DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale ...mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Stroke instigates a dynamic process of repair and remodelling of remaining neural circuits, and this process is shaped by behavioural experiences. The onset of motor disability simultaneously creates ...a powerful incentive to develop new, compensatory ways of performing daily activities. Compensatory movement strategies that are developed in response to motor impairments can be a dominant force in shaping post-stroke neural remodelling responses and can have mixed effects on functional outcome. The possibility of selectively harnessing the effects of compensatory behaviour on neural reorganization is still an insufficiently explored route for optimizing functional outcome after stroke.
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IJS, NUK, SBMB, UL, UM, UPUK
Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates ...range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has ...been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer ...prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry. Methods Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations. Results Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p < 0.001) cell levels increased as the disease progressed, their subsets: NK CD56.sup.dimCD16.sup.- (p = 0.024) and NKTs CD56.sup.+ (p = 0.008) cell levels reduced significantly. Of note is the negative association of NK CD56.sup.dimCD16.sup.- (p < 0.001) cell levels with survival time. The gene expression analyses showed no statistically significant correlation when comparing the PDAC groups with the controls. The inflammatory status of PDAC was assessed by ROS levels of serum which were elevated in CP (p = 0.025), (RPC (p = 0.003) and LAPC (p = 0.008)) while no significant change was observed in MPC, compared to the HC group. ROS was shown to be positively correlated with GlycA (R = 0.45, p = 0.0096). Single-cell analyses showed a significant difference in the ratio of NKT cells per total cell counts in LAPC (p < 0.001) and MPC (p < 0.001) groups compared with HC, confirming observations in our sample group. Conclusion The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies. Keywords: Pancreatic ductal adenocarcinoma, PDAC, Immune cells, CD4, CD8, Immunosuppression
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dementia with Lewy bodies (DLB) is increasingly recognized as a common cause of dementia in older people. However, its true frequency remains unclear, with previous studies reporting a prevalence ...range from zero to 22.8% of all dementia cases. This review aimed to establish the population prevalence and incidence for DLB and to compare this to its prevalence in secondary care settings.
A literature review of all relevant population and clinical studies was conducted using PubMed. Additional references from papers found during that process were added to this.
DLB accounted for 4.2% of all diagnosed dementias in the community. In secondary care this increased to 7.5%. The incidence of DLB was 3.8% of new dementia cases. There was a significant increase in DLB diagnoses when using the revised (2005) International Consensus Criteria (ICC) for DLB compared to the original (1996) criteria.
DLB currently accounts for around one in 25 dementia cases diagnosed in the community and one in 13 cases in secondary care. The significantly higher rates of DLB in secondary care may reflect enhanced diagnostic accuracy in specialist settings and/or the increased morbidity and carer burden of the DLB syndrome compared to other dementias. However, the true prevalence is likely to be much higher because DLB diagnoses are often missed, although there is evidence that new criteria aid case identification.
Commercialization has been slow since the FDA approved a medical device containing nanomaterials in 1980. In 2017, the FDA released draft guidance to accelerate approval. We highlight here that ...geographical and structural separation of researchers, manufacturers, and clinical servicers may slow commercialization more than FDA approval.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
C‐peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C‐peptide can be helpful in ...clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes. This article reviews the use of C‐peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C‐peptide test and its use to assist diabetes classification and choice of treatment. We provide recommendations for where C‐peptide should be used, choice of test and interpretation of results. With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important. Advances in assays have made C‐peptide measurement both more reliable and inexpensive. In addition, recent work has demonstrated that C‐peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C‐peptide:creatinine ratio), facilitating measurement in routine clinical practice. The key current clinical role of C‐peptide is to assist classification and management of insulin‐treated patients. Utility is greatest after 3–5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes. Absent C‐peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Greenspace is theoretically a valuable resource for physical activity and hence has potential to contribute to reducing obesity and improving health. This paper reports on a systematic review of ...quantitative research examining the association between objectively measured access to greenspace and (i) Physical activity, (ii) Weight status and (iii) Health conditions related to elevated weight. Literature searches were conducted in SCOPUS, Medline, Embase and PYSCHINFO. Sixty studies met the inclusion criteria and were assessed for methodological quality and strength of the evidence. The majority (68%) of papers found a positive or weak association between greenspace and obesity-related health indicators, but findings were inconsistent and mixed across studies. Several studies found the relationship varied by factors such as age, socioeconomic status and greenspace measure. Developing a theoretical framework which considers the correlates and interactions between different types of greenspace and health would help study design and interpretation of reported findings, as would improvement in quality and consistency of greenspace access measures. Key areas for future research include investigating if and how people actually use greenspace and improving understanding of the mechanisms through which greenspace can improve health and, in particular, if physical activity is one such mechanism.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Women in almost all modern populations live longer than men. Research to date provides evidence for both biological and social factors influencing this gender gap. Conditions when both men and women ...experience extremely high levels of mortality risk are unexplored sources of information. We investigate the survival of both sexes in seven populations under extreme conditions from famines, epidemics, and slavery. Women survived better than men: In all populations, they had lower mortality across almost all ages, and, with the exception of one slave population, they lived longer on average than men. Gender differences in infant mortality contributed the most to the gender gap in life expectancy, indicating that newborn girls were able to survive extreme mortality hazards better than newborn boys. Our results confirm the ubiquity of a female survival advantage even when mortality is extraordinarily high. The hypothesis that the survival advantage of women has fundamental biological underpinnings is supported by the fact that under very harsh conditions females survive better than males even at infant ages when behavioral and social differences may be minimal or favor males. Our findings also indicate that the female advantage differs across environments and is modulated by social factors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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