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Neoantigen immunogenicity prediction is a highly challenging problem in the development of personalised medicines. Low reactivity rates in called neoantigens result in a difficult prediction scenario with limited training datasets. Here we describe ImmugenX, a modular protein language modelling approach to immunogenicity prediction for CD8+ reactive epitopes. ImmugenX comprises of a pMHC encoding module trained on three pMHC prediction tasks, an optional TCR encoding module and a set of context specific immunogenicity prediction head modules. Compared with state-of-the-art models for each task, ImmugenX's encoding module performs comparably or better on pMHC binding affinity, eluted ligand prediction and stability tasks. ImmugenX outperforms all compared models on pMHC immunogenicity prediction (Area under the receiver operating characteristic curve = 0.619, average precision: 0.514), with a 7% increase in average precision compared to the next best model. ImmugenX shows further improved performance on immunogenicity prediction with the integration of TCR context information. ImmugenX performance is further analysed for interpretability, which locates areas of weakness found across existing immunogenicity models and highlight possible biases in public datasets., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A.Q. is co-founder and chief scientific officer and own shares in Achilles Therapeutics. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc., a collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. He is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the steering committee chair. He is also co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s scientific advisory board (SAB). He receives consultant fees from Achilles Therapeutics (also an SAB member); Bicycle Therapeutics (also an SAB member); Genentech; Medicxi; the China Innovation Centre of Roche (CICoR), formerly Roche Innovation Centre Shanghai; Metabomed (until July 2022); Relay Therapeutics; and the Sarah Cannon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana; previously held stock options in Apogen Biotechnologies and GRAIL; currently has stock options in Epic Bioscience and Bicycle Therapeutics; and has stock options and is co-founder of Achilles Therapeutics. S.R.H. is the cofounder of PokeAcell and is co-inventor of licensed patents related to T cell detection. H.O’B., M.S., L.M. and F.O’F. are employees of Achilles Therapeutics. H.O’B. and M.S. are both named inventors on patents for ImmugenX., (Copyright: © 2024 O’Brien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD., (© 2023. The Author(s).)

Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases., Methods: We performed an agnostic association analysis between alcohol consumption (red and white wine, beer/cider, fortified wine, and spirits) with over 7800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, phenotypes in a causal relationship with alcohol consumption as mediators, and various diseases as the outcome., Results: Of 45 phenotypes in association with alcohol consumption, 20 were in a causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β = 9.44; 95% CI = 5.94, 12.93; P fdr = 9.04 × 10 -7 ), mean sphered cell volume ( β = 0.189; 95% CI = 0.11, 0.27; P fdr = 1.00 × 10 -4 ), mean corpuscular volume ( β = 0.271; 95% CI = 0.19, 0.35; P fdr = 7.09 × 10 -10 ) and mean corpuscular haemoglobin ( β = 0.278; 95% CI = 0.19, 0.36; P fdr = 1.60 × 10 -6 ) demonstrated the strongest causal relationships. We also identified GGT and physical inactivity as mediators in the pathway between alcohol consumption, liver cirrhosis and alcohol dependence., Conclusion: Our study provides evidence of causality between alcohol consumption and 20 phenotypes and a mediation effect for physical activity on health consequences of alcohol consumption.

During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that Ras V12 ; scrib -/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: Parent-child interaction therapy refers to a group of interventions mediated by trained parents to address areas of developmental difficulties in children. In the field of speech and language therapy it is used in early intervention for children with speech, language and communication difficulties. The intervention involves training parents and caregivers on the importance of responsivity and language input in daily interactions and coaches them on strategies to implement these with the children. As the success of the intervention is heavily influenced by caregiver engagement, understanding and acceptance, it is important to consider their views. However, to date there has been limited work on synthesising parental views of this intervention. Methods: This is a protocol for a qualitative evidence synthesis of peer-reviewed qualitative papers addressing the experiences and perceptions of parent-child interaction therapy for parents of children with communication difficulties. We will complete a systematic search of 11 databases, review the reference lists and complete a cited reference search of all included studies. Two authors will independently screen tests for inclusion, initially by title and abstract, with full-text screening as necessary. Thematic synthesis will be used for all included studies. We will appraise the quality of included studies using CASP and confidence in the review findings using GRADE CERQual. Discussion: As the views of parents are pivotal in the success of this intervention, the findings from this synthesis should  help to guide best practice and policy for the future implementation of parent child interaction therapy for children with communication difficulties.., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 O'Toole C et al.)

Background: Parent-child interaction therapy is an early intervention for children with speech, language and communication difficulties. It involves training parents and caregivers on the importance of responsivity and language input in daily interactions and coaches them on strategies to implement this with the children. As the success of the intervention is heavily influenced by caregiver engagement, understanding and acceptance, it is important to consider their views. However, to date there has been limited work on synthesizing parental views of this intervention. Methods: This is a protocol for a qualitative evidence synthesis of peer-reviewed papers addressing the experiences and perceptions of parent-child interaction therapy for parents of young children with communication difficulties. We will complete a systematic search of 11 databases, review the reference lists and complete a cited reference search of all included studies. Two authors will independently screen tests for inclusion, initially by title and abstract, with full-text screening as necessary. Thematic synthesis will be used for all included studies. We will appraise the quality of included studies using CASP and confidence in the review findings using GRADE CERQual. Discussion: The findings from this synthesis will help to guide best practice and policy for the implementation of parent child interaction therapy by considering the views of parents., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 O'Toole C et al.)

The molecular mechanisms underlying the interdependence between intracellular trafficking and epithelial cell polarity are poorly understood. Here we show that inactivation of class III phosphatidylinositol-3-OH kinase (CIII-PI3K), which produces phosphatidylinositol-3-phosphate (PtdIns3P) on endosomes, disrupts epithelial organization. This is caused by dysregulation of endosomally localized Liver Kinase B1 (LKB1, also known as STK11), which shows delocalized and increased activity accompanied by dysplasia-like growth and invasive behaviour of cells provoked by JNK pathway activation. CIII-PI3K inactivation cooperates with Ras V12 to promote tumour growth in vivo in an LKB1-dependent manner. Strikingly, co-depletion of LKB1 reverts these phenotypes and restores epithelial integrity. The endosomal, but not autophagic, function of CIII-PI3K controls polarity. We identify the CIII-PI3K effector, WD repeat and FYVE domain-containing 2 (WDFY2), as an LKB1 regulator in Drosophila tissues and human organoids. Thus, we define a CIII-PI3K-regulated endosomal signalling platform from which LKB1 directs epithelial polarity, the dysregulation of which endows LKB1 with tumour-promoting properties.

As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

Objective: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair., Design: Prospective, randomized double-blinded control trial., Setting: Tertiary referral hospital., Participants: Sixty-two patients undergoing elective open AAA repair., Intervention: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff)., Measurements: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC., Conclusion: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues, but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that spare distinct tissues from starvation are poorly understood. Here, we reveal that the Ret-like receptor tyrosine kinase (RTK), Stitcher (Stit), is required for cell growth and proliferation through the PI3K-I/TORC1 pathway in the Drosophila wing disc. Both Stit and insulin receptor (InR) signaling activate PI3K-I and drive cellular proliferation and tissue growth. However, whereas optimal growth requires signaling from both InR and Stit, catabolic changes manifested by autophagy only occur when both signaling pathways are compromised. The combined activities of Stit and InR in ectodermal epithelial tissues provide an RTK-mediated, two-tiered reaction threshold to varying nutritional conditions that promote epithelial organ growth even at low levels of InR signaling., Competing Interests: The authors have declared that no competing interests exist.

Drosophila PNS sense organs arise from single sensory organ precursor (SOP) cells through a series of asymmetric divisions. In a mis-expression screen for factors affecting PNS development, we identified string and dappled as being important for the proper formation of adult external sensory (ES) organs. string is a G2 regulator. dappled has no described function but is implicated in tumorigenesis. The mis-expression effect from string was analysed using timed over expression during adult ES-organ and, for comparison, embryonic Chordotonal (Ch) organ formation. Surprisingly, string mis-expression prior to SOP division gave the greatest effect in both systems. In adult ES-organs, this lead to cell fate transformations producing structural cells, whilst in the embryo organs were lost, hence differences within the lineages exist. Mis-expression of dappled, lead to loss and duplications of entire organs in both systems, potentially affecting SOP specification, in addition to affecting neuronal guidance.