bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome
Authors: Cabelof Diane C. , Patel Hiral V. , Chen Qing , van Remmen Holly , Matherly Larry H. , Ge Yubin , Taub Jeffrey W. 
Published: July 2009

AbstractDown syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-β-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-β-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.
Therapeutic potential of an anti-CD79b antibody–drug conjugate, anti–CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma
Authors: Dornan David , Bennett Fiona , Chen Yvonne , Dennis Mark , Eaton Dan , Elkins Kristi , French Dorothy , Go Mary Ann T. , Jack Andrew , Junutula Jagath R. , Koeppen Hartmut , Lau Jeffrey , McBride Jacqueline , Rawstron Andy , Shi Xiaoyan , Yu Nancy , Yu Shang-Fan , Yue Peng , Zheng Bing , Ebens Allen , Polson Andrew G. 
Published: July 2009

AbstractHere we describe the generation of an antibody–drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti–CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti–CD79b-vcMMAE. This observation was supported by in vivo data showing that a Bcl-2 family inhibitor, ABT-263, strikingly enhanced the activity of anti–CD79b-vcMMAE. Furthermore, anti–CD79b-vcMMAE was significantly more effective than a standard-of-care regimen, R-CHOP (ie, rituximab with a single intravenous injection of 30 mg/kg cyclophosphamide, 2.475 mg/kg doxorubicin, 0.375 mg/kg vincristine, and oral dosing of 0.15 mg/kg prednisone once a day for 5 days), in 3 xenograft models of NHL. Together, these data suggest that anti–CD79b-vcMMAE could be broadly efficacious for the treatment of NHL.
ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency
Authors: Sauer Aisha V. , Mrak Emanuela , Jofra Hernandez Raisa , Zacchi Elena , Cavani Francesco , Casiraghi Miriam , Grunebaum Eyal , Roifman Chaim M. , Cervi Maria C. , Ambrosi Alessandro , Carlucci Filippo , Roncarolo Maria Grazia , Villa Anna , Rubinacci Alessandro , Aiuti Alessandro 
Published: July 2009

AbstractAdenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781.
Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis
Authors: Stumpo Deborah J. , Broxmeyer Hal E. , Ward Toni , Cooper Scott , Hangoc Giao , Chung Yang Jo , Shelley William C. , Richfield Eric K. , Ray Manas K. , Yoder Mervin C. , Aplan Peter D. , Blackshear Perry J. 
Published: July 2009

AbstractMembers of the tristetraprolin family of tandem CCCH finger proteins can bind to AU-rich elements in the 3′-untranslated region of mRNAs, leading to their deadenylation and subsequent degradation. Partial deficiency of 1 of the 4 mouse tristetraprolin family members, Zfp36l2, resulted in complete female infertility because of early embryo death. We have now generated mice completely deficient in the ZFP36L2 protein. Homozygous Zfp36l2 knockout (KO) mice died within approximately 2 weeks of birth, apparently from intestinal or other hemorrhage. Analysis of peripheral blood from KO mice showed a decrease in red and white cells, hemoglobin, hematocrit, and platelets. Yolk sacs from embryonic day 11.5 (E11.5) Zfp36l2 KO mice and fetal livers from E14.5 KO mice gave rise to markedly reduced numbers of definitive multilineage and lineage-committed hematopoietic progenitors. Competitive reconstitution experiments demonstrated that Zfp36l2 KO fetal liver hematopoietic stem cells were unable to adequately reconstitute the hematopoietic system of lethally irradiated recipients. These data establish Zfp36l2 as a critical modulator of definitive hematopoiesis and suggest a novel regulatory pathway involving control of mRNA stability in the life cycle of hematopoietic stem and progenitor cells.
Transcription of the rat testis-specific Rtdpoz-T1 and -T2 retrogenes during embryo development: co-transcription and frequent exonisation of transposable element sequences
Authors: Huang Chiu-Jung , Lin Wan-Yi , Chang Che-Ming , Choo Kong-Bung 
Published: July 2009

Abstract

Background
Retrotransposition is an important evolutionary force for the creation of new and potentially functional intronless genes which are collectively called retrogenes. Many retrogenes are expressed in the testis and the gene products have been shown to actively participate in spermatogenesis and other unique functions of the male germline. We have previously reported a cluster of retrogenes in the rat genome that encode putative TRAF- and POZ-domain proteins. Two of the genes, Rtdpoz-T1 and -T2 (abbreviated as T1 and T2), have further been shown to be expressed specifically in the rat testis.

Results
We show here that the T1 and T2 genes are also expressed in the rat embryo up to days 16–17 of development when the genes are silenced until being re-activated in the adult testis. On database interrogation, we find that some T1/T2 exons are chromosomally duplicated as cassettes of 2 or 3 exons consistent with retro-duplication. The embryonic T1/T2 transcripts, characterised by RT-PCR-cloning and rapid amplification of cDNA ends, are further found to have acquired one or more noncoding exons in the 5'-untranslated region (5'-UTR). Most importantly, the T1/T2 locus is embedded within a dense field of relics of transposable element (TE) derived mainly from LINE1 and ERV sequences, and the TE sequences are frequently exonised through alternative splicing to form the 5'-UTR sequences of the T1/T2 transcripts. In a case of T1 transcript, the 3'-end is extended into and terminated within an L1 sequence. Since the two genes share a common exon 1 and are, therefore, regulated by a single promoter, a T2-to-T1 co-transcription model is proposed. We further demonstrate that the exonised 5'-UTR TE sequences could lead to the creation of upstream open reading frames resulting in translational repression.

Conclusion
Exonisation of TE sequences is a frequent event in the transcription of retrogenes during embryonic development and in the testis and may contribute to post-transcriptional regulation of expression of retrogenes.
Retrospective analysis of nosocomial infections in the intensive care unit of a tertiary hospital in China during 2003 and 2007
Authors: Ding Ji-Guang , Sun Qing-Feng , Li Ke-Cheng , Zheng Ming-Hua , Miao Xiao-Hui , Ni Wu , Hong Liang , Yang Jin-Xian , Ruan Zhan-Wei , Zhou Rui-Wei , Zhou Hai-Jiao , He Wen-Fei 
Published: July 2009

Abstract

Background
Nosocomial infections are a major threat to patients in the intensive care unit (ICU). Limited data exist on the epidemiology of ICU-acquired infections in China. This retrospective study was carried out to determine the current status of nosocomial infection in China.

Methods
A retrospective review of nococomial infections in the ICU of a tertiary hospital in East China between 2003 and 2007 was performed. Nosocomial infections were defined according to the definitions of Centers for Disease Control and Prevention. The overall patient nosocomial infection rate, the incidence density rate of nosocomial infections, the excess length of stay, and distribution of nosocomial infection sites were determined. Then, pathogen and antimicrobial susceptibility profiles were further investigated.

Results
Among 1980 patients admitted over the period of time, the overall patient nosocomial infection rate was 26.8% or 51.0 per 1000 patient days., Lower respiratory tract infections (LRTI) accounted for most of the infections (68.4%), followed by urinary tract infections (UTI, 15.9%), bloodstream (BSI, 5.9%), and gastrointestinal tract (GI, 2.5%) infections. There was no significant change in LRTI, UTI and BSI infection rates during the 5 years. However, GI rate was significantly decreased from 5.5% in 2003 to 0.4% in 2007. In addition, A. baumannii, C. albicans and S. epidermidis were the most frequent pathogens isolated in patients with LRTIs, UTIs and BSIs, respectively. The rates of isolates resistant to commonly used antibiotics ranged from 24.0% to 93.1%.

Conclusion
There was a high and relatively stable rate of nosocomial infections in the ICU of a tertiary hospital in China through year 2003–2007, with some differences in the distribution of the infection sites, and pathogen and antibiotic susceptibility profiles from those reported from the Western countries. Guidelines for surveillance and prevention of nosocomial infections must be implemented in order to reduce the rate.
Allergy from infancy to adolescence. A population-based 18-year follow-up cohort
Authors: Kaila Minna , Rautava Päivi , Holmberg-Marttila Doris , Vahlberg Tero , Aromaa Minna , Sillanpää Matti 
Published: July 2009

AbstractBackgroundAnxious parents have many concerns about the future health of their atopic infants. Paediatricians and primary care practitioners need to seek knowledge on long-term outcomes in order to cope with the increasing caseload of suspected allergy and the concerns of parents. The aim of the study was to assess suspected and diagnosed allergy in infancy as predictors of allergy and asthma in adolescence.MethodsFamilies expecting their first baby and making their first visit to a maternity health care clinic in 1986 were selected as the study population in a random sample. There were 1278 eligible study families. The data were provided of the children at the ages of 9 and 18 months and 3, 5, 12, 15 and 18 years by health care professionals, parents, and adolescents (themselves).ResultsAt the age of 9 months, the prevalence of allergy suspicions was distinctly higher than that of allergy diagnoses. At the age of five years suspected allergy approaches were nil, and the prevalence of diagnosed allergy was about 9%. During the adolescence, the prevalence of self-reported allergy increases steadily up to the age of 18 years, and that of asthma remains at approximately 5%. Suspected allergy at the age of 9 or 18 months and at the 5 years of age does not predict allergy at adolescence. Compared with non-allergic children, children with definite allergy at the age of 5 were over 8 times more likely to have allergy and nearly 7 times more likely to have asthma in adolescence.ConclusionAn early ascertained diagnosis of allergy, but not suspicions of allergy, predicts prevailing allergy in adolescence. Efforts need to be focused on accurate diagnosis of early childhood allergies.
Hurdles at work: perceptions of hospital food handlers
Authors: Bertin Cilce Helena Figueiredo Preza , Rezende Magda Andrade , Sigulem Dirce Maria , Morais Tania Beninga 
Published: July 2009

Abstract

Background
Food handlers have a very important role in preventing food contamination during its preparation and distribution. This responsibility is even greater in hospitals, since a large number of patients have low immunity and consequently food contamination by pathogenic bacteria could be particularly harmful. Therefore, a good working environment and periodic training should be provided to food handlers by upper management.

Methods
This study is qualitative research by means of focus group and thematic content analysis methodologies to examine, in detail, the statements by food handlers working in the milk and specific-diet kitchens in a hospital to understand the problems they face in the workplace.

Results
We found that food handlers are aware of the role they play in restoring patients' health; they consider it important to offer a good-quality diet. However, according to their perceptions, a number of difficulties prevent them from reaching this aim. These include: upper management not prioritizing human and material resources to the dietetic services when making resource allocation decisions; a perception that upper management considers their work to be of lesser importance; delayed overtime payments; lack of periodic training; managers lacking administrative skills; insufficient dietitian staff assistants, leading to overwork, at the same time as there is an excess of dietitians; unhealthy environmental working conditions – high temperature, high humidity, loud and constant noise level, poor ventilation; lack of food, and kitchen utensils and equipment; and relationship conflicts with chief dieticians and co-workers.

Conclusion
From these findings, improvement in staff motivation could be achieved by considering non-financial incentives, such as improvement in working conditions and showing appreciation and respect through supervision, training and performance appraisal. Management action, such as investments in intermediary management so that managers have the capacity to provide supportive supervision, as well as better use of performance appraisal and access to training, may help overcome the identified problems.
Subchronic infusion of the product of inflammation prostaglandin J2 models sporadic Parkinson's disease in mice
Authors: Pierre Sha-Ron , Lemmens Marijke AM , Figueiredo-Pereira Maria E 
Published: July 2009

AbstractBackgroundChronic neuroinflammation is implicated in Parkinson's disease (PD). Inflammation involves the activation of microglia and astrocytes that release high levels of prostaglandins. There is a profound gap in our understanding of how cyclooxygenases and their prostaglandin products redirect cellular events to promote PD neurodegeneration. The major prostaglandin in the mammalian brain is prostaglandin D2, which readily undergoes spontaneous dehydration to generate the bioactive cyclopentenone prostaglandins of the J2 series. These J2 prostaglandins are highly reactive and neurotoxic products of inflammation shown in cellular models to impair the ubiquitin/proteasome pathway and cause the accumulation of ubiquitinated proteins. PD is a disorder that exhibits accumulation of ubiquitinated proteins in neuronal inclusions (Lewy bodies). The role of J2 prostaglandins in promoting PD neurodegeneration has not been investigated underin vivoconditions.MethodsWe addressed the neurodegenerative and behavioral effects of the administration of prostaglandin J2 (PGJ2) simultaneously into thesubstantia nigra/striatumof adult male FVB mice by subchronic microinjections. One group received unilateral injections of DMSO (vehicle, n = 6) and three groups received PGJ2 [3.4 μg or 6.7 μg (n = 6 per group) or 16.7 μg (n = 5)] per injection. Immunohistochemical and behavioral analyses were applied to assess the effects of the subchronic PGJ2 microinfusions.ResultsImmunohistochemical analysis demonstrated a PGJ2 dose-dependent significant and selective loss of dopaminergic neurons in thesubstantia nigrawhile the GABAergic neurons were spared. PGJ2 also triggered formation of aggregates immunoreactive for ubiquitin and α-synuclein in the spared dopaminergic neurons. Moreover, PGJ2 infusion caused a massive microglia and astrocyte activation that could initiate a deleterious cascade leading to self-sustained progressive neurodegeneration. The PGJ2-treated mice also exhibited locomotor and posture impairment.ConclusionOur studies establish the first model of inflammation in which administration of an endogenous highly reactive product of inflammation, PGJ2, recapitulates key aspects of PD. Our novel PGJ2-induced PD model strongly supports the view that localized and chronic production of highly reactive and neurotoxic prostaglandins, such as PGJ2, in the CNS could be an integral component of inflammation triggered by insults evoked by physical, chemical or microbial stimuli and thus establishes a link between neuroinflammation and PD neurodegeneration.
Mutation analysis of Rad18 in human cancer cell lines and non small cell lung cancer tissues
Authors: Nakamura Tadahiko , Ishikawa Shinji , Koga Yoshikatsu , Nagai Youhei , Imamura Yu , Ikeda Kouei , Mori Takeshi , Nomori Hiroaki , Baba Hideo 
Published: July 2009

Abstract

Background
Genetic instability is known as a cause of oncogenesis. Though Rad18 is reported to function in a post replication mismatch repair system, the relation between the status of Rad18 and human tumorigenesis has not been described so far.

Methods
Mutation analysis of 34 human cancer cell lines and 32 non small cell lung cancer (NSCLC) tissues were performed by RT-PCR SSCP. Expression level of Rad18 was measured by real time RT-PCR. Stable transfectant was constructed for in vitro study.

Results
No mutation was found in both cancer cell lines and NSCLC tissues. A single nucleotide polymorphism (SNP) at codon 302 was detected in 51.5% of the cell lines and 62.5% of NSCLC tissues. Interestingly, Rad18 was homozygously deleted in a pulmonary adenocarcinoma cell line PC3. Furthermore, there was no difference in the expression level of wild type Rad18 and Rad18 with SNP. The growth, cell morphology, sensitivity to anti-cancer drugs and in vitro DNA repair activity between wild type Rad18 and Rad18 with SNP revealed to have no difference in vitro.

Conclusion
Though the frequency of SNP was tended to be higher in NSCLC patients than healthy volunteers (57.7%), as the difference was not significant, we have concluded that there is no relation between Rad18 SNP and lung cancer development.
Development of a probabilistic mechanistic model for reliability assessment of gas cylinders in compressed natural gas vehicles
Authors: Chamberlain S , Chookah M , Modarres M 
Published: July 2009

Until now, there has been no probabilistic modelling or comprehensive risk analysis of the reliability of compressed natural gas (CNG) fuelled vehicles and support systems. This is due to sparse failure and accident data, which, in turn, is largely due to the small number of such vehicles in operation and the relatively new technology compared with diesel and gasoline engines. Direct estimation of the failure frequencies of system components requires a large quantity of data. However, estimation of reliability using probability physical models (i.e. the physics-of-failure approach) is another option that requires less data. This approach is used in this research and discussed in this paper. CNG fuel system components are subject to degradation caused by stress corrosion cracking and corrosion fatigue. A quick risk analysis shows that the storage cylinder is the most risk-significant component in CNG vehicles. The cylinder is a vulnerable component in the system, due to the presence of corrosive constituents in the stored CNG fuel and mechanical fatigue due to frequent fillings. Physics-of-failure modelling is used to estimate the frequency of leakages and ruptures of the CNG cylinders. The analytical model proposed in this paper is based on the probabilistic fracture mechanics of the associated corrosion-enhanced fatigue-failure mechanisms. The proposed model estimates the probability distribution function of the frequency of cylinder failure leading to particular CNG gas-release scenarios, while incorporating the impact of the manufacturing process, material properties, and inspection methodology. The estimated frequency of cylinder failure based on the physics of failure is used to update the overall risk associated with CNG bus systems, which has been the subject of research by the authors in the past.
Irradiation-Induced Grain-Boundary Solute Segregation and Its Effect on Ductile-to-Brittle Transition Temperature in Reactor Pressure Vessel Steels
Authors: Nishiyama Yutaka , Yamaguchi Masatake , Onizawa Kunio , Iwase Akihiko , Matsuzawa Hiroshi 
Published: July 2009

Abstract
A study on grain-boundary segregation and embrittlement in terms of the Charpy ductile-to-brittle transition temperature (DBTT) has been performed for the neutron-irradiated A533B steels with typical contents of impurities of Japanese reactor pressure vessel ones. The neutron irradiation was conducted at 563 K to a fluence of 1.3× 1024n/m2 (E&gt;1 MeV) using material testing reactors. The neutron irradiation induced the P and Ni segregation and the reduction in C in some cases at grain-boundaries. The increase in the P segregation at high fluence (&gt;5×10 23n/m2, E&gt;1 MeV) was less than 0.1 in monolayer coverage for the steels with the bulk content of P not exceeding 0.02 wt%. The hardening more strongly affected the DBTT shift than the P segregation for those steels. The reduction in segregated C that enhances the grain-boundary cohesion by neutron fluence is not large enough to cause the DBTT shift.