Rapid Progression of Autoimmune Gastritis after Helicobacter pylori Eradication Therapy.

We herein report a case of autoimmune gastritis (AIG) with rapid progression after Helicobacter pylori eradication therapy. The patient's previous gastritis had followed the course of type B gastritis before eradication therapy for many years. Immediately after eradication, we diagnosed her with AIG and carefully followed changes in the endoscopic and histopathological findings and serum markers. All of these clinical findings showed significant atrophic progression in the corporal area for approximately three years. We concluded that H. pylori eradication therapy exacerbated AIG in this case.

Autoimmune Gastritis with a Long-term Course of Type B Gastritis: A Report of Two Cases.

Autoimmune gastritis (AIG) typically exhibits the characteristics of type A gastritis and has been classified as a separate disease from type B gastritis that corresponds to Helicobacter pylori gastritis. However, many reports have suggested the involvement of H. pylori infection in the pathogenesis of AIG. In our two cases, the patients' previous gastritis exhibited a clear pattern in which H. pylori gastritis had progressed over many years, but ultimately transitioned to AIG with its spontaneous disappearance. These findings suggest that some cases of AIG might originate from long-standing H. pylori gastritis.

Role of Ras in regulation of intestinal epithelial cell homeostasis and crosstalk with Wnt signaling.

Cross talk between different signaling pathways is thought to be important for regulation of homeostasis of, as well as oncogenesis of, the intestinal epithelium. Expression of an active form of K-Ras specifically in intestinal epithelial cells (IECs) of mice (IEC-RasDA mice) resulted in the development of hyperplasia in the small intestine and colon of mice. IEC-RasDA mice also manifested the increased proliferation of IECs. In addition, the number of goblet cells markedly increased, while that of Paneth cells decreased in IEC-RasDA mice. Development of intestinal organoids was markedly enhanced for IEC-RasDA mice compared with control mice. Whereas, the expression of Wnt target genes was significantly reduced in the in intestinal crypts from IEC-RasDA mice compared with that apparent for the control. Our results thus suggest that K-Ras promotes the proliferation of IECs as well as generation of goblet cells. By contrast, Ras counter-regulates the Wnt signaling and thereby contribute to the proper regulation of intestinal epithelial cell homeostasis.

Photodynamic therapy for radiation maculopathy: A case report.

RATIONALE: The best treatment protocol for radiation maculopathy in children has not been determined. The purpose of this study was to determine the effect of photodynamic therapy (PDT) on radiation maculopathy. PATIENT CONCERNS: An 11-year-old boy who was originally diagnosed with orbital rhabdomyosarcoma when he was 1 year old, in October 2008. The lesion improved after peripheral blood stem cell transplantation, chemotherapy and radiation therapy. A cataract was detected in his right eye in May 2011, and he underwent cataract surgery in July 2011. Continuous amblyopia training maintained his visual acuity in his right eye. In January 2017, his visual acuity was reduced and macular edema was detected with optical coherence tomography. DIAGNOSES: We diagnosed radiation maculopathy, from the history of radiation therapy, macular edema by optical coherence tomography, and hyperfluorescent site by fluorescein angiography. INTERVENTIONS: We performed PDT in June 2017. OUTCOMES: Treatment with PDT improved macular edema and his visual acuity. LESSONS: Radiation retinopathy is progressive disorder with poor prognosis. PDT could be considered to treat radiation maculopathy.

The correlation of salivary telomere length and single nucleotide polymorphisms of the ADIPOQ, SIRT1 and FOXO3A genes with lifestyle-related diseases in a Japanese population.

BACKGROUND: It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate. OBJECTIVE: The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves. METHODS: In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university. RESULTS: In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype. CONCLUSION: Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.

Regulation of colonic epithelial cell homeostasis by mTORC1.

Cell signaling important for homeostatic regulation of colonic epithelial cells (CECs) remains poorly understood. Mammalian target of rapamycin complex 1 (mTORC1), a protein complex that contains the serine-threonine kinase mTOR, mediates signaling that underlies the control of cellular functions such as proliferation and autophagy by various external stimuli. We here show that ablation of tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, specifically in intestinal epithelial cells of mice resulted in increased activity of mTORC1 of, as well as increased proliferative activity of, CECs. Such Tsc2 ablation also reduced the population of Lgr5-positive colonic stem cells and the expression of Wnt target genes in CECs. The stimulatory phosphorylation of the kinase Akt and inhibitory phosphorylation of glycogen synthase kinase 3ß were both markedly decreased in the colon of the Tsc2 conditional knockout (CKO) mice. Development of colonic organoids with cryptlike structures was enhanced for Tsc2 CKO mice compared with control mice. Finally, Tsc2 CKO mice manifested increased susceptibility to dextran sulfate sodium-induced colitis. Our results thus suggest that mTORC1 activity promotes the proliferation of, as well as the expression of Wnt target genes in, CECs and thereby contributes to colonic organogenesis and homeostasis.

Chloroquine Inhibits Self-Renewal of Blast Progenitors Synergistically With Phytochemicals or Nonsteroidal Anti-inflammatory Drugs in Hematological Malignant Cell Lines.

BACKGROUND: This study examined whether and how chloroquine inhibits blast progenitor self-renewal (SR) synergistically with phytochemicals or nonsteroidal anti-inflammatory drugs in seven hematological malignant cell lines. MATERIALS AND METHODS: Vitamin C, resveratrol, cyclo-oxygenase inhibitor NS-398 and indomethacin heptyl ester (Ind) were added to cell culture with or without 3 µM chloroquine. RESULTS: Chloroquine synergistically inhibited blast colony formation in methylcellulose with vitamin C, resveratrol, NS-398 and Ind in one, two, none and one cell lines, respectively, in a total of four out of 28 conditions. Chloroquine synergistically inhibited blast progenitor SR in suspension with vitamin C, resveratrol, NS-398 and Ind in four, six, one and five cell lines, respectively, in a total of 16 out of 28 conditions. In contrast, chloroquine abolished SR inhibition by another agent in four out of 28 conditions. CONCLUSION: Chloroquine exerted a marked synergistic inhibition of blast progenitor SR, but not blast colony formation.

Effects of Nonsteroidal Anti-inflammatory Drugs on the Self-renewal Capacity of Blast Progenitors in Hematological Malignancies.

BACKGROUND: With our newly established long-term suspension culture, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the self-renewal capacity of blast progenitors in seven hematological malignant cell lines. MATERIALS AND METHODS: Cyclo-oxygenase inhibitors NS-398 (NS) or indomethacin heptyl ester (indomethacin) at 30 µM was added to the cell culture. In U-937 cells, indomethacin was added at 0.3 or 3 µM. RESULTS: In all cell lines, the agents significantly and markedly inhibited blast colony formation (BCF) and telomerase activity, respectively. Significant exponential clonogenic cell growth was noted under all 23 conditions with or without the agent. The relative slope (SLP) of the line (SLPagent/SLPcontrol) reflects the level of self-renewal induced by the agent and self-renewal was inhibited (relative SLP at 0.9 or below) in four out of 16 conditions, including in U-937 cells treated with 0.3 or 3 µM indomethacin, in Daudi cells treated with indomethacin and in U-266 cells treated with NS. Indomethacin enhanced senescence, necrosis and apoptosis in U-937 and Daudi cells, whereas NS reduced apoptosis in U-937 cells and had no effect on senescence, necrosis and apoptosis in Daudi cells. In U-266 cells, NS enhanced senescence and necrosis, whereas indomethacin reduced apoptosis. There was no significant correlation between the control of BCF and relative SLP. CONCLUSION: NSAIDs enhance or reduce stress responses, inhibit telomerase activity and differentially regulate BCF and self-renewal.

Establishment of a quenching probe method for detection of NPM1 mutations in acute myeloid leukemia cells.

Nucleophosmin (NPM1) mutations, generally consisting of a four base-pair insertion, are present in ~60% of all cytogenetically normal acute myeloid leukemia (AML) cases. The mutation is clinically significant as an important prognostic factor. Direct sequencing is the current standard method of mutation detection, however, it is quite costly and time consuming. The present study aimed to establish a highly sensitive quenching probe (QP) method to detect NPM1 mutations efficiently. Melting curve analysis was performed using a QP, following polymerase chain reaction for amplification of the involved region of the gene. The curve derived from the fluorescent intensity with respect to the temperature of OCI/AML3, a heterozygous NPM1 mutant AML cell line, was W-shaped with melting peaks at 61°C and 68°C. That of M-07e, the homozygous wild type cell line, was V-shaped with a melting peak at 68°C. Thus, the curve derived from the mutant allele was easily discriminated from that of the wild-type allele. The mutant allele was detected in concentrations as low as 3% as determined by a subsequent sensitivity study. With a short testing time and a high sensitivity, this assay was applicable for NPM1-mutated AML patient samples and is appropriate for screening NPM1 mutations. It does require further examination as to whether it would be useful as a detection method for other mutant alleles since NPM1 mutations may consist of 61 known types of mutant sequences. To the best of our knowledge, this is the first report describing the QP method for the detection of NPM1 mutations.

The Relationship between Corvis ST Tonometry Measured Corneal Parameters and Intraocular Pressure, Corneal Thickness and Corneal Curvature.

The purpose of the study was to investigate the correlation between Corneal Visualization Scheimpflug Technology (Corvis ST tonometry: CST) parameters and various other ocular parameters, including intraocular pressure (IOP) with Goldmann applanation tonometry. IOP with Goldmann applanation tonometry (IOP-G), central corneal thickness (CCT), axial length (AL), corneal curvature, and CST parameters were measured in 94 eyes of 94 normal subjects. The relationship between ten CST parameters against age, gender, IOP-G, AL, CST-determined CCT and average corneal curvature was investigated using linear modeling. In addition, the relationship between IOP-G versus CST-determined CCT, AL, and other CST parameters was also investigated using linear modeling. Linear modeling showed that the CST measurement 'A time-1' is dependent on IOP-G, age, AL, and average corneal curvature; 'A length-1' depends on age and average corneal curvature; 'A velocity-1' depends on IOP-G and AL; 'A time-2' depends on IOP-G, age, and AL; 'A length-2' depends on CCT; 'A velocity-2' depends on IOP-G, age, AL, CCT, and average corneal curvature; 'peak distance' depends on gender; 'maximum deformation amplitude' depends on IOP-G, age, and AL. In the optimal model for IOP-G, A time-1, A velocity-1, and highest concavity curvature, but not CCT, were selected as the most important explanatory variables. In conclusion, many CST parameters were not significantly related to CCT, but IOP usually was a significant predictor, suggesting that an adjustment should be made to improve their usefulness for clinical investigations. It was also suggested CST parameters were more influential for IOP-G than CCT and average corneal curvature.

Promotion of the self-renewal capacity of human leukemia cells by sonic hedgehog protein.

BACKGROUND: Hedgehog (Hh) signaling is involved in cancer cell growth. However, the effects of Hh stimulation on leukemia cells are unknown. MATERIALS AND METHODS: The effects of recombinant sonic Hedgehog (Shh) protein on the in vitro growth of one B-lymphoma and four myeloid leukemia cell lines were examined. RESULTS: Shh stimulation had no significant effect on the short-term growth of whole cell populations in any of the five cell lines. However, Shh promoted clonogenic cell recovery after suspension culture, suggesting promotion of leukemia stem or progenitor cell amplification in three cell lines. The lack of Hh receptors in one cell line and endogenous Shh expression in another were possible reasons for the lack of effects of Shh in these cases. CONCLUSION: These results suggest that Shh stimulation promotes the self-renewal capacity of leukemia stem cells in some cell lines. Inhibition of Hh signaling could represent a novel therapeutic approach in leukemia.

Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells.

BACKGROUND: Hedgehog (Hh) and Wnt signaling pathways are involved in the stimulation of growth of leukemia and lymphoma cells. In the present study, whether or not the Hh inhibitor, cyclopamine, and the Wnt inhibitor, quercetin, suppress cell growth was investigated. MATERIALS AND METHODS: The effects of cyclopamine and quercetin on the in vitro growth and protein expression of ten acute leukemia and B-cell lymphoma cell lines were examined. RESULTS: Cyclopamine and quercetin suppressed cell growth and induced apoptosis in seven and eight cell lines respectively. Cyclopamine decreased the level of Gli1 protein, a target gene product of Hh signaling. Quercetin decreased the level of Notch1 protein and its active fragment in the DND-41 T-lymphoblastic leukemia cell line with constitutive Notch activation. CONCLUSION: Cyclopamine and quercetin suppress the growth of a number of leukemia and lymphoma cells. This finding suggests the potential use of these compounds in molecularly-targeted therapy for leukemia and lymphoma.

Promotion of the self-renewal capacity of human acute leukemia cells by Wnt3A.

BACKGROUND: Wnt/beta-catenin signaling is involved in the growth of various types of cancer cells. Wnt3A has been reported to promote the self-renewal of hematopoietic stem cells. MATERIALS AND METHODS: The effects of recombinant Wnt3A protein on the in vitro growth of four acute myeloid leukemia (AML) and four acute T-lymphoblastic leukemia (T-ALL) cell lines was examined. RESULTS: Wnt3A stimulation either had no effect on, or slightly suppressed, the short-term growth of these cell lines. In three cell lines, Wnt3A promoted clonogenic cell recovery after suspension culture, suggesting the promotion of the self-renewal capacity of leukemic stem or progenitor cells. Immunoblot analysis showed that Wnt3A stimulation reduced phosphorylated beta-catenin and increased beta-catenin in these cells, indicating that Wnt3A stimulation activated Wnt/beta-catenin signaling. CONCLUSION: Wnt3A stimulation did not promote the growth of whole cell populations, but did promote the self-renewal of leukemic stem/progenitor cells in some AML and T-ALL cell lines.

Lactate dehydrogenase-linked immunoglobulin Akappa in a patient with nonimmune chronic idiopathic neutropenia.

A 39-year-old patient with cervical cancer, stage Ia, was successfully treated by total hysterectomy. Then, after sustained neutropenia for more than 4 years and coincident with its exacerbation, the serum lactate dehydrogenase (LD) level started to elevate and reached a plateau. A test for antineutrophil antibody was negative and LD-3-linked IgAkappa, which may be responsible for high LD activity, was confirmed. The absolute number of blood NK cells was reduced, and a diagnosis of nonimmune chronic idiopathic neutropenia of adult was made. The successive occurrence of these 3 disorders may be based on interrelated immunological abnormalities.

Serum levels of Thl/Th2 cytokines, angiogenic growth factors, and other prognostic factors in young adult patients with hemophagocytic syndrome.

Serum levels of T helper 1 (Th1)/T helper 2 (Th2) cytokines, angiogenic growth factors, and other prognostic factors were measured in 5 young adult patients with virus-associated hemophagocytic syndrome (HPS). Levels of 2 Th1 cytokines (interleukin [IL]-18 and tumor necrosis factor-alpha), 2 Th2 cytokines (IL-10 and IL-6), and 2 angiogenic growth factors (soluble intercellular adhesion molecule-1 and hepatocyte growth factor) were high in all of the patients examined, whereas those of Th1 cytokines such as IL-12 and macrophage inflammatory protein-1a were normal or low. Levels of IL-18 and IL-10 were highest in case 2, with a fatal outcome, and were lowest in case 4, with rapid recovery within 1 month. Although IFN-gamma levels were not elevated in 2 patients (cases 3 and 5), IL-18 levels were markedly high in both of these cases and the IL-6 level was highest in case 3. In contrast with the marked increase in the level of IL-10, the levels of IL-6, sIL-2R, and ferritin decreased rapidly and returned to normal within 2 months after therapy in case 3. The IL-18 level decreased somewhat, but remained elevated for 6 months, and the patient achieved a complete response within 11 months. Taken together, our findings suggest that both IL-18 and IL-10, but not IL-12, may play important roles in young adult patients with HPS via enhancing and suppressing Th1 immune responses, respectively.

Relation between chromosomal aberrations and radiation dose during the process of TBI.

PURPOSE: The purposes of this study were (1) to consider the dose-response relationship in-vivo at high dose range by using the Colcemid method, which begins with predicting the risk of future late complication caused by a fixed dose of chromosomal aberration of peripheral lymphocytes after radiation emission and (2) to compare in-vivo and in-vitro dose-responses for chromosomal aberrations in lymphocytes of cancer patients undergoing total body irradiation (TBI). METHODS: Eight patients diagnosed with hematological malignancies entered this study. TBI planning with a 6 MV linear accelerator consisted of 4 Gy/2 fractions/day, and the total treatment dose was 12 Gy. RESULTS: At the observable dose range of up to 10 Gy, the unstable chromosomal aberrations of both dicentrics and fragments increased with the increment of irradiated dose, regardless of in-vivo or in-vitro irradiated samples. However, the average number of dicentrics and fragments obtained from in-vitro samples was found to be higher than that for in-vivo samples. CONCLUSION: This result strongly suggests that in-vivo dose-response curves are necessary to estimate the absorbed dose in-vivo. In-vivo dose-response curves obtained from cancer patients would be very important for standard curves for biodosimetry.

Amplification of inhibitory activity of catechin against disease-related enzymes by conjugation on poly(epsilon-lysine).

A new inhibitor against disease-related enzymes, collagenase, hyaluronidase, and xanthine oxidase, has been developed by the laccase-catalyzed conjugation of catechin on poly(epsilon-lysine). The resulting poly(epsilon-lysine)-catechin conjugate showed greatly improved inhibition effects on activity of these enzymes, whereas the catechin monomer showed very low inhibition activity. The kinetic analysis on the inhibition of collagenase exhibited that the conjugate was a mixed-type inhibitor. The amplified activities might offer high potential as a therapeutic agent for prevention of various enzyme-related diseases.