314 results match your criteria: "National Institute for Health Research Cambridge Biomedical Research Centre[Affiliation]"

Sex differences in the intergenerational inheritance of metabolic traits.

Nat Metab

May 2022

Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Strong evidence suggests that early-life exposures to suboptimal environmental factors, including those in utero, influence our long-term metabolic health. This has been termed developmental programming. Mounting evidence suggests that the growth and metabolism of male and female fetuses differ.

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Purpose: To report the first experience of our multidisciplinary team with functional imaging using C-methionine positron emission tomography-computed tomography (C-methionine PET-CT) co-registered with MRI (Met-PET/MRI) in clinical decision making and surgical planning of patients with difficult to treat prolactinoma.

Methods: In eighteen patients with prolactinoma, referred to our tertiary referral centre because of intolerance or resistance for dopamine agonists (DA), Met-PET/MRI was used to aid decision-making regarding therapy.

Results: Met-PET/MRI was positive in 94% of the patients.

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C-methionine PET aids localization of microprolactinomas in patients with intolerance or resistance to dopamine agonist therapy.

Pituitary

August 2022

Cambridge Endocrine Molecular Imaging Group, Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.

Purpose: To assess the potential for C-methionine PET (Met-PET) coregistered with volumetric magnetic resonance imaging (Met-PET/MR) to inform clinical decision making in patients with poorly visualized or occult microprolactinomas and dopamine agonist intolerance or resistance.

Patients And Methods: Thirteen patients with pituitary microprolactinomas, and who were intolerant (n = 11) or resistant (n = 2) to dopamine agonist therapy, were referred to our specialist pituitary centre for Met-PET/MR between 2016 and 2020. All patients had persistent hyperprolactinemia and were being considered for surgical intervention, but standard clinical MRI had shown either no visible adenoma or equivocal appearances.

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Background: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by variants in . The International Registry of Werner Syndrome has identified biallelic pathogenic variants in 179/188 cases of classical WS. In the remaining nine cases, only one heterozygous pathogenic variant has been identified.

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Localization of TSH-secreting pituitary adenoma using 11C-methionine image subtraction.

EJNMMI Res

May 2022

Cambridge Endocrine Molecular Imaging Group, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.

Background: Pituitary adenomas (PA) affect ~ 1:1200 of the population and can cause a wide range of symptoms due to hormone over-secretion, loss of normal pituitary gland function and/or compression of visual pathways, resulting in significantly impaired quality of life. Surgery is potentially curative if the location of the adenoma can be determined. However, standard structural (anatomical) imaging, in the form of MRI, is unable to locate all tumors, especially microadenomas (< 1 cm diameter).

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Article Synopsis
  • - Human genetic studies show that shorter leukocyte telomere length (LTL) is linked to a higher risk of coronary artery disease (CAD), while the relationship between LTL and various cancers is less clear.
  • - Clonal hematopoiesis of indeterminate potential (CHIP), which involves the growth of blood cells with certain mutations, increases the risk for both blood cancers and CAD, with telomerase reverse transcriptase being a key genetic factor in CHIP.
  • - Research from the TOPMed program and UK Biobank reveals that longer genetically predicted LTL increases the likelihood of developing CHIP, which then leads to a decrease in measured LTL, providing insights into how these factors might contribute to CAD prevention.
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Background: Maternal deaths from unsafe abortion continue to occur globally, with particularly high rates in Sub-Saharan Africa where most abortions are classified as unsafe. Maternal death reviews are an effective part of cohesive strategies to prevent future deaths while abortion remains illegal.

Objective: This study aimed to conduct maternal death reviews for all deaths occurring following unsafe abortion during the study period, to assess preventability, and to synthesize key learning points that may help to prevent future maternal deaths following unsafe abortions.

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Association between hypertensive disorders of pregnancy and later risk of cardiovascular outcomes.

BMC Med

January 2022

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England, UK.

Background: Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data.

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BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis.

Br J Cancer

April 2022

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Background: BRCA1 and BRCA2 pathogenic variants (PVs) are associated with prostate cancer (PCa) risk, but a wide range of relative risks (RRs) has been reported.

Methods: We systematically searched PubMed, Embase, MEDLINE and Cochrane Library in June 2021 for studies that estimated PCa RRs for male BRCA1/2 carriers, with no time or language restrictions. The literature search identified 27 studies (BRCA1: n = 20, BRCA2: n = 21).

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The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.

Dev Cell

January 2022

Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0SW, UK; Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. Electronic address:

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling.

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Selenium and cancer risk: Wide-angled Mendelian randomization analysis.

Int J Cancer

April 2022

Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Evidence on the association between selenium and cancer risk is inconclusive. We conducted a Mendelian randomization study to examine the associations of selenium levels with 22 site-specific cancers and any cancer. Single nucleotide polymorphisms (SNPs) strongly associated with toenail and blood (TAB) and blood selenium levels in mild linkage disequilibrium (r  < .

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Background: Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes.

Methods: Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.

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Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process.

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Extracellular vesicles in kidney transplantation: a state-of-the-art review.

Kidney Int

March 2022

Department of Surgery, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; Blood and Transplant Research Unit in Organ Donation and Transplantation, National Institute for Health Research, University of Cambridge, Cambridge, UK. Electronic address:

Kidney transplantation is the optimal treatment for patients with kidney failure; however, early detection and timely treatment of graft injury remain a challenge. Precise and noninvasive techniques of graft assessment and innovative therapeutics are required to improve kidney transplantation outcomes. Extracellular vesicles (EVs) are lipid bilayer-delimited particles with unique biosignatures and immunomodulatory potential, functioning as intermediaries of cell signalling.

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Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Nutrients

November 2021

Integrative Cancer Epidemiology Programme (ICEP), Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use.

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Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S.

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Isolation of Uterine Innate Lymphoid Cells for Analysis by Flow Cytometry.

J Vis Exp

October 2021

Department of Obstetrics and Gynaecology, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge School of Clinical Medicine; Centre for Trophoblast Research, University of Cambridge;

Described here is a simple method to isolate and phenotype mouse group 1 uterine innate lymphoid cells (g1 uILCs) from individual pregnant uterus by flow cytometry. The protocol describes how to set up time mating to obtain multiple synchronous dams, the mechanical and enzymatic digestion of the pregnant uterus, the staining of single-cell suspensions, and a FACS strategy to phenotype and discriminate g1 uILCs. Although this method inevitably loses the spatial information of cellular distribution within the tissue, the protocol has been successfully applied to determine uILC heterogeneity, their response to maternal and foetal factors affecting pregnancy, their gene expression profile, and their functions.

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Obesity-Associated Mutations and the Melanocortin Pathway.

N Engl J Med

October 2021

From the University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge (E.M.O., J.M.K., F.T., E.H., R.A., A.P., R.B., N.W., V.A., J.M., I.S.F.), the Exeter Centre of Excellence for Diabetes Research, University of Exeter Medical School, Exeter (I.B.), Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham (D.J., M.K.), Broomfield Hospital, Chelmsford (S.L.), Hull University Teaching Hospitals NHS Trust, Hull (S.G.), East and North Hertfordshire NHS Trust Lister Hospital, Stevenage (C.M.), County Durham and Darlington NHS Foundation Trust, Darlington (P.P.), Nottingham Children's Hospital, Nottingham (T.R.), University Hospitals Dorset NHS Foundation Trust, Poole (A.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London (L.C.W.), the Translational and Clinical Research Institute, Newcastle University, and Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne (T.C.), University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (E.C.C.), and the Division of Developmental Biology and Medicine, University of Manchester, Manchester (P.C.) - all in the United Kingdom.

Background: encodes the Gα (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism).

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Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS).

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Context: The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.

Objective: This Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women.

Methods: As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels.

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Article Synopsis
  • A large-scale GWAS was conducted on leukocyte traits using data from 61,802 individuals of diverse backgrounds, focusing on over 109 million genetic variants.
  • The study identified 7 associations related to leukocyte counts, including a significant variant on chromosome X linked to lower eosinophil counts and variants prevalent in African Americans associated with monocyte and lymphocyte counts.
  • Findings suggest that the discovered eosinophil-lowering variant may reduce the risk of allergic diseases, indicating the importance of diverse samples in uncovering genetic associations often overlooked in studies focusing on European ancestry.
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Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored.

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Background: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.

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Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring.

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Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.

Am J Obstet Gynecol

February 2022

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada. Electronic address:

Background: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain.

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