Multidisciplinary team quality improves the survival outcomes of locally advanced rectal cancer patients: A post hoc analysis of the STELLAR trial.

PURPOSE: We sought to determine the association between multidisciplinary team (MDT) quality and survival of patients with locally advanced rectal cancer. METHODS: In a post hoc analysis of the randomized phase III STELLAR trial, 464 patients with distal or middle-third, clinical tumor category cT3-4 and/or regional lymph node-positive rectal cancer who completed surgery were evaluated. Disease-free survival (DFS) and Overall survival (OS) were stratified by Multidisciplinary team (MDT) quality, which was also included in the univariable and multivariable analyses of DFS and OS. RESULTS: According to the univariable analyses, a significantly worse DFS was associated with a fewer specialized medical disciplines participating in MDT (<5 vs ≥ 5; P=0.049),a lower frequency of MDT meetings ( 200; P=0.039). In addition, a lower number of specialized medical disciplines participating in MDT (<5 vs ≥ 5; P<0.001), a lower frequency of MDT meetings ( 200; P=0.001) were the variables associated with OS. These 3 factors were considered when assessing MDT quality, which was classified into 2 categories: high quality or general quality. Patients treated in hospitals with high MDT quality had longer 3-year OS (90.5 % vs 78.1 %; P=0.001) and similar 3-year DFS (70.3 % vs 61.3 %; P=0.109) compared to those treated in hospitals of the general MDT quality group. Furthermore, multivariable analyses revealed a significance for DFS (HR, 1.648; 95 % CI, 1.143-2.375; P=0.007) and OS (HR, 2.771; 95 % CI, 1.575-4.877; P<0.001) in MDT quality. CONCLUSIONS: The use of hospitals with optimized multidisciplinary infrastructure had a significant influence on survival of patients with locally advanced rectal cancer.

Gut microbiota dysbiosis: The potential mechanisms by which alcohol disrupts gut and brain functions.

Alcohol use disorder (AUD) is a high-risk psychiatric disorder and a key cause of death and disability in individuals. In the development of AUD, there is a connection known as the microbiota-gut-brain axis, where alcohol use disrupts the gut barrier, resulting in changes in intestinal permeability as well as the gut microbiota composition, which in turn impairs brain function and worsens the patient's mental status and gut activity. Potential mechanisms are explored by which alcohol alters gut and brain function through the effects of the gut microbiota and their metabolites on immune and inflammatory pathways. Alcohol and microbiota dysregulation regulating neurotransmitter release, including DA, 5-HT, and GABA, are also discussed. Thus, based on the above discussion, it is possible to speculate on the gut microbiota as an underlying target for the treatment of diseases associated with alcohol addiction. This review will focus more on how alcohol and gut microbiota affect the structure and function of the gut and brain, specific changes in the composition of the gut microbiota, and some measures to mitigate the changes caused by alcohol exposure. This leads to a potential intervention for alcohol addiction through fecal microbiota transplantation, which could normalize the disruption of gut microbiota after AUD.

Carboxypeptidase E Regulates Activity-Dependent TrkB Neuronal Surface Insertion and Hippocampal Memory.

Activity-dependent insertion of the tropomyosin-related kinase B (TrkB) receptor into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons and synapses; however, the underlying molecular mechanisms remain obscure. Here, we report a novel function for carboxypeptidase E (CPE) in controlling chemical long-term potentiation stimuli-induced TrkB surface delivery in hippocampal neurons. Total internal reflection fluorescence assays and line plot assays showed that CPE facilitates TrkB transport from dendritic shafts to the plasma membrane. The Box2 domain in the juxtamembrane region of TrkB and the C terminus of CPE are critical for the activity-dependent plasma membrane insertion of TrkB. Moreover, the transactivator of transcription TAT-CPE452-466, which could block the association between CPE and TrkB, significantly inhibited neuronal activity-enhanced BDNF signaling and dendritic spine morphologic plasticity in cultured hippocampal neurons. Microinfusion of TAT-CPE452-466 into the dorsal hippocampus of male C57BL/6 mice inhibited the endogenous interaction between TrkB and CPE and diminished fear-conditioning-induced TrkB phosphorylation, which might lead to an impairment in hippocampal memory acquisition and consolidation but not retrieval. These results suggest that CPE modulates activity-induced TrkB surface insertion and hippocampal-dependent memory and sheds light on our understanding of the role of CPE in TrkB-dependent synaptic plasticity and memory modulation.SIGNIFICANCE STATEMENT It is well known that BDNF acts preferentially on active neurons; however, the underlying molecular mechanism is not fully understood. In this study, we found that the cytoplasmic tail of CPE could interact with TrkB and facilitate the neuronal activity-dependent movement of TrkB vesicles to the plasma membrane. Blocking the association between CPE and TrkB decreased fear-conditioning-induced TrkB phosphorylation and led to hippocampal memory deficits. These findings provide novel insights into the role of CPE in TrkB intracellular trafficking as well as in mediating BDNF/TrkB function in synaptic plasticity and hippocampal memory.