Műszerügyi és Méréstechnikai Közlemények

UNIDO Workshop a Műszerügyi és Méréstechnikai Szolgálatnál Újszerű lehetőségek a Kutatófilm és Videotechnikai Főosztályon Műszerkölcsönzés Császár László: Üzemeltetési és szerviztapasztalataink (3.) A GOULD gyártmányú digitális oszcilloszkópok Új irányok a műszer- és méréstechnikában Radnai Rudolf: Gyakorlati tanácsok számítógépes mérőrendszerek üzembehelyezéséhez és üzemeltetéséhez Kőfalvi Jenő: Mikrovezetékes analitika az integrált áramkörök mintájára Szaktanácsadás Kőfalvi Jenő: Válogatás az Országos Műszernyilvántartás nagyértékű műszerújdonságaiból Külföldi műszerújdonságok. Összeállította: Csont Tamás - Fekete Gábor - Kőfalvi Jenő Könyvismertetés. Összeállította: Radnai Rudolf - Kőfalvi Jenő Műszerkölcsönzés Görgényi László: A kölcsönműszerpark szaporulata Szolgálatunk életébő

Overview mutations found and immunohistochemistry.

<p>Ex, exon; ND, not done; NA, not available; mutations indicated in bold, other samples wild type unless indicated otherwise; DG, dysgerminoma; GB, gonadoblastoma; CIS, carcinoma in situ; TE, teratoma (im: immature); YST yolk sac tumor; itSE, intratubular seminoma;</p><p>seq, sequence; LC, LightCycler; c-KIT LC, LightCycler melting curve results; case numbers in bold are bilateral cases.</p>§<p>tumor/precursor percentage below 50%.</p>‡<p>as determined by FISH on gonadal tissue.</p><p>I789I: heterozygous synonymous SNP, rs.5578615.</p><p>P567P: homozygous synonymous SNP, rs.1873778.</p

MEK and PI3K/AKT pathway inhibitors enhance the steroid response of primary T-ALL patient samples.

<p>MEK and PI3K/AKT pathway inhibitors enhance the steroid response of primary T-ALL patient samples.</p

Whole genome and targeted exome sequencing results for pediatric T-ALL patients at diagnosis.

<p>(A and B) Visualization of chromosomal breakpoint junctions in diagnostic leukemia cells of ETP-ALL patient #10793. (A) Circos plot of somatic structural variations as detected in the diagnostic sample (Dx) along with SNV densities (1-Mb window) and predicted LOH data as explained in the accompanying legend. Interchromosomal junctions are displayed as red lines, and intrachromosomal junctions are displayed as grey lines. (B) Allele-specific copy number variations as determined by Affymetric SNP Array analysis and multiple WGS-predicted chromosomal breakpoints as a consequence of chromothripsis affecting Chromosomes 7 and 14 are displayed. In the copy number plots, black dots indicate the unsmoothed allele-specific copy numbers. Red dots are the smoothed maximal allele-specific copy numbers using a sliding window of 30 SNP probes, while the green dots reflect the smoothed minimal allele-specific copy numbers. Chromosomal breakpoint junctions are displayed for translocations (red arrows), inversions (blue arrows), deletions (green arrows), duplications (purple arrows), and complex rearrangements (grey arrows). Affected (in black) and flanking (in grey) genes for the interchromosomal translocations are indicated. (C) Overview of most deregulated cellular processes among 127 genes carrying mutations/aberrations in the diagnostic material of two or more patients in the expansion cohort of 69 T-ALL patients. The number of patients with each T-ALL subtype is indicated. The <i>p</i>-value for each process represents the significance level for enrichment of mutations/aberrations that affect this pathway in ETP-ALL patients compared to other T-ALL subtypes, and was calculated by two-sided Fisher’s exact test. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s013" target="_blank">S4 Table</a>. ETP-ALL, early thymic progenitor acute lymphoblastic leukemia; LOH, loss of heterozygosity; SNV, single nucleotide variant; T-ALL, T cell acute lymphoblastic leukemia.</p

Study overview.

<p>Discovery phase: Whole genome sequencing (WGS) followed by targeted exome sequencing (TES) and prioritization of high-confidence mutations in 13 paired diagnostic (Dx)–remission (Rem) T cell acute lymphoblastic leukemia (T-ALL) patient samples. Expansion phase: TES for 254 genes on diagnostic materials of 69 T-ALL patients. Integration phase: Integration of high-confidence TES mutation and array comparative genomic hybridization loss of heterozygosity (LOH) datasets and associations with clinical and biological data. Confirmation of findings was done using an extended cohort of 146 diagnostic T-ALL patient samples, including the 69 patients (pts) in the expansion phase and 77 additional patients. Validation phase: Functional modeling in T-ALL cell lines, determination of efficacy of targeted inhibitors to revert phenotype, and testing in primary T-ALL patient samples. COALL, Co-operative Study Group for Childhood Acute Lymphoblastic Leukemia; DCOG, Dutch Childhood Oncology Group.</p

Mutations/aberrations affecting the IL7R signaling pathway in pediatric T-ALL patients at diagnosis predict diminished steroid response and poor outcome.

<p>Mutations in (A and B) <i>JAK1</i> or (C) <i>KRAS</i> detected by TES in diagnostic samples from 69 T-ALL patients are associated with diminished steroid response and/or poor survival. IL7R signaling mutations in diagnostic samples from 146 T-ALL patients are associated with reduced (D) in vitro steroid sensitivity and (E) relapse-free survival. Patients harboring <i>NR3C1</i> deletion as a consequence of a chromosomal 5q deletion were excluded from these analyses. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s015" target="_blank">S6 Table</a>. ETP-ALL, early thymic progenitor acute lymphoblastic leukemia; T-ALL, T cell acute lymphoblastic leukemia; TES, targeted exome sequencing.</p

Activating IL7R signaling mutations can confer resistance to steroid treatment.

<p>(A–F) Steroid response curves (from triplicate experiments ± standard deviation) for SUPT1 cells that express (A) JAK1, (B) JAK1^R724H, (C) JAK1^T901A, (D) JAK3, (E) JAK3^M511I, or (F) JAK3^R657Q from doxycycline-inducible lentiviral expression constructs. Steroid response curves are shown for induced (+Dox) and non-induced (−Dox) cells that have been exposed to serial dilutions of prednisolone for 72 h. (G–I) Mean survival of SUPT1 cells (triplicate experiments ± standard deviation) expressing wild-type or mutant IL7R signaling molecules (+Dox: open red bars) following a 72-h exposure to (G) prednisolone (Pred), (H) vincristine (VCR), or (I) <i>L</i>-asparaginase (ASP). Black bars represent the mean survival of all SUPT1 lines under non-induced conditions following exposure to prednisolone, vincristine, or <i>L</i>-asparaginase (−Dox control). The steroid-sensitive panel refers to SUPT1 lines that retain a similarly sensitive steroid response following expression of IL7R, JAK1, JAK3, JAK3^M511I, JAK3^R657Q, or AKT^E17K compared to non-induced control conditions. The steroid-resistant panel refers to lines that acquire steroid resistance following expression of IL7R^RFCPH, JAK1^R724H, JAK1^T901A, NRAS, NRAS^G12D, or AKT. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s005" target="_blank">S5 Fig</a>.</p

Reversal of steroid resistance by IL7R signaling inhibitors.

<p>Activity status of IL7R signaling molecules by Western blot analysis in SUPT1 cells expressing (A) JAK1^T901A or (B) wild-type AKT that are exposed to ruxolitinib (2 μM), CI1040 (10 μM), MK2206 (2 μM), or the CI1040/MK2206 combination for 24 h compared to non-induced and doxycycline-induced controls. (C and D) SUPT1 or P12 Ichikawa (D, middle panel) T cell acute lymphoblastic leukemia cell response curves following 72-h exposure to serial dilutions of prednisolone (triplicate experiments ± standard deviation) without (−Dox, grey circles) or with (+Dox, open red circles) induction of (C) IL7R^RFCPH or (D) AKT. The effect of 2 μM ruxolitinib (left panels), 10 μM CI1040 (middle panels), and 2 μM MK2206 (right panels) on the steroid response under doxycycline-induced conditions are shown (open blue triangles). (E–I) Mean survival (triplicate experiments ± standard deviation) of SUPT1 lines expressing wild-type or mutant IL7R signaling molecules following 72-h treatment with prednisolone (250 μg/ml) in the absence (open red bars) or presence (open blue bars) of (E) ruxolitinib, (F) CI1040, (G) MK2206, (H) the combination of CI1040/MK2206, or (I) GSK3 inhibitor IX. Steroid-sensitive and -resistant panels are indicated. For each experiment, the mean survival for all non-induced (−Dox) SUPT1 lines that are exposed to prednisolone (red, grey-filled bar) or prednisolone plus inhibitor (blue, grey-filled bar) is shown as a control. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s008" target="_blank">S8 Fig</a>. Dox, doxycycline; inh., inhibitor; Pred, prednisolone; Rux, ruxolitinib.</p

Steroid resistance induced by wild-type or mutant IL7R signaling molecules is associated with activation of MEK-ERK and/or AKT.

<p>(A) Western blot results for total and/or phosphorylated levels of IL7R signaling molecules following doxycycline induction (+Dox) of wild-type or mutant forms of IL7R, JAK1, JAK3, NRAS, or AKT molecules in SUPT1 cells. The steroid-sensitive and -resistant panels are indicated. Cellular lysate of parental SUPT1 cells was used as a control. (B–G) β-actin-normalized protein concentrations for (B) NR3C1, (C) pMEK, (D) pERK, (E) pAKT, (F) pGSK3B, and (G) BCLXL in doxycycline-induced steroid-sensitive and -resistant SUPT1 lines. Significance levels were calculated using the Mann-Whitney <i>U</i> test. In (E), phospho-AKT levels are shown for all lines except for lines induced to express construct-driven AKT and AKT^E17K. (H) Schematic overview of crosstalk between the proapoptotic NR3C1 response following steroid exposure and activation of MEK-ERK and AKT pathways downstream of IL7R signaling mutations. Green vectors indicate molecules that drive a proapoptotic, steroid-sensitive response, whereas red vectors indicate molecules that drive an antiapoptotic, steroid-resistant response. See also <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002200#pmed.1002200.s007" target="_blank">S7 Fig</a>.</p