Characteristic endoscopic findings of gastrointestinal malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma.

Background and study aims: The gastrointestinal (GI) tract is the most common site of extra-nodal involvement for non-Hodgkin's lymphoma (NHL). The features of GI NHLs remain unclear. The aim of this study was to clarify endoscopic characteristics of GI NHLs. Patients and methods: We retrospectively analyzed the morphological characteristics of 63 GI malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma. Lesions were diagnosed between 2005 and 2020. Macroscopic findings were classified into five subtypes: superficial (S); protruding without ulcer (P); protruding with ulcer (PU); fungating (F); and multiple nodules (MN). Results: Thirty-one lesions in the stomach were classified as S type in 3 cases (9.6%), P type in 6 (19%), PU type in 13 (42%), and F type in 9 (29%). In the stomach, the ulcerated phenotype was more frequent for diffuse large B-cell lymphoma (DLBCL) (89.5%) than for other histological types (41.7%; P = 0.01). In the intestine, 23 tumors were classified as S type in 4 cases (17%), P type in 1 (4%), PU type in 6 (26%), F type in 1 (4%), and MN in 11 (48%). Eleven of the 14 cases (78.6%) of intestinal follicular lymphoma lesions showed MN type. In the colon, eight tumors were classified as S type in 2 cases (25%), P type in 2 (25%), PU type in 1 (13%), and F type in 3 (38%). Conclusion: We have clarified the endoscopic features of GI NHL using macroscopic classifications. The ulcerated phenotype was the most frequent endoscopic finding for DLBCL.

The effectiveness of packed therapy with three drugs in Helicobacter pylori eradication in Japan.

Primary Helicobacter pylori eradication rate using triple therapy (a proton pump inhibitor [PPI] + amoxicillin [AMPC] + clarithromycin [CAM], over 7 days) is showing a declining trend. In this study we report recent eradication rates and have evaluated the usefulness of a pack preparation of three drugs. H. pylori eradication rate was 85.1% (57/67) in 2004 but then fell to 75.2% (79/105) in 2005, 70.1% (68/97) in 2006 and 69.9% (58/83) in 2007. With the introduction of packs (lansoprazole [LPZ] 60 mg, AMPC 1500 mg, CAM 400 mg) the eradication rate recovered to 78.0% (110/141) in 2008. A comparative study in 2008 delineated that the eradication rate in the pack group (88.4%, 38/43) was significantly higher than that of the conventional group (73.5%, 72/98). These results suggest that packs of eradication medicine are useful in increasing eradication success.

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers.

BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.

Marked reduction of subcutaneous tumor growth by intraperitoneal administration of recombinant human interleukin 2 with a cell accumulator, proteose-peptone, in mice.

The growth of 3-methylcholanthrene-induced fibrosarcomas, Meth 1 and Meth A, was strongly suppressed by a combination of recombinant human interleukin 2 (rIL-2) with proteose-peptone (PP) administered i.p. to syngeneic mice. When 1 ml of 10% PP was injected i.p. on Day 6 followed by rIL-2 (50 micrograms) administered i.p. on Days 7 and 8 after the s.c. inoculation of tumor cells into female BALB/c mice, the tumors regressed. A similar result was also obtained when 12.5 micrograms of rIL-2 were injected on Days 7, 8, and 9 after s.c. inoculation of Meth 1 cells. The treatment with an anti-asialo-GM1 antibody had no effect on the regression of the Meth 1 tumor induced by the combination. However, the combined treatment with rIL-2 and PP did not suppress the growth of the Meth 1 tumor in adult thymectomized, irradiated, and fetal liver cell-reconstituted BALB/c mice. Therefore, this suggests that the T-cells might be the principal effectors of this antitumor system. The cytolytic activity of splenocytes and peritoneal exudate cells from Meth 1 tumor-bearing mice against Meth 1 cells was significantly augmented by the combined treatment. This peritoneal exudate cell also showed cytolytic activity against other target cells such as Meth A, antigenically distinct from Meth 1, YAC-1, a leukemic cell line sensitive to natural killer cells, and EL-4, a lymphoma cell line resistant to natural killer cells. The cytolytic activity of these effectors was reduced by the treatment with anti-thy1.2 antibody plus complement. The adherent cells in this peritoneal cavity had only a small cytolytic activity on Meth 1 and Meth A targets. The mechanism of antitumor immunity by rIL-2 in combination with PP and the therapeutic availability of this lymphokine are discussed.

Efficacy of famotidine and omeprazole in healing symptoms of non-erosive gastro-oesophageal reflux disease: randomized-controlled study of gastro-oesophageal reflux disease.

BACKGROUND: The epidemiology and pathophysiology of non-erosive gastro-oesophageal reflux disease differs from erosive gastro-oesophageal reflux disease. There is a possibility that non-erosive gastro-oesophageal reflux disease treatment requires a different regimen/approach but it is not yet acknowledged. AIM: To investigate the efficacy of famotidine and omeprazole in the treatment of gastro-oesophageal reflux disease, especially non-erosive gastro-oesophageal reflux disease. PATIENTS AND METHODS: A randomized, open-label trial was conducted. Fifty-four gastro-oesophageal reflux disease patients were assigned to treatment with famotidine at a dosage of 20 mg twice daily; or omeprazole, 20 mg once daily, for a period of 8 weeks. The Short Form-36 Health Survey and Gastrointestinal Symptom Rating Scale administered at baseline and after 8 weeks of treatment as well as a symptom questionnaire were conducted daily. RESULTS: Short Form-36 revealed that gastro-oesophageal reflux disease has severe impact on health-related quality of life. Thirty-nine subjects (77%) were endoscopically diagnosed as non-erosive gastro-oesophageal reflux disease. The mean Gastrointestinal Symptom Rating Scale abdominal pain, and indigestion score of non-erosive gastro-oesophageal reflux disease significantly improved in famotidine-treated patients (P < 0.05), but not in the omeprazole. There was no significant change regarding improved heartburn symptoms of non-erosive gastro-oesophageal reflux disease between treatments in the daytime or night-time. CONCLUSION: Famotidine and omeprazole were both effective in improving symptoms of gastro-oesophageal reflux disease, particularly non-erosive gastro-oesophageal reflux disease.

Absolute structure-cytotoxic activity relationships of steganacin congeners and analogues.

The cytotoxic activities of optically pure and racemic steganacin congeners and analogues against KB cells in culture and the inhibitor activity of cilia regeneration in Tetrahymena were studied with regard to absolute and relative configurations. The stereochemical requirements of dibenzocyclooctadiene lignan lactones for activity were clarified.

Rescue of Schizosaccharomyces pombe from camptothecin-mediated death by a DNA topoisomerase I inhibitor, TAN-1518 A.

TAN-1518 A is a cytotoxic agent with suppressive activity against Meth A fibrosarcoma in vivo. This compound inhibits calf thymus DNA topoisomerase I (Topo I) but does not stimulate cleavable complex formation in the nuclei of Chinese hamster ovary (CHO)-K1 cells, suggesting that it inhibits Topo I in a manner different from that of camptothecin (CPT). To clarify the mode of action of TAN-1518 A, we examined its effects on the eukaryotic microorganism Schizosaccharomyces pombe (S. pombe), which does not require Topo I as an essential factor for growth. TAN-1518 A inhibited purified S. pombe Topo I as potently as did CPT. TAN-1518 A, unlike CPT, did not stimulate Topo I-induced DNA cleavage; instead, it inhibited CPT-induced cleavable complex formation. We constructed a S. pombe strain, IR9, that produced excess Topo I. IR9 was hypersensitive to CPT, but its growth was not affected by TAN-1518 A. The CPT-mediated death of IR9 cells was reduced dramatically in the presence of TAN-1518 A. These findings clearly demonstrate that TAN-1518 A is a specific inhibitor of Topo I in eukaryotic cells and also suggest that this agent inhibits some earlier step(s) that occurs before the formation of cleavable complex on DNA strands in the catalytic cycle of this enzyme.

Dnacin A1 and dnacin B1 are antitumor antibiotics that inhibit cdc25B phosphatase activity.

The p80cdc25 protein is a protein phosphatase directly involved in p34cdc2 protein kinase activation by dephosphorylation. The cdc25B gene is one of three human cdc25 homologs which can complement the temperature-sensitive cdc25 mutation of Schizosaccharomyces pombe, and is expressed a high levels in human cell lines, particularly in some cancer cells. A fusion protein of glutathione-S-transferase (GST) and the catalytic domain of cdc25B protein was constructed and found to retain phosphatase activity in the manner of a p80cdc25 phosphatase by using a chromogenic substrate, p-nitrophenylphosphate. Two benzoquinoid antitumor compounds, dnacin A1 and dnacin B1, inhibited phosphatase activity in a non-competitive manner.

Helicobacter pylori eradication decreases blood neutrophil and monocyte counts.

BACKGROUND: The effect of Helicobacter pylori infection on systemic disorders is not well understood. AIM: The purpose of this study was to elucidate the systemic effects of H. pylori infection by comparing differential counts of leukocytes and platelets in peripheral blood before and after eradication of H. pylori. METHODS: A total of 164 H. pylori-positive patients underwent eradication therapy, and populations of peripheral blood leukocytes and platelets before and 0 (just after therapy), 1, 3 and 12 months after eradication were retrospectively analysed. RESULTS: In the eradicated group (n = 138), blood leukocytes, neutrophils and monocytes decreased significantly after eradication, but there was no significant change in eosinophils, basophils, lymphocytes or platelets. In the non-eradicated group (n = 26), there was no significant change in any studied parameter. With regard to smoking status, although leukocytes and neutrophils did not decrease after eradication in the smoking group, they significantly decreased after eradication in the nonsmoking group. CONCLUSIONS: These findings suggest that: (1) H. pylori infection increases neutrophil and monocyte counts in the peripheral blood, which indicates a significant role of H. pylori infection in systemic disorders; and (2) Smoking may mask the effect of H. pylori eradication on peripheral leukocytes, which would explain the controversy in previous reports concerning H. pylori infection and peripheral leukocytes.

Social exchange and reciprocity: confusion or a heuristic?

We propose that a "social exchange heuristic" is as important as the cheater detection mechanism for attaining mutual cooperation in social exchange. The social exchange heuristic prompts people to perceive a mixed-motive situation, such as the Prisoner's Dilemma (PD), as an Assurance Game (AG) situation in which cooperation is a personally better choice than defection insofar as the partner is cooperating as well. We demonstrate the operation of the social exchange heuristic through a comparison of the ordinary one-shot, simultaneous PD with the one-shot, sequential PD. Participants in the current experiments, involving a total of 261 volunteers, committed a logical error in the direction of favoring mutual cooperation as the situation involved more serious consequences. This result strongly suggests the operation of a domain specific "bias" that encourages pursuit of mutual cooperation in social exchange.

Ewing's sarcoma/peripheral primitive neuroectodermal tumor (pPNET) arising in the omentum as a multilocular cyst with intracystic hemorrhage.

A rare case of Ewing's sarcoma/peripheral primitive neuroectodermal tumor arising in the greater omentum in a 41-year-old man is reported. The patient presented with a hemorrhagic mesenteric cyst that was disclosed by the results of an abdominal echogram, a computed tomography scan, and magnetic resonance imaging. A laparotomy showed a multilocular cyst with intra-cystic hemorrhage. Histologically, the tumor wall consisted of sheets of small round cells separated by thick desmoplastic stroma. Rosette formations or ribbon-like cell arrangements were absent. Further pathological examination revealed that the membrane of the tumor cells was positive for MIC-2, and negative for epithelial membrane antigen, cytokeratin, and desmin, which are usually positive in intra-abdominal desmoplastic small round-cell tumors. An EWS/FLI1 fused transcript was detected by reverse transcription-polymerase chain reaction. These findings confirmed the diagnosis of Ewing's sarcoma/peripheral primitive neuroectodermal tumor. The patient died of tumor recurrence 4 months after his first admission. The autopsied tumor tissue exhibited neural differentiation in certain regions. To our knowledge, this is the first case to be reported of Ewing's sarcoma/peripheral primitive neuroectodermal tumor arising in the omentum with unique pathological features and the occurrence of partial neural differentiation during the clinical course. This case pointed out to us, as gastroenterologists, that only thorough examination confirms a definitive diagnosis of small round-cell tumor of the abdomen, it also shows that Ewing's sarcoma/peripheral primitive neuroectodermal tumor should be included in the differential diagnosis of cystic lesions in the omentum.

Carcinoid of the esophagus located in lamina propria.

We report a carcinoid tumor in the mucosal layer of the esophagus of a 63-year-old man. Barium X-ray and endoscopy indicated the tumor to be a polypoid lesion in the lower esophagus. Endoscopic ultrasonography (EUS) demonstrated the lesion to be a sharply demarcated hyperechoic tumor in the mucosal layer. Biopsy yielded a diagnosis carcinoid of the esophagus. In the resected specimen of the esophagus, the tumor was 11 mm in longest dimension with a shallow depression on it smooth surface. Histologically, the tumor was located in the mucosal layer, as shown by EUS, and was composed of small round cells which were positive for argyrophil, but not argentaffine. Carcinoid tumor of the esophagus found at an early stage, and localized in the lamina propria layer, is very rare. The present case is the second report in Japan.

Direct and indirect stimulation of megakaryocytopoiesis by TAN-1511 A, a microbial lipopeptide.

TAN-1511 A, a microbial lipopeptide, stimulates granulocytopoiesis through the induction of various hematopoietic cytokines. The ability of synthetic TAN-1511 A to affect megakaryocytopoiesis was examined. TAN-1511. A augmented the activity of acetylcholine esterase (AChE), which is a cell-lineage marker enzyme of megakaryocytes in cultured murine bone marrow cells and enhanced megakaryocyte colony formation in fibrin clot culture. These effects were observed not only in the presence, but also in the absence of IL-3, which is a megakaryocyte colony-stimulating factor. The increase in AChE activity mediated by TAN-1511 A was blocked by anti-IL-6 but not anti-IL-3 or anti-GM-CSF neutralizing antibodies. RT-PCR analysis also showed that the remarkable induction of IL-6 was triggered by treatment with TAN-1511 A, while each message level of c-mpl ligand and c-mpl remained unchanged, suggesting that the IL-6 induced by the lipopeptide plays a role in enhanced megakaryocytopoiesis. TAN-1511 A also stimulated the proliferation of CMK86, a human megakaryoblastic cell line. This promoted growth was partially and additively affected by anti-IL-3, anti-IL-6, and anti-GM-CSF antibodies. TAN-1511 A slightly reduced the expression of GpIb and GpIIb/IL1a in CMK86 cells. The enhanced platelet recovery mediated by TAN-1511 A was also demonstrated in a model of myelosuppressive mice. These results suggest that TAN-1511 A directly affects megakaryocytopoiesis, and indirectly modulates megakaryocytopoiesis through the induction of cytokines such as IL-6.

Macbecins I and II, new antitumor antibiotics. I. Producing organism, fermentation and antimicrobial activities.

New antibiotics, macbecins I and II, have been found in the culture fluid of an actinomycete, which has the following properties: delayed fragmentation of vegetative mycelia, formation of coremia on solid media, the occurrence of meso-diaminopimelic acid in the cell wall, lysozyme resistance, and guanine-cytosine content of 71 +/- 1 mol%. The organism has been designated Nocardia sp. No. C-14919 (N-2001). A marked enhancement of the production of macbecins I and II was observed in cultures containing L-tyrosine. The antibiotics are moderately active against several Gram-positive bacteria and fungi. The antibiotics also inhibit the growth of Tetrahymena pyriformis W at 2 microgram/ml but show no activity against the regeneration of cilia in partially deciliated Tetrahymena at 10 microgram/ml.

Ansamitocin analogs from a mutant strain of Nocardia. I. Isolation of the mutant, fermentation and antimicrobial properties.

A mutant having a high ability to produce ansamitocins was derived from a dnacin-producing strain, Nocardia sp. No. C-14482 (N-1001), by treatment with ethidium bromide. Mutant N-1231 produced ansamitocins P-3 and P-4 as major components, but was deficient in its ability to produce dnacins. Strain N-1231 also produced fifteen novel ansamitocin analogs as minor components. These analogs showed no activity against prokaryotic micro-organisms. The results of determining the activity inhibiting cilia regeneration of deciliated Tetrahymena pyriformis suggest that hydroxylation of C15, C26 and the acyl moiety at C3 of ansamitocins may cause marked reduction of their antitubulinic activities whereas demethylation of -NCH3 at C18 slightly affected their activities.

Structures of dnacin A1 and B1, new naphthyridinomycin-type antitumor antibiotics.

Dnacin A1 and B1 were revealed to be new naphthyridinomycin-type antitumor antibiotics with formulae of C20H23N5O4 and C19H24N4O5, respectively. The gross structure of dnacin A1 was elucidated by the spectroscopic analyses. Conversion of dnacin B1 into A1 by treatment with potassium cyanide indicated the presence of an alpha-carbinolamine moiety in dnacin B1. The relative stereochemistry of dnacins was clarified by analysis of the NOESY spectra.

Dnacins, new antibiotics. I. Producing organism, fermentation, and antimicrobial activities.

Dnacins are new antibiotics produced by an actinomycete, strain No. C-14482 (N-1001). The characteristic features of the organism are: the formation of coremia on solid media, production of rod-shaped motile spores with peritrichous flagella from mature aerial mycella, fragmentation of the mature organism (at later stage of growth) in liquid media in which some fragmented elements have motility, lysozyme resistance, meso-diaminopimelic acid in the cell wall, and a guanine-cytosine content of 71 +/- 1 mol%. The organism has been designated as Nocardia sp. No. C-14482 (N-1001). Dnacins show strong activity against various GRam-negative, Gram-positive, and acid-fast bacteria, but slight activity against fungi. The antibiotics hardly affect the growth of Escherichia coli K-12 under anaerobic condition even at concentrations more than five times that of the minimum inhibitory concentrations under aerobic conditions.

Dnacins, new antibiotics II. Isolation and characterization.

Dnacins A1 and B1, new basic antibiotics with strong and broad antibacterial activities, were isolated as dark red or reddish brown needles from the culture broth of Nocardia sp. No. C-14482. The characteristic absorption maxima at 213 nm, 281 or 283 nm and 496 nm in the UV and visible range and other physicochemical properties indicated that dnacins A1 and B1 are novel antibiotics which belong to the group having aminobenzoquinone moieties.

Inhibition of coliphage multiplication and R plasmid transfer by desdanine.

Desdanine inhibited the plaque formation of male-specific coliphages but not that of other coliphages tested. Desdanine also suppressed the multiplication of both RNA phage Q beta and filamentous DNA phage f1 at the concentration of 3.13 approximately 6.25 mug/ml which had no influence on the growth of their host cells. However, the inhibitory effect on the phage multiplication was not due to the inactivation of phage particles nor the prevention of phage adsorption and penetration into the host cells. Desdanine also inhibited the transfer of R plasmid, R 100-1, in E. coli at 6.25 approximately 12.5 mug/ml without affecting the viability of donor and recipient cells.

TAN-1496 A, C and E, diketopiperazine antibiotics with inhibitory activity against mammalian DNA topoisomerase I.

Fungal metabolites with an epi-oligothiadiketopiperazine structure, TAN-1496 A, C and E, were isolated from the culture broth of Microsphaeropsis sp. FL-16144. Their molecular formulas were determined to be C22H28N2O9S2, C22H28N2O9S3 and C22H28N2O9S4, respectively. Structures were determined by comparing the NMR data with those of known diketopiperazine antibiotics, sirodesmins. These metabolites inhibited the relaxation of supercoiled pBR322 DNA by calf thymus topoisomerase I but did not affect the decatenation of kinetoplast DNA by calf thymus topoisomerase II at concentration up to 500 microM. They strongly suppressed the growth of various murine and human tumor cells and induced apoptosis. Moreover, various derivatives were synthesized to investigate the relationship of their functional groups and biological activities.