DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.

Economic evaluation of extended panel analysis in cancer patients with historical NHS diagnostic germline genetic testing - A modeling study based on real-world data.

Background: The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis and reporting for BRCA1/BRCA2/PALB2/CHEK2 1100delC only as per contemporaneous guidelines. This study investigated the cost-utility of reanalyzing existing diagnostic grade extended panel data for truncating germline pathogenic variants (GPVs) in known moderate risk cancer susceptibility genes (CSGs) and performing follow-up genetic testing for first-degree relatives if patients have an identified CSG allele.

Methods: Reanalysis of existing NGS data was undertaken in 889 samples from cancer patients contemporaneously eligible through the NHS England National Genomic Test Directory (NGTD) codes R207 (ovarian) or R208 (breast) who had tested negative for BRCA1/BRCA2/PALB2 and CHEK2 1100delC founder variant.

Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery.

Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement.

Directed evolution of hyperactive integrases for site specific insertion of transgenes.

The ability to deliver large transgenes to a single genomic sequence with high efficiency would accelerate biomedical interventions. Current methods suffer from low insertion efficiency and most rely on undesired double-strand DNA breaks. Serine integrases catalyze the insertion of large DNA cargos at attachment (att) sites.

Effect of Apolipoprotein E isoforms on the Abundance and Function of P-glycoprotein in Human Brain Microvascular Endothelial Cells.

Background: Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD. This is despite reduced abundance and function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD, which can impact brain exposure of drugs. The fundamental mechanisms leading to reduced P-gp abundance in sporadic AD remain unknown; however, it is known that the apolipoprotein E (apoE) gene has the strongest genetic link to sporadic AD development, and apoE isoforms can differentially alter BBB function.

Directed evolution of hyperactive integrases for site specific insertion of transgenes.

The ability to deliver large transgenes to a single genomic sequence with high efficiency would accelerate biomedical interventions. Current methods suffer from low insertion efficiency and most rely on undesired double-strand DNA breaks. Serine integrases catalyze the insertion of large DNA cargos at attachment (att) sites.

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing brain.

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms.

Evolution of avian heat tolerance: The role of atmospheric humidity.

The role of atmospheric humidity in the evolution of endotherms' thermoregulatory performance remains largely unexplored, despite the fact that elevated humidity is known to impede evaporative cooling capacity. Using a phylogenetically informed comparative framework, we tested the hypothesis that pronounced hyperthermia tolerance among birds occupying humid lowlands evolved to reduce the impact of humidity-impeded scope for evaporative heat dissipation by comparing heat tolerance limits (HTLs; maximum tolerable air temperature), maximum body temperatures (Tmax), and associated thermoregulatory variables in humid (19.2 g HO m) versus dry (1.

A novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy.

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues.

Selection of patients with malignant melanoma for pelvic lymph node dissection (PLND) using CT-PET.

Objectives: In melanoma patients with positive pelvic nodes, pelvic lymph node dissection (PLND) to achieve fully resected disease status facilitates adjuvant-dose systemic therapy and avoids higher treatment doses with greater toxicity. This study aimed to test the accuracy of prediction of nodal involvement of the 2010 joint BAPRAS/BAD guidance compared with Positron Emission Tomography (CT-PET).

Methods: A retrospective review was undertaken of 26 melanoma patients undergoing PLND by a single surgeon between July 2012 and July 2020.

Eye donation in hospice and hospital palliative care settings: perceptions, practice, and service development needs - findings from a national survey.

Objectives: New routes for supply of eye tissue are needed in the UK to support transplant surgery and medical research. Hospice care (HC) and Hospital-based Palliative care (HPC) services represent potential supply routes. This paper reports findings from the survey arm of the Eye Donation from Palliative and Hospice Care-Investigating potential, practice preference and perceptions study (EDiPPPP), objectives of which were to: i) Investigate existing practice in relation to eye donation across HC and HPC settings; ii) identify perceptions of HCPs toward embedding eye donation into routine end of life care planning; iii) investigate the informational, training, or support needs of clinicians regarding eye donation.

Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice.

P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs.

Proactive familial cancer risk assessment: a service development study in UK primary care.

Background: Family history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention, and Early Detection (SPED). Family History Questionnaire Service (FHQS) is a resource-efficient patient-facing online tool to facilitate this. In the UK, cancer risk assessment is usually only offered to concerned individuals proactively self-presenting to their GP, leading to inequity in accessing SPED in the community.

A Quantitative Comparison of Oil Sources on Shorelines of Prince William Sound, Alaska, 17 Years After the Exxon Valdez Oil Spill.

Environmental damage caused by accidental discharges of pollutants depends in part on the degree of prior contamination, in that increased pollution of an already heavily contaminated region will usually be considered less detrimental than equivalent pollution of a pristine region. Quantitative comparisons of specific pollution events with the extent and severity of prior contamination are rare, owing to difficulties in identifying and assessing contaminants remaining from prior pollution events, and in some cases contaminants from natural sources. The 1989 Exxon Valdez oil spill (EVOS) presents an unusual opportunity to quantitatively evaluate residual contaminants from petroleum sources on shorelines of Prince William Sound (PWS), Alaska.

Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide.

Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation.

MRC2020: improvements to Ximdisp and the MRC image-processing programs.

The great success of single-particle electron cryo-microscopy (cryoEM) during the last decade has involved the development of powerful new computer programs and packages that guide the user along a recommended processing workflow, in which the wisdom and choices made by the developers help everyone, especially new users, to obtain excellent results. The ability to carry out novel, non-standard or unusual combinations of image-processing steps is sometimes compromised by the convenience of a standard procedure. Some of the older programs were written with great flexibility and are still very valuable.

10 Eye donation in palliative and hospice care settings: patient views and missed opportunities!

Unlabelled: Eye donation in Palliative and Hospice care settings: patient views and missed opportunities.

Background: There is a global shortage of donated eye tissue for use in sight saving and sight restoring operations such as corneal transplantation. In the UK the Royal National Institute of Blind People (RNIB) report that over two million people are currently living with sight loss with this figure predicted to rise to approx.

12 The potential for eye donationfrom hospice and palliative care clinical settings in England - a retrospective case notes review of deceased patient records.

Background: There is a need to identify additional routes of supply for ophthalmic tissue in the UK due to deficits between supply and demand. In response to this need the NIHR funded study, Eye Donation from Palliative and Hospice Care: Investigating Potential, Practice, Preference, and Perceptions) (EDiPPPP) project was developed in partnership with NHSBT Tissue Services ( now Organ Tissue Donation and Transplantation).

Aim: This presentation will report findings from work package one of EDiPPPP which aimed to: scope the size and clinical characteristics of the potential eye donation (ED) population via a large-scale, multi-site retrospective case notes review across England establishing: the size of the potential ED population; describe the clinical characteristics of the potential ED population and identify challenges for clinicians in applying the standard ED criteria for assessing patient eligibility.

Reduction in ABCG2 mRNA Expression in Human Immortalised Brain Microvascular Endothelial Cells by Ferric Ammonium Citrate is Mediated by Reactive Oxygen Species and Activation of ERK1/2 Signalling.

Purpose: The ATP-binding cassette (ABC) transport protein ABCG2 (also known as breast cancer resistance protein (BCRP)) is expressed at the luminal face of the blood-brain barrier (BBB), where it limits the brain uptake of a number of therapeutic drugs. We recently reported that the ABC efflux transporter P-glycoprotein (P-gp) was downregulated in human immortalised brain endothelial (hCMEC/D3) cells treated with ferric ammonium citrate (FAC). The aim of the present study, therefore, was to assess whether BCRP expression is also affected by FAC and identify any signalling mechanisms involved.

Presentation of the septic patient to the emergency department with respect to age and sex - a retrospective cross-sectional study.

Objective: It is challenging to identify sepsis in the emergency department, in part due to the non-specific presentation of septic patients. Current clinical sepsis screening tools rely on vital signs but many patients present with near normal vital signs and are therefore not identified as septic. This suggests that variables, e.

The potential for eye donation from hospice and palliative care clinical settings in England: a retrospective case note review of deceased patients' records.

There is a need to identify additional routes of supply for ophthalmic tissue in the UK. This paper reports the findings from a national study exploring the potential for eye donation (ED) from three Hospice Care (HC) and three Hospital Palliative Care Services (HPC) in England. The objectives addressed in this paper are i.