Добірка наукової літератури з теми "371.195 0944"

Abstract Abstract 1346 Acquired resistance to the proteasome inhibitor (PI) bortezomib (BTZ) is an emerging factor limiting its efficacy in the treatment of hematologic malignancies. The clinical impact of acquired resistance has been shown in Multiple Myeloma (MM) patients who were re-treated with BTZ. Although BTZ-retreatment was found to be effective, the response rate as well as the duration of response were less as compared to initial treatment, indicating the development of BTZ-resistance in a subgroup of patients. In line with that, we previously found increased expression of constitutive proteasome (cP) subunit ß5 harbouring a mutation in the BTZ-binding pocket and a decreased expression of non-mutated immunoproteasome subunits in BTZ-resistant cell lines of hematologic malignancies (Franke and Niewerth et al, Leukemia 2012). We here explore whether upregulation of immunoproteasome (iP) expression could restore sensitivity in BTZ-resistant leukemia cells towards BTZ and two epxoyketone-based irreversible PIs; carfilzomib (CFZ) and the ß5i-targeted ONX 0914. BTZ-resistant cell lines were of multiple myeloma (8226), T-cell (CEM) and myelomonocytic (THP1) origin and displayed resistance towards cell growth inhibition in the presence of 7–200 nM BTZ. Induction of iP in wild type (WT) and BTZ-resistant 8226, CCRF-CEM and THP1 cells was achieved by exposure to 100U/ml Interferon- γ (IFN-γ) for 6–72 h. IFN-γ transiently increased (maximum between 24–48 hours) mRNA levels of β5i, β1i, and β2i up to 8-fold, 30-fold and 4-fold, respectively. These findings were corroborated at the β5i, β1i and β2i protein expression level using Western blot analysis. Following IFN-γ exposure, chymotrypsin-like proteasome activity increased up to 2.5-fold compared to unstimulated controls, trypsin-like activity increased up to 1.5-fold, whereas caspase-like activity was slightly decreased. Consistent with increased proteasome activity, there was also an increased expression of cell surface HLA Class I molecules. The impact of IFN-γ induced upregulation of iPs on the sensitivity to the PI BTZ, CFZ, and ONX 0914, defined by the decrease in IC50, is summarized in Table 1. 8226/BTZ100 cells became 4-fold more sensitive towards BTZ after IFN-γ exposure, whereas THP1/BTZ200 and CEM/BTZ200 cells displayed nearly 2-fold increased sensitivity. For CFZ, a modest level of sensitization was observed in all cell lines with high level BTZ resistance. Interestingly, for the immunoproteasome inhibitor ONX 0914, IC50 values were markedly decreased (7-fold for 8226/BTZ100 and 3-fold for THP1/BTZ200 and CEM/BTZ200 cells). Additionally, in 8226 cells with low levels of BTZ resistance (8226/BTZ7), IFN-γ restored parental cell sensitivity to ONX 0914. Restoration of PI sensitivity after IFN-γ exposure was further confirmed by activation of PARP cleavage and accumulation of ubiquitinated proteins, pointing to restoration of BTZ activity under proteasome inhibition and consequent induction of apoptosis. Finally, to provide evidence that upregulation of β5i and or β1i by IFN-γ was responsible for the observed sensitization, siRNA downregulation of β5i and β1i was applied prior to exposure to IFN-γ. Under these conditions, mRNA levels and proteasome activity of β5i remained suppressed, even after exposure to IFN-γ. Moreover, after β5i silencing, PI sensitization and apoptosis were attenuated. Silencing of β1i expression had no effect on PI-sensitization. In conclusion, down-regulation of β5i subunit expression is a major determinant of BTZ-resistance and increasing its proteasomal assembly after IFN-γ exposure facilitates restoration of sensitivity in BTZ-resistant leukemia cells towards cP inhibitors and in particular iP inhibitors. Table 1. IC50 values of PIs ± IFN-γ pre-incubation (48 hr) of wild type and BTZ-resistant hematologic cell lines Cell lines BTZ BTZ + IFNy SF ONX 0914 ONX 0914 + IFNy SF CFZ CFZ + IFNy SF 8226/wt 2.6 1.8 1.4 54 46 1.5 0.4 0.4 1 8226/BTZ7 13.5 5.8 2.3 99 47 2.1 0.9 0.8 1.1 8226/BTZ100 208 57 3.6 1837 249 7.4 28 13 2.2 CEM/wt 4.1 3.9 1.1 75 65 1.2 0.4 0.3 1.3 CEM/BTZ200 416 223 1.9 1763 566 3.1 42 26 1.6 THP1/wt 6.2 5.1 1.2 52 19 2.7 0.9 1.3 0.7 THP1/BTZ200 641 347 1.8 4236 1376 3.1 49 34 1.4 50% inhibitory concentration compared to untreated controls (IC50 nM) as determined in a 4 days growth inhibition assay (MTT). Results depicted are means of at least 3 separate experiments. SF: sensitization factor: IC50 control/IC50 with IFN-g. Disclosures: No relevant conflicts of interest to declare.

ABSTRACT Observational studies of collimation in jets in active galactic nuclei (AGN) are a key to understanding their formation and acceleration processes. We have performed an automated search for jet shape transitions in a sample of 367 AGN using VLBA data at 15 and 1.4 GHz. This search has found 10 out of 29 nearby jets at redshifts z < 0.07 with a transition from a parabolic to conical shape, while the full analysed sample is dominated by distant AGN with a typical z ≈ 1. The ten AGN are UGC 00773, NGC 1052, 3C 111, 3C 120, TXS 0815−094, Mrk 180, PKS 1514+00, NGC 6251, 3C 371, and BL Lac. We conclude that the geometry transition may be a common effect in AGN jets. It can be observed only when sufficient linear resolution is obtained. Supplementing these results with previously reported shape breaks in the nearby AGN 1H 0323+342 and M87, we estimate that the break occurs at 105–106 gravitational radii from the nucleus. We suggest that the jet shape transition happens when the bulk plasma kinetic energy flux becomes equal to the Poynting energy flux, while the ambient medium pressure is assumed to be governed by Bondi accretion. In general, the break point may not coincide with the Bondi radius. The observational data support our model predictions on the jet acceleration and properties of the break point.

Zusammenfassung. Wir untersuchten die Wirkung eines gesundheitsorientierten Krafttrainings auf verschiedene Aspekte des psychischen Wohlbefindens für einen Zeitraum von 3 (t1) und 6 Monaten (t2). N = 531 Teilnehmer führten 6 Mal monatlich ein präventives (PKT, n = 317) oder medizinisches gesundheitsorientiertes Krafttraining (MKT, n = 109) durch oder gehörten einer Warte-Kontrollgruppe (KG, n = 105) an. Nach 6 Monaten zeigten sich Verbesserungen des Körperbildes. Für beide Trainingsformen verbesserte sich die vitale Körperdynamik (PKT: d = 0.59, MKT: d = 0.40), die ablehnende Körperbewertung reduzierte sich (PKT: d = –0.44, MKT: d = –0.32). Für Selbstwirksamkeitserwartung und Lebenszufriedenheit fanden wir anhand von Strukturgleichungsmodellen und Pfadanalysen indirekte Wirkmechanismen: Das durch gesundheitsorientiertes Krafttraining verbesserte Körperbild fördert eine Zunahme der Selbstwirksamkeitserwartung, die wiederum eine höhere Lebenszufriedenheit begünstigt (χ2 = 3.35, p = .501, df = 4, NFI = .98, CFI = 1.00, RMSEA = .00). Die Ergebnisse werden im Hinblick auf das Zusammenspiel der zugrunde liegenden körperlichen und psychischen Wirkmechanismen untersucht.

During August 2012, vertical oozing cankers were sporadically observed on trunks and branches of walnut trees (Juglans regia) in the city of Zánka, near Lake Balaton and other parts of Hungary including Budapest, Győr, and Tatabánya cities. Cankers were observed on trunks and branches where brownish-black exudates staining the bark appeared mainly in the summer. Isolations were performed primarily from exudates but also from infected tissues using King's medium B (KB) (3) and EMB medium (2). Colonies similar in appearance to Brenneria nigrifluens (syn.: Erwinia nigrifluens) (1,5) were isolated. The bacterium, first reported in California, was also recorded in Iran, Spain, France, and several Italian locations, on walnut trees. The bacterial strain was gram negative and did not induce a hypersensitive response on tobacco (Nicotiana tabacum L. ‘White Burley’) leaves. The bacterium grew at 26°C. Colonies on KB were white and non-fluorescent, but on EMB medium were a typical dark purple with metallic green sheen. The results of substrate utilization profiling using the API 20E kit (Biomérieux, Marcy l'Etoile, France) showed that the bacterium belonged to the Enterobacteriaceae. The strain was positive for citrate utilization, H2S, and acetoin production and urease, glucose, inositol, saccharose, and arabinose reactions. Pathogenicity was tested by injecting five young healthy walnut branches on two separate 2-year-old grafted potted plants with a bacterial suspension containing 107 CFU/ml. Negative controls were walnut branches injected with sterile distilled water. Branches were enclosed in plastic bags and incubated in a greenhouse under 80% shade at 26°C day and 17°C night temperatures. Three months after inoculation, necrotic lesions were observed in the inner bark and dark lines were observed in internal wood, but no external cankers were observed on inoculated branches. The negative control appeared normal. B. nigrifluens was re-isolated from lesions on inoculated branches and identified as described above; thus, Koch's postulates were fulfilled. For molecular identification of the pathogen, 16S rDNA amplification was performed using genomic DNA from strain Bn-WalnutZa-Hun1 with a universal bacterial primer set (63f and 1389r) (4). The PCR products were cloned into a pGEM T-Easy vector (Promega, Madison, WI) and transformed into Escherichia coli DH5α cells. A recombinant plasmid (2A2.5) was sequenced using M13 forward and reverse primers. The sequence was deposited in NCBI GenBank (Accession No. HF936707) and showed 99% sequence identity with a number of B. nigrifluens strains, including type strains Z96095.1, AJ233415.1, JX484740.1, JX484739.1, JX484738.1, and FJ611884.1. On the basis of the symptoms, colony morphology, biochemical tests, and 16S rDNA sequence identity, the pathogen was identified as Brenneria nigrifluens. To our knowledge, this is the first report of a natural outbreak of bacterial bark canker on walnut in Hungary and the presence of the pathogen may seriously influence in local orchards and garden production in the future. References: (1) L. Hauben et al. Appl Microbiol 21:384, 1998. (2) J. E. Holt-Harris and O. Teague. J. Infect. Dis. 18:596, 1916. (3) E. O. King et al. J. Lab. Clin. Med. 44:301, 1954. (4) A. M. Osborn et al. Environ. Microbiol. 2:39, 2000. (5) E. E. Wilson et al. Phytopathology 47:669, 1957.

Stroke outcomes among young adults in Uganda are unclear. This study therefore determined the clinical characteristics and 30-day outcome among young adults with an acute stroke. In a prospective observational cohort study, 61 young adults with confirmed stroke were followed up for 30 days. Socio-demographic and clinical characteristics were collected using a study questionnaire. Kaplan–Meier curves, and modified Poisson regression were performed for factors associated with the 30-day mortality outcome. A third of the screened stroke survivors, (61/195) were young adults aged between 18 and 50 years. About two-thirds were male. More than half were diagnosed with ischaemic strokes while 42.6% had a haemorrhagic stroke. Nearly half (29/61) were known hypertensives, 43% (26/61) had a history of alcohol consumption with 95% classified as dependent on CAGE assessment. Ten percent had a prior smoking history while 29% of the female gender had a prior history of oral contraception use. Twenty-three percent (14/61) of the young stroke patients died within 30 days of stroke onset (95% CI: 0.01, 0. 901). A history of smoking (adjusted prevalence ratio: aPR;5. 094, 95% CI: 3.712, 6. 990) and stroke severity National Institutes of Health Stroke score (NIHSS) >16; Prevalence ratio (PR) -3. 301, 95%CI: 1. 395, 7. 808) and not drinking alcohol (aPR (adjusted prevalence ratio) -7. 247, 95% CI: 4. 491, 11.696) were associated with 30- day mortality. A third of all stroke survivors were young adults. About 23. 3% died within 30 days of stroke onset. Stroke severity and a history of smoking were associated with mortality. Identifying high risk patients and early outpatient follow up may help reduce the 30-day mortality in our settings.

AbstractBackgroundGaucher disease (GD), caused by a deficiency in acid β-glucosidase, leads to the accumulation of glucosylsphingosine (GluSph), which has been used as a powerful biomarker for the diagnosis and follow-up of GD. Our aim was to perform the first retrospective study of GluSph in Spanish patients, analyzing its relationship with classical biomarkers and other parameters of disease and its utility regarding treatment monitoring.MethodsClassical biomarkers were evaluated retrospectively by standard methods in a total of 145 subjects, including 47 GD patients, carriers, healthy controls and patients suffering from other lysosomal lipidoses. GluSph was also measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed as part of the present study.ResultsThe optimized method presented intra- and inter-assay variations of 3.1 and 11.5%, respectively, overall recovery higher than 96% and linearity up to plasma concentrations of 1000 ng/mL with 100% specificity and sensitivity. Only GD patients displayed GluSph levels above 5.4 ng/mL at diagnosis and this was significantly correlated with the classical biomarkers chitotriosidase (r = 0.560) and the chemokine CCL18/PARC (CCL18/PARC) (ρ = 0.515), as well as with the Spanish magnetic resonance imaging index (S-MRI, r = 0.364), whereas chitotriosidase correlated with liver volume (r = 0.372) and CCL18/PARC increased in patients with bone manifestations (p = 0.005). GluSph levels decreased with treatment in naïve patients.ConclusionsPlasma GluSph is the most disease-specific biomarker for GD with demonstrated diagnostic value and responsiveness to therapy. GluSph in the present series of patients failed to demonstrate better correlations with clinical characteristics at onset than classical biomarkers.

BackgroundPsoriatic arthritis (PsA) is a heterogenous disease that can present with various musculokeletal manifestations. Several studies have assessed the rate of sacroileitis in PsA population, however data on the involvement of other pelvic structures that may cause symptoms, such as major entheseal or hip involvevement, and progression rates during follow-up is scarce.ObjectivesThis study aimed to understand overall pelvis radiography findings and progression rates during follow-up in a cohort of patients with PsA under biologic treatment.MethodsPsA patients from the Hacettepe University biological database (HUR-BIO), were retreospectively analyzed for their pelvis radiographs. All radiographs for individual patient were consecutively scored. Modified New York (mNY) criteria was used to assess sacroileitis and ischium/ iliac wing/ greater-lesser trochanteric enthesopathy and symphysis pubis osteitis assessments were done using a grade 0, no changes, 1, minimal changes and grade 2 and more counted as significant changes (1). Hip involvement was scored using BASRI-hip score and data on prosthesis were noted (2). All of the assessments were done by an experienced rheumatologis (UK) and in cases with suspicion, another experienced rheumatologist reviewed the cases (LK) and a consensus was reached.ResultsOverall 273 patients (69.6% of females) with the mean (SD) age at the time of first radiography 43.3 (12) years were included. At their initial radiographic assessment, the median (IQR) PsA duration was 2 (7) years. Baseline radiographs showed 10 (%3.7) of the patients had transitional vertebra and 137 (50.2%) patients had sacroiletis according to mNY criteria. From patients without sacroileitis (n=136), 67 patients had following radiographs. After a mean (SD) 47.1 (37) months, 16 (23.8%) of them progressed to sacroiletitis according to mNY criteria. Regarding the major enthesopathies, Regarding significant changes, 26.8 % of the patients had ischium enthesopathy, 19.3% of the patients ad symphysis pubis involvement and 13.2% of the patients had iliac wing enthesopathy. Trochantor major enthesopathy rates were 2.4% and 1.4 % at right and left sites respectively. Only one patient had trochanter minor enthesitis on the left site (Table 1). Prosthesis requirement was observed in 4 hip joints and 4 hip joints had prosthesis. There was no correlation between meeting mNY criteria and having iliac, ischium, and pubis involvement ≥ 2. On the other hand, patients with when there is ischium enthesopathy ≥2 (17/46 (36.9%) vs 18/96 (18.7%), p=0.013) or iliac wing enthesopathy ≥2 above (10/18 (55.5%) vs. 26/129 (20.1%), p=0.001), any syndesmophyte in the spine is more commonly seen.Table 1.Distribution of major entheseal involvement and BASRI-hip socres and progression ratesLocationGradesFirst assessmentN (%)Progression rate*Ischium (n=164)409/65 (13.8)311 (6.7)233 (20.1)174 (45.1)046 (28)Symphysis Pubis408/78 (10.2)(n=191)35 (2.6)232(16.8)160 (31.4)094 (49.2)Iliac wing403/72 (4.1)(n=174)39 (5.2)214 (8.0)128 (16.1)0124 (71.3)BASRI score43 (1.4)0(right)32 (0.9)(n=220)21 (0.5)100214 (97.3)BASRI score400(left)34 (1.8)(n=219)22 (0.9)100213 (97.3)*Defined as one unit increase in the gradeConclusionHalf of the patients with PsA requiring advanced treatment modalities, had sacroileitis in a median 2 years of disease duration and the rest may progress to sacroileitis during the follow-up period. Major enthesopathy involvement was also seen in more than half of the patients. Ischium, iliac wing enthesopathies and spinal syndesmophytes may be all a part of the osteoproliferative process. Further assessment is needed to correlate those radiographic changes to clinical symptoms.References[1]van der Linden S, et al. Arthritis Rheum. 1984 Apr;27(4):361-8.[2]Calin A, et al. J Rheumatol 1999;26:988-92Disclosure of InterestsNone declared

Leipotylenchus abulbosus (Thorne, 1949) Sher, 1974 belongs to the family Tylenchidae, subfamily Leipotylenchinae, and order Tylenchida. During the spring and autumn months of 2008 to 2010, 80 samples were collected from rhizosphere soil of symptomatic plants including wheat (Tritichum aestivum L.), beet (Beta vulgaris L.), and maize (Zea mays L.) from Meighan and Gavar regions of Markazi Province in central Iran. Plants were dwarfed and leaves were chlorotic. Diseased plants comprised ~7% of all plants in the field. Sandy loam soil was collected from roots up to 15 cm from the base of the plants. Nematodes were extracted from the soil by sieving and centrifugation (3). For species identification, nematodes were transferred to anhydrous glycerin (2) and mounted on slides by the paraffin ring method. Identification was based on morphometric and morphological characteristics of females and males. No other forms of the nematode were isolated from collected samples. L. abulbosus was found in 10% of the collected samples. The nematodes showed typical characteristics of the genus Leipotylenchus: striated and anteriorly flattened lip region, stylet without basal knobs, didelphic gonads, four incisures in lateral fields that were areolated in the posterior portion, presence of deirids and adanal caudal alae, amphid inconspicuous in males. Males contained bursa in tail. Females contained an almost straight body, tapering anteriorly from median bulb and posteriorly beyond the anus; cuticle thick, annules fine. Labial framework was moderately sclerotized. Median bulb with prominent valvular apparatus in the center, oval, occupied two-thirds of the body. Deirids were prominent and at the level of the excretory pore. Vagina a transverse slit at right angles to body axis, extending less than half width into body. Tai1 finely annulated, short, tapering to a narrow tip but becoming broader just before the terminus. Phasmids small in anterior half of the tail. Measurements of 12 females: body length = 1,377 ± 90 (1,276 to 1,469) μm; a = 39.2 ± 1.62 (36.8 to 41.1); b = 7.2 ± 0.34 (6.6 to 8.30); c = 11.1 ± 0.16 (10.7 to 11.3); V% = 52.6 ± 1.42 (50.4 to 53.8); stylet length = 17 ± 0.22 (16.6 to 18) μm; tail length = 124 ± 6.83 (116 to 137) μm); and 7 males: (body length = 1,150 ± 56.84 (1,090 to 1,246) μm; a = 39.5 ± 1.48 (37.5 to 41.5); b = 6.4 ± 0.21 (6.1 to 6.8); c = 9.5 ± 0.06 (9.4 to 9.6); T% = 55.1 ± 0.91 (54.4 to 56.20); stylet length = 17.6 ± 0.36 (17 to 18) μm; tail length = 120 ± 3.77 (115 to 129) μm) conformed to the description of L. abulbosus. L. abulbosus, originally isolated from crop plants in surveyed regions, was cultured on beet (B. vulgaris L.) in the greenhouse. Pure cultures of the nematode were inoculated on beet seedlings at the 4- to 6-leaf stage as described previously (1). Sterilized soils were inoculated with 1,000 infective mature nematodes with three replications. Infection of beet roots by the nematode resulted in leaf chlorosis and reduction in plant height. Previously, L. amiri was collected from soils associated with the roots of onion (Allium cepa L.) plants in Pakistan (4). However there have not been any reports of L. abulbosus in crop plants before. To our knowledge, this is also the first report of L. abulbosus infecting wheat, beet, and maize plants in Iran. References: (1) K. R. Barker. Methodology 2:19, 1985. (2) A. De Grisse. Meded. Rijksfac. Landbouwwet. Gent. 34:351, 1969. (3) W. R. Jenkins. Plant Dis. Rep. 48:692, 1964. (4) M. A. Maqbool and F. Shahina. Rev. Nèmatol. 7:363, 1984.