Gastric and duodenal pseudomelanosis: a new insight into its pathogenesis.
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ABSTRACT:
SUBMITTER: Tang SJ
PROVIDER: S-EPMC6831910 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Gastric and duodenal pseudomelanosis: a new insight into its pathogenesis.
Tang Shou-Jiang SJ Zhang Shengyu S Grunes Dianne E DE
VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 20190805 10
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Project description:BackgroundHypertensive nephropathy (HN) is a high-burden disorder and a leading cause of end-stage renal disease. Despite huge investigations, the underlying mechanisms are yet largely unknown. Systems biology is a promising approach to providing a comprehensive insight into this complex disorder.MethodsProteome profiles of kidney tubulointerstitium and outer and inner cortex from a rat model of HN were retrieved from the proteomics identification database, and the quality of the datasets was assessed. Proteins that exhibited differential expression were detected and their interactions were analyzed in the kidney sub-compartments. Furthermore, enzymes were linked to the attributed metabolites. Functional enrichment analyses were performed to identify key pathways and processes based on the differentially expressed proteins and predicted metabolites.ResultsProteasome-mediated protein degradation, actin cytoskeleton organization, and Rho GTPase signaling pathway are involved in the pathogenesis of HN. Furthermore, tissue hypoxia and dysregulated energy homeostasis are among the key underlying events. The metabolism of purine and amino acids is also affected in HN.ConclusionAlthough the proposed pathogenic mechanisms remain to be further validated in experimental studies, this study contributes to the understanding of the molecular mechanisms of HN through a systematic unsupervised approach. Considering the significant alterations of metabolic pathways, HN can be viewed as an "acquired error of metabolism."
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Project description:After infecting a mammalian host, the facultative intracellular bacterium, Francisella tularensis, encounters an elevated environmental temperature. We hypothesized that this temperature change may regulate genes essential for infection.Microarray analysis of F. tularensis LVS shifted from 26 degrees C (environmental) to 37 degrees C (mammalian) showed approximately 11% of this bacterium's genes were differentially-regulated. Importantly, 40% of the protein-coding genes that were induced at 37 degrees C have been previously implicated in virulence or intracellular growth of Francisella in other studies, associating the bacterial response to this temperature shift with pathogenesis. Forty-four percent of the genes induced at 37 degrees C encode proteins of unknown function, suggesting novel Francisella virulence traits are regulated by mammalian temperature. To explore this possibility, we generated two mutants of loci induced at 37 degrees C [FTL_1581 and FTL_1664 (deoB)]. The FTL_1581 mutant was attenuated in a chicken embryo infection model, which was likely attributable to a defect in survival within macrophages. FTL_1581 encodes a novel hypothetical protein that we suggest naming temperature-induced, virulence-associated locus A, tivA. Interestingly, the deoB mutant showed diminished entry into mammalian cells compared to wild-type LVS, including primary human macrophages and dendritic cells, the macrophage-like RAW 264.7 line, and non-phagocytic HEK-293 cells. This is the first study identifying a Francisella gene that contributes to uptake into both phagocytic and non-phagocytic host cells.Our results provide new insight into mechanisms of Francisella virulence regulation and pathogenesis. F. tularensis LVS undergoes considerable gene expression changes in response to mammalian body temperature. This temperature shift is important for the regulation of genes that are critical for the pathogenesis of Francisella. Importantly, the compilation of temperature-regulated genes also defines a rich collection of novel candidate virulence determinants, including tivA (FTL_1581). An analysis of tivA and deoB (FTL_1664) revealed that these genes contribute to intracellular survival and entry into mammalian cells, respectively.
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Project description:The obesity paradox is reported to exist in various diseases. However, obesity is a pivotal issue in gastric cancer (GC) patients because of the surgical difficulty related to postoperative abdominal infectious complications (PAIC). This study clarified the existence of the obesity paradox in GC. Between 1997 and 2015, 1536 consecutive patients underwent curative gastrectomy. Of all patients, 18.6% (285/1536) were obese and tended to have a better prognosis (P = 0.073). In patients without PAIC, obesity was a significant prognostic factor for 5-year overall survival (P = 0.017). PAIC was an independent poor prognostic factor in both obese and non-obese patients (P < 0.001; hazard ratio [HR] 4.22 and 1.82). In pStage II-III patients, there was a large and significant prognostic difference between non-PAIC and PAIC obese patients (P = 0.006; 5-year overall survival: 69.7% vs. 43.8%) related to the higher incidence of peritoneal recurrence in PAIC obese patients (P = 0.035; 31% vs. 10%). Whereas, there was a small prognostic difference between non-PAIC and PAIC non-obese patients (P = 0.102; 5-year overall survival: 56.5% vs. 51.9%). Although the obesity paradox is present in GC, PAIC had a more negative prognostic impact through peritoneal recurrence in obese GC patients.
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Project description:BackgroundJuvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear.MethodsTo prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk.ResultsWe have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks.ConclusionOur findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.
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Project description:Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.
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Project description:BACKGROUND:Surgical resection of upper gastrointestinal (GI) subepithelial tumors (SETs) is associated with significant morbidity and mortality. A new over-the-scope (OTS) clip can be used for endoscopic full-thickness resection (eFTR). We aimed to prospectively evaluate feasibility and safety of upper GI eFTR with a new, flat-based OTS clip. METHODS:Consecutive patients with a gastric or duodenal SET < 20 mm were prospectively included. After identification of the lesion, the clip was placed and lesions were resected. Patients were followed for 1 month to assess severe adverse events (SAEs); 3-6 months after eFTR, endoscopy was performed. RESULTS:eFTR was performed on 13 lesions in 12 patients: 7 gastric and 6 duodenal SETs. Technical success was achieved in 11 cases (85%). In all 11 cases, R0-resection was achieved. In all 6 duodenal cases and in one gastric case, FTR was achieved (64%). One SAE (pain) was observed after eFTR of a gastric SET. After eFTR of duodenal SETs, several SAEs were observed: perforation (n = 1), microperforation (n = 3), and hemorrhage (n = 1). During follow-up endoscopy, the clip was no longer in situ in most patients (7 of 10; 70%). CONCLUSIONS:eFTR with this new flat-based OTS clip is feasible and effective. Although gastric eFTR was safe, eFTR in the duodenum was complicated by (micro)perforation in several patients. Therefore, the design of the clip or the technique of resection needs further refinement to improve safety of resection of SET in thin-walled areas such as the duodenum before being applied in clinical practice. Dutch trial register: NTR5023.
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Project description:Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that can adapt to the various nutrients available during its life cycle. However, in the nutritionally stringent environment of the macrophage phagolysosome, Mtb relies mainly on cholesterol. In previous studies, we demonstrated that Mtb can accumulate and utilize cholesterol as the sole carbon source. However, a growing body of evidence suggests that a lipid-rich environment may have a much broader impact on the pathogenesis of Mtb infection than previously thought. Therefore, we applied high-resolution transcriptome profiling and the construction of various mutants to explore in detail the global effect of cholesterol on the tubercle bacillus metabolism. The results allow re-establishing the complete list of genes potentially involved in cholesterol breakdown. Moreover, we identified the modulatory effect of vitamin B12 on Mtb transcriptome and the novel function of cobalamin in cholesterol metabolite dissipation which explains the probable role of B12 in Mtb virulence. Finally, we demonstrate that a key role of cholesterol in mycobacterial metabolism is not only providing carbon and energy but involves also a transcriptome remodeling program that helps in developing tolerance to the unfavorable host cell environment far before specific stress-inducing phagosomal signals occur.
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