bluuebunny/crossref_metadata_2025_split huggingface dataset:
MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo
Authors: Fournel Marielle , Bonfils Claire , Hou Yu , Yan Pu Theresa , Trachy-Bourget Marie-Claude , Kalita Ann , Liu Jianhong , Lu Ai-Hua , Zhou Nancy Z. , Robert Marie-France , Gillespie Jeffrey , Wang James J. , Ste-Croix Hélène , Rahil Jubrail , Lefebvre Sylvain , Moradei Oscar , Delorme Daniel , MacLeod A. Robert , Besterman Jeffrey M. , Li Zuomei 
Published: April 2008

Abstract
Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759–68]
Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia
Authors: Chou C. James , Farkas Michelle E. , Tsai Sherry M. , Alvarez David , Dervan Peter B. , Gottesfeld Joel M. 
Published: April 2008

Abstract
We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(4):769–78]
Impact of Economic, Regulatory, and Patent Policies on Innovation in Cancer Chemoprevention
Authors: Grabowski Henry G. , Moe Jeffrey L. 
Published: April 2008

Abstract
Chemoprevention agents are an emerging new scientific area that holds out the promise of delaying or avoiding a number of common cancers. These new agents face significant scientific, regulatory, and economic barriers, however, which have limited investment in their research and development (R&D). These barriers include above-average clinical trial scales, lengthy time frames between discovery and Food and Drug Administration approval, liability risks (because they are given to healthy individuals), and a growing funding gap for early-stage candidates. The longer time frames and risks associated with chemoprevention also cause exclusivity time on core patents to be limited or subject to significant uncertainties. We conclude that chemoprevention uniquely challenges the structure of incentives embodied in the economic, regulatory, and patent policies for the biopharmaceutical industry. Many of these policy issues are illustrated by the recently Food and Drug Administration–approved preventive agents Gardasil® and raloxifene. Our recommendations to increase R&D investment in chemoprevention agents include (a) increased data exclusivity times on new biological and chemical drugs to compensate for longer gestation periods and increasing R&D costs; chemoprevention is at the far end of the distribution in this regard; (b) policies such as early-stage research grants and clinical development tax credits targeted specifically to chemoprevention agents (these are policies that have been very successful in increasing R&D investment for orphan drugs); and (c) a no-fault liability insurance program like that currently in place for children's vaccines.
Recent Changes in Downward Longwave Radiation at King Sejong Station, Antarctica
Authors: Cho Hi Ku , Kim Jhoon , Jung Yeonjin , Lee Yun Gon , Lee Bang Yong 
Published: April 2008

AbstractEffects of cloud, air temperature, and specific humidity on downward longwave irradiance and their long-term variabilities are examined by analyzing the measurements made at the King Sejong Station in the Antarctic Peninsula during the period of 1996–2006.It has been shown that the downward longwave irradiance (DLR) is significantly correlated with three variables: air temperature, specific humidity, and cloudiness. Based on the relationship of the three variables with DLR, a multiple linear regression model has been developed in order to evaluate the relative contribution of each of the variables to the variation of DLR. The three variables together explained 75% of all the variance in daily mean DLR. The respective contribution from specific humidity and cloudiness to the variation of DLR was 46% and 23%; thus most of the DLR variability can be explained by the variations in the two variables. The annual mean of longwave cloud forcing shows 52 W m−2 with no remarkable seasonal cycle. It is also noted that the overcast cloud effect gives an increase by 65 W m−2 with respect to clear-sky flux throughout the year. It is suggested that the multiple regression model can be used to estimate the radiative forcings of variables influencing the DLR variability.A highly significant decrease in DLR with an average of −1.52 W m−2 yr−1 (−0.54% yr−1) is found in an analysis from the time series of the deseasonalized monthly mean values. Accordingly, the atmospheric flux emissivity, air temperature, and specific humidity have also decreased in their time series, while the cloudiness has increased insignificantly. Consequently, it may be concluded that the recent decrease in DLR is mainly attributed to the net cooling effect due to the decrease in air temperature and specific humidity, which overwhelm the slight warming effect in cloudiness. Analysis of mean monthly trends for individual months shows that, as for the annual data, the variations in DLR are mostly associated with those of air temperature, specific humidity, and cloudiness.
Independent Estimations of the Asymptotic Variability in an Ensemble Forecast System
Authors: Bengtsson Lisa K. , Magnusson Linus , Källén Erland 
Published: April 2008

Abstract
One desirable property within an ensemble forecast system is to have a one-to-one ratio between the root-mean-square error (rmse) of the ensemble mean and the standard deviation of the ensemble (spread). The ensemble spread and forecast error within the ECMWF ensemble prediction system has been extrapolated beyond 10 forecast days using a simple model for error growth. The behavior of the ensemble spread and the rmse at the time of the deterministic predictability are compared with derived relations of rmse at the infinite forecast length and the characteristic variability of the atmosphere in the limit of deterministic predictability. Utilizing this methodology suggests that the forecast model and the atmosphere do not have the same variability, which raises the question of how to obtain a perfect ensemble.
Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia
Authors: Tam Constantine S. , O'Brien Susan , Wierda William , Kantarjian Hagop , Wen Sijin , Do Kim-Anh , Thomas Deborah A. , Cortes Jorge , Lerner Susan , Keating Michael J. 
Published: April 2008

Abstract
Early results of the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia. In this report, we present the final results of all 300 study patients at a median follow up of 6 years. The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, and partial remission due to residual disease in 6%. Two patients (< 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival were 77% and 51%, respectively. Median time to progression was 80 months. Pretreatment characteristics independently associated with inferior response were age 70 years or older, β2-microglobulin twice the upper limit of normal (2N) or more, white cell count 150 × 109/L or more, abnormal chromosome 17, and lactate dehydrogenase 2N or more. No pretreatment characteristic was independently associated with decreased complete remission duration. The risk of late infection was 10% and 4% for the first and second years of remission, respectively, and less than 1.5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival.
ReXSpecies – a tool for the analysis of the evolution of gene regulation across species
Authors: Struckmann Stephan , Araúzo-Bravo Marcos J , Schöler Hans R , Reinbold Rolland A , Fuellen Georg 
Published: April 2008

Abstract

Background
Annotated phylogenetic trees that display the evolution of transcription factor binding in regulatory regions are useful for e.g. 1) narrowing down true positive predicted binding sites, providing predictions for binding sites that can be tested experimentally, and 2) giving insight into the evolution of gene regulation and regulatory networks.

Results
We describe ReXSpecies, a web-server that processes the sequence information of a regulatory region for multiple species and associated (predicted) transcription factor binding sites into two figures: a) An annotated alignment of sequence and binding sites, consolidated and filtered for ease of use, and b) an annotated tree labeled by the gain and loss of binding sites, where the tree can be calculated from the data or taken from a trusted taxonomy, and the labels are calculated based on standard or Dollo parsimony. For genes involved in mammalian pluripotency, ReXSpecies trees highlight useful patterns of transcription factor binding site gain and loss, e.g. for the Oct and Sox group of factors in the 3' untranslated region of the cystic fibrosis transmembrane conductance regulator gene, which closely match experimental data.

Conclusion
ReXSpecies post-processes the information provided by transcription factor binding site prediction tools, in order to compare data from many species. The tool eases visualization and successive interpretation of transcription factor binding data in an evolutionary context. The ReXSpecies URL can be found in the Availability and requirements section.
Genome-wide search reveals a novel GacA-regulated small RNA in Pseudomonas species
Authors: González Nicolas , Heeb Stephan , Valverde Claudio , Kay Elisabeth , Reimmann Cornelia , Junier Thomas , Haas Dieter 
Published: April 2008

Abstract

Background
Small RNAs (sRNAs) are widespread among bacteria and have diverse regulatory roles. Most of these sRNAs have been discovered by a combination of computational and experimental methods. In Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium and opportunistic human pathogen, the GacS/GacA two-component system positively controls the transcription of two sRNAs (RsmY, RsmZ), which are crucial for the expression of genes involved in virulence. In the biocontrol bacterium Pseudomonas fluorescens CHA0, three GacA-controlled sRNAs (RsmX, RsmY, RsmZ) regulate the response to oxidative stress and the expression of extracellular products including biocontrol factors. RsmX, RsmY and RsmZ contain multiple unpaired GGA motifs and control the expression of target mRNAs at the translational level, by sequestration of translational repressor proteins of the RsmA family.

Results
A combined computational and experimental approach enabled us to identify 14 intergenic regions encoding sRNAs in P. aeruginosa. Eight of these regions encode newly identified sRNAs. The intergenic region 1698 was found to specify a novel GacA-controlled sRNA termed RgsA. GacA regulation appeared to be indirect. In P. fluorescens CHA0, an RgsA homolog was also expressed under positive GacA control. This 120-nt sRNA contained a single GGA motif and, unlike RsmX, RsmY and RsmZ, was unable to derepress translation of the hcnA gene (involved in the biosynthesis of the biocontrol factor hydrogen cyanide), but contributed to the bacterium's resistance to hydrogen peroxide. In both P. aeruginosa and P. fluorescens the stress sigma factor RpoS was essential for RgsA expression.

Conclusion
The discovery of an additional sRNA expressed under GacA control in two Pseudomonas species highlights the complexity of this global regulatory system and suggests that the mode of action of GacA control may be more elaborate than previously suspected. Our results also confirm that several GGA motifs are required in an sRNA for sequestration of the RsmA protein.
Epidemiology of foodborne Norovirus outbreaks in Catalonia, Spain
Authors: Martinez Ana , Dominguez Angela , Torner Nuria , Ruiz Laura , Camps Neus , Barrabeig Irene , Arias Cesar , Alvarez Josep , Godoy Pere , Balaña Pilar Jorgina , Pumares Analia , Bartolome Rosa , Ferrer Dolors , Perez Unai , Pinto Rosa , Buesa Javier ,   The Catalan Viral Gastroenteritis Study Group
Published: April 2008

Abstract

Background
Noroviruses are one of the principal biological agents associated with the consumption of contaminated food. The objective of this study was to analyse the size and epidemiological characteristics of foodborne outbreaks of gastroenteritis in Catalonia, a region in the northeast of Spain.

Methods
In all reported outbreaks of gastroenteritis associated with food consumption, faecal samples of persons affected were analysed for bacteria and viruses and selectively for parasites. Study variables included the setting, the number of people exposed, age, sex, clinical signs and hospital admissions. The study was carried out from October 2004 to October 2005.

Results
Of the 181 outbreaks reported during the study period, 72 were caused by Salmonella and 30 by norovirus (NoV); the incidence rates were 14.5 and 9.9 per 100,000 person-years, respectively. In 50% of the NoV outbreaks and 27% of the bacterial outbreaks (p = 0.03) the number of persons affected was ≥10; 66.7% of NoV outbreaks occurred in restaurants; no differences in the attack rates were observed according to the etiology. Hospitalizations were more common (p = 0.03) in bacterial outbreaks (8.6%) than in NoV outbreaks (0.15%). Secondary cases accounted for 4% of cases in NoV outbreaks compared with 0.3% of cases in bacterial outbreaks (p < 0.001)

Conclusion
Norovirus outbreaks were larger but less frequent than bacterial outbreaks, suggesting that underreporting is greater for NoV outbreaks. Food handlers should receive training on the transmission of infections in diverse situations. Very strict control measures on handwashing and environmental disinfection should be adopted in closed or partially-closed institutions.
Complex rearranged small supernumerary marker chromosomes (sSMC), three new cases; evidence for an underestimated entity?
Authors: Trifonov Vladimir , Fluri Simon , Binkert Franz , Nandini Adayapalam , Anderson Jasen , Rodriguez Laura , Gross Madeleine , Kosyakova Nadezda , Mkrtchyan Hasmik , Ewers Elisabeth , Reich Daniela , Weise Anja , Liehr Thomas 
Published: April 2008

Abstract

Background
Small supernumerary marker chromosomes (sSMC) are present ~2.6 × 106 human worldwide. sSMC are a heterogeneous group of derivative chromosomes concerning their clinical consequences as well as their chromosomal origin and shape. Besides the sSMC present in Emanuel syndrome, i.e. der(22)t(11;22)(q23;q11), only few so-called complex sSMC are reported.

Results
Here we report three new cases of unique complex sSMC. One was a de novo case with a dic(13 or 21;22) and two were maternally derived: a der(18)t(8;18) and a der(13 or 21)t(13 or 21;18). Thus, in summary, now 22 cases of unique complex sSMC are available in the literature. However, this special kind of sSMC might be under-diagnosed among sSMC-carriers.

Conclusion
More comprehensive characterization of sSMC and approaches like reverse fluorescence in situ hybridization (FISH) or array based comparative genomic hybridization (array-CGH) might identify them to be more frequent than only ~0.9% among all sSMC.
Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy
Authors: Sloand Elaine M. , Wu Colin O. , Greenberg Peter , Young Neal , Barrett John 
Published: April 2008

Purpose Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group. Patients and Methods One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care. Results Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival. Conclusion IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.
Breast Cancer Subtype Approximated by Estrogen Receptor, Progesterone Receptor, and HER-2 Is Associated With Local and Distant Recurrence After Breast-Conserving Therapy
Authors: Nguyen Paul L. , Taghian Alphonse G. , Katz Matthew S. , Niemierko Andrzej , Abi Raad Rita F. , Boon Whitney L. , Bellon Jennifer R. , Wong Julia S. , Smith Barbara L. , Harris Jay R. 
Published: April 2008

Purpose To determine whether breast cancer subtype is associated with outcome after breast-conserving therapy (BCT) consisting of lumpectomy and radiation therapy. Patients and Methods We studied 793 consecutive patients with invasive breast cancer who received BCT from July 1998 to December 2001. Among them, 97% had pathologically negative margins of resection, and 90% received adjuvant systemic therapy. No patient received adjuvant trastuzumab. Receptor status was used to approximate subtype: estrogen receptor (ER) or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 negative = luminal A; ER+ or PR+ and HER-2+ = luminal B; ER–and PR –and HER-2+ = HER-2; and ER–and PR –and HER-2–= basal. Competing risks methodology was used to analyze time to local recurrence and distant metastases. Results Median follow-up was 70 months. The overall 5-year cumulative incidence of local recurrence was 1.8% (95% CI, 1.0 to 3.1); 0.8% (0.3, 2.2) for luminal A, 1.5% (0.2, 10) for luminal B, 8.4% (2.2, 30) for HER-2, and 7.1% (3.0, 16) for basal. On multivariable analysis (MVA) with luminal A as baseline, HER-2 (adjusted hazard ratio [AHR] = 9.2; 95% CI, 1.6 to 51; P = .012) and basal (AHR = 7.1; 95% CI, 1.6 to 31; P = .009) subtypes were associated with increased local recurrence. On MVA, luminal B (AHR = 2.9; 95% CI, 1.3 to 6.5; P = .007) and basal (AHR = 2.3; 95% CI, 1.1 to 5.2; P = .035) were associated with increased distant metastases. Conclusion Overall, the 5-year local recurrence rate after BCT was low, but varied by subtype as approximated using ER, PR, and HER-2 status. Local recurrence was particularly low for the luminal A subtype, but was less than 10% at 5 years for all subtypes. Although further follow-up is needed, these results may be useful in counseling patients about their anticipated outcome after BCT.
Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer
Authors: Horwitz Eric M. , Bae Kyounghwa , Hanks Gerald E. , Porter Arthur , Grignon David J. , Brereton Harmar D. , Venkatesan Varagur , Lawton Colleen A. , Rosenthal Seth A. , Sandler Howard M. , Shipley William U. 
Published: April 2008

Purpose To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT). Patients and Methods Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms. Results At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P ≤ .0001), and overall survival (51.6% v 53.9%, P = .36). One subgroup analyzed consisted of all cancers with a Gleason score of 8 to 10 cancers. An overall survival difference was observed (31.9% v 45.1%; P = .0061), as well as in all other end points herein. Conclusion LTAD as delivered in this study for the treatment of locally advanced prostate cancer is superior to STAD for all end points except survival. A survival advantage for LTAD + RT in the treatment of locally advanced tumors with a Gleason score of 8 to 10 suggests that this should be the standard of treatment for these high-risk patients.