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Tumor cells commonly express abnormally glycosylated glycoproteins such as MUC1. Burchell and colleagues show that tumor-specific MUC1-ST interacts with the lectin Siglec-9 on myeloid cells and induces their conversion into suppressive tumor-associated macrophages. Siglec-9 is a sialic-acid-binding lectin expressed predominantly on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers and results in increased sialylation. Thus, when the mucin MUC1 is expressed on cancer cells, it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we found that this cancer-specific MUC1 glycoform, through engagement of Siglec-9, ‘educated’ myeloid cells to release factors associated with determination of the tumor microenvironment and disease progression. Moreover, MUC1-ST induced macrophages to display a tumor-associated macrophage (TAM)-like phenotype, with increased expression of the checkpoint ligand PD-L1. Binding of MUC1-ST to Siglec-9 did not activate the phosphatases SHP-1 or SHP-2 but, unexpectedly, induced calcium flux that led to activation of the kinases MEK-ERK. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway that follows engagement of Siglec-9.

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers. In this review, we evaluate the current literature regarding the regulation and the function of TXNIP, highlighting its emerging role in modulating signaling between different cell types within the TME. We then assess current and future translational opportunities and the associated challenges in this area. An improved understanding of the functions and mechanisms of TXNIP in cancers may enhance its suitability as a therapeutic target.

In existing breast cancer prediction research, most models rely solely on a single type of imaging data, which limits their performance. To overcome this limitation, the present study explores breast cancer prediction models based on multimodal medical images (mammography and ultrasound images) and compares them with single-modal models. We collected medical imaging data from 790 patients, including 2,235 mammography images and 1,348 ultrasound images, and conducted a comparison using six deep learning classification models to identify the best model for constructing the multimodal classification model. Performance was evaluated using metrics such as area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, and accuracy to compare the multimodal and single-modal classification models. Experimental results demonstrate that the multimodal classification model outperforms single-modal models in terms of specificity (96.41% (95% CI:93.10%-99.72%)), accuracy (93.78% (95% CI:87.67%-99.89%)), precision (83.66% (95% CI:76.27%-91.05%)), and AUC (0.968 (95% CI:0.947-0.989)), while single-modal models excel in sensitivity. Additionally, heatmap visualization was used to further validate the classification performance of the multimodal model. In conclusion, our multimodal classification model shows strong potential in breast cancer screening tasks, effectively assisting physicians in improving screening accuracy.

Aberrant glycosylation occurs in the majority of human cancers and changes in mucin-type O-glycosylation are key events that play a role in the induction of invasion and metastases. These changes generate novel cancer-specific glyco-antigens that can interact with cells of the immune system through carbohydrate binding lectins. Two glyco-epitopes that are found expressed by many carcinomas are Tn (GalNAc-Ser/Thr) and STn (NeuAcα2,6GalNAc-Ser/Thr). These glycans can be carried on many mucin-type glycoproteins including MUC1. We show that the majority of breast cancers carry Tn within the same cell and in close proximity to extended glycan T (Galβ1,3GalNAc) the addition of Gal to the GalNAc being catalysed by the T synthase. The presence of active T synthase suggests that loss of the private chaperone for T synthase, COSMC, does not explain the expression of Tn and STn in breast cancer cells. We show that MUC1 carrying both Tn or STn can bind to the C-type lectin MGL and using atomic force microscopy show that they bind to MGL with a similar dead adhesion force. Tumour associated STn is associated with poor prognosis and resistance to chemotherapy in breast carcinomas, inhibition of DC maturation, DC apoptosis and inhibition of NK activity. As engagement of MGL in the absence of TLR triggering may lead to anergy, the binding of MUC1-STn to MGL may be in part responsible for some of the characteristics of STn expressing tumours.

BackgroundFluorouracil (FU)-based chemotherapy regimens are indispensable in the comprehensive treatment of colorectal cancer (CRC). However, the heterogeneity of treated individuals and the severe adverse effects of chemotherapy results in limited overall benefit.MethodsFirstly, Weighted gene co-expression network analysis (WGCNA) identified modules tightly associated with chemotherapy response. Then, the in-house cohort and prognostic cohorts from TCGA and GEO were subjected to Cox proportional hazards model and survival analysis to ascertain the predictable function of SCG2 on the prognosis of CRC patients. Finally, we performed In vitro experiments, functional analysis, somatic mutation, and copy number variation research to explore the biological characteristics of SCG2.ResultsWe identified red and green as the modules most associated with chemotherapy response, in which SCG2 was considered a risky factor with higher expression predicting poorer prognosis. SCG2 expression in the APC non-mutation group was remarkably higher than in the mutation group. The mutation frequencies of amplified genes differed significantly between different SCG2 expression subgroups. Besides, CRC cell lines with SCG2 knockdown have reduced invasive, proliferative, and proliferative capacity. We discovered that the SCG2 high expression subgroup was the immune hot type and considered more suitable for immunotherapy.ConclusionThis study demonstrates the clinical significance and biological characteristics of SCG2, which could serve as a promising biomarker to identify patients who may benefit from chemotherapy and immunotherapy.

Background Low muscle mass, a component of sarcopenia, is increasingly recognised as a marker of poor physiological reserve in chronic diseases. While observed in patients with interstitial lung disease (ILD), its prevalence and clinical associations remain inadequately characterised. Furthermore, heterogeneous diagnostic approaches from CT-derived indices to consensus definitions complicate evidence interpretation. Methods We conducted a systematic review and meta-analysis to estimate the prevalence of low muscle mass and/or consensus-defined sarcopenia in ILD. Six databases were searched (1988–March 2024). Eight studies comprising 829 patients (701 with idiopathic pulmonary fibrosis [IPF]) met inclusion criteria. The included CT-based studies defined low muscle mass using cohort-specific lowest-quartile cut-offs, which do not meet consensus diagnostic criteria for sarcopenia. Results The pooled prevalence of low muscle mass and/or sarcopenia was 24.3% (95% CI: 19.7–29.0) with substantial heterogeneity (I²=59.2%). A sensitivity analysis restricted to consensus-defined sarcopenia yielded a 27.5% prevalence with moderate heterogeneity (I²=62.5%); however, studies within their respective consensus frameworks (EWGSOP2 or AWGS) demonstrated zero internal heterogeneity (I²=0%). In contrast, CT-based studies using cohort-specific thresholds showed marked variability (I²=75.8%). Meta-regression confirmed diagnostic method ( p  = 0.044) and mean BMI ( p  = 0.003) as significant moderators. Low muscle mass was significantly associated with reduced pulmonary function, including lower FVC% predicted (effect size − 0.477, p  < 0.001) and DLCO% predicted (effect size − 0.389, p  = 0.003), as well as advancing age and lower BMI. Conclusions While low muscle mass or consensus-defined sarcopenia affects approximately one in four ILD patients, this prevalence is largely representative of the IPF phenotype. Muscle mass abnormalities are significantly associated with respiratory decline, supporting muscle depletion as a clinically relevant marker with potential prognostic implication. However, substantial heterogeneity, driven by CT-based cohort-specific quartiles rather than externally validated thresholds, restricts the precision of current prevalence estimates. Future research should employ standardised consensus definitions, differentiate isolated muscle depletion from systemic wasting syndromes, use externally validated cut-offs, adopt multicentre prospective designs.

There is growing recognition that mucus and mucin biology have a considerable impact on respiratory health, and subsequent global morbidity and mortality. Mucins play a critical role in chronic lung disease, not only by providing a physical barrier and clearing pathogens, but also in immune homeostasis. The aim of this review is to familiarise the reader with the role of mucins in both lung health and disease, with particular focus on function in immunity, infection and inflammation. We will also discuss their receptors, termed glycan‐binding proteins, and how they provide an attractive prospect for therapeutic intervention. This review article explores the role of mucins in respiratory health and disease, with particular focus on their receptors, the glycan‐binding proteins.

T regulatory cell therapy presents a novel therapeutic strategy for patients with autoimmune diseases or who are undergoing transplantation. At present, the CD4+ Treg population has been extensively characterized, as a result of defined phenotypic and functional readouts. In this review article, we discuss the development and biology of CD8+ Tregs and their role in murine and human disease indications. A subset of CD8+ Tregs that lack the surface expression of CD28 (CD8+CD28− Treg) has proved efficacious in preclinical models. CD8+CD28− Tregs are present in healthy individuals, but their impaired functionality in disease renders them less effective in mediating immunosuppression. We primarily focus on harnessing CD8+ Treg cell therapy in the clinic to support current treatment for patients with autoimmune or inflammatory conditions.

The overexpression and aberrant glycosylation of MUC1 is associated with a wide variety of cancers, making it an ideal target for immunotherapeutic strategies. This review highlights the main avenues of research in this field, focusing on adenocarcinomas, from the preclinical to clinical; the problems and possible solutions associated with each approach; and speculates on the direction of MUC1 immunotherapeutic research over the next 5-10 years.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.