bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Significance of Microbial Infection and Adaptation in Cystic Fibrosis
Authors: Hauser Alan R. , Jain Manu , Bar-Meir Maskit , McColley Susanna A. 
Published: January 2011

SUMMARYA select group of microorganisms inhabit the airways of individuals with cystic fibrosis. Once established within the pulmonary environment in these patients, many of these microbes adapt by altering aspects of their structure and physiology. Some of these microbes and adaptations are associated with more rapid deterioration in lung function and overall clinical status, whereas others appear to have little effect. Here we review current evidence supporting or refuting a role for the different microbes and their adaptations in contributing to poor clinical outcomes in cystic fibrosis.
Fig1 Facilitates Calcium Influx and Localizes to Membranes Destined To Undergo Fusion during Mating in Candida albicans
Authors: Yang Meng , Brand Alexandra , Srikantha Thyagarajan , Daniels Karla J. , Soll David R. , Gow Neil A. R. 
Published: January 2011

ABSTRACT

Few mating-regulated genes have been characterized in
Candida albicans. C. albicans FIG1
(Ca
FIG1
) is a fungus-specific and mating-induced gene encoding a putative 4-transmembrane domain protein that shares sequence similarities with members of the claudin superfamily. In
Saccharomyces cerevisiae
, Fig1 is required for shmoo fusion and is upregulated in response to mating pheromones. Expression of Ca
FIG1
was also strongly activated in the presence of cells of the opposite mating type. CaFig1-green fluorescent protein (GFP) was visible only during the mating response, when it localized predominantly to the plasma membrane and perinuclear zone in mating projections and daughter cells. At the plasma membrane, CaFig1-GFP was visualized as discontinuous zones, but the distribution of perinuclear CaFig1-GFP was homogeneous. Exposure to pheromone induced a 5-fold increase in Ca
2+
uptake in mating-competent opaque cells. Uptake was reduced substantially in the
fig1
Δ null mutant. CaFig1 is therefore involved in Ca
2+
influx and localizes to membranes that are destined to undergo fusion during mating.
Plasmids with a Chromosome-Like Role in Rhizobia
Authors: Landeta Cristina , Dávalos Araceli , Cevallos Miguel Ángel , Geiger Otto , Brom Susana , Romero David 
Published: January 2011

ABSTRACTReplicon architecture in bacteria is commonly comprised of one indispensable chromosome and several dispensable plasmids. This view has been enriched by the discovery of additional chromosomes, identified mainly by localization of rRNA and/or tRNA genes, and also by experimental demonstration of their requirement for cell growth. The genome ofRhizobium etliCFN42 is constituted by one chromosome and six large plasmids, ranging in size from 184 to 642 kb. Five of the six plasmids are dispensable for cell viability, but plasmid p42e is unusually stable. One possibility to explain this stability would be that genes on p42e carry out essential functions, thus making it a candidate for a secondary chromosome. To ascertain this, we made an in-depth functional analysis of p42e, employing bioinformatic tools, insertional mutagenesis, and programmed deletions. Nearly 11% of the genes in p42e participate in primary metabolism, involving biosynthetic functions (cobalamin, cardiolipin, cytochromeo, NAD, and thiamine), degradation (asparagine and melibiose), and septum formation (minCDE). Synteny analysis and incompatibility studies revealed highly stable replicons equivalent to p42e in content and gene order in otherRhizobiumspecies. A systematic deletion analysis of p42e allowed the identification of two genes (RHE_PE00001 and RHE_PE00024), encoding, respectively, a hypothetical protein with a probable winged helix-turn-helix motif and a probable two-component sensor histidine kinase/response regulator hybrid protein, which are essential for growth in rich medium. These data support the proposal that p42e and its homologous replicons (pA, pRL11, pRLG202, and pR132502) merit the status of secondary chromosomes.
Identification and Characterization of ZapC, a Stabilizer of the FtsZ Ring in
Escherichia coli
Authors: Durand-Heredia Jorge M. , Yu Helen H. , De Carlo Sacha , Lesser Cammie F. , Janakiraman Anuradha 
Published: January 2011

ABSTRACT

In
Escherichia coli
, spatiotemporal control of cell division occurs at the level of the assembly/disassembly process of the essential cytoskeletal protein FtsZ. A number of regulators interact with FtsZ and modulate the dynamics of the assembled FtsZ ring at the midcell division site. In this article, we report the identification of an FtsZ stabilizer, ZapC (Z-associated protein C), in a protein localization screen conducted with
E. coli
. ZapC colocalizes with FtsZ at midcell and interacts directly with FtsZ, as determined by a protein-protein interaction assay in yeast. Cells lacking or overexpressing ZapC are slightly elongated and have aberrant FtsZ ring morphologies indicative of a role for ZapC in FtsZ regulation. We also demonstrate the ability of purified ZapC to promote lateral bundling of FtsZ in a sedimentation reaction visualized by transmission electron microscopy. While ZapC lacks sequence similarity with other nonessential FtsZ regulators, ZapA and ZapB, all three Zap proteins appear to play an important role in FtsZ regulation during rapid growth. Taken together, our results suggest a key role for lateral bundling of the midcell FtsZ polymers in maintaining FtsZ ring stability during division.
Complete Genome Sequences for the Anaerobic, Extremely Thermophilic Plant Biomass-Degrading Bacteria
Caldicellulosiruptor hydrothermalis
,
Caldicellulosiruptor kristjanssonii
,
Caldicellulosiruptor kronotskyensis
,
Caldicellulosiruptor owensensis
, and
Caldicellulosiruptor lactoaceticus
Authors: Blumer-Schuette Sara E. , Ozdemir Inci , Mistry Dhaval , Lucas Susan , Lapidus Alla , Cheng Jan-Fang , Goodwin Lynne A. , Pitluck Samuel , Land Miriam L. , Hauser Loren J. , Woyke Tanja , Mikhailova Natalia , Pati Amrita , Kyrpides Nikos C. , Ivanova Natalia , Detter John C. , Walston-Davenport Karen , Han Shunsheng , Adams Michael W. W. , Kelly Robert M. 
Published: January 2011

ABSTRACT

The genus
Caldicellulosiruptor
contains the most thermophilic, plant biomass-degrading bacteria isolated to date. Previously, genome sequences from three cellulolytic members of this genus were reported (
C. saccharolyticus
,
C. bescii
, and
C. obsidiansis
). To further explore the physiological and biochemical basis for polysaccharide degradation within this genus, five additional genomes were sequenced:
C. hydrothermalis
,
C. kristjanssonii
,
C. kronotskyensis
,
C. lactoaceticus
, and
C. owensensis
. Taken together, the seven completed and one draft-phase
Caldicellulosiruptor
genomes suggest that, while central metabolism is highly conserved, significant differences in glycoside hydrolase inventories and numbers of carbohydrate transporters exist, a finding which likely relates to variability observed in plant biomass degradation capacity.
Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases
Authors: Corbière Véronique , Chapiro Jacques , Stroobant Vincent , Ma Wenbin , Lurquin Christophe , Lethé Bernard , van Baren Nicolas , Van den Eynde Benoît J. , Boon Thierry , Coulie Pierre G. 
Published: January 2011

AbstractA core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly tumor-specific antigens contributes decisively to tumor regression. Cancer Res; 71(4); 1253–62. ©2011 AACR.
LOXL2-Mediated Matrix Remodeling in Metastasis and Mammary Gland Involution
Authors: Barker Holly E. , Chang Joan , Cox Thomas R. , Lang Georgina , Bird Demelza , Nicolau Monica , Evans Holly R. , Gartland Alison , Erler Janine T. 
Published: January 2011

Abstract
More than 90% of cancer patient mortality is attributed to metastasis. In this study, we investigated a role for the lysyl oxidase-related enzyme lysyl oxidase-like 2 (LOXL2) in breast cancer metastasis, in both patient samples and in vivo models. Analysis of a published microarray data set revealed that LOXL2 expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer. In immunocompetent or immunocompromised orthotopic and transgenic breast cancer models we showed that genetic, chemical or antibody-mediated inhibition of LOXL2 resulted in decreased metastasis. Mechanistic investigations revealed that LOXL2 promotes invasion by regulating the expression and activity of the extracellular proteins tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9). We found that LOXL2, TIMP1, and MMP9 are coexpressed during mammary gland involution, suggesting they function together in glandular remodeling after weaning. Finally, we found that LOXL2 is highly expressed in the basal/myoepithelial mammary cell lineage, like many other genes that are upregulated in basal-like breast cancers. Our findings highlight the importance of LOXL2 in breast cancer progression and support the development of anti-LOXL2 therapeutics for the treatment of metastatic breast cancer. Cancer Res; 71(5); 1561–72. ©2011 AACR.
Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
Authors: Zuo Tao , Liu Ta-Ming , Lan Xun , Weng Yu-I , Shen Rulong , Gu Fei , Huang Yi-Wen , Liyanarachchi Sandya , Deatherage Daniel E. , Hsu Pei-Yin , Taslim Cenny , Ramaswamy Bhuvaneswari , Shapiro Charles L. , Lin Huey-Jen L. , Cheng Alfred S. L. , Jin Victor X. , Huang Tim H.-M. 
Published: January 2011

Abstract
Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future. Cancer Res; 71(5); 1752–62. ©2011 AACR.
Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations
Authors: Rosell Rafael , Molina Miguel Angel , Costa Carlota , Simonetti Sara , Gimenez-Capitan Ana , Bertran-Alamillo Jordi , Mayo Clara , Moran Teresa , Mendez Pedro , Cardenal Felipe , Isla Dolores , Provencio Mariano , Cobo Manuel , Insa Amelia , Garcia-Campelo Rosario , Reguart Noemi , Majem Margarita , Viteri Santiago , Carcereny Enric , Porta Ruth , Massuti Bartomeu , Queralt Cristina , de Aguirre Itziar , Sanchez Jose Miguel , Sanchez-Ronco Maria , Mate Jose Luis , Ariza Aurelio , Benlloch Susana , Sanchez Jose Javier , Bivona Trever G , Sawyers Charles L , Taron Miquel 
Published: January 2011

Abstract
Purpose: Advanced non–small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.
Experimental Design: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined.
Results: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P &lt; 0.0001), and high BRCA1 levels (HR, 8.46; P &lt; 0.0001) emerged as markers of shorter progression-free survival.
Conclusions: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression. Clin Cancer Res; 17(5); 1–9. ©2011 AACR.
Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth
Authors: Huang Hanhua , Lai Jing-Yu , Do Janet , Liu Dingguo , Li Lingna , Del Rosario Joselyn , Doppalapudi Venkata R. , Pirie-Shepherd Steven , Levin Nancy , Bradshaw Curt , Woodnutt Gary , Lappe Rodney , Bhat Abhijit 
Published: January 2011

Abstract
Purpose: Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.
Experimental Design: Various linker tethering sites on peptides were examined for their effect on CovX-Body in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC50s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.
Results: Bivalent Ang2 CovX-Bodies selectively block the Ang2–Tie2 interaction (IC50 &lt; 1 nmol/L) with dramatically improved pharmacokinetics (T½ &gt; 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%–63%, P &lt; 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P &lt; 0.01), whereas tumor microvessel density (P &lt; 0.01) and intratumor proangiogenic Tie2+CD11b+ cells (P &lt; 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy (∼80% TGI, P &lt; 0.01).
Conclusion: CovX-Bodies provide an elegant solution to overcome the pharmacokinetic–pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents. Clin Cancer Res; 17(5); 1001–11. ©2011 AACR.
JAK1 Activates STAT3 Activity in Non-Small–Cell Lung Cancer Cells and IL-6 Neutralizing Antibodies Can Suppress JAK1-STAT3 Signaling
Authors: Song Lanxi , Rawal Bhupendra , Nemeth Jeffrey A. , Haura Eric B. 
Published: January 2011

Abstract
Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small–cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations, yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells, and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets. Mol Cancer Ther; 10(3); 481–94. ©2011 AACR.
Silencing of Tubulin Binding Cofactor C Modifies Microtubule Dynamics and Cell Cycle Distribution and Enhances Sensitivity to Gemcitabine in Breast Cancer Cells
Authors: Hage-Sleiman Rouba , Herveau Stéphanie , Matera Eva-Laure , Laurier Jean-Fabien , Dumontet Charles 
Published: January 2011

Abstract
Tubulin binding cofactor C (TBCC) is essential for the proper folding of α- and β-tubulins into microtubule polymerizable heterodimers. Because microtubules are considered major targets in the treatment of breast cancer, we investigated the influence of TBCC silencing on tubulin pools, microtubule dynamics, and cell cycle distribution of breast cancer cells by developing a variant MCF7 cells with reduced content of TBCC (MC−). MC− cells displayed decreased content in nonpolymerizable tubulins and increased content of polymerizable/microtubule tubulins when compared with control MP6 cells. Microtubules in MC− cells showed stronger dynamics than those of MP6 cells. MC− cells proliferated faster than MP6 cells and showed an altered cell cycle distribution, with a higher percentage in S-phase of the cell cycle. Consequently, MC− cells presented higher sensitivity to the S-phase–targeting agent gemcitabine than MP6 cells in vitro. Although the complete duration of mitosis was shorter in MC− cells and their microtubule dynamics was enhanced, the percentage of cells in G2-M phase was not altered nor was there any difference in sensitivity to antimicrotubule-targeting agents when compared with MP6 cells. Xenografts derived from TBCC variants displayed significantly enhanced tumor growth in vivo and increased sensitivity to gemcitabine in comparison to controls. These results are the first to suggest that proteins involved in the proper folding of cytoskeletal components may have an important influence on the cell cycle distribution, proliferation, and chemosensitivity of tumor cells. Mol Cancer Ther; 10(2); 303–12. ©2011 AACR.
Interpreting Mammalian Target of Rapamycin and Cell Growth Inhibition in a Genetically Engineered Mouse Model of Nf1-Deficient Astrocytes
Authors: Banerjee Sutapa , Gianino Scott M. , Gao Feng , Christians Uwe , Gutmann David H. 
Published: January 2011

Abstract
The identification of mammalian target of rapamycin (mTOR) as a major mediator of neurofibromatosis-1 (NF1) tumor growth has led to the initiation of clinical trials using rapamycin analogs. Previous studies from our laboratory have shown that durable responses to rapamycin treatment in a genetically engineered mouse model of Nf1 optic glioma require 20 mg/kg/day, whereas only transient tumor growth suppression was observed with 5 mg/kg/day rapamycin despite complete silencing of ribosomal S6 activity. To gain clinically relevant insights into the mechanism underlying this dose-dependent effect, we used Nf1-deficient glial cells in vitro and in vivo. First, there was an exponential relationship between blood and brain rapamycin levels. Second, we show that currently used biomarkers of mTOR pathway inhibition (phospho-S6, phospho-4EBP1, phospho-STAT3, and Jagged-1 levels) and tumor proliferation (Ki67) do not accurately reflect mTOR target inhibition or Nf1-deficient glial growth suppression. Third, the incomplete suppression of Nf1-deficient glial cell proliferation in vivo following 5 mg/kg/day rapamycin treatment reflects mTOR-mediated AKT activation, such that combined 5 mg/kg/day rapamycin and PI3-kinase (PI3K) inhibition or dual PI3K/mTOR inhibition recapitulates the growth suppressive effects of 20 mg/kg/day rapamycin. These new findings argue for the identification of more accurate biomarkers for rapamycin treatment response and provide reference preclinical data for comparing human rapamycin levels with target effects in the brain. Mol Cancer Ther; 10(2); 279–91. ©2011 AACR.