Sitagliptin and Acute Pancreatitis: A Systematic Review and Meta-analysis

Background and Objectives: Sitagliptin is a dipepidyl peptidase inhibitor (DPP-4i) with gentle antidiabetic effects with a lower risk of hypoglycemia. The association with acute pancreatitis is controversial. The current meta-analysis aimed to assess the relationship of sitagliptin and acute pancreatitis. Methods: The literature in PubMed and Google Scholar was searched for relevant articles published in the last ten years up to September 2021. The keywords sitagliptins, DPP-4i, acute pancreatitis were used with the protean AND or OR. Among the 204 articles retrieved, 24 full-texts were assessed for eligibility and only five studies (Three from the USA, one from Asia, and one from Canada) met the inclusion criteria for the systematic review. The author name, year of publication, country, type of study, number of patients, and the duration of the study were reported. Results: There were five studies. The total number of patients were 729808 with 6459 events. The studies showed no increased rate of acute pancreatitis following sitagliptin use, odd ratio, 0.79, 95% CI, 0.29-2.15, a significant heterogeneity was observer, I2 for heterogeneity=98%, P-value, <001, the P-value for overall effect was 0.65 and the chi-square, 160.15. Interpretation and Conclusion: Sitagliptin use is not associated with acute pancreatitis.

SPINT1 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of serine peptidase inhibitor, Kunitz type 1, encoded by SPINT1 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SPINT1 expression was correlated with distant metastasis-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SPINT1 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

SERPINB6 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of serpin peptidase inhibitor, clade B (ovalbumin), member 6, encoded by SERPINB6 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SERPINB6 expression was correlated with post-progression survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SERPINB6 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

SERPINB9 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of serpin peptidase inhibitor, clade B (ovalbumin), member 9, encoded by SERPINB9 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SERPINB9 expression was correlated with recurrence-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SERPINB9 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion

Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p < 0.0001). The area under the curve (AUC) for SLPI’s ability to distinguish BAPE from MPM was 0.902, with a sensitivity of 82.4% and a specificity of 86.5%. This AUC was not only favourable but was better than the AUC for the ability of CYFRA21-1 to distinguish BAPE (0.853). The combination of SLPI and CYFRA21-1 achieved an AUC of 0.965 for the differentiation between BAPE and MPM. Pleural fluid SLPI as well as CYFRA21-1 and HA is useful as a biomarker to diagnose BAPE, which needs to be distinguished from early-stage MPM.

POS0002 PI16 REPRESSES FOXP3 EXPRESSION IN T REGULATORY CELLS AND EXACERBATES AUTOIMMUNE ARTHRITIS VIA INHIBITING THE K48-LINKED POLYUBIQUITIN DEGRADATION OF BMI-1

Background:Regulatory T cells (Tregs) play an essential role in maintaining self-tolerance and immune homeostasis. Abnormalities in the quantity or function of Treg cells are believed in RA patients, contributing to the inability to suppress autoimmunity and proinflammatory cytokines. Forkhead box P3 (Foxp3) is a crucial transcription factor for the development and differentiation of Tregs. How Tregs lose Foxp3 expression under inflammatory milieu remains largely unknown. Peptidase inhibitor 16 (PI16) is a member of the CAP (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1) protein family and its function are largely poor understood. In a genome-wide expression profiling study for identifying human Foxp3 target genes revealed PI16 was expressed on the cell surface of >80% of resting human CD25+ Foxp3+ Tregs. In the inflamed joint of juvenile idiopathic arthritis revealed a low number of PI16+ Tregs but high number of Th17 cells. However, little is known the function role of PI16 on Tregs or on RA development.Objectives:To investigate the role of peptidase inhibitor 16 (PI16) on the key T regulatory (Tregs) cells transcription factor Foxp3 expression and on the development of autoimmune arthritis.Methods:The expression of PI16 in blood, synovial fluid, inflamed joints were examined in Rheumatoid arthritis (RA) patients and in arthritic mice. Arthritis symptom, histological features and Foxp3 expression in PI16 transgenic (PI16Tg) arthritic mice were examined. Posttranslational mechanisms on PI16-mediated Foxp3 expression were analyzed. The specific role PI16 on Foxp3 expression was validated in conditional knockout (KO) mice.Results:The expression of PI16 was significantly increased in PBMC, serum, synovial tissue from RA patients or arthritic mice compared with controls. PI16Tg arthritic mice exhibited obvious inflammation, synovial hyperplasia and articular cartilage destruction in the joints compared with those in wild-type mice (WT) arthritic mice.Foxp3 is downregulated in splenic T cells and synovial tissue from PI16Tg arthritic mice. Naïve T cells derived from PI16Tg arthritic mice showed the decreased capacity to differentiate into Tregs. Polycomb-group (PcG) proteins complex molecule of Bmi-1 was significant increase in Tregs and joint tissue from PI16Tg arthritic mice. A direct interaction between 1-95AA domains of PI16 and 169 and 436 domains of Bmi-1 in Tregs promoter was observed. The binding of PI16 with Bmi-1 in the Foxp3 promoter inhibit the K48-linked polyubiquitin degradation of Bmi-1 at lysine site 72 and 153 region, which prompts the repressive histone modification of H3K27me3 and H2AK119ub, and inhibits the active histone modification of H3K4me3. Furthermore, conditional knockout of PI16 in Tregs retarded Foxp3 loss and blunted disease progression in experimental arthritis.Conclusion:PI16 represses Foxp3 expression by mediating histone modification via inhibiting K48-linked polyubiquitin degradation of Bmi-1 in Foxp3 promoter, contributing to disease progression in arthritic mice.Disclosure of Interests:None declared.

Differential expression of peptidase inhibitor 16 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding the peptidase inhibitor 16, PI16, when comparing primary tumors of the breast to the tissue of origin, the normal breast. PI16 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of PI16 in primary tumors of the breast was correlated with overall survival in patients with basal subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. PI16 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

A Novel SPINK5 Gene Mutation Associated with Netherton Syndrome in an Omani Patient

Netherton syndrome (NS) is an autosomal recessive primary immunodeficiency which is characterized by substantial skin barrier defects and is often misdiagnosed as severe atopic dermatitis or Hyper IgE syndrome. Although, over 80 pathogenic mutations in the SPINK5 gene have been reported worldwide in association with NS, only one NS-associated mutation has been reported in Arab populations to-date. This case report presents a novel association between the c.1887+1G>A mutation in the SPINK5 gene and NS in an Omani-Arab patient born in 2014. Accurate genetic diagnosis facilitated tailored clinical management of the index patient and enabled the provision of genetic counseling and offering of future reproductive options to the related individuals of the index patient. Keywords: Netherton syndrome, autosomal recessive, Serine Peptidase Inhibitor Kazal-Type 5, Congenital Ichthyosiform Erythroderma, genetics

Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans

Cystatin F encoded by CST7 is a cysteine peptidase inhibitor known to be expressed in natural killer (NK) and CD8+ T cells during steady-state conditions. However, little is known about its expression during inflammatory disease states in humans. We have developed an analytic approach capable of not only identifying previously poorly characterized disease-associated genes but also defining regulatory mechanisms controlling their expression. By exploring multiple cohorts of public transcriptome data comprising 43 individual datasets, we showed that CST7 is upregulated in the blood during a diverse set of infectious and non-infectious inflammatory conditions. Interestingly, this upregulation of CST7 was neutrophil-specific, as its expression was unchanged in NK and CD8+ T cells during sepsis. Further analysis demonstrated that known microbial products or cytokines commonly associated with inflammation failed to increase CST7 expression, suggesting that its expression in neutrophils is induced by an endogenous serum factor commonly present in human inflammatory conditions. Overall, through the identification of CST7 upregulation as a marker of acute inflammation in humans, our study demonstrates the value of publicly available transcriptome data in knowledge generation and potential biomarker discovery.