BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1 ) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis

Patient preferences for whole-body MRI or conventional staging pathways in lung and colorectal cancer:a discrete choice experiment

OBJECTIVES: To determine the importance placed by patients on attributes associated with whole-body MRI (WB-MRI) and standard cancer staging pathways and ascertain drivers of preference.METHODS: Patients recruited to two multi-centre diagnostic accuracy trials comparing WB-MRI with standard staging pathways in lung and colorectal cancer were invited to complete a discrete choice experiment (DCE), choosing between a series of alternate pathways in which 6 attributes (accuracy, time to diagnosis, scan duration, whole-body enclosure, radiation exposure, total scan number) were varied systematically. Data were analysed using a conditional logit regression model and marginal rates of substitution computed. The relative importance of each attribute and probabilities of choosing WB-MRI-based pathways were estimated.RESULTS: A total of 138 patients (mean age 65, 61% male, lung n = 72, colorectal n = 66) participated (May 2015 to September 2016). Lung cancer patients valued time to diagnosis most highly, followed by accuracy, radiation exposure, number of scans, and time in the scanner. Colorectal cancer patients valued accuracy most highly, followed by time to diagnosis, radiation exposure, and number of scans. Patients were willing to wait 0.29 (lung) and 0.45 (colorectal) weeks for a 1% increase in pathway accuracy. Patients preferred WB-MRI-based pathways (probability 0.64 [lung], 0.66 [colorectal]) if they were equivalent in accuracy, total scan number, and time to diagnosis compared with a standard staging pathway.CONCLUSIONS: Staging pathways based on first-line WB-MRI are preferred by the majority of patients if they at least match standard pathways for diagnostic accuracy, time to diagnosis, and total scan number.KEY POINTS: • WB-MRI staging pathways are preferred to standard pathways by the majority of patients provided they at least match standard staging pathways for accuracy, total scan number, and time to diagnosis. • For patients with lung cancer, time to diagnosis was the attribute valued most highly, followed by accuracy, radiation dose, number of additional scans, and time in a scanner. Preference for patients with colorectal cancer was similar. • Most (63%) patients were willing to trade attributes, such as faster diagnosis, for improvements in pathway accuracy and reduced radiation exposure.</p

Inhibition of hydroxyapatite formation in the presence of titanocene–aminoacid complexes: an experimental and computational study

Organometallic compounds have been used in various fields of chemistry, medicine and materials science. Central metal, stereochemical configuration and functional groups of the substitutes give to the organometallic compounds very special and selective properties. These properties have been used successfully in selective-antitumor-targeting, as well as anti-arthritic drugs. In the present investigation we study the influence of two organometallic compounds on the inhibition of crystallization of hydroxyapatite. These compounds are complexes of Ti(IV) with the general formula [Cp2Ti(aa)2]2+2Cl−, where Cp = η5-C5H5 cyclopentadienyl and aa the amino acid glycine or alanine. The experiments were conducted according to the constant composition technique in supersaturated solutions containing calcium and phosphate ions. The kinetic results indicate a surface diffusion controlled mechanism of the hydroxyapatite (HAP) crystals. The experiments prove that the presence of [Cp2Ti(Ala)2]2+2Cl− and [Cp2Ti(Gly)2]2+2Cl− complexes affects drastically the profile formation rate of the HAP crystals under biological conditions. The complex with the amino acid alanine provides a stronger inhibition of the formation rate comparing to the complex with glycine. The experimental observations are supported by computer calculations. © 2014, Springer Science+Business Media New York

Exploring the initial experience of hospitalisation to an acute psychiatric ward.

BACKGROUND: Patient-reported satisfaction with inpatient psychiatric services, within the first few days of admission, is related to positive future outcomes. Despite its predictive value, little is known about this initial experience and what underlies these appraisals. The aim of this study was to qualitatively explore the initial experience of being admitted to an inpatient psychiatric ward. METHODS: Semi-structured interviews were conducted with 61 recently admitted patients across five psychiatric hospitals in London, England. Participants were purposively sampled to ensure a mix of experiences including people with high and low satisfaction scores as measured by the Client Assessment of Treatment. Thematic analysis was used to identify, analyse and report patterns within the data, with content analysis applied to determine whether certain themes were more common to either negative or positive appraisals. RESULTS: Four broad themes were evident 1) 'Best place for me right now?' 2) 'Different from out in society' 3) 'Moving from uncertainty to being informed' and 4) 'Relating & Alienating'. Individuals with very positive appraisals spoke most frequently of helpful relationships with both staff and other patients, and feeling cared for. They also spoke of having had previous admissions and the assessment process on entering the ward suggesting that these may be valuable experiences. Conversely, the group with very negative appraisals spoke of relationships that were alienating or where there was a perceived abuse of power. They described restrictions to their freedom, compared hospital to prison and generally had the view that hospital makes you worse. CONCLUSIONS: The experience of hospital within the first few days of admission determines whether an individual has a positive or negative experience of their inpatient care. Reducing the impact of uncertainty and promoting good relationships may help services to improve the initial experience of hospital admission and ultimately improve future outcomes for patients.European Commission 7th Framework Programme, Grant agreement number is 602645 to S.P

Molecular characteristics of early-onset pancreatic ductal adenocarcinoma.

The median age of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis is 71 years; however, around 10% present with early-onset pancreatic cancer (EOPC), i.e., before age 50. The molecular mechanisms underlying such an early onset are unknown. We assessed the role of common PDAC drivers (KRAS, TP53, CDKN2A and SMAD4) and determined their mutational status and protein expression in 90 formalin-fixed, paraffin-embedded tissues, including multiple primary and matched metastases, from 37 EOPC patients. KRAS was mutated in 88% of patients; p53 was altered in 94%, and p16 and SMAD4 were lost in 86% and 71% of patients, respectively. Meta-synthesis showed a higher rate of p53 alterations in EOPC than in late-onset PDAC (94% vs. 69%, P = 0.0009) and significantly higher loss of SMAD4 (71% vs. 44%, P = 0.0025). The majority of EOPC patients accumulated aberrations in all four drivers; in addition, high tumour heterogeneity was observed across all tissues. The cumulative effect of an exceptionally high rate of alterations in all common PDAC driver genes combined with high tumour heterogeneity suggests an important mechanism underlying the early onset of PDAC