Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

Characterization of Pancreatic Fistula after Post-pancreatectomy Acute Pancreatitis.

OBJECTIVE: This study aimed to investigate the clinical significance and risk factors of postoperative pancreatic fistula (POPF) after post-pancreatectomy acute pancreatitis (PPAP) in patients who underwent pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: PPAP has been recognized as a critical factor in the pathophysiology of POPF after PD. METHODS: A total of 817 consecutive patients who underwent elective PD between January 2020 and June 2022 were included. PPAP and POPF were defined in accordance with the International Study Group for Pancreatic Surgery (ISGPS) definitions. Multivariate logistic analyses were performed to investigate the risk factors for POPF. Comparisons between PPAP-associated POPF and non-PPAP-associated POPF were made to further characterize this intriguing complication. RESULTS: Overall, 159 (19.5%) patients developed POPF after PD, of which 73 (45.9%) occurred following PPAP, and the remaining 86 (54.1%) had non-PPAP-associated POPF. Patients with PPAP-associated POPF experienced significantly higher morbidity than patients without POPF. Multivariate analyses revealed distinct risk factors for each POPF type. For PPAP-associated POPF, independent risk factors included estimated blood loss >200 mL (OR 1.93), MPD ≤3 cm (OR 2.88), and soft pancreatic texture (OR 2.01), largely overlapping with FRS (Fistula Risk Score) elements. On the other hand, non-PPAP-associated POPF was associated with age >65 years (OR 1.95), male (OR 2.10), and MPD ≤3 cm (OR 2.57). Notably, among patients with PPAP, the incidence of POPF consistently hovered around 50% regardless of the FRS stratification. CONCLUSIONS: PPAP-associated POPF presents as a distinct pathophysiology in the development of POPF after PD, potentially opening doors for future prevention strategies targeting the early postoperative period.

A machine learning-based model for predicting the risk of early-stage inguinal lymph node metastases in patients with squamous cell carcinoma of the penis.

Objective: Inguinal lymph node metastasis (ILNM) is significantly associated with poor prognosis in patients with squamous cell carcinoma of the penis (SCCP). Patient prognosis could be improved if the probability of ILNM incidence could be accurately predicted at an early stage. We developed a predictive model based on machine learning combined with big data to achieve this. Methods: Data of patients diagnosed with SCCP were obtained from the Surveillance, Epidemiology, and End Results Program Research Data. By combing variables that represented the patients' clinical characteristics, we applied five machine learning algorithms to create predictive models based on logistic regression, eXtreme Gradient Boosting, Random Forest, Support Vector Machine, and k-Nearest Neighbor. Model performance was evaluated by ten-fold cross-validation receiver operating characteristic curves, which were used to calculate the area under the curve of the five models for predictive accuracy. Decision curve analysis was conducted to estimate the clinical utility of the models. An external validation cohort of 74 SCCP patients was selected from the Affiliated Hospital of Xuzhou Medical University (February 2008 to March 2021). Results: A total of 1,056 patients with SCCP from the SEER database were enrolled as the training cohort, of which 164 (15.5%) developed early-stage ILNM. In the external validation cohort, 16.2% of patients developed early-stage ILNM. Multivariate logistic regression showed that tumor grade, inguinal lymph node dissection, radiotherapy, and chemotherapy were independent predictors of early-stage ILNM risk. The model based on the eXtreme Gradient Boosting algorithm showed stable and efficient prediction performance in both the training and external validation groups. Conclusion: The ML model based on the XGB algorithm has high predictive effectiveness and may be used to predict early-stage ILNM risk in SCCP patients. Therefore, it may show promise in clinical decision-making.

Identifying TME signatures for cervical cancer prognosis based on GEO and TCGA databases.

The mortality rate from cervical cancer (CESC), a malignant tumor that affects women, has increased significantly globally in recent years. The discovery of biomarkers points to a direction for the diagnosis of cervical cancer with the advancement of bioinformatics technology. The goal of this study was to look for potential biomarkers for the diagnosis and prognosis of CESC using the GEO and TCGA databases. Because of the high dimension and small sample size of the omic data, or the use of biomarkers generated from a single omic data, the diagnosis of cervical cancer may be inaccurate and unreliable. The purpose of this study was to search the GEO and TCGA databases for potential biomarkers for the diagnosis and prognosis of CESC. We begin by downloading CESC (GSE30760) DNA methylation data from GEO, then perform differential analysis on the downloaded methylation data and screen out the differential genes. Then, using estimation algorithms, we score immune cells and stromal cells in the tumor microenvironment and perform survival analysis on the gene expression profile data and the most recent clinical data of CESC from TCGA. Then, using the 'limma' package and Venn plot in R language to perform differential analysis of genes and screen out overlapping genes, these overlapping genes were then subjected to GO and KEGG functional enrichment analysis. The differential genes screened by the GEO methylation data and the differential genes screened by the TCGA gene expression data were intersected to screen out the common differential genes. A protein-protein interaction (PPI) network of gene expression data was then created in order to discover important genes. The PPI network's key genes were crossed with previously identified common differential genes to further validate them. The Kaplan-Meier curve was then used to determine the prognostic importance of the key genes. Survival analysis has shown that CD3E and CD80 are important for the identification of cervical cancer and can be considered as potential biomarkers for cervical cancer.

Preoperative Systemic Inflammatory Markers as a Significant Prognostic Factor After TURBT in Patients with Non-Muscle-Invasive Bladder Cancer.

Introduction: Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) have been widely proposed to have predictive value for the patient prognosis of many malignancies, including bladder cancer. However, the predictive value of their combination in non-muscle-invasive bladder cancer (NMIBC) is unclear. Methods: Cases of NMIBC patients who underwent transurethral resection of the bladder tumor were recruited from two tertiary public medical centers. A systemic inflammatory marker (SIM) score was calculated based on comprehensive consideration of NLR, PLR, and LMR. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. The Log rank test was used to compare differences between the groups. Cox regression was used to screen risk factors affecting RFS and PFS. Nomogram models were established and validated, and patients were stratified based on the model scores. Results: The study dataset was grouped according to a 7:3 randomization, with the training cohort consisting of 292 cases and the validation cohort consisting of 124 cases. Cox regression analysis showed that SIM score is an independent predictor of RFS and PFS in NMIBC patients. The novel models were established based on the SIM score and other statistically significant clinicopathological features. The area under the curve (AUC) for predicting 1-, 2-, and 3-year RFS was 0.667, 0.689, and 0.713, respectively. The AUC for predicting 1-, 2-, and 3-year PFS was 0.807, 0.775, and 0.862, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. The established models were applied to the patient evaluation of the validation cohort, which proved the great performance of the novel models. Conclusion: The novel models based on the SIM score and clinicopathological characteristics can accurately predict the survival prognosis of NMIBC patients, and the models can be used by clinicians for individualized patient assessment and to assist in clinical decision-making.

Retrospective validation of bone risk stratification criteria for men with de novo metastatic hormone-naive prostate cancer in China.

Background: Bone metastasis has been suggested to be a significant impactor on the prognosis of newly diagnosed de novo metastatic hormone-sensitive prostate cancer (mHSPC), and some risk stratification models have been proposed on the basis of this hypothesis. However, the effectiveness of these risk stratification criteria has not been fully evaluated in China. This study aimed to evaluate the effectiveness of the risk stratification models in China. Methods: A total of 140 patients who were newly diagnosed with metastatic prostate cancer followed by primary androgen deprivation-based therapy from January 2008 to June 2021 at our institution were enrolled in this study. The patients were divided into different groups on the basis of high- and low-volume disease (H/LVD) criteria, high-and low-risk disease (H/LRD) criteria, extremity bone metastasis criteria (EBM), and extent of disease (EOD) criteria. The area under the receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) were used to compare the validity and net benefit of these models. Using the Cox proportional hazards model, we performed univariable and multivariable analyses of the factors influencing overall survival (OS) and the time of progression to metastatic castration-resistant prostate cancer (CRPC). Results: The median patient age was 72 years. Most patients had a Gleason score ≥8 (102 cases, 72.9%) and clinical T stage >2 (75 cases, 53.6%). The median follow-up time was 25 months (range, 2-95 months). Ninety-two patients progressed to CRPC and fifty-seven patients died during the follow-up. The AUC of OS and CRPC showed that the EOD model had higher validity than the other risk stratification models. DCA shows that the net benefit of the EOD model on OS was better than that of the other risk stratification models. As for CRPC, the net benefit of the EOD model was second only to that of the H/LRD model when the threshold was <0.5; however, when the threshold was >0.5, the EOD model outperformed the other models. The effectiveness of EOD as an independent prognostic variable was verified through univariable and multivariable analyses. Conclusion: The EOD model yields reasonable risk stratification for use in Chinese mHSPC patients, providing further evidence supporting its role in clinical decision-making.

Development and validation of a novel risk model in newly diagnosed de novo bone metastatic prostate cancer (M1b): a retrospective study.

Background: Previous studies suggested that bone metastasis has a significant effect on the time of progression to metastatic castration-resistant prostate cancer (CRPC) for newly diagnosed de novo bone metastatic hormone-sensitive prostate cancer (mHSPC). Nevertheless, the effect of different bone metastasis sites was not fully evaluated. This study aimed to develop and validate a novel bone metastatic risk model. Methods: We enrolled 122 patients who were newly diagnosed with de novo bone metastatic prostate cancer following primary androgen deprivation based therapy at our institution from January 2008 to June 2021. The metastatic bone sites were classified into six sites: skull; cervical, thoracic, and lumbar vertebrae; chest (ribs and sternum); pelvis; upper limbs; and lower limbs. We calculated the bone metastatic score (BMS) for each site: 0 points were assigned for non-metastasis and 1 point was assigned for metastasis. The X-tile was adopted to acquire optimal cutoff points of BMS. We defined high-risk group (HRG) as BMS ≥ 3 and low-risk group (LRG) as BMS < 3. The new bone risk stratification was validated by calculating the area under the receiver operating characteristic curve (AUC). Subsequently, the relevant clinical prognostic variables were added to construct a predictive nomogram for predicting CRPC. Results: The median patient age was 73 years. Most patients had Gleason score ≤8 (93 cases, 76.2%). The median follow-up duration was 11.5 months (range: 2-92 months). Eighty-six patients progressed to CRPC during the follow-up. The most common bone metastatic site was the pelvis (90.2%). The median BMS was 4. Seventy-six patients had HRG, while forty-six had LRG. The 1-, 2-, and 3-year AUCs for H/LRG were 0.620, 0.754, and 0.793, respectively. The HRG was associated with earlier time to CRPC. A nomogram based on four parameters (Gleason score, H/LRG, prostate-specific antigen [PSA] nadir, and time to PSA nadir) was developed to predict CRPC. Internal validation using bootstrapping demonstrated good accuracy for predicting the CRPC (C-index: 0.727). The calibration analysis demonstrated that the model performed well. Conclusion: We established a novel H/LRG risk model for newly diagnosed de novo bone metastatic prostate cancer, which provided evidence to support clinical decision-making.

Preoperative systemic immune-inflammation index as a significant prognostic factor after TURBT in patients with non-muscle-invasive bladder cancer: A retrospective study based on propensity score matching analysis.

OBJECTIVE: To investigate the association of the preoperative systemic immune-inflammation index (SII) with recurrence-free survival (RFS) after transurethral resection of the bladder tumor (TURBT) of non-muscle-invasive bladder cancer (NMIBC) using propensity score matching (PSM) analysis. METHODS: The clinicopathological characteristics and follow-up data of NMIBC patients were collected retrospectively from two tertiary medical centers. A 1:1 PSM analysis was carried out using the nearest-neighbor method (caliper size: 0.02). Cox regression analysis was used to identify the risk factors associated with RFS. RESULTS: A total of 416 NMIBC patients were included in this study. Before and after matching, patients with increased SII had worse RFS (p < 0.0001 and p = 0.027, respectively). Multivariate Cox analysis identified SII as an independent predictor of RFS before (HR [95% CI]: 1.789 [1.232, 2.599], p = 0.002) and after matching (HR [95% CI]: 1.646 [1.077, 2.515], p = 0.021). In the matched subgroup analysis, an elevated SII had a significant association with postoperative worse RFS in the T1 stage (p = 0.025), primary status (p = 0.049), high-grade (p = 0.0015), and multiple lesions (p = 0.043) subgroups. CONCLUSION: SII could accurately stratify the prognosis of NMIBC patients before and after PSM analysis. An elevated SII was significantly associated with worse RFS in NMIBC patients.

Development and external validation of a novel nomogram model for predicting postoperative recurrence-free survival in non-muscle-invasive bladder cancer.

Background: Transurethral resection of the bladder tumor with or without adjuvant intravesical instillation (IVI) has been the standard treatment for non-muscle-invasive bladder cancer (NMIBC), whereas a high percentage of patients still experience local tumor recurrence and disease progression after receiving the standard treatment modalities. Unfortunately, current relevant prediction models for determining the recurrent and progression risk of NMIBC patients are far from impeccable. Methods: Clinicopathological characteristics and follow-up information were retrospectively collected from two tertiary medical centers between October 2018 and June 2021. The least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were used to screen potential risk factors affecting recurrence-free survival (RFS) of patients. A nomogram model was established, and the patients were risk-stratified based on the model scores. Both internal and external validation were performed by sampling the model with 1,000 bootstrap resamples. Results: The study included 299 patient data obtained from the Affiliated Hospital of Xuzhou Medical University and 117 patient data obtained from the First Affiliated Hospital of Guangxi Medical University. Univariate regression analysis suggested that urine red blood cell count and different tumor invasion locations might be potential predictors of RFS. LASSO-Cox regression confirmed that prior recurrence status, times of IVI, and systemic immune-inflammation index (SII) were independent factors for predicting RFS. The area under the curve for predicting 1-, 2-, and 3-year RFS was 0.835, 0.833, and 0.871, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. A user-friendly risk calculator based on the model is deposited at https://dl0710.shinyapps.io/nmibc_rfs/. Conclusion: Internal and external validation analyses showed that our model had excellent predictive discriminatory ability and stability. The risk calculator can be used for individualized assessment of survival risk in NMIBC patients and can assist in guiding clinical decision-making.

HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer.

HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. SIGNIFICANCE: The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.

ITGA2 overexpression inhibits DNA repair and confers sensitivity to radiotherapies in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a 5-year survival rate of less than 10%, despite the recent advances in chemoradiotherapy. The sensitivity of the PDAC patients to chemoradiotherapy varies widely, especially to radiotherapy, suggesting the need for more elucidation of the underlying mechanisms. In this study, a novel function of the nuclear ITGA2, the alpha subunit of transmembrane collagen receptor integrin alpha-2/beta-1, regulating the DNA damage response (DDR), was identified. First, analyzing The Cancer Genome Atlas (TCGA) PDAC data set indicated that the expression status of ITGA2 was negatively correlated with the genome stability parameters. The study further demonstrated that ITGA2 specially inhibited the activity of the non-homologous end joining (NHEJ) pathway and conferred the sensitivity to radiotherapy in PDAC by restraining the recruitment of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to Ku70/80 heterodimer during DDR. Considering the overexpression of ITGA2 and its associated with the poor prognosis of PDAC patients, this study suggested that the ITGA2 expression status could be used as an indicator for radiotherapy and DNA damage reagents, and the radiotherapy in combination with the overexpression of ITGA2 might be a viable treatment strategy for the PDAC patients.

Targeted Delivery of Drugs and Genes Using Polymer Nanocarriers for Cancer Therapy.

Cancer is one of the primary causes of worldwide human deaths. Most cancer patients receive chemotherapy and radiotherapy, but these treatments are usually only partially efficacious and lead to a variety of serious side effects. Therefore, it is necessary to develop new therapeutic strategies. The emergence of nanotechnology has had a profound impact on general clinical treatment. The application of nanotechnology has facilitated the development of nano-drug delivery systems (NDDSs) that are highly tumor selective and allow for the slow release of active anticancer drugs. In recent years, vehicles such as liposomes, dendrimers and polymer nanomaterials have been considered promising carriers for tumor-specific drug delivery, reducing toxicity and improving biocompatibility. Among them, polymer nanoparticles (NPs) are one of the most innovative methods of non-invasive drug delivery. Here, we review the application of polymer NPs in drug delivery, gene therapy, and early diagnostics for cancer therapy.

Self-assembled polymeric nanocarrier-mediated co-delivery of metformin and doxorubicin for melanoma therapy.

Malignant melanoma is a life-threatening form of skin cancer with a low response rate to single-agent chemotherapy. Although combined therapies of metformin (MET) and doxorubicin (DOX) are effective in treating a variety of cancers, including breast cancer, their different physicochemical properties and administration routines reduce the effective co-accumulation of both drugs in tumors. Nanoparticles (NPs) have been demonstrated to potentially improve drug delivery efficiency in cancer therapy of, for example, liver and lung cancers. Hence, in this study, we prepared pH-sensitive, biocompatible, tumor-targeting NPs based on the conjugation of biomaterials, including sodium alginate, cholesterol, and folic acid (FCA). As expected, since cholesterol and folic acid are two essentials, but insufficient, substrates for melanoma growth, we observed that the FCA NPs specifically and highly effectively accumulated in xenograft melanoma tumors. Taking advantage of the FCA NP system, we successfully co-delivered a combination of MET and DOX into melanoma tumors to trigger pyroptosis, apoptosis, and necroptosis (PANoptosis) of the melanoma cells, thus blocking melanoma progression. Combined, the establishment of such an FCA NP system provides a promising vector for effective drug delivery into melanoma and increases the possibility and efficiency of drug combinations for cancer treatment.

Assessment of the responsibility between a road traffic accident and medical defects after the traffic accident injury of knee joint.

A 48-year-old Chinese woman was hit by a car in a road traffic accident. Local county hospital considered that her right knee was injured, but didn't find any sign of fracture from X-ray imaging. Then the hospital gave diagnosis of soft tissue contusion and the patient started to exercise with burden 21 days after her right lower limb was fixed by plaster slab. Four months later, she had to go back to the county hospital for recheck due to persistent pain on her right knee. Then, the right tibia outer plateau fracture was found. The patient rejected the advice of open reduction and internal fixation of right tibia plateau fracture. Instead, she accepted the unicompartmental knee arthroplasty in a hospital affiliated to a medical college. The patient felt the knee pain alleviated after surgery However, the joint dysfunction was aggravated even more. The patient used the legal procedure for personal compensation. Both driver and the insurance company disputed that the final consequence of the injured knee was due to not only the traffic accident, but also poor medical practice involved. Therefore the court consigned us to make judicial judgment of expertise. After investigation, we found the earliest X-ray graph after the accident had shown the fracture of right tibia outer plateau and right knee valgum, with articular surface involvement, and the traffic accident was considered as the primary cause of sequelae. At the same time, the county hospital missed the diagnosis of fracture, and led to insufficient fixation of right lower limb, which was not good for rehabilitation from fracture and joint injury. This was the secondary cause of sequelae. Additionally, instead of the standard therapy, the affiliated hospital of medical college made the unicompartmental knee arthroplasty four months later, which also had a little defect. It was the minor reason for the result.