CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor–positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor–positive breast cancer

Systematic review of factors influencing patient and practitioner delay in diagnosis of upper gastrointestinal cancer

As knowledge on the causation of cancers advances and new treatments are developed, early recognition and accurate diagnosis becomes increasingly important. This review focused on identifying factors influencing patient and primary care practitioner delay for upper gastrointestinal cancer. A systematic methodology was applied, including extensive searches of the literature published from 1970 to 2003, systematic data extraction, quality assessment and narrative data synthesis. Included studies were those evaluating factors associated with the time interval between a patient first noticing a cancer symptom and presenting to primary care, between a patient first presenting to primary care and being referred to secondary care, or describing an intervention designed to reduce those intervals. Twenty-five studies were included in the review. Studies reporting delay intervals demonstrated that the patient phase of delay was greater than the practitioner phase, whilst patient-related research suggests that recognition of symptom seriousness is more important than recognition of the presence of the symptom. The main factors related to practitioner delay were misdiagnosis, application and interpretation of tests, and the confounding effect of existing disease. Greater understanding of patient factors is required, along with evaluation of interventions to ensure appropriate diagnosis, examination and investigation

Endophenotypes in a Dynamically Connected Brain

We examined the longitudinal genetic architecture of three parameters of functional brain connectivity. One parameter described overall connectivity (synchronization likelihood, SL). The two others were derived from graph theory and described local (clustering coefficient, CC) and global (average path length, L) aspects of connectivity. We measured resting state EEG in 1,438 subjects from four age groups of about 16, 18, 25 and 50 years. Developmental curves for SL and L indicate that connectivity is more random at adolescence and old age, and more structured in middle-aged adulthood. Individual variation in SL and L were moderately to highly heritable at each age (SL: 40–82%; L: 29–63%). Genetic factors underlying these phenotypes overlapped. CC was also heritable (25–49%) but showed no systematic overlap with SL and L. SL, CC, and L in the alpha band showed high phenotypic and genetic stability from 16 to 25 years. Heritability for parameters in the beta band was lower, and less stable across ages, but genetic stability was high. We conclude that the connectivity parameters SL, CC, and L in the alpha band show the hallmarks of a good endophenotype for behavior and developmental disorders

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro. In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research

HIV's evasion of the cellular immune response

Despite a strong cytotoxic T-lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV-1) develop AIDS, We have found that primary T cells infected with HIV-1 downregulate surface MHC class I antigens and are resistant to lysis by HLA-A2-restricted CTL clones. In contrast, cells infected with an HIV-1 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide-specific manner. In primary T cells HLA-A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on ceils expressing individual MHC class I alietes have revealed that nef does not downmodulate HLA-C and HLA-E antigens, This selective downmodulation allows Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA-A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV-1 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV-1 from immune surveillance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75570/1/j.1600-065X.1999.tb01283.x.pd

A draft genome sequence of the elusive giant squid, Architeuthis dux

Background: The giant squid (Architeuthis dux; Steenstrup, 1857) is an enigmatic giant mollusc with a circumglobal distribution in the deep ocean, except in the high Arctic and Antarctic waters. The elusiveness of the species makes it difficult to study. Thus, having a genome assembled for this deep-sea-dwelling species will allow several pending evolutionary questions to be unlocked. Findings: We present a draft genome assembly that includes 200 Gb of Illumina reads, 4 Gb of Moleculo synthetic long reads, and 108 Gb of Chicago libraries, with a final size matching the estimated genome size of 2.7 Gb, and a scaffold N50 of 4.8 Mb. We also present an alternative assembly including 27 Gb raw reads generated using the Pacific Biosciences platform. In addition, we sequenced the proteome of the same individual and RNA from 3 different tissue types from 3 other species of squid (Onychoteuthis banksii, Dosidicus gigas, and Sthenoteuthis oualaniensis) to assist genome annotation. We annotated 33,406 protein-coding genes supported by evidence, and the genome completeness estimated by BUSCO reached 92%. Repetitive regions cover 49.17% of the genome. Conclusions: This annotated draft genome of A. dux provides a critical resource to investigate the unique traits of this species, including its gigantism and key adaptations to deep-sea environments

HPV infection and number of lifetime sexual partners are strong predictors for ‘natural’ regression of CIN 2 and 3

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3

The chemical interactome space between the human host and the genetically defined gut metabotypes

The bacteria that colonize the gastrointestinal tracts of mammals represent a highly selected microbiome that has a profound influence on human physiology by shaping the host's metabolic and immune system activity. Despite the recent advances on the biological principles that underlie microbial symbiosis in the gut of mammals, mechanistic understanding of the contributions of the gut microbiome and how variations in the metabotypes are linked to the host health are obscure. Here, we mapped the entire metabolic potential of the gut microbiome based solely on metagenomics sequencing data derived from fecal samples of 124 Europeans (healthy, obese and with inflammatory bowel disease). Interestingly, three distinct clusters of individuals with high, medium and low metabolic potential were observed. By illustrating these results in the context of bacterial population, we concluded that the abundance of the Prevotella genera is a key factor indicating a low metabolic potential. These metagenome-based metabolic signatures were used to study the interaction networks between bacteria-specific metabolites and human proteins. We found that thirty-three such metabolites interact with disease-relevant protein complexes several of which are highly expressed in cells and tissues involved in the signaling and shaping of the adaptive immune system and associated with squamous cell carcinoma and bladder cancer. From this set of metabolites, eighteen are present in DrugBank providing evidence that we carry a natural pharmacy in our guts. Furthermore, we established connections between the systemic effects of non-antibiotic drugs and the gut microbiome of relevance to drug side effects and health-care solutions.link_to_subscribed_fulltex

Dense sampling of bird diversity increases power of comparative genomics

© 2020, The Author(s). Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1–4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families—including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species

Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression

INTRODUCTION: Genomic and transcriptomic alterations affecting key cellular processes such us cell proliferation, differentiation and genomic stability are considered crucial for the development and progression of cancer. Most invasive breast carcinomas are known to derive from precursor in situ lesions. It is proposed that major global expression abnormalities occur in the transition from normal to premalignant stages and further progression to invasive stages. Serial analysis of gene expression (SAGE) was employed to generate a comprehensive global gene expression profile of the major changes occurring during breast cancer malignant evolution. METHODS: In the present study we combined various normal and tumor SAGE libraries available in the public domain with sets of breast cancer SAGE libraries recently generated and sequenced in our laboratory. A recently developed modified t test was used to detect the genes differentially expressed. RESULTS: We accumulated a total of approximately 1.7 million breast tissue-specific SAGE tags and monitored the behavior of more than 25,157 genes during early breast carcinogenesis. We detected 52 transcripts commonly deregulated across the board when comparing normal tissue with ductal carcinoma in situ, and 149 transcripts when comparing ductal carcinoma in situ with invasive ductal carcinoma (P < 0.01). CONCLUSION: A major novelty of our study was the use of a statistical method that correctly accounts for the intra-SAGE and inter-SAGE library sources of variation. The most useful result of applying this modified t statistics beta binomial test is the identification of genes and gene families commonly deregulated across samples within each specific stage in the transition from normal to preinvasive and invasive stages of breast cancer development. Most of the gene expression abnormalities detected at the in situ stage were related to specific genes in charge of regulating the proper homeostasis between cell death and cell proliferation. The comparison of in situ lesions with fully invasive lesions, a much more heterogeneous group, clearly identified as the most importantly deregulated group of transcripts those encoding for various families of proteins in charge of extracellular matrix remodeling, invasion and cell motility functions