Single-cell transcriptomics and Mendelian randomization reveal LUCAT1's role in right-sided colorectal cancer risk.

Background: Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided and right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, and prognosis. Methods: This study employed single-cell transcriptomic data and various bioinformatics approaches, such as two-sample Mendelian randomization, reverse Mendelian randomization, colocalization analysis, directed filtering, pseudotime analysis, and intercellular communication analysis. It analyzed cellular-level disparities between left-sided and right-sided CRC, identifying distinct subpopulations with characteristic variations. For these cells, two-sample Mendelian randomization was utilized to explore gene-to-one-sided CRC causality. Results: LUCAT1 was enriched in high-abundance monocyte subpopulations in right-sided CRC and demonstrated potential risk factor status through Mendelian randomization analysis. The specific single-nucleotide polymorphism (SNP) rs10774624 was associated with an increased risk of CRC. Moreover, metabolic pathway analysis revealed that LUCAT1+ monocytes exhibit lower communication activity in the tumor microenvironment and heightened activity in metabolic functions like glycosaminoglycan degradation. Its biological functions are related to the positive regulation of interleukin-6 production and NF-kappa B signaling, among others. Conclusion: This study confirmed a potential causal relationship between LUCAT1 and right-sided CRC risk through Mendelian randomization analysis. These findings provide novel insights into the pathogenesis of right-sided CRC and may aid in developing early detection and treatment strategies for right-sided CRC.

Multiple-matrix metabolomics analysis for the distinct detection of colorectal cancer and adenoma.

OBJECTIVES: Although colorectal cancer (CRC) is the leading cause of cancer-related morbidity and mortality, current diagnostic tests for early-stage CRC and colorectal adenoma (CRA) are suboptimal. Therefore, there is an urgent need to explore less invasive screening procedures for CRC and CRA diagnosis. METHODS: Untargeted gas chromatography-mass spectrometry (GC-MS) metabolic profiling approach was applied to identify candidate metabolites. We performed metabolomics profiling on plasma samples from 412 subjects including 200 CRC patients, 160 CRA patients and 52 normal controls (NC). Among these patients, 45 CRC patients, 152 CRA patients and 50 normal controls had their fecal samples tested simultaneously. RESULTS: Differential metabolites were screened in the adenoma-carcinoma sequence. Three diagnostic models were further developed to identify cancer group, cancer stage, and cancer microsatellite status using those significant metabolites. The three-metabolite-only classifiers used to distinguish the cancer group always keeps the area under the receiver operating characteristic curve (AUC) greater than 0.7. The AUC performance of the classifiers applied to discriminate CRC stage is generally greater than 0.8, and the classifiers used to distinguish microsatellite status of CRC is greater than 0.9. CONCLUSION: This finding highlights potential early-driver metabolites in CRA and early-stage CRC. We also find potential metabolic markers for discriminating the microsatellite state of CRC. Our study and diagnostic model have potential applications for non-invasive CRC and CRA detection.

Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90ß accessibility.

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.

α-Hederin induces paraptosis by targeting GPCRs to activate Ca2+/MAPK signaling pathway in colorectal cancer.

BACKGROUND: Non-apoptotic cell death is presently emerging as a potential direction to overcome the apoptosis resistance of cancer cells. In the current study, a natural plant agent α-hederin (α-hed) induces caspase-independent paraptotic modes of cell death. PURPOSE: The present study is aimed to investigate the role of α-hed induces paraptosis and the associated mechanism of it. METHODS: The cell proliferation was detected by CCK-8. The cytoplasm organelles were observed under electron microscope. Calcium (Ca2+) level was detected by flow cytometry. Swiss Target Prediction tool analyzed the potential molecule targets of α-hed. Molecular docking methods were used to evaluate binding abilities of α-hed with targets. The expressions of genes and proteins were analyzed by RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. Xenograft models in nude mice were established to evaluate the anticancer effects in vivo. RESULTS: α-hed exerted significant cytotoxicity against a panel of CRC cell lines by inhibiting proliferation. Besides, it induced cytoplasmic vacuolation in all CRC cells. Electron microscopy images showed the aberrant dilation of endoplasmic reticulum and mitochondria. Both mRNA and protein expressions of Alg-2 interacting proteinX (Alix), the marker of paraptosis, were inhibited by α-hed. Besides, both Swiss prediction and molecular docking showed that the structure of α-hed could tightly target to GPCRs. GPCRs were reported to activate the phospholipase C (PLC)-ß3/ inositol 1,4,5-trisphosphate receptor (IP3R)/ Ca2+/ protein kinase C alpha (PKCα) pathway, and we then found all proteins and mRNA expressions of PLCß3, IP3R, and PKCα were increased by α-hed. After blocking the GPCR signaling, α-hed could not elevate Ca2+ level and showed less CRC cell cytotoxicity. MAPK cascade is the symbol of paraptosis, and we then demonstrated that α-hed activated MAPK cascade by elevating Ca2+ flux. Since non-apoptotic cell death is presently emerging as a potential direction to overcome chemo-drug resistance, we then found α-hed also induced paraptosis in 5-fluorouracil-resistant (5-FU-R) CRC cells, and it reduced the growth of 5-FU-R CRC xenografts. CONCLUSIONS: Collectively, our findings proved α-hed as a promising candidate for inducing non-apoptotic cell death, paraptosis. It may overcome the resistance of apoptotic-based chemo-resistance in CRC.

Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites.

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.

Efficacy and safety of Shenbai Granules for recurrent colorectal adenoma: A multicenter randomized controlled trial.

BACKGROUND: Colorectal adenoma is benign glandular tumor of colon, the precursor of colorectal cancer. But no pharmaceutical medication is currently available to treat and prevent adenomas. PURPOSE: To evaluate efficacy of Shenbai Granules, an herbal medicine formula, in reducing the recurrence of adenomas. STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by eight hospitals in China. METHODS: Patients who had received complete polypectomy and were diagnosed with adenomas within the recent 6 months were randomly assigned (1:1) to receive either Shenbai granules or placebo twice a day for 6 months. An annual colonoscopy was performed during the 2-year follow-up period. The primary outcome was the proportion of patients with at least one adenoma detected in the modified intention-to-treat (mITT) population during follow-up for 2 years. The secondary outcomes were the proportion of patients with sessile serrated lesions and other specified polypoid lesions. The data were analyzed using logistic regression. RESULTS: Among 400 randomized patients, 336 were included in the mITT population. We found significant differences between treatment and placebo groups in the proportion of patients with at least one recurrent adenoma (42.5 % vs. 58.6 %; OR, 0.47; 95 % CI, 0.29-0.74; p = 0.001) and sessile serrated lesion (1.8 % vs. 8.3 %; OR, 0.20; 95 % CI, 0.06-0.72; p = 0.01). There was no significant difference in the proportion of patients developing polypoid lesions (70.7 % vs. 77.5 %; OR, 1.43; 95 % CI, 0.88-2.34; p = 0.15) or high-risk adenomas (9.0 % vs. 13.6 %; OR, 0.63; 95 % CI, 0.32-1.25; p = 0.18). CONCLUSION: Shenbai Granules significantly reduced the recurrence of adenomas, indicating that they could be an effective option for adenomas. Future studies should investigate its effects in larger patient populations and explore its mechanism of action to provide more comprehensive evidence for the use of Shenbai Granules in adenoma treatment.

Causal relationship of genetically predicted gut microbiota with thyroid cancer: a bidirectional two-sample mendelian randomization study.

Background: Previous investigations have demonstrated a correlation between the composition of gut microbiota and the development of thyroid cancer (TC). Nonetheless, there was no consensus on the causal effect of gut microbiota composition on TC risk. Therefore, the present study aimed to perform a bidirectional two-sample Mendelian randomization (MR) analysis to explore potential causal associations between gut microbiota and TC risk. Methods: Utilizing data from the MiBioGen consortium's genome-wide association studies (GWAS) meta-analysis involving a sample size of 18,340, we identified instrumental variables for 211 gut microbiota taxa. The summary statistics for TC was from relevant large-scale GWAS conducted by the FinnGen consortium. In the first stage, the Inverse-variance weighted (IVW) method was used as the primary estimate method, and the stability of estimations was tested by a battery of sensitivity analyses. In the second stage, a reverse MR analysis was applied to determine whether reverse causality existed. Results: According to the IVW method, we identified 9 genetically predicted gut microbiota that were causally correlated with TC risk. Among them, we observed a positive causal effect of Family Christensenellaceae (OR = 1.664, 95% CI: 1.103-2.511, P = 0.015), Family Victivallaceae (OR = 1.268, 95% CI: 1.009-1.594, P = 0.042), Genus Methanobrevibacter (OR = 1.505, 95% CI: 1.049-2.159, P = 0.027), Genus Ruminococcus2 (OR = 1.846, 95% CI: 1.261-2.704, P = 0.002), Genus Subdoligranulum (OR = 1.907, 95% CI: 1.165-3.121, P = 0.010), Phylum Verrucomicrobia (OR = 1.309, 95% CI: 1.027-1.668, P = 0.029) on TC risk, while Class Betaproteobacteria (OR = 0.522, 95% CI: 0.310-0.879, P = 0.015), Family Family XI (OR = 0.753, 95% CI: 0.577-0.983, P = 0.037), Genus Sutterella (OR = 0.596, 95% CI: 0.381-0.933, P = 0.024) might be correlated with a decreased risk of TC. Subsequently, various sensitivity analyses indicated no heterogeneity, directional pleiotropy or outliers. In addition, reverse analysis demonstrated a negative causal effect of TC risk on the abundance of the gut microbiota (Genus Ruminococcus2, OR = 0.947, 95% CI: 0.907-0.989, P = 0.014). Conclusion: Genetic evidence suggested that bidirectional causal associations of specific bacteria taxa and the risk of TC, highlighting the association of the "gut-thyroid" axis. Further exploration of the potential microbiota-related mechanisms might have profound implications for public health in terms of the early prevention and treatment of TC.

DPP2/7 is a Potential Predictor of Prognosis and Target in Immunotherapy in Colorectal Cancer: An Integrative Multi-omics Analysis.

BACKGROUND: Colorectal cancer (CRC) ranks among the leading causes of cancerrelated deaths. OBJECTIVE: This study aimed to illuminate the relationship between DPP7 (also known as DPP2) and CRC through a combination of bioinformatics and experimental methodologies. METHODS: A multi-dimensional bioinformatic analysis on DPP7 was executed, covering its expression, survival implications, clinical associations, functional roles, immune interactions, and drug sensitivities. Experimental validations involved siRNA-mediated DPP7 knockdown and various cellular assays. RESULTS: Data from the Cancer Genome Atlas (TCGA) identified high DPP7 expression in solid CRC tumors, with elevated levels adversely affecting patient prognosis. A shift from the N0 to the N2 stage in CRC was associated with increased DPP7 expression. Functional insights indicated the involvement of DPP7 in cancer progression, particularly in extracellular matrix disassembly. Immunological analyses showed its association with immunosuppressive entities, and in vitro experiments in CRC cell lines underscored its oncogenic attributes. CONCLUSION: DPP7 could serve as a CRC prognosis marker, functioning as an oncogene and representing a potential immunotherapeutic target.

Sophocarpine alleviates intestinal fibrosis via inhibition of inflammation and fibroblast into myofibroblast transition by targeting the Sirt1/p65 signaling axis.

In this study, we used alkaloids from Sophora flavescens to inhibit the SASP, leading to fibroblast-into-myofibroblast transition (FMT) to maintain intestinal mucosal homeostasis in vitro and in vivo. We used western blotting (WB) and immunofluorescence staining (IF) to assess whether five kinds of alkaloids inhibit the major inflammatory pathways and chose the most effective compound (sophocarpine; SPC) to ameliorate colorectal inflammation in a dextran sulfate sodium (DSS)-induced UC mouse model. IF, Immunohistochemistry staining (IHC), WB, disease activity index (DAI), and enzyme-linked immunosorbent assay (ELISA) were conducted to investigate the mechanism of action of this compound. Next, we detected the pharmacological activity of SPC on the senescence-associated secretory phenotypes (SASP) and FMT in interleukin 6 (IL-6)-induced senescence-like fibroblasts and discussed the mucosal protection ability of SPC on a fibroblast-epithelium/organoid coculture system and organ-on-chip system. Taken together, our results provide evidence that SPC alleviates the inflammatory response, improves intestinal fibrosis and maintains intestinal mucosal homeostasis in vivo. Meanwhile, SPC was able to prevent IL-6-induced SASP and FMT in fibroblasts, maintain the expression of TJ proteins, and inhibit inflammation and genomic stability of colonic mucosal epithelial cells by activating SIRT1 in vitro. In conclusion, SPC treatment attenuates intestinal fibrosis by regulating SIRT1/NF-κB p65 signaling, and it might be a promising therapeutic agent for inflammatory bowel disease.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

Association between the dietary inflammatory index and all-cause mortality in the U.S. cancer survivors: A prospective cohort study using the National Health and Nutrition Examination Survey database.

Background: Cancer remains one of the leading causes of mortality worldwide. Diet can impact inflammation and consequently affect cancer outcomes. The Dietary Inflammatory Index (DII) can serve as a tool to assess the inflammatory potential of cancer survivors' diets and further predict their survival. Objectives: To investigate the relationship between the DII and the survival of cancer survivors in National Health and Nutrition Examination Survey (NHANES). Methods: An overall sample of 2359 U.S. cancer survivors from the 2005-2014 cohorts of the NHANES were studied. The DII scores were calculated using 28 dietary components and the mortality status was ascertained until December 31, 2015. Based on the multiple analyses, the relationship between DII and all-cause mortality was examined. Results: The weighted mean age at baseline was 65.17 ± 14.46 years, 53.16 % were female and 71.30 % were non-Hispanic white. The average DII was 1.51 ± 1.97. After accounting for multiple covariates, positive associations were observed (P < 0.01). Based on Kaplan-Meier survival curves, their significant relationship remains same and the survival probability was decreased among the groups of anti-inflammatory diets (DII < 0) versus pro-inflammatory diets (DII ≥ 0) significantly (Log rank test; P = 0.03). Further analyses were conducted on subgroups and the results are still robust. Conclusions: An elevated DII was associated with a rising mortality rate among cancer survivors. DII might serve as a potential inflammatory predictor of cancer mortality prognosis, as well as guide nutritional care and even clinical treatment of cancer survivors.

Long­term survival of a patient with advanced lung cancer treated with targeted therapy and anti­PD­1 immunotherapy as multi­line therapy: A case report.

Lung cancer is the most common type of cancer worldwide. Lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), is a common type of lung cancer. In recent years, immunotherapy has become the primary method of treatment for several solid cancers, including NSCLC. In the present study, the case of a patient with NSCLC following left superior lobectomy is reported. Different systemic therapies failed, such as a pemetrexed + carboplatin regimen, paclitaxel liposome + cisplatin and pembrolizumab, and albumin-bound paclitaxel + toripalimab, but long-term survival was achieved following targeted therapy and anti-programmed cell death protein-1 (PD-1) immunotherapy. The patient survived for >4 years following lung cancer progression, which is notably longer than expected for patients with advanced lung cancer. In conclusion, the present case demonstrated the efficacy of targeted therapy and anti-PD-1 immunotherapy for the treatment of advanced lung cancer following the occurrence of drug resistance and progressive disease.

Advanced gastric cancer with metachronous intracranial oligometastases without recurrence after multidisciplinary team discussion and comprehensive treatment: a case report.

This article describes the process of multidisciplinary team (MDT) discussion and comprehensive treatment of a case of advanced gastric cancer that tested positive for programmed death ligand 1 (PD-L1). During diagnosis, the patient presented with advanced gastric cancer and numerous unresectable metastases in the lesser omental lymph nodes, both lungs, liver, and left parietal occipital lobe. A meeting was arranged for the departments of oncology, gastrointestinal surgery, radiotherapy, imaging, and pathology to discuss the case. Initially, the patient had a partial response to the first-line treatment, which was a combination of pembrolizumab and chemotherapy. However, after nineteen months, the patient presented with a metachronous isolated lesion in the left frontal lobe. After mutual agreement among the oncology, brain surgery, gastrointestinal surgery, radiotherapy, imaging, and pathology departments, the intracranial lesion underwent resection. Following this, the operation was supplemented by stereotactic radiation therapy (SRT) and whole-brain radiation therapy (WBRT). The patient showed excellent signs of recovery after the operation, and her general condition remained favorable after 16 months of follow-up. Nonetheless, the outlook for patients facing advanced-stage gastric cancer remains distressing. Through multidisciplinary team (MDT) discussions, patients diagnosed with advanced gastric cancer can receive standardized diagnostic and treatment approaches to develop reasonable and personalized comprehensive treatment plans. Such plans help to improve the quality of life of patients and effectively prolong their survival time.

Research progress on the biological basis of Traditional Chinese Medicine syndromes of gastrointestinal cancers.

Gastrointestinal cancers account for 11.6 % of all cancers, and are the second most frequently diagnosed type of cancer worldwide. Traditional Chinese medicine (TCM), together with Western medicine or alone, has unique advantages for the prevention and treatment of cancers, including gastrointestinal cancers. Syndrome differentiation and treatment are basic characteristics of the theoretical system of TCM. TCM syndromes are the result of the differentiation of the syndrome and the basis of treatment. Genomics, transcriptomics, proteomics, metabolomics, intestinal microbiota, and serology, generated around the central law, are used to study the biological basis of TCM syndromes in gastrointestinal cancers. This review summarizes current research on the biological basis of TCM syndrome in gastrointestinal cancers and provides useful references for future research on TCM syndrome in gastrointestinal cancers.

Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.

Liquid chromatography-tandem mass spectrometry analysis of a ratio-optimized drug pair of Sophora flavescens Aiton and Coptis chinensis Franch and study on the mechanism of anti-colorectal cancer effect of two alkaloids thereof.

The drug pair consisting of Sophora flavescens Aiton (Sophorae flavescentis radix, Kushen) and Coptis chinensis Franch. (Coptidis rhizoma, Huanglian), as described in Prescriptions for Universal Relief (Pujifang), is widely used to treat laxation. Matrine and berberine are the major active components of Kushen and Huanglian, respectively. These agents have shown remarkable anti-cancer and anti-inflammatory effects. A mouse model of colorectal cancer was used to determine the most effective combination of Kushen and Huanglian against anti-colorectal cancer. The results showed that the combination of Kushen and Huanglian at a 1:1 ratio exerted the best anti-colorectal cancer effect versus other ratios. Moreover, the anti-colorectal cancer effect and potential mechanism underlying the effects of matrine and berberine were evaluated by the analysis of combination treatment or monotherapy. In addition, the chemical constituents of Kushen and Huanglian were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 67 chemical components were identified from the Kushen-Huanglian drug pair (water extraction), and the levels of matrine and berberine were 129 and 232 µg/g, respectively. Matrine and berberine reduced the growth of colorectal cancer and relieved the pathological conditions in mice. In addition, the combination of matrine and berberine displayed better anti-colorectal cancer efficacy than monotherapy. Moreover, matrine and berberine reduced the relative abundance of Bacteroidota and Campilobacterota at phylum level and that of Helicobacter, Lachnospiraceae_NK4A136_group, Candidatus_Arthromitus, norank_f_Lachnospiraceae, Rikenella, Odoribacter, Streptococcus, norank_f_Ruminococcaceae, and Anaerotruncus at the genus level. Western blotting results demonstrated that treatment with matrine and berberine decreased the protein expressions of c-MYC and RAS, whereas it increased that of sirtuin 3 (Sirt3). The findings indicated that the combination of matrine and berberine was more effective in inhibiting colorectal cancer than monotherapy. This beneficial effect might depend on the improvement of intestinal microbiota structure and regulation of the RAS/MEK/ERK-c-MYC-Sirt3 signaling axis.

Fully convolutional neural network and PPG signal for arterial blood pressure waveform estimation.

Objective. The quality of the arterial blood pressure (ABP) waveform is crucial for predicting the value of blood pressure. The ABP waveform is predicted through experiments, and then Systolic blood pressure (SBP), Diastolic blood pressure, (DBP), and Mean arterial pressure (MAP) information are estimated from the ABP waveform.Approach. To ensure the quality of the predicted ABP waveform, this paper carefully designs the network structure, input signal, loss function, and structural parameters. A fully convolutional neural network (CNN) MultiResUNet3+ is used as the core architecture of ABP-MultiNet3+. In addition to performing Kalman filtering on the original photoplethysmogram (PPG) signal, its first-order derivative and second-order derivative signals are used as ABP-MultiNet3+ enter. The model's loss function uses a combination of mean absolute error (MAE) and means square error (MSE) loss to ensure that the predicted ABP waveform matches the reference waveform.Main results. The proposed ABP-MultiNet3+ model was tested on the public MIMIC II databases, MAE of MAP, DBP, and SBP was 1.88 mmHg, 3.11 mmHg, and 4.45 mmHg, respectively, indicating a small model error. It experiment fully meets the standards of the AAMI standard and obtains level A in the DBP and MAP prediction standard test under the BHS standard. For SBP prediction, it obtains level B in the BHS standard test. Although it does not reach level A, it has a certain improvement compared with the existing methods.Significance. The results show that this algorithm can achieve sleeveless blood pressure estimation, which may enable mobile medical devices to continuously monitor blood pressure and greatly reduce the harm caused by Cardiovascular disease (CVD).

CCDC85C suppresses colorectal cancer cells proliferation and metastasis through activating GSK-3ß and promoting ß-catenin degradation.

Coiled-coil domain-containing 85C (CCDC85C) is a member of the DIPA family and contains a pair of conserved coiled-coil motifs, which was found to be related to a therapeutic target for colorectal cancer, however, its biological effects require further elucidation. This study aimed to determine the effect of CCDC85C on Colorectal Cancer (CRC) progression and to explore the related mechanism. pLV-PURO plasmid was used to construct CCDC85C-overexpressing cells while CRISPR-CasRx was used to construct CCDC85C knockdown cells. Effects of CCDC85C on cell proliferation, cycle and migration were examined using cell counting kit-8 assay, flow cytometry, wound healing assay and transwell assay. Immunofluorescence staining, immunoprecipitation, Western blot, co-immunoprecipitation and qPCR were performed to explore the mechanism. The overexpression of CCDC85C inhibited the proliferation and migration of HCT-116 and RKO cells in vitro and in vivo, but its knockdown promoted the proliferation of HCT-116 and RKO cells in vitro. Moreover, co-immunoprecipitation experiment confirmed that CCDC85C binding with GSK-3ß in RKO cells. Excess CCDC85C promoted phosphorylation and ubiquitination of ß-catenin. Our results suggested that CCDC85C binds to GSK-3ß to promote its activity and facilitates ubiquitination of ß-catenin. ß-catenin degradation is responsible for the inhibitory effect of CCDC85C on CRC cell proliferation and migration.

Overview of research progress and application of experimental models of colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC.

Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial.

INTRODUCTION: Colon cancer remains one of the most prevalent cancers worldwide. Unfortunately, there are no recognized and effective therapeutic strategies to prevent tumor recurrence after radical resection and chemotherapy, and the disease-free survival (DFS) in patients with stage IIIB or IIIC disease remains unsatisfactory. Xian-Lian-Jie-Du optimization decoction (XLJDOD) is a Chinese herbal medicine (CHM) empirical prescription, which has been validated experimentally and clinically that could inhibit the progression of colorectal cancer and ameliorate the symptoms. The purpose of this study is to evaluate the efficacy and safety of XLJDOD in prevention of recurrence of colon cancer. METHODS: This study is a multi-center, double-blind, randomized, placebo-controlled trial conducted at 13 hospitals of China. Following the completion of surgery and adjuvant 5- fluorouracil-based chemotherapy, a total of 730 subjects with stage IIIB or IIIC colon cancer will be randomized in a 1:1 ratio to an intervention group (n = 365; XLJDOD compound granule) and a control group (n = 365; Placebo). Patients will receive 6-month treatments and be followed up with 3 monthly assessments for 2 years. The primary outcome is 2-year DFS rate and the secondary outcomes are 1, 2-year relapse rate (RR), overall survival (OS) and quality of life (QoL). Safety outcomes such as adverse events will be also assessed. A small number of subgroup analysis will be carried out to explore the heterogeneity of effects of XLJDOD. DISCUSSION: The outcomes from this randomized controlled trial will provide objective evidences to evaluate XLJDOD's role as an adjuvant treatment in colon cancer. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT05709249. Registered on 31 Jan 2023.