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71.
Jobe O Lumsden J Mueller AK Williams J Silva-Rivera H Kappe SH Schwenk RJ Matuschewski K Krzych U 《The Journal of infectious diseases》2007,196(4):599-607
At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate. 相似文献
72.
Janion M Ciuraszkiewicz K Sielski J Grabowska U Gawor Z 《Echocardiography (Mount Kisco, N.Y.)》2007,24(10):1029-1034
BACKGROUND: Postinfarction intraventricular conduction defects lead to asynchronous activation of the myocardium.Hypothesis: The aim of the current study is to evaluate contraction asynchrony in postinfarction patients with intraventricular conduction defects. METHODS: A total of 158 patients 6 months postmyocardial infarction and 15 healthy subjects underwent echocardiography to evaluate atrioventricular, interventricular, intraventricular asynchrony, and myocardial performance index (MPI). A subgroup of 126 patients had intraventricular conduction defects in ECG, whereas 32 with normal QRS complex served as controls. RESULTS: All patients postmyocardial infarction showed intraventricular asynchrony and markedly higher MPI. Comparing groups with and without intraventricular conduction defects postmyocardial infarction, those with left bundle branch block (BBB) had significantly higher parameters of all asynchrony types; those with right BBB and left posterior hemiblock (LPH) had significantly higher interventricular asynchrony parameters; those with left anterior hemiblock did not show significant differences in asynchrony parameters as compared with subjects without postinfarction conduction defects. CONCLUSIONS: (1) Patients 6 months postmyocardial infarction show intraventricular asynchrony and markedly higher MPI. (2) Postinfarction patients with LBBB have the highest parameters of atrioventricular, interventricular and intraventricular asynchrony as compared with postinfarction patients with other and without conduction defects. (3) In postinfarction patients with RBBB or LPH parameters of interventricular asynchrony are significantly higher as compared with postinfarction patients without intraventricular conduction defects. 相似文献
73.
Rong-Hua Tao Li Bai Zuzana Berkova Jillian Wise Rezaeian Hossein Urszula Daniluk Xue Ao Felipe Samaniego 《Clinical Lymphoma, Myeloma & Leukemia》2011
Presence of potential inhibitors of Fas could block Fas signaling and explain cancer cells resistance to apoptosis. In this study, we found that PMLRARα binds to Fas and blocks Fas-mediated apoptosis through recruiting c-FLIP in APL. Targeting tissue-specific inhibitors of Fas such as PMLRARα would improve cancer therapy. 相似文献
Full Abstract
Fas plays a critical role in cell proliferation and in the selective killing of autoreactive lymphocytes and abnormal cells, including infected cells. To explain the common expression of Fas and the resistance to the Fas-induced apoptosis observed in some normal and cancer cells, we have screened cells for potential regulators of the Fas death receptor. By using mass spectrometry analysis of Fas-associated proteins, we identified peptides derived from promyelocytic leukemia (PML).PML enhances74.
Lee KP Piskurewicz U Turecková V Strnad M Lopez-Molina L 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(44):19108-19113
Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In Arabidopsis and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a "seed coat bedding" assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant aba seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene RGL2, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy. 相似文献
75.
76.
Jokihaara J Pörsti IH Kööbi P Jolma PM Mustonen JT Saha HH Sievänen H Kannus P Iwaniec UT Turner RT Järvinen TL 《Kidney international》2008,74(3):319-327
We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increased compared to rats with a uninephroctomy and none of these parameters was affected by pamidronate treatment. In the femoral midshaft, chronic renal disease reduced cortical bone mineral density and content. No difference was observed in the breaking load of the femoral midshaft. In the distal femur, a high-turnover renal osteodystrophy was found but pamidronate suppressed this bone turnover and increased bone mineral content. Treatment had no effect on chronic disease-induced augmentation of osteoid volume or fibroblast surface. These studies show that in this model of stage 3 renal disease, pamidronate increased mineral content in the femoral midshaft and distal metaphysis primarily by adding bone to endocortical and trabecular surfaces but did not reduce osteitis fibrosa. 相似文献
77.
Fichera A Little N Jagadeeswaran S Dougherty U Sehdev A Mustafi R Cerda S Yuan W Khare S Tretiakova M Gong C Tallerico M Cohen G Joseph L Hart J Turner JR Bissonnette M 《Cancer research》2007,67(2):827-835
Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2+/-1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6+/-2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2+/-4.0%; <0.005). Azoxymethane significantly induced pro-transforming growth factor-alpha (6.4+/-1.3-fold) and increased phospho-(active) EGFR (5.9+/-1.1-fold), phospho-(active) ErbB2 (2.3+/-0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3+/-0.4-fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by >75% (P<0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P<0.05). Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies. 相似文献
78.
Tufail M Siegel DS McBride L Bilotti E Bello E Anand P Olivo K Bendarz U McNeill A Vesole DH 《Clinical Lymphoma, Myeloma & Leukemia》2012,12(3):186-190
IntroductionOver the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity.Patients and MethodsTwenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy.ResultsThe median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity.ConclusionWe conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone. 相似文献
79.
Rydzanicz M Cywińska K Wróbel M Pollak A Gawęcki W Wojsyk-Banaszak I Lechowicz U Mueller-Malesińska M Ołdak M Płoski R Skarżyński H Szyfter K Szyfter W 《Molecular genetics and metabolism》2011,104(1-2):153-159
Mutations in mitochondrial DNA have been implicated in both, non-syndromic and aminoglycoside-induced hearing loss. In the present study, we have performed the systematic mutation screening of the COI/tRNA(Ser(UCN)) genes in 250 unrelated Polish subjects with hearing impairment. Three different homoplasmic sequence variants were identified, including one common polymorphism m.7476 C>T in tRNA(Ser(UCN)) and two mutations, m.7444 G>A and m.7445 A>G localized in the COI/precursor of tRNA(Ser(UCN)). The incidence of m.7444 G>A substitution was estimated at 1.6% (4/250), however variable penetrance of hearing loss, age of onset and hearing thresholds among m.7444 G>A carriers was observed. Two subjects had the positive history of aminoglycoside exposure and one of them harbored both m.7444 G>A and 12S rRNA m.1555 A>G mutations. Those suggest that m.7444 G>A itself is not sufficient to produce a clinical phenotype and additional modifier factors are required for pathogenic manifestation of m.7444 G>A substitution. Moreover, we have described the first Polish family with non-syndromic hearing loss, harboring m.7445 A>G mutation. The penetrance of hearing loss in this pedigree was 58% when aminoglycoside-induced hearing impairment was included, and 8% when ototoxic effect was excluded. This finding strongly suggests the possible role of m.7445 A>G in susceptibility to aminoglycoside induced-hearing loss. 相似文献
80.
Nowak A Pachocka L Targosz U Kłosiewicz-Latoszek L 《Roczniki Państwowego Zak?adu Higieny》2007,58(1):301-305
Increased calcium intake has been associated with lower body weight, BMI and adiposity, mostly in children, youth and women. In men results are inconclusive. In this study the relation between calcium intake and body weight and body fat in obese men was investigated. 200 men, the mean age 45.1 +/- 9.4 y, the mean BMI 33.2 +/- 4.8 kg/m2, were divided into 4 groups on the basis of their calcium/protein index. No significant differences in body weight, BMI, fat mass, percentage of body fat were found across subgroups and no significant correlations between calcium intake and body variables were stated. This study did not confirm the association between calcium intake and body weight and adiposity in men. 相似文献