bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Thiolase of
Mycobacterium tuberculosis
Is Required for Virulence and Production of Androstenedione and Androstadienedione from Cholesterol
Authors: Nesbitt Natasha M. , Yang Xinxin , Fontán Patricia , Kolesnikova Irina , Smith Issar , Sampson Nicole S. , Dubnau Eugenie 
Published: October 2009

ABSTRACT

Mycobacterium tuberculosis
, the causative agent of tuberculosis, is an intracellular pathogen that shifts to a lipid-based metabolism in the host. Moreover, metabolism of the host lipid cholesterol plays an important role in
M. tuberculosis
infection. We used transcriptional profiling to identify genes transcriptionally regulated by cholesterol and KstR (Rv3574), a TetR-like repressor. The
fadA5
(Rv3546) gene, annotated as a lipid-metabolizing thiolase, the expression of which is upregulated by cholesterol and repressed by KstR, was deleted in
M. tuberculosis
H37Rv. We demonstrated that
fadA5
is required for utilization of cholesterol as a sole carbon source in vitro and for full virulence of
M. tuberculosis
in the chronic stage of mouse lung infection. Cholesterol is not toxic to the
fadA5
mutant strain, and, therefore, toxicity does not account for its attenuation. We show that the wild-type strain, H37Rv, metabolizes cholesterol to androst-4-ene-3,17-dione (AD) and androsta-1,4-diene-3,17-dione (ADD) and exports these metabolites into the medium, whereas the
fadA5
mutant strain is defective for this activity. We demonstrate that FadA5 catalyzes the thiolysis of acetoacetyl-coenzyme A (CoA). This catalytic activity is consistent with a β-ketoacyl-CoA thiolase function in cholesterol β-oxidation that is required for the production of androsterones. We conclude that the attenuated phenotype of the
fadA5
mutant is a consequence of disrupted cholesterol metabolism that is essential only in the persistent stage of
M. tuberculosis
infection and may be caused by the inability to produce AD/ADD from cholesterol.
Characterization of the Highly Regulated Antigen BBA05 in the Enzootic Cycle of
Borrelia burgdorferi
Authors: Xu Haijun , He Ming , Pang Xiujuan , Xu Zao C. , Piesman Joseph , Yang X. Frank 
Published: October 2009

ABSTRACT

Dramatic alteration of surface lipoprotein profiles is a key strategy that
Borrelia burgdorferi
, the Lyme disease pathogen, has evolved for adapting to the diverse environments of arthropod and mammalian hosts. Several of these differentially expressed lipoproteins have been shown to play important roles in the enzootic cycle of
B. burgdorferi
. The BBA05 protein is a previously identified putative lipoprotein (P55 or S1 antigen) that elicits antibody responses in mammals. Recent microarray analyses indicate that the BBA05 gene is differentially expressed by many environmental factors, including temperature. However, the role of the BBA05 protein in the life cycle of
B. burgdorferi
has not been elucidated. Here we show that expression of the BBA05 gene was exclusively induced in feeding nymphal ticks during the spirochetal transmission from ticks to mammals. Upon generating a BBA05 mutant in an infectious strain of
B. burgdorferi
, we showed that the BBA05 mutant remained capable of establishing infection in mice, being acquired by ticks, persisting through tick molting, and reinfecting new mammalian hosts. These results indicate that, despite being a highly conserved and regulated antigen, the BBA05 protein has a nonessential role in the transmission cycle of
B. burgdorferi
, at least in the animal model.
Smoking among rural and urban young women in China
Authors: Ho Michael G , Ma Shaojun , Chai Wanxing , Xia Wan , Yang Gonghuan , Novotny Thomas E 
Published: October 2009

MethodsA survey of 11 095 urban and rural women attending high school or college, aged 14–24 years, in 6 Chinese provinces was conducted. Ever-smoking (ES), current smoking, established smoking and intention to smoke frequencies were calculated. Bivariate analyses were conducted to identify possible correlates of smoking, and those found to be significant at the p=0.1 level were included in a multivariate logistical regression model to obtain adjusted OR for correlates of ES.ResultsES prevalence was 20.1%, with urban female students (UFS) at 22.0% and rural female students (RFS) at 19.0% (p<0.01). Established smoking prevalence was higher among UFS than RFS (2.4% vs 0.9%, p<0.01). Similarly, current smoking prevalence was higher among UFS than RFS (4.2% vs 1.9%, p<0.01). The intention to smoke prevalence was higher among UFS than RFS (3.5% vs 1.7%, p<0.01). The majority were aware that smoking was harmful to health, but were less aware of specific diseases associated with smoking. ES was associated with awareness of cigarettes made for women (OR, 1.66, 95% CI 1.49 to 1.86) and thinking that they were less harmful than other cigarettes (OR 1.54, 95% CI 1.33 to 1.79). The strongest correlate of ES was low refusal self-efficacy (OR 6.35, 95% CI 5.32 to 7.57).ConclusionsThis is the first report that having heard of women's cigarettes is a correlate of smoking among young Chinese women. ES among young Chinese women has increased in the last decade, and thus, specific prevention strategies need to be developed to prevent the tobacco epidemic from spreading among this vulnerable population.
Long-term declines in phosphorus export from forested catchments in south-central Ontario
Authors: Eimers M. Catherine , Watmough Shaun A. , Paterson Andrew M. , Dillon Peter J. , Yao Huaxia 
Published: October 2009

Total phosphorus (TP) levels in many Canadian Shield lakes in central Ontario have declined over recent decades, despite increases in human activity in most watersheds. To investigate the contribution of changes in catchment export to long-term declines in lake TP, we examined temporal and spatial patterns in TP concentrations and export (1980–1981 to 2001–2002) across 11 subcatchments that drain into three lakes in which average ice-free TP levels have declined by approximately 35%. Annual stream export of TP decreased significantly by 30%–89% in eight of the 11 subcatchments, and decreases in export were driven by declines in TP concentration, not changes in stream flow. Annual average TP concentrations varied fivefold among adjacent subcatchments, and temporal patterns in annual average TP concentrations were poorly correlated. Seasonal patterns of TP concentration were most similar among streams in the spring (March–April–May), and TP export in the spring declined significantly in 10 of the 11 subcatchments. Because spring melt is the principal hydrologic event in these seasonally snow-covered basins, decreases in TP export during the spring were primarily responsible for declines observed in annual export. The drivers of changes in TP over time are unclear at this point but are the focus of current research.
Behavioral thermoregulation and associated mortality trade-offs in migrating adult steelhead (Oncorhynchus mykiss): variability among sympatric populations
Authors: Keefer Matthew L. , Peery Christopher A. , High Brett 
Published: October 2009

We used radiotelemetry to assess thermoregulatory behaviors for 14 populations (n = 3985) of adult summer steelhead ( Oncorhynchus mykiss ) as they passed through the Columbia River migration corridor. Steelhead use of small cool-water tributaries (“thermal refugia”) rapidly increased when the Columbia River reached a temperature threshold of about 19 °C. When main stem temperatures were warmest (i.e., >21 °C), more than 70% of the tagged fish used refugia sites and these fish had median refugia residence times of 3–4 weeks. Thermoregulatory responses were similar across populations, but there were large among-population differences in the incidence and duration of refugia use likely linked to population-specific migration timing patterns. In survival analyses using 1285 known-origin steelhead, fish that used thermal refugia were significantly less likely to survive to natal basins, were harvested at relatively high rates in refugia tributaries, and had greater unknown mortality in the main stem. These results highlight the trade-off between the presumed physiological benefits of thermal refugia use and a likely increase in harvest and other mortality risks that arise when preferred thermal habitats are severely constricted.
Light-dependent predation by the invertebrate planktivore Bythotrephes longimanus
Authors: Pangle Kevin L. , Peacor Scott D. 
Published: October 2009

We evaluated predation by the invasive invertebrate planktivore Bythotrephes longimanus on a Lake Michigan prey assemblage as a function of light intensity. Daphnia mendotae was the only prey type significantly reduced and light intensity strongly affected this reduction. Specifically, Bythotrephes consumption of D. mendotae was not detected under low light intensity (<1 µmol·m–2·s–1) but increased with greater light intensity and leveled off under high light intensity (>100 µmol·m–2·s–1) at which point Bythotrephes ingestion rate was 2.3 Daphnia per hour. These results indicate that Bythotrephes predation is more sensitive to light than previously thought, a discrepancy that can be explained after considering the ability of D. mendotae to detect Bythotrephes’ hydromechanic disturbance. The observed effect of light intensity on Bythotrephes predation is more like that of planktivorous fish than that of other previously studied invertebrate planktivores. Our findings elucidate the role that Bythotrephes plays in the food web and provide a novel explanation for its tendency to invade lakes of high water clarity. The importance of light-dependent predation found here may extend to other visually oriented predatory cladocerans.
An epidermal growth factor receptor variant III–targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme
Authors: Sampson John H. , Archer Gary E. , Mitchell Duane A. , Heimberger Amy B. , Herndon James E. , Lally-Goss Denise , McGehee-Norman Sharon , Paolino Alison , Reardon David A. , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. 
Published: October 2009

Abstract
Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)–based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 × 107 ± 2.9 × 107 SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 ± 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.95), 2.5–8.8], and median survival time from vaccination was 18.7 months (C.I.95, 14.5–25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.95, 17.5–29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy. [Mol Cancer Ther 2009;8(10):2773–9]
Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: Inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma
Authors: Gao Chong-Feng , Xie Qian , Zhang Yu-Wen , Su Yanli , Zhao Ping , Cao Brian , Furge Kyle , Sun Jan , Rex Karen , Osgood Tao , Coxon Angela , Burgess Teresa L. , Vande Woude George F. 
Published: October 2009

Abstract
Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, have been implicated in the growth and progression of a variety of solid human tumors. Thus, inhibiting HGF/SF:c-Met signaling may provide a novel therapeutic approach for treating human tumors. We have generated and characterized fully human monoclonal antibodies that bind to and neutralize human HGF/SF. In this study, we tested the effects of the investigational, human anti-human HGF/SF monoclonal antibody, AMG 102, and a mixture of mouse anti-human HGF/SF monoclonal antibodies (Amix) on HGF/SF-mediated cell migration, proliferation, and invasion in vitro. Both agents had high HGF/SF-neutralizing activity in these cell-based assays. The HGF/SF:c-Met pathway has been implicated in the growth of sarcomas; thus, we also investigated the effect of AMG 102 on the growth of human leiomyosarcoma (SK-LMS-1) in HGF/SF transgenic C3H severe combined immunodeficient mice engineered to express high levels of human HGF/SF, as well as tumor growth of an autocrine variant of the SK-LMS-1 cell line (SK-LMS-1TO) in nude mice. The results indicate that interrupting autocrine and/or paracrine HGF/SF:c-Met signaling with AMG 102 has profound antitumor effects. These findings suggest that blocking HGF/SF:c-Met signaling may provide a potent intervention strategy to treat patients with HGF/SF:c-Met–dependent tumors. [Mol Cancer Ther 2009;8(10):2803–10]
A modeling analysis of the effects of molecular size and binding affinity on tumor targeting
Authors: Schmidt Michael M. , Wittrup K. Dane 
Published: October 2009

Abstract
A diverse array of tumor targeting agents ranging in size from peptides to nanoparticles is currently under development for applications in cancer imaging and therapy. However, it remains largely unclear how size differences among these molecules influence their targeting properties. Here, we develop a simple, mechanistic model that can be used to understand and predict the complex interplay between molecular size, affinity, and tumor uptake. Empirical relationships between molecular radius and capillary permeability, interstitial diffusivity, available volume fraction, and plasma clearance were obtained using data in the literature. These relationships were incorporated into a compartmental model of tumor targeting using MATLAB to predict the magnitude, specificity, time dependence, and affinity dependence of tumor uptake for molecules across a broad size spectrum. In the typical size range for proteins, the model uncovers a complex trend in which intermediate-sized targeting agents (MW, ∼25 kDa) have the lowest tumor uptake, whereas higher tumor uptake levels are achieved by smaller and larger agents. Small peptides accumulate rapidly in the tumor but require high affinity to be retained, whereas larger proteins can achieve similar retention with &gt;100-fold weaker binding. For molecules in the size range of liposomes, the model predicts that antigen targeting will not significantly increase tumor uptake relative to untargeted molecules. All model predictions are shown to be consistent with experimental observations from published targeting studies. The results and techniques have implications for drug development, imaging, and therapeutic dosing. [Mol Cancer Ther 2009;8(10):2861–71]
Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells
Authors: Hu Hongbo , Chai Yubo , Wang Lei , Zhang Jinhui , Lee Hyo Jeong , Kim Sung-Hoon , Lü Junxuan 
Published: October 2009

Abstract
Penta-1,2,3,4,6-O-galloyl-β-d-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer xenografts in nude mice, suggesting potential utility as a prostate cancer chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP prostate cancer cells as one mechanism for the anticancer activity. We show here that, in the more aggressive PC-3 prostate cancer cell line, PGG induced programmed cell deaths lacking the typical caspase-mediated apoptotic morphology and biochemical changes. In contrast, PGG induced patent features of autophagy, including formation of autophagosomes and lipid modification of light chain 3 after 48 hours of PGG exposure. The “autophagic” responses were also observed in the murine TRAMP-C2 cells. Caspase inhibition exacerbated PGG-induced overall death. As for molecular changes, we observed a rapid inhibition of the phosphorylation of mammalian target of rapamycin–downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP-C2 cells but not that of mammalian target of rapamycin itself, along with increased AKT phosphorylation. Whereas the inhibition of phosphatidylinositol 3-kinase increased PGG-induced apoptosis and autophagy, experiments with pharmacologic inducer or inhibitor of autophagy or by knocking down autophagy mediator Beclin-1 showed that autophagy provided survival signaling that suppressed caspase-mediated apoptosis. Knocking down of death receptor-interacting protein 1 kinase increased overall death without changing light chain 3-II or caspase activation, thus not supporting death receptor-interacting protein 1–necroptosis for PGG-induction of autophagy or other programmed cell death. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent programmed cell death in aggressive prostate cancer cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent prostate cancer. [Mol Cancer Ther 2009;8(10):2833–43]
Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2
Authors: To Kenneth K.W. , Robey Robert W. , Knutsen Turid , Zhan Zhirong , Ried Thomas , Bates Susan E. 
Published: October 2009

Abstract
Overexpression of ABCG2 has been reported in cell lines selected for drug resistance and it is widely believed to be important in the clinical pharmacology of anticancer drugs. We and others have previously identified and validated two microRNAs (miRNA; hsa-miR-519c and hsa-miR-520h) targeting ABCG2. In this study, the shortening of the ABCG2 3′ untranslated region (3′UTR) was found to be a common phenomenon in several ABCG2-overexpressing resistant cell lines, which as a result removes the hsa-miR-519c binding site and its repressive effects on mRNA stability and translation blockade, thereby contributing to drug resistance. On the other hand, reduced expression of hsa-miR-520h, previously thought to have allowed ABCG2 overexpression, was found to be caused by the sequestering of the miRNA by the highly expressed ABCG2. In drug-sensitive cells, inhibitors against hsa-miR-519c and hsa-miR-520h could augment the cytotoxic effect of mitoxantrone, suggesting a substantial role for both miRNAs in controlling ABCG2 level and thereby anticancer drug response. However, in drug-resistant cells, altering the levels of the two miRNAs did not have any effect on sensitivity to mitoxantrone. Taken together, these studies suggest that in ABCG2-overexpressing drug-resistant cells, hsa-miR-519c is unable to affect ABCG2 expression because the mRNA lacks its binding site, whereas hsa-miR-520h is sequestered and unable to limit ABCG2 expression. Given the recent observation that a truncated 3′UTR is also observed in ABCG2-overexpressing human embryonic stem cells, our results in drug-resistant cell lines suggest that 3′UTR truncation is a relatively common mechanism of ABCG2 regulation. [Mol Cancer Ther 2009;8(10):2959–68]
Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin
Authors: Kuznetsov Galina , TenDyke Karen , Towle Murray J. , Cheng Hongsheng , Liu Junke , Marsh Joanne P. , Schiller Shawn E.R. , Spyvee Mark R. , Yang Hu , Seletsky Boris M. , Shaffer Christina J. , Marceau Veronique , Yao Ye , Suh Edward M. , Campagna Silvio , Fang Francis G. , Kowalczyk James J. , Littlefield Bruce A. 
Published: October 2009

Abstract
E7974 is a synthetic analogue of the marine sponge natural product hemiasterlin. Here, we show that E7974, such as parental hemiasterlin, acts via a tubulin-based antimitotic mechanism. E7974 inhibits polymerization of purified tubulin in vitro with IC50 values similar to those of vinblastine. In cultured human cancer cells, E7974 induces G2-M arrest and marked disruption of mitotic spindle formation characteristic of tubulin-targeted anticancer drugs. Extensive hypodiploid cell populations are seen in E7974-treated cells, indicating initiation of apoptosis after prolonged G2-M blockage. Consistent with this observation, E7974 induces caspase-3 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis. Only a short cellular exposure to E7974 is sufficient to induce maximum mitotic arrest, suggesting that E7974's antitumor effects in vivo may persist even after blood levels of the drug decrease after drug administration. Interactions of E7974 with purified tubulin were investigated using two synthetic tritiated photoaffinity analogues incorporating a benzophenone photoaffinity moiety at two different positions of the E7974 scaffold. Both analogues preferentially photolabeled α-tubulin, although minor binding to β-tubulin was also detected. E7974 thus seems to share a unique, predominantly α-tubulin–targeted mechanism with other hemiasterlin-based compounds, suggesting that, unlike many tubulin-targeted natural products and related drugs, the hemiasterlins evolved to mainly target α-tubulin, not β-tubulin subunits. [Mol Cancer Ther 2009;8(10):2852–60]
Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models
Authors: Daenen Laura G. , Shaked Yuval , Man Shan , Xu Ping , Voest Emile E. , Hoffman Robert M. , Chaplin David J. , Kerbel Robert S. 
Published: October 2009

Abstract
Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway–targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy. [Mol Cancer Ther 2009;8(10):2872–81]