bluuebunny/crossref_metadata_2025 huggingface dataset:
Simple Motion Evasion Differential Game of Many Pursuers and One Evader with Integral Constraints on Control Functions of Players
Authors: Ibragimov Gafurjan , Salleh Yusra
Published: October 2012

We consider an evasion differential game of many pursuers and one evader with integral constraints in the plane. The game is described by simple equations. Each component of the control functions of players is subjected to integral constraint. Evasion is said to be possible if the state of the evader does not coincide with that of any pursuer. Strategy of the evader is constructed based on controls of the pursuers with lag. A sufficient condition of evasion from many pursuers is obtained and an illustrative example is provided.
Numerical Studies of the Gas-Solid Hydrodynamics at High Temperature in the Riser of a Bench-Scale Circulating Fluidized Bed
Authors: Hodapp Maximilian J. , Ramirez-Behainne Jhon J. , Mori Milton , Goldstein Leonardo
Published: October 2012

The hydrodynamics of circulating fluidized beds (CFBs) is a complex phenomenon that can drastically vary depending on operational setup and geometrical configuration. A research of the literature shows that studies for the prediction of key variables in CFB systems operating at high temperature still need to be implemented aiming at applications in energy conversion, such as combustion, gasification, or fast pyrolysis of solid fuels. In this work the computational fluid dynamics (CFD) technique was used for modeling and simulation of the hydrodynamics of a preheating gas-solid flow in a cylindrical bed section. For the CFD simulations, the two-fluid approach was used to represent the gas-solid flow with the k-epsilon turbulence model being applied for the gas phase and the kinetic theory of granular flow (KTGF) for the properties of the dispersed phase. The information obtained from a semiempirical model was used to implement the initial condition of the simulation. The CFD results were in accordance with experimental data obtained from a bench-scale CFB system and from predictions of the semiempirical model. The initial condition applied in this work was shown to be a viable alternative to a more common constant solid mass flux boundary condition.
Diagnosis of Rosai-Dorfman Disease in Elderly Female on Fine Needle Aspiration Cytology: A Case Report
Authors: Aziz Meher , Ray Prasenjit Sen , Haider Nazima , Rathore Sumit Prakash
Published: October 2012

Rosai-Dorfman disease (RDD) is a rare benign disorder of histiocytic proliferation that usually presents with bilateral cervical lymphadenopathy in children. We describe the case of a 50-year-old lady suffering from this disease who presented with generalized lymphadenopathy and a left sided chest wall lump. Fine needle aspiration cytology (FNAC) from all the lesions showed abundant benign histiocytes with lymphophagocytosis which was compatible with the diagnosis of RDD. This case is being reported for its rarity in presentation in an elderly female with both generalized nodal as well as extranodal manifestations.
Some Fixed‐Point Results for a G‐Weak Contraction in G‐Metric Spaces
Authors: Shatanawi Wasfi , Postolache Mihai
Published: October 2012

We introduce the concepts of a G‐weak contraction
mapping of types A and B and we establish some fixed point theorems for a
G‐weak contraction mapping of types A and B in complete G‐metric spaces.
Our results generalize several well‐known comparable results in the literature.
The Role of Anticoagulation Clinics in the Era of New Oral Anticoagulants
Authors: Testa Sophie , Paoletti Oriana , Zimmermann Anke , Bassi Laura , Zambelli Silvia , Cancellieri Emilia
Published: October 2012

Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs) have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs.
Medium- and Short-Term Interventions with Ma-Pi 2 Macrobiotic Diet in Type 2 Diabetic Adults of Bauta, Havana
Authors: Porrata-Maury Carmen , Hernández-Triana Manuel , Rodríguez-Sotero Eduardo , Vilá-Dacosta-Calheiros Raúl , Hernández-Hernández Héctor , Mirabal-Sosa Mayelín , Campa-Huergo Concepción , Pianesi Mario
Published: October 2012

Background.In Cuba, the Ma-Pi 2 macrobiotic diet has shown positive results in 6-month assays with type 2 diabetic patients. The objective of this study was to assess the influence of this diet at short and medium terms.Methods.Sixty-five type 2 diabetic volunteers were included for dietary intervention, institutionally based for 21 days and followed later at home, until completing 3 months. 54 of them stayed until assay end. Before intervention, and after both assay periods, they were submitted to anthropometric records, body composition analyses and measurements of serum biochemical indicators, glycemic profile in capillary blood, blood pressure, and medication consumption; food intake was evaluated by the 3-day dietary recall.Results.During the intervention, the energy intake was 200 kcal higher at instance of more complex carbohydrates and dietary fiber and despite less fat and protein. Blood pressure and serum biochemical indicators decreased significantly in both periods; the safety nutritional indicators (hemoglobin, serum total proteins, and albumin) showed no variations. The global cardiovascular risk decreased and insulin consumption dropped by 46% and 64%, in both periods, respectively.Conclusions.The Ma-Pi 2 macrobiotic diet was a successful therapy at short term and after 3-month home-based intervention, for type 2 diabetics.
Invalidity of SUV Measurements of Lesions in Close Proximity to Hot Sources due to “Shine-Through” Effect on FDG PET-CT Interpretation
Authors: Liu Yiyan
Published: October 2012

It is well known that many technical and physiologic factors can affect the reliability of the standardized uptake value (SUV) on FDG PET-CT. Another potential problem of which we may be aware but has not been previously discussed is significant SUV overestimation of lesions in the direct neighborhood of large hot sources, namely, areas with high FDG uptake or activity such as a tumor, myocardium, urinary bladder, kidney, or gastrointestinal tract. The magnitude of SUV overestimation of the lesions directly neighboring the large hot sources is varied among the different cases, and it is possibly secondary to “shine-through” effect of the hot sources, which would warrant further systematic investigation such as phantom simulation experiment. If the lesion is in the close territory of the hot source, measured SUV is often overestimated and invalid. Visual interpretation should be used for evaluation of FDG avidity of the lesion.
Study ofαB-Crystallin Expression in Gerbil BCAO Model of Transient Global Cerebral Ischemia
Authors: Li Ting , Mo Xiaoye , Jiang Zheng , He Wenfang , Lu Wei , Zhang He , Zhang Jie , Zeng Liuwang , Yang Binbin , Xiao Han , Hu Zhiping
Published: October 2012

αB-crystallin (α-BC), the fifth member of mammalian small heat shock protein family (HspB5), is known to be expressed in many tissues and has a distinctive interaction with cytoskeleton components. In this study, we investigated thatα-BC and microtubule-associated protein-2 (MAP-2), a neuron-specific cytoskeleton protein, were coexpressed in neurons of Gerbil cortex, while in subcortex Gerbil brains, we found that several MAP-2-negative glia cells also expressα-BC. When subjected to 10-minute bilateral carotid artery occlusion (BCAO), an increment was observed inα-BC-positive cells after 6-hour reperfusion and peaked at around 7 days after. In the same circumstances, the number and the staining concentration of MAP-2 positive neurons significantly decreased immediately after 6-hour reperfusion, followed by a slow recovery, which is consistent with the increase ofα-BC. Our results suggested thatα-BC plays an important role in brain ischemia, providing the early protection of neurons by giving intracellular supports through the maintenance of cytoskeleton and extracellular supports through the protection of glia cells.
Smoking Cessation Intervention in a Cardiovascular Hospital Based Clinical Setting
Authors: Samaan Zainab , Nowacki Barb , Schulze Karleen , Magloire Patrick , Anand Sonia S.
Published: October 2012

Introduction. Smoking is a leading cause of morbidity and mortality globally and it is a significant modifiable risk factor for cardiovascular disease (CVD) and other chronic diseases. Efforts to encourage and support smokers to quit are critical to prevent premature smoking-associated morbidity and mortality. Hospital settings are seldom equipped to help patients to quit smoking thus missing out a valuable opportunity to support patients at risk of smoking complications. We report the impact of a smoking cessation clinic we have established in a tertiary care hospital setting to serve patients with CVD. Methods. Patients received behavioural and pharmacological treatments and were followed up for a minimum of 6 months (mean 541 days, SD 197 days). The main study outcome is ≥50% reduction in number of cigarettes smoked at followup. Results. One hundred and eighty-six patients completed ≥6 months followup. More than half of the patients (52.7%) achieved ≥50% smoking reduction at follow up. Establishment of a plan to quit smoking and use of nicotine replacement therapy (NRT) were significantly associated with smoking reduction at followup. Conclusions. A hospital-based smoking cessation clinic is a beneficial intervention to bring about smoking reduction in approximately half of the patients.
Development and Validation of a Reversed‐Phase HPLC Method for the Estimation of Zolpidem in Bulk Drug and Tablets
Authors: Konoz E. , Mohsen Sarrafi A. H. , Abdolahnejad R. , Bahrami-Zonoz M.
Published: October 2012

In the present study an isocratic reversed‐phase high‐performance liquid chromatography method was developed for the estimation of zolpidem in bulk drug and pharmaceutical dosage forms. The quantification was carried out on C18 columns. A mixture of acetonitrile‐ammonium acetate (pH = 8.0, 0.02 M) (60 : 40 v/v) was used as the mobile phase, at flow rate of 1.0 mL/min and the determination wavelength at 245 nm. The retention time of zolpidem was found to be 3–5 min. The validation of the proposed method was carried out for specificity, linearity, accuracy, precision, limit of detection, limit of quantification, and robustness. The linear dynamic range was from 2.5 to 30 μg mL−1. Regression equation was found to be y = 0.1416x + 0.0183 with correlation coefficient r = 0.9996. The percentage recovery obtained for zolpidem was greater than 96.5%. Limit of quantification and limit of detection were found to be 2.5 μg mL−1 and 0.83 μg mL−1, respectively. The developed method can be used for routine quality control analysis of zolpidem in tablet formulations.
Infrared Optical Constants and Computational Studies of Neat Liquid -Butylethylether
Authors: Beć K. B. , Hawranek J. P.
Published: October 2012

Aliphatic ethers are of interest to researchers due to their wide application in the fuel, chemical, and pharmaceutical industry. In this paper we studied vibrational properties of neat liquidn-butylethylether (NBEE), including the determination of complex refractive index in the NIR and MIR range (11700–560 cm−1). The high absorption of neat liquid in the MIR range required the use of thin-film transmission recordings. The spectra analysis was based on conformational analysis and anharmonic calculations on B2PLYP/N07D level of theory. Final band assignments procedure was based on potential energy distributions. The theoretical investigation revealed that although 26 conformers of NBEE can be expected to exist in the liquid phase at 298 K, only few of them are essential for the forming of the spectrum. This study is important for the proper understanding of vibrational properties of other aliphatic ethers.
NF-κB Activity Regulates Mesenchymal Stem Cell Accumulation at Tumor Sites
Authors: Uchibori Ryosuke , Tsukahara Tomonori , Mizuguchi Hiroyuki , Saga Yasushi , Urabe Masashi , Mizukami Hiroaki , Kume Akihiro , Ozawa Keiya
Published: October 2012

Mesenchymal stem cells (MSC) accumulate at tumor sites when injected into tumor-bearing mice, perhaps offering cellular vectors for cancer-targeted gene therapy. However, the molecular mechanisms involved in MSC targeting the tumors are presently little understood. We focused on MSC–endothelial cell (EC) adhesion following TNF-α stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-α enhanced the adhesion of MSCs to endothelial cells in vitro. This adhesion was partially inhibited by blocking antibodies against vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4). It is well known that TNF-α induces VCAM-1 expression via the NF-κB signaling pathway. Parthenolide has an anti-inflammatory activity and suppressed NF-κB activity by inhibition of IκBα phosphorylation after TNF-α stimulation and strongly inhibited TNF-α–induced VCAM-1 expression on MSCs. In vivo imaging using luciferase-expressing MSCs revealed that the bioluminescent signal gradually increased at tumor sites in mice injected with untreated MSCs. In contrast, we observed very weak signals at tumor sites in mice injected with parthenolide-treated MSCs. Our results suggest that NF-κB activity regulates MSC accumulation at tumors, by inducing VCAM-1 and thereby its interaction with tumor vessel endothelial cells. These findings have implications for the ongoing development of efficient MSC-based gene therapies for cancer treatment. Cancer Res; 73(1); 364–72. ©2012 AACR.
Clinicopathological Features of Homologous Recombination–Deficient Epithelial Ovarian Cancers: Sensitivity to PARP Inhibitors, Platinum, and Survival
Authors: Mukhopadhyay Asima , Plummer Elizabeth R. , Elattar Ahmed , Soohoo San , Uzir Bisha , Quinn Jennifer E. , McCluggage W. Glenn , Maxwell Perry , Aneke Harriet , Curtin Nicola J. , Edmondson Richard J.
Published: October 2012

Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination–deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome. Cancer Res; 72(22); 5675–82. ©2012 AACR.
Raf Kinase Inhibitor RKIP Inhibits MDA-9/Syntenin-Mediated Metastasis in Melanoma
Authors: Das Swadesh K. , Bhutia Sujit K. , Sokhi Upneet K. , Azab Belal , Su Zhao-zhong , Boukerche Habib , Anwar Talha , Moen Erika L. , Chatterjee Devasis , Pellecchia Maurizio , Sarkar Devanand , Fisher Paul B.
Published: October 2012

Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma. Tumor array and cell line analyses confirmed an inverse relationship between expression of MDA-9 and RKIP during melanoma progression. We found that MDA-9 transcriptionally downregulated RKIP in support of a suggested cross-talk between these two proteins. Furthermore, MDA-9 and RKIP physically interacted in a manner that correlated with a suppression of FAK and c-Src phosphorylation, crucial steps necessary for MDA-9 to promote FAK/c-Src complex formation and initiate signaling cascades that drive the MDA-9–mediated metastatic phenotype. Finally, ectopic RKIP expression in melanoma cells overrode MDA-9–mediated signaling, inhibiting cell invasion, anchorage-independent growth, and in vivo dissemination of tumor cells. Taken together, these findings establish RKIP as an inhibitor of MDA-9–dependent melanoma metastasis, with potential implications for targeting this process therapeutically. Cancer Res; 72(23); 6217–26. ©2012 AACR.
Methylome Profiling Reveals Distinct Alterations in Phenotypic and Mutational Subgroups of Myeloproliferative Neoplasms
Authors: Nischal Sangeeta , Bhattacharyya Sanchari , Christopeit Maximilian , Yu Yiting , Zhou Li , Bhagat Tushar D. , Sohal Davendra , Will Britta , Mo Yongkai , Suzuki Masako , Pardanani Animesh , McDevitt Michael , Maciejewski Jaroslaw P. , Melnick Ari M. , Greally John M. , Steidl Ulrich , Moliterno Alison , Verma Amit
Published: October 2012

Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis than essential thrombocytosis or polycythemia vera, the molecular distinctions between these subgroups are not well elucidated. We conducted the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in polycythemia vera, essential thrombocytosis, and PMF samples compared with healthy controls. We determined that polycythemia vera and essential thrombocytosis are characterized by aberrant promoter hypermethylation, whereas PMF is an epigenetically distinct subgroup characterized by both aberrant hyper- and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non-CpG island loci, showing further qualitative differences between the disease subgroups. The differentially methylated genes in polycythemia vera and essential thrombocytosis were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1, LEF1, and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of myeloproliferative neoplasms (MPN) with TET2 mutations showed decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was shown by sensitivity of MPN-derived cell lines to decitabine. These results show epigenetic differences between PMF and polycythemia vera/essential thrombocytosis and reveal methylomic signatures of ASXL1 and TET2 mutations. Cancer Res; 73(3); 1076–85. ©2012 AACR.
Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma
Authors: Chan Isaac S. , Guy Cynthia D. , Chen Yuping , Lu Jiuyi , Swiderska-Syn Marzena , Michelotti Gregory A. , Karaca Gamze , Xie Guanhua , Krüger Leandi , Syn Wing-Kin , Anderson Blair R. , Pereira Thiago A. , Choi Steve S. , Baldwin Albert S. , Diehl Anna Mae
Published: October 2012

Hepatocellular carcinoma (HCC) typically develops in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts. Although Hh signaling generally regulates stromal–epithelial interactions that support epithelial viability, the role of Hh-dependent myofibroblasts in hepatocarcinogenesis is unknown. Here, we used human HCC samples, a mouse HCC model, and hepatoma cell/myofibroblast cocultures to examine the hypothesis that Hh signaling modulates myofibroblasts' metabolism to generate fuels for neighboring malignant hepatocytes. The results identify a novel paracrine mechanism whereby malignant hepatocytes produce Hh ligands to stimulate glycolysis in neighboring myofibroblasts, resulting in release of myofibroblast-derived lactate that the malignant hepatocytes use as an energy source. This discovery reveals new diagnostic and therapeutic targets that might be exploited to improve the outcomes of cirrhotic patients with HCCs. Cancer Res; 72(24); 6344–50. ©2012 AACR.
A Novel Evolutionarily Conserved Element Is a General Transcriptional Repressor of p21WAF1/CIP1
Authors: Xu Weiguo , Zhu Qi , Wu Zhenghua , Guo Hao , Wu Fengjuan , Mashausi Dhahiri S. , Zheng Chengjie , Li Dawei
Published: October 2012

The effective induction of p21WAF1/CIP1/Cdkn1a (p21) expression in p53-negative cancer cells is an important avenue in cancer management. We investigated the ability of various common chemotherapeutic drugs to induce p21 expression in p53-negative cancer cells and showed that the induction of p21 expression by oxaliplatin is caused by the derepression of a previously unrecognized negative regulatory element with a Sp1/Sp3 palindrome sequence core at −216 to −236 of the p21 proximal promoter. Electrophoretic mobility shift and antibody super-shift assays confirmed the specific binding of Sp1/Sp3, and showed that the oxaliplatin-mediated derepression of p21 transcription was associated with an increased Sp1/Sp3 phosphorylation and binding affinity to the oxaliplatin-responsive element. A search of the ENCODE database for vertebrate-conserved genomic elements identified the Sp1/Sp3 palindrome element as the only vertebrate-conserved element within the 500-bp proximal p21 promoter region, indicating its fundamental importance. In in vivo competition assays, transfected synthetic Sp1/Sp3 palindrome elements derepressed the cotransfected or endogenous p21 promoter in a dosage-dependent manner. This derepression was not seen in oxaliplatin-treated cells, suggesting that the exogenous Sp1/Sp3 palindrome and oxaliplatin had the same downstream signaling target. Taken together, our results revealed, for the first time, this evolutionarily conserved Sp1/Sp3 palindrome element in the proximal p21 promoter that serves as a regulatory repressor to maintain p21 basal level expression. Cancer Res; 72(23); 6236–46. ©2012 AACR.
PIK3CA Mutation H1047R Is Associated with Response to PI3K/AKT/mTOR Signaling Pathway Inhibitors in Early-Phase Clinical Trials
Authors: Janku Filip , Wheler Jennifer J. , Naing Aung , Falchook Gerald S. , Hong David S. , Stepanek Vanda M. , Fu Siqing , Piha-Paul Sarina A. , Lee J. Jack , Luthra Rajyalakshmi , Tsimberidou Apostolia M. , Kurzrock Razelle
Published: October 2012

PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02–43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration. Cancer Res; 73(1); 276–84. ©2012 AACR.
Evolutionary Approaches to Prolong Progression-Free Survival in Breast Cancer
Authors: Silva Ariosto S. , Kam Yoonseok , Khin Zayar P. , Minton Susan E. , Gillies Robert J. , Gatenby Robert A.
Published: October 2012

Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to maintain resistance mechanisms, so adaptive therapy strategies explicitly aim to maintain a stable population of therapy-sensitive cells to suppress growth of resistant phenotypes through intratumoral competition. We used computational models parameterized by in vitro experiments to illustrate the efficacy of such approaches. Here, we show that low doses of verapamil and 2-deoxyglucose, to accentuate the cost of resistance and to decrease energy production, respectively, could suppress the proliferation of drug-resistant clones in vivo. Compared with standard high-dose-density treatment, the novel treatment we developed achieved a 2-fold to 10-fold increase in time to progression in tumor models. Our findings challenge the existing flawed paradigm of maximum dose treatment, a strategy that inevitably produces drug resistance that can be avoided by the adaptive therapy strategies we describe. Cancer Res; 72(24); 6362–70. ©2012 AACR.
p38 MAPK in Myeloma Cells Regulates Osteoclast and Osteoblast Activity and Induces Bone Destruction
Authors: He Jin , Liu Zhiqiang , Zheng Yuhuan , Qian Jianfei , Li Haiyan , Lu Yong , Xu Jingda , Hong Bangxing , Zhang Mingjun , Lin Pei , Cai Zhen , Orlowski Robert Z. , Kwak Larry W. , Yi Qing , Yang Jing
Published: October 2012

p38 mitogen-activated protein kinase (MAPK), which is constitutively activated in human myeloma, has been implicated in bone destruction by this cancer, but the processes it recruits are obscure. In this study, we show that p38 activity in myeloma inhibits osteoblast differentiation and bone formation, but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Attenuating p38, DKK-1, or MCP-1 were each sufficient to reduce bone lesions in vivo. Although it is well known that DKK-1 inhibits osteoblast differentiation, we found that together with MCP-1, it could also promote osteoclast differentiation and bone resorption. The latter effects were mediated by enhancing expression of RANK in osteoclast progenitor cells and by upregulating secretion of its ligand RANKL from stromal cells and mature osteoblasts. In summary, our study defined the mechanisms by which p38 signaling in myeloma cells regulates osteoblastogenesis, osteoclastogenesis, and bone destruction. Our findings, which may have implications for bone invasion by other cancers where p38 is elevated, strongly suggests that targeting p38 for inhibition may offer an effective therapeutic approach to treat osteolytic bone lesions in patients with myeloma. Cancer Res; 72(24); 6393–402. ©2012 AACR.
Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy
Authors: Meijer Tineke W.H. , Kaanders Johannes H.A.M. , Span Paul N. , Bussink Johan
Published: October 2012

Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1–controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation. Clin Cancer Res; 18(20); 5585–94. ©2012 AACR.
Predicting Drug Targets and Biomarkers of Cancer via Genome-Scale Metabolic Modeling
Authors: Jerby Livnat , Ruppin Eytan
Published: October 2012

The metabolism of cancer cells is reprogrammed in various ways to support their growth and survival. Studying these phenomena to develop noninvasive diagnostic tools and selective treatments is a promising avenue. Metabolic modeling has recently emerged as a new way to study human metabolism in a systematic, genome-scale manner by using pertinent high-throughput omics data. This method has been shown in various studies to provide fairly accurate estimates of the metabolic phenotype and its modifications following genetic and environmental perturbations. Here, we provide an overview of genome-scale metabolic modeling and its current use to model human metabolism in health and disease. We then describe the initial steps made using it to study cancer metabolism and how it may be harnessed to enhance ongoing experimental efforts to identify drug targets and biomarkers for cancer in a rationale-based manner. Clin Cancer Res; 18(20); 5572–84. ©2012 AACR.
p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis
Authors: Habbous Steven , Pang Vincent , Eng Lawson , Xu Wei , Kurtz Goldie , Liu Fei-Fei , Mackay Helen , Amir Eitan , Liu Geoffrey
Published: October 2012

Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15–1.62; P < 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407–15. ©2012 AACR.
Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop
Authors: LoRusso Patricia M. , Canetta Renzo , Wagner John A. , Balogh Erin P. , Nass Sharyl J. , Boerner Scott A. , Hohneker John
Published: October 2012

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways—even if showing an initial response—often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. Clin Cancer Res; 18(22); 6101–9. ©2012 AACR.
Inactivation of the E-Prostanoid 3 Receptor Attenuates the Angiotensin II Pressor Response via Decreasing Arterial Contractility
Authors: Chen Lihong , Miao Yifei , Zhang Yahua , Dou Dou , Liu Limei , Tian Xiaoyu , Yang Guangrui , Pu Dan , Zhang Xiaoyan , Kang Jihong , Gao Yuansheng , Wang Shiqiang , Breyer Matthew D. , Wang Nanping , Zhu Yi , Huang Yu , Breyer Richard M. , Guan Youfei
Published: October 2012

Objective—

The present studies aimed at elucidating the role of prostaglandin E
2
receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure.

Methods and Results—

Mice bearing a genetic disruption of the EP3 gene (EP
3
−/−
) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3
−/−
mice, whereas the reduction of blood pressure induced by prostaglandin E
2
was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (Ang II) was attenuated in EP3
−/−
mice. Ang II-induced vasoconstriction in mesenteric arteries decreased in EP3
−/−
group. In mesenteric arteries from wild-type mice, Ang II-induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished Ang II-induced phosphorylation of myosin light chain 20 and myosin phosphatase target subunit 1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells, Ang II–induced intracellular Ca
2+
increase was potentiated by EP3 agonist sulprostone but inhibited by DG-041.

Conclusion—

Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II–dependent hypertension at least partially via enhancing Ca
2+
sensitivity and intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension.
Dominant Role of the Protein-Tyrosine Phosphatase CD148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B
Authors: Mori Jun , Wang Ying-Jie , Ellison Stuart , Heising Silke , Neel Benjamin G. , Tremblay Michel L. , Watson Steve P. , Senis Yotis A.
Published: October 2012

Objective—

The receptor-like protein-tyrosine phosphatase (PTP) CD148 and the nontransmembrane PTP1-B have been shown to be net positive regulators of Src family kinases in platelets. In the present study, we compared the relative contributions of these PTPs in platelet activation by the major glycoprotein, glycoprotein VI, α
IIb
β
3
, and C-type lectin-like receptor 2 (CLEC-2).

Methods and Results—

PTP-1B–deficient mouse platelets responded normally to the glycoprotein VI–specific agonist collagen-related peptide and antibody-mediated CLEC-2 activation. However, they exhibited a marginal reduction in α
IIb
β
3
-mediated Src family kinase activation and tyrosine phosphorylation. In contrast, CD148-deficient platelets exhibited a dramatic reduction in activation by glycoprotein VI and α
IIb
β
3
and a marginal reduction in response to activation by CLEC-2, which was further enhanced in the absence of PTP-1B. These defects were associated with reduced activation of Src family kinase and spleen tyrosine kinase, suggesting a causal relationship. Under arteriolar flow conditions, there was defective aggregate formation in the absence of PTP-1B and, to a greater extent, CD148 and a severe abrogation of both adhesion and aggregation in the absence of both PTPs.

Conclusion—

Findings from this study demonstrate that CD148 plays a dominant role in activating Src family kinases in platelets relative to PTP-1B. Both PTPs are required for optimal platelet activation and aggregate formation under high arterial shear rates.
Myeloid Krüppel-Like Factor 4 Deficiency Augments Atherogenesis in ApoE
−/−
Mice—Brief Report
Authors: Sharma Nikunj , Lu Yuan , Zhou Guangjin , Liao Xudong , Kapil Parul , Anand Puneet , Mahabeleshwar Ganapati H. , Stamler Jonathan S. , Jain Mukesh K.
Published: October 2012

Objective—

To investigate the role of Krüppel-like factor 4 (KLF4), an essential transcriptional regulator of macrophage polarization (M1/M2), in the pathogenesis of atherosclerosis.

Methods and Results—

Despite the acknowledged importance of macrophages in atherosclerosis, the role of M1 (classically activated or proinflammatory) versus M2 (alternatively activated or anti-inflammatory) macrophages in this process remains incompletely understood. We recently identified KLF4 as a regulator of macrophage subset specification; that is, KLF4 promotes M2 and inhibits M1 phenotype. Here, we provide evidence that KLF4-deficient macrophages exhibit enhanced proinflammatory activation and foam cell formation in response to oxidized lipids. In vivo, myeloid KLF4-deficient mice (ApoE
−/−
background) develop significantly more vascular inflammation and atherosclerotic lesion formation.

Conclusion—

Our findings identify myeloid KLF4 as an essential regulator of vascular inflammation and experimental atherogenesis.
Soluble ST2 Is Regulated by p75 Neurotrophin Receptor and Predicts Mortality in Diabetic Patients With Critical Limb Ischemia
Authors: Caporali Andrea , Meloni Marco , Miller Ashley M. , Vierlinger Klemens , Cardinali Alessandro , Spinetti Gaia , Nailor Audrey , Faglia Ezio , Losa Sergio , Gotti Ambra , Fortunato Orazio , Mitić Tijana , Hofner Manuela , Noehammer Christa , Madeddu Paolo , Emanueli Costanza
Published: October 2012

Objective—

The p75 neurotrophin receptor (p75
NTR
) contributes to diabetes mellitus−induced defective postischemic neovascularization. The interleukin-33 receptor ST2 is expressed as transmembrane (ST2L) and soluble (sST2) isoforms. Here, we studied the following: (1) the impact of p75
NTR
in the healing of ischemic and diabetic calf wounds; (2) the link between p75
NTR
and ST2; and (3) circulating sST2 levels in critical limb ischemia (CLI) patients.

Methods and Results—

Diabetes mellitus was induced in
p75

NTR

knockout (
p75KO
) mice and wild-type (
WT
) littermates by streptozotocin. Diabetic and nondiabetic
p75KO
and
WT
mice received left limb ischemia induction and a full-thickness wound on the ipsilateral calf. Diabetes mellitus impaired wound closure and angiogenesis and increased ST2 expression in
WT
, but not in
p75KO
wounds. In cultured endothelial cells, p75
NTR
promoted ST2 (both isoforms) expression through p38
MAPK
/activating transcription factor 2 pathway activation. Next, sST2 was measured in the serum of patients with CLI undergoing either revascularization or limb amputation and in the 2 nondiabetic groups (with CLI or nonischemic individuals). Serum sST2 increased in diabetic patients with CLI and was directly associated with higher mortality at 1 year from revascularization.

Conclusion—

p75
NTR
inhibits the healing of ischemic lower limb wounds in diabetes mellitus and promotes ST2 expression. Circulating sST2 predicts mortality in diabetic CLI patients.
A Novel Disease Gene for Brugada Syndrome
Authors: Ishikawa Taisuke , Sato Akinori , Marcou Cherisse A. , Tester David J. , Ackerman Michael J. , Crotti Lia , Schwartz Peter J. , On Young Keun , Park Jeong-Euy , Nakamura Kazufumi , Hiraoka Masayasu , Nakazawa Kiyoshi , Sakurada Harumizu , Arimura Takuro , Makita Naomasa , Kimura Akinori
Published: October 2012

Background—

Mutations in genes including
SCN5A
encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum.

Methods and Results—

We analyzed 190 unrelated Brugada syndrome patients for mutations in
SLMAP
. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant
SLMAP
by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant
SLMAP
confirmed the reduced hNav1.5 current.

Conclusions—

The mutations in
SLMAP
may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.
Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient Cohort
Authors: Ahmad Zahid , Adams-Huet Beverley , Chen Chiyuan , Garg Abhimanyu
Published: October 2012

Background—

Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low-density lipoprotein (LDL)-cholesterol, is caused by variants in at least 3 different genes: LDL receptor (
LDLR
), apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multiethnic patient cohort from lipid clinics in a large, urban US city.

Methods and Results—

A total of 38 men and 53 women, aged 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of
LDLR
, and in selected exons of apolipoprotein B-100 and proprotein convertase subtilisin-like kexin type 9. Deletions and duplications of
LDLR
exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in
LDLR
were identified in 30 patients and in apolipoprotein B-100 in 1 patient. The remaining 60 patients (65%) had unexplained ADH. A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with
LDLR
variants, those with unexplained ADH had lower levels of LDL-cholesterol (292±47 mg/dL versus 239±42 mg/dL, respectively;
P
<0.0001) and higher levels of high-density lipoprotein cholesterol (45±12 mg/dL versus 54±13 mg/dL, respectively;
P
=0.003).

Conclusions—

Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.
Health Status and Depression Remission in Patients With Chronic Heart Failure
Authors: Xiong Glen L. , Fiuzat Mona , Kuchibhatla Maragatha , Krishnan Ranga , O’Connor Christopher M. , Jiang Wei ,   on behalf of the SADHART-CHF Investigators
Published: October 2012

Background—

Depression is a common comorbidity in heart failure and is strongly associated with increased mortality, morbidity, and reduced health status. Whether depression treatment may result in improvement of health status in heart failure patients with comorbid depression remains unknown.

Methods and Results—

The Sertraline Against Depression and Heart Disease in Chronic Heart Failure study randomized 469 participants with chronic heart failure (left ventricular ejection fraction 45% and New York Heart Association class II) and major depressive disorder based on Diagnostic Statistics Manual fourth edition criteria to sertraline or placebo for 12 weeks. The Kansas City Cardiomyopathy Questionnaire, 36-Item Short-Form Health Survey, and 6-minute walk test were used to assess health status. Health status changes between treatment arms and remission status were evaluated adjusting for baseline variables and treatment assignment. The final Hamilton Depression Rating Scale scores were 3.50±2.08 and 12.97±4.33 in the remission and nonremission groups, respectively (
P
value=0.0001). Of 469 total participants, 378 (80.6%) completed the 6-minute walk test and 285 (70.1%) completed Kansas city cardiomyopathy questionnaire and 36-item short-form health survey, at baseline and at week 12. Depression remission was significantly associated with higher improvements in Kansas City Cardiomyopathy Questionnaire subscale scores (
P
<0.001) except on the Self-Efficacy (
P
=0.18) and Symptom Stability (
P
=0.91). On the 36-Item Short-Form Health Survey, depression remission was associated with significant improvement in subscales of the physical and mental component summary except the Pain Index (
P
=0.34). The 6-minute walk test improved more in depression remission compared with nonremission group (difference from baseline: 63.51±238.78 versus 16.24±115.70 m,
P
=0.03).

Conclusions—

Patients with heart failure whose depressive symptoms remitted had significantly greater improvement in physical function, social function, and quality of life.