bluuebunny/crossref_metadata_2025 huggingface dataset:
The quest for chron E23r at Partridge Island, Bay of Fundy, Canada: CAMP emplacement postdates the end-Triassic extinction event at the North American craton
Authors: Deenen M.H.L. , Krijgsman W. , Ruhl M.
Published: August 2011

The Partridge Island stratigraphic section at the Bay of Fundy, Maritime Canada, reveals a continental sedimentary succession with the end-Triassic mass extinction level closely followed by basalts of the Central Atlantic Magmatic Province (CAMP). New Paleomagnetic data show that a short reverse magnetic polarity chron, correlative to E23r of the Newark Geomagnetic Polarity Time Scale (GPTS), is present below the extinction event. Organic carbon isotope data and basalt geochemistry further indicate that the onset of CAMP emplacement in the Bay of Fundy was roughly synchronous with emplacement in the Newark basin, but slightly postdates the oldest CAMP volcanism in Morocco by ∼20 ka. These results confirm the potential for long-distance CAMP correlations based on geochemical trace elements, indicate substantiate provincialism of latest Triassic palynoflora, and suggest a very concise period (<<100 ka) of CAMP emplacement in the northern Atlantic region.
Geological and depositional setting of the Sirius Passet Lagerstätte (Early Cambrian), North Greenland
Authors: Ineson Jon R. , Peel John S.
Published: August 2011

The Early Cambrian Sirius Passet Lagerstätte of North Greenland occurs in marine mudstones (Buen Formation) deposited in a slope environment along the eroded scarp of a pre-existing carbonate platform. The shallow-water platform is represented by dolostones of the Portfjeld Formation (Neoproterozoic – earliest Cambrian), which record a belt of tide-swept subtidal ooid shoals and microbial patch reefs at the outer edge of the platform. Solution features and meteoric cements attest to exposure of the platform, accompanied by fracturing, mass wastage and erosional retreat of the escarpment producing slope talus, and extensive debris sheets and olistoliths in basinal deposits. The marine mud-dominated siliciclastics of the Buen Formation, deposited in slope and shelf environments, record the transgression and onlap of the degraded platform in the Early Cambrian. The Sirius Passet Lagerstätte has yielded an arthropod-dominated fossil assemblage of over 40 species, many showing exceptional preservation of soft tissues; the finely laminated mudstones hosting this fauna accumulated from suspension in a poorly oxygenated slope sub-environment, such as an erosional embayment or abandoned slope gully. Although taphonomic features suggest that the fauna is mainly parautochthonous, some components (e.g., sponges, worms, the halkieriids and certain sightless arthropods) may be truly autochthonous. Comparison of the Sirius Passet locality with the renowned Middle Cambrian Burgess Shale of western Canada reveals similarities in overall depositional and tectonic setting: both accumulated in deep water adjacent to the steep, eroded margins of carbonate platforms — settings that subsequently sheltered the faunas from tectonic and metamorphic obliteration.
Antifungal activity of a Pinus monticola antimicrobial peptide 1 (Pm-AMP1) and its accumulation in western white pine infected with Cronartium ribicola
Authors: Zamany Arezoo , Liu Jun-Jun , Ekramoddoullah Abul , Sniezko Richard
Published: August 2011

Pinus monticola antimicrobial peptide 1 (Pm-AMP1) was expressed and purified from bacterial cell lysate and its identity and purity confirmed by Western blot analysis using the Pm-AMP1 antibody. Application of Pm-AMP1 resulted in visible hyphal growth inhibition of Cronartium ribicola , Phellinus sulphurascens , Ophiostoma montium , and Ophiostoma clavigerum 3–12 days post-treatment. Pm-AMP1 also inhibited spore germination of several other phytopathogenic fungi by 32%–84% 5 days post-treatment. Microscopic examination of C. ribicola hyphae in contact with Pm-AMP1 showed distinct morphological changes. Seven western white pine ( Pinus monticola Douglas ex D. Don) families (Nos. 1, 2, 5, 6, 7, 8, 10) showing partial resistance to C. ribicola in the form of bark reaction (BR) were assessed by Western immunoblot for associations between Pm-AMP1 accumulation and family, phenotype, canker number, and virulence of C. ribicola. There was a significant difference (p < 0.001) in mean Pm-AMP1 protein accumulation between families, with higher levels detected in the full-sib BR families (Nos. 1, 2, 5) than the half-sib BR families (Nos. 6, 7). Family 8, previously described as a Mechanism ‘X’ BR family, had the highest number of BR seedlings and displayed high Pm-AMP1 levels, whereas the susceptible family (No. 10) showed the lowest levels (p < 0.05). Family 1 showed a significant association between Pm-AMP1 accumulation and overall seedling health (p < 0.01, R = 0.533), with higher protein levels observed in healthy versus severely infected seedlings. In general, low Pm-AMP1 levels were observed with an increase in the number of cankers per seedling (p < 0.05), and seedlings inoculated with the avirulent source of C. ribicola showed significantly higher Pm-AMP1 levels (p < 0.05) in the majority of BR families. Cis-acting regulatory elements, such as CCAAT binding factors, and an AG-motif binding protein were identified in the Pm-AMP1 promoter region. Multiple polymorphic sites were identified within the 5′ untranslated region and promoter regions. Our results suggest that Pm-AMP1 is involved in the western white pine defense response to fungal infection, as observed by its antifungal activity on C. ribicola and a range of phytopathogens as well as through its association with different indicators of resistance to C. ribicola.
Use of Physiologic Reasoning to Diagnose and Manage Shock States
Authors: Lighthall Geoffrey
Published: August 2011

Shock states are defined by stereotypic changes in well-known physiologic parameters. While these well-known changes provide a convenient entry point into further evaluation of patients in shock or at risk for shock, use of such physiologic evaluation is not commonly seen in clinical medicine. A formal description of physiologic reasoning in the diagnosis of shock states is presented in this paper. Included with this conceptual framework is a discussion of key tests or findings that can be used to differentiate between possible diagnoses, and the pairing of treatment strategies to distinct classes of physiologic abnormalities. It is hoped that the methodology presented here will demonstrate the primacy of physiologic reasoning in the diagnosis and treatment of hemodynamic instability. Advantages of this method are speed and accuracy, efficient use of resources, and mitigation against sources of medical errors.
Flow and Heat Transfer of Two Immiscible Fluids in the Presence of Uniform Inclined Magnetic Field
Authors: Nikodijević Dragiša , Stamenković Živojin , Milenković Dragica , Blagojević Bratislav , Nikodijevic Jelena
Published: August 2011

The magnetohydrodynamic (MHD) Couette flow of two immiscible fluids in a horizontal channel with isothermal walls in the presence of an applied electric and inclined magnetic field has been investigated in the paper. Both fluids are electrically conducting, while the channel plates are electrically insulated. The general equations that describe the discussed problem under the adopted assumptions are reduced to ordinary differential equations, and closed‐form solutions are obtained in both fluid regions of the channel. Separate solutions with appropriate boundary conditions for each fluid have been obtained, and these solutions have been matched at the interface using suitable matching conditions. The analytical results for various values of the Hartmann number, the angle of magnetic field inclination, loading parameter, and the ratio of fluid heights have been presented graphically to show their effect on the flow and heat transfer characteristics.
Use of Ghrelin as a Treatment for Inflammatory Bowel Disease: Mechanistic Considerations
Authors: DeBoer Mark D.
Published: August 2011

Inflammatory bowel diseases (IBD)—and in particular Crohn's disease—are immune-mediated processes that result in denuded intestinal mucosa and can produce decreased appetite, weight loss, and systemic inflammation. Current treatments include anti-inflammatory medications, immunomodulators, and feeding interventions. Ghrelin is an endogenous orexigenic hormone that directly stimulates growth hormone release, increases gut motility, and has cardiovascular and anti-inflammatory properties. Although ghrelin levels are elevated in active IBD, administration of ghrelin in most (but not all) animal models of colitis has produced improvements in disease activity and systemic inflammation. The mechanism for these effects is not known but may relate to decreased inflammation, increased motility, increased appetite, and increased colonic blood flow. Human trials have not been performed, however, and more research is clearly needed.
Cayley Graphs of Order 27p Are Hamiltonian
Authors: Ghaderpour Ebrahim , Morris Dave Witte
Published: August 2011

Suppose that G
is a finite group, such that |G|=27p, where p is prime. We show that if S is any generating set of G, then there is a Hamiltonian cycle in the corresponding Cayley graph Cay (G;S).
Comparison of Two Models for Radiative Heat Transfer in High Temperature Thermal Plasmas
Authors: Melot Matthieu , Trépanier Jean-Yves , Camarero Ricardo , Petro Eddy
Published: August 2011

Numerical simulation of the arc‐flow interaction in high‐voltage circuit breakers requires a radiation model capable of handling high‐temperature participating thermal plasmas. The modeling of the radiative transfer plays a critical role in the overall accuracy of such CFD simulations. As a result of the increase of computational power, CPU intensive methods based on the radiative transfer equation, leading to more accurate results, are now becoming attractive alternatives to current approximate models. In this paper, the predictive capabilities of the finite volume method (RTE‐FVM) and the P1 model are investigated. A systematic comparison between these two models and analytical solutions are presented for a variety of relevant test cases. Two implementations of each approach are compared, and a critical evaluation is presented.
Mechanism(s) of Toxic Action of Zn2+and Selenite: A Study on AS-30D Hepatoma Cells and Isolated Mitochondria
Authors: Belyaeva Elena A. , Saris Nils-Erik L.
Published: August 2011

Mitochondria of AS-30D rat ascites hepatoma cells are found to be the main target for Zn2+and sodium selenite (Na2SeO3). High [mu]M concentrations of Zn2+or selenite were strongly cytotoxic, killing the AS-30D cells by both apoptotic and necrotic ways. Both Zn2+and selenite produced strong changes in intracellular generation of reactive oxygen species (ROS) and the mitochondrial dysfunction via the mitochondrial electron transport chain (mtETC) disturbance, the membrane potential dissipation, and the mitochondrial permeability transition pore opening. The significant distinctions in toxic action of Zn2+and selenite on AS-30D cells were found. Selenite induced a much higher intracellular ROS level (the early event) compared to Zn2+but a lower membrane potential loss and a lower decrease of the uncoupled respiration rate of the cells, whereas the mtETC disturbance was the early and critical event in the mechanism of Zn2+cytotoxicity. Sequences of events manifested in the mitochondrial dysfunction produced by the metal/metalloid under test are compared with those obtained earlier for Cd2+, Hg2+, and Cu2+on the same model system.
Quality Assessment of Transient Response Analysis Method for Detecting Radiation‐Induced Faults
Authors: Peralta José , Peretti Gabriela , Romero Eduardo , Demarco Gustavo , Marqués Carlos
Published: August 2011

We evaluate the ability of transient response analysis method (TRAM), a simple test strategy proposed for filters, to detect deviations in circuit specifications beyond established limits. Particularly, we focus our attention on deviations produced by displacement damage in integrated resistors. This damage is produced by the impact of high‐energy particles like the encountered in space environments. For this purpose, we formulate a simple deviation‐fault model that takes into consideration the degradation addressed. Additionally, more transient response parameters are taken into account in order to improve the fault coverage. We adopt for our evaluations two typical second‐order filters as cases of study. For these filters, the simulation results show that TRAM reaches excellent fault coverage for both filters, suggesting that its use in space applications is encouraging.
Adaptive Neurofuzzy Inference System‐Based Pollution Severity Prediction of Polymeric Insulators in Power Transmission Lines
Authors: Muniraj C. , Chandrasekar S.
Published: August 2011

This paper presents the prediction of pollution severity of the polymeric insulators used in power transmission lines using adaptive neurofuzzy inference system (ANFIS) model. In this work, laboratory‐based pollution performance tests were carried out on 11 kV silicone rubber polymeric insulator under AC voltage at different pollution levels with sodium chloride as a contaminant. Leakage current was measured during the laboratory tests. Time domain and frequency domain characteristics of leakage current, such as mean value, maximum value, standard deviation, and total harmonics distortion (THD), have been extracted, which jointly describe the pollution severity of the polymeric insulator surface. Leakage current characteristics are used as the inputs of ANFIS model. The pollution severity index “equivalent salt deposit density” (ESDD) is used as the output of the proposed model. Results of the research can give sufficient prewarning time before pollution flashover and help in the condition based maintenance (CBM) chart preparation.
EfficientIn VitroTRAIL-Gene Delivery in Drug-Resistant A2780/DDP Ovarian Cancer Cell Line via Magnetofection
Authors: Li Fang , Niu Sumei , Sun Jing , Zhu Huaishi , Ba Qiujie , Guo Yi , Shi Donglu
Published: August 2011

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) presents great promise as an anticancer agent for human cancer therapy. In this study, a magnetofection agent (polyMAG-l000) was evaluated forin vitrodelivery of TRAIL gene towards drug-resistant A2780/DDP ovarian cancer cells. Transfection experiments showed that polyMAG-l000 was able to transfect A2780/DDP cellsin vitro, leading to a higher level of TRAIL gene expression in the presence of a static magnetic field as compared to other transfection agent, such as Lipofectamine 2000. TRAIL gene expression in the A2780/DDP cells was also confirmed by Western blot analysis. Moreover, the TRAIL gene expression exhibited remarkable decrease in the cell viability, as determined by MTT assay. Importantly, PolyMAG-l000-mediated TRAIL gene transfection in the presence of anticancer drug cisplatin (CDDP) induced much higher percentages of apoptotic A2780/DDP cells, compared to TRAIL gene transfection or CDDP treatment alone. A further study by Western blot analysis indicated that cytochromecrelease and caspase-9 cleavage pathway were associated with the initiation of the apoptosis in A2780/DDP cells. The results of this study indicate that polyMAG-l000 can be used as an efficient agent for TRAIL gene transfection in ovarian cancer cells.
A Case History Study of the Recycling Efforts from the United States Army Corps of Engineers Hurricane Katrina Debris Removal Mission in Mississippi
Authors: Brandon Dennis Leroy , Medina Victor Frank , Morrow Agnes Belinda
Published: August 2011

In support of the Federal Emergency Management Agency (FEMA), the US Army Corps of Engineers (USACE) managed the removal of Hurricane Katrina storm debris in several states. This paper focuses on the debris removal practices in 16 southern Mississippi counties and the recycling efforts. Debris was removed from public and private property. The debris included vegetation, construction material, electronic waste, vehicles, and vessels. The scope of the USACE mission was expanded several times. The scope within the respective counties varied from vegetation only to the removal of every eligible form of debris. The recommendations proposed should enhance recycling efforts during future debris removal missions.
Risk Factors and Seroprevalence of Hepatitis C among Patients Hospitalized at Mulago Hospital, Uganda
Authors: O'Reilly J. I. , Ocama P. , Opio C. K. , Alfred A. , Paintsil E. , Seremba E. , Sofair A. N.
Published: August 2011

The emergence of hepatitis C virus (HCV) and its associated sequelae in Africa is a cause for significant concern. Human immunodeficiency virus (HIV) positive patients are at an increased risk of contracting HCV infection due to similar risk factors and modes of transmission. We investigated the seroprevalence of hepatitis C in hospitalized HIV-positive and HIV-negative patients in Mulago Hospital, an academic hospital in Uganda. Blood samples were first tested for HCV antibodies, and positive tests were confirmed with HCV RNA PCR. We enrolled five hundred patients, half HIV-positive and half HIV negative. Overall, 13/500 patients (2.6%) tested positive for HCV antibodies. There was no difference in HCV antibody detection among HIV-positive and HIV-negative patients. Out of all risk factors examined, only an age greater than 50 years was associated with HCV infection. Traditional risk factors for concurrent HIV and HCV transmission, such as intravenous drug use, were exceedingly rare in Uganda. Only 3 of 13 patients with detectable HCV antibodies were confirmed by HCV RNA detection. This result concurs with recent studies noting poor performance of HCV antibody testing when using African sera. These tests should be validated in the local population before implementation.
Community-Based Mental Health Intervention for Underprivileged Women in Rural India: An Experiential Report
Authors: Rao Kiran , Vanguri Prameela , Premchander Smita
Published: August 2011

Objective. To share experiences from a project that integrates a mental health intervention within a developmental framework of microcredit activity for economically underprivileged women in rural India. Method. The mental health intervention had two components: group counseling and stress management. The former comprised of ventilation and reassurance and the latter strengthening of coping skills and a relaxation technique. Focus group discussions were used to understand women's perception of how microcredit economic activity and the mental health intervention had affected their lives. Results. Women in the mental health intervention group reported reduction in psychological distress and bodily aches and pains. Majority (86%) reported that the quality of their sleep had improved with regular practice of relaxation and that sharing their problems in the group had helped them to unburden. The social support extended by the members to each other, made them feel that they were not alone and could face any life situation. Conclusion. The study provided qualitative evidence that adding the mental health intervention to the ongoing economic activity had made a positive difference in the lives of the women. Addressing mental health concerns along with livelihood initiatives can help to enhance both economic and social capital in rural poor women.
The Cost of Mating: Influences of Life History Traits and Mating Strategies on Lifespan in Two Closely RelatedYponomeutaSpecies
Authors: Bakker A. C. , Campos Louçã J. , Roessingh P. , Menken S. B. J.
Published: August 2011

Theory predicts that in monandrous butterfly species males should not invest in a long lifespan because receptive females quickly disappear from the mating population. In polyandrous species, however, it pays for males to invest in longevity, which increases the number of mating opportunities and thus reproductive fitness. We tested an extension of this idea and compared male and female lifespan of two closely relatedYponomeutaspecies with different degree of polyandry. Our results confirmed the theoretical prediction that male lifespan is fine-tuned to female receptive lifespan; once-mated males and females of both polyandrous species had an equal lifespan. However, the degree of polyandry was not reflected in male relative to female lifespan. The observed similar female and male lifespan could largely be attributed to a dramatic reduction of female lifespan after mating.
Global Dynamics of a Delayed HIV‐1 Infection Model with CTL Immune Response
Authors: Li Yunfei , Xu Rui , Li Zhe , Mao Shuxue
Published: August 2011

A delayed HIV‐1 infection model with CTL immune response
is investigated. By using suitable Lyapunov functionals, it is proved that the infection‐free equilibrium is globally asymptotically stable if the basic reproduction ratio for viral infection is less than or equal to unity; if the basic reproduction ratio for CTL immune response is less than or equal to unity and the basic reproduction ratio for viral infection is greater than unity, the CTL‐inactivated infection equilibrium is globally asymptotically stable; if the basic reproduction ratio for CTL immune
response is greater than unity, the CTL‐activated infection equilibrium is globally
asymptotically stable.
Kaposi Sarcoma of the Adrenal Gland Resembling Epithelioid Angiosarcoma: A Case Report
Authors: Huwait Hassan , Meneghetti Adam , Nielsen Torsten O.
Published: August 2011

Patients with human immunodeficiency virus infection are known to have increased risk of various neoplasms, including Kaposi sarcoma, which classically involves the skin and mucosal locations. The anaplastic variant of Kaposi sarcoma is rare and poorly documented in the literature. It is characterised clinically by a more aggressive behaviour and increased metastatic potential, and histologically by increased cellularity, mitotic rate, and rarely by epithelioid angiosarcoma-like morphology. We report herein a 64-year-old man with a long-standing history of human immunodeficiency virus infection who developed a right adrenal tumor with a high-grade anaplastic angiosarcoma-like morphology. Immunohistochemistry for human herpes virus-8 was strongly positive in the tumor cells. To the best of our knowledge, this is the first report of an anaplastic Kaposi sarcoma in the adrenal gland.
Screening for Cytomegalovirus during Pregnancy
Authors: Adler Stuart P.
Published: August 2011

The epidemiology and pathogenesis of CMV infections among pregnant women have been intensely studied over the last three decades. This paper highlights recent developments that make either universal or limited serologic screening for CMV during pregnancy potentially attractive. The developments include an understanding of the pathogenesis of CMV infections, a knowledge of high-risk women, the availability of accurate methods for the serologic diagnosis of a primary CMV infection using either single or serial blood samples, accurate methods for the diagnosis of fetal infection via amniotic fluid, sensitive fetal and placental indicators for neonatal outcomes, and the availability of potentially effective interventions.
Cytokine and Phenotypic Cell Profiles ofLeishmania infantumInfection in the Dog
Authors: Maia Carla , Campino Lenea
Published: August 2011

Leishmaniasis has reemerged in recent years showing a wider geographic distribution and increased global incidence of human and canine disease than previously known. Dogs are the main domestic/peridomestic reservoir hosts of zoonotic visceral leishmaniasis caused byLeishmania infantum. Since the evolution of leishmaniasis and clinical appearance is a consequence of complex interactions between the parasite and host immune response, a profound knowledge about the immune profile developed in dog's infection is crucial for vaccine and immunomodulatory therapy design. The main goal of this paper is to compile the recent advances made on cytokine and phenotypic cell profiles in different tissues and organs of dogs infected withL. infantum. This paper also stressed that the knowledge of the immune responses developed, namely, in liver, lymph node, and spleen is very limited. All data emphasizes that more research on canine leishmaniasis is necessary for the development of new and efficacious tools to control zoonotic leishmaniasis.
Resuscitating Cancer Immunosurveillance: Selective Stimulation of DLL1-Notch Signaling in T cells Rescues T-cell Function and Inhibits Tumor Growth
Authors: Huang Yuhui , Lin Luping , Shanker Anil , Malhotra Anshu , Yang Li , Dikov Mikhail M. , Carbone David P.
Published: August 2011

Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth. Cancer Res; 71(19); 6122–31. ©2011 AACR.
Genome-wide Methylation Analysis Identifies Genes Specific to Breast Cancer Hormone Receptor Status and Risk of Recurrence
Authors: Fackler Mary Jo , Umbricht Christopher B. , Williams Danielle , Argani Pedram , Cruz Leigh-Ann , Merino Vanessa F. , Teo Wei Wen , Zhang Zhe , Huang Peng , Visvananthan Kala , Marks Jeffrey , Ethier Stephen , Gray Joe W. , Wolff Antonio C. , Cope Leslie M. , Sukumar Saraswati
Published: August 2011

To better understand the biology of hormone receptor–positive and–negative breast cancer and to identify methylated gene markers of disease progression, we carried out a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples, using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor–positive tumors displayed more hypermethylated loci than estrogen receptor (ER)-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared with ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER subtypes. A total of 40 (32 novel and 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER subtype–specific loci was validated in silico, using an independent, publicly available methylome dataset from the Cancer Genome Atlas. In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study shows the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER subtypes of breast cancer. Furthermore, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups. Cancer Res; 71(19); 6195–207. ©2011 AACR.
Upregulation of Rac GTPase-Activating Protein 1 Is Significantly Associated with the Early Recurrence of Human Hepatocellular Carcinoma
Authors: Wang Suk Mei , Ooi London Lucien P.J. , Hui Kam M.
Published: August 2011

Purpose: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease.

Experimental Design: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan–Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes.

Results: Kaplan–Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results.

Conclusions: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. Clin Cancer Res; 17(18); 6040–51. ©2011 AACR.
Preclinical Pharmacokinetics and Safety of Sym004: A Synergistic Antibody Mixture Directed against Epidermal Growth Factor Receptor
Authors: Skartved Niels Jørgen Østergaard , Jacobsen Helle Jane , Pedersen Mikkel Wandahl , Jensen Pernille Foged , Sen Jette Wagtberg , Jørgensen Thomas Kjærsgaard , Hey Adam , Kragh Michael
Published: August 2011

Purpose: Sym004 is a novel therapeutic antibody mixture product comprising two unmarketed monoclonal antibodies (mAb) targeting the epidermal growth factor receptor (EGFR). In previous preclinical proof-of-concept studies, Sym004 was shown to elicit superior cancer cell growth inhibition activities compared with marketed anti-EGFR mAbs. This article describes the design and results of the preclinical safety program conducted to support early clinical development of Sym004.

Experimental Design: Tissue cryosections from various species were stained with Sym004 to evaluate tissue cross reactivity. The pharmacokinetics of Sym004 were evaluated in a mouse xenograft model and in Cynomolgus monkeys. Monkeys received once weekly intravenous infusions of Sym004 in the range 2 to 24 mg/kg for 6 to 8 weeks. Cetuximab (a marketed anti-EGFR mAb) and the individual antibodies comprising Sym004 were included in the repeat-dose toxicity studies at single-dose level.

Results: Sym004 had a staining pattern similar to cetuximab in tissue panels from both human and non-human primates. Once weekly dosing of Sym004 to Cynomolgus monkeys did not cause accumulation, whereas administration of the individual antibodies resulted in prolonged half-life and accumulation. In direct comparisons with cetuximab, Sym004 did not induce any distinct or novel adverse findings in the animals. However, an early onset of pronounced, reversible, and anticipated anti-EGFR–mediated pharmacologic effects, such as skin rash, dehydration, and liquid feces, was observed. Only minor adverse effects were recorded in animals treated with the individual antibodies comprising Sym004.

Conclusion: Sym004 was well tolerated and did not induce any unexpected toxicities. The preclinical safety data enabled initiation of the ongoing clinical development. Clin Cancer Res; 17(18); 5962–72. ©2011 AACR.
The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors
Authors: Floris Giuseppe , Debiec-Rychter Maria , Wozniak Agnieszka , Stefan Cristiana , Normant Emmanuel , Faa Gavino , Machiels Kathleen , Vanleeuw Ulla , Sciot Raf , Schöffski Patrick
Published: August 2011

The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504–treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies. Mol Cancer Ther; 10(10); 1897–908. ©2011 AACR.
Antitumor Activity of Ridaforolimus and Potential Cell-Cycle Determinants of Sensitivity in Sarcoma and Endometrial Cancer Models
Authors: Squillace Rachel M. , Miller David , Cookson Michelle , Wardwell Scott D. , Moran Lauren , Clapham David , Wang Frank , Clackson Tim , Rivera Victor M.
Published: August 2011

Ridaforolimus is a nonprodrug rapamycin analogue that potently inhibits mTOR and has shown significant activity in patients with metastatic sarcoma and endometrial cancer, two diseases where high unmet need remains. Here, we evaluated the activity of ridaforolimus in preclinical models of these tumor types and used these models to explore molecular correlates of sensitivity. The in vitro sensitivity of a panel of sarcoma and endometrial cancer cell lines was established by measuring the effect of ridaforolimus on cell proliferation rate, revealing broad inhibition at low nanomolar concentrations. Additional benefit was found when ridaforolimus was combined with agents used to treat sarcoma and endometrial cancer patients. In vivo, potent antitumor activity of ridaforolimus associated with inhibition of mTOR signaling was observed in sarcoma and endometrial xenograft models. Immunoblot analysis was conducted to assess the expression and activation state of multiple signaling proteins in the phosphoinositide-3-kinase/AKT/mTOR and cell-cycle pathways. In endometrial but not sarcoma cell lines, the absence of PTEN or elevated levels of phosphorylated or total AKT was associated with greater sensitivity. However, in both tumor types, the proportion of cells in the G0–G1 phase before treatment correlated significantly with ridaforolimus sensitivity. Consistent with this, expression of several G1 phase cell-cycle proteins, notably p21 and p27, was higher in more sensitive lines. These results underscore the promise of ridaforolimus as a single agent or combination treatment of these tumor types and suggest novel potential predictive biomarkers of sensitivity to an mTOR inhibitor based on cell-cycle status. Mol Cancer Ther; 10(10); 1959–68. ©2011 AACR.
Inhibition of PARP-1 by Olaparib (AZD2281) Increases the Radiosensitivity of a Lung Tumor Xenograft
Authors: Senra Joana M. , Telfer Brian A. , Cherry Kim E. , McCrudden Cian M. , Hirst David G. , O'Connor Mark J. , Wedge Stephen R. , Stratford Ian J.
Published: August 2011

PARP-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, although the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here, we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non–small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (P = 0.007) relative to radiotherapy alone. To determine whether this radiosensitization was solely due to effects on DNA repair, we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC. Mol Cancer Ther; 10(10); 1949–58. ©2011 AACR.
Analgesic Efficacy of Forced Coughing versus Local Anesthesia during Cervical Punch Biopsy
Authors: Naki M.Murat , Api Olus , Acioglu Hasniye Celik , Uzun Mine Guray , Kars Bulent , Unal Orhan
Published: August 2011

Background/Aims: To compare local anesthesia and forced coughing in terms of subjective pain perception during cervical punch biopsy. Methods: In this randomized controlled trial, 114 patients (mean age: 38.9 ± 9.0 years) scheduled for colposcopically directed cervical punch biopsy were randomly assigned to local anesthesia (n = 39), forced coughing (n = 39) and control (n = 36) groups. Pain perception was measured on a 10-cm visual analog scale (VAS) during the insertion of the speculum, injection of the local anesthetic to the cervix and the taking of the first cervical biopsy, as well as for the overall pain perceived during the entire procedure. Results: Experimental groups were similar in age, gravidity, parity and prior curettage. The pain score obtained during the first cervical biopsy was significantly lower if local anesthesia was applied (p = 0.016). Groups were similar in other pain subscores. The duration of the entire procedure was significantly longer (p < 0.001) in the local anesthesia group, while it was not significantly different in forced coughing patients compared to controls. Conclusion: Local anesthesia, but not forced coughing, provides significant pain relief during cervical biopsy. Based on similarity to control data in terms of pain relief and shortening of the operation, forced coughing per se seems related neither to pain relief nor a faster cervical biopsy.
Hearing Evaluation in Preeclamptic Patients
Authors: Ozdemir Ismail , Yilmaz Suleyman , Albayrak Mustafa , Yıldızbas Sahnur , Guven Damla Guclu , Yaman Huseyin , Guclu Ender
Published: August 2011

Objective: To evaluate the pathological effects of preeclampsia on hearing levels in pregnant women by pure-tone audiometry and brainstem auditory-evoked potentials (BAEPs). Methods: Both ears in 30 preeclamptic patients and 38 women with uncomplicated pregnancy matched by maternal age and gestational age were investigated based on BAEPs and pure-tone audiometry. Hearing thresholds were within the normal ranges in all subjects prior to pregnancy. We compared the results of hearing levels and auditory pathway functions between the two groups. Results: Statistically significant differences in pure-tone audiometry results were found between the two groups (p < 0.05). However, these results were not clinically significant because all pure-tone thresholds were lower than 20 dB (normal hearing abilities). The differences between BAEPs were not statistically significant (p > 0.05). Conclusion: This study suggests that preeclampsia does not markedly affect hearing function unless it causes secondary vascular occlusion of microcirculation related to hearing.
Psychological Factors in Chronic Pelvic Pain due to Endometriosis: A Comparative Study
Authors: Roth Randy S. , Punch Margaret , Bachman Jan E.
Published: August 2011

Background/Aims: This study compared women suffering chronic pelvic pain (CPP) secondary to endometriosis (n = 30) with women experiencing CPP due to either myofascial abdominal/pelvic pain (n = 70) or pelvic adhesions (n = 38) to determine if there are specific psychological variables uniquely associated with endometriosis. Methods: This is a cross-sectional study of 138 women drawn from a convenience sample of 192 consecutive women with CPP presenting for evaluation to a university hospital chronic pain clinic. Subjects were categorized into groups based on their CPP diagnosis. Each subject completed a battery of validated inventories assessing demographic status, pain experience and other pain-related symptoms, pain disability, frequency of depressive symptoms, level of affective distress, satisfaction with pain treatment and satisfaction with their marital relationship. Results: No differences were obtained across the three groups for any of the outcome measures. Effect size computation supported the absence of clinical differences across the groups for these measures. Conclusion: These findings fail to support the presence of a unique psychological profile or disproportionate psychological disturbance for women with CPP due to endometriosis. These data illustrate the importance of considering control groups that include chronic pain when exploring psychological contributions to specific chronic pain conditions.
Radionuclide Hysterosalpingography Is Not a Reliable Tool for Investigation of Fallopian Tube Transport – A Controlled Randomized Study Using Particles of Two Sizes during Three Different Parts of the Menstrual Cycle
Authors: Wånggren Kjell , Wramsby Håkan , Bremmer Staffan , Lundberg Steffan , Jacobsson Hans
Published: August 2011

Background/Aims: Earlier studies with radionuclide hysterosalpingography (RN-HSG) using either small or large particles have shown different results. Some studies have questioned the clinical relevance of RN-HSG. The aim of this study was to evaluate the RN-HSG method using two different sizes of radio-labelled particles during different parts of the menstrual cycle. Methods: Ten healthy women, 28–40 years of age (mean 34.5), with proven fertility, regular menstrual cycle, not using oral contraceptives and due to undergo laparoscopic sterilization, were randomized to RN-HSG after deposition of a solution with either small Albures or large MAASOL, 99mTc-radio-labelled particles into the cervix uteri. Investigations were, for every patient, performed during the follicular, peri-ovulatory and mid-luteal parts of the menstrual cycle. Transport of radioactivity from cervix to uterus and Fallopian tubes was evaluated. Results: The RN-HSG investigations could not show any difference between the two different sizes of radio-labelled particles. Transport of radioactivity to the Fallopian tube was seen only in some cases and most frequently during the peri-ovulatory period. Conclusion: We found the RN-HSG investigations inconclusive. The RN-HSG method does not seem to be a reliable tool for the investigation of Fallopian tube transport.
Cordycepin (3′-Deoxyadenosine), an Inhibitor of mRNA Polyadenylation, Suppresses Proliferation and Activates Apoptosis in Human Epithelial Endometriotic Cells in vitro
Authors: Imesch Patrick , Hornung René , Fink Daniel , Fedier André
Published: August 2011

Background/Aims: Endometriosis is a benign but chronic disorder associated with pelvic pain and infertility. Enhanced proliferation and reduced apoptosis susceptibility are characteristics of endometriosis. Cordycepin is a poly(A) polymerase inhibitor. It induces shortening of poly(A) tails, leading to destabilization of mRNAs and finally to proliferation inhibition and cell death in normal and tumor cells. The potential of cordycepin to block proliferation and survival of 11z human immortalized epithelial endometriotic cells was determined. Methods: 11z cell cultures were treated with cordycepin. Cordycepin-induced inhibition of proliferation and alterations in protein expression and protein phosphorylation were determined by the methyl thiazolyl tetrazolium assay and immunoblot analysis, respectively. Results: Cordycepin induced the rapid and significant upregulation of the cell cycle progression inhibitor p21 and the downregulation of the cell cycle progression promoter cyclin D1, finally leading to the inhibition of the proliferation of 11z human epithelial endometriotic cells. Cordycepin reduced the phosphorylation of the p38 mitogen-activated protein kinase and the retinoblastoma protein. It also activated caspase-dependent, intrinsic apoptosis, as documented by the proteolytic cleavage of the caspase-9, caspase-3 and the poly(ADP ribose) polymerase 1 precursor. Conclusion: The mRNA polyadenylation inhibitor cordycepin inhibits proliferation and survival of endometriotic cells.
Role of Extended Chemotherapy in Advanced Ovarian Cancer Patients with High Posttreatment Serum CA-125 Levels
Authors: Kang Sokbom , Kim Tae-Joong , Seo Sang-Soo , Kim Byoung-Gie , Bae Duk-Soo , Park Sang-Yoon
Published: August 2011

Background: We aimed to determine whether the inclusion of additional cycles of carboplatin-paclitaxel is beneficial to patients with high posttreatment serum CA-125 levels. Methods: Among patients who achieved remission after six cycles of carboplatin-paclitaxel chemotherapy, those with CA-125 of 10–35 U/ml at the time of remission were divided into two groups (group A: six cycles of standard chemotherapy vs. group B: two or more additional cycles) and were analyzed. Results: Among the 436 patients with advanced epithelial ovarian cancer, 154 patients (46.8%) had CA-125 of 10–35 U/ml at the time of remission. Fifty-six patients (36.4%) received two or more cycles after the first six cycles of chemotherapy (group B). The addition of two or more cycles of chemotherapy did not improve the progression-free survival (p = 0.660). There was no statistical difference in the rates of CA-125 falling to <10 U/ml between the two groups (p = 0.256). Moreover, the degree of CA-125 decrease after six cycles of chemotherapy was similar regardless of the additional cycles (p = 0.656). Conclusion: The addition of two or more cycles of standard chemotherapy based on posttreatment CA-125 levels was not beneficial.