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The value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for T-staging in patients with extrahepatic bile duct cancer was evaluated. This single-center, retrospective study included consecutive patients with extrahepatic bile duct cancer who underwent surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced CT (CE-CT) examinations between June 2014 and August 2017. The capacity of these modalities for T-staging of extrahepatic bile duct cancer was evaluated by assessing invasion beyond the biliary wall into the surrounding tissue, gallbladder, liver, pancreas, duodenum, portal vein system (portal vein and/or superior mesenteric vein), inferior vena cava, and hepatic arteries (proper hepatic artery, right. and/or left. hepatic artery). Blind reading of EUS, CH-EUS, and CE-CT images was performed by two expert reviewers each. 38 patients were eligible for analysis, of which eight had perihilar bile duct cancer and 30 had distal bile duct cancer. Postoperative T-staging was T1 in 6, T2 in 16, and T3 in 16 cases. CH-EUS was superior to CE-CT for diagnosing invasion beyond the biliary wall into surrounding tissue (92.1% vs. 45.9%, P = 0.0002); the ability to detect invasion to other organs did not differ significantly between the two modalities. The accuracy of CH-EUS for T-staging of tumors was better than that of CE-CT (73.7% vs. 39.5%, P = 0.0059). CH-EUS tended to have a better accuracy than EUS for the diagnosis of invasion beyond the biliary wall into the surrounding tissue (92.1% vs. 78.9%, P = 0.074) and T-staging (73.7% vs. 60.5%, P = 0.074). CH-EUS is useful for T-staging of extra hepatic bile duct cancer, especially in terms of invasion beyond the biliary wall into the surrounding tissue.

The value of contrast-enhanced harmonic EUS (CH-EUS) for diagnosis of portal vein invasion in patients with pancreatic cancer was evaluated.This single-center, retrospective study included consecutive patients with pancreatic cancer who underwent both surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced computed tomography (CE-CT) examinations between April 2015 and August 2017. CH-EUS evaluation was performed during the late phase. Portal vein invasion on EUS and CH-EUS was defined as no continuity in the line of the vessel wall. Definition of portal vein invasion on CE-CT was based on the Loyer's criteria. The accuracy of three modalities for diagnosis of invasion into the portal vein was compared using the McNemar's test.Eighty-eight patients (mean age: 71.0 years, ratio of male to female: 48:40) were eligible. Postoperative pathological results were as follows: seven cases of portal vein invasion; 81 cases without. Diagnostic accuracy of EUS, CH-EUS, and CE-CT for diagnosing invasion into the portal vein was 72.7%, 93.2%, and 81.8%, respectively. The differences between CH-EUS and CE-CT (P = 0.0094) and CH-EUS and EUS (P = 0.0022) were significant. EUS and CE-CT were comparable.CH-EUS is useful for diagnosis of portal vein invasion by pancreatic cancer.

Aim: Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. Subjects and Method: In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C>A:T mutations the mutations in CpG and non-CpG sites were divided. Furthermore, 40 cases of Rwanda GC were compared in the world for mutation spectrum. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. Results: The most frequent base substitutions were G:C>A:T transition in all the areas investigated. The G:C>A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C>A:T transition in CpG sites and A:T>G:C mutation was more prevalent in Asian countries. Conclusion: The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia. Whether the Rwanda pattern belong to Asian or East European would be interesting. Citation Format: Hiroko Natsume, Kinga Szczepaniak, Hidetaka Yamada, Yuji Iwashita, Marta Gędek, Jelena Šuto, Rika Kasajima, Felix Manirakiza, Augustin Nzitakera, Rei Ishikawa, Eric Rutaganda, François Ngabonziza, Benoit Seminega, Placide Kamali, Vincent Dusabejambo, Belson Rugwizangoga, Nobuhito Nobuhito, Yaping Wang, Yohei Miyagi, Simona Gurzu, Haruhiko Sugimura. Non-CpG sites preference in G:C>A:T transition of TP53 in gastric cancer of Eastern Europe (Poland, Romania and Hungary) compared to East Asian countries (China and Japan) : gastric cancer in the world, mutation spectrum revisited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2609.

BACKGROUND AND AIMS Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for predicting the prognosis of PanNENs. METHODS This single-center, retrospective study included 47 consecutive patients who underwent CH-EUS and were diagnosed with PanNEN by surgical resection or EUS-guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non-aggressive groups according to the degree of clinical malignancy. CH-EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. RESULTS There were 19 cases of aggressive PanNEN and 28 cases of non-aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non-neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH-EUS was superior to contrast-enhanced computed tomography for the diagnosis of aggressive PanNEN (P

BACKGROUND Although several techniques for endoscopic ultrasound-guided biliary drainage (EUS-BD) are available at present, an optimal treatment algorithm of EUS-BD has not yet been established. AIM To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD. METHODS This was a single-center retrospective analysis using a prospectively accumulated database. Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included. The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session. Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success, clinical success, and adverse events (AEs). RESULTS A total of 208 patients underwent EUS-BD during the study period. For 18.8% (39/208) of the patients, the treatment methods were converted to another EUS-BD technique from the initial plan. Biliary obstruction was caused by pancreatobiliary malignancies, other malignant lesions, biliary stones, and other benign lesions in 22, 11, 4, and 2 patients, respectively. The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures: Target puncture (n = 13), guidewire manipulation (n = 18), and puncture tract dilation (n = 8). Technical success was achieved in 97.4% (38/39) of the cases and clinical success was achieved in 89.5% of patients (34/38). AEs occurred in 10.3% of patients, including bile leakage (n = 2), bleeding (n = 1), and cholecystitis (n = 1). The puncture target and drainage technique were altered in subsequent EUS-BD procedures in 25 and 14 patients, respectively. The final technical success rate with 95%CI for all 208 cases was 97.1% (95%CI: 93.8%-98.9%), while that of the initially planned EUS-BD was 78.8% (95%CI: 72.6%-84.2%). CONCLUSION Among multi-step procedures in EUS-BD, guidewire manipulation appeared to be the most technically challenging. When initially planned EUS-BD is technically difficult, treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.

Objective In this study, we investigated whether and how the COVID-19 pandemic affected glycemic control and blood pressure (BP) control in patients with diabetes mellitus (DM). Methods DM patients whose HbA1c level was measured regularly before and after the declaration of a state of emergency were included in this study. Some patients were given questionnaires about changes in their lifestyle to determine the factors affecting glycemic control and BP control. Results The median HbA1c level of the 804 patients increased significantly from 6.8% before the state of emergency to 7.1% and 7.0% during and after the state of emergency, respectively. This was in contrast to the decrease one year earlier due to seasonal variations. In the 176 patients who responded to the questionnaire, the HbA1c level also increased significantly during and after the state of emergency. The worsening of glycemic control was more pronounced in the group that had achieved HbA1c of7% before the state of emergency than in those with higher values. Unlike the rise in HbA1c, the BP did not rise during the state of emergency but did rise significantly afterwards. There was no marked decrease in HbA1c or BP after the state of emergency, even in patients who responded that they were much more careful with their diet, ate less, or exercised more. Conclusions The COVID-19 pandemic worsened glycemic control and BP control, even in patients who perceived no marked change in their diet or exercise, suggesting that more active lifestyle guidance is necessary for good treatment of DM patients.

Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is useful for the diagnosis of lesions inside and outside the digestive tract. This study evaluated the value of artificial intelligence (AI) in the diagnosis of gastric submucosal tumors by CH-EUS.This retrospective study included 53 patients with gastrointestinal stromal tumors (GISTs) and leiomyomas, all of whom underwent CH-EUS between June 2015 and February 2020. A novel technology, SiamMask, was used to track and trim the lesions in CH-EUS videos. CH-EUS was evaluated by AI using deep learning involving a residual neural network and leave-one-out cross-validation. The diagnostic accuracy of AI in discriminating between GISTs and leiomyomas was assessed and compared with that of blind reading by two expert endosonographers.Of the 53 patients, 42 had GISTs and 11 had leiomyomas. Mean tumor size was 26.4 mm. The consistency rate of the segment range of the tumor image extracted by SiamMask and marked by the endosonographer was 96% with a Dice coefficient. The sensitivity, specificity, and accuracy of AI in diagnosing GIST were 90.5%, 90.9%, and 90.6%, respectively, whereas those of blind reading were 90.5%, 81.8%, and 88.7%, respectively (P = 0.683). The κ coefficient between the two reviewers was 0.713.The diagnostic ability of CH-EUS results evaluated by AI to distinguish between GISTs and leiomyomas was comparable with that of blind reading by expert endosonographers.

Objectives The transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP-D) cannot be performed without fluoroscopy, and there are many situations in which fluoroscopy is required even in endoscopic ultrasound-guided drainage (EUS-D). Previous studies have compared the efficacy, but not the radiation exposure of EUS-D and ERCP-D. While radiation exposure in ERCP-D has been previously evaluated, there is a paucity of information regarding radiation doses in EUS-D. This study aimed to assess radiation exposure in EUS-D compared with that in ERCP-D. Methods This retrospective single-center cohort study included consecutive patients who underwent EUS-D and ERCP-D between October 2017 and March 2019. The air kerma (AK: mGy), kerma-area product (KAP: Gycm2 ), fluoroscopy time (FT: min), and procedure time (PT: min) were assessed. The invasive probability weighting method was used to qualify the comparisons. Results We enrolled 372 and 105 patients who underwent ERCP-D and EUS-D, respectively. The mean AK, KAP, and FT in the EUS-D group were higher by 53%, 28%, and 27%, respectively, than those in the ERCP-D group, whereas PT was shorter by approximately 11% (AK; 135.0 vs. 88.4, KAP; 28.1 vs. 21.9, FT; 20.4 vs. 16.0, PT; 38.7 vs. 43.5). The sub-analysis limited to biliary drainage cases showed the same trend (AK; 128.3 vs. 90.9, KAP; 27.0 vs. 22.2, FT; 16.4 vs. 16.1, PT; 32.5 vs. 44.4). Conclusions This is the first study to assess radiation exposure in EUS-D compared with that in ERCP-D. Radiation exposure was significantly higher in EUS-D than in ERCP-D, despite the shorter procedure time.

Background and aims Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the diagnosis of pancreatic cancer (PC). Here, we examined the usefulness of CH-EUS for evaluating therapeutic responses in PC. Methods The study included 23 patients with PC who received chemotherapy. Patients underwent contrast-enhanced computed tomography (CE-CT) and CH-EUS before chemotherapy and at the time of evaluation of the therapeutic response. Patients with a ≧50% reduction in serum carbohydrate antigen 19–9 levels after chemotherapy were defined as “super responders”. The incidence of an avascular area in the tumor on CH-EUS after chemotherapy was compared between “super responders” and non-super responders. Results Nine patients were included in the “super responders” group.Tumor reduction rates did not differ significantly between CE-CT and CH-EUS in the “super responders”. The appearance of an avascular area was detected in 7 of 9 super responders (77.8%) and in 4 of 14 non-super responders (28.6%), and the difference was significant (P = 0.036). The mean survival time of patients with an avascular area after chemotherapy was longer than that of without an avascular area. Conclusions Detection of avascular areas by CH-EUS after chemotherapy may predict long-term survival of patients with PC.

Objective Although modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. Methods Advanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. Results Among 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. Conclusion The scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles.

Hepatic angiomyolipoma (AML) is a rare stromal tumor composed of variable admixtures of thick-walled vessels, smooth muscles and adipose tissue. One of the specific radiological findings of hepatic AML is an early drainage vein noted via enhanced computed tomography (CT). We report a case of hepatic AML showing early drainage veins into both the hepatic and portal vein. The case involved a 46-year-old woman who was referred to our hospital because of a giant hepatic tumor. CT revealed well-enhanced 14 cm and 1 cm tumors in the left and right lobes, respectively. Magnetic resonance imaging demonstrated the existence of adipose tissues in the larger tumor. Hepatic arteriography revealed early drainage veins draining into both the hepatic and portal vein. Based on a diagnosis of hepatic AML, left hepatectomy and partial hepatectomy were performed. Pathology revealed both tumors as hepatic AML based on human melanoma black-45 immuno-positivity. Hepatic AML with early drainage veins into both the hepatic and portal vein is rare. The dilated and retrogressive vein drains the abundant arterial blood flow of the tumor. The finding of early drainage veins into not only the hepatic vein but also the portal vein should be helpful for diagnosing hepatic AMLs.

We appreciate invaluable comments by Tamanini et al. on our recently published manuscript in the Digestive Endoscopy. In this study, extensive pathological analyses revealed that aggressive pancreatic neuroendocrine neoplasms (PanNENs) are characterized by increased intra-tumoral fibrosis and decreased number, diameter, and area of blood vessels1 .

Background: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). Methods: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. Results: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. Conclusions: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS.

Background: The ultrasound-based imaging procedures are known to be safer than those based on X-ray fluoroscopy as they do not involve ionising radiation. There is a natural tendency to look for ultrasound guidance wherever clinical needs can be met. While radiation exposure in endoscopic retrograde cholangiopancreatography (ERCP) has been evaluated, there is paucity of information on radiation doses in endoscopic ultrasound-guided transluminal drainage (EUS-D), which also utilises fluoroscopy in addition to ultrasound. In our study, we compared radiation exposures in EUS-D and ERCP. Methods: This retrospective, single-centre cohort study included consecutive EUS-D and ERCP performed between October 2017 and March 2019. The air kerma (Ka,r: mGy), kerma-area product (PKA: mGycm2), fluoroscopy time (FT: min), and procedure time (PT: min) were noted. The invasive probability weighting method was used to qualify comparison. Findings: In total 918 ERCPs and 105 EUS-Ds were enrolled. The median Ka,r, PKA, and FT in the EUS-D group were higher by 65%, 40%, and 40%, respectively, than those in the ERCP group, whereas PT was shorter by approximately 15% (Ka,r; 135·2 vs 82·5, PKA; 28275·0 vs 20399·9, FT; 20·4 vs 14·7, PT; 38·7 vs 45·2). Interpretation: This is the first report to assess radiation exposure in EUS-D and compare it with that in ERCP, which unexpectedly found that radiation exposure parameters were significantly higher in EUS-D than in ERCP, despite the shorter PT. This finding is of significance for future design of the equipment and for selection strategy for the procedure. Knowledge of these findings would raise awareness among endoscopists to minimise radiation risks to patients and staff. Funding Statement: There was no funding support for this study. Declaration of Interests: All authors had no conflicts of interest with other people or organisations. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board of Kindai University (IRB No. R02-121). The study was conducted according to the provisions of the Declaration of Helsinki as revised in Fortleza, Brazil, in 2013.

Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) has been reported to be effective for patients with surgically altered gastrointestinal anatomy. However, selective biliary cannulation remains difficult in BE-ERCP. We examined the usefulness of a modified double-guidewire technique using an uneven double lumen cannula (the uneven method) for BE-ERCP in patients with surgically altered gastrointestinal anatomy. To clarify the usefulness of the uneven method for selective biliary cannulation in BE-ERCP in comparison to the pancreatic guidewire (PGW) method, 40 patients with surgically altered gastrointestinal anatomy who underwent BE-ERCP with successful placement of a guidewire in the pancreatic duct were evaluated. The uneven method was used in 18 cases (uneven group) and the PGW method was used in the remaining 22 cases (PGW group). The technical success rate of biliary cannulation was higher in the uneven group than in the PGW group (83.3 vs. 59.0%; P = 0.165). In addition, the time to biliary cannulation were significantly shorter in the uneven group than in the PGW group (6 vs. 18 min; P = 0.004; respectively). In the PGW group, post-ERCP pancreatitis (PEP) occurred in 3 of 22 cases (13.6%). No adverse events, including PEP, occurred in the uneven group. The uneven method may be a useful option of selective biliary cannulation in BE-ERCP for the patients with surgically altered gastrointestinal anatomy.

This study aimed to investigate whether the incorporation of contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) into the international consensus guidelines (ICG) for the management of intraductal papillary mucinous neoplasm (IPMN) could improve its malignancy diagnostic value. In this single-center retrospective study, 109 patients diagnosed with IPMN who underwent preoperative CH-EUS between March 2010 and December 2018 were enrolled. We analyzed each malignancy diagnostic value (sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV)) by replacing fundamental B-mode EUS with CH-EUS as the recommended test for patients with worrisome features (WF) (the CH-EUS incorporation ICG) and comparing the results to those obtained using the 2017 ICG. The malignancy diagnostic values as per the 2017 ICG were 78.9%, 42.3%, 60.0%, and 64.7% for Se, Sp, PPV, and NPV, respectively. The CH-EUS incorporation ICG plan improved the malignancy diagnostic values (Se 78.9%/Sp, 53.8%/PPV, 65.2%/NPV 70.0%). CH-EUS may be useful in determining the appropriate treatment strategies for IPMN.

The substitution effects on various parameters, which may influence the hydrogen bond strengths of Watson–Crick-type base pairs, were investigated for DNA dodecamers containing 5-substituted-2′-deoxyuridine derivatives. In doing so, a series of [3-15N]-2′-deoxyuridine derivatives, including thymidine, 2′-deoxyuridine, 5-bromo-2′-deoxyuridine, 5-fluoro-2′-deoxyuridine and 5-cyano-2′-deoxyuridine, and [ul-15N]-2′-deoxyadenosine, were synthesized and incorporated into the DNA dodecamer, d(CGCGA* ATX* CGCG)2, where X* and A* were a [3-15N]-2′-deoxyuridine derivative and [ul-15N]-2′-deoxyadenosine, respectively. The imino proton chemical shift and the spin coupling constant between the imino proton and nitrogen [1J(N,H)] were measured for the Watson–Crick-type A*–X* base pair of all five duplexes. The substitution with an electron-withdrawing group results in downfield shift of the imino proton and a concomitant decrease in magnitude of the 1J(N,H) value, and a good, linear correlation was found between the two effects. These substitution effects on the NMR parameters were linearly correlated with the pKa values of the 2′-deoxyuridine derivatives and also with the theoretically calculated hydrogen bond energy. The linear correlations found here indicate that the DNA oligomers with 5-substituted-2′-deoxyuridine provide a good model to study the nature of the hydrogen bond in Watson–Crick-type base pairs. Copyright © 2001 John Wiley & Sons, Ltd.

Dependency injection is a hot topic among industrial developers using component frameworks. This paper first mentions that dependency injection and aspect-oriented programming share the same goal, which is to reduce dependency among components for better reus- ability. However, existing aspect-oriented programming languages/ frameworks, in particular, AspectJ, are not perfectly suitable for expressing inter-component dependency with a simple and straightforward representation. Their limited kinds of implicit construction of aspect instances (or implementations) cannot fully express inter-component dependency. This paper points out this fact and proposes our aspect-oriented programming system named GluonJ to address this problem. GluonJ allows developers to explicitly construct and associate an aspect implementation with aspect targets.

The effects of substitutions on various NMR parameters, which may influence the hydrogen bond strengths of Watson-Crick base pairs, were investigated for DNA dodecamers containing 5-substituted-2'-deoxyuridine derivatives and 2'-deoxynebularine in the oligomers, 5'-d(CGCGNA TX CGCG)-3'; where N and X are 2'-deoxy nebularine and [N3-(15)N]-2'-deoxyuridine derivatives. The substitution effects on NMR parameters were linearly correlated with the pKa values of the 2'-dexoyuridine derivatives.

effects of substitutions on various NMR parameters, which may influence the hydrogen bond strengths of Watson- Crick base pairs, were investigated for DNA dodecamers containing 5-substituted-2'-deoxyuridine derivatives and 2'-deoxynebularine in the oligomers, 5'-d(CGCGNA TIJ CGCG)-3' ; where and X are 2'-deoxy nebularine and ~3-15N)-2'-deogyoridine derivatives. The substitution effects on NMR parameters were linearly correlated with the pKa values of the 2'-dexoyuridine derivatives. INTRODUCTION the nitrogen-nitro en coupling constant through the hydrogen bond ( J") was observed for base airs in RNA and DNA duplexes and triplexes',*. bonds in nucleic acids can be characterized by NMR parameters, such as ZhJNN, 'JNH, etc. In our previous report, N3 selectively I5N labeled 2'-deoxy uridine derivatives and (15N5) -2'-deoxyadenosine were introduced into DNA oligomers. The dodecamers, which have self-complementary sequences, formed duplex structures in solution, and A and X are paired fi

The effects on various NMR parameters of substitutions, which may influence the hydrogen bond strengths of Watson-Crick-type base pairs, were investigated for DNA dodecamers containing 5-substituted-2'-deoxyuridine derivatives in oligomers, 5'-d(CGCGAATXCGCG)-3', where A and X were [ul-15N]-2'-deoxyadenosine and [3(-15)N]-2'-deoxyuridine derivatives. The substitution effects on the NMR parameters were linearly correlated with the pKa values of the 2'-deoxyuridine derivatives.