A CASE OF EARLY GASTRIC CANCER ACCOMPANIED BY DIEULAFOY ULCER IN A YOUNG WOMAN

A case of early gastric carcinoma accompanied by Dieulafoy ulcer is presented. The patient, a 26‐year‐old female, visited our emergency room with chief complaints of massive hematemesis and tarry stool. The initial endoscopic examination revealed a superficial depressed lesion with a faded color accompanied by a tiny ulcer with converging folds at the anterior wall of the middle gastric body. Although no active bleeding vessel was found at that time, the patient was admitted to our hospital for further check‐ups and treatment. On the 6th hospital day, she developed massive hematemesis resulting in shock. Urgent endoscopy, this time, disclosed an exposed bleeding vessel at the small ulcer floor previously mentioned, and endoscopic hemostasis was achieved. Since, however, a biopsy at initial examination from the surrounding depressed area proved carcinoma, a partial distal gastrectomy was subsequently carried out. Histological examination of the resected specimen confirmed the diagnosis of carcinoma limited to the mucosa and submucosa along with findings consistent with Dieulafoy ulcer. This is a rare case of combination of early cancer and Dieulafoy ulcer particularly in such a young patient. A review of the literature is also presented.     

Identification of CD56dim subpopulation marked with high expression of GZMB/PRF1/PI-9 in CD56+ interferon-α-induced dendritic cells

As the sentinels of innate and adaptive immune system, dendritic cells (DCs) have been considered to hold a great promise for medical application. Among the diverse types of DCs, monocyte-derived DCs (mo-DCs) generated in vitro have been most commonly employed. We have been improving the culture protocol and devised a protocol to produce mature interferon-α-induced DCs (IFN-DCs), hereinafter called (mat)IFN-DCs. While exploring the relationship between the expression of CD56 and the cytotoxic activity of (mat)IFN-DCs, we unexpectedly found that sorting of (mat)IFN-DCs with CD56 antibody-coated microbeads (MB) resulted in fractionating cells with tumoricidal activity into the flow-through (FT) but not MB-bound fraction. We uncovered that the FT fraction contains cells expressing low but substantial level of CD56. Moreover, those cells express granzyme B (GrB), perforin (PFN), and serpin B9 at high levels. By employing a specific inhibitor of PFN, we confirmed that direct tumoricidal activity relies on the GrB/PFN pathway. We designated subpopulation in FT fraction as CD56^dim and that in CD56 positively sorted fraction as CD56^bright, respectively. This is the first time, to our knowledge, to identify subpopulations of CD56-positive IFN-DCs with distinct tumoricidal activity which is ascribed to high expression of the components of GrB/PFN pathway.     

Substance P Activates p38 Mitogen-Activated Protein Kinase to Promote IL-6 Induction in Human Dental Pulp Fibroblasts

Substance P (SP) induces the expression of proinflammatory cytokines, such as interleukin (IL)-6, which are implicated in pulp inflammation. To determine the signal pathway of SP-induced IL-6, we examined the activities of the mitogen-activated protein kinases (MAPKs) in human dental pulp cell (PF-10) cultures. SP induced the phosphorylation of p38 MAPK within 5 min; this activation persisted for up to 40 min and was independent of the activation of extracellular signal-related kinases (ERK-1 and ERK-2) that were induced after SP stimulation of PF-10 cells. As shown by electrophoretic mobility shift assay p38 MAPK was not involved in SP-induced activation of nuclear factor-kappa B (NF-κB). However, p38 MAPK mediated SP-induced IL-6 production, as shown by the use of specific inhibitors of this kinase. Our results suggest that the activation of p38 MAPK is important for NF-κB-independent regulator of neurogenic inflammation in dental pulp tissues.     

Distinct roles of GSK-3α and GSK-3β phosphorylation in the heart under pressure overload

Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3α and GSK-3β by upstream kinases (e.g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S)21 and S9 phosphorylation of GSK-3α and GSK-3β in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3α S21A knock-in (αKI) and GSK-3β S9A knock-in (βKI) mice. Although inhibition of S9 phosphorylation during PO in the βKI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the αKI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3α, but not of S9 phosphorylation in GSK-3β, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3α in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the αKI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3β mediates pathological hypertrophy, S21 phosphorylation of GSK-3α plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.     

Vascular-Resident CD169-Positive Monocytes and Macrophages Control Neutrophil Accumulation in the Kidney with Ischemia-Reperfusion Injury

Monocytes and kidney-resident macrophages are considered to be involved in the pathogenesis of renal ischemia-reperfusion injury (IRI). Several subsets of monocytes and macrophages are localized in the injured tissue, but the pathologic roles of these cells are not fully understood. Here, we show that CD169⁺ monocytes and macrophages have a critical role in preventing excessive inflammation in IRI by downregulating intercellular adhesion molecule-1 (ICAM-1) expression on vascular endothelial cells. Mice depleted of CD169⁺ cells showed enhanced endothelial ICAM-1 expression and developed irreversible renal damage associated with infiltration of a large number of neutrophils. The perivascular localization of CD169⁺ monocytes and macrophages indicated direct interaction with blood vessels, and coculture experiments showed that the direct interaction of CD169⁺ cell-depleted peripheral blood leukocytes augments the expression levels of ICAM-1 on endothelial cells. Notably, the transfer of Ly6C^lo monocytes into CD169⁺ cell-depleted mice rescued the mice from lethal renal injury and normalized renal ICAM-1 expression levels, indicating that the Ly6C^lo subset of CD169⁺ monocytes has a major role in the regulation of inflammation. Our findings highlight the previously unknown role of CD169⁺ monocytes and macrophages in the maintenance of vascular homeostasis and provide new approaches to the treatment of renal IRI.     

Impact of cytomegalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan

Cytomegalovirus (CMV) disease is one of the major infectious complications after allogeneic hematopoietic stem cell transplantation (SCT). Several studies have shown that CMV-seropositive patients have a substantial survival disadvantage after bone marrow transplantation (BMT) or peripheral blood SCT (PBSCT). Between August 1998 and February 2006, 101 adult patients underwent myeloablative cord blood transplantation (CBT) from unrelated donors at our institution. Sixteen and 85 patients were CMV-seronegative and CMV-seropositive, respectively, prior to CBT. Outcomes of CBT were compared between CMV-seronegative and CMV-seropositive patients. The cumulative incidences of neutrophil engraftment at 60 d after CBT did not differ between CMV-seronegative and CMV-seropositive patients (100% and 94%, P = 0.09); however, the cumulative incidence of platelet engraftment at 100 d was higher in CMV-seronegative patients than CMV-seropositive patients (100% vs. 86%, P < 0.005). The cumulative incidence of CMV antigenemia at 100 d was lower in CMV-seronegative patients than CMV-seropositive patients (0% vs. 77%, P < 0.001); however, the cumulative incidences of CMV disease did not differ between CMV-seronegative and CMV-seropositive patients (0% vs. 1%, P = 0.84). The probabilities of disease-free survival at 2 yr also did not differ between CMV-seronegative and CMV-seropositive patients (92% vs. 72%, P = 0.16). The outcomes of CBT for CMV-seropositive patients as well as CMV-seronegative patients in our series were favorable. This might be due to effective antiviral therapy for CMV infection. Large-scale studies are needed to determine the impact of recipient CMV serostatus on the outcome of CBT for adults.     

A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukaemia in complete remission

We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease-free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT.