173 research outputs found
The Role of Regulation in the Control of Housing Conditions
Historically the control of housing conditions was based upon a concern for the health of the community and was safeguarded by the enforced repair and improvement of substandard property. In the United Kingdom the high cost of repair eventually induced a policy based upon subsidy to both home owners and private landlords as the price of healthier housing. This paper outlines the process by which the legislative standards invoked to protect health were modified to distribute subsidy. In 1989 the standards are poised to become criteria for the measurement of poverty rather than the identification of unhealthy housing conditions. In this process the protection of public health is being overlooked. There is strong evidence to suggest that the health of occupiers is at risk from modern and traditional housing hazards. Unless health is readopted as a concern of housing policy, the regulatory response needs radical rethinking
Assessing housing quality and its impact on health, safety and sustainability
Background The adverse health and environmental
effects of poor housing quality are well established. A
central requirement for evidence-based policies and
programmes to improve housing standards is a valid,
reliable and practical way of measuring housing quality
that is supported by policy agencies, the housing sector,
researchers and the public.
Methods This paper provides guidance on the
development of housing quality-assessment tools that
link practical measures of housing conditions to their
effects on health, safety and sustainability, with
particular reference to tools developed in New Zealand
and England.
Results The authors describe how information on
housing quality can support individuals, agencies and the
private sector to make worthwhile improvements to the
health, safety and sustainability of housing. The
information gathered and the resultant tools developed
should be guided by the multiple purposes and end users
of this information. Other important issues outlined
include deciding on the scope, detailed content, practical
administration issues and how the information will be
analysed and summarised for its intended end users.
There are likely to be considerable benefits from
increased international collaboration and standardisation
of approaches to measuring housing hazards. At the
same time, these assessment approaches need to
consider local factors such as climate, geography,
culture, predominating building practices, important
housing-related health issues and existing building
codes.
Conclusions An effective housing quality-assessment
tool has a central role in supporting improvements to
housing. The issues discussed in this paper are designed
to motivate and assist the development of such tools
Single-Cell Transcriptomics in Cancer Immunobiology: The Future of Precision Oncology
Cancer is a heterogeneous and complex disease. Tumors are formed by cancer cells and a myriad of non-cancerous cell types that together with the extracellular matrix form the tumor microenvironment. These cancer-associated cells and components contribute to shape the progression of cancer and are deeply involved in patient outcome. The immune system is an essential part of the tumor microenvironment, and induction of cancer immunotolerance is a necessary step involved in tumor formation and growth. Immune mechanisms are intimately associated with cancer progression, invasion, and metastasis; as well as to tumor dormancy and modulation of sensitivity to drug therapy. Transcriptome analyses have been extensively used to understand the heterogeneity of tumors, classifying tumors into molecular subtypes and establishing signatures that predict response to therapy and patient outcomes. However, the classification of the tumor cell diversity and specially the identification of rare populations has been limited in these transcriptomic analyses of bulk tumor cell populations. Massively-parallel single-cell RNAseq analysis has emerged as a powerful method to unravel heterogeneity and to study rare cell populations in cancer, through unsupervised sampling and modeling of transcriptional states in single cells. In this context, the study of the role of the immune system in cancer would benefit from single cell approaches, as it will enable the characterization and/or discovery of the cell types and pathways involved in cancer immunotolerance otherwise missed in bulk transcriptomic information. Thus, the analysis of gene expression patterns at single cell resolution holds the potential to provide key information to develop precise and personalized cancer treatment including immunotherapy. This review is focused on the latest single-cell RNAseq methodologies able to agnostically study thousands of tumor cells as well as targeted single-cell RNAseq to study rare populations within tumors. In particular, we will discuss methods to study the immune system in cancer. We will also discuss the current challenges to the study of cancer at the single cell level and the potential solutions to the current approaches
Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue
E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and
quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining
E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during
disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53
or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments
HENMT1 and piRNA Stability Are Required for Adult Male Germ Cell Transposon Repression and to Define the Spermatogenic Program in the Mouse
piRNAs are critical for transposable element (TE) repression and germ cell survival during the early phases of spermatogenesis, however, their role in adult germ cells and the relative importance of piRNA methylation is poorly defined in mammals. Using a mouse model of HEN methyltransferase 1 (HENMT1) loss-of-function, RNA-Seq and a range of RNA assays we show that HENMT1 is required for the 2ā O-methylation of mammalian piRNAs. HENMT1 loss leads to piRNA instability, reduced piRNA bulk and length, and ultimately male sterility characterized by a germ cell arrest at the elongating germ cell phase of spermatogenesis. HENMT1 loss-of-function, and the concomitant loss of piRNAs, resulted in TE de-repression in adult meiotic and haploid germ cells, and the precocious, and selective, expression of many haploid-transcripts in meiotic cells. Precocious expression was associated with a more active chromatin state in meiotic cells, elevated levels of DNA damage and a catastrophic deregulation of the haploid germ cell gene expression. Collectively these results define a critical role for HENMT1 and piRNAs in the maintenance of TE repression in adult germ cells and setting the spermatogenic program
ELF5 modulates the estrogen receptor cistrome in breast cancer.
Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance
Association of latent class analysis-derived multimorbidity clusters with adverse health outcomes in patients with multiple long-term conditions: Comparative results across three UK cohorts
Background
It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use.
Methods
Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01st Jan 2011 and 31st Dec 2020 for SAIL).
Findings
Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the āPain+ā cluster in the age-group 18ā36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the āHypertension, Diabetes & Heart diseaseā cluster in the age-group 37ā54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the āCancer, Thyroid disease & Rheumatoid arthritisā cluster in the age group 37ā54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18ā36 years.
Interpretation
Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs.
Funding
This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)āNIHR202020)
Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.</p
Bio-impedance spectroscopy added to a fluid management protocol does not improve preservation of residual kidney function in incident hemodialysis patients in a randomized controlled trial
Avoiding excessive dialysis-associated volume depletion may help preserve residual kidney function (RKF). To establish whether knowledge of the estimated normally hydrated weight from bioimpedance measurements (BI-NHW) when setting the post-hemodialysis target weight (TW) might mitigate rate of loss of RKF, we undertook an open label, randomized controlled trial in incident patients receiving HD, with clinicians and patients blinded to bioimpedance readings in controls. A total of 439 patients with over 500 ml urine/day or residual GFR exceeding 3 ml/min/1.73m2 were recruited from 34 United Kingdom centers and randomized 1:1, stratified by center. Fluid assessments were made for up to 24 months using a standardized proforma in both groups, supplemented by availability of BI-NHW in the intervention group. Primary outcome was time to anuria, analyzed using competing-risk survival models adjusted for baseline characteristics, by intention to treat. Secondary outcomes included rate of RKF decline (mean urea and creatinine clearance), blood pressure and patient-reported outcomes. There were no group differences in cause-specific hazard rates of anuria (0.751; 95% confidence interval (0.459, 1.229)) or sub-distribution hazard rates (0.742 (0.453, 1.215)). RKF decline was markedly slower than anticipated, pooled linear rates in year 1: ā0.178 (ā0.196, ā0.159)), year 2: ā0.061 (ā0.086, ā0.036)) ml/min/1.73m2/month. Blood pressure and patient-reported outcomes did not differ by group. The mean difference agreement between TW and BI-NHW was similar for both groups, Bioimpedance: ā0.04 kg; Control: ā0.25 kg. Thus, use of a standardized clinical protocol for fluid assessment when setting TW is associated with excellent preservation of RKF. Hence, bioimpedance measurements are not necessary to achieve this
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