patients.
Neutrophils Promote Liver Metastasis via Mac-1–Mediated Interactions with Circulating Tumor Cells
Authors: Spicer Jonathan D. , McDonald Braedon , Cools-Lartigue Jonathan J. , Chow Simon C. , Giannias Betty , Kubes Paul , Ferri Lorenzo E.
Published: July 2012

Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, it remains unclear whether neutrophils play an active causal role in the metastatic cascade. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and, thereby, influence metastasis. Neutrophil depletion before cancer cell inoculation resulted in a decreased number of gross metastases in an intrasplenic model of liver metastasis. This effect was reversed when inflamed neutrophils were co-inoculated with cancer cells. In addition, early adhesion within liver sinusoids was inhibited in the absence of neutrophils and partially restored with a short perfusion of isolated activated neutrophils. Intravital microscopy showed that cancer cells adhered directly on top of arrested neutrophils, indicating that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver parenchyma. The adhesion of lipopolysaccharide-activated neutrophils to cancer cells was mediated by neutrophil Mac-1/ICAM-1. Our findings, therefore, show a novel role for neutrophils in the early adhesive steps of liver metastasis. Cancer Res; 72(16); 3919–27. ©2012 AACR.
Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche
Authors: Sceneay Jaclyn , Chow Melvyn T. , Chen Anna , Halse Heloise M. , Wong Christina S.F. , Andrews Daniel M. , Sloan Erica K. , Parker Belinda S. , Bowtell David D. , Smyth Mark J. , Möller Andreas
Published: July 2012

Hypoxia within a tumor acts as a strong selective pressure that promotes angiogenesis, invasion, and metastatic spread. In this study, we used immune competent bone marrow chimeric mice and syngeneic orthotopic mammary cancer models to show that hypoxia in the primary tumor promotes premetastatic niche formation in secondary organs. Injection of mice with cell-free conditioned medium derived from hypoxic mammary tumor cells resulted in increased bone marrow–derived cell infiltration into the lung in the absence of a primary tumor and led to increased metastatic burden in mammary and melanoma experimental metastasis models. By characterizing the composition of infiltrating bone marrow–derived cells, we identified CD11b+/Ly6Cmed/Ly6G+ myeloid and CD3−/NK1.1+ immune cell lineages as key constituents of the premetastatic niche. Furthermore, the cytotoxicity of natural killer (NK) cells was significantly decreased, resulting in a reduced antitumor response that allowed metastasis formation in secondary organs to a similar extent as ablation of NK cells. In contrast, metastatic burden was decreased when active NK cells were present in premetastatic lungs. Together, our findings suggest that primary tumor hypoxia provides cytokines and growth factors capable of creating a premetastatic niche through recruitment of CD11b+/Ly6Cmed/Ly6G+ myeloid cells and a reduction in the cytotoxic effector functions of NK cell populations. Cancer Res; 72(16); 3906–11. ©2012 AACR.
Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis
Authors: Dulak Austin M. , Schumacher Steven E. , van Lieshout Jasper , Imamura Yu , Fox Cameron , Shim Byoungyong , Ramos Alex H. , Saksena Gordon , Baca Sylvan C. , Baselga Jose , Tabernero Josep , Barretina Jordi , Enzinger Peter C. , Corso Giovanni , Roviello Franco , Lin Lin , Bandla Santhoshi , Luketich James D. , Pennathur Arjun , Meyerson Matthew , Ogino Shuji , Shivdasani Ramesh A. , Beer David G. , Godfrey Tony E. , Beroukhim Rameen , Bass Adam J.
Published: July 2012

A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential use of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared with colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions. Cancer Res; 72(17); 4383–93. ©2012 AACR.
Differentially Expressed Genes Regulating the Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer
Authors: Lee Sangjun , Stewart Sheila , Nagtegaal Iris , Luo Jingqin , Wu Yun , Colditz Graham , Medina Dan , Allred D. Craig
Published: July 2012

Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain largely unknown. We used gene expression profiling of human DCIS (n = 53) and invasive breast cancer (n = 51) to discover uniquely expressed genes that may also regulate progression. There were 470 total differentially expressed genes (≥2-fold; P < 0.05). Elevated expression of genes involved in synthesis and organization of extracellular matrix was particularly prominent in the epithelium of invasive breast cancer. The degree of overlap of the genes with nine similar studies in the literature was determined to help prioritize their potential importance, resulting in 74 showing overlap in ≥2 studies (average 3.6 studies/gene; range 2–8 studies). Using hierarchical clustering, the 74-gene profile correctly categorized 96% of samples in this study and 94% of samples from 3 similar independent studies. To study the progression of DCIS to invasive breast cancer in vivo, we introduced human DCIS cell lines engineered to express specific genes into a “mammary intraductal DCIS” xenograft model. Progression of xenografts to invasive breast cancer was dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, including a protease inhibitor (CSTA) and genes involved in cell adhesion and signaling (FAT1, DST, and TMEM45A), strongly suggesting that they normally function to suppress progression. In summary, we have identified unique gene expression profiles of human DCIS and invasive breast cancer, which include novel genes regulating tumor progression. Targeting some of these genes may improve the detection, diagnosis, and therapy of DCIS. Cancer Res; 72(17); 4574–86. ©2012 AACR.
Worth Adapting? Revisiting the Usefulness of Outcome-Adaptive Randomization
Authors: Lee J. Jack , Chen Nan , Yin Guosheng
Published: July 2012

Outcome-adaptive randomization allocates more patients to the better treatments as the information accumulates in the trial. Is it worth it to apply outcome-adaptive randomization in clinical trials? Different views permeate the medical and statistical communities. We provide additional insights to the question by conducting extensive simulation studies. Trials are designed to maintain the type I error rate, achieve a specified power, and provide better treatment to patients. Generally speaking, equal randomization requires a smaller sample size and yields a smaller number of nonresponders than adaptive randomization by controlling type I and type II errors. Conversely, adaptive randomization produces a higher overall response rate than equal randomization with or without expanding the trial to the same maximum sample size. When there are substantial treatment differences, adaptive randomization can yield a higher overall response rate as well as a lower average sample size and a smaller number of nonresponders. Similar results are found for the survival endpoint. The differences between adaptive randomization and equal randomization quickly diminish with early stopping of a trial due to efficacy or futility. In summary, equal randomization maintains balanced allocation throughout the trial and reaches the specified statistical power with a smaller number of patients in the trial. If the trial's results are positive, equal randomization may lead to early approval of the treatment. Adaptive randomization focuses on treating patients best in the trial. Adaptive randomization may be preferred when the difference in efficacy between treatments is large or when the number of patients available is limited. Clin Cancer Res; 18(17); 4498–507. ©2012 AACR.
Myeloma-Specific Multiple Peptides Able to Generate Cytotoxic T Lymphocytes: A Potential Therapeutic Application in Multiple Myeloma and Other Plasma Cell Disorders
Authors: Bae Jooeun , Smith Robert , Daley John , Mimura Naoya , Tai Yu-Tzu , Anderson Kenneth C. , Munshi Nikhil C.
Published: July 2012

Purpose: The efficacy of peptide vaccines may be enhanced by stimulating immune cells with multiple peptides derived from distinct tumor-associated antigens. We have evaluated the heteroclitic XBP1-US184–192 (YISPWILAV), heteroclitic XBP1-SP367–375 (YLFPQLISV), native CD138260–268 (GLVGLIFAV), and native CS1239–247 (SLFVLGLFL) peptides, which have strong HLA-A2 affinity and immunogenicity in combination, for their ability to elicit multiple myeloma antigen–specific responses.

Experimental Design: Multipeptide-specific cytotoxic T lymphocytes (MP-CTL) were generated by the stimulation of CD3+ T lymphocytes from HLA-A2+ individuals with either autologous mature dendritic cells or T2 cells pulsed with a cocktail of these four peptides.

Results: The peptide cocktail did not compromise tumor antigen–specific activity of CTLs. MP-CTLs displayed increased total, effector memory (CCR7−CD45RO+), and activated (CD69+) CD3+CD8+ T lymphocytes. In addition, MP-CTL showed IFN-γ production, cell proliferation, and cytotoxicity against HLA-A2+ multiple myeloma cells, including cells of HLA-A2+ patients with multiple myeloma. Importantly, MP-CTLs showed specific responses in functional assays to each relevant peptide but not to an irrelevant HLA-A2–specific CMV pp65 (NLVPMVATV) peptide.

Conclusions: These results highlight the potential therapeutic application of vaccination with a cocktail of HLA-A2–specific peptides to induce CTLs with a broad spectrum of immune responses against multiple myeloma antigens. Clin Cancer Res; 18(17); 4850–60. ©2012 AACR.
Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model
Authors: Fraedrich Katharina , Schrader Jörg , Ittrich Harald , Keller Gunhild , Gontarewicz Artur , Matzat Verena , Kromminga Arno , Pace Andrea , Moll Jürgen , Bläker Michael , Lohse Ansgar W. , Hörsch Dieter , Brümmendorf Tim H. , Benten Daniel
Published: July 2012

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.

Experimental Design: Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.

Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.

Conclusions: These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs. Clin Cancer Res; 18(17); 4621–32. ©2012 AACR.
Overestimation of the Effect Size in Group Sequential Trials
Authors: Zhang Jenny J. , Blumenthal Gideon M. , He Kun , Tang Shenghui , Cortazar Patricia , Sridhara Rajeshwari
Published: July 2012

Group sequential designs (GSD), which provide for interim monitoring of efficacy data and allow potential early trial termination while preserving the type I error rate, have become commonplace in oncology clinical trials. Although ethically appealing, GSDs tend to overestimate the true treatment effect size at early interim analyses. Overestimation of the treatment effect may exaggerate the benefit of a drug and provide imprecise information for physicians and their patients about a drug's true effect. The cause and effect of such a phenomenon are generally not well understood by many in clinical trial practice. In this article, we provide a graphical explanation for why the phenomenon of overestimation in GSDs occurs. The potential overestimation of the magnitude of the treatment effect is of particular concern in oncology, in which the more subjective endpoint of progression-free survival has increasingly been adopted as the primary endpoint in pivotal phase III trials. Clin Cancer Res; 18(18); 4872–6. ©2012 AACR.
Specific Mutations inKRASCodons 12 and 13, and Patient Prognosis in 1075BRAFWild-Type Colorectal Cancers
Authors: Imamura Yu , Morikawa Teppei , Liao Xiaoyun , Lochhead Paul , Kuchiba Aya , Yamauchi Mai , Qian Zhi Rong , Nishihara Reiko , Meyerhardt Jeffrey A. , Haigis Kevin M. , Fuchs Charles S. , Ogino Shuji
Published: July 2012

Purpose: To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared with codon 13 mutations, we hypothesized that KRAS codon 12–mutated colorectal cancers might behave more aggressively than KRAS wild-type tumors and codon 13 mutants.

Experimental design: Using molecular pathological epidemiology database of 1,261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1,075 BRAF wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality HR, adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation.

Results: Compared with patients with KRAS wild-type/BRAF wild-type cancers (N = 635), those with KRAS codon 12 mutations (N = 332) experienced significantly higher colorectal cancer–specific mortality [log-rank P = 0.0001; multivariate HR, 1.30; 95% confidence interval (CI), 1.02–1.67; P = 0.037], whereas KRAS codon 13–mutated cases (N = 108) were not significantly associated with prognosis. Among the seven most common KRAS mutations, c.35G>T (p.G12V; N = 93) was associated with significantly higher colorectal cancer–specific mortality (log-rank P = 0.0007; multivariate HR, 2.00; 95% CI, 1.38–2.90, P = 0.0003) compared with KRAS wild-type/BRAF wild-type cases.

Conclusions: KRAS codon 12 mutations (in particular, c.35G>T), but not codon 13 mutations, are associated with inferior survival in BRAF wild-type colorectal cancer. Our data highlight the importance of accurate molecular characterization in colorectal cancer. Clin Cancer Res; 18(17); 4753–63. ©2012 AACR.
Prolonged Postovulatory Proinflammatory Signaling in the Fallopian Tube Epithelium May Be Mediated through a BRCA1/DAB2 Axis
Authors: Tone Alicia A. , Virtanen Carl , Shaw Patricia , Brown Theodore J.
Published: July 2012

Purpose: To assess inflammation-related gene expression in nonmalignant fallopian tube epithelium (FTE) from BRCA1/2 mutation carriers and control patients obtained during the luteal and follicular phase, and to determine the impact of BRCA1 and disabled homolog 2 (DAB2) on NF-κB–mediated proinflammatory signaling.

Experimental Design: A list of inflammation-related and NF-κB–responsive genes was compiled through gene set enrichment and PubMed database search, corresponding probes identified, and unpaired t tests conducted to identify differentially expressed genes in previously profiled FTE samples. ES2 and A549 cells were cotransfected with DAB2- or BRCA1-targeting siRNA and an NF-κB–responsive luciferase reporter, treated with TNF-α and luciferase activity determined. To determine whether DAB2 or BRCA1 alters mRNA expression of NF-κB target genes, cells were transfected with siRNA, treated with TNF-α, and harvested for total RNA extraction and quantitative real-time PCR.

Results: A subset of BRCA1-mutated luteal phase samples previously found to group with adnexal high–grade serous carcinomas (HGSCs) differentially expressed 124 inflammation–associated probesets relative to remaining FTE samples. These samples also differentially expressed 264 probes relative to other luteal phase samples exposed to the same postovulatory environment. Both BRCA1- and DAB2–targeting siRNA increased TNF-α-induced NF-κB activity and mRNA expression of NF-κB–dependent target gene SOD2 relative to nontargeting siRNA, suggesting that both proteins repress proinflammatory signaling.

Conclusions: These data provide evidence of elevated proinflammatory signaling in a subset of BRCA1-mutated luteal phase FTE, consistent with an altered response to ovulation-associated cytokines. Furthermore, both BRCA1 and DAB2 affect NF-κB activity, indicating a novel link between BRCA mutation status, ovulation, and predisposition to HGSC. Clin Cancer Res; 18(16); 4334–44. ©2012 AACR.
Genetically Defined Subsets of Human Pancreatic Cancer Show Unique In Vitro Chemosensitivity
Authors: Cui Yunfeng , Brosnan Jacqueline A. , Blackford Amanda L. , Sur Surojit , Hruban Ralph H. , Kinzler Kenneth W. , Vogelstein Bert , Maitra Anirban , Diaz Luis A. , Iacobuzio-Donahue Christine A. , Eshleman James R.
Published: July 2012

Purpose: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs.

Experimental Design: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control).

Results: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC.

Conclusions: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo. Clin Cancer Res; 18(23); 6519–30. ©2012 AACR.
A New Approach to Reducing Postsurgical Cancer Recurrence: Perioperative Targeting of Catecholamines and Prostaglandins
Authors: Neeman Elad , Zmora Oded , Ben-Eliyahu Shamgar
Published: July 2012

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases—the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous “immune-resistant” tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous β-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period. Clin Cancer Res; 18(18); 4895–902. ©2012 AACR.
Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901
Authors: Torti Vince R. , Wojciechowicz Donald , Hu Wenyue , John-Baptiste Annette , Evering Winston , Troche Gabriel , Marroquin Lisa D. , Smeal Tod , Yamazaki Shinji , Palmer Cynthia L. , Burns-Naas Leigh Ann , Bagrodia Shubha
Published: July 2012

Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal–regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor–induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers. Mol Cancer Ther; 11(10); 2274–83. ©2012 AACR.