CAF-associated genes putatively representing distinct prognosis by in silico landscape of stromal components of colon cancer.

Comprehensive understanding prognostic relevance of distinct tumor microenvironment (TME) remained elusive in colon cancer. In this study, we performed in silico analysis of the stromal components of primary colon cancer, with a focus on the markers of cancer-associated fibroblasts (CAF) and tumor-associated endothelia (TAE), as well as immunological infiltrates like tumor-associated myeloid cells (TAMC) and cytotoxic T lymphocytes (CTL). The relevant CAF-associated genes (CAFG)(representing R index = 0.9 or beyond with SPARC) were selected based on stroma specificity (cancer stroma/epithelia, cS/E = 10 or beyond) and expression amounts, which were largely exhibited negative prognostic impacts. CAFG were partially shared with TAE-associated genes (TAEG)(PLAT, ANXA1, and PTRF) and TAMC-associated genes (TAMCG)(NNMT), but not with CTL-associated genes (CTLG). Intriguingly, CAFG were prognostically subclassified in order of fibrosis (representing COL5A2, COL5A1, and COL12A1) followed by exclusive TAEG and TAMCG. Prognosis was independently stratified by CD8A, a CTL marker, in the context of low expression of the strongest negative prognostic CAFG, COL8A1. CTLG were comprehensively identified as IFNG, B2M, and TLR4, in the group of low S/E, representing good prognosis. Our current in silico analysis of the micro-dissected stromal gene signatures with prognostic relevance clarified comprehensive understanding of clinical features of the TME and provides deep insights of the landscape.

Effects of DNA Methylation on Leukemia Cell Proliferation.

BACKGROUND: In this study, we aimed to investigate the effect of DNA methyltransferase 1 gene (DNMT1) expression on leukemia cell proliferation. METHODS: Following stimulation with interferon-α (IFN-α) or methylation inhibitor for three days, we evaluated changes in the DNMT1 expression levels, cell proliferation activity, and Bcl-2-Associated X Protein (BAX) expression levels in the chronic myelogenous leukemia cell line K562 and the acute monocytic leukemia cell line THP-1. RESULTS: DNMT1 expression levels and cell proliferation activity decreased in K562 and THP-1 cells, whereas BAX expression levels increased. CONCLUSIONS: These results suggest that the enzymatic activity of DNMT1 promotes the proliferation of tumor cells and that tumor cell proliferation can be suppressed by inhibiting DNMT1 enzymatic activity. Furthermore, because DNA methylation is associated with apoptosis, a process critical to cell growth and injury in leukemia, assessing DNMT1expression levels might help in treatment decisions for leukemia patients.

Comparison of histopathological features of pancreatic carcinoma and type 1 autoimmune pancreatitis.

Type 1 autoimmune pancreatitis (AIP-1) is an immunoglobulin G (IgG)-4-related disease (IgG4-RD), characterized by elevated serum immunoglobulin G4 (IgG4) and infiltration by IgG4(+) plasma cells. Pancreatic carcinoma (PC) sometimes shows infiltration by IgG4(+) plasma cells, but details have been unclear. We compared pathological findings and expression of IgG4 and IgG in fibroses in 18 PC patients to those from 9 AIP-1 patients. Fibroses were divided into areas of ductal adenocarcinoma (DA) and obstructive pancreatitis (OP). Serum IgG4 levels were lower than the cut-off value in all PC patients with no IgG4-RD. Diffuse lymphoplasmacytic infiltration and eosinophil infiltration were characteristic of fibroses in PC. Though AIP-1 samples often had storiform fibrosis even in biopsies, PC did not show storiform fibrosis. Ratios of IgG4(+) plasma cells/IgG(+) plasma cells (IgG4/IgG ratios) in DA and OP were significantly lower than in AIP-1. However, high-density IgG4(+) plasma cell foci were detected in PC fibroses, particularly around peripheral nerves, vessels, and lymphoid follicles; between lobules and invasion fronts; and within neutrophilic abscesses. In conclusion, the IgG4/IgG ratio is useful in distinguishing PC from AIP-1, and should be evaluated in three or more areas, as PC can show localized high-density IgG4(+) plasma cell areas.

Inflammation of colon adenoma in the setting of type 1 autoimmune pancreatitis.

Although immunoglobulin G4-related diseases (IgG4-RD) have been found to affect many organs, little is known about their effects on the colonic mucosae. Pathological examination of colon adenomas has shown inflammatory cell infiltration into the stroma. We therefore assessed the clinicopathological characteristics of colon adenomas in patients with type 1 autoimmune pancreatitis (AIP-1), a representative IgG4-RD. Both colon adenomas from patients with (IgG4 adenomas) and without (Non-IgG4 adenomas) IgG4-RD were characterized by moderate to severe lymphoplasmacytic and eosinophilic inflammation without fibrosis or phlebitis. The ratio of IgG4-positive to IgG-positive plasma cells (IgG4/IgG ratio) and the numbers of IgG4-positive plasma cells were significantly higher in IgG4 adenomas than in Non-IgG4 adenomas. IgG4-positive plasma cells tended to be distributed diffusely in lower areas of the mucosae in IgG4 adenomas. We were unable to confirm whether IgG4 adenomas constituted an IgG4-RD. However, IgG4 adenomas in the setting of IgG4-RD may provide useful pathological information, supplementing a diagnosis of IgG4-RD outside the colon, or may facilitate examination for IgG4-RD, especially AIP-1. IgG4 adenomas warrant further investigation.

IgG4-related disease-like fibrosis as an indicator of IgG4-related lymphadenopathy.

The significance of IgG4-related diseases including IgG4-related lymphadenopathy has recently been recognized worldwide. Inflammatory pseudotumors in lymph nodes, as well as in other organs, are also recognized as IgG4-related diseases. Only a few case reports have described IgG4-related lymphadenopathy with fibrosis (IgG4-fibrosing lymphadenopathy), and IgG4-fibrosing lymphadenopathy has not been compared clinicopathologically with non-IgG4-related lymphadenopathy with fibrosis. We have evaluated the pathologic features in 13 patients with IgG4-fibrosing lymphadenopathy, including IgG4 and IgG expression in lymph nodes, and compared these features with those of patients with non-IgG4-related lymphadenopathy with fibrosis with reactive inguinal lymphadenopathy and focal fibrosis and lymph nodes at least 10 mm in diameter. IgG4-fibrosing lymphadenopathy was characterized by lymphoplasmacytic and eosinophilic infiltration, many IgG4-positive plasma cells in fibrotic areas, and high serum IgG4 concentrations. The IgG4-positive/IgG-positive plasma cell ratio was significantly higher in the IgG4-fibrosing lymphadenopathy than in the non-IgG4-fibrosing lymphadenopathy group. The presence of even minor fibrosis with characteristics of IgG4-related disease such as IgG4-fibrosing lymphadenopathy may facilitate the diagnosis of IgG4-related lymphadenopathy.

Chronic gastritis in the setting of autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a recently recognized disease entity. In some patients, this disease is associated with other inflammatory diseases. In this study, we aimed to elucidate the pathologic characteristics of AIP-associated gastritis (AIP-G). We evaluated and compared the pathologic findings and immunohistochemical expressions of immunoglobulin G (IgG)4 and IgG in gastric biopsy specimens from 13 AIP-G patients with those from patients of 2 control groups. We divided the AIP-G patients who did not receive steroid therapy [AIP-G-ST(-)] into the following 2 groups: without Helicobacter pylori (HP) infection [AIP-G-HP(-)] and with HP infection [AIP-G-HP(+)]. The control groups comprised 19 patients who were diagnosed with chronic active gastritis associated with HP infection and 7 patients with nonsteroidal anti-inflammatory drug-induced gastritis. We classified the findings for the gastric mucosa into those for the upper and the lower lamina propria. The characteristic finding of AIP-G groups was diffusely lymphoplasmacytic infiltration in the lamina propria. The IgG4-positive plasma cell/IgG-positive plasma cell ratios (IgG4/IgG ratios) in both the upper and lower lamina propria in the AIP-G-ST(-) groups were predominantly higher than the corresponding values in the other groups. In the AIP-G-ST(-) groups, the IgG4/IgG ratio in the lower lamina propria was predominantly higher than that in the upper lamina propria, irrespective of the HP status. In conclusion, diffuse lymphoplasmacytic infiltration in the lamina propria and increased IgG4/IgG ratio in the gastric mucosa (notably in the lower lamina propria) may be the characteristic findings of AIP-G.

Autoimmune pancreatitis-associated prostatitis: distinct clinicopathological entity.

Autoimmune pancreatitis (AIP) has been recently proposed as a disease entity, and an elevated serum IgG4 level is a characteristic finding in it. This disease is sometimes associated with other inflammatory diseases, such as retroperitoneal fibrosis and sclerosing cholangitis. To elucidate the clinicopathological characteristics of AIP-associated prostatitis (AIP-P), the clinicopathological findings of AIP-P patients were evaluated, and the immunohistochemical expression of the IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in six AIP-P patients was compared with that in 10 control patients who were clinically diagnosed as suspicious for carcinoma but who had focal inflammation without adenocarcinoma on histological examination of the prostate. All AIP-P patients had the characteristic findings of AIP, and their lower urinary tract symptoms (LUTS) improved after steroid therapy. In four of five AIP-P patients, digital rectal examination indicated prostate enlargement. Histologically, AIP-P had lymphoplasmacytic and scattered eosinophilic infiltration and obliterative phlebitis accompanying gland atrophy with dense fibrosis. Immunohistochemically, the IgG4-positive plasma cell/mononuclear cell ratio was significantly higher in the AIP-P group than in the control group (P = 0.0011). AIP-P is a distinct clinicopathological entity, and a mechanism similar to that implicated in AIP may be involved in it as well.