Localizing spontaneously hemostatic colonic diverticular bleeding using VISCOCLEAR gel: A case report.

Colonic diverticular bleeding is the most common type of gastrointestinal bleeding. We report a case of an 82-year-old man with a chief complaint of melena. Enhanced computed tomography showed multiple diverticula, and water-assisted colonoscopy could not help identify the diverticulum responsible for bleeding. We injected VISCOCLEAR, a novel gel formulation, into the digestive tract endoscopically and successfully localized the bleeding point. Moreover, the use of VISCOCLEAR secured a clear visual field with reduced glare, as seen in the digital endoscopic image. Subsequently, we performed hemostatic clipping. The course after the endoscopic treatment was unremarkable. In this case, we could identify the exposed bleeding vessels in the diverticulum using VISCOCLEAR and perform hemostatic clipping. We intend to evaluate the effectiveness of VISCOCLEAR further by analyzing a series of cases.

Eosinophilic esophagitis induced by sublingual immunotherapy with cedar pollen: a case report.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease associated with eosinophilic infiltration of the esophageal mucosa mostly due to exposure to allergens. However, the causes and pathogenesis of EoE are not fully understood. We encountered a case of EoE that was triggered by sublingual immunotherapy (SLIT) for cedar pollen allergy. A 40-year-old man who was treated with Japanese cedar pollen tablet SLIT for cedar pollen allergy developed heartburn 3 weeks after the initiation of the treatment. He took vonoprazan for the heartburn, but the heartburn did not improve. Then, esophagogastroduodenoscopy was performed; it revealed longitudinal furrows and white spots on the esophageal mucosa, decreased vascular permeability, and erosions. Consequently, the patient was diagnosed with EoE. Heartburn and chest discomfort disappeared 1 week after the discontinuation of Japanese cedar pollen tablet SLIT, and the patient tested positive for drug allergy to Japanese cedar pollen tablet SLIT. In this study, we found that if heartburn persists during SLIT for cedar pollen allergy, and does not improve on administration of vonoprazan or proton pump inhibitors, EoE should be suspected. In addition, the occurrence of EoE due to drug allergy is indicated.

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70-75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70-80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.

Effects of vonoprazan on gastric PH and clinical course after gastric ESD: A retrospective and prospective study.

BACKGROUND: Vonoprazan has been more widely used for artificial ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer; however, no reports have examined intragastric pH during ESD. The present study aimed to measure gastric pH at the time of ESD and the clinical course afterwards for patients treated with vonoprazan the night before undergoing ESD. MATERIALS AND METHODS: We examined medication status regarding gastric acid secretion and antithrombotic drugs, post-ESD bleeding as a perioperative complication, and the timing of upper gastrointestinal endoscopy after ESD and ulcer healing in 156 patients who underwent gastric ESD at our hospital from January 2014 to December 2019. The gastric pH was measured at the time of ESD after administration of 20 mg vonoprazan on the night before gastric ESD. RESULTS: There were 14 cases of post-ESD bleeding in patients treated with proton-pump inhibitors (PPIs), including oozing during second-look endoscopy compared to only 1 case of bleeding with vonoprazan administration (p < 0.05). Vonoprazan was also associated with better post-ESD ulcer healing than PPIs. Gastric pH during ESD after vonoprazan administration on the night before gastric ESD was ≥6.96 in all 11 patients. CONCLUSION: Post-ESD bleeding was reduced, and ulcer healing was improved in patients treated with vonoprazan the night before their procedure. Our results suggest high gastric pH during ESD due to vonoprazan administration may be beneficial for hemostasis and ulcer healing following ESD.

Vonoprazan-based triple therapy is non-inferior to susceptibility-guided proton pump inhibitor-based triple therapy for Helicobacter pylori eradication.

BACKGROUND: All Helicobacter pylori-infected patients are recommended for eradication with an appropriate regimen in each geographic area. The choice of the therapy is somewhat dependent on the antimicrobial susceptibility. The rate of clarithromycin resistance has been increasing and is associated with failure; thus, susceptibility testing is recommended before triple therapy with clarithromycin. However, antimicrobial susceptibility testing is not yet clinically available and an alternative newly developed acid inhibitor vonoprazan is used for triple therapy in Japan. The aim of this study was to determine whether vonoprazan-based triple therapy is plausible treatment in H. pylori eradication. METHODS: A retrospective observational study of H. pylori eradication was conducted in a single institute. The patients who requested antimicrobial susceptibility testing were treated with susceptibility-guided proton pump inhibitor-based triple therapy in International University of Health and Welfare Hospital from 2013 to 2016. Other patients were treated with empirical treatment with a proton pump inhibitor. From 2015 to 2016, vonoprazan-based triple treatment (vonoprazan, 20 mg; amoxicillin, 750 mg; and clarithromycin, 200 or 400 mg, b.i.d.) was conducted, and its effectiveness was compared with susceptibility-guided proton pump inhibitor-based triple therapy. We also investigated the improvement in eradication rate when antimicrobial susceptibility testing was performed, and compared the outcomes of vonoprazan-based and proton pump inhibitor-based empirical therapy. RESULTS: A total of 1355 patients who received first-line eradication treatment were enrolled in the present study. The eradication rates of the empirical proton pump inhibitor-based therapy and the vonoprazan-based therapy group in a per-protocol analysis were 86.3% (95% CI 83.8-88.8) and 97.4% (95% CI 95.7-99.1), respectively. In 212 patients who received antimicrobial susceptibility testing, the rate of clarithromycin resistant was 23.5% and the eradication rate in susceptibility-guided treatment was 95.7% (95% CI 92.9-98.4). The difference between susceptibility-guided and vonoprazan-based therapy was - 1.7% (95% CI - 4.9 to 1.5%), and the non-inferiority of vonoprazan-based triple therapy was confirmed. CONCLUSIONS: Vonoprazan-based triple therapy was effective as susceptibility-guided triple therapy for H. pylori eradication. An empirical triple therapy with vonoprazan is preferable even in area with high rates of clarithromycin-resistance. Trial registration The study was retrospectively registered in University Hospital Medical Information Network (UMIN000032351).

Efficacy of Vonoprazan-Based Triple Therapy for Helicobacter pylori Eradication: A Multicenter Study and a Review of the Literature.

BACKGROUND: Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment. MATERIALS AND METHODS: Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature. RESULTS: The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies. CONCLUSIONS: Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

Phenylethylchromones with In Vitro Antitumor Promoting Activity from Aquilaria filaria.

A new chromone, 2-(2-hydroxy-2-phenylethyl)chromone (1), was isolated together with ten known phenylethyl chromones from MeOH extracts of agarwood (Aquilaria filaria). The selected compounds were evaluated in an antiproliferative assay against five human tumor cell lines, including a multidrug-resistant cell line. They were also tested for antitumor promoting activity, as mediated by 12-O-tetradecanoylphorbol-13-acetate-induced activation of the Epstein-Barr virus early antigen in Raji cells. Among all compounds, 4',7-dimethyoxy-6-hydroxychromone (2) displayed broad spectrum antiproliferative activity against all tumor cell lines tested with IC50 values of 25-38 µM, while 8 was selectively inhibitory against multidrug-resistant cells. All tested compounds suppressed tumor promotion at noncytotoxic concentrations. 4',6-Dihydroxyphenylethylchromone (7) exhibited the most potent effect with an IC50 value of 319 mol ratio relative to 12-O-tetradecanoylphorbol-13-acetate. This study is the first to report the antitumor promoting activity of 2-(2-phenylethyl)chromone derivatives, as well as the selective antiproliferative activity of 8 against a multidrug-resistant tumor cell line.

Total Synthesis and in Vitro Anti-Tumor-Promoting Activities of Racemic Acetophenone Monomers from Acronychia trifoliolata.

Six acetophenone derivatives, acronyculatins I (1), J (2), K (3), L (4), N (5), and O (6), were recently isolated from Acronychia trifoliolata, and the structure of the known acronyculatin B (7) was revised. Because of the limited quantities of isolated products as well as their structure similarity, racemic acronyculatins I-L, N, O, and B (1-7) were synthesized to confirm their structures and to obtain sufficient material for biological evaluation. Trihydroxyacetophenone was converted to the target compounds by various sequences of hydroxy group protection, allylation or prenylation, and epoxidation followed by cyclization. C-Prenylations were carried out by direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic rearrangement. The synthesized racemic compounds were evaluated in an anti-tumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds significantly inhibited EBV-EA activation. Especially, racemic acronyculatin I (1) displayed the most potent inhibitory effects, with an IC50 value of 7.3 µM.

Absolute Configuration of Dihydro-ß-agarofuran Sesquiterpenes from Maytenus jelskii and Their Potential Antitumor-Promoting Effects.

Chemoprevention of human cancer appears to be a feasible strategy for cancer control, especially when chemopreventive intervention is involved during early stages of the carcinogenesis process. As a part of our ongoing research program into new chemopreventive agents, herein are reported the isolation, structural elucidation, and biological evaluation of 10 new (1-10) and three known (11-13) sesquiterpenes with a dihydro-ß-agarofuran skeleton from the leaves of Maytenus jelskii Zahlbr. Their stereostructures have been elucidated by means of spectroscopic analysis, including 1D and 2D NMR techniques, ECD studies, and biogenetic considerations. The isolated metabolites and eight previously reported sesquiterpenes (14-21) were screened for their antitumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Six compounds from this series (4, 5, 11, and 13-15) were found to exhibit higher efficacies than ß-carotene, used as reference inhibitor for EBV-EA activation. In particular, promising antitumor activity was observed for compound 5, exhibiting inhibition even at the lowest concentration assayed (10 mol ratio/TPA). Preliminary structure-activity relationship analysis revealed that the acetate, benzoate, and hydroxy groups are the most desirable substituents on the sesquiterpene scaffold for activity in the EBV-EA activation assay.

The clinical importance of "bamboo joint-like appearance" on upper gastrointestinal endoscopy for the diagnosis of Crohn's disease.

Upper gastrointestinal (GI) lesions are frequently reported in Crohn's disease, in which the entire GI tract is affected. In these cases, erosive fissures regularly transversing folds that are longitudinally aligned along the lesser curvature of the gastric body and cardia are described as having a "bamboo joint-like appearance". We designed a blinded experiment in which upper GI imaging without a final diagnosis was checked by three observers to determine the usefulness of the bamboo joint-like appearance in the diagnosis of Crohn's disease. For the three observers, sensitivities of appearance were 30.5%, 56.9%, and 51.4%, while specificities were 99.6%, 98.5%, and 99.3%. Thus, the bamboo joint-like appearance was not useful for the identification of Crohn's disease patients. Nevertheless, patients exhibiting the bamboo joint-like appearance in upper GI imaging should undergo further examination due to the high probability of Crohn's disease.

Dihydro-ß-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-ß-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of ß-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model.

[Diagnosis and treatment of aspirin--and NSAID-induced peptic ulcers].

A Japanese case-control study showed the odds ratio of upper gastrointestinal bleeding was 5.5 for aspirin and 6.1 for other NSAIDs. A Japanese cohort study showed that peptic ulcers were found in 6.5% of 1,454 patients receiving low-dose aspirin (LDA). Some endoscopic studies reported that NSAID users often had antral, multiple, and irregular ulcers, irrespective of Helicobacter pylori status. Proton-pump inhibitor (PPI) and misoprostol should be used for therapy for NSAID-ulcers. Maintenance therapy with PPI should be given for prevention of relapse of ulcers of NSAIDs and LDA users. PPI and histamine 2-recetor antagonist were effective for prevention of upper GI mucosal injury in patients receiving LDA.

Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers.

Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemoprevention of cancers.

Chemoprevention of skin cancer: effect of Lawsonia inermis L. (Henna) leaf powder and its pigment artifact, lawsone in the Epstein- Barr virus early antigen activation assay and in two-stage mouse skin carcinogenesis models.

In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.

Oral chemoprevention of skin cancer in mice by benzophenone sunscreens dioxybenzone and octabenzone in drinking water.

BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (±)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 µl of acetone). One week later, TPA (1.7 nmol in 100 µl of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.

Trends in diagnostic biochip development.

Technological advancements in biochips for diagnosis and prevention lead to improved healthcare cost containment with a decreasing birth rate and an aging population. Biochips have been attracting attention as a tool for improving healthcare costs. There are technological, standardization-related, ethical and societal problems in biochip development. For biochip market expansion, in addition to technological problems, it is necessary to overcome social, institutional, marketing and economic problems all together. It is expected that the application of biochip technologies will facilitate not only 'super' early diagnosis of diseases and disease prevention based on the diagnosis, but also early treatment.

Chemopreventive effect of sarcophine-diol on NOR-1-induced TPA-promoted skin carcinogenesis in female HOS:HR-1 mice.

The cancer chemopreventive potential of sarcophine-diol in a chemical carcinogen initiation-promotion experimental tumor model in mice was evaluated. Sarcophine-diol, when given orally, afforded significant protection in the mouse skin cancer model initiated by the topical administration of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). These findings, along with our initial reports, suggest that sarcophine-diol is an effective cancer chemopreventive agent, even when administered orally and at a very low dose and thus indicating possible potential human applications in the control of malignancy.

Myristic Acid, A Side Chain of Phorbol Myristate Acetate (PMA), Can Activate Human Polymorphonuclear Leukocytes to Produce Oxygen Radicals More Potently than PMA.

Myristic acid (MyA), which is a saturated fatty acid (C14:0) and a side chain of phorbol 12-myristate 13-acetate (PMA), was examined if MyA stimulates human polymorphonuclear leukocytes (PMNs) to release oxygen radicals comparable to PMA by applying electron paramagnetic resonance (EPR)-spin-trapping method. When MyA was added to isolated human PMNs, spin adducts of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-OH and DMPO-OOH were time-dependently observed. The amounts of these spin adducts were larger than those of PMNs stimulated by PMA. These results clearly show that MyA is more potent agent to prime human PMNs than PMA, in a point of view of not only O(2) (.-) but also .OH production. This fact calls attention that too much intake of MyA that is known to be contained vegetable oils can lead to crippling effect through uncontrolled production of reactive oxygen species.

A graph theoretical approach for assessing bio-macromolecular complex structural stability.

Fast and proper assessment of bio macro-molecular complex structural rigidity as a measure of structural stability can be useful in systematic studies to predict molecular function, and can also enable the design of rapid scoring functions to rank automatically generated bio-molecular complexes. Based on the graph theoretical approach of Jacobs et al. [Jacobs DJ, Rader AJ, Kuhn LA, Thorpe MF (2001) Protein flexibility predictions using graph theory. Proteins: Struct Funct Genet 44:150-165] for expressing molecular flexibility, we propose a new scheme to analyze the structural stability of bio-molecular complexes. This analysis is performed in terms of the identification in interacting subunits of clusters of flappy amino acids (those constituting regions of potential internal motion) that undergo an increase in rigidity at complex formation. Gains in structural rigidity of the interacting subunits upon bio-molecular complex formation can be evaluated by expansion of the network of intra-molecular inter-atomic interactions to include inter-molecular inter-atomic interaction terms. We propose two indices for quantifying this change: one local, which can express localized (at the amino acid level) structural rigidity, the other global to express overall structural stability for the complex. The new system is validated with a series of protein complex structures reported in the protein data bank. Finally, the indices are used as scoring coefficients to rank automatically generated protein complex decoys.