Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium.

Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia.

Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.

Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3ca mutation drives clonal expansion by tilting cell fate toward proliferation.

Comparative pharmacokinetics of phenylbutazone in healthy young-adult and geriatric horses.

Objective: To evaluate the effects of aging on phenylbutazone (PBZ) disposition in older horses (≥ 25 years old) compared to young adults (4 to 10 years old) by characterizing the pharmacokinetic profile of PBZ and its active metabolite, oxyphenbutazone (OPBZ), following a 2.2-mg/kg dose, IV. We hypothesized that the disposition of PBZ will be affected by age.

Risk factors for tick attachment in companion animals in Great Britain: a spatiotemporal analysis covering 2014-2021.

Background: Ticks are an important driver of veterinary health care, causing irritation and sometimes infection to their hosts. We explored epidemiological and geo-referenced data from > 7 million electronic health records (EHRs) from cats and dogs collected by the Small Animal Veterinary Surveillance Network (SAVSNET) in Great Britain (GB) between 2014 and 2021 to assess the factors affecting tick attachment in an individual and at a spatiotemporal level.

Methods: EHRs in which ticks were mentioned were identified by text mining; domain experts confirmed those with ticks on the animal.

Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin.

Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations.

Somatic mutations in facial skin from countries of contrasting skin cancer risk.

The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK, despite Singapore receiving 2-3 times more ultraviolet (UV) radiation. Aging skin contains somatic mutant clones from which such cancers develop. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape.

Modelling red blood cell optical trapping by machine learning improved geometrical optics calculations.

Optically trapping red blood cells allows for the exploration of their biophysical properties, which are affected in many diseases. However, because of their nonspherical shape, the numerical calculation of the optical forces is slow, limiting the range of situations that can be explored. Here we train a neural network that improves both the accuracy and the speed of the calculation and we employ it to simulate the motion of a red blood cell under different beam configurations.

Mutations observed in somatic evolution reveal underlying gene mechanisms.

Highly sensitive DNA sequencing techniques have allowed the discovery of large numbers of somatic mutations in normal tissues. Some mutations confer a competitive advantage over wild-type cells, generating expanding clones that spread through the tissue. Competition between mutant clones leads to selection.

Ray Optics Model for Optical Trapping of Biconcave Red Blood Cells.

Red blood cells (RBCs) or erythrocytes are essential for oxygenating the peripherical tissue in the human body. Impairment of their physical properties may lead to severe diseases. Optical tweezers have in experiments been shown to be a powerful tool for assessing the biochemical and biophysical properties of RBCs.

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling.

p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition.

Aging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic TP53 disruption is almost universal. However, how p53 mutant clones expand and contribute to cancer development is unclear.

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

Somatic Mutation: What Shapes the Mutational Landscape of Normal Epithelia?

Unlabelled: Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and persist to acquire further genome alterations. After a transient expansion, mutant stem cells must revert to homeostatic behavior so normal tissue architecture is maintained.

Influence of slow light effect on trapping force in optical tweezers.

We investigate the optical trapping of polystyrene microspheres in optical tweezers. The transverse capture gradient forces of polystyrene microspheres with different numerical aperture are theoretically and experimentally evaluated by the power spectral density roll-off method. It is found that the trapping force of the experimental measurement is much stronger than that of the theoretical results.

Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours.

Simulations reveal that different responses to cell crowding determine the expansion of and mutant clones in squamous epithelia.

During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are and , both of which are also recurrently mutated in cancers of these tissues.

Greater than expected reduction in low-density lipoprotein-cholesterol (LDL-C) with bempedoic acid in a patient with heterozygous familial hypercholesterolemia (HeFH).

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces levels of low-density lipoprotein-cholesterol (LDL-C) in the plasma by inhibition of cholesterol synthesis in hepatic cells, which leads to up-regulation of hepatic LDL receptors. Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. In this case study, we describe a patient with HeFH who had a prior excellent response to statin but unable to take the same, and a less than expected response to PCSK9i, in whom initiation of bempedoic acid led to a substantial reduction of LDL-C.

Methods for analysing lineage tracing datasets.

A single population of progenitor cells maintains many epithelial tissues. Transgenic mouse cell tracking has frequently been used to study the growth dynamics of competing clones in these tissues. A mathematical model (the 'single-progenitor model') has been argued to reproduce the observed progenitor dynamics accurately.

Backyard poultry cases in UK small animal practices: Demographics, health conditions and pharmaceutical prescriptions.

Background: Backyard poultry ownership is of keen interest in the United Kingdom. However, despite this, little is known about veterinary care engagement and outcomes of visits in this group of species.

Methods: This study described and characterised veterinary practice-visiting backyard poultry, utilising electronic health record data supplied by veterinary practices voluntarily participating in the Small Animal Veterinary Surveillance Network between 1st April 2014 and 31st March 2019.

Developmental cell programs are co-opted in inflammatory skin disease.

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease.

'We need to do more than just stick the Good Veterinary Workplaces policy up in practices'.

argues that although publication of this new BVA policy is a great first step to improving working environments, more needs to be done to ensure it will succeed in making a difference.