Journal Information
ISSN / EISSN : 0017-5749 / 1468-3288
Published by: BMJ (10.1136)
Total articles ≅ 25,537
Current Coverage
SCOPUS
LOCKSS
MEDLINE
PUBMED
MEDICUS
SCIE
Archived in
EBSCO
SHERPA/ROMEO
Filter:

Latest articles in this journal

Martin J Lett, Hema Mehta, Adrian Keogh, Tina Jaeger, Maxime Jacquet, Kate Powell, Marie-Anne Meier, Isabel Fofana, Hassan Melhem, Jürg Vosbeck, et al.
Published: 20 January 2022
by BMJ
Abstract:
Objective Mucosal-associated invariant T (MAIT) cells are the most abundant T cells in human liver. They respond to bacterial metabolites presented by major histocompatibility complex-like molecule MR1. MAIT cells exert regulatory and antimicrobial functions and are implicated in liver fibrogenesis. It is not well understood which liver cells function as antigen (Ag)-presenting cells for MAIT cells, and under which conditions stimulatory Ags reach the circulation. Design We used different types of primary human liver cells in Ag-presentation assays to blood-derived and liver-derived MAIT cells. We assessed MAIT cell stimulatory potential of serum from healthy subjects and patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt stent, and patients with inflammatory bowel disease (IBD). Results MAIT cells were dispersed throughout healthy human liver and all tested liver cell types stimulated MAIT cells, hepatocytes being most efficient. MAIT cell activation by liver cells occurred in response to bacterial lysate and pure Ag, and was prevented by non-activating MR1 ligands. Serum derived from peripheral and portal blood, and from patients with IBD stimulated MAIT cells in MR1-dependent manner. Conclusion Our findings reveal previously unrecognised roles of liver cells in Ag metabolism and activation of MAIT cells, repression of which creates an opportunity to design antifibrotic therapies. The presence of MAIT cell stimulatory Ags in serum rationalises the observed activated MAIT cell phenotype in liver. Increased serum levels of gut-derived MAIT cell stimulatory ligands in patients with impaired intestinal barrier function indicate that intrahepatic Ag-presentation may represent an important step in the development of liver disease.
, , Roberta Maselli, Marhieu Pioche, , Jérémie Jacques, Amyn Haji, Dennis Yang, Eduardo Albéniz, Michal Filip Kaminski, et al.
Published: 20 January 2022
by BMJ
Abstract:
Objective Endoscopic submucosal dissection (ESD) in a curative intent for submucosa-invasive early (T1) colorectal cancers (T1-CRCs) often leads to subsequent surgical resection in case of histologic parameters indicating higher risk of nodal involvement. In some cases, however, the expected benefit may be offset by the surgical risks, suggesting a more conservative approach. Design Retrospective analysis of consecutive patients with T1-CRC who underwent ESD at 13 centres ending inclusion in 2019 (n=3373). Cases with high risk of nodal involvement (non-curative ESD: G3, submucosal invasion>1000 µm, lymphovascular involvement, budding or incomplete resection/R1) were analysed if follow-up data (endoscopy/imaging) were available, regardless of the postendoscopic management (follow-up vs surgery) selected by the multidisciplinary teams in these institutions. Comorbidities were classified according to Charlson Comorbidity Index (CCI). Outcomes were disease recurrence, death and disease-related death rates in the two groups. Rate of residual disease (RD) at both the previous resection site and regional lymph nodes was assessed in the surgical cases as well as from follow-up in the follow-up group. Results Of 604 patients treated by colorectal ESD for submucosally invasive cancer, 207 non-curative resections (34.3%) were included (138 male; mean age 67.6±10.9 years); in 65.2% of cases, no complete resection was achieved (R1). Of the 207 cases, 60.9% (n=126; median CCI: 3; IQR: 2–4) underwent surgical treatment with RD in 19.8% (25/126), while 39.1% (n=81, median CCI: 5; IQR: 4–6) were followed up by endoscopy in all cases. Patients in the follow-up group had a higher overall mortality (HR=3.95) due to non-CRC causes (n=9, mean survival after ESD 23.7±13.7 months). During this follow-up time, tumour recurrence and disease-specific survival rates were not different between the groups (median follow-up 30 months; range: 6–105). Conclusion Following ESD for a lesion at high risk of RD, follow-up only may be a reasonable choice in patients at high risk for surgery. Also, endoscopic resection quality should be improved. Trial registration number NCT03987828.
, Miri Yavzori, Ella Fudim, Orit Picard, Uri Kopylov, Rami Eliakim, Dror Shouval, Yishai Levin, Alon Savidor, Shani Ben-Moshe, et al.
Published: 19 January 2022
by BMJ
Abstract:
Background: Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features.Aims: To assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls.Methods: In this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes.Results: We analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10−12). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve >0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells.Conclusions: Faecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.
Andrea Szentesi, Nelli Farkas, Zoltán Sipos, Péter Mátrai, Áron Vincze, Ferenc Izbéki, Andrea Párniczky,
Published: 19 January 2022
by BMJ
Melissa Chew, , Prithi Bhathal, Tom R Sutherland,
Published: 19 January 2022
by BMJ
Abstract:
Blood tests showed elevated C reactive protein of 56 mg/L and normal full blood count, electrolytes, liver biochemistry, iron and B12 stores. HLA-B51 and interferon gamma release assay for Mycobacterium tuberculosis were negative. Faecal calprotectin was elevated at 583 µg/g. CT of the abdomen and pelvis revealed bowel wall thickening in the caecum and ascending colon with mesenteric lymphadenopathy (figure 1A). A gastroscopy showed …
Jonas Nørskov Søndergaard, Christian Sommerauer, Ionut Atanasoai, Laura C Hinte, Keyi Geng, Giulia Guiducci, , , , , et al.
Published: 12 January 2022
by BMJ
Abstract:
Objective: To better comprehend transcriptional phenotypes of cancer cells, we globally characterised RNA-binding proteins (RBPs) to identify altered RNAs, including long non-coding RNAs (lncRNAs).Design: To unravel RBP-lncRNA interactions in cancer, we curated a list of ~2300 highly expressed RBPs in human cells, tested effects of RBPs and lncRNAs on patient survival in multiple cohorts, altered expression levels, integrated various sequencing, molecular and cell-based data.Results: High expression of RBPs negatively affected patient survival in 21 cancer types, especially hepatocellular carcinoma (HCC). After knockdown of the top 10 upregulated RBPs and subsequent transcriptome analysis, we identified 88 differentially expressed lncRNAs, including 34 novel transcripts. CRISPRa-mediated overexpression of four lncRNAs had major effects on the HCC cell phenotype and transcriptome. Further investigation of four RBP-lncRNA pairs revealed involvement in distinct regulatory processes. The most noticeable RBP-lncRNA connection affected lipid metabolism, whereby the non-canonical RBP CCT3 regulated LINC00326 in a chaperonin-independent manner. Perturbation of the CCT3-LINC00326 regulatory network led to decreased lipid accumulation and increased lipid degradation in cellulo as well as diminished tumour growth in vivo.Conclusions: We revealed that RBP gene expression is perturbed in HCC and identified that RBPs exerted additional functions beyond their tasks under normal physiological conditions, which can be stimulated or intensified via lncRNAs and affected tumour growth.
, Evangelos Tsipotis, Yuhong Yuan, Grigorios I Leontiadis, Paul Moayyedi
Published: 12 January 2022
by BMJ
Abstract:
Objective: Functional dyspepsia (FD) is a chronic disorder that is difficult to treat. Helicobacter pylori may contribute to its pathophysiology. A Cochrane review from 2006 suggested that eradication therapy was beneficial, but there have been numerous randomised controlled trials (RCTs) published since. We evaluated impact of eradication therapy on both cure and improvement of FD, as well as whether any benefit was likely to arise from eradication of H. pylori.Design: We searched the medical literature through October 2021 to identify RCTs examining efficacy of eradication therapy in H. pylori-positive adults with FD. The control arm received antisecretory therapy or prokinetics, with or without placebo antibiotics, or placebo alone. Follow-up was for ≥3 months. We pooled dichotomous data to obtain a relative risk (RR) of symptoms not being cured or symptoms not improving with a 95% CI. We estimated the number needed to treat (NNT).Results: Twenty-nine RCTs recruited 6781 H. pylori-positive patients with FD. Eradication therapy was superior to control for symptom cure (RR of symptoms not being cured=0.91; 95% CI 0.88 to 0.94, NNT=14; 95% CI 11 to 21) and improvement (RR of symptoms not improving=0.84; 95% CI 0.78 to 0.91, NNT=9; 95% CI 7 to 17). There was no significant correlation between eradication rate and RR of FD improving or being cured (Pearson correlation coefficient=−0.23, p=0.907), but the effect was larger in patients with successful eradication of H. pylori than with unsuccessful eradication (RR=0.65; 95% CI 0.52 to 0.82, NNT=4.5, 95% CI 3 to 9). Adverse events (RR=2.19; 95% 1.10 to 4.37) and adverse events leading to withdrawal (RR=2.60; 95% CI 1.47 to 4.58) were more common with eradication therapy.Conclusion: There is high quality evidence to suggest that H. pylori eradication therapy leads to both cure and improvement in FD symptoms, although the benefit is modest.
Gaia Bellomo, Carolyn Rainer, Valeria Quaranta, Yuliana Astuti, Meirion Raymant, Elzbieta Boyd, Ruth Stafferton, Fiona Campbell, Paula Ghaneh, Christopher M Halloran, et al.
Published: 12 January 2022
by BMJ
Abstract:
Objective Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood. Design The impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment. Results We show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants. Conclusion Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.
Back to Top Top