A conformational variant of p53 (U-p53AZ) as blood-based biomarker for the prediction of the onset of symptomatic Alzheimer\u27s disease

BACKGROUND: Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer\u27s disease (AD). OBJECTIVE: The unfolded conformational variant of p53 (U-p53AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years. DESIGN: Retrospective Longitudinal Prognostic biomarker study. SETTING: Single-center study based on the AIBL cohort. PARTICIPANTS: 482 participants of the AIBL cohort, aged 60-85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses. MEASUREMENTS: The AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid β-positron emission tomography (Aβ-PET) and supporting clinical information were included where possible. RESULTS: U-p53AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aβ-PET and survival analyses with different risk factors (gender, Aβ-PET and APOE ε4 allele status) were also performed. U-p53AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53AZ achieved area under the curve (AUC) \u3e98%, significantly higher than Aβ-PET AUCs (between 84% and 93%, P respectively \u3c0.0001 and \u3c0.001). As single factor, U-p53AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53AZ levels as a major independent predictor of AD onset. CONCLUSIONS: These findings support use of U-p53AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53AZ in screening processes could support refined participant stratification for interventional studies

Friction and wear of human hair fibres

An experimental study of the tribological properties of hair fibres is reported, and the effect of surface treatment on the evolution of friction and wear during sliding. Specifically, orthogonally crossed fibre/fibre contacts under a compressive normal load over a series of 10,000 cycle studies are investigated. Reciprocating sliding at a velocity of 0.4 mm/s−1, over a track length of 0.8 mm, was performed at 18oC and 40-50% relative humidity. Hair fibres retaining their natural sebum were studied, as well as those stripped of their sebum via hexane cleaning, and hair fibres conditioned using a commercially available product. Surface topography modifications resulting from wear were imaged using scanning electron microscopy and quantified using white light interferometry. Hair fibres that presented sebum or conditioned product at the fibre/fibre junction exhibited initial coefficients of friction at least 25% lower than those that were cleaned with hexane. Coefficients of friction were observed to depend on the directionality of sliding for hexane cleaned hair fibres after sufficient wear cycles that cuticle lifting was present, typically on the order 1,000 cycles. Cuticle flattening was observed for fibre/fibre junctions exposed to 10 mN compressive normal loads, whereas loads of 100 mN introduced substantial cuticle wear and fibre damage

CD44 and OTP are strong prognostic markers for pulmonary carcinoids

textabstractPurpose: Pulmonary carcinoids are well-differentiated neuroendocrine tumors showing usually a favorable prognosis. However, there is a risk for late recurrence and/or distant metast

Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken

Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer.

Background: Genetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy. Patients and methods: Multi-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; ClinicalTrials.gov identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R. Results: Unsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment. Conclusions: Demonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for biomarker research.This work was supported by: Chief Scientist Office, Scotland (grant number ETM37 to GDS and DJH); Cancer Research UK (Experimental Cancer Medicine Centre) (to TP, London and DJH, Edinburgh), Medical Research Council (to AL, DJH), Royal College of Surgeons of Edinburgh (to AL), Melville Trust (to AL), Renal Cancer Research Fund (to GDS), Kidney Cancer Scotland (to GDS), the Special Research Fund of Ghent University (grant number 01MR0410 to TDM, GT, WVC, CVN, FVN and DD) and an educational grant from Pfizer (to TP).This is the final version of the article. It first appeared from Impact Journals via https://doi.org/10.18632/oncotarget.830

BHS GUIDELINES ON THE MANAGEMENT OF RELAPSED AND REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: PART 2

peer reviewedApproximately 30-40% of patients with diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), will relapse or are unable to obtain a complete remission (CR) after frontline treatment. These patients have a poor prognosis and represent a therapeutic challenge. In this article, we reviewed the recent literature to update the practice guidelines of the Belgian Hematology Society (BHS) Lymphoproliferative Disease Committee for the treatment of relapsed or refractory (R/R) DLBCL. In the first part, we will focus on first relapse and the role of CAR T-cell therapy in first and second relapse. In the second part, we will focus on novel treatment options for patients with a second or higher relapse, secondary central nervous system (CNS) relapse and high-grade lymphoma

BHS guidelines on the management of relapsed and refractory diffuse large B-cell lymphoma: Part 1

peer reviewedApproximately 30-40% of patients with diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), will relapse or are unable to obtain a complete remission (CR) after frontline treatment. These patients have a poor prognosis and represent a therapeutic challenge. In this article, we reviewed the recent literature to update the practice guidelines of the Belgian Hematology Society (BHS) Lymphoproliferative Disease Committee for the treatment of relapsed or refractory (R/R) DLBCL. In the first part, we will focus on first relapse and the role of CAR T-cell therapy in first and second relapse. In the second part, we will focus on novel treatment options for patients with a second or higher relapse, secondary central nervous system (CNS) relapse and high-grade lymphoma