The primary impediment to the success of immunotherapy lies in the immune evasion orchestrated by tumors, contributing to the suboptimal overall response rates observed. Despite this recognition, the intricacies of the underlying mechanisms remain incompletely understood. Through preliminary detection of clinical patient tissues, we have found that ALDH1A1 was a key gene for the prognosis of cancer patients and tumor glycolysis. In vitro experiments and tumor formation in nude mice suggested that targeting ALDH1A1 could inhibit tumor growth. Through further analysis of xenograft tumor models in immune-normal mice and flow cytometry, we found that deficiency in ALDH1A1 could promote immune system suppression of tumors in vivo. Specifically, RNA-seq analysis, combined with qPCR and western blot, identified the transcription factor ZBTB7B as downstream of ALDH1A1. The binding sites of the transcription factor ZBTB7B on the LDHA promoter region, which is responsible for regulating the rate-limiting enzyme gene LDHA in glycolysis, were determined using luciferase reporter gene detection and Chip-qPCR, respectively. In addition, the increased SUMOylation of ZBTB7B stabilized its transcriptional activity. Further in vivo and in vitro experiments confirmed that the combination of targeting ALDH1A1 and ZBTB7B with immune checkpoint inhibitors could synergistically inhibit tumors in vivo. Finally, after conducting additional verification of patient tissue and clinical data, we have confirmed the potential translational value of targeting ALDH1A1 and ZBTB7B for tumor immunotherapy. These results emphasize the potential translational significance of targeting ALDH1A1 and ZBTB7B in the realm of tumor immunotherapy. The convergence of ALDH1A1 inhibition and immune checkpoint blockade, particularly with PD-L1/PD-1 mAb, presents a compelling avenue for curtailing tumor immune escape.

UNASSIGNED: Prognostic factors-based nomograms have been utilised to detect the likelihood of the specific cancer events. We have focused on the roles of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the prognosis of BC patients. This study was designed to establish nomograms based on the integration of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the disease-free survival (DFS) and overall survival (OS) of breast cancer (BC) patients.
UNASSIGNED: Demographic and clinical data were obtained from BC patients admitted to our hospital between September 2015 and August 2016. Univariate and multivariate Cox regression analyses were utilised to analyse the risk factors of recurrence and mortality. The nomograms for predicting the DFS and OS were established using the screened risk factors. Stratified analysis was performed with the cut-off value of exp (pi) of 4.0-fold in DFS and OS, respectively.
UNASSIGNED: Multivariate Cox regression analysis indicated that ALDH, p-AKT and pathological stage III were independent risk factors for the recurrence among BC patients. ALDH1, p-AKT, pathological stage III and ER-/PR-/HER2- were independent risk factors for the mortality among BC patients. The established nomograms based on these factors were effective for predicting the DFS and OS with good agreement to the calibration curve and acceptable area under the receiver operating characteristic (ROC) curve. Finally, stratified analyses showed patients with a low pi showed significant decrease in the DFS and OS compared with those of high risk.
UNASSIGNED: We established nomograms for predicting the DFS and OS of BC patients based on ALDH1, p-AKT and pathological stages. The ER-/PR-/HER2- may be utilised to predict the OS rather than DFS in the BC patients.
Many breast cancer patients show poor response after treatment due to recurrence and metastasis. Therefore, early prediction of the disease-free survival and overall survival is crucial to the treatment outcome and clinical decision-making. In this study, we established nomograms with the demographic and clinical data from breast cancer patients admitted to our hospital between September 2015 and August 2016. Univariate and multivariate Cox regression analyses showed that some important proteins and signalling pathways were risk factors for decreased disease-free survival and overall survival of breast cancer patients. On this basis, we established an effective nomogram for predicting the disease-free survival and overall survival of these patients based on these factors. This study offers new options in the predicting the treatment outcome of breast cancer patients.

This research aims to explore the mechanism by which microRNAs may regulate the biological behavior of tumor cells in ALDH1+ fibrosarcoma. We identified differentially expressed miRNAs in ALDH + NMFH-1 cells, screened genes related to sarcoma metastasis in the TCGA database, and finally obtained key genes regulated by miRNAs that are involved in metastasis. The function and mechanism of these key genes were then validated at the cellular level. Using the ULCAN database, a significant correlation was found between hsa-mir-206 and mortality in sarcoma patients. WGCNA analysis identified 352 genes related to tumor metastasis. Through Venn diagrams, we obtained 15 metastasis-related genes regulated by hsa-mir-206. Survival analysis showed that SYNPO2 expression is significantly correlated with survival rate and is significantly underexpressed in multiple tumors. SYNPO2 showed a negative correlation with macrophages and a positive correlation with CD8+ T cells. After inhibiting the expression of hsa-mir-206 with siRNA plasmids, the mRNA expression of SYNPO2 was significantly upregulated. The results of CCK8 assay, scratch assay, and transwell assay showed that the proliferation and migration ability of NFMH-1 cells were promoted after SYNPO2 was inhibited. ALDH1+ tumor stem cells promote the proliferation and invasion of malignant fibrous histiocytoma cells by inhibiting SYNPO2 through hsa-mir-206.

Aldehyde dehydrogenase 1A1 (ALDH1A1) stands out as one of the most reliable intracellular biomarkers for stem cells because it is expressed in both cancer stem cells (CSCs) and normal somatic stem cells (NSCs). Although several turn-on fluorescent probes for ALDH1A1 have been developed to visualize CSCs in cancer cells, the discrimination of CSCs from NSCs is difficult. We here report an AND-type dual-responsive fluorescent probe, CHO_βgal, the near-infrared fluorescence of which can be turned on after responding to both ALDH1A1 and β-galactosidase. The AND-type dual responsiveness enables CSCs to be clearly visualized, whereas NSCs are non-emissive in microscopy. CSC-positive metastasis model lungs were successfully discriminated from normal lungs in ex vivo staining experiments using CHO_βgal, whereas the single-input ALDH1A1-responsive probe failed to achieve this discrimination owing to pronounced false-positive fluorescence output from lung NSCs. In tissue slice staining experiments, even in the presence of adjacent normal tissues, the peripheral region-specific localization of CSCs was clear. The versatility of CHO_βgal holds promise not only as a fundamental in vitro research tool for visualizing CSCs but also as a valuable asset in practical tissue staining diagnosis, significantly contributing to the assessment of cancer malignancy.

Breast cancer severely affects women health. 70% of breast cancer are estrogen receptor positive. Breast cancer stem cells are a group of tumor with plasticity, causing tumor relapse and metastasis. RUNX3 is a tumor suppressor frequently inactivated in estrogen receptor positive breast cancer. However, the mechanism of how RUNX3 is involved in the regualation of cancer stem cell traits in estrogen receptor positive breast cancer remains elusive. In this study, we utilized cut-tag assay to investigate the binding profile RUNX3 in BT474 and T47D cell, and confirmed EXOSC4 as the bona-fide target of RUNX3; RUNX3 could bind to the promoter are of EXOSC4 to suppress its expression. Furthermore, EXOSC4 could increase the colony formation, cell invasion and mammosphere formation ability of breast cancer cells and upregulate the the expression of SOX2 and ALDH1. Consistent with these findings, EXOSC4 was associated with poorer survival for Luminal B/Her2 breast cancer patiens. At last, we confirmed that EXOSC4 mediated the tumor suppressive role of RUNX3 in breast cancer cells. In conclusion, we demonstrate that RUNX3 directly binds to the promoter region of EXOSC4, leading to the suppression of EXOSC4 expression and exerting a tumor-suppressive effect in estrogen receptor postivive breast cancer cells.

BACKGROUND: We examined associations of CD44, CD24 and ALDH1A1 breast stem cell markers with mammographic breast density (MBD), a well-established breast cancer (BCa) risk factor.
METHODS: We included 218 cancer-free women with biopsy-confirmed benign breast disease within the Nurses\' Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as percent of positively stained cells for each marker out of the total cell count. MBD was assessed with computer-assisted techniques. Generalised linear regression was used to examine the associations of each marker with square root-transformed percent density (PD), absolute dense and non-dense areas (NDA), adjusted for BCa risk factors.
RESULTS: Stromal CD44 and ALDH1A1 expression was positively associated with PD (≥ 10% vs. <10% β = 0.56, 95% confidence interval [CI] [0.06; 1.07] and β = 0.81 [0.27; 1.34], respectively) and inversely associated with NDA (β per 10% increase = -0.17 [-0.34; -0.01] and β for ≥10% vs. <10% = -1.17 [-2.07; -0.28], respectively). Epithelial CD24 expression was inversely associated with PD (β per 10% increase = -0.14 [-0.28; -0.01]. Stromal and epithelial CD24 expression was positively associated with NDA (β per 10% increase = 0.35 [0.2 × 10-2; 0.70] and β per 10% increase = 0.34 [0.11; 0.57], respectively).
CONCLUSIONS: Expression of stem cell markers is associated with MBD.

Aldehyde dehydrogenase 1 (ALDH1), a crucial aldehyde metabolizing enzyme, has six family members. The ALDH1 family is expressed in various tissues, with a significant presence in the liver. It plays a momentous role in several pathophysiological processes, including aldehyde detoxification, oxidative stress, and lipid peroxidation. Acetaldehyde detoxification is the fundamental function of the ALDH1 family in participating in vital pathological mechanisms. The ALDH1 family can catalyze retinal to retinoic acid (RA) that is a hormone-signaling molecule and plays a vital role in the development and adult tissues. Furthermore, there is a need for further and broader research on the role of the ALDH1 family as a signaling molecule. The ALDH1 family is widely recognized as a cancer stem cell (CSC) marker and plays a significant role in the proliferation, invasion, metastasis, prognosis, and drug resistance of cancer. The ALDH1 family also participates in other human diseases, such as neurodegenerative diseases, osteoarthritis, diabetes, and atherosclerosis. It can inhibit disease progression by inhibiting/promoting the expression/activity of the ALDH1 family. In this review, we comprehensively analyze the tissue distribution, and functions of the ALDH1 family. Additionally, we review the involvement of the ALDH1 family in diseases, focusing on the underlying pathological mechanisms and briefly talk about the current status and development of ALDH1 family inhibitors. The ALDH1 family presents new possibilities for treating diseases, with both its upstream and downstream pathways serving as promising targets for therapeutic intervention. This offers fresh perspectives for drug development in the field of disease research.

Nasal xenobiotic metabolizing enzymes (XMEs) are important for the sense of smell because they influence odorant availability and quality. Since the major part of the human nasal cavity is lined by a respiratory mucosa, we hypothesized that this tissue contributed to nasal odorant metabolism through XME activity. Thus, we built human respiratory tissue models and characterized the XME profiles using single-cell RNA sequencing. We focused on the XMEs dicarbonyl and l-xylulose reductase, aldehyde dehydrogenase (ALDH) 1A1, and ALDH3A1, which play a role in food odorant metabolism. We demonstrated protein abundance and localization in the tissue models and showed the metabolic activity of the corresponding enzyme families by exposing the models to the odorants 3,4-hexandione and benzaldehyde. Using gas chromatography coupled with mass spectrometry, we observed, for example, a significantly higher formation of the corresponding metabolites 4-hydroxy-3-hexanone (39.03 ± 1.5%, p = 0.0022), benzyl alcohol (10.05 ± 0.88%, p = 0.0008), and benzoic acid (8.49 ± 0.57%, p = 0.0004) in odorant-treated tissue models compared to untreated controls (0 ± 0, 0.12 ± 0.12, and 0.18 ± 0.18%, respectively). This is the first study that reveals the XME profile of tissue-engineered human respiratory mucosa models and demonstrates their suitability to study nasal odorant metabolism.

Alcohol-associated liver disease (ALD) is a prevalent liver disease, yet research is hampered by the lack of suitable and reliable human ALD models. Herein, we generated human adipose stromal/stem cell (hASC)-derived hepatocellular organoids (hAHOs) and hASC-derived liver organoids (hALOs) in a three-dimensional system using hASC-derived hepatocyte-like cells and endodermal progenitor cells, respectively. The hAHOs were composed of major hepatocytes and cholangiocytes. The hALOs contained hepatocytes and nonparenchymal cells and possessed a more mature liver function than hAHOs. Upon ethanol treatment, both steatosis and inflammation were present in hAHOs and hALOs. The incubation of hALOs with ethanol resulted in increases in the levels of oxidative stress, the endoplasmic reticulum protein thioredoxin domain-containing protein 5 (TXNDC5), the alcohol-metabolizing enzymes ADH1B and ALDH1B1, and extracellular matrix accumulation, similar to those of liver tissues from patients with ALD. These results present a useful approach for understanding the pathogenesis of ALD in humans, thus facilitating the discovery of effective treatments.

Identifying marker combinations for robust prognostic validation in primary tumour compartments remains challenging. We aimed to assess the prognostic significance of CSC markers (ALDH1, CD44, p75NTR, BMI-1) and E-cadherin biomarkers in OSCC. We analysed 94 primary OSCC and 67 metastatic lymph node samples, including central and invasive tumour fronts (ITF), along with clinicopathological data. We observed an increase in ALDH1+/CD44+/BMI-1- tumour cells in metastatic lesions compared to primary tumours. Multivariate analysis highlighted that elevated p75NTR levels (at ITF) and reduced E-cadherin expression (at the tumour centre) independently predicted metastasis, whilst ALDH1high exhibited independent predictive lower survival at the ITF, surpassing the efficacy of traditional tumour staging. Then, specifically at the ITF, profiles characterized by CSChighE-cadherinlow (ALDH1highp75NTRhighE-cadherinlow) and CSCintermediateE-cadherinlow (ALDH1 or p75NTRhighE-cadherinlow) were significantly associated with worsened overall survival and increased likelihood of metastasis in OSCC patients. In summary, our study revealed diverse tumour cell profiles in OSCC tissues, with varying CSC and E-cadherin marker patterns across primary tumours and metastatic sites. Given the pivotal role of reduced survival rates as an indicator of unfavourable prognosis, the immunohistochemistry profile identified as CSChighE-cadherinlow at the ITF of primary tumours, emerges as a preferred prognostic marker closely linked to adverse outcomes in OSCC.