SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment‐related morbidity, additional parameters need to be evaluated to enable risk‐adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki‐67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.     

Characteristics of differentiated CD8+ and CD4+ T cells present in the human brain

Immune surveillance of the central nervous system (CNS) by T cells is important to keep CNS-trophic viruses in a latent state, yet our knowledge of the characteristics of CNS-populating T cells is incomplete. We performed a comprehensive, multi-color flow-cytometric analysis of isolated T cells from paired corpus callosum (CC) and peripheral blood (PB) samples of 20 brain donors. Compared to PB, CC T cells, which were mostly located in the perivascular space and sporadically in the parenchyma, were enriched for cells expressing CD8. Both CD4⁺ and CD8⁺ T cells in the CC had a late-differentiated phenotype, as indicated by lack of expression of CD27 and CD28. The CC contained high numbers of T cells expressing chemokine receptor CX3CR1 and CXCR3 that allow for homing to inflamed endothelium and tissue, but hardly cells expressing the lymph node-homing receptor CCR7. Despite the late-differentiated phenotype, CC T cells had high expression of the IL-7 receptor α-chain CD127 and did not contain the neurotoxic cytolytic enzymes perforin, granzyme A, and granzyme B. We postulate that CNS T cells make up a population of tissue-adapted differentiated cells, which use CX3CR1 and CXCR3 to home into the perivascular space, use IL-7 for maintenance, and lack immediate cytolytic activity, thereby preventing immunopathology in response to low or non-specific stimuli. The presence of these cells in this tightly regulated environment likely enables a fast response to local threats. Our results will enable future detailed exploration of T-cell subsets in the brain involved in neurological diseases.     

Experience and attitudes toward menopause in Chinese women living in Sydney--a cross sectional survey

OBJECTIVES: To investigate the menopausal experience of Chinese women living in Sydney and to explore the prevalence of symptoms, and the relationship between the frequency of symptoms and various socio-demographic factors. METHODS: A cross-sectional survey was conducted among 310 Chinese women aged between 45 and 65 years. The menopause-specific quality of life (MENQOL) questionnaire was used to collect information on menopausal symptoms. The MENQOL questionnaire was translated into Chinese by an experienced bilingual health worker and then translated back into English by a different interpreter for accuracy. RESULTS: The mean and median ages at menopause for this study were 50.3 and 50.5 years, respectively (95% CI 49.8-50.8 years). Only 34% of women reported hot flushes, and 27% reported night sweats. Chinese women in Sydney more commonly reported psychological symptoms such as poor memory and physical symptoms such as dry skin, aching in muscles and joints and decreased physical strength. Changes in sexual desire and vaginal dryness were significantly different in perimenopausual women, compared with premenopausal and postmenopausal women. CONCLUSIONS: Chinese women living in Sydney report fewer vasomotor symptoms compared with Caucasian women. Menopause was still experienced negatively, especially in its impact on sexual function and muscular-skeletal symptoms.     

Properties of global‐ and local‐ancestry adjustments in genetic association tests in admixed populations

Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry‐adjusted and ‐unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real‐world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global‐ancestry adjustment should be used for screening, but local‐ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.     

Emergence of GABAergic-dependent regulation of input-specific plasticity in the adult rat prefrontal cortex during adolescence

Objective

The prefrontal cortex (PFC) receives multiple cortical and subcortical afferents that regulate higher order cognitive functions, many of which emerge late in adolescence. However, it remains unclear how these afferents influence PFC processing, especially in light of the protracted, late adolescent maturation of prefrontal GABAergic function. Here we investigated the role of PFC GABAergic transmission in regulating plasticity elicited from the ventral hippocampus and basolateral amygdala, and how such modulation undergoes functional changes during adolescence in rats.

Methods

In vivo local field potential recordings, combined with prefrontal microinfusion of the GABA-A receptor antagonist picrotoxin, were employed to study the impact of ventral hippocampal and basolateral amygdala high-frequency stimulation on PFC plasticity.

Results

Ventral hippocampal-induced PFC plasticity begins to appear only by postnatal days (P) 45–55 with a transient suppression of the evoked response. A switch from transient to long-lasting depression (LTD) of the PFC response emerges after P55 and throughout adulthood (P65–120). Recordings conducted in the presence of picrotoxin revealed that PFC GABAergic transmission is critical for the expression of LTD. In contrast, basolateral amygdala stimulation resulted in PFC long-term potentiation, a form of plasticity that is already enabled by P30 and is insensitive to picrotoxin.

Conclusions

The development of ventral hippocampal-dependent PFC LTD is contingent upon the recruitment of local prefrontal GABAergic transmission during adolescence whereas plasticity elicited from the basolateral amygdala is not. Thus, different mechanisms contribute to the refinement of prefrontal plasticity during adolescence as inputs from these two regions are critical for shaping PFC functions.     

An Amplicon-Based Approach for the Whole-Genome Sequencing of Human Metapneumovirus

Human metapneumovirus (HMPV) is an important cause of upper and lower respiratory tract disease in individuals of all ages. It is estimated that most individuals will be infected by HMPV by the age of five years old. Despite this burden of disease, there remain caveats in our knowledge of global genetic diversity due to a lack of HMPV sequencing, particularly at the whole-genome scale. The purpose of this study was to create a simple and robust approach for HMPV whole-genome sequencing to be used for genomic epidemiological studies. To design our assay, all available HMPV full-length genome sequences were downloaded from the National Center for Biotechnology Information (NCBI) GenBank database and used to design four primer sets to amplify long, overlapping amplicons spanning the viral genome and, importantly, specific to all known HMPV subtypes. These amplicons were then pooled and sequenced on an Illumina iSeq 100 (Illumina, San Diego, CA, USA); however, the approach is suitable to other common sequencing platforms. We demonstrate the utility of this method using a representative subset of clinical samples and examine these sequences using a phylogenetic approach. Here we present an amplicon-based method for the whole-genome sequencing of HMPV from clinical extracts that can be used to better inform genomic studies of HMPV epidemiology and evolution.     

Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.