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A Coupled Stochastic Model Explains Differences in Circadian Behavior of Cry1 and Cry2 Knockouts  [PDF]
John H. Abel,Lukas A. Widmer,Peter C. St. John,J?rg Stelling,Francis J. Doyle III
Quantitative Biology , 2014,
Abstract: In the mammalian suprachiasmatic nucleus (SCN), a population of noisy cell-autonomous oscillators synchronizes to generate robust circadian rhythms at the organism-level. Within these cells two isoforms of Cryptochrome, Cry1 and Cry2, participate in a negative feedback loop driving circadian rhythmicity. Previous work has shown that single, dissociated SCN neurons respond differently to Cry1 and Cry2 knockouts: Cry1 knockouts are arrhythmic while Cry2 knockouts display more regular rhythms. These differences have led to speculation that CRY1 and CRY2 may play different functional roles in the oscillator. To address this proposition, we have developed a new coupled, stochastic model focused on the Period (Per) and Cry feedback loop, and incorporating intercellular coupling via vasoactive intestinal peptide (VIP). Due to the stochastic nature of molecular oscillations, we demonstrate that single-cell Cry1 knockout oscillations display partially rhythmic behavior, and cannot be classified as simply rhythmic or arrhythmic. Our model demonstrates that intrinsic molecular noise and differences in relative abundance, rather than differing functions, are sufficient to explain the range of rhythmicity encountered in Cry knockouts in the SCN. Our results further highlight the essential role of stochastic behavior in understanding and accurately modeling the circadian network and its response to perturbation.
Vascular Endothelial Growth Factor A (VEGFA) Gene Polymorphisms Have an Impact on Survival in a Subgroup of Indolent Patients with Chronic Lymphocytic Leukemia  [PDF]
Carol Lozano-Santos, Jimena Martinez-Velasquez, Belen Fernandez-Cuevas, Natividad Polo, Belen Navarro, Isabel Millan, Jose Miguel Garcia, Rosa Collado, Pedro Sanchez-Godoy, Felix Carbonell, Jose Antonio Garcia-Vela, Jose Antonio Garcia-Marco, Natalia Gomez-Lozano
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101063
Abstract: Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL). We investigated the impact of VEGFA gene diversity on the clinical outcome of patients with this disease. A VEGFA haplotype conformed by positions rs699947 (–1540C>A), rs833061 (–460T>C) and rs2010963 (405C>G) and two additional single-nucleotide polymorphisms (SNPs), rs3025039 (936C>T) and rs25648 (1032C>T), were analysed in 239 patients at the time of their CLL diagnosis. Here, we showed that homozygosity for rs699947/rs833061/rs2010963 ACG haplotype (ACG+/+ genotype) correlated with a reduced survival in CLL patients (ACG+/+ vs other genotypes: HR = 2.3, p = 0.002; recessive model). In multivariate analysis, the ACG+/+ genotype was identified as a novel independent prognostic factor (HR = 2.1, p = 0.005). Moreover, ACG homozygosity subdivided patients with CLL with otherwise indolent parameters into prognostic subgroups with different outcomes. Specifically, patients carrying the ACG+/+ genotype with mutated IgVH, very low and low-risk cytogenetics, initial clinical stage, CD38 negative status or early age at diagnosis showed a shorter survival (ACG+/+ vs other genotypes: HR = 3.5, p = 0.035; HR = 3.4, p = 0.001; HR = 2.2, p = 0.035; HR = 3.4, p = 0.0001 and HR = 3.1, p = 0.009, respectively). In conclusion, VEGFA ACG+/+ genotype confers an adverse effect in overall survival in CLL patients with an indolent course of the disease. These observations support the biological and prognostic implications of VEGFA genetics in CLL.
Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia
Evgeny A Moskalev, Katrin Luckert, Ivan A Vorobjev, Sergey E Mastitsky, Aleena A Gladkikh, Achim Stephan, Marita Schrenk, Kamil D Kaplanov, Olga B Kalashnikova, Oliver P?tz, Thomas O Joos, J?rg D Hoheisel
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-213
Abstract: Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models.For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2′-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2′-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect.The results suggest an epigenetic silencing mechanism of the Wnt/β-catenin pathway inhibitor genes in CLL. Hypermethylation and silencing of functionally related genes may not be completely stochastic but result from the tumour epigenome reprogramming orchestrated by Polycomb-group repressive complexes. The data are of interest in the context of epigenetic-based therapy.
The Trichoderma reesei Cry1 Protein Is a Member of the Cryptochrome/Photolyase Family with 6–4 Photoproduct Repair Activity  [PDF]
Jesús Guzmán-Moreno, Alberto Flores-Martínez, Luis G. Brieba, Alfredo Herrera-Estrella
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100625
Abstract: DNA-photolyases use UV-visible light to repair DNA damage caused by UV radiation. The two major types of DNA damage are cyclobutane pyrimidine dimers (CPD) and 6–4 photoproducts (6-4PP), which are repaired under illumination by CPD and 6–4 photolyases, respectively. Cryptochromes are proteins related to DNA photolyases with strongly reduced or lost DNA repair activity, and have been shown to function as blue-light photoreceptors and to play important roles in circadian rhythms in plants and animals. Both photolyases and cryptochromes belong to the cryptochrome/photolyase family, and are widely distributed in all organisms. Here we describe the characterization of cry1, a member of the cryptochrome/photolyase protein family of the filamentous fungus Trichoderma reesei. We determined that cry1 transcript accumulates when the fungus is exposed to light, and that such accumulation depends on the photoreceptor Blr1 and is modulated by Envoy. Conidia of cry1 mutants show decreased photorepair capacity of DNA damage caused by UV light. In contrast, strains over-expressing Cry1 show increased repair, as compared to the parental strain even in the dark. These observations suggest that Cry1 may be stimulating other systems involved in DNA repair, such as the nucleotide excision repair system. We show that Cry1, heterologously expressed and purified from E. coli, is capable of binding to undamaged and 6-4PP damaged DNA. Photorepair assays in vitro clearly show that Cry1 repairs 6-4PP, but not CPD and Dewar DNA lesions.
The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma  [cached]
Ibrahim T Aldoss,Susan M Blumel,Philip J Bierman
Cancer Management and Research , 2009,
Abstract: Ibrahim T Aldoss1, Susan M Blumel2, Philip J Bierman21Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, USA; 2Section of Hematology – Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NEAbstract: There is no consensus on recommendations for the treatment of relapsed and refractory indolent non-Hodgkin lymphoma (NHL). Bendamustine hydrochloride (bendamustine) has recently been approved for treatment of these patients. Bendamustine is a uniquely structured alkylating agent that lacks cross-resistance with other alkylators. This agent has a high degree of activity against a variety of tumor cell lines. Clinically, bendamustine has demonstrated activity against indolent NHL, chronic lymphocytic lymphoma, multiple myeloma and mantle cell lymphoma. Moreover, studies have validated its activity in patients with indolent NHL who are resistant to purine analogs and rituximab. The cytotoxic activity of bendamustine has been shown to be synergistic with rituximab in hematological malignancies. The incidence of alopecia is significantly less than with other alkylating agents. Myelosuppression is the major toxicity associated with bendamustine.Keywords: bendamustine, Treanda, indolent non-Hodgkin lymphoma, alkylating agent, chronic lymphocytic lymphoma
Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice  [PDF]
Dimitri De Bundel,Giuseppe Gangarossa,Anne Biever,Xavier Bonnefont,Emmanuel Valjent
Frontiers in Behavioral Neuroscience , 2013, DOI: 10.3389/fnbeh.2013.00152
Abstract: The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1?/?Cry2?/?) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1?/?Cry2?/? mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1?/?Cry2?/? mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1?/?Cry2+/+ and Cry1+/+Cry2?/? mice. Moreover, we further observed elevated anxiety in Cry1?/?Cry2+/+ and Cry1+/+Cry2?/? mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.
Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males
Jean-Brice Marteau, Odile Rigaud, Thibaut Brugat, Nathalie Gault, Laurent Vallat, Mogens Kruhoffer, Torben F Orntoft, Florence Nguyen-Khac, Sylvie Chevillard, Hélène Merle-Beral, Jozo Delic
BMC Medical Genomics , 2010, DOI: 10.1186/1755-8794-3-53
Abstract: Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test.Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these, RELB was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells.The molecular defects in the silencing of RELB involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic RELB silencing as a new marker of the progressive disease in males.The CLL is currently incurable and is associated with a high incidence of morbidity and mortality in the elderly. Men are more frequently affected than women (0.6/0.4), develop the disease at a younger age [1,2] and often exhibit a more aggressive form of this disease [3]. Consistent with these observations, CLL cells in
Postnatal Constant Light Compensates Cryptochrome1 and 2 Double Deficiency for Disruption of Circadian Behavioral Rhythms in Mice under Constant Dark  [PDF]
Daisuke Ono, Sato Honma, Ken-ichi Honma
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080615
Abstract: Clock genes Cryptochrome (Cry1) and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD). However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN) of neonatal Cry1 and Cry2 double deficient (Cry1-/-/Cry2-/-) mice. A lack of circadian rhythms in adult Cry1-/-/Cry2-/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL) developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1-/-/Cry2-/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1-/-/Cry2-/- mice, but failed to detect the rhythms in Cry1-/-/Cry2-/- mice raised under light-dark cycles (LD). By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1-/-/Cry2-/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1-/-/Cry2-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1-/-/Cry2-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in adulthood.
AMPK Regulates Circadian Rhythms in a Tissue- and Isoform-Specific Manner  [PDF]
Jee-Hyun Um,Julie S. Pendergast,Danielle A. Springer,Marc Foretz,Benoit Viollet,Alexandra Brown,Myung K. Kim,Shin Yamazaki,Jay H. Chung
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018450
Abstract: AMP protein kinase (AMPK) plays an important role in food intake and energy metabolism, which are synchronized to the light-dark cycle. In vitro, AMPK affects the circadian rhythm by regulating at least two clock components, CKIα and CRY1, via direct phosphorylation. However, it is not known whether the catalytic activity of AMPK actually regulates circadian rhythm in vivo.
Risk stratification for indolent lymphomas
Hallack Neto, Abrah?o Elias;Costa, Renata Oliveira;Atalla, Angelo;Dulley, Frederico Luiz;Chamone, Dalton Alencar Fischer;Pereira, Juliana;
Revista Brasileira de Hematologia e Hemoterapia , 2010, DOI: 10.1590/S1516-84842010000500015
Abstract: indolent b-cell lymphomas account for approximately 40% of all non-hodgkin lymphomas (nhls). advances in technology have contributed to improvements in the diagnosis and classification of indolent non-hodgkin lymphomas. follicular lymphomas are the most common although the frequency varies significantly throughout the world. the description of the follicular lymphoma international prognostic index (flipi) was an important step in identifying patient subgroups, but its use in the clinical practice has not been established yet. the use of a larger number of paraffin active monoclonal antibodies for immunohistochemistry, molecular cytogenetic studies including standard cytogenetics, multi-color fluorescence in-situ hybridization (fish), polymerase chain reaction and locus-specific fluorescence insitu hybridization as well as developments in high-resolution techniquesincluding microarray gene expression profiling allow more accurate diagnosis andprecise definition of biomarkers of value in risk stratification. the identification ofdiseasespecific gene lists resulting from expression profiling provides a number ofpotential protein targets that can be validated using immunohistochemistry. analysesof gene expression profiles or constitutive gene variations may also provide additional insight for prognostication in the near future. a comprehensive understanding of the biology of these distinct lymphoid tumors will allow us to identify novel diseaserelated genes and should facilitate the development of improved diagnosis, outcome prediction, and personalized approaches to treatment.
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