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71.
Score J Hidalgo-Curtis C Jones AV Winkelmann N Skinner A Ward D Zoi K Ernst T Stegelmann F Döhner K Chase A Cross NC 《Blood》2012,119(5):1208-1213
The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes. 相似文献
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The ventrolateral subdivision of the periaqueductal gray (vlPAG) and the adjacent dorsal mesencephalic reticular formation (dMRF) are involved in the modulation of active (rapid eye movement) sleep (AS). In order to determine the effects on AS of the suppression of neuronal activity in these regions, muscimol, a GABA receptor A (GABA(A)) receptor agonist, and bicuculline, a GABA(A) receptor antagonist, were microinjected bilaterally in guinea pigs and the states of sleep and wakefulness were examined. The main effect of muscimol was an increase in AS; this increase occurred in conjunction with a reduction in the time spent in wakefulness. The powerful effect of muscimol was striking especially when considering the small amount of naturally-occurring AS that is present in this species. Additional observable effects that were induced by muscimol were: 1) long lasting episodes of hypotonia/atonia during wakefulness and quiet sleep that included a lack of extensor tone in the hind limbs, and 2) frequently occurring cortical spindles, similar to those observed during naturally-occurring quiet sleep (sleep spindles), that were present during wakefulness. Conversely, bilateral microinjections of bicuculline induced a prolonged state of wakefulness and blocked the effect of subsequent injections of muscimol. These data suggest that endogenous GABA acts on GABA(A) receptors within the vlPAG and dMRF to promote AS in the guinea pig. 相似文献
75.
Lisovsky M Patel K Cymes K Chase D Bhuiya T Morgenstern N 《Archives of pathology & laboratory medicine》2007,131(8):1304-1311
Anal gland carcinoma (AGC) is a rare perianal invasive cancer composed of tubular glands lined by cuboidal epithelium. The clinical features and histogenesis of AGC are not well understood and its origin from anal glands is often difficult to prove. Little is known about immunophenotypic features of AGC that could be useful in establishing the diagnosis. This study evaluated the immunohistochemical profile of 2 cases of AGC in comparison to anal glands from 11 hemorrhoidectomy specimens. Sections from the specimens were routinely processed and immunostained using commercial antibodies to cytokeratin (CK) 7, CK20, CK5/ 6, p63, CDX2, smooth muscle actin, calponin, heavy chain smooth muscle myosin, p53, and p16. In case 1 of AGC, radiation and chemotherapy preceded an abdominoperineal resection. In biopsies from this case, the neoplastic anal glands had a tubular pattern, whereas most glands in the resection specimen exhibited mucinous features. The histologic pattern in case 2 was tubular. Normal anal glands showed immunoreactivity for myoepithelial and basal cell markers CK5/6 and p63 in basal and parabasal cell layers and for CK7 in superficial cell layers. In contrast, both cases of AGC were negative for CK5/6 and p63 and were diffusely positive for CK7. Normal glands and both cases of AGC were negative for the intestinal differentiation marker CDX2, CK20, smooth muscle actin, calponin, smooth muscle myosin heavy chain, p16, and p53. Our data suggest that loss of p63 and CK5/6 expression is a feature of AGC. Anal gland carcinoma shares negativity for CDX2 and CK7+/CK20- profile with normal anal glands. No evidence of myoepithelial cells was found in normal or malignant anal glands. These data may be useful in establishing the diagnosis of AGC. 相似文献
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77.
Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist,in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations,prolactin levels,mammary histopathology findings and toxicokinetics 下载免费PDF全文
Eric J. de Waal Maria Desmidt Sven Korte Marc Niehoff Kevan Chase Wayne Arrowsmith Ann Lampo 《Journal of applied toxicology : JAT》2014,34(9):974-992
JNJ‐37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague–Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ‐37822681 in terms of extrapyramidal (EPS)‐like clinical signs and prolactin‐mediated tissue changes in the mammary gland. Monkeys showed severe EPS‐like clinical signs such as abnormal posture, abnormal eye movements and hallucination‐like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ‐37822681‐induced EPS‐like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin‐related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ‐37822681. The monkey toxicology studies did not provide an exposure‐based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ‐37822681‐associated adverse events in humans than the Sprague–Dawley rat. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
78.
Microtubule reassembly in surface-activated platelets 总被引:2,自引:0,他引:2
It is generally accepted that a circumferential microtubule supports the discoid shape of resting platelets. The fate of the many-coiled polymer following platelet activation, however, has been a subject of considerable debate. Morphological investigations have suggested that the circumferential coils are constricted into tight rings around centrally concentrated organelles during platelet shape change. Biochemical studies employing colchicine-binding assays, on the other hand, have indicated that the bundle of microtubules dissolves almost completely within seconds after activation and reassembles in a new location one to four minutes later. The present study has accepted the latter hypothesis in order to examine the second part of the disassembly-reassembly theory proposed in biochemical studies. Platelets exposed to low temperatures sufficient to remove all microtubules were placed on glass slides and microscope grids to cause surface activation during rewarming. The combined stimuli of rewarming and surface activation might have been expected to cause more rapid assembly than warming alone or activation alone. This was not the case. Reassembly of microtubules during rewarming and simultaneous surface activation was not accelerated. In contrast to the constriction of microtubule rings observed during activation in control platelets, the diameters of coils that developed in chilled platelets one to two hours after rewarming and surface activation were twice those of control cells. 相似文献
79.
Putative receptor binding sites on alphaviruses as visualized by cryoelectron microscopy. 总被引:6,自引:0,他引:6 下载免费PDF全文
T J Smith R H Cheng N H Olson P Peterson E Chase R J Kuhn T S Baker 《Proceedings of the National Academy of Sciences of the United States of America》1995,92(23):10648-10652
The structures of Sindbis virus and Ross River virus complexed with Fab fragments from monoclonal antibodies have been determined from cryoelectron micrographs. Both antibodies chosen for this study bind to regions of the virions that have been implicated in cell-receptor recognition and recognize epitopes on the E2 glycoprotein. The two structures show that the Fab fragments bind to the outermost tip of the trimeric envelope spike protein. Hence, the same region of both the Sindbis virus and Ross River virus envelope spike is composed of E2 and is involved in recognition of the cellular receptor. 相似文献
80.
Platelet activation by fMLP-stimulated polymorphonuclear leukocytes: the activity of cathepsin G is not prevented by antiproteinases 总被引:2,自引:0,他引:2
Human polymorphonuclear leukocytes (PMN) activated by fMLP (in the presence of CaCl2, fibrinogen, and cytochalasin B) were able to induce aggregation, cytoplasmic Ca2+ increase, and thromboxane A2 production in coincubated autologousplatelets. Cell-free supernatants prepared from n-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN were able also to induce platelet activation. Antibodies against cathepsin G and different serin protease inhibitors completely suppressed the activity of PMN-derived supernatants, indicating that cathepsin G is the major platelet activator released by PMN in our system. However, antiproteinases only partially affected platelet activation induced by PMN in mixed cell suspensions. Superoxide dismutase and catalase added to the cell suspension did not affect platelet activation nor potentiated serin protease inhibitors, making a role for short-lived oxygen radicals in our experimental system unlikely. Electron microscopic observation of stirred mixed cell suspensions preincubated for 2 minutes at 37 degrees C before stimulation showed a close PMN- platelets contact without any morphologic or biochemical event suggesting platelet activation. Preincubation of the cells without stirring to minimize PMN-platelet interaction before stimulation did not modify subsequent aggregation and platelet cytoplasmic Ca2+ increase in control samples. However, in this condition trypsin inhibitor from soybean completely prevented PMN-induced platelet activation. In samples preincubated without stirring in the presence of the antiproteinase, activated PMN stuck together but platelets preserved their discoid shape and did not appear significantly activated. We propose that membrane-to-membrane contact could create a microenvironment in which cathepsin G, discharged from stimulated PMN on adherent platelets, is protected from antiproteinases. 相似文献