bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional characterization of two CITED3 homologs (gcCITED3a and gcCITED3b) in the hypoxia-tolerant grass carp, Ctenopharyngodon idellus
Authors: Ng Patrick KS , Chiu Sung-Kay , Kwong Theresa FN , Yu Richard MK , Wong Minnie ML , Kong Richard YC
Published: November 2009

Background

CITED proteins belong to a family of non-DNA-binding transcriptional co-regulators that are characterized by a conserved ED-rich domain at the C-terminus. This family of genes is involved in the regulation of a variety of transcriptional responses through interactions with the CBP/p300 integrators and various transcription factors. In fish, very little is known about the expression and functions of CITEDs.

Results

We have characterized two closely related but distinct CITED3 genes, gcCited3a and gcCited3b, from the hypoxia-tolerant grass carp. The deduced gcCITED3a and gcCITED3b proteins share 72% amino acid identity, and are highly similar to the CITED3 proteins of both chicken and Xenopus. Northern blot analysis indicates that the mRNA expression of gcCited3a and gcCited3b is strongly induced by hypoxia in the kidney and liver, respectively. Luciferase reporter assays demonstrated that both gene promoters are activated by gcHIF-1. Further, ChIP assays comparing normal and hypoxic conditions reveal differential in vivo binding of gcHIF-1 to both gene promoters in kidney and liver tissues. HRE-luciferase reporter assays demonstrated that both gcCITED3a and gcCITED3b proteins inhibit gcHIF-1 transcriptional activity, and GST pull-down assays confirmed that both proteins bind specifically to the CH1 domain of the grass carp p300 protein.

Conclusion

The grass carp gcCITED3a and gcCITED3b genes are differentially expressed and regulated in different fish organs in response to hypoxic stress. This is the first report demonstrating in vivo regulation of two closely-related CITED3 isogenes by HIF-1, as well as CITED3 regulation of HIF-1 transcriptional activity in fish. Overall, our findings suggest that unique molecular mechanisms operate through these two gcCITED3 isoforms that likely play an important regulatory role in the hypoxic response in the grass carp.
Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure
Authors: Mansur Alfredo José , Fontes Rosana Seleri , Canzi Regina Airoldi , Nishimura Raphael , Alencar Airlane Pereira , de Lima Antonio Carlos Pedroso , Krieger José Eduardo , Pereira Alexandre Costa
Published: November 2009

Background -

Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly and Thr164Ile were suggested to have an effect in heart failure. We evaluated these polymorphisms relative to clinical characteristics and prognosis of alarge cohort of patients with heart failure of different etiologies.

Methods -

We studied 501 patients with heart failure of different etiologies. Mean age was 58 years (standard deviation 14.4 years), 298 (60%) were men. Polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism.

Results -

During the mean follow-up of 12.6 months (standard deviation 10.3 months), 188 (38%) patients died. Distribution of genotypes of polymorphism Arg16Gly was different relative to body mass index (χ2 = 9.797;p = 0.04). Overall the probability of survival was not significantly predicted by genotypes of Gln27Glu, Arg16Gly, or Thr164Ile. Allele and haplotype analysis also did not disclose any significant difference regarding mortality. Exploratory analysis through classification trees pointed towards a potential association between the Gln27Glu polymorphism and mortality in older individuals.

Conclusion -

In this study sample, we were not able to demonstrate an overall influence of polymorphisms Gln27Glu and Arg16Gly of beta-2 receptor gene on prognosis. Nevertheless, Gln27Glu polymorphism may have a potential predictive value in older individuals.
Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-β and extracellular matrix proteins
Authors: del Pilar Alatorre-Carranza María , Miranda-Díaz Alejandra , Yañez-Sánchez Irinea , Pizano-Martínez Oscar , Hermosillo-Sandoval José M , Vázquez-Del Mercado Mónica , Hernández-Hoyos Sebastián , Martínez-Abundis Ricardo , Fafutis-Morris Mary , Segura-Ortega Jorge , Delgado-Rizo Vidal
Published: October 2009

Background

Liver fibrosis is the result of continuous liver injury stemming from different etiological factors. Bile duct injury induces an altered expression of TGF-β, which has an important role in liver fibrosis because this cytokine induces the expression of target genes such as collagens, PAI-1, TIMPs, and others that lead to extracellular matrix deposition. Smad7 is the principal inhibitor that regulates the target gene transcription of the TGF-β signaling. The aim of the study was to determine whether Smad7 mRNA expression correlates with the gene expression of TGF-β, Col I, Col III, Col IV, or PAI-1 in liver fibrosis secondary to bile duct injury (BDI).

Results

Serum TGF-β concentration was higher in BDI patients (39 296 pg/ml) than in liver donors (9008 pg/ml). Morphometric analysis of liver sections showed 41.85% of tissue contained fibrotic deposits in BDI patients. mRNA expression of Smad7, Col I, and PAI-1 was also significantly higher (P < 0.05) in patients with BDI than in controls. Smad7 mRNA expression correlated significantly with TGF-β concentration, Col I and Col III expression, and the amount of fibrosis.

Conclusion

We found augmented serum concentration of TGF-β and an increase in the percentage of fibrotic tissue in the liver of BDI patients. Contrary to expected results, the 6-fold increase in Smad7 expression did not inhibit the expression of TGF-β, collagens, and PAI-1. We also observed greater expression of Col I and Col III mRNA in BDI patients and significant correlations between their expression and TGF-β concentration and Smad7 mRNA expression.
A frailty index to predict the mortality risk in a population of senior mexican adults
Authors: García-González José Juan , García-Peña Carmen , Franco-Marina Francisco , Gutiérrez-Robledo Luis Miguel
Published: November 2009

Background

Frailty in the elderly can be regarded as nonspecific vulnerability to adverse health outcomes, caused by multiple factors. The aim was to analyze the relationships between the frailty index, age and mortality in a two year follow up study of Mexican elderly.

Methods

A frailty index was developed using 34 variables. To obtain the index, the mean of the total score for each individual was obtained. Survival analyses techniques were used to examine the risk ratios for the different levels of the frailty index. Kaplan-Meier estimates were obtained, adjusted for age and gender. Cox proportional hazards models were also built to obtain hazard ratio estimates.

Results

A total of 4082 participants was analyzed. Participants had an average age of 73 years and 52.5% were women. On average, participants were followed-up for 710 days (standard deviation = 111 days) and 279 of them died. Mortality increased with the frailty index level, especially in those with levels between .21 to .65, reaching approximately 17% and 21%, respectively. Cox proportional hazards models showed that participants with frailty index levels associated to increased mortality (.21 and higher) represent 24.0% of those aged 65-69 years and 47.6% of those 85 and older.

Conclusion

The frailty index shows the properties found in the other studies, it allows stratifying older Mexican into several groups different by the degree of the risk of mortality, and therefore the frailty index can be used in assessing health of elderly.
ALDH1A2 (RALDH2) genetic variation in human congenital heart disease
Authors: Pavan Marilene , Ruiz Viviane F , Silva Fábio A , Sobreira Tiago J , Cravo Roberta M , Vasconcelos Michelle , Marques Lívia P , Mesquita Sonia MF , Krieger José E , Lopes Antônio AB , Oliveira Paulo S , Pereira Alexandre C , Xavier-Neto José
Published: November 2009

Background

Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus.

Methods

One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay.

Results

We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls.

Conclusion

In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.
Prevalence of chronic kidney disease in Thai adults: a national health survey
Authors: Ong-ajyooth Leena , Vareesangthip Kriengsak , Khonputsa Panrasri , Aekplakorn Wichai
Published: October 2009

Background

The prevalence of patients with end stage renal disease (ESRD) who need dialysis and/or transplantation has more than doubled in Thailand during the past two decades. It has been suggested that therapeutic strategies to reduce the risk of ESRD and other complications in CKD are now available, thus the early recognition and the institution of proven therapeutic strategies are important and beneficial. We, therefore, aimed to determine the prevalence of CKD in Thai adults from the National Health Examination Survey of 2004.

Methods

Data from a nationally representative sample of 3,117 individuals aged 15 years and older was collected using questionnaires, physical examination and blood samples. Serum creatinine was measured by Jaffé method. GFR was estimated using the Chinese modified Modification of Diet in Renal Disease Study equation. Chronic kidney Disease (CKD) stages were classified based on Kidney Disease Outcome Quality Initiative (K/DOQI).

Results

The prevalence of CKD in Thai adults weighted to the 2004 Thai population by stage was 8.1% for stage 3, 0.2% and 0.15% for stage 4 and 5 respectively. Compared to non-CKD, individuals with CKD were older, had a higher level of cholesterol, and higher blood pressure. Those with cardiovascular risk factors were more likely to have CKD (stage 3-5) than those without, including hypertension (OR 1.6, 95%CI 1.1, 3.4), diabetes (OR 1.87, 95%CI 1.0, 3.4). CKD was more common in northeast (OR 2.1, 95%CI 1.3, 3.3) compared to central region. Urinalysis was not performed, therefore, we could not have data on CKD stage 1 and 2. We have no specific GFR formula for Thai population.

Conclusion

The identification of CKD patients should be evaluated and monitored for appropriate intervention for progression to kidney disease from this screening.
Affinity maturation generates greatly improved xyloglucan-specific carbohydrate binding modules
Authors: von Schantz Laura , Gullfot Fredrika , Scheer Sebastian , Filonova Lada , Cicortas Gunnarsson Lavinia , Flint James E , Daniel Geoffrey , Nordberg-Karlsson Eva , Brumer Harry , Ohlin Mats
Published: October 2009

Background

Molecular evolution of carbohydrate binding modules (CBM) is a new approach for the generation of glycan-specific molecular probes. To date, the possibility of performing affinity maturation on CBM has not been investigated. In this study we show that binding characteristics such as affinity can be improved for CBM generated from the CBM4-2 scaffold by using random mutagenesis in combination with phage display technology.

Results

Two modified proteins with greatly improved affinity for xyloglucan, a key polysaccharide abundant in the plant kingdom crucial for providing plant support, were generated. Both improved modules differ from other existing xyloglucan probes by binding to galactose-decorated subunits of xyloglucan. The usefulness of the evolved binders was verified by staining of plant sections, where they performed better than the xyloglucan-binding module from which they had been derived. They discriminated non-fucosylated from fucosylated xyloglucan as shown by their ability to stain only the endosperm, rich in non-fucosylated xyloglucan, but not the integument rich in fucosylated xyloglucan, on tamarind seed sections.

Conclusion

We conclude that affinity maturation of CBM selected from molecular libraries based on the CBM4-2 scaffold is possible and has the potential to generate new analytical tools for detection of plant carbohydrates.
TRIM5α and TRIMCyp form apparent hexamers and their multimeric state is not affected by exposure to restriction-sensitive viruses or by treatment with pharmacological inhibitors
Authors: Nepveu-Traversy Marie-Édith , Bérubé Julie , Berthoux Lionel
Published: November 2009

Proteins of the TRIM5 family, such as TRIM5α and the related TRIMCyp, are cytoplasmic factors that can inhibit incoming retroviruses. This type of restriction requires a direct interaction between TRIM5 proteins and capsid proteins that are part of mature, intact retroviral cores. In such cores, capsids are arranged as hexameric units. Multiple lines of evidence imply that TRIM5 proteins themselves interact with retroviral cores as multimers. Accordingly, stabilization by crosslinking agents has revealed that TRIM5α and TRIMCyp are present as trimers in mammalian cells. We report here that TRIM5 proteins seem to form dimers, trimers, hexamers and multimers of higher complexity in mammalian cells. The hexameric form in particular seems to be the most abundant multimer. Multimerization did not involve disulfide bridges and was not affected by infection with restriction-sensitive viruses or by treatment with the known TRIM5 inhibitors arsenic trioxide, MG132 and cyclosporine A. We conclude that TRIM5 multimerization results from more than one protein-protein interface and that it is seemingly not triggered by contact with retroviral cores.
The Infectious Diseases BioBank at King's College London: archiving samples from patients infected with HIV to facilitate translational research
Authors: Williams Rachel , Mant Christine , Cason John
Published: November 2009

The King's College London (KCL) Infectious Diseases BioBank opened in 2007 and collects peripheral venous blood (PVB) from individuals infected with pathogens including human immunodeficiency virus (HIV). PVBs are fractionated into plasmas, lymphocytes and DNA and are then frozen. All donations are from subjects who have given 'open consent' so samples can be used for virtually any type of biomedical research. The HIV component of the BioBank contains samples from over 400 donations from 138 HIV+ patients. Thus, the KCL Infectious Diseases BioBank - together with establishments such as the Spanish HIV BioBank - is likely to expedite translational research into this infection.
Encapsidation of APOBEC3G into HIV-1 virions involves lipid raft association and does not correlate with APOBEC3G oligomerization
Authors: Khan Mohammad A , Goila-Gaur Ritu , Kao Sandra , Miyagi Eri , Walker Robert C , Strebel Klaus
Published: November 2009

Background

The cellular cytidine deaminase APOBEC3G (A3G), when incorporated into the human immunodeficiency virus type 1 (HIV-1), renders viral particles non-infectious. We previously observed that mutation of a single cysteine residue of A3G (C100S) inhibited A3G packaging. In addition, several recent studies showed that mutation of tryptophan 127 (W127) and tyrosine 124 (Y124) inhibited A3G encapsidation suggesting that the N-terminal CDA constitutes a viral packaging signal in A3G. It was also reported that W127 and Y124 affect A3G oligomerization.

Results

Here we studied the mechanistic basis of the packaging defect of A3G W127A and Y124A mutants. Interestingly, cell fractionation studies revealed a strong correlation between encapsidation, lipid raft association, and genomic RNA binding of A3G. Surprisingly, the presence of a C-terminal epitope tag affected lipid raft association and encapsidation of the A3G W127A mutant but had no effect on wt A3G encapsidation, lipid raft association, and interaction with viral genomic RNA. Mutation of Y124 abolished A3G encapsidation irrespective of the presence or absence of an epitope tag. Contrasting a recent report, our co-immunoprecipitation studies failed to reveal a correlation between A3G oligomerization and A3G encapsidation. In fact, our W127A and Y124A mutants both retained the ability to oligomerize.

Conclusion

Our results confirm that W127 and Y124 residues in A3G are important for encapsidation into HIV-1 virions and our data establish a novel correlation between genomic RNA binding, lipid raft association, and viral packaging of A3G. In contrast, we were unable to confirm a role of W127 and Y124 in A3G oligomerization and we thus failed to confirm a correlation between A3G oligomerization and virus encapsidation.
Loeys-Dietz syndrome type I and type II: clinical findings and novel mutations in two Italian patients
Authors: Drera Bruno , Ritelli Marco , Zoppi Nicoletta , Wischmeijer Anita , Gnoli Maria , Fattori Rossella , Calzavara-Pinton Pier Giacomo , Barlati Sergio , Colombi Marina
Published: November 2009

Background

Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder showing the involvement of cutaneous, cardiovascular, craniofacial, and skeletal systems. In particular, LDS patients show arterial tortuosity with widespread vascular aneurysm and dissection, and have a high risk of aortic dissection or rupture at an early age and at aortic diameters that ordinarily are not predictive of these events. Recently, LDS has been subdivided in LDS type I (LDSI) and type II (LDSII) on the basis of the presence or the absence of cranio-facial involvement, respectively. Furthermore, LDSII patients display at least two of the major signs of vascular Ehlers-Danlos syndrome. LDS is caused by mutations in the transforming growth factor (TGF) beta-receptor I (TGFBR1) and II (TGFBR2) genes. The aim of this study was the clinical and molecular characterization of two LDS patients.

Methods

The exons and intronic flanking regions of TGFBR1 and TGFBR2 genes were amplified and sequence analysis was performed.

Results

Patient 1 was a boy showing dysmorphic signs, blue sclerae, high-arched palate, bifid uvula; skeletal system involvement, joint hypermobility, velvety and translucent skin, aortic root dilatation, tortuosity and elongation of the carotid arteries. These signs are consistent with an LDSI phenotype. The sequencing analysis disclosed the novel TGFBR1 p.Asp351Gly de novo mutation falling in the kinase domain of the receptor. Patient 2 was an adult woman showing ascending aorta aneurysm, with vascular complications following surgery intervention. Velvety and translucent skin, venous varicosities and wrist dislocation were present. These signs are consistent with an LDSII phenotype. In this patient and in her daughter, TGFBR2 genotyping disclosed in the kinase domain of the protein the novel p.Ile510Ser missense mutation.

Conclusion

We report two novel mutations in the TGFBR1 and TGFBR2 genes in two patients affected with LDS and showing marked phenotypic variability. Due to the difficulties in the clinical approach to a TGFBR-related disease, among patients with vascular involvement, with or without aortic root dilatation and LDS cardinal features, genotyping is mandatory to clarify the diagnosis, and to assess the management, prognosis, and counselling issues.
Bone marrow mesenchymal stem cells from leukemia patients inhibit growth and apoptosis in serum-deprived K562 cells
Authors: Wei Zhaohui , Chen Naiyao , Guo Hongxing , Wang Xueming , Xu Fangyun , Ren Qian , Lu ShiHong , Liu Bin , Zhang Lei , Zhao Hui
Published: November 2009

Background

The regulation of growth and apoptosis in K562 cells by human bone marrow mesenchymal stem cells (MSCs) from leukemia patients was investigated.

Methods

K562 cells were cocultured with leukemic MSCs under serum deprivation. Cell Counting Kit-8 (CCK-8), PI staining, Annexin V/PI binding and FACS assays were used to investigate cell proliferation, cell cycle status, and apoptosis of K562 cells cultures in the presence or absence of 10% serum. Western blotting was used to determine the levels of Akt, phosphorylated Akt (p-Akt), the BCL-2 family member Bad, and phosphorylated Bad (p-Bad) proteins in K562 cells after coculturing with MSCs. The effects of LY294002 (a specific inhibitor of PI3K) on protein expression were also determined.

Results

K562 cell proliferation was inhibited by coculture with MSCs and the dominant cell cycle was the G0-G1 phase. The proportion of apoptotic K562 cells was decreased and the levels of p-Akt and p-Bad were upregulated after exposing K562 cells to MSCs. However, when LY294002 was used, p-Akt and p-Bad proteins inK562 cells showed a significant reduction, while no distinct variation was seen in the nonphosphorylated Akt and Bad protein levels.

Conclusion

Leukemic MSCs can inhibit K562 cell expansion and modulate the cell cycle to a state of relative quiescence. This allows the K562 cells to endure adverse conditions such as serum starvation. The PI3K-Akt-Bad signaling pathway may be involved in this antiapoptotic process via phosphorylation of the Akt and Bad proteins. Blocking MSC-induced transduction of the PI3K-Akt-Bad pathway may be a potential strategy for a targeted therapy to combat leukemia.
Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators
Authors: Choi Hyun-Mi , Lee Yeon-Ah , Lee Sang-Hoon , Hong Seung-Jae , Hahm Dae-Hyun , Choi Sang-Yun , Yang Hyung-In , Yoo Myung Chul , Kim Kyoung Soo
Published: November 2009

Introduction

The role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).

Methods

Synovial cells from RA patients were treated with adiponectin or interleukin (IL)-1β for 24 hours. The culture supernatant was collected and analyzed for the levels of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs by enzyme-linked immunosorbent assay. The levels of adiponectin, VEGF, MMP-1, and MMP-13 in the joint fluids from 30 RA or osteoarthritis (OA) patients were also measured.

Results

Adiponectin at the concentration of 10 μg/mL stimulated the production of IL-6, IL-8, and PGE2 in RA fibroblast-like synoviocytes (FLSs), although the level of these was much lower than with 1 ng/mL IL-1β. However, adiponectin stimulated the production of VEGF, MMP-1, and MMP-13 at the same level as IL-1β. In addition, the level of adiponectin and MMP-1 in the joint fluid of RA patients was significantly higher than in OA patients. Adiponectin was positively correlated with VEGF in RA patients but not in OA patients, while the level of MMPs in joint fluid was not correlated with adiponectin in either RA or OA patients.

Conclusions

Adiponectin may play a significant role in the pathogenesis of RA by stimulating the production of VEGF and MMPs in FLSs, leading to joint inflammation and destruction, respectively.
Sinus aspergilloma in rheumatoid arthritis before or during tumor necrosis factor-alpha antagonist therapy
Authors: Leboime Ariane , Berthelot Jean-Marie , Allanore Yannick , Khalil-Kallouche Lama , Herman Philippe , Orcel Philippe , Lioté Frédéric
Published: November 2009

Introduction

In 2008, the Food and Drugs Administration required manufacturers of TNFα antagonists to strengthen their warnings about the risk of serious fungal infections in patients with rheumatoid arthritis (RA). Sinus aspergilloma occurs occasionally in RA patients and can progress to invasive Aspergillus disease. The purpose of this study was to describe symptomatic sinus aspergilloma in RA patients treated with TNFα antagonists.

Methods

Retrospective descriptive study of symptomatic cases of sinus aspergilloma in patients with RA followed in three French university hospitals. A systematic literature review was performed.

Results

Among 550 RA patients treated with TNFα antagonists, six (1.1%) had symptomatic maxillary aspergilloma diagnosed by computed tomography before or during TNFα antagonist therapy. None had chronic neutropenia. Aspergilloma treatment was with surgery only in all six patients. In the literature, we found 20 reports of Aspergillus infection in patients with chronic inflammatory joint diseases (including 10 with RA). Only 5/20 patients were treated with TNFα antagonists (invasive lung aspergillosis, n = 3; intracranial aspergillosis, n = 1; and sphenoidal sinusitis, n = 1).

Conclusions

Otorhinolaryngological symptoms must be evaluated before starting or switching TNFα antagonists. Routine computed tomography of the sinuses before starting or switching TNFα antagonists may deserve consideration.
Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies
Authors: Rhee Chin Kook , Kang Ji Young , Kim Yong Hyun , Kim Jin Woo , Yoon Hyung Kyu , Kim Seok Chan , Kwon Soon Suk , Kim Young Kyoon , Kim Kwan Hyung , Moon Hwa Sik , Park Sung Hak , Kim Hee Je , Lee Seok , Song Jeong Sup
Published: November 2009

Introduction

Neutropenia recovery may be associated with deterioration in oxygenation and exacerbation of pre-existing pulmonary disease. However, risk factors for acute respiratory distress syndrome (ARDS) during neutropenia recovery in patients with hematologic malignancies have not been studied.

Methods

We studied critically ill patients with hematologic malignancies with the dual objectives of describing patients with ARDS during neutropenia recovery and identifying risk factors for ARDS during neutropenia recovery. A cohort of consecutive neutropenic patients with hematologic malignancies who were admitted to the intensive care unit (ICU) was studied. During a 6-year period, 71 patients recovered from neutropenia, of whom 38 (53.5%) developed ARDS during recovery.

Results

Compared with non-ARDS patients, patients who experienced ARDS during neutropenia recovery were more likely to have pneumonia, be admitted to the ICU for respiratory failure, and receive mechanical ventilator therapy. The in-ICU mortality was significantly different between the two groups (86.8% versus 51.5%, respectively, for patients who developed ARDS during neutropenia recovery versus those who did not during neutropenia recovery). In multivariate analysis, only occurrence of pneumonia during the neutropenic episode was associated with a marked increase in the risk of ARDS (odds ratio, 4.76).

Conclusions

Patients with hematologic malignancies complicated by pneumonia during neutropenia are at increased risk for ARDS during neutropenia recovery.
Divergence of exonic splicing elements after gene duplication and the impact on gene structures
Authors: Zhang Zhenguo , Zhou Li , Wang Ping , Liu Yang , Chen Xianfeng , Hu Landian , Kong Xiangyin
Published: November 2009

Background

The origin of new genes and their contribution to functional novelty has been the subject of considerable interest. There has been much progress in understanding the mechanisms by which new genes originate. Here we examine a novel way that new gene structures could originate, namely through the evolution of new alternative splicing isoforms after gene duplication.

Results

We studied the divergence of exonic splicing enhancers and silencers after gene duplication and the contributions of such divergence to the generation of new splicing isoforms. We found that exonic splicing enhancers and exonic splicing silencers diverge especially fast shortly after gene duplication. About 10% and 5% of paralogous exons undergo significantly asymmetric evolution of exonic splicing enhancers and silencers, respectively. When compared to pre-duplication ancestors, we found that there is a significant overall loss of exonic splicing enhancers and the magnitude increases with duplication age. Detailed examination reveals net gains and losses of exonic splicing enhancers and silencers in different copies and paralog clusters after gene duplication. Furthermore, we found that exonic splicing enhancer and silencer changes are mainly caused by synonymous mutations, though nonsynonymous changes also contribute. Finally, we found that exonic splicing enhancer and silencer divergence results in exon splicing state transitions (from constitutive to alternative or vice versa), and that the proportion of paralogous exon pairs with different splicing states also increases over time, consistent with previous predictions.

Conclusions

Our results suggest that exonic splicing enhancer and silencer changes after gene duplication have important roles in alternative splicing divergence and that these changes contribute to the generation of new gene structures.
Regulatory interdependence of myeloid transcription factors revealed by Matrix RNAi analysis
Authors: Tomaru Yasuhiro , Simon Christophe , Forrest Alistair RR , Miura Hisashi , Kubosaki Atsutaka , Hayashizaki Yoshihide , Suzuki Masanori
Published: November 2009

Background

With the move towards systems biology, we need sensitive and reliable ways to determine the relationships between transcription factors and their target genes. In this paper we analyze the regulatory relationships between 78 myeloid transcription factors and their coding genes by using the matrix RNAi system in which a set of transcription factor genes are individually knocked down and the resultant expression perturbation is quantified.

Results

Using small interfering RNAs we knocked down the 78 transcription factor genes in monocytic THP-1 cells and monitored the perturbation of the expression of the same 78 transcription factors and 13 other transcription factor genes as well as 5 non-transcription factor genes by quantitative real-time RT-PCR, thereby building a 78 × 96 matrix of perturbation and measurement. This approach identified 876 cases where knockdown of one transcription factor significantly affected the expression of another (from a potential 7,488 combinations). Our study also revealed cell-type-specific transcriptional regulatory networks in two different cell types.

Conclusions

By considering whether the targets of a given transcription factor are naturally up- or downregulated during phorbol 12-myristate 13-acetate-induced differentiation, we could classify these edges as pro-differentiative (229), anti-differentiative (76) or neither (571) using expression profiling data obtained in the FANTOM4 study. This classification analysis suggested that several factors could be involved in monocytic differentiation, while others such as MYB and the leukemogenic fusion MLL-MLLT3 could help to maintain the initial undifferentiated state by repressing the expression of pro-differentiative factors or maintaining expression of anti-differentiative factors.
Leukotriene B4 mediates γδ T lymphocyte migration in response to diverse stimuli
Authors: Costa Maria Fernanda de Souza , de Souza-Martins Raquel , de Souza Mariana C , Benjamim Cláudia F , Piva Bruno , Diaz Bruno L , Peters-Golden Marc , Henriques Maria das Graças , Canetti Cláudio , Penido Carmen
Published: October 2009

γδ T cell migration into mouse pleural cavities during inflammatory responses triggered by LPS, Mycobacterium bovis BCG, or ovalbumin depends on leukotriene B4 and BLT1 receptor.

Herein, we investigated the involvement of the 5-LO-derived lipid mediator LTB4 in γδ T cell migration. When injected into the i.pl. space of C57BL/6 mice, LTB4 triggered γδ T lymphocyte mobilization in vivo, a phenomenon also observed in in vitro chemotaxis assays. The i.pl. injection of Escherichia coli endotoxin (LPS) triggered increased levels of LTB4 in pleural cavities. The in vivo inhibition of LTB4 biosynthesis by the 5-LO inhibitor zileuton or the FLAP inhibitor MK886 attenuated LPS-induced γδ T cell accumulation into pleural cavities. Accordingly, 5-LO KO mice failed to recruit γδ T cells into the inflammatory site after i.pl. LPS. Antagonists of the high-affinity LTB4 receptor BLT1, CP105,696, and LY292476 also attenuated LPS-induced γδ T cell accumulation in pleural cavities as well as in vitro chemotaxis toward pleural washes obtained from LPS-simulated mice. LTB4/BLT1 also accounted for γδ T cell migration induced by i.pl. administration of Mycobacterium bovis BCG or antigen in sensitized mice. BLT1 was expressed on naïve, resident as well as LPS-recruited γδ T cells. Isolated γδ T cells were found to undergo F-actin cytoskeleton reorganization when incubated with LTB4 in vitro, confirming that γδ T lymphocytes can respond directly to LTB4. In addition to its direct effect on γδ T cells, LTB4 triggered their accumulation indirectly, via modulation of CCL2 production in mouse pleural cavities. These data show that γδ T cell migration into the pleural cavity of mice during diverse inflammatory responses is dependent on LTB4/BLT1.
Antipsychotic long-acting injections: Mind the gap
Authors: Patel Maxine X. , Taylor Mark , David Anthony S.
Published: October 2009

Long-acting injections of antipsychotic medication (or depots) were developed specifically to promote treatment adherence and are a valuable option for maintenance medication in psychotic illnesses. Approximately 40–60% of patients with schizophrenia are partially or totally non-adherent to their antipsychotic regimen, but only 30% or less are prescribed a long-acting injection. The use of such injections has declined in recent years after the introduction of second-generation (atypical) oral antipsychotic drugs. Research shows that possible reasons for this decline include concerns that may be based on suboptimal knowledge, as well as an erroneous assumption that one's own patient group is more adherent than those of one's colleagues. Research on attitudes has also revealed that psychiatrists feel that long-acting injections have an ‘image’ problem. This editorial addresses the gaps in knowledge and behaviour associated with possible underutilisation of these formulations, highlighting the role of stigma and the need for more research.
Psychopharmacology and adverse effects of antipsychotic long-acting injections: A review
Authors: Taylor David
Published: October 2009

Background

Depot antipsychotics are widely used in clinical practice. Long-acting formulations of second-generation antipsychotics are now being developed and introduced.

Aims

To review the pharmacology, pharmacokinetics and adverse effect profiles of currently available antipsychotic long-acting injections (LAIs).

Method

The psychopharmacological properties of first- and second-generation antipsychotic LAIs are reviewed using data available up to October 2008.

Results

First-generation antipsychotic (FGA) LAIs are associated with a high rate of acute and chronic movement disorders. Risperidone LAI is better tolerated in this respect, but is associated with hyperprolactinaemia and weight gain. Olanzapine LAI causes weight gain and other metabolic effects but appears not to be associated with an important incidence of movement disorders.

Conclusions

Dosing of LAIs is complicated by delayed release of drug, changes in plasma levels without change in dose, and by the lack of data establishing clear dose requirements. All LAIs offer the prospect of assured adherence (although patients may still default on treatment) but their use is complicated by adverse effects, complex pharmacokinetics and confusion over dose–response relationships.
First-generation antipsychotic long-acting injections v. oral antipsychotics in schizophrenia: Systematic review of randomised controlled trials and observational studies
Authors: Haddad Peter M. , Taylor Mark , Niaz Omair S.
Published: October 2009

Background

Antipsychotic long-acting injections (LAIs) are often used in an attempt to improve medication adherence in people with schizophrenia.

Aims

To compare first-generation antipsychotic long-acting injections (FGA–LAIs) with first- and second-generation oral antipsychotics in terms of clinical outcome.

Method

Systematic literature review.

Results

A meta-analysis of randomised controlled trials (RCTs) showed no difference in relapse or tolerability between oral antipsychotics and FGA–LAIs but global improvement was twice as likely with FGA–LAIs. Four prospective observational studies were identified; two studies reported lower discontinuation rates for FGA–LAIs compared with oral medication and two found that outcome was either no different or better with oral antipsychotics. Mirror-image studies consistently showed reduced in-patient days and admissions following a switch from oral antipsychotics to FGA–LAIs.

Conclusions

The results are variable and inconclusive. Some evidence suggests that FGA–LAIs may improve outcome compared with oral antipsychotics. Methodological issues may partly explain the variable results. Selective recruitment in RCTs and lack of randomisation in observational studies are biases against LAIs, whereas regression to the mean in mirror-image studies favours LAIs. In terms of future research, a long-term pragmatic RCT of an FGA–LAI against an oral antipsychotic, in patients with problematic adherence, would be of value.
Negative parental discipline, conduct problems and callous–unemotional traits: monozygotic twin differences study
Authors: Viding Essi , Fontaine Nathalie M. G. , Oliver Bonamy R. , Plomin Robert
Published: October 2009

Background

Negative parenting practices may be an environmental risk factor for subsequent conduct problems. Research on the association between parenting practices and callous–unemotional traits, a risk factor for conduct problems, has produced mixed findings.

Aims

To investigate whether negative parental discipline is a non-shared environmental risk factor for the development of conduct problems and callous–unemotional traits.

Method

Longitudinal, multi-informant data from a community sample of twins were analysed using the monozygotic (MZ) twin differences design for 4508 twins (2254 twin pairs).

Results

Within MZ twin pairs, the twin receiving more negative parental discipline at 7 years had more conduct problems (but not more callous–unemotional traits) at 12 years.

Conclusions

During the transition to early adolescence, negative parental discipline operates as a non-shared environmental risk factor for development of conduct problems, but not for the development of callous–unemotional traits.
Response Modification Factors for RC Case-Study Buildings with Structural Walls
Authors: Kim Taewan , Foutch Douglas A. , Wilcoski James , LaFave James M.
Published: October 2009

A rational approach for determining the response modification factor, [Formula: see text], has been applied to reinforced concrete (RC) shear wall buildings designed under current codes and standards of practice. The approach is founded upon the performance-based evaluation framework from the SAC project; however, new values for various parameters were derived specifically for RC shear wall buildings because the SAC parameters were for steel moment frame buildings. Typical RC shear wall buildings were designed consisting of solid, flexure-dominated structural walls for lateral load resistance and a flat plate floor system for gravity loads. The performance of each building was then evaluated by calculating the confidence level of achieving the design objective. The buildings designed per the current [Formula: see text]-value of 6 demonstrated good performances, meaning that the confidence levels of avoiding collapse were greater than the target value of 90%. The confidence levels for shear wall buildings with greater [Formula: see text]-values were also determined, suggesting that further study could provide the basis for justifying an [Formula: see text]-value of 7 for the special RC shear wall structural system.
One-Year Outcomes of a Behavioral Therapy Intervention Trial on Sleep Quality and Cancer-Related Fatigue
Authors: Berger Ann M. , Kuhn Brett R. , Farr Lynne A. , Von Essen Susanna G. , Chamberlain Julie , Lynch James C. , Agrawal Sangeeta
Published: November 2009

Purpose

To determine 1-year outcomes of a four-component behavioral therapy (BT) sleep intervention (Individualized Sleep Promotion Plan [ISPP]) versus a healthy eating control (HEC) on cancer-related fatigue in women receiving breast cancer adjuvant chemotherapy treatment (CTX).

Patients and Methods

A total of 219 participants from 12 oncology clinics were randomly assigned in a clinical trial. Before CTX, research nurses coached intervention participants to develop a BT plan including stimulus control, modified sleep restriction, relaxation therapy, and sleep hygiene. BT plans were revised before each CTX and 30, 60, and 90 days after the last CTX and reinforced 7 to 9 days later. HEC participants received nutritional information and equal attention. Pittsburgh Sleep Quality Index (PSQI), Daily Diary, Wrist Actigraph, and Piper Fatigue Scale measures and Repeated Linear Mixed Model analysis following the Intent to Treat paradigm were used.

Results

Sleep quality differed over 1 years time (F [4,162] = 7.7, P < .001; by group, F [1,173] = 4.8, P = .029; and over time by group, F [4,162] = 3.3, P = .013). Pairwise comparisons revealed significant differences between groups at 90 days (P = .002) but not at 1 year (P = .052). Seven days of diary and actigraphy data did not corroborate with monthly reflections (PSQI). The night awakenings (Actigraph) pattern was significantly different by group over time (P = .046), with no differences between groups at 90 days or at 1 year. Fatigue was lower at 1 year than before CTX; no group effects were found.

Conclusion

The BT group, on average, experienced significant improvement on global sleep quality compared with the HEC group, but not on objective sleep or fatigue outcomes.
Clinical Relevance of HER2 Overexpression/Amplification in Patients With Small Tumor Size and Node-Negative Breast Cancer
Authors: Curigliano Giuseppe , Viale Giuseppe , Bagnardi Vincenzo , Fumagalli Luca , Locatelli Marzia , Rotmensz Nicole , Ghisini Raffaella , Colleoni Marco , Munzone Elisabetta , Veronesi Paolo , Zurrida Stefano , Nolè Franco , Goldhirsch Aron
Published: November 2009

Purpose

To assess the prognostic role of HER2 overexpression/amplification in patients with node-negative, pT1a-b breast cancers.

Patients and Methods

All patients with HER2-positive breast cancer were identified among a population of 2,130 patients whose diseases were staged as pT1a-b, pN0 and who underwent surgery at the European Institute of Oncology from 1999 to 2006. A matched cohort was selected by using variables of hormone receptor status, age, and year of surgery. We estimated rates of local and distant recurrence, disease-free survival (DFS), and overall survival (OS) in the two groups.

Results

We identified 150 consecutive patients with pT1a-b, pN0, HER2-positive tumors. No patient received adjuvant trastuzumab. The median follow-up was 4.6 years (range, 1.0 to 9.0 years). In the hormone receptor–positive group, 5-year DFS rates were 99% (95% CI, 96% to 100%) for HER2-negative disease and 92% (95% CI, 86% to 99%) for HER2-positive disease. In the hormone receptor–negative group, 5-year DFS rates were 92% (95% CI, 84% to 100%) for HER2-negative disease and 91% (95% CI, 84% to 99%) for HER2-positive disease. Overall, the hazard ratio (HR) associated with HER2 overexpression was 2.4 (95% CI, 0.9 to 6.5; P = .09). After analysis was adjusted for pT1 stage, hormone receptor–positive disease with HER2-positive status was associated with a worse prognosis (HR, 5.1; 95% CI, 1.0 to 25.7). OS in HER2-positive, pT1a-b, pN0 breast cancer was similar irrespective of the hormone receptor status (P = .93).

Conclusion

Patients with node-negative, HER2 positive, pT1a-b breast cancer have a low risk of recurrence at 5 years of follow-up. In patients with hormone receptor–positive disease and pT1a-b, N0 tumors, HER2 overexpression was associated with a worse DFS.
Understanding the Mechanisms Behind Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Spector Neil L. , Blackwell Kimberly L.
Published: November 2009

Purpose

Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) –positive breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clinical benefit also is discussed.

Methods

An extensive literature review of trastuzumab and proposed mechanisms of action was performed.

Results

At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclinical setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, reduction of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clinical benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clinical benefit observed with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1).

Conclusion

Trastuzumab is the foundation of care for patients with HER2-positive BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clinical benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.