Future experiments are using silicon detectors in a high radiation environment and in high magnetic fields. The radiation tolerance of silicon improves by cooling it to temperatures below 180 K. At ...low temperatures the mobility increases, which leads to larger deflections of the charge carriers by the Lorentz force. A good knowledge of the Lorentz angle is needed for design and operation of silicon detectors. We present measurements of the Lorentz angle between 77 K and 300 K before and after irradiation with a primary beam of 21 MeV protons.
The CERN RD39 Collaboration studies the possibility to extend the detector lifetime in a hostile radiation environment by operating them at low temperatures. The outstanding illustration is the ...Lazarus effect, which showed a broad operational temperature range around 130 K for neutron irradiated silicon detectors.
This contribution summarizes an extensive simulation study of three different bias rail approaches for segmented strip and pixel sensors, comparing their charge collection efficiency and the maximum ...electric field in the bulk. Therefore a combined heavy ion and transient simulation was performed. By moving the interception point of the particle and integrating over the induced current at the pixel contacts and the backside, a spatial dependency of the charge collection efficiency (CCE) was obtained. The results show that a common p-stop configuration, where the bias rail is effectively shielded by the p+ implantation, leads to a constant CCE close to 100% along the sensor and the lowest maximal electric field in the bulk. The results have been utilized in the design process of a new macro-pixel prototype which is shown at the end of this contribution.
•TCAD simulations of bias rail approaches for segmented silicon sensors was performed.•A spatial dependency of the charge collection efficiency (CCE) was obtained.•Common p-stop configuration leads to a constant CCE close to 100%.•Common p-stop shows lowest maximum electric field in the bulk.
Abnormalities of the long arm of chromosome 1 (1q) represent the most frequent secondary chromosomal aberrations in Burkitt lymphoma (BL) and are observed almost exclusively in EBV-negative BL cell ...lines (BL-CLs). To verify chromosomal abnormalities, we cytogenetically investigated EBV-negative BL patient material, and to elucidate the 1q gain impact on gene expression, we performed qPCR with six 1q-resident genes and analyzed miRNA expression in BL-CLs. We observed 1q aberrations in the form of duplications, inverted duplications, isodicentric chromosome idic(1)(q10), and the accumulation of 1q12 breakpoints, and we assigned 1q21.2–q32 as a commonly gained region in EBV-negative BL patients. We detected MCL1, ARNT, MLLT11, PDBXIP1, and FCRL5, and 64 miRNAs, showing EBV- and 1q-gain-dependent dysregulation in BL-CLs. We observed MCL1, MLLT11, PDBXIP1, and 1q-resident miRNAs, hsa-miR-9, hsa-miR-9*, hsa-miR-92b, hsa-miR-181a, and hsa-miR-181b, showing copy-number-dependent upregulation in BL-CLs with 1q gains. MLLT11, hsa-miR-181a, hsa-miR-181b, and hsa-miR-183 showed exclusive 1q-gains-dependent and FCRL5, hsa-miR-21, hsa-miR-155, hsa-miR-155*, hsa-miR-221, and hsa-miR-222 showed exclusive EBV-dependent upregulation. We confirmed previous data, e.g., regarding the EBV dependence of hsa-miR-17-92 cluster members, and obtained detailed information considering 1q gains in EBV-negative and EBV-positive BL-CLs. Altogether, our data provide evidence for a non-random involvement of 1q gains in BL and contribute to enlightening and understanding the EBV-negative and EBV-positive BL pathogenesis.
The fungal prenyltransferase ShPT from
Stereum hirsutum
was believed to prenylate 4-hydroxybenzyl alcohol and thereby be involved in the vibralactone biosynthesis. In this study, we demonstrate that ...hydroxynaphthalenes instead of benzyl alcohol or aldehyde were accepted by ShPT for regular C-prenylation in the presence of both dimethylallyl and geranyl diphosphate. Although the natural substrate of ShPT remains unknown, our results provide one additional prenyltransferase from basidiomycetes, which are less studied, in comparison to those from other sources. Furthermore, this study expands the chemical toolbox for regioselective production of prenylated naphthalene derivatives.
Key points
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Basidiomycetous prenyltransferase
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Biochemical characterization
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A DMATS prenyltransferase prenylating hydroxynaphthalene derivatives
A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue ...transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.
CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector ...cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.
The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish ...subgroups in other types of mature aggressive B-cell lymphomas.
We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization.
We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course.
Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.
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