我们进行了一项前瞻性、随机、对照、多中心研究(NCT03331224)。有内镜证据显示急性NVUGIB和再出血高风险(定义为完整的Rockall评分≥7)的患者纳入研究。主要终点为临床成功,定义为内镜下止血成功,无复发出血的证据。< / p > < /秒> 246 patients were screened and 100 patients were finally randomised (mean of 5 cases/centre and year; 70% male, 30% female, mean age 78 years; OTSC group n=48, standard group n=52). All but one case in the standard group were treated with conventional clips. Clinical success was 91.7% (n=44) in the OTSC group compared with 73.1% (n=38) in the ST group (p=0.019), with persistent bleeding occurring in 0 vs 6 in the OTSC versus standard group (p=0.027), all of the latter being successfully managed by rescue therapy with OTSC. Recurrent bleeding was observed in four patients (8.3%) in the OTSC group and in eight patients (15.4%) in the standard group (p=0.362). OTSC therapy appears to be superior to standard treatment with clips when used by trained physicians for selected cases of primary therapy of NVUGIB with high risk of rebleeding. Further studies are necessary with regards to patient selection to identify subgroups benefiting most from OTSC haemostasis.
分析了12例胃发育不良或胃癌患者的胃体、胃窦组织和胃液中的菌群分布。然后,从慢性浅表性胃炎、肠化生或胃癌患者(n=15和n=12)的活检体、胃窦组织和胃液中接种42只GF C57BL/6小鼠。用扩增子测序法分析胃菌群。接种后1个月免疫组化分析小鼠胃组织病理学特征。另外一组独立的15只GF小鼠也在1年后进行分析。< / p > < /秒> The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation. Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
一名33岁男性患者出现消化不良和恶心2个月的病史。22年前因病因不明的肾衰竭接受肾移植。由于反复肾衰竭,他接受了14年的腹膜透析。14个月前,他接受了活体捐赠者的第二次KT移植。移植后一直服用强的松龙和他克莫司。实验室研究结果如下:血尿素氮11.0 mg/dL(正常范围8.0和ndash;23.0 mg/dL);肌酐,0.92 mg/dL(正常范围,0.7–1.2 mg/dL);总钙,11.1 mg/dL(正常范围8.6和ndash;10.2 mg/dL);校正钙,11.3 mg/dL;磷酸盐,2.6 mg/dL(正常范围,2.5–4.5 mg/dL)和碱性磷酸酶,156 U/L(正常范围,40–129 U/L)。上消化道内镜检查评估患者的恶心和消化不良情况。 Multiple white flat plaques of various sizes and patch-like or nodule-like mucosal changes in a watermelon pattern were observed across the whole stomach. Small, shiny, white plaques were scattered across the bulb of the duodenum...
癌症的表观基因组改变与免疫微环境相互作用,决定了肿瘤的进化和治疗反应。我们的目标是通过在胃癌中使用表观遗传交替启动子来研究肿瘤免疫微环境的调节,并将我们的发现扩展到其他胃肠道肿瘤。< / p > < /秒> Alternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes. APBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032). These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.
我们对CD样本的纤维化进行了组织学和转录分析。我们通过反复对小鼠进行结肠活检,建立了cd样纤维化表型模型,并通过组织学、I型胶原靶向正电子发射断层扫描(PET)和全局基因表达分析模型。我们生成了肠系膜纤维化的基本特征的基因集列表,并将其与炎症性肠病患者的粘膜活检数据集进行比较,以确定与临床结果相关的精制基因集。
CD患者肠系膜纤维化与肠各层纤维化区相互连接,定义为穿透性纤维化。我们发现在具有高水平纤维化的乳糜泻受试者的肠系膜脂肪区域富集了差异表达基因的转录特征。经多次结肠活检的小鼠,组织学、PET成像和转录分析均显示为穿透性纤维化。最后,我们合成了与炎症成纤维细胞相关并与治疗反应相关的24个复合基因集列表。< / p > < /秒> We linked histopathological and molecular features of CD penetrating fibrosis to a mouse model of repeated biopsy injuries. This experimental system provides an innovative approach for functional investigations of underlying profibrotic mechanisms and therapeutic concepts in CD.
We performed small RNA and shotgun metagenomic sequencing in faecal samples and dietary recording from 120 healthy volunteers, equally distributed for the different diets and matched for sex and age.
We found 49 miRNAs differentially expressed among vegans, vegetarians and omnivores (adj. p <0.05) and confirmed trends of expression levels of such miRNAs in vegans and vegetarians compared with an independent cohort of 45 omnivores. Two miRNAs related to lipid metabolism, miR-636 and miR-4739, were inversely correlated to the non-omnivorous diet duration, independently of subject age. Seventeen miRNAs correlated (|rho|>0.22, adj. p <0.05) with the estimated intake of nutrients, particularly animal proteins, phosphorus and, interestingly, lipids. In omnivores, higher Prevotella and Roseburia and lower Bacteroides abundances than in vegans and vegetarians were observed. Lipid metabolism-related miR-425-3p and miR-638 expression levels were associated with increased abundances of microbial species, such as Roseburia sp. CAG 182 and Akkermansia muciniphila, specific of different diets. An integrated analysis identified 25 miRNAs, 25 taxa and 7 dietary nutrients that clearly discriminated (area under the receiver operating characteristic curve=0.89) the three diets.
Stool miRNA profiles are associated with specific diets and support the role of lipids as a driver of epigenetic changes and host-microbial molecular interactions in the gut.
Integrated analysis of untargeted serum metabolomics by liquid chromatography-mass spectrometry and metagenome sequencing of paired faecal samples was applied to identify gut microbiome-associated metabolites with significantly altered abundance in patients with CRC and adenoma. The ability of these metabolites to discriminate between CRC and colorectal adenoma was tested by targeted metabolomic analysis. A model based on gut microbiome-associated metabolites was established and evaluated in an independent validation cohort.
In total, 885 serum metabolites were significantly altered in both CRC and adenoma, including eight gut microbiome-associated serum metabolites (GMSM panel) that were reproducibly detected by both targeted and untargeted metabolomics analysis and accurately discriminated CRC and adenoma from normal samples. A GMSM panel-based model to predict CRC and colorectal adenoma yielded an area under the curve (AUC) of 0.98 (95% CI 0.94 to 1.00) in the modelling cohort and an AUC of 0.92 (83.5% sensitivity, 84.9% specificity) in the validation cohort. The GMSM model was significantly superior to the clinical marker carcinoembryonic antigen among samples within the validation cohort (AUC 0.92 vs 0.72) and also showed promising diagnostic accuracy for adenomas (AUC=0.84) and early-stage CRC (AUC=0.93).
Gut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.
We conducted a 5-day audit (cross-sectional study) of all endoscopies performed at two US academic medical centres with low and a high endoscopy volume (2000 and 13 000 procedures annually, respectively). We calculated the average disposable waste (excluding waste from reprocessing) generated during one endoscopic procedure to estimate waste of all endoscopic procedures generated in the USA annually (18 million). We further estimated the impact of changing from reusable to single-use endoscopes taking reprocessing waste into account.
278 endoscopies were performed for 243 patients. Each endoscopy generated 2.1 kg of disposable waste (46 L volume). 64% of waste was going to the landfill, 28% represented biohazard waste and 9% was recycled. The estimated total waste generated during all endoscopic procedures performed in the USA annually would weigh 38 000 metric tons (equivalent of 25 000 passenger cars) and cover 117 soccer fields to 1 m depth. If all endoscopic procedures were performed with single-use endoscopes and accounting for reprocessing, the net waste mass would increase by 40%. Excluding waste from ancillary supplies, net waste generated from reprocessing and endoscope disposal would quadruple with only using single-use endoscopes.
This quantitative assessment of the environmental impact of endoscopic procedures highlights that a large amount of waste is generated from disposable instruments. Transitioning to single-use endoscopes may reduce reprocessing waste but would increase net waste.
The Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California (N=18 751 live births among 14 507 mothers). Clinical information was abstracted from mothers’ medical records 6 months prior to pregnancy through delivery. Diagnoses of CRC in adult (age ≥18 years) offspring were ascertained through 2019 by linkage with the California Cancer Registry. We used Cox proportional hazards models to estimate adjusted HR (aHR); we examined effect measure modification using single-referent models to estimate the relative excess risk due to interaction (RERI).
68 offspring were diagnosed with CRC over 738 048 person-years of follow-up, and half (48.5%) were diagnosed younger than age 50 years. Maternal obesity (≥30 kg/m2) increased the risk of CRC in offspring (aHR 2.51, 95% CI 1.05 to 6.02). Total weight gain modified the association of rate of early weight gain (RERI –4.37, 95% CI –9.49 to 0.76), suggesting discordant growth from early to late pregnancy increases risk. There was an elevated association with birth weight (≥4000 g: aHR 1.95, 95% CI 0.8 to 4.38).
Our results suggest that in utero events are important risk factors for CRC and may contribute to increasing incidence rates in younger adults.
We conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up.
The RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type.
This prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.
一项多中心、前瞻性、国际队列研究。< / p > < /秒> 43 gastroenterology and endoscopy centres located in Europe and South America. 2215 patients (2198 completing the study) at the first diagnosis of diverticulosis/diverticular disease were enrolled. Patients were scored according to DICA classifications. A 3-year follow-up was performed. To predict the acute diverticulitis and the surgery according to DICA classification. Survival methods for censored observation were used to develop and validate a novel combined endoscopic-clinical score for predicting diverticulitis and surgery (CODA score). The 3-year cumulative probability of diverticulitis and surgery was of 3.3% (95% CI 2.5% to 4.5%) in DICA 1, 11.6% (95% CI 9.2% to 14.5%) in DICA 2 and 22.0% (95% CI 17.2% to 28.0%) in DICA 3 (p<0.001), and 0.15% (95% CI 0.04% to 0.59%) in DICA 1, 3.0% (95% CI 1.9% to 4.7%) in DICA 2 and 11.0% (95% CI 7.5% to 16.0%) in DICA 3 (p<0.001), respectively. The 3-year cumulative probability of diverticulitis and surgery was ≤4%, and ≤0.7% in CODA A; <10% and <2.5% in CODA B; >10% and >2.5% in CODA C, respectively. The CODA score showed optimal discrimination capacity in predicting the risk of surgery in the development (c-statistic: 0.829; 95% CI 0.811 to 0.846) and validation cohort (c-statistic: 0.943; 95% CI 0.905 to 0.981). DICA classification has a significant role in predicting the risk of diverticulitis and surgery in patients with diverticulosis, which is significantly enhanced by the CODA score.
最近的证据表明,微生物组在胰腺导管腺癌(PDAC)的病因和进展中起作用。
探讨粪便和唾液菌群作为潜在的诊断生物标志物。< / p > < /秒> We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case–control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case–control study (n=76), in the validation phase. Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19–9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
钠+/牛磺胆酸共转运多肽(NTCP)是影响胆汁酸(BAs)肠肝循环的膜转运体。我们的目的是评估NTCP&rsquo在人类和动物肝纤维化(LF)模型中的作用。< / p > < /秒> Primary hepatic stellate cells (pHSCs) isolated from livers biopsies of patients with LF with different fibrosis grading were stained for NTCP. NTCP gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG) and HA-100 dihydrochloride (HA-100) were used as tools to modulate NTCP expression on human HSC line (LX2). BA trafficking/uptake were assessed extracellularly (LX2 culture medium) and intracellularly following treatment with/without NTCP neutralizing antibody. LF models of C57/BL6 mice of carbon tetrachloride (CCl4) and leptin-deficient (Ob/Ob) fed with high-fat diet (Ob/Ob HFD ) were evaluated for pHSCs-NTCP expressions, metabolic and LF profiles following intraperitoneal injections of NTCP neutralizing antibody. pHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p<0.0001). Sorted-activated HSCs (LX2αSMA+) showed high expressions of NTCP and high TCA uptake in vitro and triggered a further increase in their activations. This phenomenon was inhibited with NTCP small interfering RNA and the NTCP neutralizing antibody. Sorted LX2NTCP+ (high alpha smooth muscle actin (αSMA)/high NTCP) cells showed high phosphorylated pathways of AKT/mTOR and protein kinase C (PKC) accompanied with a decrease in farnesoid X receptor expression. Moreover, LX2NTCP+ cells treated with EGCG, OCA and PKC inhibitor HA-100 significantly decreased NTCP and αSMA. NTCP neutralizing antibody inhibited NTCP (less TCA uptake); it attenuated LF in both CCl4 and Ob/Ob HFD animal models with ameliorated metabolic profile. NTCP expression is linearly correlated with fibrosis severity. Modulated BA trafficking could be an important step in LF pathogenesis. Antagonising BA uptake may suggest a therapeutic strategy for preventing disease progression.
肝内胆管癌(iCCA)发病率呈上升趋势,目前有效的全身治疗方法有限。iCCA肿瘤被基质细胞浸润,包括肿瘤相关巨噬细胞(TAMs)和髓源性抑制细胞(MDSCs)在内的抑郁性髓系细胞普遍存在。在本研究中,我们发现肿瘤来源的粒细胞和巨噬细胞集落刺激因子(GM-CSF)和宿主骨髓是TAMs的单细胞增殖和增强的中心,而在一个新的iCCA模型中,这一信号轴的缺失促进了抗肿瘤免疫。
分析iCCA患者和对照组的血液和肿瘤。用抗gm - csf单克隆抗体治疗原位和原位iCCA肿瘤的小鼠,进行治疗和相关研究。< / p > < /秒> Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.
组织驻留记忆T细胞(TRM)是提供保护性免疫的重要免疫哨兵。虽然肝脏CD8+ TRM已有很好的描述,但CD4+ TRM的位置、表型和功能却知之甚少。< / p > < /秒> We used multiparametric flow cytometry, histological assessment and novel human tissue coculture systems to interrogate the ex vivo phenotype, function and generation of the intrahepatic CD4+ T-cell compartment. We also used leukocytes isolated from human leukocyte antigen (HLA)-disparate liver allografts to assess long-term retention. Hepatic CD4+ T cells were delineated into three distinct populations based on CD69 expression: CD69–, CD69INT and CD69HI. CD69HICD4+ cells were identified as tissue-resident CD4+ T cells on the basis of their exclusion from the circulation, phenotypical profile (CXCR6+CD49a+S1PR1–PD-1+) and long-term persistence within the pool of donor-derived leukcoocytes in HLA-disparate liver allografts. CD69HICD4+ T cells produced robust type 1 polyfunctional cytokine responses on stimulation. Conversely, CD69INTCD4+ T cells represented a more heterogenous population containing cells with a more activated phenotype, a distinct chemokine receptor profile (CX3CR1+CXCR3+CXCR1+) and a bias towards interleukin-4 production. While CD69INTCD4+ T cells could be found in the circulation and lymph nodes, these cells also formed part of the long-term resident pool, persisting in HLA-mismatched allografts. Notably, frequencies of CD69INTCD4+ T cells correlated with necroinflammatory scores in chronic hepatitis B infection. Finally, we demonstrated that interaction with hepatic epithelia was sufficient to generate CD69INTCD4+ T cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HICD4+ T cells. High and intermediate CD69 expressions mark human hepatic CD4+ TRM and a novel functionally distinct recirculating population, respectively, both shaped by the liver microenvironment to achieve diverse immunosurveillance.
白东,姚亮,张勇,et al. 0。人体肠道细菌产生TH17-调节胆汁酸代谢物。自然<我> < / I > 2022;603:907– 912年。doi: 10.1038 / s41586 - 022 - 04480 - z。肠道微生物介导的胆汁酸代谢与宿主免疫反应密切相关,这种相互作用的干扰与包括炎症性肠病(IBD)在内的人类疾病有关。然而,这些相互作用背后的途径仍然只被部分了解。在先前研究的基础上,证实了一种特定的胆油酸,3-氧化胆酸(3-oxoLCA),可以抑制促炎T辅助因子17 (TH17)细胞的分化,Paik 等首先筛选了990株来自人类粪便的细菌分离株,研究它们将石胆酸(LCA)生物转化为3-氧化胆酸的能力;共鉴定出238株具有该功能的菌株。许多这些确定的菌株也被注意到产生isoLCA,一种丰富的胆汁…
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