Circulating tumor cell-derived exosome-transmitted long non-coding RNA TTN-AS1 can promote the proliferation and migration of cholangiocarcinoma cells.

BACKGROUND: Exosomes assume a pivotal role as essential mediators of intercellular communication within tumor microenvironments. Within this context, long noncoding RNAs (LncRNAs) have been observed to be preferentially sorted into exosomes, thus exerting regulatory control over the initiation and progression of cancer through diverse mechanisms. RESULTS: Exosomes were successfully isolated from cholangiocarcinoma (CCA) CTCs organoid and healthy human serum. Notably, the LncRNA titin-antisense RNA1 (TTN-AS1) exhibited a conspicuous up-regulation within CCA CTCs organoid derived exosomes. Furthermore, a significant elevation of TTN-AS1 expression was observed in tumor tissues, as well as in blood and serum exosomes from patients afflicted with CCA. Importantly, this hightened TTN-AS1 expression in serum exosomes of CCA patients manifested a strong correlation with both lymph node metastasis and TNM staging. Remarkably, both CCA CTCs organoid-derived exosomes and CCA cells-derived exosomes featuring pronounced TTN-AS1 expression demonstrated the capability to the proliferation and migratory potential of CCA cells. Validation of these outcomes was conducted in vivo experiments. CONCLUSIONS: In conclusion, our study elucidating that CCA CTCs-derived exosomes possess the capacity to bolster the metastasis tendencies of CCA cells by transporting TTN-AS1. These observations underscore the potential of TTN-AS1 within CTCs-derived exosomes to serve as a promising biomarker for the diagnosis and therapeutic management of CCA.

PCK1 activates oncogenic autophagy via down-regulation Serine phosphorylation of UBAP2L and antagonizes colorectal cancer growth.

Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme in gluconeogenesis. PCK1 is considered an anti-oncogene in several human cancers. In this study, we aimed to determine the functions of PCK1 in colorectal cancer (CRC). PCK1 expression in CRC tissues was tested by western blot and immunohistochemistry analyses and associations of PCK1 level with clinicopathological characteristics and disease survival evaluated. Further, we studied the effect of PCK1 on CRC cell proliferation and the underlying mechanisms. Our results show that PCK1 is expressed at significantly lower levels in CRC than in control tissues. High PCK1 expression was correlated with smaller tumor diameter and less bowel wall invasion (T stage). Overexpression and knockdown experiments demonstrated that PCK1 inhibits CRC cell growth both in vitro and in vivo. Mechanistically, PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454 and enhancing autophagy. Overall, our findings reveal a novel molecular mechanism involving PCK1 and autophagy, and highlight PCK1 as a promising candidate therapeutic target in CRC.

Short-term clinical outcomes of laparoscopic duodenum-preserving pancreatic head resection for the management of pancreatic-head cystic neoplasms.

BACKGROUND: In this study, we aimed to investigate the short-term clinical outcomes of laparoscopic duodenum-preserving pancreatic-head resection (LDPPHR) for the management of pancreatic-head cystic neoplasms. METHODS: This retrospective study included 60 patients who were treated with pancreatic-head cystic neoplasms at the Shandong Provincial Hospital Affiliated to Shandong First Medical University from December 2019 to July 2022. RESULTS: No significant difference was found between the two groups in terms of the baseline and pathological characteristics of patients (P > 0.05). The postoperative exhaust time was shorter in the LDPPHR group compared with the laparoscopic pancreaticoduodenectomy (LPD) group (2 (2 and 4) vs. 4 (3 and 5) days; P = 0.003). No significant difference was found between the two groups in terms of operative time, estimated blood loss, intraoperative transfusion, hemoglobin levels on the first postoperative day, total bilirubin before discharge, direct bilirubin before discharge, postoperative hospital stay, postoperative pancreatic fistula, bile leakage, hemorrhage, peritoneal effusion, abdominal infection, delayed gastric emptying, interventional embolization hemostasis, reoperation, and 30-day readmission (P > 0.05). No conversion and 90-day mortality were found in the two groups. The LDPPHR group showed a higher 3-month postoperative PNI, 6-month postoperative TG and 6-month postoperative BMI than the LPD group (P < 0.05). CONCLUSIONS: Compared with LPD, LDPPHR can decrease the postoperative exhaust time of patients, improve the short-term postoperative nutritional status, and does not decrease the safety of the perioperative period.

Potential prognosis index for m6A-related mRNA in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CHOL) is a malignant tumor that originates in the extrahepatic bile duct and can extend from the hilar region to the lower end of the common bile duct. The prognosis of CHOL patients is particularly poor; therefore, in this study, we screened mRNAs correlated with N6-methyladenosine (m6A) to construct a risk model for prognosis in CHOL. METHODS: The TCGA-CHOL dataset was applied to obtain and analyze the coexpression of 1281 m6A-related mRNAs, from which 14 were selected for further analysis through univariate proportional hazards (cox) regression analysis. Aryl hydrocarbon receptor interacting protein (AIP), CCAAT/enhancer binding protein beta (CEBPB), syndecan1 (SDC1), vacuolar protein sorting 25 homolog (VPS25) and syntaxin binding protein 2 (STXBP2) were then screened out through the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis to develop a precise m6A-related mRNA prognosis risk model (MRMRPM) with an area under curve (AUC) of 0.908 and 0.923 after 1 and 2 years, respectively. We divided the samples into high-risk and low-risk groups using the m6A-related mRNA prognosis risk model. RESULTS: Kaplan-Meier analysis indicated poor overall survival (OS) for the high-risk group. Two Gene Expression Omnibus (GEO) datasets (GSE89748 and GSE107943) were used to validate the risk model. The results of drug sensitivity and immune cell infiltration analysis showed that the risk model could serve as a prognosis index of potential immunotherapeutic characteristics and drug sensitivity. Furthermore, the proportion of resting dendritic cells and regulatory T cells was positively associated with an increased expression of four m6A-related mRNAs - AIP, CEBPB, SDC1, and VPS25 - in the high-risk CHOL group. CONCLUSIONS: Our findings suggest that this model can be a prognostic indicator for CHOL patients.

Safety and effectiveness of laparoscopic intratumoral resection facilitated by coagulation of giant hepatic hemangioma: a matched case-control study and literature review.

BACKGROUND: To report the safety and effectiveness of laparoscopic intratumoral resection facilitated by coagulation (LIRC) compared with laparoscopic hepatectomy (LH) in treating giant hepatic hemangioma. METHODS: From 2017 to 2020, 19 consecutive patients with giant hepatic hemangioma (≥ 10 cm) received LIRC in one center. We selected a subgroup of 103 patients treated by LH in other four centers who well matched the 19 consecutive patients treated with LIRC, in a 1:1 fashion based on the tumor location, tumor size, and body mass index. Furthermore, the differences in technical success, operative time, operative blood loss, change of laboratory indexes, hospital stays, complication and clinical responds are compared between the two groups. RESULTS: Technical success was achieved in all 38 patients. Patients in the LIRC group had a relative shorter operative time (P < 0.001) and less operative blood loss (P = 0.003). The serum levels of C-reactive protein (CRP), total bilirubin (TBil), alanine aminotransferase (ALT), and aspartate transaminase (AST) were elevated significantly (P < 0.05) 1 day after the resection and returned to normal within 7 days in both groups; however, relatively lower serum levels of those indexes were observed in the LIRC group (P < 0.05). The total complication rate was relatively lower in the LIRC group compared with the LH group (P = 0.029). Patients in the LIRC group had shorter hospital stays than those in the LH group (P = 0.010). The clinical response was similar in the two groups. CONCLUSIONS: LIRC is safe and effective for treating giant hepatic hemangioma.

Resveratrol and Puerarin loaded polymeric nanoparticles to enhance the chemotherapeutic efficacy in spinal cord injury.

Spinal cord injury includes inflammation and apoptosis of neurons, which is difficult to cure by systemic drug administration. Administration of natural active compounds (resveratrol and also Puerarin) by advance drug delivery technology improves the patient's conditions. Oil-in-water emulsion method was utilized to prepare resveratrol as well as puerarin loaded PLGA nanoparticles. The nanoparticles were subjected to mean zeta potential, mean particle size, encapsulation efficiency as well as in vitro drug release studies. The biochemical parameters i.e. malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), advanced oxidation products (AOPP), catalase (CAT) and nitrite/nitrate levels were tested for the loaded nanoparticles. Reperfusion injury induced rats treated with 10 mg/kg resveratrol and puerarin loaded nanoparticles protects spine from ischemia injury and supports biological parameters. The mean particle size varies from 238 nm to 274 nm and also particle size distribution was mono-dispersed (0.239 to 0.318). Zeta potential value of nanoparticles was observed to be -12.6 ± 2.1 mV. Optimized nanoparticles reveals 72% -79% of drug release over 36 h by diffusion mechanism. Significantly, lowers the levels of plasma nitrite/nitrate level as well as phosphorylation of p38MAPK pathways in reperfusion injury induced rats. The resveratrol and puerarin loaded nanoparticles decreases free radicals produced by reperfusion injury induced rats, as well as decrease of oxidative stress because of IRI. Resveratrol and puerarin loaded nanoparticles decreases GSH, SOD and CAT antioxidant level, which helps in overall health improvement of patients.

LHPP Inhibits the Viability, Migration, and Proliferation of PDAC Cells and Significantly Affects the Expression of SDC1 and S100p.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor response to chemotherapy and an extremely poor prognosis. Recent studies have revealed that phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) can inhibit the growth of various cancers. Therefore, the current study was conducted to investigate the antitumor effects of LHPP in PDAC and to explore its mechanism using proteomics analysis. METHODS AND RESULTS: Immunohistochemical analysis of clinical samples demonstrated that LHPP expression levels were lower in tumor tissues compared to adjacent nontumor tissues. Moreover, multivariate COX regression analysis showed that LHPP expression level was an independent prognostic factor for the patients with PDAC. Patients with high LHPP expression had a better prognosis. The lentiviral vectors for normal control (NC), LHPP knockdown (KD), and LHPP overexpression (OE) were infected with BxPC-3 and PANC-1 cell lines. Cell counting kit-8 assay, Transwell assay, and flow cytometry analyses showed that LHPP overexpression significantly inhibited the cell viability, migration, and proliferation of BxPC-3 and PANC-1 cells. Moreover, xenograft tumor model demonstrated that LHPP overexpression inhibited xenograft tumor growth in vivo. Subsequently, proteins with significantly altered expression in BxPC-3 cells after lentivirus infection were detected using proteomics analyses. Interestingly, compared to the NC group, the expression of Syndecan 1 (SDC1) was significantly upregulated in the KD group, while that of S100P was significantly downregulated in the OE group. CONCLUSION: LHPP might emerge as an important target for delaying the advancement of PDAC, thereby providing a novel therapeutic approach for the treatment of PDAC.

Development and validation of a mitochondrial energy metabolism-related risk model in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and ranks third inmortality. Mitochondria are the energy manufacturers of cells. Disruption of mitochondrial energy metabolism pathways is strongly correlated with the onset and progression of HCC. Aberrant genes in mitochondrial energy metabolism pathways may represent a unique diagnostic and therapeutic targets that act as indicators for HCC. METHODS: Gene expression data from 374 HCC patients and 50 controls were acquired from TCGA database. A total of 188 mitochondrial energy metabolism-related genes (MMRGs) were obtained from KEGG PATHWAY database. A total of 368 patients with survival data were randomly split into training and validation groups in a 7: 3 ratio. Prognosis-related MMRGs were selected by univariate Cox and LASSO analyses. Kaplan-Meier and ROC curves were employed to analyze the model precision, whereas the validation set was used for model verification. Furthermore, clinical examinations, immune infiltration analysis, GSVA, and immunotherapy analysis were conducted in the high- and low-risk groups. Finally, the risk model was combined with the clinical variables of HCC patients to perform univariate and multivariate Cox regression analyses to obtain independent risk indicators and draw a nomogram. Therefore, we evaluated the accuracy of the predictions using calibration curves. RESULTS: A total of 6032 differentially expressed genes (DEGs) were detected in the HCC and control samples. After overlapping DEGs with 188 MMRGs, 42 mitochondrial energy metabolism-related DEGs (DEMMRGs) were identified. A 17 specific genes-based risk score model of HCC was created, which revealed effectiveness in each TCGA training and validation dataset. Moreover, patients categorized by risk scores exhibited distinct immune infiltration status, immunotherapy responsiveness, and functional properties. Finally, univariate and multivariate Cox regression analyses revealed that risk score and stage T were independent predictive variables. Based on the T stage and risk score, a nomogram for estimating the survival of HCC patients was created. The calibration curves demonstrated that the prediction model had a high level of accuracy. CONCLUSIONS: Our study constructed a mitochondrial energy metabolism-related risk model, that may be utilized to anticipate HCC prognosis and represent the immunological microenvironment of HCC.

Prediction of small molecule drug-miRNA associations based on GNNs and CNNs.

MicroRNAs (miRNAs) play a crucial role in various biological processes and human diseases, and are considered as therapeutic targets for small molecules (SMs). Due to the time-consuming and expensive biological experiments required to validate SM-miRNA associations, there is an urgent need to develop new computational models to predict novel SM-miRNA associations. The rapid development of end-to-end deep learning models and the introduction of ensemble learning ideas provide us with new solutions. Based on the idea of ensemble learning, we integrate graph neural networks (GNNs) and convolutional neural networks (CNNs) to propose a miRNA and small molecule association prediction model (GCNNMMA). Firstly, we use GNNs to effectively learn the molecular structure graph data of small molecule drugs, while using CNNs to learn the sequence data of miRNAs. Secondly, since the black-box effect of deep learning models makes them difficult to analyze and interpret, we introduce attention mechanisms to address this issue. Finally, the neural attention mechanism allows the CNNs model to learn the sequence data of miRNAs to determine the weight of sub-sequences in miRNAs, and then predict the association between miRNAs and small molecule drugs. To evaluate the effectiveness of GCNNMMA, we implement two different cross-validation (CV) methods based on two different datasets. Experimental results show that the cross-validation results of GCNNMMA on both datasets are better than those of other comparison models. In a case study, Fluorouracil was found to be associated with five different miRNAs in the top 10 predicted associations, and published experimental literature confirmed that Fluorouracil is a metabolic inhibitor used to treat liver cancer, breast cancer, and other tumors. Therefore, GCNNMMA is an effective tool for mining the relationship between small molecule drugs and miRNAs relevant to diseases.

Inhibition of neuropilin-1 enhances the therapeutic effects of lenvatinib in suppressing cholangiocarcinoma cells via the c-Met pathway.

Neuropilin-1 (NRP-1) participates in the progression of cholangiocarcinoma (CCA) and lenvatinib is an approved tyrosine kinase inhibitor treating several other cancers. Our exploratory study reveals that the inhibitory activities of lenvatinib largely rely on the expression levels of NRP-1 in CCA cells, leading to the present study that aims to investigate whether inhibition of NRP-1 could enhance the effects of lenvatinib in suppressing CCA. By using stable transfected CCA cells depleted of NRP-1 and EG00229, a specific NRP-1 inhibitor, we examined cell proliferation, cell cycle distribution and apoptosis, and detected the expression of key molecules and the involvement of the c-Met pathway. Xenograft mouse models were employed to verify the in vitro results. NRP-1 depletion and EG00229 strengthened lenvatinib in inhibiting the proliferation and promoting the apoptosis of CCA cells, and their additive or synergistic effects were confirmed in animal models. Mechanistically, lenvatinib induced the activation of the c-Met pathway, while either NRP-1 depletion or EG00229 inhibited this activation, which could be stimulated by its ligand hepatocyte growth factor. NRP-1 inhibition resulted in a significant alteration in the expression/activation of downstream pathways and molecules, which are key factors regulating cell proliferation and apoptosis. In conclusion, the present results indicate that the inhibition of NRP-1 enhances the efficacy of lenvatinib via the c-Met pathway, and warrant further studies on the pharmacological utility of EG00229, particularly, in the combination of lenvatinib as a promising adjunct therapeutic strategy for combating CCA.

Seroprevalence of Toxoplasma gondii infection in women with a gynecological tumor living in eastern China.

The association between Toxoplasma gondii (T. gondii) infection and malignancy has attracted increased attention in recent years, but little is known of T. gondii infection among women diagnosed with a gynecological tumor (GT) in China. We conducted a case-control study involving 460 women diagnosed with a GT and 460 age-matched healthy controls (HCs) to estimate the infection process of T. gondii and understand the risk factors of T. gondii infection in patients with a GT. Levels of anti-T. gondii IgG and IgM were measured by enzyme-linked immunoassays every 12 months. After a median follow-up time of 4.3 years (range 4 to 5 years), 55/460 (11.96%) patients with a GT and 15/460 (3.26%) HCs were seroprevalence for T. gondii antibodies, respectively (P = 0.001). IgG antibodies against T. gondii were found in 54 GT patients (11.74%) and 15 HCs (3.26%), respectively (P = 0.001). The seroprevalence of T. gondii IgM antibodies was similar in patients with a GT and with HCs (2.83% vs 1.3%, P = 0.105). Multivariate stepwise logistic regression analysis revealed contact with cats (OR, 6.67; 95% CI [2.89-10.75]; P = 0.001), exposure to soil (OR, 2.16; 95% CI [1.14-4.10]; P = 0.019), being a farm-worker (OR, 4.17; 95% CI [1.20-11.49]; P = 0.006) and history of chemotherapy (OR, 3.16; 95% CI [1.56-6.45]; P = 0.001) to be independent risk factors for T. gondii infection. Women with an ovarian cancer or endometrial cancer had higher T. gondii seroprevalence than that of HCs. Moreover, T. gondii infection in patients with a GT mostly acquired within two years of diagnosis, but the infection in healthy controls had no obvious time characteristics. Here, we demonstrated that T. gondii infection is significantly higher in patients with a GT (especially in women with an ovarian tumor) compared to HCs. Thus, infection with this parasite should be avoided in patients with a GT, and the causal relationship between T. gondii and GTs should be studied in detail.

The SIRT3 and SIRT6 Promote Prostate Cancer Progression by Inhibiting Necroptosis-Mediated Innate Immune Response.

The sirtuins (SIRTs), including seven family members, belong to class III histone deacetylase (HDAC) enzymes, which have been intensively investigated in cancers. Although the function of SIRTs in the cancer immunology is explored, SIRT-specific mechanisms regulating necroptosis-related innate immune response are not clear. In our present study, we found that both the mRNA and protein expression levels of SIRT3 and SIRT6 are significantly increased in the PCa tissues (HR, CI P = 3.30E - 03; HR, CI P = 2.35E - 08; and HR, CI P = 9.20E - 08) and were associated with patients' Gleason score and nodal metastasis. Furthermore, multivariate analysis showed that the PCa patients with higher expression levels of SIRT3 and SIRT6 had shorter overall survival (OS). Mechanistically, we found that SIRT3 and SIRT6 promote prostate cancer progress by inhibiting RIPK3-mediated necroptosis and innate immune response. Knockdown of both SIRT3 and SIRT6 not only activates TNF-induced necroptosis but also refreshes the corresponding recruitment of macrophages and neutrophils. Overall, our study identified that SIRT3 and SIRT6 are key regulators of necroptosis during prostate cancer progression.

Increased Risk of Toxoplasma gondii Infection in Patients with Colorectal Cancer in Eastern China: Seroprevalence, Risk Factors, and a Case-Control Study.

The aim of this study was to explore the epidemiology of Toxoplasma gondii infection in patients with colorectal cancer (CRC) in eastern China. Therefore, 287 primary CRC patients and 287 age-matched healthy control subjects were recruited to estimate the seroprevalence of T. gondii and identify the risk factors of infection. Enzyme-linked immunoassays were used to test for anti-T. gondii immunoglobulin G (IgG) and IgM antibodies. Forty-six (16%) samples were positive for anti-T. gondii IgG antibodies in patients with CRC, compared with 26 (9.1%) in the healthy controls, a significant difference (P = 0.007). By contrast, eight (2.8%) patients tested positive for T. gondii IgM antibodies, compared with three (1.1%) in the controls, a difference that was not significant (P = 0.13). Multivariable backward stepwise logistic regression analysis revealed that a rural residence (OR 2.83; 95% CI 1.15-7.01; P = 0.024) and treatment with chemotherapy (OR 2.16; 95% CI 1.02-4.57; P = 0.045) were risk factors for T. gondii infection in patients with CRC. Thus, T. gondii infection is serious in patients with CRC, and a rural residence and treatment with chemotherapy are independent risk factors for infection by this parasite. Therefore, medical professionals should be aware of this pathogen in patients with CRC, and the causes of T. gondii infection in these patients need to be explored further.