We examine the challenges and advantages of using an actor framework for programming and execution of scientific workflows. The following specific topics are studied: implementing workflow semantics and typical workflow patterns in the actor model, parallel and distributed execution of workflow activities using actors, leveraging event sourcing as a novel approach for workflow state persistence and recovery, and applying supervision as a fault tolerance model for workflows. In order to practically validate our research, we have created Scaflow, an Akka-based programming library and workflow execution engine. We study an example workflow implemented in Scaflow, and present experimental measurements of workflow persistence overhead.
Abstract Background The Montreal classification of inflammatory bowel disease (IBD) recognizes distinct subgroups based on location of disease, age at onset and behaviour for Crohn’s disease (CD) and extent in ulcerative colitis (UC). CD with ileal involvement is in part genetically determined and tends to progress to surgery and to be more refractory to medical therapy compared to colonic disease location. We investigated the association of different aspects of the Montreal classification with the ileal and colonic mucosa-associated microbiota. Methods Healthy control (HC) and IBD patients underwent colonoscopy with biopsy samples taken from terminal ileum, ascending and sigmoid colon. Mucosal 16s rRNA gene profiling was analysed and an amplicon sequence variant table was generated and normalized. Patients with prior intestinal resection, IBD-unclassified and recent antibiotic exposure were excluded. Endoscopic activity was defined as a segmental Mayo endoscopic subscore > 0 in UC and a simple endoscopic score > 2 in CD. Blood samples were drawn for genotyping and a weighted genetic risk score (GRS) was built based on 169 IBD risk variants. Pooled ileal and colonic samples were analysed for taxonomic differential abundance (DA) among the variables of the Montreal classification using a linear mixed-effects model (MaAsLin2) with age, sex, biopsy site, endoscopic activity and GRS as covariates. P-values were corrected for false discovery rate (FDR) and < 5% was considered significant. Results A total of 546 biopsy samples from 201 IBD patients and 48 HC were analysed. The characteristics of the cohort and Montreal classification are depicted in the Table. At colonoscopy 168 samples (31.4%) showed endoscopic activity. The multivariate analysis revealed that the genera Agathobacter and Faecalibacterium, as well as the family Ruminococacceae and the order Oscillospirales were significantly reduced in CD with ileal involvement (L1+L3) when compared to either isolated colonic CD (L2), UC (any extent) and HC independent of age, sex, endoscopic activity, biopsy site, and GRS (Figure). Samples from UC and isolated colonic CD patients did not show differences in their microbial profile irrespective of biopsy site. No differences in DA were observed in subgroups based on age at onset and disease behaviour in CD or extent in UC. GRS was not associated with microbial composition. Conclusion These data suggest that CD with ileal involvement (Montreal L1+L3) is a major determinant of the tissue-associated microbial composition in both ileal and colonic mucosa irrespective of variables such as endoscopic activity and GRS. The reduction of several beneficial microbes in CD with ileal involvement might partially explain the more progressive phenotype in such patients.
Abstract Background Therapeutic drug monitoring (TDM) helps guide use of anti-TNF drugs in IBD patients. In addition, higher anti-TNF levels during induction therapy have been shown to be associated with better clinical and endoscopic outcomes. The role of TDM for more novel biologics such as ustekinumab (an anti- IL-12/23 antibody used to treat Crohn’s disease) remains to be elucidated. Aims We set out to investigate correlations between ustekinumab drug levels measured during induction with clinical and biochemical outcomes in patients with Crohn’s disease. Methods Patients with Crohn’s disease commencing treatment with ustekinumab were recruited from a single tertiary referral centre. Standard weight-based induction dosing was used. TDM was performed at week 2 and week 6 following IV induction dose. A drug-tolerant assay (Prometheus) was used. Kruskal-Wallis test was used to examine association between induction dose and ustekinumab levels. CDAI, CRP, and faecal calprotectin (FCP) were measured at week 12. Pearson correlation co-efficient was used to assess the relationship between ustekinumab levels and i)CDAI ii)CRP and iii)FCP at week 12. Results A total of 38 ustekinumab levels in 21 patients were measured. Week 2 ustekinumab levels were available for 17 patients, 16 (94.1%) of whom had levels of greater or equal to 25μg/mL. (1 patient had a level of 19.5μg/mL.) Week 6 ustekinumab levels were available for 21 patients; median 15μg/mL (IQR 9.9–21.3). No patients had detectable antibodies to ustekinumab. There was no significant association between absolute induction dose and week 6 ustekinumab levels; p=0.46. Of the 21 patients with week 6 levels, CDAI, CRP and FCP were available for 18, 18 and 16 patients respectively; Median CDAI 103(IQR 42–249), median CRP 2.3mg/L(IQR 1.0–11.3), median FCP 269μg/g(IQR109-932). There was a significant negative correlation between week 6 ustekinumab levels and CDAI; r=-.609, p=0.007. A negative correlation between week 6 ustekinumab levels and FCP was also significant; r=-.526, p=0.037. There was no significant correlation between week 6 ustekinumab levels and CRP; r=-.259, p=0.298. Conclusions We have demonstrated inter-patient variation in drug pharmacokinetics at week 6 following induction dose of ustekinumab in patients with Crohn’s disease. Drug levels at week 6 are significantly associated with clinical and biochemical markers of disease activity (CDAI, faecal calprotectin) at week 12. Measurement of week 6 ustekinumab levels may aid early identification of patients at risk of primary non-response to ustekinumab. Funding Agencies Testing provided by Prometheus
Abstract Background and Aims Microbial-derived bile acids can modulate host gene expression, and their faecal abundance is decreased in active inflammatory bowel disease [IBD]. We analysed the impact of endoscopic inflammation on microbial genes involved in bile acid biotransformation, and their interaction with host transcriptome in the intestinal mucosa of IBD patients. Methods Endoscopic mucosal biopsies were collected from non-inflamed and inflamed terminal ileum, ascending and sigmoid colon of IBD patients. Prediction of imputed metagenome functional content from 16S rRNA profile and real-time quantitative polymerase chain reaction [qPCR] were utsed to assess microbial bile acid biotransformation gene abundance, and RNA-seq was used for host transcriptome analysis. Linear regression and partial Spearman correlation accounting for age, sex, and IBD type were used to assess the association between microbial genes, inflammation, and host transcriptomics in each biopsy location. A Bayesian network [BN] analysis was fitted to infer the direction of interactions between IBD traits and microbial and host genes. Results The inferred microbial gene pathway involved in secondary bile acid biosynthesis [ko00121 pathway] was depleted in inflamed terminal ileum of IBD patients compared with non-inflamed tissue. In non-inflamed sigmoid colon, the relative abundance of bile acid-inducible [baiCD] microbial genes was positively correlated with the host Angiopoietin-like 4 [Angptl4] gene expression. The BN analysis suggests that the microbial baiCD gene abundance could affect Angptl4 expression, and this interaction appears to be lost in the presence of inflammation. Conclusions Endoscopic inflammation affects the abundance of crucial microbial bile acid-metabolising genes and their interaction with Angptl4 in intestinal mucosa of IBD patients.
The need for novel methods of visualizing microarray data is growing. New perspectives are beneficial to finding patterns in expression data. The Bluejay genome browser provides an integrative way of visualizing gene expression datasets in a genomic context. We have now developed the functionality to display multiple microarray datasets simultaneously in Bluejay, in order to provide researchers with a comprehensive view of their datasets linked to a graphical representation of gene function. This will enable biologists to obtain valuable insights on expression patterns, by allowing them to analyze the expression values in relation to the gene locations as well as to compare expression profiles of related genomes or of different experiments for the same genome.
Abstract Background Patients with inflammatory bowel disease (IBD) are at higher risk for developing colitis-associated colorectal cancer (CAC). Clinical and endoscopic features are used to stratify the risk of CAC, but new biomarkers are necessary to improve this stratification. Recent studies have shown that loss of expression of special AT-rich sequence binding protein 2 (SATB2) is frequent in CAC compared to sporadic colorectal cancer and this SATB2 status is found in pre-cancerous dysplastic lesions as well. However, the relationship of known clinical risk factors for CAC and loss of SATB2 has not been explored. Aims To assess the association of loss of SATB2 expression in CAC with clinical characteristics of IBD. Methods Patients with a known diagnosis of ileocolonic or colonic Crohn’s disease (CD), ulcerative colitis (UC), or IBD unclassified (IBDU) who underwent colectomy between October 2010 and December 2017 for CAC were included. SATB2 expression in neoplastic tissue was evaluated using immunohistochemistry (IHC), where less than 5% of tumor cells showing staining was considered loss of SATB2. Tumor grade, P53 and mismatch repair (MMR) status were assessed as well. Available clinical data such as sex, smoking status, IBD diagnosis (CD, UC or IBDU), age at IBD diagnosis, duration of IBD, extent of colitis and previous medications were collected. We used a generalized linear model to assess the association between these biomarkers and clinical data. Results A total of 58 patients with mean age at CAC diagnosis of 50.3 ±13 years, 27 (46%) females were analyzed. Mean IBD duration was 17.6 ±10 years and 22 (37.9%), 34 (58.6%) and 2 (3.4%) were CD, UC and IBDU, respectively. Thirty-two (55.2%) CACs had loss of SATB2 expression. There was no association between age at CAC diagnosis or grade of the tumor and loss of SATB2. However, longer duration of IBD (21.2 ± 9 years vs 13.7 ± 9 years, p = 0.01) was significantly associated with loss of SATB2. There was no association between SATB2 status and other explored clinical or endoscopic variables. Tumors with P53 mutation were associated with a younger age at diagnosis of CAC (47.2 ±13 vs 55.0 ±12 years, p = 0.03), but no other associations of this marker or MMR with clinical or endoscopic variables of IBD were found. Conclusions Loss of SATB2 expression is significantly associated with IBD duration, a well-known risk factor for CAC. This association with duration of IBD could denote an effect of longer chronic inflammation on SATB2 status. Given the previously reported association of loss of expression of SATB2 with pre-cancerous lesions in IBD patients, this could be a potential biomarker for risk of CAC. Funding Agencies National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
