Alterations of the bile microbiome is associated with progression-free survival in pancreatic ductal adenocarcinoma patients.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. METHODS: Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. RESULTS: PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. CONCLUSION: PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.

Proteomic profiling of prostate cancer reveals molecular signatures under antiandrogen treatment.

BACKGROUND: Tumorigenesis and progression of prostate cancer (PCa) are indispensably dependent on androgen receptor (AR). Antiandrogen treatment is the principal preference for patients with advanced PCa. However, the molecular characteristics of PCa with antiandrogen intervention have not yet been fully uncovered. METHODS: We first performed proteome analysis with 32 PCa tumor samples and 10 adjacent tissues using data-independent acquisition (DIA)- parallel accumulation serial fragmentation (PASEF) proteomics. Then label-free quantification (LFQ) mass spectrometry was employed to analyze protein profiles in LNCaP and PC3 cells. RESULTS: M-type creatine kinase CKM and cartilage oligomeric matrix protein COMP were demonstrated to have the potential to be diagnostic biomarkers for PCa at both mRNA and protein levels. Several E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) were significantly altered in PCa and PCa cells under enzalutamide treatment, and these proteins might reprogram proteostasis at protein levels in PCa. Finally, we discovered 127 significantly varied proteins in PCa samples with antiandrogen therapy and further uncovered 4 proteins in LNCaP cells upon enzalutamide treatment. CONCLUSIONS: Our research reveals new potential diagnostic biomarkers for prostate cancer and might help resensitize resistance to antiandrogen therapy.

LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.

The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 µM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.

2-4 weeks is the optimal time to operate on colorectal liver metastasis after neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is generally accepted for treatment of liver metastasis of colorectal cancer (CRLM), but what is a reasonable interval between the latest NAC and surgery is still unknown. The aim of the current study was to investigate the proper timing of surgery after NAC. Subjects were 141 patients with CRLM who underwent NAC and then surgery were retrospectively identified from 2008 to 2020. They were divided into a short interval group (SIG, ≤ 4 weeks) and long interval group (LIG, > 4 weeks) using the software X-tile. The SIG was subclassified group into 3 time periods (1-2 weeks, 2-3 weeks, and 3-4 weeks) to assess the incidence of complications. Patients in the SIG were more likely to have significantly better recurrence-free survival (RFS) (3-year RFS of 47.4% vs. 20.5%, P = 0.043) and no difference in overall survival (OS) (3-year OS 76.1% vs. 79.9%, P = 0.635). The postoperative complication rate was 23.5% in the SIG and 14.0% in the LIG (P = 0.198). The postoperative complication rate in the 1-2 weeks subgroup was marginally higher than that in the > 4 weeks subgroup (35% vs. 14.3% P = 0.055). Multivariate analysis revealed that chemotherapy-free intervals of 1-2 weeks were an independent predictor of increased postoperative complications (OR = 0.263, 95% CI 0.7-0.985 P = 0.048). Patients who underwent surgery within 4 weeks of NAC had better RFS. In addition, 1-2 weeks was an independent factor influencing the development of more complications. For patients with CRLM, performing surgery within 2-4weeks of NAC was feasible and safe, and it did not increase the incidence of postoperative complications but it did prolong RFS.

Neoadjuvant Chemotherapy Followed by Radiofrequency Ablation May Be a New Treatment Modality for Colorectal Liver Metastasis: A Propensity Score Matching Comparative Study.

Background: Most colorectal liver metastases (CRLM) are not candidates for liver resection. Radiofrequency ablation (RFA) plays a key role in selected CRLM patients. Neoadjuvant chemotherapy (NAC) followed by liver resection has been widely used for resectable CRLM. Whether NAC followed by radiofrequency ablation (RFA) can achieve a similar prognosis to NAC followed by hepatectomy remains is unclear. The present study aimed to provide a new treatment modality for CRLM patients. Methods: This comparative retrospective research selected CRLM patients from 2009 to 2022. They were divided into NAC + RFA group and NAC + hepatectomy group. The propensity score matching (PSM) was used to reduce bias. We used multivariate cox proportional hazards regression analysis to explore independent factors affecting prognosis. The primary study endpoint was the difference in the progression-free survival (PFS) between the two groups. Results: A total of 190 locally curable CRLM patients were in line with the inclusion criteria. A slight bias was detected in the comparison of basic clinical characteristics between the two groups. RFA showed a significant advantage in the length of hospital stay (median; 2 days vs. 7 days; p < 0.001). The 1- and 3-year PFS in the liver resection and the RFA groups was 57.4% vs. 86.9% (p < 0.001) and 38.8% vs. 55.3% (p = 0.035), respectively. The 1-year and 3-year OS in the liver resection and RFA groups was 100% vs. 96.7% (p = 0.191) and 73.8% vs. 73.6% (p = 0.660), respectively. Conclusions: NAC followed by RFA has rapid postoperative recovery, fewer complications, and better prognosis.

Neoadjuvant Chemotherapy Followed by Radiofrequency Ablation Prolongs Survival for Ablatable Colorectal Liver Metastasis: A Propensity Score Matching Comparative Study.

BACKGROUND: Typically, colorectal liver metastasis (CRLM) is not a candidate for hepatectomy. Radiofrequency ablation (RFA) plays a critical role in unresectable CRLM patients. Nevertheless, high local tumor progression (LTP) and distant metastasis limit the development and further adoption and use of RFA. Neoadjuvant chemotherapy (NAC) has been widely used in resectable CRLM and is recommended by the guidelines. There are no studies on whether NAC can improve the prognosis in ablatable CRLM patients. The present study aimed to determine the feasibility and effectiveness of RFA plus NAC. METHODS: This retrospective cohort included CRLM patients from Zhejiang Cancer Hospital records, who received RFA from January 2009 to June 2020 and were divided into two groups according to the presence or absence of NAC. The Kaplan-Meier method was used to evaluate the 3-year local tumor progression-free survival (LTPFS), progression-free survival (PFS), and overall survival (OS) of the two groups. The propensity score matching was used to reduce bias when assessing survival. Multivariate Cox proportional hazards regression analysis was used to study the independent factors affecting LTPFS, PFS, and OS. RESULTS: A total of 149 CRLM patients (88 in the RFA alone group and 61 in the plus NAC group) fulfilled the inclusion criteria. Post-RFA complications were 3.4% in the RFA alone group and 16.4% in the plus NAC group. The 3-year LTPFS, PFS, and OS of the RFA only group were 60.9%, 17.7%, and 46.2%, respectively. The 3-year LTPF, PFS, and OS of the plus NAC group were 84.9%, 46.0%, and 73.6%, respectively. In the 29 pairs of propensity score matching cohorts, the 3-year LTPFS, PFS, and OS in the plus NAC group were longer than those in the RFA group (P < 0.05). NAC was an independent protective factor for LTPFS, PFS, and OS (P < 0.05). CONCLUSIONS: For ablatable CRLM patients, RFA plus NAC obtained a better prognosis than RFA alone. Based on the current results, the application of NAC before RFA may become the standard treatment.

[Correlation of phosphorylated S6 protein expression in blood and brain tissue in mice and rats with kainic acid-induced seizure].

OBJECTIVE: To determine the correlation of phosphorylated ribosomal S6 protein (P-S6) content in blood and brain tissue in mice and rats with seizure. METHODS: Seizure models were induced by intraperitoric injection of kainic acid (KA) in C57BL/mice and SD rats. Flow cytometry was used to detect the content of P-S6 in blood; Western blot was used to detect the expression of P-S6 in brain tissues. The correlation between P-S6 expression in blood and in brain tissue was examine by Pearson analysis, and the correlation between P-S6 expression in blood and the severity of seizure was also observed. RESULTS: Western blotting analysis showed that the expression of P-S6 was significantly increased in peripheral blood and brain tissue in mice 1 h after KA-induced seizure,and the expression levels increased to (1.49±0.45) times (P<0.05) and (2.55±0.66) times (P <0.01) of the control group, respectively. Flow cytometry showed that the positive percentage and average fluorescence intensity of P-S6 in the blood of mice increased significantly 1 h after KA-induced seizures (P<0.01), which was consistent with the expression of P-S6 in brain tissue (r=0.8474, P<0.01). Flow cytometry showed that the average fluorescence intensity of P-S6 in blood increased from 14.89±9.75 to 52.35±21.72 (P<0.01) in rats with seizure, which was consistent with the change of P-S6 in brain tissue (r=0.9385, P<0.01). Rats with higher levels of seizure were of higher levels of P-S6 in peripheral blood. CONCLUSIONS: Consistent correlation of P-S6 expression is demonstrated in peripheral blood and in brain tissue after KA-induced seizure, suggesting that the expression of P-S6 in blood can accurately reflect the changes of mTOR signaling pathway in brain tissue.