Nomogram for preoperative estimation of microvascular invasion risk in hepatocellular carcinoma.

Microvascular invasion (MVI) is an adverse prognostic indicator of tumor recurrence after surgery for hepatocellular carcinoma (HCC). Therefore, developing a nomogram for estimating the presence of MVI before liver resection is necessary. We retrospectively included 260 patients with pathologically confirmed HCC at the Fifth Medical Center of Chinese PLA General Hospital between January 2021 and April 2024. The patients were randomly divided into a training cohort (n = 182) for nomogram development, and a validation cohort (n = 78) to confirm the performance of the model (7:3 ratio). Significant clinical variables associated with MVI were then incorporated into the predictive nomogram using both univariate and multivariate logistic analyses. The predictive performance of the nomogram was assessed based on its discrimination, calibration, and clinical utility. Serum carnosine dipeptidase 1 ([CNDP1] OR 2.973; 95 % CI 1.167-7.575; p = 0.022), cirrhosis (OR 8.911; 95 % CI 1.922-41.318; p = 0.005), multiple tumors (OR 4.095; 95 % CI 1.374-12.205; p = 0.011), and tumor diameter ≥3 cm (OR 4.408; 95 % CI 1.780-10.919; p = 0.001) were independent predictors of MVI. Performance of the nomogram based on serum CNDP1, cirrhosis, number of tumors and tumor diameter was achieved with a concordance index of 0.833 (95 % CI 0.771-0.894) and 0.821 (95 % CI 0.720-0.922) in the training and validation cohorts, respectively. It fitted well in the calibration curves, and the decision curve analysis further confirmed its clinical usefulness. The nomogram, incorporating significant clinical variables and imaging features, successfully predicted the personalized risk of MVI in HCC preoperatively.

Association of age at diagnosis of diabetes with subsequent risk of age-related ocular diseases and vision acuity.

BACKGROUND: The importance of age on the development of ocular conditions has been reported by numerous studies. Diabetes may have different associations with different stages of ocular conditions, and the duration of diabetes may affect the development of diabetic eye disease. While there is a dose-response relationship between the age at diagnosis of diabetes and the risk of cardiovascular disease and mortality, whether the age at diagnosis of diabetes is associated with incident ocular conditions remains to be explored. It is unclear which types of diabetes are more predictive of ocular conditions. AIM: To examine associations between the age of diabetes diagnosis and the incidence of cataract, glaucoma, age-related macular degeneration (AMD), and vision acuity. METHODS: Our analysis was using the UK Biobank. The cohort included 8709 diabetic participants and 17418 controls for ocular condition analysis, and 6689 diabetic participants and 13378 controls for vision analysis. Ocular diseases were identified using inpatient records until January 2021. Vision acuity was assessed using a chart. RESULTS: During a median follow-up of 11.0 years, 3874, 665, and 616 new cases of cataract, glaucoma, and AMD, respectively, were identified. A stronger association between diabetes and incident ocular conditions was observed where diabetes was diagnosed at a younger age. Individuals with type 2 diabetes (T2D) diagnosed at < 45 years [HR (95%CI): 2.71 (1.49-4.93)], 45-49 years [2.57 (1.17-5.65)], 50-54 years [1.85 (1.13-3.04)], or 50-59 years of age [1.53 (1.00-2.34)] had a higher risk of AMD independent of glycated haemoglobin. T2D diagnosed < 45 years [HR (95%CI): 2.18 (1.71-2.79)], 45-49 years [1.54 (1.19-2.01)], 50-54 years [1.60 (1.31-1.96)], or 55-59 years of age [1.21 (1.02-1.43)] was associated with an increased cataract risk. T2D diagnosed < 45 years of age only was associated with an increased risk of glaucoma [HR (95%CI): 1.76 (1.00-3.12)]. HRs (95%CIs) for AMD, cataract, and glaucoma associated with type 1 diabetes (T1D) were 4.12 (1.99-8.53), 2.95 (2.17-4.02), and 2.40 (1.09-5.31), respectively. In multivariable-adjusted analysis, individuals with T2D diagnosed < 45 years of age [ß 95%CI: 0.025 (0.009,0.040)] had a larger increase in LogMAR. The ß (95%CI) for LogMAR associated with T1D was 0.044 (0.014, 0.073). CONCLUSION: The younger age at the diagnosis of diabetes is associated with a larger relative risk of incident ocular diseases and greater vision loss.

Entropy-Regulated Cathode with Low Strain and Constraint Phase-Change Toward Ultralong-Life Aqueous Al-Ion Batteries.

During multivalent ions insertion processes, intense electrostatic interaction between charge carriers and host makes the high-performance reversible Al3+ storage remains an elusive target. On account of the strong electrostatic repulsion and poor robustness, Prussian Blue analogues (PBAs) suffer severely from the inevitable and large strain and phase change during reversible Al3+ insertion. Herein, we demonstrate an entropy-driven strategy to realize ultralong life aqueous Al-ion batteries (AIBs) based on medium entropy PBAs (ME-PBAs) host. By multiple redox active centers introduction, the intrinsic poor conductivity can be enhanced simultaneously, resulting in outstanding capabilities of electrochemical Al3+ storage. Meanwhile, the co-occupation at metal sites in PBA frameworks can also increase the M-N bond intensity, which is beneficial for constraining the phase change during consecutive Al3+ reversible insertion, to realize an extended lifespan over 10,000 cycles. Based on the calculation at different operation states, the fluctuation of ME-PBA lattice parameters is only 1.2 %. Assembled with MoO3 anodes, the full cells can also deliver outstanding electrochemical properties. The findings highlight that, the entropy regulation strategy could uncover the isochronous constraint on both strain and phase transition for long-term reversible Al3+ storage, providing a promising design for advanced electrode materials for aqueous multivalent ions batteries.

Identification of a novel m6A-related lncRNAs signature and immunotherapeutic drug sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related with poor prognosis and immunotherapeutic effect in PDAC. The aim of this study is to construct and validate a m6A-related lncRNAs signature and assess immunotherapeutic drug sensitivity in PDAC. METHODS: RNA-seq data for 178 cases of PDAC patients and 167 cases of normal pancreatic tissue were obtained from TCGA and GTEx databases, respectively. A set of 21 m6A-related genes were downloaded based on the previous report. Co-expression network was conducted to identify m6A-related lncRNAs in PDAC. Cox analyses and least absolute shrinkage and selection operator (Lasso) regression model were used to construct a risk prognosis model. The relationship between signature genes and immune function was explored by single-sample GSEA (ssGSEA). The tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB) were utilized to evaluate the response to immunotherapy. Furthermore, the expression levels of 4 m6A-related lncRNAs on PDAC cell lines were measured by the quantitative real-time PCR (qPCR). The drug sensitivity between the high- and low-risk groups was validated using PDAC cell lines by Cell-Counting Kit 8 (CCK8). RESULTS: The risk prognosis model was successfully constructed based on 4 m6A-related lncRNAs, and PDAC patients were divided into the high- and low-risk groups. The overall survival (OS) of the high-risk groups was more unfavorable compared with the low-risk groups. Receiver operating characteristic (ROC) curves demonstrated that the risk prognosis model reasonably predicted the 2-, 3- and 5-year OS of PDAC patients. qPCR analysis confirmed the decreased expression levels of 4 m6A-related lncRNAs in PDAC cells compared to the normal pancreatic cells. Furthermore, CCK8 assay revealed that Phenformin exhibited higher sensitivity in the high-risk groups, while Pyrimethamine exhibited higher sensitivity in the low-risk groups. CONCLUSION: The prognosis of patients with PDAC were well predicted in the risk prognosis model based on m6A-related lncRNAs, and selected immunotherapy drugs have potential values for the treatment of pancreatic cancer.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Harnessing 3D in vitro systems to model immune responses to solid tumours: a step towards improving and creating personalized immunotherapies.

In vitro 3D models are advanced biological tools that have been established to overcome the shortcomings of oversimplified 2D cultures and mouse models. Various in vitro 3D immuno-oncology models have been developed to mimic and recapitulate the cancer-immunity cycle, evaluate immunotherapy regimens, and explore options for optimizing current immunotherapies, including for individual patient tumours. Here, we review recent developments in this field. We focus, first, on the limitations of existing immunotherapies for solid tumours, secondly, on how in vitro 3D immuno-oncology models are established using various technologies - including scaffolds, organoids, microfluidics and 3D bioprinting - and thirdly, on the applications of these 3D models for comprehending the cancer-immunity cycle as well as for assessing and improving immunotherapies for solid tumours.

Incidence, prevalence, and comorbidities of chronic pancreatitis: A 7-year population-based study.

BACKGROUND: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to reduced quality of life and shortened life expectancy. Population-based estimates of the incidence, prevalence, and comorbidities of CP in China are scarce. AIM: To characterize the incidence, prevalence, and comorbidities of CP in Sichuan Province, China, with population-based data. METHODS: Data on CP from 2015 to 2021 were obtained from the Health Information Center of Sichuan Province. During the study period, a total of 38090 individuals were diagnosed with CP in Sichuan Province. The yearly incidence rate and point prevalence rate (December 31, 2021) of CP were calculated. The prevalence of comorbid conditions in CP patients was estimated. The annual number of CP-related hospitalizations, hospital length of stay, and hospitalization costs for CP were evaluated. Yearly incidence rates were standardized for age by the direct method using the permanent population of Sichuan Province in the 2020 census as the standard population. An analysis of variance test for the linearity of scaled variables and the Cochran-Armitage trend test for categorical data were performed to investigate the yearly trends, and a two-sided test with P < 0.05 was considered statistically significant. RESULTS: The 38090 CP patients comprised 23280 males and 14810 females. The mean age of patients at CP diagnosis was 57.83 years, with male patients (55.87 years) being younger than female patients (60.11 years) (P < 0.001). The mean incidence rate of CP during the study period was 6.81 per 100000 person-years, and the incidence of CP increased each year, from 4.03 per 100000 person-years in 2015 to 8.27 per 100000 person-years in 2021 (P < 0.001). The point prevalence rate of CP in 2021 was 45.52 per 100000 individuals for the total population, with rates of 55.04 per 100000 individuals for men and 35.78 per 100000 individuals for women (P < 0.001). Individuals aged 65 years or older had the highest prevalence of CP (113.38 per 100000 individuals) (P < 0.001). Diabetes (26.32%) was the most common comorbidity in CP patients. The number of CP-related hospitalizations increased from 3739 in 2015 to 11009 in 2021. The total costs for CP-related hospitalizations for CP patients over the study period were 667.96 million yuan, with an average of 17538 yuan per patient. CONCLUSION: The yearly incidence of CP is increasing, and the overall CP hospitalization cost has increased by 1.4 times during the last 7 years, indicating that CP remains a heavy health burden.

Seasonal resource selection of free-ranging Zhongwei goats in the semi-arid grassland.

Goats rarely move and forage randomly. They tend to move in ways generally influenced by biotic and abiotic factors, respectively. However, few studies have explored the foraging behaviour of goats in the absence of predation and human disturbance. Based on step selection function modelling framework, Normalised Difference Vegetation Index, vegetation surveys, and Global Positioning System tracking of 124 free-ranging domestic adult male Zhongwei goats over one year (2016-2017) were used to assess how biotic and abiotic environmental factors affected their spatiotemporal distribution, and developed a conceptual model to represent the goats' trade-off between forage quantity and preference at different seasons, in the semi-arid grassland of Loess Plateau of 1 178 hectare. The results showed that spatial distributions of goats responded to spatiotemporal variation of biotic factors rather than abiotic factors of elevation, slope and solar radiation, which indicated that biotic factors were of priority to abiotic factors in the foraging process for the goats. According to the season changing, the goats positively used areas with higher forage quantity in the spring and winter, areas of higher forage quantity and preferred species in summer, and areas of abundance of preferred species in autumn. We developed a model to describe the phenomenon that the goats selected areas with higher preferred species only when the forage quantity was plentiful, otherwise they selected areas with higher forage quantity. Better understanding of the patterns and drivers of spatiotemporal distribution of the goats can improve our ability to predict foraging behaviour of livestock in heterogeneous environment and lead to better management practices and policies for the sustainability of these semi-arid landscapes and associated ecosystem services.

Tuning oxygen release of sodium-ion layered oxide cathode through synergistic surface coating and doping.

Layered transition metal oxides have the greatest potential for commercial application as cathode materials for sodium-ion batteries. However, transition metal oxides inevitably undergo an irreversible oxygen loss process during cycling, which leads to structural changes in the material and ultimately to severe capacity degradation. In this work, using density function theory (DFT) calculations, the Ni-O bond is revealed to be the weakest of the M-O bonds, which may lead to structural failure. Herein, the synergistic surface CeO2 modification and the trace doping of Ce elements stimulate oxygen redox and improve its reversibility, thus improving the structural stability and electrochemical performance of the material. Theoretical calculations prove that Na0.67Mn0.7Ni0.2Co0.1O2 (MNC) obtains electrons from CeO2, avoiding destruction of the Ni-O bond by over-energy released during the charging process and inhibiting oxygen loss. The capacity retention was 77.37% for 200 cycles at 500 mA g-1, compared to 33.84% for the unmodified Na0.67Mn0.7Ni0.2Co0.1O2. Overall, the present work demonstrates that the synergistic effect of surface coating and doping is an effective strategy for realizing tuning oxygen release and high electrochemical performance.

[Construction of cell factories for production of patchoulol in Saccharomyces cerevisiae].

Patchoulol is an important sesquiterpenoid in the volatile oil of Pogostemon cablin, and is also considered to be the main contributing component to the pharmacological efficacy and fragrance of P. cablin oil, which has antibacterial, antitumor, antioxidant, and other biological activities. Currently, patchoulol and its essential oil blends are in high demand worldwide, but the traditional plant extraction method has many problems such as wasting land and polluting the environment. Therefore, there is an urgent need for a new method to produce patchoulol efficiently and at low cost. To broaden the production method of patchouli and achieve the heterologous production of patchoulol in Saccharomyces cerevisiae, the patchoulol synthase(PS) gene from P. cablin was codon optimized and placed under the inducible strong promoter GAL1 to transfer into the yeast platform strain YTT-T5, thereby obtaining strain PS00 with the production of(4.0±0.3) mg·L~(-1) patchoulol. To improve the conversion rate, this study used protein fusion method to fuse SmFPS gene from Salvia miltiorrhiza with PS gene, leading to increase the yield of patchoulol to(100.9±7.4) mg·L~(-1) by 25-folds. By further optimizing the copy number of the fusion gene, the yield of patchoulol was increased by 90% to(191.1±32.7) mg·L~(-1). By optimizing the fermentation process, the strain was able to achieve a patchouli yield of 2.1 g·L~(-1) in a high-density fermentation system, which was the highest yield so far. This study provides an important basis for the green production of patchoulol.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells.

PURPOSE: Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. METHODS: The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. RESULTS: By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. CONCLUSION: In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner.

PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.

Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.

To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

CCBE1 promotes mitochondrial fusion by inhibiting the TGFß-DRP1 axis to prevent the progression of hepatocellular carcinoma.

The extracellular matrix (ECM), as an important component of the tumor microenvironment, exerts various roles in tumor formation. Mitochondrial dynamic disorder is closely implicated in tumorigenesis, including hyperfission in HCC. We aimed to determine the influence of the ECM-related protein CCBE1 on mitochondrial dynamics in HCC. Here, we found that CCBE1 was capable of promoting mitochondrial fusion in HCC. Initially, CCBE1 expression was found to be significantly downregulated in tumors compared with nontumor tissues, which resulted from hypermethylation of the CCBE1 promoter in HCC. Furthermore, CCBE1 overexpression or treatment with recombinant CCBE1 protein dramatically inhibited HCC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, CCBE1 functioned as an inhibitor of mitochondrial fission by preventing the location of DRP1 on mitochondria through inhibiting its phosphorylation at Ser616 by directly binding with TGFßR2 to inhibit TGFß signaling activity. In addition, a higher percentage of specimens with higher DRP1 phosphorylation was present in patients with lower CCBE1 expression than in patients with higher CCBE1 expression, which further confirmed the inhibitory effect of CCBE1 on DRP1 phosphorylation at Ser616. Collectively, our study highlights the crucial roles of CCBE1 in mitochondrial homeostasis, suggesting strong evidence for this process as a potential therapeutic strategy for HCC.

Correlation of catecholamine content and clinical influencing factors in depression among psoriasis patients: a case-control study.

OBJECTIVE: Our study sought to investigate the clinical influencing factors of psoriasis patients with depression, and analyze whether the content of monoamine neurotransmitters in plasma was correlated with depression incidence among psoriasis patients. METHODS: Ninety patients with psoriasis and 40 healthy volunteers (aged from18 to 60) were recruited and interviewed with a piloted questionnaire in both groups to obtain relevant information. The catecholamine in plasma from the two groups was analyzed by radioimmunoassay. The data were analyzed by SPSS statistical software. RESULTS: The mean Hamilton Depression Scale (HAMD) and mean Athens Insomnia Scale (AIS) scores of the psoriasis patients were higher than the control group. Dopamine content in the plasma was lower (comparing psoriasis patients without depression and the control group, and was negatively correlated with HAMD, AIS, and Psoriasis Area and Severity Index (PASI) scores in the psoriasis patients with depression. There was no significant difference in the epinephrine and norepinephrine contents in all groups. PASI scores were positively correlated with HAMD scores in psoriasis patients. The low dopamine content, Dermatology Life Quality Index, and high PASI scores were the risk factors for depression among the psoriasis patients. CONCLUSION: Psoriasis patients have a significantly higher risk of depression than healthy people, and higher PASI scores were linked to a higher incidence of depression. The dopamine levels of patients were influenced by both psoriasis and depression. The risk factors for depression in psoriasis patients are low dopamine levels in the plasma, severe skin lesions, and lower quality of life.

Spatiotemporal quantification of metastatic tumour cell growth and distribution in lymph nodes by whole-mount tissue 3D imaging.

Lymph nodes (LNs) are a common site of metastasis in many solid cancers. Tumour cells can migrate to LNs for further metastatic colonization of distant organs, indicating poor prognosis and requiring different clinical interventions. The histopathological diagnostic methods currently used to detect clinical lymph node metastasis (LNM) have limitations, such as incomplete visualization. To obtain a complete picture of metastatic LNs on the spatial and temporal scales, we used ultimate 3D imaging of solvent-cleared organs (uDISCO) and 3D rapid immunostaining. MC38 cells labelled with EGFP were injected into the left footpads of C57BL/6 mice. Draining lymph nodes (DLNs) harvested from these mice were cleared using the uDISCO method. Metastatic colorectal cancer (CRC) cells in various regions of DLNs from mice at different time points were quantified using 3D imaging of whole-mount tissue. Several stages of tumour cell growth and distribution in LNs were identified: 1) invasion of lymphatic vessels (LVs) and blood vessels (BVs); 2) dispersion outside LVs and BVs for proliferation and expansion; and 3) re-entry into BVs and efferent lymphatic vessels (ELVs) for further distant metastasis. Moreover, these data demonstrated that mouse fibroblast cells (MFCs) could not only promote LNM of tumour cells but also metastasize to LNs together with tumour cells, thus providing a "soil" for tumour cell colonization. In conclusion, 3D imaging of whole-mount tissue and spatiotemporal analysis of LNM may collectively constitute an auxiliary method to improve the accuracy of clinical LNM detection.

S100A14: A novel negative regulator of cancer stemness and immune evasion by inhibiting STAT3-mediated programmed death-ligand 1 expression in colorectal cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) has functional roles in cancer stem-like cell (CSC) phenotypes and chemoresistance besides immune evasion. Chemotherapy is a common treatment choice for colorectal cancer (CRC) patients; however, chemoresistance limits its effectiveness of treatment. METHODS: We examined the role of S100A14 (SA14) in CRC by adopting PD-L1high subpopulations within CRC cell lines and patient tumours, by establishing PD-L1high chemoresistant CRC sublines through prolonged exposure to 5-fluorouracil/oxaliplatin-based chemotherapy in vitro and in vivo, and by analysing a public database. RESULTS: We identified a novel function of SA14 as a regulator of immune surveillance, major CSC phenotypes, and survival capacity under hostile microenvironments, including those harbouring chemotherapeutics, and as a prognostic biomarker in CRC. Mechanistically, SA14 inhibits PD-L1 expression by directly interacting with signal transducer and activator of transcription 3 (STAT3) and inducing its proteasome-mediated degradation. While gain-of-SA14 causes loss of PD-L1 expression and tumourigenic potential and sensitisation to chemotherapy-induced apoptosis in chemoresistant CRC cells, loss-of-SA14 causes increases in PD-L1 expression, tumourigenic potential, and chemoresistance in vitro and in vivo. We further show that a combinatorial treatment with chemotherapy and recombinant SA14 protein effectively induces apoptosis in PD-L1high chemoresistant CRC cells. CONCLUSIONS: Our results suggest that SA14-based therapy is an effective strategy to prevent tumour progression and that SA14 is a predictive biomarker for anti-PD-L1 immunotherapy and chemotherapy in combination.