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Background Lemur Tail Kinase 3 (LMTK3) promotes cell proliferation, invasiveness and therapy resistance, and its expression correlates with poor survival in several different malignancies, including breast cancer. Crosstalk through extracellular vesicles (EVs) is an increasingly appreciated mechanism of cell communication within the tumour immune microenvironment, which contributes to different aspects of cancer progression and plays a pivotal role in shaping tumour fate. Methods Nanoparticle tracking analysis and transmission electron microscopy were used to study the effects of LMTK3 on EV size, while single particle interferometry allowed us to examine LMTK3-dependent effects on the subpopulation distribution of EVs. Quantitative mass spectrometry was used to profile LMTK3-dependent proteomics changes in breast cancer-derived EVs. Bioinformatics analysis of clinical data along with in vitro and cell-based assays were implemented to explore the effects of LMTK3-dependent EV protein cargo on the tumour immune microenvironment. To elucidate the mechanism through which LMTK3 impacts endosomal trafficking and regulates EV biogenesis, we used a variety of approaches, including in vitro kinase assays, confocal and electron microscopy, as well as in vivo subcutaneous and orthotopic breast cancer mouse models. Results Here, we report that LMTK3 increases the average size of EVs, modulates immunoregulatory EV proteomic cargo and alters the subpopulation distribution of EVs released by breast cancer cells. Mechanistically, we provide evidence that LMTK3 phosphorylates Rab7, a key regulator of multivesicular body (MVB) trafficking, thereby reducing the fusion of MVBs with lysosomes and subsequent degradation of intralumenal vesicles, resulting in altered EV release. Moreover, LMTK3 causes increased packaging of phosphoserine aminotransferase 1 (PSAT1) in EVs, leading to a paracrine upregulation of phosphoglycerate dehydrogenase (PHGDH) in monocytes when these EVs are taken up. PSAT1 and PHGDH play key roles in the serine biosynthesis pathway, which is closely linked to cancer progression and regulation of monocyte behaviour. LMTK3 EV-induced elevated PHGDH expression in monocytes reduces their infiltration into breast cancer 3D spheroids and in vivo breast cancer mouse models. Furthermore, these infiltrating monocytes preferentially differentiate into pro-tumourigenic M2-like macrophages. Additional breast cancer mouse studies highlight the contribution of LMTK3-dependent EVs in the observed immunosuppressive macrophage phenotype. Finally, in vitro experiments show that pharmacological inhibition of LMTK3 reverses the pro-tumourigenic and immunomodulatory effects mediated by EVs derived from LMTK3 overexpressing cells. Conclusion Overall, this study advances our knowledge on the mechanisms of EV biogenesis and highlights a novel oncogenic role of LMTK3 in the breast TME, further supporting it as a target for cancer therapy.

ObjectiveAlcohol-related liver disease (ArLD) is a leading cause of liver-related mortality, but affects a minority of people with alcohol use disorder (AUD). Of people with AUD, only those with ArLD require hepatologist input, necessitating case stratification. However, many are referred with established cirrhosis, when opportunities for intervention are limited. We report the evaluation of a novel primary care pathway using the enhanced liver fibrosis (ELF) test for early detection and stratification of ArLD patients.MethodsThe ELF alcohol pathway (EAP) was established in January 2020 and evaluated in May 2023. General practitioner referrals to a single liver centre using the EAP were compared with standard care (SC) referrals. The presence of steatosis constituted an ‘appropriate’ referral. The prevalence of structural ArLD and each stage of fibrosis was assessed, with liver status ascertained through electronic patient records.ResultsThe EAP was followed by 121 patients. Unnecessary referral (ELF<9.8) was avoided for 24.8% (n=30), with the 91 remaining EAP referrals compared with 197 contemporaneous SC referrals. Most referrals were deemed appropriate (97.5% vs 92.3% for SC and EAP, respectively), but significantly more SC referrals had advanced fibrosis (OR 2.68 (1.50 to 4.93); p<0.001), cirrhosis (OR 6.58 (2.84 to 17.79); p<0.0001) or decompensated cirrhosis (10.7% vs 0%; p<0.001).ConclusionUsing the EAP facilitated earlier detection of ArLD, with 8% of EAP referrals having established cirrhosis versus 35.5% of SC referrals. Unnecessary specialist referral was avoided for one-quarter of those assessed on the EAP. Pathway uptake was impacted by poor dissemination during the COVID-19 pandemic. Better implementation is warranted.

Practical project experience is enabling a degree apprentice to consolidate her learning, understand the Building Regulations and develop her portfolio, the fifth piece in our series explains

Taking a competency test, inspiring younger people into the profession and presenting at a conference have helped an apprentice surveyor gain confidence, the fourth article of a series explains

Joining colleagues on site has helped an apprentice building control surveyor gain confidence in the technical understanding developed on her degree, she explains in the third article of a series

A young building control surveyor reflects on how her studies have underpinned her practice in the second of a series on her degree apprenticeship

Revision and mock interviews testing technical knowledge and practical experience helped a degree apprentice successfully pass her end-point assessment, as she explains in the last of our series In the six months since my previous article, I have been completing my degree apprenticeship in building control while working for a registered building control approver and studying with the University - of the Built Environmgefdrmerly known as the University College of Estate Management. During this period, I have been focusing on revision and training exercises to ensure I am in the best position to complete my end-point assessment (EPA), which is the final stage of a building control surveyor degree apprenticeship. Related article Work and study offer mutual reinforcement Degree result reflects hard work and opportunities I am pleased to say I achieved a distinction in both my exam and interview, and have been awarded a first-class BSc (Hons) in building control.

In the first of a new series, one young building control surveyor explains how a degree apprenticeship is enabling her to put her passion for construction and the built environment to good work

The reciprocal relationship between classroom and construction site continue for a degree apprentice heading into the final year of her course, as she describes in the sixth article in our series 21 November 2023 In September, I entered the final year of my degree in building control, having successfully completed three years of academic study and workplace training. Inspections ground understanding on site Throughout the past six months, I have developed m experience significantly by attending inspections with workplace mentors on complex commercial sites, including multiple large industrial units with ancillary offices. The experience has also been extremely valuable in reinforcing my understanding of key technical areas of commercial construction, such as fire safety and structure generally.

Breast Cancer (BC) is the most common form of cancer worldwide, responsible for 25% of cancers in women. Whilst treatment is effective and often curative in early BC, metastatic disease is incurable, highlighting the need for early detection. Currently, early detection relies on invasive procedures, however recent studies have shown extracellular vesicles (EVs) obtained from liquid biopsies may have clinical utility. EVs transport diverse bioactive cargos throughout the body, play major roles in intercellular communication and, importantly, mirror their cell of origin. In cancer cells, EVs alter the behaviour of the tumour microenvironment (TME), forming a bridge of communication between cancerous and non-cancerous cells to alter all aspects of cancer progression, including the formation of a pre-metastatic niche. Through gene regulatory frameworks, non-coding RNAs (ncRNAs) modulate vital molecular and cellular processes and can act as both tumour suppressors and oncogenic drivers in various cancer types. EVs transport and protect ncRNAs, facilitating their use clinically as liquid biopsies for early BC detection. This review summarises current research surrounding ncRNAs and EVs within BC, focusing on their roles in cancer progression through bi-directional communication with the microenvironment and their diagnostic implications. The role of EV ncRNAs in breast cancer. A representation of the different EV ncRNAs involved in tumourigenic processes in breast cancer. Pro-tumourigenic ncRNAs displayed in green and ncRNAs which inhibit oncogenic processes are shown in red.