Navigating reflux disease after achalasia treatments:Balancing risks and benefits

The peroral endoscopic myotomy(POEM)procedure has revolutionized the management of achalasia in many centres around the world as it offers patients a minimally invasive endoscopic solution to their dysphagia caused by achalasia.Alongside its success in alleviating dysphagia,concerns regarding postoperative gastroesophageal reflux disease have emerged as a pertinent issue which are not fully resolved.In this study,Nabi et al have comprehensively reviewed the topic of the prediction,prevention and management of gastroesophageal reflux after POEM.POEM is a purely endoscopic procedure which is usually performed without any anti-reflux procedure.Certain patients may be better served by a laparoscopic Heller’s myotomy and fundoplication and it is important that gastroenterologists and surgeons provide comprehensive risks and benefits of each achalasia treatment option so that patients can decide what treatment is best for them.This article by Nabi et al provides a comprehensive review of the current status of this issue to allow these discussions to occur.

Association between Exposure to Metals during Pregnancy,Childhood Gut Microbiome,and Risk of Intestinal Inflammation in Late Childhood

Alterations to the gut microbiome and exposure to metals during pregnancy have been suggested to impact inflammatory bowel disease.Nonetheless,how prenatal exposure to metals eventually results in long-term effects on the gut microbiome,leading to subclinical intestinal inflammation,particularly during late childhood,has not been studied.It is also unknown whether such an interactive effect drives a specific subgroup of children toward elevated susceptibility to intestinal inflammation.We used an amalgamation of machine-learning techniques with a regression-based framework to explore if children with distinct sets of gut microbes and certain patterns of exposure to metals during pregnancy(metal−microbial clique signature)had a higher likelihood of intestinal inflammation,measured based on fecal calprotectin(FC)in late childhood.We obtained samples from a well-characterized longitudinal birth cohort from Mexico City(n=108),Mexico.In the second and third trimesters of pregnancy,11 metals were measured in whole blood.Gut microbial abundances and FC were measured in stool samples from children 9−11 years of age.Elevated FC was defined as having FC above 100μg/g of stool.We identified subgroups of children in whom microbial and metal−microbial clique signatures were associated with elevated FC(false discovery rate(FDR)<0.05).In particular,we found two metal−microbial clique signatures significantly associated with elevated FC:(1)low cesium(Cs)and copper(Cu)in the third trimester and low relative abundance of Eubacterium ventriosum(OR[95%CI]:10.27[3.57,29.52],FDR<0.001)and(2)low Cu in the third trimester and high relative abundances of Roseburia inulinivorans and Ruminococcus torques(OR[95%CI]:7.21[1.81,28.77],FDR<0.05).This exploratory study demonstrates that children with specific gut microbes and specific exposure patterns to metals during pregnancy may have higher fecal calprotectin levels in late childhood,denoting an elevated risk of intestinal inflammation.

LPA_(1) antagonist-derived LNPs deliver A20 mRNA and promote anti-fibrotic activities

Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.

Engineering bionic T cells: signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms

Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy(ACT).The provision of proper costimulatory receptor activity and cytokine stimuli,along with the repression of inhibitory mechanisms,will conceivably make the most of these treatment strategies.In this sense,T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion,last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant tissues.Their antitumor effects can be dramatically augmented with permanent or transient gene transfer maneuvers to express or delete/repress genes.A combination of such interventions seeks the creation of the ultimate bionic T cell,perfected to seek and destroy cancer cells upon systemic or local intratumor delivery.