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.

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.

Astroglial adrenoreceptors modulate synaptic transmission and contextual fear memory formation in dentate gyrus.

Astrocytes perform various supporting functions, including ion buffering, metabolic supplying and neurotransmitter clearance. They can also sense neuronal activity owing to the presence of specific receptors for neurotransmitters. In turn, astrocytes can regulate synaptic activity through the release of gliotransmitters. Evidence has shown that astrocytes are very sensitive to the locus coeruleus (LC) afferents. However, little is known about how LC neuromodulatory norepinephrine (NE) modulates synaptic transmission through astrocytic activity. In mouse dentate gyrus (DG), we demonstrated an increase in the frequency of miniature excitatory postsynaptic currents (mEPSC) in response to NE, which required the release of glutamate from astrocytes. The rise in glutamate release probability is likely due to the activation of presynaptic GluN2B-containing NMDA receptors. Moreover, we showed that the activation of NE signaling in DG is necessary for the formation of contextual learning memory. Thus, NE signaling activation during fear conditioning training contributed to enduring changes in the frequency of mEPSC in DG. Our results strongly support the physiological neuromodulatory role of NE signaling, which is derived from activation of astrocytes.