bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signal Transducers and Activators of Transcription 5a–Dependent Cross-talk between Follicular Lymphoma Cells and Tumor Microenvironment Characterizes a Group of Patients with Improved Outcome after R-CHOP
Authors: Taskinen Minna , Valo Erkka , Karjalainen-Lindsberg Marja-Liisa , Hautaniemi Sampsa , Meri Seppo , Leppä Sirpa 
Published: April 2010

Abstract
Purpose: Tumor microenvironment has a strong effect on the survival of follicular lymphoma (FL) patients. The aim of this study was to determine what are the signaling pathways that mediate the cross-talk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the clinical outcome of FL patients.
Experimental Design: Gene expression profiling and pathway impact analyses were done from pretreatment lymphoma tissue of 24 patients. The findings were validated immunohistochemically in an independent cohort of 81 patients. All patients were treated with the combination of rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone chemotherapy. In addition, microarray was used to screen the genes differentially expressed between control and rituximab-stimulated B-cell lymphoma cells in culture.
Results: Among the transcripts differentially expressed in the FL tissues between the patients with favorable or adverse outcomes, an overrepresentation of genes associated with the signal transducers and activators of transcription (STAT)5a pathway was observed. In a validation set, a better progression-free survival was observed among the patients with high STAT5a protein expression. In the FL tissue, STAT5a positivity was barely detectable in the neoplastic B cells, but a subpopulation of follicular dendritic cells and T lymphocytes showed prominent STAT5a expression. Rituximab was found to induce the expression of STAT5a-associated interleukin-15 in B-lymphoma cells in culture, thereby providing a possible explanation for the cross-talk between rituximab-stimulated FL cells and their microenvironment.
Conclusion: The findings suggest that STAT5a activity in immunologically active nonmalignant cells acts as molecular predictor for rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone–treated FL patients. Clin Cancer Res; 16(9); 2615–23. ©2010 AACR.
Honokiol Inhibits Epidermal Growth Factor Receptor Signaling and Enhances the Antitumor Effects of Epidermal Growth Factor Receptor Inhibitors
Authors: Leeman-Neill Rebecca J. , Cai Quan , Joyce Sonali C. , Thomas Sufi M. , Bhola Neil E. , Neill Daniel B. , Arbiser Jack L. , Grandis Jennifer R. 
Published: April 2010

Abstract
Purpose: This study aimed to investigate the utility of honokiol, a naturally occurring compound, in the treatment of head and neck squamous cell carcinoma (HNSCC) as well as its ability to target the epidermal growth factor receptor (EGFR), a critical therapeutic target in HNSCC, and to enhance the effects of other EGFR-targeting therapies.
Experimental Design: Human HNSCC cell lines and the xenograft animal model of HNSCC were used to test the effects of honokiol treatment.
Results: Honokiol was found to inhibit growth in human HNSCC cell lines, with 50% effective concentration (EC50) values ranging from 3.3 to 7.4 μmol/L, and to induce apoptosis, as shown through Annexin V staining. These effects were associated with inhibition of EGFR signaling, including downstream inhibition of mitogen-activated protein kinase, Akt, and signal transducer and activator of transcription 3 (STAT3), and expression of STAT3 target genes, Bcl-XL and cyclin D1. Furthermore, honokiol enhanced the growth inhibitory and anti-invasion activity of the EGFR-targeting agent erlotinib. Although HNSCC xenograft models did not show significant inhibition of in vivo tumor growth with honokiol treatment alone, the combination of honokiol plus cetuximab, a Food and Drug Administration–approved EGFR inhibitor for this malignancy, significantly enhanced growth inhibition. Finally, HNSCC cells rendered resistant to erlotinib retained sensitivity to the growth inhibitory effects of honokiol.
Conclusions: These results suggest that honokiol may be an effective therapeutic agent in HNSCC, in which it can augment the effects of EGFR inhibitors and overcome drug resistance. Clin Cancer Res; 16(9); 2571–9. ©2010 AACR.
Activity of the Aurora Kinase Inhibitor VX-680 against Bcr/Abl-Positive Acute Lymphoblastic Leukemias
Authors: Fei Fei , Stoddart Sonia , Groffen John , Heisterkamp Nora 
Published: April 2010

Abstract
The emergence of resistance to tyrosine kinase inhibitors due to point mutations in Bcr/Abl is a challenging problem for Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL) patients, especially for those with the T315I mutation, against which neither nilotinib or dasatinib shows significant activity. VX-680 is a pan-Aurora kinase inhibitor active against all Bcr/Abl proteins but has not been extensively examined in preclinical models of Ph-positive ALL. Here, we have tested VX-680 for the treatment of Bcr/Abl-positive ALL when leukemic cells are protected by the presence of stroma. Under these conditions, VX-680 showed significant effects on primary human Ph-positive ALL cells both with and without the T315I mutation, including ablation of tyrosine phosphorylation downstream of Bcr/Abl, decreased viability, and induction of apoptosis. However, drug treatment of human Ph-positive ALL cells for 3 days followed by drug removal allowed the outgrowth of abnormal cells 21 days later, and on culture of mouse Bcr/Abl ALL cells on stroma with lower concentrations of VX-680, drug-resistant cells emerged. Combined treatment of human ALL cells lacking the T315I mutation with both VX-680 and dasatinib caused significantly more cytotoxicity than each drug alone. We suggest that use of VX-680 together with a second effective drug as first-line treatment for Ph-positive ALL is likely to be safer and more useful than second-line treatment with VX-680 as monotherapy for drug-resistant T315I Ph-positive ALL. Mol Cancer Ther; 9(5); 1318–27. ©2010 AACR.
Deficiency in the 15-kDa Selenoprotein Inhibits Tumorigenicity and Metastasis of Colon Cancer Cells
Authors: Irons Robert , Tsuji Petra A. , Carlson Bradley A. , Ouyang Ping , Yoo Min-Hyuk , Xu Xue-Ming , Hatfield Dolph L. , Gladyshev Vadim N. , Davis Cindy D. 
Published: April 2010

Abstract
Selenium has cancer-preventive activity that is mediated, in part, through selenoproteins. The role of the 15-kDa selenoprotein (Sep15) in colon cancer was assessed by preparing and using mouse colon CT26 cells stably transfected with short hairpin RNA constructs targeting Sep15. Metabolic 75Se labeling and Northern and Western blot analyses revealed that &gt;90% of Sep15 was downregulated. Growth of the resulting Sep15-deficient CT26 cells was reduced (P &lt; 0.01), and cells formed significantly (P &lt; 0.001) fewer colonies in soft agar compared with control CT26 cells. Whereas most (14 of 15) BALB/c mice injected with control cells developed tumors, few (3 of 30) mice injected with Sep15-deficient cells developed tumors (P &lt; 0.0001). The ability to form pulmonary metastases had similar results. Mice injected with the plasmid-transfected control cells had &gt;250 lung metastases per mouse; however, mice injected with cells with downregulation of Sep15 only had 7.8 ± 5.4 metastases. To investigate molecular targets affected by Sep15 status, gene expression patterns between control and knockdown CT26 cells were compared. Ingenuity Pathways Analysis was used to analyze the 1,045 genes that were significantly (P &lt; 0.001) affected by Sep15 deficiency. The highest-scored biological functions were cancer and cellular growth and proliferation. Consistent with these observations, subsequent analyses revealed a G2-M cell cycle arrest in cells with targeted downregulation of Sep15. In contrast to CT26 cells, Sep15-targeted downregulation in Lewis lung carcinoma (LLC1) cells did not affect anchorage-dependent or anchorage-independent cell growth. These data suggest tissue specificity in the cancer-protective effects of Sep15 downregulation, which are mediated, at least in part, by influencing the cell cycle. Cancer Prev Res; 3(5); 630–9. ©2010 AACR.
National Law: A Small but Neat Utensil in the Toolbox of International Criminal Tribunals
Authors: van der Wilt Harmen 
Published: April 2010

AbstractThis article explores to what extent the ad hoc tribunals have made use of the national law of the state where the crimes have allegedly been committed in their quest for elements of crimes, concepts of criminal responsibility, grounds for excluding criminal responsibility and guidelines for sentencing. At first sight, one would expect the legislation of the territorial state to feature only as an indication of 'general principles of law' or 'international customary law'. However, the investigation of case law reveals that the law of the territorial state holds a far more prominent place. In search for rationales, the author suggests that, initially, national legislation has been used to plug the legal gaps in international criminal law. However, more recently the ad hoc tribunals have canvassed the national legislation of the territorial state, in order to find out whether this state would qualify to take over criminal proceedings against mid-level perpetrators. The author suggests that the International Criminal Court might follow suit, in order to give shape to its policy of 'positive complementarity'.
Investigating the Crimes of the Franco Regime: Legal Possibilities, Obligations of the Spanish State and Duties Towards the Victims
Authors: Barbeito Mónica Zapico 
Published: April 2010

AbstractThe opening on 16th October 2008 by the Examining Judge of the High Court Baltasar Garzón of the first cause to investigate crimes committed during the Spanish Civil War and Franco's regime has initiated a vigorous debate about not only the convenience, but also the legal possibilities to carry out this research and can meet the demands of the families of the victims, who are dissatisfied with the Law of Historical Memory. This article attempts to analyze the main problems posed by the possibility that these crimes are investigated: the problem of non-retroactivity of criminal law and the classification of the facts committed as crimes against humanity; the question of the permanence of the crime of illegal detention and, in relation to this, the question of the statute of limitations; the existence of an amnesty law; the international obligations of the Spanish State and the duties towards the victims.
Armless Giants: Cooperation, State Responsibility and Suggestions for the ICC Review Conference
Authors: Demirdjian Alexis 
Published: April 2010

AbstractInternational criminal courts and tribunals regularly face difficulties in obtaining cooperation from States, a stumbling block that hinders the process of bringing criminals to justice and trying them before a court of law. In doing so, States can be held accountable under the rules of state responsibility. This possibility was raised in key decisions and scholarly texts on the issue. This paper seeks to expand the discussion on the matter and analyze the responsibility of States for their failure to cooperate with international courts. Additionally, this paper suggests amendments to the ICC Rome Statute to strengthen the judicial assistance regime, considering that this court is designed to become the permanent court dealing with war crimes and crimes against humanity and that a review of the Statute is to take place in May or June 2010.
Has the United Nations Security Council Implicitly Removed Al Bashir's Immunity?
Authors: Papillon Sophie 
Published: April 2010

AbstractOn 4 March 2009, the ICC issued an arrest warrant for Omar Hassan Ahmad Al Bashir, the incumbent Head of State of Sudan. This article's purpose is to suggest a legal basis for reconciling the well established rule on personal immunities under customary international law with the prosecution of Heads of State from non-parties to the ICC Statute. While arguing for the legality of Al Bashir's warrant as well as the legality of the warrant's enforcement, this article explores the basis upon which the UN Security Council can remove immunities. By giving special attention to the concept of waivers, the article suggests that the UN organ implicitly removed Al Bashir's immunity when it referred the situation of Sudan to the ICC in 2005.
Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development
Authors: Böiers Charlotta , Buza-Vidas Natalija , Jensen Christina T. , Pronk Cornelis J. H. , Kharazi Shabnam , Wittmann Lilian , Sitnicka Ewa , Hultquist Anne , Jacobsen Sten Eirik W. 
Published: April 2010

Abstract
Mice deficient in c-fms–like tyrosine kinase 3 (FLT3) signaling have reductions in early multipotent and lymphoid progenitors, whereas no evident myeloid phenotype has been reported. However, activating mutations of Flt3 are among the most common genetic events in acute myeloid leukemia and mice harboring internal tandem duplications within Flt3 (Flt3-ITD) develop myeloproliferative disease, with characteristic expansion of granulocyte-monocyte (GM) progenitors (GMP), possibly compatible with FLT3-ITD promoting a myeloid fate of multipotent progenitors. Alternatively, FLT3 might be expressed at the earliest stages of GM development. Herein, we investigated the expression, function, and role of FLT3 in recently identified early GMPs. Flt3-cre fate-mapping established that most progenitors and mature progeny of the GM lineage are derived from Flt3-expressing progenitors. A higher expression of FLT3 was found in preGMP compared with GMP, and preGMPs were more responsive to stimulation with FLT3 ligand (FL). Whereas preGMPs and GMPs were reduced in Fl−/− mice, megakaryocyte-erythroid progenitors were unaffected and lacked FLT3 expression. Notably, mice deficient in both thrombopoietin (THPO) and FL had a more pronounced GMP phenotype than Thpo−/− mice, establishing a role of FL in THPO-dependent and -independent regulation of GMPs, of likely significance for myeloid malignancies with Flt3-ITD mutations.
Novel insights into the genomic basis of citrus canker based on the genome sequences of two strains of Xanthomonas fuscans subsp. aurantifolii
Authors: Moreira Leandro M , Almeida Nalvo F , Potnis Neha , Digiampietri Luciano A , Adi Said S , Bortolossi Julio C , da Silva Ana C , da Silva Aline M , de Moraes Fabrício E , de Oliveira Julio C , de Souza Robson F , Facincani Agda P , Ferraz André L , Ferro Maria I , Furlan Luiz R , Gimenez Daniele F , Jones Jeffrey B , Kitajima Elliot W , Laia Marcelo L , Leite Rui P , Nishiyama Milton Y , Rodrigues Neto Julio , Nociti Letícia A , Norman David J , Ostroski Eric H , Pereira Haroldo A , Staskawicz Brian J , Tezza Renata I , Ferro Jesus A , Vinatzer Boris A , Setubal João C 
Published: April 2010

Abstract

Background
Citrus canker is a disease that has severe economic impact on the citrus industry worldwide. There are three types of canker, called A, B, and C. The three types have different phenotypes and affect different citrus species. The causative agent for type A is Xanthomonas citri subsp. citri, whose genome sequence was made available in 2002. Xanthomonas fuscans subsp. aurantifolii strain B causes canker B and Xanthomonas fuscans subsp. aurantifolii strain C causes canker C.

Results
We have sequenced the genomes of strains B and C to draft status. We have compared their genomic content to X. citri subsp. citri and to other Xanthomonas genomes, with special emphasis on type III secreted effector repertoires. In addition to pthA, already known to be present in all three citrus canker strains, two additional effector genes, xopE3 and xopAI, are also present in all three strains and are both located on the same putative genomic island. These two effector genes, along with one other effector-like gene in the same region, are thus good candidates for being pathogenicity factors on citrus. Numerous gene content differences also exist between the three cankers strains, which can be correlated with their different virulence and host range. Particular attention was placed on the analysis of genes involved in biofilm formation and quorum sensing, type IV secretion, flagellum synthesis and motility, lipopolysacharide synthesis, and on the gene xacPNP, which codes for a natriuretic protein.

Conclusion
We have uncovered numerous commonalities and differences in gene content between the genomes of the pathogenic agents causing citrus canker A, B, and C and other Xanthomonas genomes. Molecular genetics can now be employed to determine the role of these genes in plant-microbe interactions. The gained knowledge will be instrumental for improving citrus canker control.
The impact of ColRS two-component system and TtgABC efflux pump on phenol tolerance of Pseudomonas putida becomes evident only in growing bacteria
Authors: Putrinš Marta , Ilves Heili , Lilje Liisa , Kivisaar Maia , Hõrak Rita 
Published: April 2010

AbstractBackgroundWe have recently found thatPseudomonas putidadeficient in ColRS two-component system is sensitive to phenol and displays a serious defect on solid glucose medium where subpopulation of bacteria lyses. The latter phenotype is significantly enhanced by the presence of phenol in growth medium. Here, we focused on identification of factors affecting phenol tolerance of thecolR-deficientP. putida.ResultsBy using transposon mutagenesis approach we identified a set of phenol-tolerant derivatives ofcolR-deficient strain. Surprisingly, half of independent phenol tolerant clones possessed miniTn5 insertion in thettgABCoperon. However, though inactivation of TtgABC efflux pump significantly enhanced phenol tolerance, it did not affect phenol-enhanced autolysis of thecolRmutant on glucose medium indicating that phenol- and glucose-caused stresses experienced by thecolR-deficientP. putidaare not coupled. Inactivation of TtgABC pump significantly increased the phenol tolerance of the wild-typeP. putidaas well. Comparison of phenol tolerance of growingversusstarving bacteria revealed that both ColRS and TtgABC systems affect phenol tolerance only under growth conditions and not under starvation. Flow cytometry analysis showed that phenol strongly inhibited cell division and to some extent also caused cell membrane permeabilization to propidium iodide. Single cell analysis of populations of thettgC-andcolRttgC-deficient strains revealed that their membrane permeabilization by phenol resembles that of the wild-type and thecolRmutant, respectively. However, cell division ofP. putidawith inactivated TtgABC pump seemed to be less sensitive to phenol than that of the parental strain. At the same time, cell division appeared to be more inhibited in thecolR-mutant strain than in the wild-typeP. putida.ConclusionsColRS signal system and TtgABC efflux pump are involved in the phenol tolerance ofP. putida. However, as they affect phenol tolerance of growing bacteria only, this indicates that they participate in the regulation of processes which are active during the growth and/or cell division. Single cell analysis data indicated that the cell division step of cell cycle is particularly sensitive to the toxic effect of phenol and its inhibition can be considered as an adaptive response under conditions of phenol stress.
Adverse events, bone mineral density and discontinuation associated with generic alendronate among postmenopausal women previously tolerant of brand alendronate: a retrospective cohort study
Authors: Grima Daniel T , Papaioannou Alexandra , Airia Parisa , Ioannidis George , Adachi Jonathan D 
Published: April 2010

Abstract

Background
A rise in gastrointestinal (GI) adverse events (AEs) and a decline in bone mineral density (BMD) was observed in patients previously tolerant to brand alendronate shortly after generic versions were introduced in July 2005 to the Canadian market. The objective of our study was to quantify changes in AE rates and BMD scores, as well as associated alendronate discontinuation among patients before and after switch from brand to generic alendronate.

Methods
A chart review of postmenopausal women 50 years of age and older between 2003 and 2007 was conducted in two specialized tertiary care referral centers. Patients on alendronate both before and after July 2005 were included. The change in the number of AEs, changes in BMD and associated alendronate discontinuation was compared before and after the switch from brand to generic alendronate.

Results
301 women with an average age of 67.6 years (standard deviation (SD) = 9.5) had a total of 47 AEs between July 2003 and December 2007 that resulted in discontinuation of the medication. There was a significant increase in the rate of AEs per patient-months-at-risk from 0.0001 before to 0.0044 after October 2005 (p < 0.001). The most common AEs were GI in nature (stomach pain, GI upset, nausea, and reflux). In addition, 23 patients discontinued alendronate due to BMD reduction after January 2006. In these patients, BMD scores were significantly reduced from their prior BMD measures (change of -0.0534, p < 0.001 for spine BMD and change of -0.0338, p = 0.01 for femur BMD). Among patients who discontinued due to BMD reduction, BMD was stable in the period prior to January 2006 (change of -0.0066, p = 0.5 for spine BMD and change of 0.0011, p = 0.9 for femur BMD); however, testing for reduction after January 2006 in BMD measures (one-sided T-test) revealed there was a significant reduction in BMD scores for both anatomic sites (change of -0.0321, p = .005 for spine, change of -0.0205, p = 0.05 for femur).

Conclusions
Patients who were previously stable on doses of brand alendronate experienced an increase in AEs causing discontinuation after introduction of automatic substitution to generic alendronate. In addition, reductions in BMD were observed in some patients who had stable BMDs before January 2006. Given the substantial increase in AEs, generic alendronate may not be as well tolerated as brand alendronate.
CD7 in acute myeloid leukemia: correlation with loss of wild-type CEBPA, consequence of epigenetic regulation
Authors: Röhrs Sonja , Scherr Michaela , Romani Julia , Zaborski Margarete , Drexler Hans G , Quentmeier Hilmar 
Published: April 2010

Abstract

Background
CD7 is a negative prognostic marker in myeloid malignancies. In acute myeloid leukemia (AML), an inverse correlation exists between expression of wild-type CEBPA and CD7. Aim of this study was to find out whether C/EBPα is a negative regulator of CD7 and which other regulatory mechanisms might be involved.

Results
As already described for primary AML cells, the majority of AML cell lines tested were either C/EBPα+/CD7- or C/EBPα-/CD7+. However, the existence of isolated CD7+ cell lines expressing wild-type C/EBPα challenges the notion that C/EBPα acts as a unique repressor of CD7. Furthermore, ectopic expression of CEBPA did not reduce CD7 in CD7+ cells and knock-down of C/EBPα failed to induce CD7 in CD7- cells. In contrast, the DNA demethylating agent Aza-2'deoxycytidine triggered CD7 expression in CD7- AML and in T-cell lines suggesting epigenetic regulation of CD7. Bisulfite sequencing data confirmed that CpGs in the CD7 exon1 region are methylated in CD7- cell lines, and unmethylated in CD7+ cell lines.

Conclusion
We confirmed an inverse correlation between the expression of wild-type CEBPA and of CD7 in AML cells. Our results contradict the hypothesis that C/EBPα acts as repressor for CD7, and instead show that epigenetic mechanisms are responsible for CD7 regulation, in AML cells as well as in T-cells, the typical CD7 expressing cell type.