bluuebunny/crossref_metadata_2025_split huggingface dataset:
CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer Therapy
Authors: Sakamoto Kathleen M. , Frank David A. 
Published: April 2009

Abstract
Transcription factors are key regulators of the pattern of gene expression in a cell and directly control central processes such as proliferation, survival, self-renewal, and invasion. Given this critical role, the function of transcription factors is normally regulated closely, often through transient phosphorylation. Although transcription factors are not often directly modified by mutations in cancer cells, they frequently become activated constitutively through mutations affecting “upstream” pathways. By continually driving the expression of key target genes, these oncogenic transcription factors play a central role in tumor pathogenesis. One such transcription factor is the cAMP-regulatory element-binding protein (CREB), which can be activated through phosphorylation by a number of kinases, including Akt, p90Rsk, protein kinase A, and calcium/calmodulin-dependent kinases and regulates genes whose deregulated expression promotes oncogenesis, including cyclins, Bcl-2 family members, and Egr-1. CREB is overexpressed and constitutively phosphorylated in a number of forms of human cancer, including acute myeloid leukemia (AML) and non–small cell lung cancer, and appears to play a direct role in disease pathogenesis and prognosis. Although transcription factors have not been a central focus of drug development, recent advances suggest that CREB and other such proteins may be worthwhile targets for cancer therapy.
β-Catenin Small Interfering RNA Successfully Suppressed Progression of Multiple Myeloma in a Mouse Model
Authors: Ashihara Eishi , Kawata Eri , Nakagawa Yoko , Shimazaski Chihiro , Kuroda Junya , Taniguchi Kyoko , Uchiyama Hitoji , Tanaka Ruriko , Yokota Asumi , Takeuchi Miki , Kamitsuji Yuri , Inaba Tohru , Taniwaki Masafumi , Kimura Shinya , Maekawa Taira 
Published: April 2009

Abstract
Purpose: β-catenin is the downstream effector of the Wnt signaling pathway, and it regulates cell proliferation. β-catenin overexpression correlates positively with prognosis in several types of malignancies. We herein assessed its effects on growth of multiple myeloma cells using a xenograft model.
Experimental Design: We first investigated the expression of β-catenin in multiple myeloma cell lines and multiple myeloma cells obtained from patients. Next, we investigated the growth inhibitory effects of β-catenin small interfering RNA on the growth of multiple myeloma cells in vivo. Six-week-old male BALB/c nu/nu mice were inoculated s.c. in the right flank with 5 × 106 RPMI8226 cells, followed by s.c. injections of β-catenin small interfering RNA, scramble small interfering RNA, or PBS/atelocollagen complex twice a week for a total of eight injections.
Results: Significantly higher levels of β-catenin expression were observed in multiple myeloma cell lines and in samples from patients with multiple myeloma than those found in mononuclear cells obtained from healthy volunteers. In in vivo experiments, no inhibitory effects were observed following treatment with scramble small interfering RNA or PBS/atelocollagen complexes, whereas treatment with β-catenin small interfering RNA/atelocollagen complex significantly inhibited growth of multiple myeloma tumors (P &lt; 0.05).
Conclusions: β-catenin small interfering RNA treatment inhibited the growth of multiple myeloma tumors in a xenograft model. To our knowledge, this is the first report showing that the treatment with β-catenin small interfering RNA produces an inhibitory effects on growth of hematologic malignancies in vivo. Because treatment with β-catenin small interfering RNA inhibited growth of multiple myeloma cells, β-catenin is the attractive novel target for treating multiple myeloma.
Translating the Metastasis Paradigm from Scientific Theory to Clinical Oncology
Authors: Dong Fei , Budhu Anuradha S. , Wang Xin Wei 
Published: April 2009

Abstract
Cancer metastasis contributes to significant morbidity and mortality. Patients with metastatic cancer, often considered incurable, are provided with either supportive care or aggressive management without curative intent. Despite decades of research toward unraveling cancer progression mechanisms, the current body of knowledge has not translated into effective antimetastasis therapies, but recent findings challenge the classic notion that metastases develop during the late stages of carcinogenesis. Here, we evaluate the scientific evidence in the context of the multistage metastasis model. The resolution of current controversies has implications on both the prognostic value of molecular technology and the future of targeted therapies for the clinical benefit of metastasis patients.
p65 Activity and ZAP-70 Status Predict the Sensitivity of Chronic Lymphocytic Leukemia Cells to the Selective IκB Kinase Inhibitor BMS-345541
Authors: López-Guerra Mónica , Roué Gaël , Pérez-Galán Patricia , Alonso Roberto , Villamor Neus , Montserrat Emili , Campo Elias , Colomer Dolors 
Published: April 2009

Abstract
Purpose: Constitutive nuclear factor-κB (NF-κB) activation has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL). Our purpose was to characterize the molecular mechanisms underlying for the selective IκB kinase inhibitor BMS-345541 in CLL cells together with the analysis of its combination with several antineoplasic drugs.
Experimental Design: Primary cells from 34 CLL patients were incubated with different doses of BMS-345541. NF-κB DNA-binding activity was analyzed by ELISA-based kits and the characterization of the apoptotic pathway was done by flow cytometry, immunoblotting, quantitative reverse transcription-PCR, and immunofluorescence techniques.
Results: BMS-345541 selectively induced apoptosis in CLL cells in the low micromolar range irrespective of p53 status. Noteworthy, the high ZAP-70 group was significantly more sensitive to BMS-345541 than the low ZAP-70 group, in correlation with high levels of p65 phosphorylation and DNA-binding activity. Following NF-κB inhibition, BMS-345541 led to induction of the mitochondrial apoptotic pathway and activation of both caspase-dependent and caspase-independent factors. Moreover, BMS-345541-induced apoptosis was accompanied by down-regulation of several antiapoptotic NF-κB-target genes, including both BCL2 family members and apoptotic endogenous inhibitors. In addition, we showed a strong synergism between BMS-345541 and conventional chemotherapeutics such as mitoxantrone and dexamethasone as well as with new promising drugs such as the BH3-mimetic GX15-070/Obatoclax or the anti-TRAIL-R1 monoclonal antibody mapatumumab.
Conclusions: These data confirm that NF-κB is a relevant target in CLL and indicate that inhibitors of IκB kinase, alone or in combination, represent a novel therapeutic strategy for the treatment of CLL patients, especially for the group with high ZAP-70.
Induction of Wilms' Tumor Protein (WT1)–Specific Antitumor Immunity Using a Truncated WT1-Expressing Adenovirus Vaccine
Authors: Osada Takuya , Woo Christopher Y. , McKinney Matthew , Yang Xiao Yi , Lei Gangjun , LaBreche Heather G. , Hartman Zachary C. , Niedzwiecki Donna , Chao Nelson , Amalfitano Andrea , Morse Michael A. , Lyerly H. Kim , Clay Timothy M. 
Published: April 2009

Abstract
Purpose: Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide–based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen–specific immunity across a broad array of HLA types and multiple class I and class II epitopes.
Experimental Design: We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors.
Results: Despite encoding a transcription factor, we found that Ad-tWT1–transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth.
Conclusions: This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.
Motility Induction in Breast Carcinoma by Mammary Epithelial Laminin 332 (Laminin 5)
Authors: Carpenter Philip M. , Dao Anh V. , Arain Zahida S. , Chang Michelle K. , Nguyen Hoa P. , Arain Shehla , Wang-Rodriguez Jessica , Kwon Soon-Young , Wilczynski Sharon P. 
Published: April 2009

Abstract
Host interactions with tumor cells contribute to tumor progression by several means. This study was done to determine whether mammary epithelium could interact with breast carcinoma by producing substances capable of inducing motility in the cancer cells. Conditioned medium of immortalized 184A1 mammary epithelium collected in serum-free conditions induced dose-dependent motility in the MCF-7 breast carcinoma cell line by both a semiquantitative scattering assay and a Boyden chamber assay. Purification of the motility factor revealed that it was laminin 332 (formerly laminin 5) by mass spectroscopy. A Western blot of the 184A1 conditioned medium using a polyclonal antibody confirmed the presence of laminin 332 in the conditioned medium. Blockage of the motility with antibodies to the laminin 332 and its receptor components, α3 and β1 integrins, provided further evidence that tumor cell motility was caused by the laminin 332 in the conditioned medium. Invasion of MCF-7, BT-20, and MDA-MB-435S was induced by purified laminin 332 and 184A1 conditioned medium and blocked by an anti-α3 integrin antibody. Staining of carcinoma in situ from breast cancer specimens revealed that laminin 332 in the myoepithelium adjacent to the preinvasive cells provided a source of laminin 332 that could potentially encourage the earliest steps of stromal invasion. In metaplastic breast carcinomas, the presence of laminin 332-producing cells coexpressing α3 integrin and the greater metastatic potential of tumors with higher laminin 332 levels suggest that laminin 332 expression is associated with aggressive features in these human breast cancers.(Mol Cancer Res 2009;7(4):462–75)
Assortative mating among Lake Malawi cichlid fish populations is not simply predictable from male nuptial colour
Authors: Blais Jonatan , Plenderleith Martin , Rico Ciro , Taylor Martin I , Seehausen Ole , van Oosterhout Cock , Turner George F 
Published: April 2009

Abstract

Background
Research on the evolution of reproductive isolation in African cichlid fishes has largely focussed on the role of male colours and female mate choice. Here, we tested predictions from the hypothesis that allopatric divergence in male colour is associated with corresponding divergence in preference.

Methods
We studied four populations of the Lake Malawi Pseudotropheus zebra complex. We predicted that more distantly-related populations that independently evolved similar colours would interbreed freely while more closely-related populations with different colours mate assortatively. We used microsatellite genotypes or mesh false-floors to assign paternity. Fisher's exact tests as well as Binomial and Wilcoxon tests were used to detect if mating departed from random expectations.

Results
Surprisingly, laboratory mate choice experiments revealed significant assortative mating not only between population pairs with differently coloured males, but between population pairs with similarly-coloured males too. This suggested that assortative mating could be based on non-visual cues, so we further examined the sensory basis of assortative mating between two populations with different male colour. Conducting trials under monochromatic (orange) light, intended to mask the distinctive male dorsal fin hues (blue v orange) of these populations, did not significantly affect the assortative mating by female P. emmiltos observed under control conditions. By contrast, assortative mating broke down when direct contact between female and male was prevented.

Conclusion
We suggest that non-visual cues, such as olfactory signals, may play an important role in mate choice and behavioural isolation in these and perhaps other African cichlid fish. Future speciation models aimed at explaining African cichlid radiations may therefore consider incorporating such mating cues in mate choice scenarios.
Histone acetylations mark origins of polycistronic transcription in Leishmania major
Authors: Thomas Sean , Green Amanda , Sturm Nancy R , Campbell David A , Myler Peter J 
Published: April 2009

Abstract

Background
Many components of the RNA polymerase II transcription machinery have been identified in kinetoplastid protozoa, but they diverge substantially from other eukaryotes. Furthermore, protein-coding genes in these organisms lack individual transcriptional regulation, since they are transcribed as long polycistronic units. The transcription initiation sites are assumed to lie within the 'divergent strand-switch' regions at the junction between opposing polycistronic gene clusters. However, the mechanism by which Kinetoplastidae initiate transcription is unclear, and promoter sequences are undefined.

Results
The chromosomal location of TATA-binding protein (TBP or TRF4), Small Nuclear Activating Protein complex (SNAP50), and H3 histones were assessed in Leishmania major using microarrays hybridized with DNA obtained through chromatin immunoprecipitation (ChIP-chip). The TBP and SNAP50 binding patterns were almost identical and high intensity peaks were associated with tRNAs and snRNAs. Only 184 peaks of acetylated H3 histone were found in the entire genome, with substantially higher intensity in rapidly-dividing cells than stationary-phase. The majority of the acetylated H3 peaks were found at divergent strand-switch regions, but some occurred at chromosome ends and within polycistronic gene clusters. Almost all these peaks were associated with lower intensity peaks of TBP/SNAP50 binding a few kilobases upstream, evidence that they represent transcription initiation sites.

Conclusion
The first genome-wide maps of DNA-binding protein occupancy in a kinetoplastid organism suggest that H3 histones at the origins of polycistronic transcription of protein-coding genes are acetylated. Global regulation of transcription initiation may be achieved by modifying the acetylation state of these origins.
Sequence analysis of percent G+C fraction libraries of human faecal bacterial DNA reveals a high number of Actinobacteria
Authors: Krogius-Kurikka Lotta , Kassinen Anna , Paulin Lars , Corander Jukka , Mäkivuokko Harri , Tuimala Jarno , Palva Airi 
Published: April 2009

Abstract

Background
The human gastrointestinal (GI) tract microbiota is characterised by an abundance of uncultured bacteria most often assigned in phyla Firmicutes and Bacteroidetes. Diversity of this microbiota, even though approached with culture independent techniques in several studies, still requires more elucidation. The main purpose of this work was to study whether the genomic percent guanine and cytosine (%G+C) -based profiling and fractioning prior to 16S rRNA gene sequence analysis reveal higher microbiota diversity, especially with high G+C bacteria suggested to be underrepresented in previous studies.

Results
A phylogenetic analysis of the composition of the human GI microbiota of 23 healthy adult subjects was performed from a pooled faecal bacterial DNA sample by combining genomic %G+C -based profiling and fractioning with 16S rRNA gene cloning and sequencing. A total of 3199 partial 16S rRNA genes were sequenced. For comparison, 459 clones were sequenced from a comparable unfractioned sample. The most important finding was that the proportional amount of sequences affiliating with the phylum Actinobacteria was 26.6% in the %G+C fractioned sample but only 3.5% in the unfractioned sample. The orders Coriobacteriales, Bifidobacteriales and Actinomycetales constituted the 65 actinobacterial phylotypes in the fractioned sample, accounting for 50%, 47% and 3% of sequences within the phylum, respectively.

Conclusion
This study shows that the %G+C profiling and fractioning prior to cloning and sequencing can reveal a significantly larger proportion of high G+C content bacteria within the clones recovered, compared with the unfractioned sample in the human GI tract. Especially the order Coriobacteriales within the phylum Actinobacteria was found to be more abundant than previously estimated with conventional sequencing studies.
Members of miR-169 family are induced by high salinity and transiently inhibit the NF-YA transcription factor
Authors: Zhao Botao , Ge Liangfa , Liang Ruqiang , Li Wei , Ruan Kangcheng , Lin Hongxuan , Jin Youxin 
Published: April 2009

Abstract

Background
MicroRNAs (miRNAs) are endogenously expressed small RNAs with a length of about 21 nt. MiRNAs silence their target genes at the post-transcriptional level. In plants, miRNAs play various developmental and physiological roles by cleavaging mRNAs predominantly. Drought and high salinity are the most severe environmental abiotic stresses and cause crop losses all over the world.

Results
In this study, we identified miR-169g and miR-169n (o) as high salinity-responsive miRNAs in rice. MiR-169n and miR169o were in a miRNA cluster with a distance of 3707 base pairs (bp). The high degree of conservation and close phylogenic distance of pre-miR-169n and pre-miR-169o indicated that they were derived from a very recent tandem duplication evolutionary event. The existence of a cis-acting abscisic acid responsive element (ABRE) in the upstream region of miR-169n (o) suggested that miR-169n (o) may be regulated by ABA. In our previous study, we found that miR-169g was induced by the osmotic stress caused by drought via a dehydration-responsive element (DRE). Thus, our data showed that there were both overlapping and distinct responses of the miR-169 family to drought and salt stresses. We also showed that these miR-169 members selectively cleaved one of the NF-YA genes, Os03g29760, which is a CCAAT-box binding transcription factor and participates in transcriptional regulation of large number genes. Finally, we found one or more ath-miR-169 member that was also induced by high salinity.

Conclusion
We identified members of the miR-169 family as salt-induced miRNAs and analyzed their evolution, gene organization, expression, transcriptional regulation motif and target gene. Our data also indicated that the salt-induction of some miR-169 members was a general property in plants.
Removing celiac disease-related gluten proteins from bread wheat while retaining technological properties: a study with Chinese Spring deletion lines
Authors: van den Broeck Hetty C , van Herpen Teun WJM , Schuit Cees , Salentijn Elma MJ , Dekking Liesbeth , Bosch Dirk , Hamer Rob J , Smulders Marinus JM , Gilissen Ludovicus JWJ , van der Meer Ingrid M 
Published: April 2009

Abstract

Background
Gluten proteins can induce celiac disease (CD) in genetically susceptible individuals. In CD patients gluten-derived peptides are presented to the immune system, which leads to a CD4+ T-cell mediated immune response and inflammation of the small intestine. However, not all gluten proteins contain T-cell stimulatory epitopes. Gluten proteins are encoded by multigene loci present on chromosomes 1 and 6 of the three different genomes of hexaploid bread wheat (Triticum aestivum) (AABBDD).

Results
The effects of deleting individual gluten loci on both the level of T-cell stimulatory epitopes in the gluten proteome and the technological properties of the flour were analyzed using a set of deletion lines of Triticum aestivum cv. Chinese Spring. The reduction of T-cell stimulatory epitopes was analyzed using monoclonal antibodies that recognize T-cell epitopes present in gluten proteins. The deletion lines were technologically tested with respect to dough mixing properties and dough rheology. The results show that removing the α-gliadin locus from the short arm of chromosome 6 of the D-genome (6DS) resulted in a significant decrease in the presence of T-cell stimulatory epitopes but also in a significant loss of technological properties. However, removing the ω-gliadin, γ-gliadin, and LMW-GS loci from the short arm of chromosome 1 of the D-genome (1DS) removed T-cell stimulatory epitopes from the proteome while maintaining technological properties.

Conclusion
The consequences of these data are discussed with regard to reducing the load of T-cell stimulatory epitopes in wheat, and to contributing to the design of CD-safe wheat varieties.
Erratum to: Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors
Authors: Serrao Erik , Odde Srinivas , Ramkumar Kavya , Neamati Nouri 
Published: April 2009

Abstract
Correction to Erik Serrao, Srinivas Odde, Kavya Ramkumar and Nouri Neamati: Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009, 6:25. Since the recent publication of our article (Neamati, Retrovirology 2009, 6:25), we have noticed an error which we would like to correct and we would like to apologise to the readers for this mistake.
Induction of p21CIP1/WAF1expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization
Authors: Zhang Ling , Zhi Huijun , Liu Meihong , Kuo Yu-Liang , Giam Chou-Zen 
Published: April 2009

Abstract
HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21CIP1/WAF1 and p27KIP1. Tax increases p27KIP1 protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCFSkp2, the E3 ligase that targets p27KIP1. The rate of p21CIP1/WAF1 protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21CIP1/WAF1 is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21CIP1/WAF1 by Tax occurs in a p53-independent manner and requires two tumor growth factor-β-inducible Sp1 binding sites in the -84 to -60 region of the p21CIP1/WAF1 promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21CIP1/WAF1 trans-activation. Tax also increases the stability of p21CIP1/WAF1 transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21CIP1/WAF1 mRNA, and were less proficient in increasing p21CIP1/WAF1 expression. The possible involvement of Tax-mediated APC/C activation in p21CIP1/WAF1 mRNA stabilization is discussed.