Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression

Mesozoic-Cenozoic evolution of the Xining-Minhe and Dangchang basins, northeastern Tibetan Plateau: Magnetostratigraphic and biostratigraphic results

Accurate stratigraphic ages are crucial to understanding the deformation history of the Tibetan Plateau prior to and during the Indo-Asian collision. Efforts to quantify Mesozoic-Cenozoic ages are hindered by limited fossils and a paucity of volcanic horizons and regionally correlative strata. Magnetostratigraphic and biostratigraphic results from the Xining-Minhe-Longzhong basin complex and Dangchang basin provide an improved chronology of nonmarine basin development over a large region of the northeastern Tibetan Plateau (34–37°N, 101–105°E). Analyses of 171 magnetostratigraphic levels and 24 palynological assemblages (\u3e120 species) indicate Late Jurassic-Early Cretaceous to mid-Tertiary deposition. Although magnetic polarity zonation is incomplete, independent palynological age control partially restricts possible correlations to the Geomagnetic Polarity Timescale. The sediment accumulation record, basin provenance, structural geology, and published thermochronological data support a history of Jurassic exhumation, Late Jurassic-Early Cretaceous fault-related basin initiation, and Cretaceous-Paleogene reduced accumulation. These patterns, which are compatible with Late Jurassic-Early Cretaceous extension and Cretaceous-Paleogene postrift thermal subsidence, were disrupted at about 40–30 Ma, when shortening related to the Indo-Asian collision induced localized range uplift, vertical axis rotation, and amplified subsidence

Thiols as markers of redox status in type 1 diabetes mellitus

Introduction: Type 1 diabetes mellitus (T1DM) is associated with inflammation and the production of reactive oxygen species (ROS). Systemically, free thiols (R-SH) can be oxidized by ROS and circulating R-SH concentrations may directly reflect the systemic redox status. In this study the association between R-SH and clinical parameters of T1DM, including glycated haemoglobin A1c (HbA1c), was investigated. This is of particular interest since thiols are amendable to therapeutic intervention. Methods: As part of a prospective cohort study, data from 216 patients with a mean age of 45 (12) years, 57% male, diabetes duration 22 (16, 30) years and HbA1c of 60 (11) mmol/mol were examined. Baseline data were collected in 2002 and follow-up data in 2018. Cox proportional hazards regression analysis, with age, sex, HbA1c and R-SH, was used to assess prognostic factors for the development of complications. Results: At baseline, the plasma concentration of R-SH was 281.8 ± 34.0 μM. In addition to a lower concentration of NT-proBNP in the highest R-SH quartile (305–379 µM) there were no differences in baseline characteristics between the quartiles of R-SH. The Pearson correlation coefficient for R-SH and NT-proBNP was −0.290 (p &lt; 0.001). No significant correlation between R-SH and baseline HbA1c (r = −0.024, p = 0.726) was present. During follow-up, 42 macrovascular and 92 microvascular complications occurred. In Cox regression, R-SH was not a prognostic factor for the development of microvascular [hazard ratio (HR) 0.999 (95% confidence interval (CI) 0.993, 1.005)] and macrovascular [HR 0.993 (95% CI 0.984, 1.002)] complications. Conclusions: In addition to a negative association with NT-proBNP, no relevant relationships between R-SH and parameters of T1DM, including HbA1c, were present in this study.</p

Sigma-phase in Fe-Cr and Fe-V alloy systems and its physical properties

A review is presented on physical properties of the sigma-phase in Fe-Cr and Fe-V alloy systems as revealed both with experimental -- mostly with the Mossbauer spectroscopy -- and theoretical methods. In particular, the following questions relevant to the issue have been addressed: identification of sigma and determination of its structural properties, kinetics of alpha-to-sigma and sigma-to-alpha phase transformations, Debye temperature and Fe-partial phonon density of states, Curie temperature and magnetization, hyperfine fields, isomer shifts and electric field gradients.Comment: 26 pages, 23 figures and 83 reference

Current challenges in software solutions for mass spectrometry-based quantitative proteomics

This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

\ua9 2023, The Author(s).BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m−2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Comparison of Extensive Protein Fractionation and Repetitive LC-MS/MS Analyses on Depth of Analysis for Complex Proteomes

In-depth, reproducible coverage of complex proteomes is challenging because the complexity of tryptic digests subjected to LC-MS/MS analysis frequently exceeds mass spectrometer analytical capacity, which results in undersampling of data. In this study, we used cancer cell lysates to systematically compare the commonly used GeLC-MS/MS (1-D protein + 1-D peptide separation) method using four repetitive injections (2-D/repetitive) with a 3-D method that included solution isoelectric focusing and involved an equal number of LC-MS/MS runs. The 3-D method detected substantially more unique peptides and proteins, including higher numbers of unique peptides from low-abundance proteins, demonstrating that additional fractionation at the protein level is more effective than repetitive analyses at overcoming LC-MS/MS undersampling. Importantly, more than 90 % of the 2-D/repetitive protein identifications were found in the 3-D method data in a direct protein level comparison, and the reproducibility between data sets increased to greater than 96 % when factors such as database redundancy and use of rigid scoring thresholds were considered. Hence, high reproducibility of complex proteomes, such as human cancer cell lysates, readily can be achieved when using multidimensional separation methods with good depth of analysis