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Identification of Subtypes of Barrett's Esophagus and Esophageal Adenocarcinoma Based on DNA Methylation Profiles and Integration of Transcriptome and Genome Data.
No full textBACKGROUND & AIMS
Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity.
METHODS
In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs.
RESULTS
BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs.
CONCLUSIONS
In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy
Bony cystic lesion with associated submandibular lymphadenopathy on a background of breast carcinoma: an unexpected case of cervicofacial actinomycosis.
No full textActinomycosis is an uncommon, chronic suppurative granulomatous infection and needs to be considered as a differential diagnosis. A 56-year-old woman with a background of type 2 diabetes mellitus and breast carcinoma was referred to the Oral and Maxillofacial Surgery 2-week wait clinic, regarding a tender sublingual mass and firm erythematous swelling in the right submandibular and submental region. This was slowly progressive and had not responded to oral co-amoxiclav. An orthopantomogram showed a well-defined radiolucency and smaller radiolucent lesions throughout the edentulous right body of the mandible. A contrast-enhanced CT confirmed a right submandibular abscess communicating with cavitating lesions. The differentials included osteomyelitis, bony metastases, multiple myeloma or other cystic lesions. The patient underwent incision and drainage of the abscess, alongside biopsies, and intravenous co-amoxiclav was given. Microbiology cultures confirmed the presence of and a diagnosis of cervicofacial actinomycosis with mandibular osteomyelitis. The patient was successfully treated with prolonged antibiotics
Probable etoricoxib-induced fixed drug eruption involving the oral mucosa: A case report.
No full textFixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by recurrence of lesions at the same sites each time a specific drug is taken. Oral mucosal involvement is rare. Nonsteroidal anti-inflammatory drugs are one of the most common offending drug groups in FDE; however, selective cyclooxygenase-2 inhibitors, such as etoricoxib, are rarely implicated. We present a case of oral mucosal and cutaneous FDE induced by etoricoxib that, to the best of our knowledge, is the first reported case of this nature. We describe the diagnostic challenges and review the pertinent literature. The value of drug provocation testing and patch testing in FDE is also discussed
Thoracic Injury in Patients Injured by Explosions on the Battlefield and in Terrorist Incidents.
No full textThoracic injury is common on the battlefield and in terrorist attacks, occurring in 10% to 70% of patients depending on the type of weapons used. Typical injuries seen include bullet, blast, and fragment injuries to the thorax, which are often associated with injuries to other parts of the body. Initial treatment prehospital and in the ED is carried out according to the principles of Tactical Combat Casualty Care or other standard trauma management systems. Immediately life-threatening problems including catastrophic hemorrhage are dealt with rapidly, and early consideration is given to CT scanning or rapid surgical intervention where appropriate. All patients should be given lung-protective ventilation. Treatment of these patients in the critical care unit is complicated by the severity of associated injuries and by features specific to combat trauma including blast lung injury, a high incidence of delirium, unusual infections such as colonization with multidrug-resistant Acinetobacter baumannii complex, and sometimes invasive fungal infections. A minority of patients with blast lung injury in published series have been successfully treated with prolonged respiratory support with high-frequency oscillatory ventilation and extracorporeal membrane oxygenation. The role of newer treatment options such as resuscitative endovascular balloon occlusion of the aorta is not yet known. In this article we review the relatively sparse literature on this group of patients and provide practical advice based on the literature and our institution's extensive experience of managing battlefield casualties
Simulation training using WhatsApp (Sim-thru-WhatsApp) improves doctors' confidence in endocrine and diabetes case management.
No full textPreoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.
No full textBACKGROUND
Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes.
METHODS
In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants.
FINDINGS
Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints.
INTERPRETATION
Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery.
FUNDING
UK National Institute of Health Research Health Technology Assessment Program
Brief O uploading during continuous hypothermic machine perfusion is simple yet effective oxygenation method to improve initial kidney function in a porcine autotransplant model.
No full textWith oxygenation proposed as a resuscitative measure during hypothermic models of preservation, the aim of this study was to evaluate the optimal start time of oxygenation during continuous hypothermic machine perfusion (HMP). In this porcine ischemia-reperfusion autotransplant model, the left kidney of a ±40 kg pig was exposed to 30 minutes of warm ischemia prior to 22 hours of HMP and autotransplantation. Kidneys were randomized to receive 2 hours of oxygenation during HMP either at the start (n=6), or end of the perfusion (n=5) and outcomes were compared to standard, non-oxygenated HMP (n=6) and continuous oxygenated HMP (n=8). The brief initial and continuous oxygenated HMP groups were associated with superior graft recovery compared to either standard, non-oxygenated HMP or kidneys oxygenated at the end of HMP. This correlated with significant metabolic differences in perfusate (e.g. lactate, succinate, flavin mononucleotide) and tissues (e.g. succinate, ATP, HIF-1α, Nrf2) suggesting superior mitochondrial preservation with initial oxygenation. Brief initial O uploading during HMP at procurement site might be an easy and effective preservation strategy to maintain aerobic metabolism, protect mitochondria and achieve an improved early renal graft function compared with standard HMP or oxygen supply shortly at the end of HMP preservation
Pneumonia in exacerbations of COPD: what is the clinical significance?
No full texthttp://bit.ly/2q2vH2J
MCTR1 alleviates lipopolysaccharide-induced acute lung injury by protecting lung endothelial glycocalyx.
No full textEndothelial glycocalyx degradation, critical for increased pulmonary vascular permeability, is thought to facilitate the development of sepsis into the multiple organ failure. Maresin conjugates in tissue regeneration 1 (MCTR1), a macrophage-derived lipid mediator, which exhibits potentially beneficial effects via the regulation of bacterial phagocytosis, promotion of inflammation resolution, and regeneration of tissue. In this study, we show that MCTR1 (100 ng/mouse) enhances the survival of mice with lipopolysaccharide (LPS)-induced (15 mg/kg) sepsis. MCTR1 alleviates LPS (10 mg/kg)-induced lung dysfunction and lung tissue inflammatory response by decreasing inflammatory cytokines (tumor necrosis factor-α, interleukin-1β [IL-1β], and IL-6) expression in serum and reducing the serum levels of heparan sulfate (HS) and syndecan-1. In human umbilical vein endothelial cells (HUVECs) experiments, MCTR1 (100 nM) was added to the culture medium with LPS for 6 hr. MCTR1 treatment markedly inhibited HS degradation by downregulating heparanase (HPA) protein expression in vivo and in vitro. Further analyses indicated that MCTR1 upregulates sirtuin 1 (SIRT1) expression and decreases NF-κB p65 phosphorylation. In the presence of BOC-2 or EX527, the above effects of MCTR1 were abolished. These results suggest that MCTR1 protects against LPS-induced sepsis in mice by attenuating pulmonary endothelial glycocalyx injury via the ALX/SIRT1/NF-κB/HPA pathway