Mismatch-repair protein expression in high-grade gliomas: A large retrospective multicenter study

Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients

Shielding efficiency and E(J) characteristics measured on large melt cast Bi-2212 hollow cylinders in axial magnetic fields

We show that tubes of melt cast Bi-2212 used as current leads for LTS magnets can also act as efficient magnetic shields. The magnetic screening properties under an axial DC magnetic field are characterized at several temperatures below the liquid nitrogen temperature (77 K). Two main shielding properties are studied and compared with those of Bi-2223, a material that has been considered in the past for bulk magnetic shields. The first property is related to the maximum magnetic flux density that can be screened, Blim; it is defined as the applied magnetic flux density below which the field attenuation measured at the centre of the shield exceeds 1000. For a cylinder of Bi-2212 with a wall thickness of 5 mm and a large ratio of length over radius, Blim is evaluated to 1 T at T = 10 K. This value largely exceeds the Blim value measured at the same temperature on similar tubes of Bi-2223. The second shielding property that is characterized is the dependence of Blim with respect to variations of the sweep rate of the applied field, dBapp/dt. This dependence is interpreted in terms of the power law E = Ec(J/Jc)^n and allows us to determine the exponent n of this E(J) characteristics for Bi-2212. The characterization of the magnetic field relaxation involves very small values of the electric field. This gives us the opportunity to experimentally determine the E(J) law in an unexplored region of small electric fields. Combining these results with transport and AC shielding measurements, we construct a piecewise E(J) law that spans over 8 orders of magnitude of the electric field.Comment: 16 pages, 7 figure

Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

BackgroundSeveral chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis.ObjectivesThe objective of this study was to provide a detailed characterization of molecular and biochemical responses of female fathead minnows to a model aromatase inhibitor, fadrozole (FAD).MethodsFish were exposed via water to 0, 3, or 30 microg FAD/L for 8 days and then held in clean water for 8 days, with samples collected at four time points during each 8-day period. We quantified ex vivo steroid production, plasma steroids, and plasma vitellogenin (Vtg) concentrations and analyzed relative transcript abundance of 10 key regulatory genes in ovaries and 3 in pituitary tissue by real-time polymerase chain reaction.ResultsEx vivo 17beta-estradiol (E2) production and plasma E2 and Vtg concentrations were significantly reduced after a single day of exposure to 3 microg or 30 microg FAD/L. However, plasma E2 concentrations recovered by the eighth day of exposure in the 3-microg/L group and within 1 day of cessation of exposure in the 30-microg/L group, indicating concentration- and time-dependent physiologic compensation and recovery. Concentration-dependent increases in transcripts coding for aromatase (A isoform), cytochrome P450 side-chain cleavage, steroidogenic acute regulatory protein, and follicle-stimulating hormone receptor all coincided with increased E2 production and recovery of plasma E2 concentrations.ConclusionsResults of this research highlight the need to consider compensation/adaptation and recovery when developing and interpreting short-term bioassays or biomarkers or when trying to predict the effects of chemical exposures based on mode of action

Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild‐Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

Background. O6‐methylguanine (O6‐MeG)‐DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild‐type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) ≤2, and radio‐chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time‐dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut‐off of 15% for MGMT methylation. The 2‐year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p <0.00001). However, we also found a non‐linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0–4%, 18.9 months for MGMT in 4–40%, and 29.9 months for MGMT in 40– 100%. Conclusions. Our findings suggested a non‐linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild‐type glioblastoma patients treated with chemoradiotherapy

Adaptabilidade e estabilidade de híbridos de sorgo biomassa semeados em três locais na safra 2021/2022.

O objetivo desse trabalho foi avaliar a adaptabilidade e estabilidade para a produtividade (t.ha-1) de 25 híbridos de sorgo destinadas à produção de biomassa.Evento híbrido

Low Temperature Ferromagnetism in Chemically Ordered FeRh Nanocrystals

In sharp contrast to previous studies on FeRh bulk, thin films, and nanoparticles, we report the persistence of ferromagnetic order down to 3 K for size-selected 3.3 nm diameter nanocrystals embedded into an amorphous carbon matrix. The annealed nanoparticles have a B2 structure with alternating atomic Fe and Rh layers. X-ray magnetic dichroism and superconducting quantum interference device measurements demonstrate ferromagnetic alignment of the Fe and Rh magnetic moments of 3 and 1 mu(B), respectively. The ferromagnetic order is ascribed to the finite-size induced structural relaxation observed in extended x-ray absorption spectroscopy. DOI: 10.1103/PhysRevLett.110.08720

Avaliação da produção de insumos oriundos do sorgo sacarino usados na geração de bioenergia.

Evento híbrido

In Vivo-Restricted and Reversible Malignancy Induced by Human Herpesvirus-8 KSHV: A Cell and Animal Model of Virally Induced Kaposi's Sarcoma

Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to non-tumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene up-regulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth-restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS