bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pivotal Roles of Snail Inhibition and RKIP Induction by the Proteasome Inhibitor NPI-0052 in Tumor Cell Chemoimmunosensitization
Authors: Baritaki Stavroula , Yeung Kam , Palladino Michael , Berenson James , Bonavida Benjamin 
Published: October 2009

Abstract
The novel proteasome inhibitor NPI-0052 has been shown to sensitize tumor cells to apoptosis by various chemotherapeutic drugs and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), although the mechanisms involved are not clear. We hypothesized that NPI-0052–mediated sensitization may result from NF-κB inhibition and downstream modulation of the metastasis inducer Snail and the metastasis suppressor/immunosurveillance cancer gene product Raf-1 kinase inhibitory protein (RKIP). Human prostate cancer cell lines were used as models, as they express different levels of these proteins. We show that NPI-0052 inhibits both NF-κB and Snail and induces RKIP expression, thus resulting in cell sensitization to CDDP and TRAIL. The direct role of NF-κB inhibition in sensitization was corroborated with the NF-κB inhibitor DHMEQ, which mimicked NPI-0052 in sensitization and inhibition of Snail and induction of RKIP. The direct role of Snail inhibition by NPI-0052 in sensitization was shown with Snail small interfering RNA, which reversed resistance and induced RKIP. Likewise, the direct role of RKIP induction in sensitization was revealed by both overexpression of RKIP (mimicking NPI-0052) and RKIP small interfering RNA that inhibited NPI-0052–mediated sensitization. These findings show that NPI-0052 modifies the NF-κB-Snail-RKIP circuitry in tumor cells and results in downstream inhibition of antiapoptotic gene products and chemoimmunosensitization. The findings also identified Snail and RKIP as targets for reversal of resistance. [Cancer Res 2009;69(21):8376–85]
Interleukin 12 Stimulates IFN-γ–Mediated Inhibition of Tumor-Induced Regulatory T-Cell Proliferation and Enhances Tumor Clearance
Authors: Cao Xuefang , Leonard Karen , Collins Lynne I. , Cai Sheng F. , Mayer Joshua C. , Payton Jacqueline E. , Walter Michael J. , Piwnica-Worms David , Schreiber Robert D. , Ley Timothy J. 
Published: October 2009

AbstractTo define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor–dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN-γ mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-γ–independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN-γ signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12–IFN-γ axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo. [Cancer Res 2009;69(22):8700–9]
ATAD2 Is a Novel Cofactor for MYC, Overexpressed and Amplified in Aggressive Tumors
Authors: Ciró Marco , Prosperini Elena , Quarto Micaela , Grazini Ursula , Walfridsson Julian , McBlane Fraser , Nucifero Paolo , Pacchiana Giovanni , Capra Maria , Christensen Jesper , Helin Kristian 
Published: October 2009

Abstract
The E2F and MYC transcription factors are critical regulators of cell proliferation and contribute to the development of human cancers. Here, we report on the identification of a novel E2F target gene, ATAD2, the predicted protein product of which contains both a bromodomain and an ATPase domain. The pRB-E2F pathway regulates ATAD2 expression, which is limiting for the entry into the S phase of the cell cycle. We show that ATAD2 binds the MYC oncogene and stimulates its transcriptional activity. ATAD2 maps to chromosome 8q24, 4.3 Mb distal to MYC, in a region that is frequently found amplified in cancer. Consistent with this, we show that ATAD2 expression is high in several human tumors and that the expression levels correlate with clinical outcome of breast cancer patients. We suggest that ATAD2 links the E2F and MYC pathways and contributes to the development of aggressive cancer through the enhancement of MYC-dependent transcription. [Cancer Res 2009;69(21):8491–8]
Hijacking the Chromatin Remodeling Machinery: Impact ofSWI/SNFPerturbations in Cancer
Authors: Weissman Bernard , Knudsen Karen E. 
Published: October 2009

AbstractThere is increasing evidence that alterations in chromatin remodeling play a significant role in human disease. The SWI/SNF chromatin remodeling complex family mobilizes nucleosomes and functions as a master regulator of gene expression and chromatin dynamics whose functional specificity is driven by combinatorial assembly of a central ATPase and association with 10 to 12 unique subunits. Although the biochemical consequence of SWI/SNF in model systems has been extensively reviewed, the present article focuses on the evidence linking SWI/SNF perturbations to cancer initiation and tumor progression in human disease. [Cancer Res 2009;69(21):8223–30]
Nuclear Receptor Coregulators in Cancer Biology
Authors: O'Malley Bert W. , Kumar Rakesh 
Published: October 2009

AbstractCoregulators (coactivators and corepressors) occupy the driving seat for actions of all nuclear receptors, and consequently, selective receptor modulator drugs. The potency and selectivity for subreactions of transcription reside in the coactivators, and thus, they are critically important for tissue-selective gene function. Each tissue has a “quantitative finger print” of coactivators based on its relative inherited concentrations of these molecules. When the cellular concentration of a coactivator is altered, genetic dysfunction usually leads to a pathologic outcome. For example, many cancers overexpress “growth coactivators.” In this way, the cancer cell can hijack these coactivator molecules to drive proliferation and metastasis. The present review contains summaries of selective coactivators and corepressors that have been demonstrated to play important roles in the malignant process and emphasizes their importance for future therapeutic interventions. [Cancer Res 2009;69(21):8217–22]
A Role for BRCA1 in Uterine Leiomyosarcoma
Authors: Xing Deyin , Scangas George , Nitta Mai , He Lei , Xu Xuan , Ioffe Yevgeniya J.M. , Aspuria Paul-Joseph , Hedvat Cyrus Y. , Anderson Matthew L. , Oliva Esther , Karlan Beth Y. , Mohapatra Gayatry , Orsulic Sandra 
Published: October 2009

Abstract
Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)–driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. [Cancer Res 2009;69(21):8231–5]
Macrophage Inhibitory Cytokine 1: A New Prognostic Marker in Prostate Cancer
Authors: Brown David A. , Lindmark Fredrik , Stattin Pär , Bälter Katarina , Adami Hans-Olov , Zheng Sigun L. , Xu Jianfeng , Isaacs William B. , Grönberg Henrik , Breit Samuel N. , Wiklund Fredrik E. 
Published: October 2009

Abstract
Purpose: High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis.
Experimental Design: We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1-6.8 years).
Results: MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82-4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73-36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis.
Conclusions: Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis. (Clin Cancer Res 2009;15(21):6658–64)
Regional Brain Activation during Verbal Declarative Memory in Metastatic Breast Cancer
Authors: Kesler Shelli R. , Bennett F. Chris , Mahaffey Misty L. , Spiegel David 
Published: October 2009

Abstract
Purpose: To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures.
Experimental Design: We used functional magnetic resonance imaging to test our hypothesis that women with breast cancer would show significantly lower brain activation during verbal declarative memory tasks compared with age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would show higher stress and this would contribute to brain activation deficits during memory tasks.
Results: Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared with controls. However, the breast cancer group showed significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy showed lower prefrontal cortex activation during memory encoding.
Conclusions: These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process. (Clin Cancer Res 2009;15(21):6665–73)
T Cell–Based Immunotherapy of Metastatic Renal Cell Carcinoma: Modest Success and Future Perspective
Authors: Shablak Alaaeldin , Hawkins Robert E. , Rothwell Dominic G. , Elkord Eyad 
Published: October 2009

AbstractMetastatic renal cell carcinoma (MRCC) remains a challenging malignancy to treat. Cancer immunotherapies have been extensively explored in melanoma and RCC as they poorly respond to conventional cytotoxic agents but show responses to a variety of immunologic agents. The recent considerable success of T cell–based immunotherapy in melanoma warrants further efforts to apply this treatment to other cancers including MRCC. Although RCC is an immunosensitive cancer, similar attempts in MRCC have shown a very limited success. In this review, we summarize the clinical data on T cell–based immunotherapies for MRCC showing the modest success that has been achieved to date. More importantly, we discuss potential strategies for improving its efficacy for the treatment of MRCC in light of the important achievements for treating metastatic melanoma. In particular, the growing evidence of success by combining expanded tumor-infiltrating lymphocytes with lymphodepletion merits investigation in MRCC. Identifying new RCC-associated antigens, optimized methods, and conditions for detection, isolation, and/or modification and expansion of tumor-specific T cells are all important strategies to be pursued for improving T cell–based immunotherapy of MRCC. (Clin Cancer Res 2009;15(21):6503–10)
Relationship between soil properties, crop management, plant growth and vigour, nematode occurrence and root damage in East African Highland banana-cropping systems: a case study in Rwanda
Authors: Gaidashova Svetlana V. , van Asten Piet , De Waele Dirk , Delvaux Bruno 
Published: October 2009

Abstract
Parasitic nematodes are widespread in Musa cropping systems in African
lowlands where they are known to limit crop production. However, their
distribution is very poorly known in the large parts of the East African
Highland banana ecology. We carried out a survey in 188 fields in Rwanda to
assess and understand nematode occurrence and damage under a wide range of
agroecological conditions. Altitude varied from 900 to 1800 m above sea
level and soil types were distinctly different in the five eco-regions
sampled and derived from diverse parent materials; i.e., Ruhengeri
(Andosol), Gitarama-Butare (Acrisol), Kibungo (Nitisol), Gashonga
(Ferralsol) and Bugarama (Fluvisol and Vertisol). Crop management practices,
root health parameters and nematode infection in roots were recorded for a
single East African highland banana cultivar (Intuntu, AAA-EA).
Plant-parasitic nematodes from five genera were identified: Pratylenchus
goodeyi, Helicotylenchus multicinctus, Meloidogyne spp., Radopholus similis
and Hoplolaimus pararobustus. Pratylenchus goodeyi was the dominant species
in all eco-regions except in Bugarama (lowland). Only the presence of P.
goodeyi significantly correlated with root necroses. Altitude was strongly
correlated with root densities of P. goodeyi and R. similis. A possible
negative impact by P. goodeyi on banana yields was masked by the fact that
nematode populations were positively correlated with high plant density
and/or mulching practices, which led to relatively high plant vigour
irrespective of soil type. Therefore, controlled field experiments will be
needed to assess whether root necrosis caused by P. goodeyi at high altitude
(>1400 m) actually has a detrimental impact on banana yields, similar to
that observed for root-lesion nematodes at lower altitudes.
Morphological and molecular characterisation of Enchodelus babakicus n. sp. and E. macrodorus Thorne, 1939 (Nematoda: Nordiidae) from Iran
Authors: Pedram Majid , Niknam Gholamreza , Guerrero Pablo , Ye Weimin , Robbins Robert T. 
Published: October 2009

Abstract
A new species with a rounded tail belonging to the Enchodelus
macrodorus-group is described from a natural habitat in the vicinity of
Kaleibar City, north-west Iran. Enchodelus babakicus n. sp. is characterised
by its medium sized body (1.21-1.56 mm), lip region offset by a marked
constriction, odontostyle 40-45 μm long, tripartite uterus and presence of
abundant males with 49-61 μm long spicules and 10-14 spaced ventromedian
supplements. The new species is close to E. distinctus, E. groenlandicus, E.
macrodorus, E. microdoroides and E. saxifragae. A population of E.
macrodorus was also found in the same sample as the new species. Molecular
analysis was inferred from sequencing of 18S rDNA and ITS1 regions of three
species of the genus from Iran, including E. babakicus n. sp., E. macrodorus
and E. veletensis, together with other available sequences in GenBank. The
sequences showed that E. babakicus n. sp. belongs to a clade formed by
Enchodelus species characterised by a rounded tail.
Effective concentration and range of activity of abamectin as seed treatment against root-knot nematodes in tomato under glasshouse conditions
Authors: Cabrera J. Alfonso , Kiewnick Sebastian , Grimm Christoph , Dababat Abd el-Fattah A. , Sikora Richard A. 
Published: October 2009

Abstract
The objectives of this study were to determine the efficacy, range of
activity and effective concentrations (EC50 and EC80) of abamectin as a seed
treatment of tomato against Meloidogyne incognita, M. arenaria and M.
javanica. The study revealed that abamectin seed treatment at concentrations
ranging between 0.3 and 1 mg a.s. seed−1 is highly effective against the
three species of root-knot nematodes, retaining its efficacy in the soil for
8 weeks. The highest EC50 found was reached at 0.2 mg a.s. seed−1. The
highest EC80 for the number of egg masses per g root in the three
Meloidogyne species was attained at 0.51 mg a.s. seed−1. Abamectin as a seed
treatment is promising for the control of root-knot nematodes in the field
since only low amounts of active ingredient are required to give adequate
protection in the most sensitive stages of tomato root growth and
development.
Influence of substrate on the body-waving behaviour of nematodes
Authors: Kruitbos Laura M. , Heritage Stuart , Hapca Simona , Wilson Michael J. 
Published: October 2009

Abstract
The soil-dwelling nematodes Steinernema carpocapsae, S. scapterisci, S.
feltiae, S. glaseri, Heterorhabditis bacteriophora, H. megidis,
Phasmarhabditis hermaphrodita and Caenorhabditis elegans were placed on agar
plates each containing four substrates (peat, sand, sandy loam and leaf
litter). The body-waving behaviour of infective juveniles was recorded over
a 10-day period in the presence or absence of an insect, Galleria
mellonella, a susceptible host of some species. Body-waving behaviour
differed amongst species and varied significantly in relation to substrate,
time and the presence of G. mellonella. Steinernema carpocapsae showed
body-waving behaviour more than other species and this tendency increased
significantly with time. More S. carpocapsae were seen body waving on peat
and leaf litter than on either sandy loam or sand. Conversely, sand promoted
body waving in S. scapterisci. Body waving by C. elegans was more common on
peat than on any of the other substrates. Heterorhabditis megidis, not
previously known to body wave, did so in low numbers on peat and sandy loam.
The remaining four species did not body wave. Previous work has shown that
the presence of S. glaseri increases body waving by S. carpocapsae. We
investigated whether substrate influenced this interaction and also included
S. scapterisci in the study. The presence of S. glaseri significantly
altered rates of body waving in S. carpocapsae and S. scapterisci in a way
that was substrate-dependent. Our data suggest that body-waving behaviour is
determined by substrate quality and differing body-waving behaviours may be
a mechanism by which nematodes avoid competition.
Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team
Authors: Crowe Brenda J , Xia H. Amy , Berlin Jesse A , Watson Douglas J , Shi Hongliang , Lin Stephen L , Kuebler Juergen , Schriver Robert C , Santanello Nancy C , Rochester George , Porter Jane B , Oster Manfred , Mehrotra Devan V , Li Zhengqing , King Eileen C , Harpur Ernest S , Hall David B 
Published: October 2009

Background The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America. Purpose SPERT’s goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period. Methods SPERT’s recommendations are based on our review of relevant literature and on consensus reached in our discussions. Results An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of adverse events and highlight proposals for reducing "false positive" safety findings. We recommend that sponsors review the aggregated safety data on a regular and ongoing basis throughout the development program, rather than waiting until the time of submission. Limitations We recognize that there may be other valid approaches. Conclusions The proactive approach we advocate has the potential to benefit patients and health care providers by providing more comprehensive safety information at the time of new product marketing and beyond. Clinical Trials 2009; 6: 430—440. http://ctj.sagepub.com
Aspergillus fumigatus inhibits angiogenesis through the production of gliotoxin and other secondary metabolites
Authors: Ben-Ami Ronen , Lewis Russell E. , Leventakos Konstantinos , Kontoyiannis Dimitrios P. 
Published: October 2009

AbstractIn susceptible hosts, angioinvasion by Aspergillus fumigatus triggers thrombosis, hypoxia, and proinflammatory cytokine release, all of which are stimuli for angiogenesis. We sought to determine whether A fumigatus directly modulates angiogenesis. A fumigatus culture filtrates profoundly inhibited the differentiation, migration, and capillary tube formation of human umbilical vein endothelial cells in vitro. To measure angiogenesis at the site of infection, we devised an in vivo Matrigel assay in cyclophosphamide-treated BALB/c mice with cutaneous invasive aspergillosis. Angiogenesis was significantly suppressed in Matrigel plugs implanted in A fumigatus–infected mice compared with plugs from uninfected control mice. The antiangiogenic effect of A fumigatus was completely abolished by deletion of the global regulator of secondary metabolism, laeA, and to a lesser extent by deletion of gliP, which controls gliotoxin production. Moreover, pure gliotoxin potently inhibited angiogenesis in vitro in a dose-dependent manner. Finally, overexpression of multiple angiogenesis mediator–encoding genes was observed in the lungs of cortisone-treated mice during early invasive aspergillosis, whereas gene expression returned rapidly to baseline levels in cyclophosphamide/cortisone-treated mice. Taken together, these results indicate that suppression of angiogenesis by A fumigatus both in vitro and in a neutropenic mouse model is mediated through secondary metabolite production.