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41.
Pérez-Mancera PA Rust AG van der Weyden L Kristiansen G Li A Sarver AL Silverstein KA Grützmann R Aust D Rümmele P Knösel T Herd C Stemple DL Kettleborough R Brosnan JA Li A Morgan R Knight S Yu J Stegeman S Collier LS ten Hoeve JJ de Ridder J Klein AP Goggins M Hruban RH Chang DK Biankin AV Grimmond SM;Australian Pancreatic Cancer Genome Initiative Wessels LF Wood SA Iacobuzio-Donahue CA Pilarsky C Largaespada DA Adams DJ Tuveson DA 《Nature》2012,486(7402):266-270
Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA. 相似文献
42.
A. Pessina P. Brambilla Daniela Balzarin 《Cellular and molecular life sciences : CMLS》1978,34(11):1518-1519
Summary Treatment of Ehrlich ascites carcinoma (EAC) cells with carbonyl iron (20 mg/ml) produces a significant decrease in growth rate of tumor inoculum both in Swiss and in C57BL/6 mice. Possible interaction of the carbonyl iron or Fe+++ions with cell surface is suggested.Supported by a grant from the Consiglio Nazionale delle Ricerche.Acknowledgments. The authors are grateful to Dr M. M. Clynes (University College, Dublin, Ireland) for his helpful discussion. 相似文献
43.
Carollo D Beers TC Lee YS Chiba M Norris JE Wilhelm R Sivarani T Marsteller B Munn JA Bailer-Jones CA Fiorentin PR York DG 《Nature》2007,450(7172):1020-1025
The halo of the Milky Way provides unique elemental abundance and kinematic information on the first objects to form in the Universe, and this information can be used to tightly constrain models of galaxy formation and evolution. Although the halo was once considered a single component, evidence for its dichotomy has slowly emerged in recent years from inspection of small samples of halo objects. Here we show that the halo is indeed clearly divisible into two broadly overlapping structural components--an inner and an outer halo--that exhibit different spatial density profiles, stellar orbits and stellar metallicities (abundances of elements heavier than helium). The inner halo has a modest net prograde rotation, whereas the outer halo exhibits a net retrograde rotation and a peak metallicity one-third that of the inner halo. These properties indicate that the individual halo components probably formed in fundamentally different ways, through successive dissipational (inner) and dissipationless (outer) mergers and tidal disruption of proto-Galactic clumps. 相似文献
44.
<正>Esterification of Aspen Wood with Maleic Anhydride$罗马尼亚布拉索夫大学木材工业系1MatsudaH.Preparationofesterifiedwoodsbearingcarboxylgroups.WodScienceandTechnology,1987,21:75~882MatsudaH,UedaM,MoriH.Preparationandcroslinkingofoligoest.... 相似文献
45.
Carvalho CM Ramocki MB Pehlivan D Franco LM Gonzaga-Jauregui C Fang P McCall A Pivnick EK Hines-Dowell S Seaver LH Friehling L Lee S Smith R Del Gaudio D Withers M Liu P Cheung SW Belmont JW Zoghbi HY Hastings PJ Lupski JR 《Nature genetics》2011,43(11):1074-1081
We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat-mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events. 相似文献
46.
Renna MD Oyadeyi AS Bossi E Kottra G Peres A 《Cellular and molecular life sciences : CMLS》2011,68(17):2961-2975
The functional and structural basis of reverse operation of PepT1 has been studied in Xenopus oocytes expressing the wild-type
and mutated forms of this protein. Using brief pulses from a negative holding potential, wild-type and Arg282 mutants exhibit
outward currents in the presence of Gly-Gln. The reversal potential of these currents is affected by both pH and substrate
concentration, confirming coupled transport in the wild type and in the mutants as well. Long-lasting voltage and current-clamp
experiments show that the outward currents are only temporary, and reflect accumulation and/or depletion effects near the
membrane. The ability to operate in reverse mode was confirmed in all isoforms by intracellular injection of substrate. The
role of Arg282 and Asp341 in the reverse transport was also investigated using charged substrates. Positive Lys-Gly (but not
Gly-Lys) showed enhanced transport currents in the Arg282 mutants. In contrast, negative Gly-Asp and Asp-Gly elicited modest
currents in all isoforms. 相似文献
47.
Jürgen Schnekenburger Ina-Alexandra Weber Daniela Hahn Igor Buchwalow Burkhard Krüger Elke Albrecht Wolfram Domschke Markus M. Lerch 《Cellular and molecular life sciences : CMLS》2009,66(15):2525-2537
The regulated secretion of pancreatic zymogens depends on a functional cytoskeleton and intracellular vesicle transport. To
study the dynamics of tubulin and its motor proteins dynein and kinesin during secretion in pancreatic acinar cells, we infused
rats with 0.1 μg/kg/h caerulein. Electron and fluorescence microscopy detected neither dynein nor kinesin at the apical secretory
pole, nor on the surface of mature zymogen granules. After 30 min of secretagogue stimulation, kinesin and the Golgi marker
protein 58 K were reallocated towards the apical plasma membrane and association of kinesin with tubulin was enhanced. Disruption
of acinar cell microtubules had no effect on initial caerulein-induced amylase release but completely blocked secretion during
a second stimulus. Our results suggest that mature zymogen granule exocytosis is independent of intact microtubules, kinesin
and dynein. However, microtubule-dependent mechanisms seem to be important for the replenishment of secretory vesicles by
redistribution of Golgi elements towards the apical cell pole.
J. Schnekenburger and I.-A. Weber have contributed equally to this work. 相似文献
48.
Daniela Corda Pasquale Zizza Alessia Varone Beatrice Maria Filippi Stefania Mariggiò 《Cellular and molecular life sciences : CMLS》2009,66(21):3449-3467
The glycerophosphoinositols are cellular products of phospholipase A2 and lysolipase activities on the membrane phosphoinositides. Their intracellular concentrations can vary upon oncogenic transformation,
cell differentiation and hormonal stimulation. Specific glycerophosphodiester phosphodiesterases are involved in their catabolism,
which, as with their formation, is under hormonal regulation. With their mechanisms of action including modulation of adenylyl
cyclase, intracellular calcium levels, and Rho-GTPases, the glycerophosphoinositols have diverse effects in multiple cell
types: induction of cell proliferation in thyroid cells; modulation of actin cytoskeleton organisation in fibroblasts; and
reduction of the invasive potential of tumour cell lines. More recent investigations include their effects in inflammatory
and immune responses. Indeed, the glycerophosphoinositols enhance cytokine-dependent chemotaxis in T-lymphocytes induced by
SDF-1α-receptor activation, indicating roles for these compounds as modulators of T-cell signalling and T-cell responses. 相似文献
49.
Ferrari D Zalfa C Nodari LR Gelati M Carlessi L Delia D Vescovi AL De Filippis L 《Cellular and molecular life sciences : CMLS》2012,69(7):1193-1210
Cell therapy is reaching the stage of phase I clinical trials for post-traumatic, post-ischemic, or neurodegenerative disorders,
and the selection of the appropriate cell source is essential. In order to assess the capacity of different human neural stem
cell lines (hNSC) to contribute to neural tissue regeneration and to reduce the local inflammation after an acute injury,
we transplanted GMP-grade non-immortalized hNSCs and v-myc (v-IhNSC), c-myc T58A (T-IhNSC) immortalized cells into the corpus
callosum of adult rats after 5 days from focal demyelination induced by lysophosphatidylcholine. At 15 days from transplantation,
hNSC and T-IhNSC migrated to the lesioned area where they promoted endogenous remyelination and differentiated into mature
oligodendrocytes, while the all three cell lines were able to integrate in the SVZ. Moreover, where demyelination was accompanied
by an inflammatory reaction, a significant reduction of microglial cells’ activation was observed. This effect correlated
with a differential migratory pattern of transplanted hNSC and IhNSC, significantly enhanced in the former, thus suggesting
a specific NSC-mediated immunomodulatory effect on the local inflammation. We provide evidence that, in the subacute phase
of a demyelination injury, different human immortalized and non-immortalized NSC lines, all sharing homing to the stem niche,
display a differential pathotropism, both through cell-autonomous and non-cell autonomous effects. Overall, these findings
promote IhNSC as an inexhaustible cell source for large-scale preclinical studies and non-immortalized GMP grade hNSC lines
as an efficacious, safe, and reliable therapeutic tool for future clinical applications. 相似文献
50.