Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine.

BACKGROUND/AIMS: Neuroendocrine neoplasms of the small intestine (SI-NENs) constitute 25-30% of all gastroenteropancreatic NEN. These tumors arise from enterochromaffin cells, and little is known about their microRNA (miRNA) expression. The purpose of this study was to characterize the expression of miRNAs in SI-NEN and to determine the potential of miRNAs as noninvasive blood-based biomarkers. METHODS: miRNA was purified from 15 tumor and 7 control tissue samples, converted to cDNA, and applied to a miScript miRNA PCR. The small nucleolar RNA, SNORD95, was used as an endogenous control. RESULTS: Microarray analysis revealed 7 miRNAs that showed a promising distinction between tumorous and healthy tissue. The miRNAs miR-7-5p and miR-96-5p were clearly upregulated in the tumor compared to the healthy tissue. In contrast, miRNAs miR-9-5p, miR-122-5p, miR-124-3p, miR-143-3p, and miR-144-3p showed a distinct downregulation in the tumor compared to the healthy tissue. These results were validated on a further 15 tumor samples, and the findings held true. As the miR-7-5p was significantly upregulated and revealed a low range across tumor samples, its presence was tested in the sera of 32 tumor patients and 25 healthy controls. Sera from all patients with SI-NENs had significantly higher levels of miR-7-5p than those from the 25 healthy controls (p = 0.0002), whereas there was no correlation with age, gender, or T-stage or UICC stage. CONCLUSION: The miRNA miR-7-5p may be a promising biomarker test for SI-NEN, which should be validated in a large-scale prospective study.

Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.

Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition.

Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix-remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors.

The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer.

Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families.