Widespread parainflammation in human cancer.

BackgroundChronic inflammation has been recognized as one of the hallmarks of cancer. We recently showed that parainflammation, a unique variant of inflammation between homeostasis and chronic inflammation, strongly promotes mouse gut tumorigenesis upon p53 loss. Here we explore the prevalence of parainflammation in human cancer and determine its relationship to certain molecular and clinical parameters affecting treatment and prognosis.ResultsWe generated a transcriptome signature to identify parainflammation in many primary human tumors and carcinoma cell lines as distinct from their normal tissue counterparts and the tumor microenvironment and show that parainflammation-positive tumors are enriched for p53 mutations and associated with poor prognosis. Non-steroidal anti-inflammatory drug (NSAID) treatment suppresses parainflammation in both murine and human cancers, possibly explaining a protective effect of NSAIDs against cancer.ConclusionsWe conclude that parainflammation, a low-grade form of inflammation, is widely prevalent in human cancer, particularly in cancer types commonly harboring p53 mutations. Our data suggest that parainflammation may be a driver for p53 mutagenesis and a guide for cancer prevention by NSAID treatment

Low ALT Is Associated with IBD and Disease Activity: Results from a Nationwide Study

Background: Sarcopenia is underdiagnosed in patients with inflammatory bowel disease (IBD). Low alanine transaminase (ALT) is associated with sarcopenia. We evaluated the association between low ALT and the presence of IBD and disease activity. Methods: Data were collected from a national Israeli health insurer cohort comprising 976,615 patients. Patients with a diagnosis of IBD were compared to healthy controls. After exclusion of patients with liver disease, ALT > 40 IU/L and age Results: Low ALT was more common amongst patients with IBD than in healthy controls (7.76% vs. 5.7% p p p p p p = 0.057, 4.50 mg/L [1.90–11.62] vs. 2.30 [1.00–6.20], p p p Conclusions: Low ALT is more common in patients with IBD and is associated with biochemical disease activity indices

Additional file 9: of Widespread parainflammation in human cancer

Parainflammation (PI) scores for 6523 primary tumors and 582 patient-matched normal samples of 18 cancer types from TCGA. The PI score is calculated using ssGSEA for the 40 PI genes using the immune-adjusted expression profiles. (XLSX 260 kb

Additional file 4: of Widespread parainflammation in human cancer

Results from an Ingenuity upstream regulator analysis performed on the 40 PI genes. (XLSX 123 kb

Additional file 8: of Widespread parainflammation in human cancer

Spearman coefficients of correlations between gene expression profiles and the PI scores across the carcinoma cell lines. Many genes not in part of the PI signature are highly correlated with the PI score, suggesting their role in PI. (XLSX 422 kb

Additional file 3: Figure S1. of Widespread parainflammation in human cancer

qPCR of PI genes in organoids. Figure S2. Expression of PI genes in cell lines. Figure S3. Correlation between the PI scores derived from up- and downregulated genes. Figure S4. Adjusting TCGA expression levels to immune infiltrations. Figure S5. Correlation of the PI score with CD45 expression. Figure S6. PI scores in TCGA cancer and adjacent normal samples. Figure S7. The PI score is correlated with the number of activated PI genes. Figure S8. PI-associated gene responses to aspirin treatment. Table S1. Parainflammation gene signature. Table S2. Down-regulated parainflammation genes. Table S3. List of samples acquired from TCGA. Table S4. Transcription factor binding enrichment analysis of PI genes. Table S5. Immune gene signatures. Table. S6. PI score and functional immune gene sets. Table S7. PI score and immune subsets estimated by hematoxylin and eosin staining. Table S8. PI score and immune subset estimate by gene signatures. Table S9. Survival and parainflammation. Table S10. Clinical features and parainflammation. Table S11. Primers used for qPCR analyses. (PDF 1608 kb

Additional file 1: of Widespread parainflammation in human cancer

List of 840 inflammatory response genes based on three manually curated databases: inflammatory response gene lists curated by Ingenuity, InnateDB innate immunity genes, and the Immunogenetic Related Information Source (IRIS). (XLSX 74 kb

Additional file 6: of Widespread parainflammation in human cancer

Results from a differential expression analysis of organoid cultures from adenomatous polyps of APCmin/+ mice (Adenoma) versus adenomatous polyps of APCmin/+ mice treated with sulindac. See “Methods” for organoid culture and sulindac treatment. Each set has three biological replicates. Raw reads and counts are available at the GEO under accession GSE81836. The analysis was performed using the RSEM software package. (XLSX 731 kb

COVID-19 in Patients with Inflammatory Bowel Disease: The Israeli Experience

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated inflammatory bowel diseases (IBD) affecting millions of people worldwide. IBD therapies, designed for continuous immune suppression, often render patients more susceptible to infections. The effect of the immune suppression on the risk of coronavirus disease-19 (COVID-19) is not fully determined yet. Objective: To describe COVID-19 characteristics and outcomes and to evaluate the association between IBD phenotypes, infection outcomes and immunomodulatory therapies. Methods: In this multi-center study, we prospectively followed IBD patients with proven COVID-19. De-identified data from medical charts were collected including age, gender, IBD type, IBD clinical activity, IBD treatments, comorbidities, symptoms and outcomes of COVID-19. A multivariable regression model was used to examine the effect of immunosuppressant drugs on the risk of infection by COVID-19 and the outcomes. Results: Of 144 IBD patients, 104 (72%) were CD and 40 (28%) were UC. Mean age was 32.2 ± 12.6 years. No mortalities were reported. In total, 94 patients (65.3%) received biologic therapy. Of them, 51 (54%) at escalated doses, 10 (11%) in combination with immunomodulators and 9 (10%) with concomitant corticosteroids. Disease location, behavior and activity did not correlate with the severity of COVID-19. Biologics as monotherapy or with immunomodulators or corticosteroids were not associated with more severe infection. On the contrary, patients receiving biologics had significantly milder infection course (p = 0.001) and were less likely to be hospitalized (p = 0.001). Treatment was postponed in 34.7% of patients until recovery from COVID-19, without consequent exacerbation. Conclusion: We did not witness aggravated COVID-19 outcomes in patients with IBD. Patients treated with biologics had a favorable outcome