bluuebunny/crossref_metadata_2025_split huggingface dataset:
Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis
Authors: Guo Hong , Ma Ou , Speck Nancy A. , Friedman Alan D. 
Published: March 2012

AbstractDeletion of Runx1 in adult mice produces a myeloproliferative phenotype. We now find that Runx1 gene deletion increases marrow monocyte while reducing granulocyte progenitors and that exogenous RUNX1 rescues granulopoiesis. Deletion of Runx1 reduces Cebpa mRNA in lineage-negative marrow cells and in granulocyte-monocyte progenitors or common myeloid progenitors. Pu.1 mRNA is also decreased, but to a lesser extent. We also transduced marrow with dominant-inhibitory RUNX1a. As with Runx1 gene deletion, RUNX1a expands lineage−Sca-1+c-kit+ and myeloid cells, increased monocyte CFUs relative to granulocyte CFUs, and reduced Cebpa mRNA. Runx1 binds a conserved site in the Cebpa promoter and binds 4 sites in a conserved 450-bp region located at +37 kb; mutation of the enhancer sites reduces activity 6-fold in 32Dcl3 myeloid cells. Endogenous Runx1 binds the promoter and putative +37 kb enhancer as assessed by ChIP, and RUNX1-ER rapidly induces Cebpa mRNA in these cells, even in cycloheximide, consistent with direct gene regulation. The +37 kb region contains strong H3K4me1 histone modification and p300-binding, as often seen with enhancers. Finally, exogenous C/EBPα increases granulocyte relative to monocyte progenitors in Runx1-deleted marrow cells. Diminished CEBPA transcription and consequent impairment of myeloid differentiation may contribute to leukemic transformation in acute myeloid leukemia cases associated with decreased RUNX1 activity.
Perturbation of cytokinin and ethylene-signalling pathways explain the strong rooting phenotype exhibited by Arabidopsis expressing the Schizosaccharomyces pombe mitotic inducer, cdc25
Authors: Spadafora Natasha D , Parfitt David , Marchbank Angela , Li Sherong , Bruno Leonardo , Vaughan Rhys , Nieuwland Jeroen , Buchanan-Wollaston Vicky , Herbert Robert J , Bitonti Maria Beatrice , Doonan John , Albani Diego , Prinsen Els , Francis Dennis , Rogers Hilary J 
Published: March 2012

Abstract

Background
Entry into mitosis is regulated by cyclin dependent kinases that in turn are phosphoregulated. In most eukaryotes, phosphoregulation is through WEE1 kinase and CDC25 phosphatase. In higher plants a homologous CDC25 gene is unconfirmed and hence the mitotic inducer Schizosaccharomyces pombe (Sp) cdc25 has been used as a tool in transgenic plants to probe cell cycle function. Expression of Spcdc25 in tobacco BY-2 cells accelerates entry into mitosis and depletes cytokinins; in whole plants it stimulates lateral root production. Here we show, for the first time, that alterations to cytokinin and ethylene signaling explain the rooting phenotype elicited by Spcdc25 expression in Arabidopsis.

Results
Expressing Spcdc25 in Arabidopsis results in increased formation of lateral and adventitious roots, a reduction of primary root width and more isodiametric cells in the root apical meristem (RAM) compared with wild type. Furthermore it stimulates root morphogenesis from hypocotyls when cultured on two way grids of increasing auxin and cytokinin concentrations. Microarray analysis of seedling roots expressing Spcdc25 reveals that expression of 167 genes is changed by > 2-fold. As well as genes related to stress responses and defence, these include 19 genes related to transcriptional regulation and signaling. Amongst these was the up-regulation of genes associated with ethylene synthesis and signaling. Seedlings expressing Spcdc25 produced 2-fold more ethylene than WT and exhibited a significant reduction in hypocotyl length both in darkness or when exposed to 10 ppm ethylene. Furthermore in Spcdc25 expressing plants, the cytokinin receptor AHK3 was down-regulated, and endogenous levels of iPA were reduced whereas endogeous IAA concentrations in the roots increased.

Conclusions
We suggest that the reduction in root width and change to a more isodiametric cell phenotype in the RAM in Spcdc25 expressing plants is a response to ethylene over-production. The increased rooting phenotype in Spcdc25 expressing plants is due to an increase in the ratio of endogenous auxin to cytokinin that is known to stimulate an increased rate of lateral root production. Overall, our data reveal important cross talk between cell division and plant growth regulators leading to developmental changes.
Quality of life of Chinese urban community residents: a psychometric study of the mainland Chinese version of the WHOQOL-BREF
Authors: Xia Ping , Li Ningxiu , Hau Kit-Tai , Liu Chaojie , Lu Yubo 
Published: March 2012

Abstract

Background
The short version of the World Health Organization's Quality of Life Instrument (WHOQOL-BREF) is widely validated and popularly used in assessing the subjective quality of life (QOL) of patients and the general public. We examined its psychometric properties in a large sample of community residents in mainland China.

Methods
The WHOQOL-BREF was administered to 1052 adult community residents in a major metropolitan city in southern China. The structural integrity of the 4-factor model in confirmatory factor analyses (CFA) and the relationship of QOL with demographic variables were examined. Validity was assessed using the known-group comparison (229 with vs. 823 without chronic illness), item-domain correlations, and CFA using the ML estimation in LISREL.

Results
Internal consistency reliability of the whole instrument (26 items) was 0.89, and the psychological, social, and environment domains had acceptable reliability (alpha = 0.76, 0.72, 0.78 respectively), while that of the physical domain was slightly lower (α = 0.67). The respective mean scores of these domains were 13.69, 14.11, 12.33 and 14.56. Item-domain correlations were much higher for corresponding domains than for non-corresponding domains, indicating good convergent validity. CFA provided a marginally acceptable fit to the a priori four-factor model when two matching content item pairs were allowed to be correlated; χ2 (244) = 1836, RMSEA = 0.088, NNFI = 0.898, CFI = 0.909. This factorial structure was shown to be equivalent between the participants with and without chronic illness. The differences in means between these two groups were significant but small in some domains; effect size = 0.55, 0.15, 0.18 in the physical, psychological, and social relationship domains respectively. Furthermore, males had significantly higher QOL scores than females in the psychological domain, while individuals with a younger age, higher income, and higher education levels also had significantly higher QOL. Compared with the international data, the Chinese in this study had relatively low QOL scores with about 5% of males and 16% of females being at risk for poor QOL.

Conclusions
This study has provided psychometric properties of the WHOQOL-BREF as used in China and should definitely be useful for researchers who would like to use or further refine the instrument.
Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq
Authors: Al-Musawi Bassam MS , Al-Allawi Nasir , Abdul-Majeed Ban A , Eissa Adil A , Jubrael Jaladet MS , Hamamy Hanan 
Published: March 2012

AbstractBackgroundAlthough G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent.MethodsA total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT), with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) for four deficient molecular variants, namely G6PD Mediterranean (563 C→T), Chatham (1003 G→A), A- (202 G→A) and Aures (143 T→C). A subset of those with the Mediterranean variant, were further investigated for the 1311 (C→T) silent mutation.ResultsG6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%). Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%), G6PD Chatham in 5 cases (5.0%), G6PD A- in two cases (2.0%), and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%).ConclusionsThree polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to other Asian Arab countries, neighboring Turkey and Iran.
A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease
Authors: Kaur Punit , Nagaraja Ganachari M , Zheng Hongying , Gizachew Dawit , Galukande Moses , Krishnan Sunil , Asea Alexzander 
Published: March 2012

Abstract

Background
Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems.

Methods
To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis.

Results
We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A).

Conclusions
Taken together, we have developed a TNBC-TICs model system based on the 4T1 cells which is a very useful metastasis model with the advantage of being able to be transplanted into immune competent recipients. Our data demonstrates that the TNBC-TICs model system could be a useful tool for studies on the pathogenesis and therapeutic treatment for TNBC.
JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells
Authors: Laschak Martin , Spindler Klaus-Dieter , Schrader Andres J , Hessenauer Andrea , Streicher Wolfgang , Schrader Mark , Cronauer Marcus V 
Published: March 2012

AbstractBackgroundNitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC).MethodsProstate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay.ResultsThe NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway.ConclusionsOur results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.
Potential relevance of pre-operative quality of life questionnaires to identify candidates for surgical treatment of genital prolapse: a pilot study
Authors: Chauvin Christian , Chéreau Elisabeth , Ballester Marcos , Daraï Emile 
Published: March 2012

Abstract

Background
To evaluate prolapse-related symptoms, quality of life and sexuality of patients with validated questionnaires before and after surgery for genital prolapse and assess relevance of such an evaluation to select women for surgery.

Methods
From November 2009 to April 2010, 16 patients operated on for genital prolapse of grade greater than or equal to 2 (POP-Q classification) were evaluated prospectively by three questionnaires of quality of life Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Organ Prolaps/Urinary Incontinence Sexual Questionnaire (PISQ-12). Data were collected the day before surgery and 6 weeks postoperatively.

Results
Eleven patients had laparoscopic surgery and five vaginal surgery. There was a significant decrease in pelvic heaviness, vaginal discomfort and urinary symptoms after surgery. The score of symptoms of prolapse, the PFDI-20 score was 98.5 preoperatively and 31.8 postoperatively (p < 0.0001). The score for quality of life, the PFIQ-7 score was 54.5 preoperatively and 7.4 postoperatively (p = 0.001). The score of sexuality, the PISQ-12 score was 35.3 preoperatively and 37.5 postoperatively (p = 0.1). Two of the 3 patients with a PFIQ 7 under or equal to 20 were not improved while all the women with a preoperative PFIQ-7 over 20 were improved after surgery.

Conclusions
This study suggests that surgery improves quality of life of patients with genital prolapse. Quality of life questionnaires could help select good candidates for surgery. Further studies are required to determine threshold to standardize indications of surgery.
Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models
Authors: Plengsuriyakarn Tullayakorn , Viyanant Vithoon , Eursitthichai Veerachai , Picha Porntipa , Kupradinun Piengchai , Itharat Arunporn , Na-Bangchang Kesara 
Published: March 2012

Abstract

Background
Chemotherapy of cholangiocarcinoma (CCA), a devastating cancer with increasing worldwide incidence and mortality rates, is largely ineffective. The discovery and development of effective chemotherapeutics is urgently needed.

Methods/Design
The study aimed at evaluating anticancer activities, toxicity, and pharmacological activities of the curcumin compound (CUR), the crude ethanolic extracts of rhizomes of Zingiber officinale Roscoe (Ginger: ZO) and Atractylodes lancea thung. DC (Khod-Kha-Mao: AL), fruits of Piper chaba Hunt. (De-Plee: PC), and Pra-Sa-Prao-Yhai formulation (a mixture of parts of 18 Thai medicinal plants: PPF) were investigated in animal models. Anti-cholangiocarcinoma (anti-CCA) was assessed using CCA-xenograft nude mouse model. The antihypertensive, analgesic, anti-inflammatory, antipyretic, and anti-ulcer activities and effects on motor coordination were investigated using Rota-rod test, CODA tail-cuff system, writhing and hot plate tests, carrageenan-induced paw edema test, brewer's yeast test, and alcohol-induced gastric ulcer test, respectively. Acute and subacute toxicity tests were performed according to the OECD guideline for testing of chemicals with modification.

Results
Promising anticancer activity against CCA in nude mouse xenograft model was shown for the ethanolic extract of AL at all oral dose levels (1000, 3000, and 5000 mg/kg body weight) as well as the extracts of ZO, PPF, and CUR compound at the highest dose level (5000, 4000, and 5000 mg/kg body weight, respectively). PC produced no significant anti-CCA activity. Results from acute and subacute toxicity tests both in mice and rats indicate safety profiles of all the test materials in a broad range of dose levels. No significant toxicity except stomach irritation and general CNS depressant signs were observed. Investigation of pharmacological activities of the test materials revealed promising anti-inflammatory (ZO, PPF, and AL), analgesic (CUR and PPF), antipyretic (CUR and AL), antihypertensive (ZO and AL), and anti-ulcer (CUR, ZO, and AL) activities.

Conclusion
Plants used in Thai traditional medicine for the treatment of various ailments may provide reservoirs of promising candidate chemotherapeutics for the treatment of CCA.
Specific tagging of the egress-related osmiophilic bodies in the gametocytes of Plasmodium falciparum
Authors: Sannella Anna Rosa , Olivieri Anna , Bertuccini Lucia , Ferrè Fabrizio , Severini Carlo , Pace Tomasino , Alano Pietro 
Published: March 2012

Abstract

Background
Gametocytes, the blood stages responsible for Plasmodium falciparum transmission, contain electron dense organelles, traditionally named osmiophilic bodies, that are believed to be involved in gamete egress from the host cell. In order to provide novel tools in the cellular and molecular studies of osmiophilic body biology, a P. falciparum transgenic line in which these organelles are specifically marked by a reporter protein was produced and characterized.

Methodology
A P. falciparum transgenic line expressing an 80-residue N-terminal fragment of the osmiophilic body protein Pfg377 fused to the reporter protein DsRed, under the control of pfg377 upstream and downstream regulatory regions, was produced.

Results
The transgenic fusion protein is expressed at the appropriate time and stage of sexual differentiation and is trafficked to osmiophilic bodies as the endogenous Pfg377 protein. These results indicate that a relatively small N-terminal portion of Pfg377 is sufficient to target the DsRed reporter to the gametocyte osmiophilic bodies.

Conclusions
This is the first identification of a P. falciparum aminoacid sequence able to mediate trafficking to such organelles. To fluorescently tag such poorly characterized organelles opens novel avenues in cellular and imaging studies on their biogenesis and on their role in gamete egress.
Loss of HLTF function promotes intestinal carcinogenesis
Authors: Sandhu Sumit , Wu Xiaoli , Nabi Zinnatun , Rastegar Mojgan , Kung Sam , Mai Sabine , Ding Hao 
Published: March 2012

Abstract

Background
HLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown.

Results
To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apc

min/+
mutant background, Hltf

-
deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf
-/-
/Apc

min/+
mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apc

min/+
mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased.

Conclusion
Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.