Does true Gleason pattern 3 merit its cancer descriptor?

Nearly five decades following its conception, the Gleason grading system remains a cornerstone in the prognostication and management of patients with prostate cancer. In the past few years, a debate has been growing whether Gleason score 3 + 3 = 6 prostate cancer is a clinically significant disease. Clinical, molecular and genetic research is addressing the question whether well characterized Gleason score 3 + 3 = 6 disease has the ability to affect the morbidity and quality of life of an individual in whom it is diagnosed. The consequences of treatment of Gleason score 3 + 3 = 6 disease are considerable; few men get through their treatments without sustaining some harm. Further modification of the classification of prostate cancer and dropping the label cancer for Gleason score 3 + 3 = 6 disease might be warranted

Candidate target genes for loss of heterozygosity on human chromosome 17q21

Loss of heterozygosity (LOH) on chromosome 17q21 has been detected in 30% of primary human breast tumours. The smallest common region deleted occurred in an interval between the D17S746 and D17S846 polymorphic sequences tagged sites that are located on two recombinant PI-bacteriophage clones of chromosome 17q21: 122F4 and 50H1, respectively. To identify the target gene for LOH, we defined a map of this chromosomal region. We found the following genes: JUP, FK506BP10, SC65, Gastrin (GAS) and HAP1. Of the genes that have been identified in this study, only JUP is located between D17S746 and D17S846. This was of interest since earlier studies have shown that JUP expression is altered in breast, lung and thyroid tumours as well as cell lines having LOH in chromosome 17q21. However, no mutations were detected in JUP using single-strand conformation polymorphism analysis of primary breast tumour DNAs having LOH at 17q21. We could find no evidence that the transcription promoter for JUP is methylated in tumour DNAs having LOH at 17q21. We suspect that the target gene for LOH in primary human breast tumours on chromosome 17q21 is either JUP and results in a haploinsufficiency for expression or may be an unidentified gene located in the interval between D17S846 and JUP. © 2004 Cancer Research UK

Metagenomic binning of a marine sponge microbiome reveals unity in defense but metabolic specialization

Marine sponges are ancient metazoans that are populated by distinct and highly diverse microbial communities. In order to obtain deeper insights into the functional gene repertoire of the Mediterranean sponge Aplysina aerophoba, we combined Illumina short-read and PacBio long-read sequencing followed by un-targeted metagenomic binning. We identified a total of 37 high-quality bins representing 11 bacterial phyla and two candidate phyla. Statistical comparison of symbiont genomes with selected reference genomes revealed a significant enrichment of genes related to bacterial defense (restriction-modification systems, toxin-antitoxin systems) as well as genes involved in host colonization and extracellular matrix utilization in sponge symbionts. A within-symbionts genome comparison revealed a nutritional specialization of at least two symbiont guilds, where one appears to metabolize carnitine and the other sulfated polysaccharides, both of which are abundant molecules in the sponge extracellular matrix. A third guild of symbionts may be viewed as nutritional generalists that perform largely the same metabolic pathways but lack such extraordinary numbers of the relevant genes. This study characterizes the genomic repertoire of sponge symbionts at an unprecedented resolution and it provides greater insights into the molecular mechanisms underlying microbial-sponge symbiosis

Diagnostic performance of clinical likelihood models of obstructive coronary artery disease to predict myocardial perfusion defects.

AIMS: Clinical likelihood (CL) models are designed based on a reference of coronary stenosis in patients with suspected obstructive coronary artery disease (CAD). However, a reference standard of a myocardial perfusion defects (MPD) could be more appropriate.We aimed to investigate the ability of the 2019 European Society of Cardiology pre-test probability (ESC-PTP), the risk factor-weighted (RF-CL) and coronary artery calcium score-weighted (CACS-CL) models to diagnose MPDs. METHODS AND RESULTS: Symptomatic stable de novo chest pain patients (n = 3374) underwent coronary computed tomography angiography (CTA) and subsequent myocardial perfusion imaging by single photon emission tomography (SPECT), positron emission tomography (PET) or cardiac magnetic resonance (CMR). For all modalities, MPD was defined as coronary CTA with suspected stenosis and stress-perfusion abnormality in ≥2 segments. The ESC-PTP was calculated based on age, sex and symptom typicality, and the RF-CL and CACS-CL additionally included a number of risk factors and CACS.In total, 219/3374 (6.5%) patients had a MPD. Both the RF-CL and CACS-CL classified substantially more patients to low CL (<5%) of obstructive CAD compared to the ESC-PTP (32.5% and 54.1% vs. 12.0%, p < 0.001) with preserved low prevalences of MPD (<2% for all models). Compared to the ESC-PTP (AUC 0.74 (0.71-0.78), the discrimination of having a MPD was higher for the CACS-CL (AUC 0.88 (0.86-0.91), p < 0.001) while similar for the RF-CL model (AUC 0.73 (0.70-0.76), p = 0.32). CONCLUSIONS: Compared to basic CL models, the RF-CL and CACS-CL models improve down-classification of patients to a very low-risk group with low prevalence of MPD

Uncertain survival and time discounting: intertemporal consumption plans for family trusts

Intertemporal choice, Family extinction, Hyperbolic discounting, G0, D91, D81,