| 1. |
- Birney, Ewan, et al.
(author)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Dong, X.-P., et al.
(author)
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The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
- 2008
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7215, s. 992-996
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Journal article (peer-reviewed)abstract
- TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4). ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+-bound transferrin receptors, or after lysosomal degradation of ferritin-iron complexes and autophagic ingestion of iron-containing macromolecules, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+ transport protein. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1-/-ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe 2+ levels and an accumulation of lipofuscin-like molecules in TRPML1-/- cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients. ©2008 Macmillan Publishers Limited. All rights reserved.
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| 3. |
- Duggan, D., et al.
(author)
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Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP
- 2007
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 99:24, s. 1836-1844
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Journal article (peer-reviewed)abstract
- Background: The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment. Methods: We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study. Results: Among the approximately 60000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value =. 004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value =. 02). Conclusion: A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.
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| 4. |
- Hua, Dong, et al.
(author)
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Small interfering RNA-directed targeting of toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity
- 2009
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In: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 46:15, s. 2876-2884
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Journal article (peer-reviewed)abstract
- A major cause of tumor treatment failure is cancer cell metastasis. Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. In this study, we investigated the biological roles of TLR4 in prostate metastatic cell invasion and survival, and the potential of gene silencing of TLR4 using small interfering RNA (siRNA) for treatment of cancer. In cultured human prostate cancer cell lines, TLR4 were higher PC3 and DU145 as compared with the poorly metastatic LNCaP indicating that up-regulation of TLR4 was positively correlated with metastasis of tumor cell. In the highly metastatic cancer cell PC3, gene silencing of TLR4 using siRNA significantly inhibited TLR4 mRNA expression and protein level. Knockdown of TLR4 in PC3 cells resulted in a dramatic reduction of tumor cell migration and invasion as indicated by a Matrigel invasion assay. Furthermore, TLR4 siRNA suppressed cell viability and ultimately caused the induction of apoptotic cell death. The effects were associated with abrogating TLR4-mediated signaling to downstream target molecules such as myeloid differentiation factor 88 (MyD88), adaptor-inducing IFN-beta (TRIF), and interferon regulatory factor-1 (IRF-1). In a mouse prostate cancer model, administration with the plasmid construct expressing siRNA for TLR4 obviously inhibited established tumor growth and survival. These studies revealed evidence of a multifaceted signaling network operating downstream of TLR4-mediated tumor cell invasion, proliferation, and survival. Thus, RNA interference-directed targeting of TLR4 may raise the potential of its application for cancer therapy.
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| 5. |
- Li, T, et al.
(author)
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Systemic hypothermia induced within 10 hours after birth improved neurological outcome in newborns with hypoxic-ischemic encephalopathy
- 2009
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In: Hospital Practice. - : Informa UK Limited. - 0018-5809 .- 2154-8331 .- 2377-1003. ; 37:1, s. 1-6
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Journal article (peer-reviewed)abstract
- Objective: To evaluate the efficacy of systemic hypothermia when applied within 10 hours after birth to neonates with hypoxic-ischemic encephalopathy (HIE). Study Design: Ninety-three term infants with moderate-to-severe HIE were randomly assigned to either systemic hypothermia (n = 46) or conventional treatment (n = 47). Hypothermia was induced within 10 hours after birth, decreasing rectal temperature to 33.5°C for 72 hours, followed by slow rewarming to 36.5°C. Neurodevelopmental outcome was assessed at 18 months old. The primary outcome was death or moderate-to-severe disability. Results: Outcome data were available for 82 infants. Death or moderate-to-severe disability occurred in 21 of 44 infants (47.7%) in the control group and in 7 of 38 infants (18.4%) in the hypothermia group (P = 0.01) at 18 months. The primary outcome was not different whether hypothermia was started within 6 hours or 6 to 10 hours after birth. Subgroup analysis suggested that systemic hypothermia improved long-term outcome only in infants with moderate HIE (P = 0.009), but not in those with severe HIE. No severe hypothermia-related adverse events were observed. Conclusion: Systemic hypothermia reduced the risk of disability in infants with moderate HIE, in accordance with earlier studies. Hypothermia was induced within 6 hours in most infants, but delaying the onset to 6 to 10 hours after birth did not negatively affect primary outcome. Further studies with a large number of patients are needed to confirm that delayed cooling is equally effective.
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| 6. |
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| 7. |
- Schain, Frida, et al.
(author)
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Differential expression of cysteinyl leukotriene receptor 1 and 15-lipoxygenase-1 in non-Hodgkin lymphomas
- 2008
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In: Clinical lymphoma & myeloma. - 1557-9190. ; 8:6, s. 340-7
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Journal article (peer-reviewed)abstract
- BACKGROUND: Arachidonic acid metabolites have been suggested to play an important role in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1) are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma and certain Hodgkin lymphoma cell lines, and that these cells convert arachidonic acid to the novel proinflammatory eoxins. MATERIALS AND METHODS: The expression of the CysLT1 receptor and 15-LO-1 was investigated in a broad range of non-Hodgkin lymphomas (NHLs) by immunohistochemistry. The functionality of the CysLT1 receptor in primary mediastinal B-cell lymphoma (PMBCL) cell lines was studied by calcium mobilization assays. RESULTS: Primary mediastinal B-cell lymphoma was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. Furthermore, the tumor cells in 1 of 4 T-cell-derived anaplastic large-cell lymphomas, in contrast to all other studied NHLs, strongly expressed 15-LO-1. CONCLUSION: Among the NHL entities included in this study, the CysLT1 receptor was exclusively expressed by the tumor cells of PMBCL. Thus, this further corroborates the pathologic overlap between PMBCL and classical Hodgkin lymphoma.
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| 8. |
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| 9. |
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| 10. |
- Xu, Li, et al.
(author)
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Nano-Thermal Interface Material with CNT Nano-Particles For Heat Dissipation Application
- 2008
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In: 2008 International Conference on Electronic Packaging Technology and High Density Packaging, ICEPT-HDP 2008; Pudong, Shanghai; China; 28 July 2008 through 31 July 2008. - 9781424427406
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Conference paper (peer-reviewed)abstract
- Heat dissipation of electronic packages has become one of the limiting factors to miniaturization. The removal of the heat generated is a critical issue in electronic packaging. With the development of thermal management, thermal interface material (TIM) plays a more and more important role in electronics packaging. A new nano-TIM with nanofibers prepared by using electrospinning has been suggested in recent years. In this experiment study, the carbon nanotube (CNT) nano-particles were added into the polymer solution before the electrospinning to improve the thermal conductivity of nano-TIM. The polymer solution of Polyurethane was used for present electrospinning. The effects of a number of process parameters in the electrospinning were studied in this work. Different variables such as the distance between needle tip and collector, the voltage applied, and CNT nano-particles content were studied. The Scanning Electron Microscopy (SEM) was used to characterize nano-TIMs with CNT nano-particles.
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| 11. |
- Yang, Han-Xin, et al.
(author)
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Diversity-optimized cooperation on complex networks
- 2009
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In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics. - : American physical society. - 1063-651X .- 1095-3787. ; 79:5, s. 056107-
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Journal article (peer-reviewed)abstract
- We propose a strategy for achieving maximum cooperation in evolutionary games on complex networks. Each individual is assigned a weight that is proportional to the power of its degree, where the exponent α is an adjustable parameter that controls the level of diversity among individuals in the network. During the evolution, every individual chooses one of its neighbors as a reference with a probability proportional to the weight of the neighbor, and updates its strategy depending on their payoff difference. It is found that there exists an optimal value of α, for which the level of cooperation reaches maximum. This phenomenon indicates that, although high-degree individuals play a prominent role in maintaining the cooperation, too strong influences from the hubs may counterintuitively inhibit the diffusion of cooperation. Other pertinent quantities such as the payoff, the cooperator density as a function of the degree, and the payoff distribution are also investigated computationally and theoretically. Our results suggest that in order to achieve strong cooperation on a complex network, individuals should learn more frequently from neighbors with higher degrees, but only to a certain extent.
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| 12. |
- Yveborg, Moa, et al.
(author)
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Photon-counting CT with silicon detectors : feasibility for pediatric imaging
- 2009
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In: Medical Imaging 2009. - : SPIE. - 9780819475091
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Conference paper (peer-reviewed)abstract
- X-ray detectors made of crystalline silicon have several advantages including low dark currents, fast charge collection and high energy resolution. For high-energy x-rays, however, silicon suffers from its low atomic number, which might result in low detection efficiency, as well as low energy and spatial resolution due to Compton scattering. We have used a monte-carlo model to investigate the feasibility of a detector for pediatric CT with 30 to 40 mm of silicon using x-ray spectra ranging from 80 to 140 kVp. A detection efficiency of 0.74 was found at 80 kVp, provided the noise threshold could be set low. Scattered photons were efficiently blocked by a thin metal shielding between the detector units, and Compton scattering in the detector could be well separated from photo absorption at 80 kVp. Hence, the detector is feasible at low acceleration voltages, which is also suitable for pediatric imaging. We conclude that silicon detectors may be an alternative to other designs for this special case.
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| 13. |
- Zhang, Wen-Chao, et al.
(author)
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Clinical and pathological analysis of malignant carotid body tumour : a report of nine cases
- 2009
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In: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 129:11, s. 1320-1325
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Journal article (peer-reviewed)abstract
- Conclusions. Malignant carotid body tumour (MCBT) is a clinically rare disease that often invades the carotid artery and cranial nerves. Diagnosis of malignant tumour should be based on extensive invasion of neighbouring organs and distant metastasis. Extensive resection should be undertaken early. Radiotherapy is effective, whereas chemotherapy is uncertain. Objective. To summarize the clinical pathological and prognostic characteristics of MCBT and explore methods for diagnosis and treatment. Materials and methods. The study material comprised clinical, pathological, therapeutic and follow-up data concerning nine patients (four males, five females) with MCBT, treated at Tianjin Cancer Hospital between January 1956 and June 2006. The material was analysed retrospectively. Disease duration averaged 6.4 years. Shamblin classification was: one case, type ?; 8 cases, type ?. All nine patients underwent ultrasound examination, four underwent digital subtraction arteriography (DSA) and three had magnetic resonance angiography (MRA). Five patients underwent preoperative training of compression of the carotid (Matas test). Extensive resection was performed in all nine cases. Results. The carotid artery was blocked in three patients. In one of these the artery was reconstructed with a vascular prosthesis, while two underwent carotid ligation. Eight patients suffered from a cranial nerve dysfunction (defect) and two suffered postoperatively from a hoarse voice, four had a glossal deviation, five had Horner's syndrome and one had a deviation of the lip angle. One patient had a congestive cough. The histopathological diagnosis in all nine cases was MCBT. One patient had metastases to a cervical lymph node and lung and another had liver metastasis. The median follow-up period was 3 years (range 6 months to 14 years). Six patients survived surgery, of whom two underwent radiotherapy. Two patients died and one could not be traced.
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| 14. |
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| 15. |
- Zhu, Changlian, 1964, et al.
(author)
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Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy.
- 2009
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In: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 124:2
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design. METHODS: A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting <48 hours after birth. The primary outcome was death or disability. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed. CONCLUSION: Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.
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| 16. |
- Zhu, Changlian, 1964, et al.
(author)
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Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia-ischemia
- 2006
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In: Eur J Neurosci. ; 23:2, s. 387-93
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Journal article (peer-reviewed)abstract
- The effectiveness of hypothermia in preventing ischemic brain damage depends on when it is started. The purpose of this study was to investigate the effects of temperature reduction during a hypoxic-ischemic (HI) insult on brain injury and signalling pathways of neuronal cell death and survival. Seven-day-old mice were subjected to left common carotid artery ligation and hypoxia (10% oxygen) at different temperatures (37, 36 or 34 degrees C) for 50 min. Brain injury at 7 days post-HI was significantly reduced from 67.4% at 37 degrees C to 31.6% at 36 degrees C and 10% at 34 degrees C, with no observable injury in the cortex of the 34 degrees C group. Cytochrome c release, caspase-3 activation and apoptosis-inducing factor translocation from mitochondria to nuclei were all significantly inhibited after intraischemic temperature reduction. Concurrently, the cell survival signalling pathway involving Akt was significantly sustained (the phosphorylated form of Akt was maintained) when the hypoxia temperature was decreased. These results indicate that intraischemic hypothermia diminished apoptosis through inhibition of both caspase-dependent and caspase-independent neuronal cell death pathways and promoted cell survival by inhibition of phosphorylated Akt dephosphorylation in the neonatal brain, thereby preventing neuronal cell death.
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| 17. |
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