OBJECTIVE: Dihydropyrimidinase deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway, with fewer than 40 patients published. Clinical findings are variable and some patients may remain asymptomatic. Global developmental delay and increased susceptibility to 5-fluorouracil are commonly reported. Here we present atrioventricular septal defect as a novel feature in dihydropyrimidinase deficiency.
METHODS: A four-year-old male with global developmental delay, dysmorphic facies, autistic features and a history of seizures was diagnosed with dihydropyrimidinase deficiency based on strikingly elevated urinary dihydrouracil and dihydrothymine and a homozygous pathogenic nonsense variant in DPYS gene. He had a history of complete atrioventricular septal defect corrected surgically in infancy.
CONCLUSIONS: This is the second report of congenital heart disease in dihydropyrimidinase deficiency, following a single patient with a ventricular septal defect. The rarity of the disease and the variability of the reported findings make it difficult to describe a disease-specific clinical phenotype. The mechanism of neurological and other systemic findings is unclear. Dihydropyrimidinase deficiency should be considered in patients with microcephaly, developmental delay, epilepsy and autistic traits. We suggest that congenital heart disease may also be a rare phenotypic feature.

DNA-protein complexes are attractive components with broad applications in various research fields, such as DNA aptamer-enzyme complexes as biosensing elements. However, noncovalent DNA-protein complexes often decrease detection sensitivity because they are highly susceptible to environmental conditions. In this study, we developed a versatile DNA-protein covalent-linking patch (D-Pclip) for fabricating covalent and stoichiometric DNA-protein complexes. We comprehensively explored the database to determine the DNA-binding ability of the candidates and selected UdgX as the only uracil-DNA glycosylase known to form covalent bonds with DNA via uracil, with a binding efficiency >90%. We integrated a SpyTag/SpyCatcher protein-coupling system into UdgX to create a universal and convenient D-Pclip. The usability of D-Pclip was shown by preparing a stoichiometric model complex of a hemoglobin (Hb)-binding aptamer and glucose oxidase (GOx) by mixing at 4 °C. The prepared aptamer-GOx complexes detected Hb in a dose-dependent manner within the clinically required detection range in buffer and human serum without any washing procedures. D-Pclip covalently connects any uracil-inserted DNA sequence and any SpyCatcher-fused protein stoichiometrically; therefore, it has a high potential for various applications.

Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 μM) displaying ∼24-fold potency over the uracil ring.

Background: Dipeptidyl peptidase (DPP)-4 inhibitors are commonly used agents to treat type 2 diabetes mellitus (T2DM). Although generally well tolerated, stomatitis has been previously reported as an adverse event with sitagliptin and linagliptin. Stomatitis with alogliptin has not been reported in post-marketing data to date. Objective: To report a case of suspected drug-induced stomatitis in a patient who received alogliptin for T2DM which resolved upon discontinuation of the offending agent. Summary: A 60-year-old male with T2DM began treatment with a DPP-4 inhibitor, alogliptin. After 4 doses of alogliptin, the patient reported inflammation and irritation along the lateral borders of his tongue, along with open fissures and oral ulcerations on the dorsal surface of the mucosa. He was subsequently diagnosed with stomatitis. Patient discontinued alogliptin and reported improvement in symptoms within 48 hours. Lesions re-epithelialized within 4 weeks after cessation of alogliptin. The Naranjo Algorithm was used to assess causality. The total score was 7, which when interpreted, implicates alogliptin as a \"probable\" cause of the reaction. Conclusion: A causality assessment determined alogliptin was a \"probable\" cause of stomatitis experienced by this patient. This adverse effect has not been reported with alogliptin to the authors\' knowledge.

Oral uracil and tegafur plus Leucovorin(UFT/LV)therapy is one of the standard adjuvant chemotherapies for colorectal cancer, and is widely used without any serious adverse events. Herein, we describe a case of UFT/LV-induced acute liver failure in a 75-year-old woman who underwent laparoscopic sigmoidectomy for sigmoid colon cancer. She was diagnosed with advanced colon cancer and lymph node metastasis by postoperative histopathological analysis, and adjuvant chemotherapy was initiated. After 30 days of commencing the therapy, the patient visited our hospital with complaints of severe diarrhea and difficulty in food intake. The apparent cause of these symptoms was unclear on computed tomography(CT), and mild liver damage was revealed in blood test results. The hepatic disorder gradually progressed after the hospitalization, and the condition was diagnosed as acute hepatic insufficiency. Additionally, obvious atrophy of the liver parenchyma and significant ascites were confirmed on CT. Two months later, the platelet count decreased markedly, but fortunately, no bleeding occurred. There has been no recurrence since 2 years after the surgery without any additional adjuvant therapy.

In Japan, oral administration of tegafur-uracil is recommended as postoperative adjuvant chemotherapy for patients diagnosed with primary lung adenocarcinomas of >2 cm size and staged as IA, IB, and IIA. Reports on chemotherapy-induced pericardial effusion are rare. Herein, we report a rare case of tegafur-uracil-induced pericardial effusion during postoperative adjuvant chemotherapy for primary lung cancer. A 60-year-old man underwent left lower lobectomy and mediastinal lymph node dissection for left lower lung adenocarcinoma. Lung cancer was staged as IB, and tegafur-uracil was administered as postoperative adjuvant chemotherapy from 1 month after the surgery. A computed tomography (CT) scan revealed a pericardial effusion 5 months after the surgery. A malignant pericardial effusion was suspected, and tegafur-uracil was discontinued. Pericardiocentesis could not be performed owing to a small amount of pericardial effusion. An 18 F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan revealed no abnormal FDG uptake. During a short follow-up period after discontinuation of tegafur-uracil, a CT scan revealed a decrease in pericardial effusion, suggesting that the pericardial effusion was induced by tegafur-uracil. Follow-up of pericardial effusion is required while administering tegafur-uracil. In cases of pericardial effusion without symptoms and no suspicious metastatic lesions in other organs, we should be concerned about tegafur-uracil-induced pericardial effusion.

We present an explicit solvation protocol for the calculation of electron affinity values of the solvated nucleobases. The protocol uses a quantum mechanics/molecular mechanics (QM/MM) approach based on the newly implemented domain-based pair natural orbital EOM-CCSD (equation-of-motion coupled-cluster single-double) method. The stability of the solvated nucleobase anion is sensitive to the local distribution of the water molecules around the nucleobase, and the calculated electron affinity values converge slowly with respect to the number of snapshots and the size of the water box. The use of nonpolarizable water molecules leads to an overestimation of the electron affinity and makes the result sensitive to the size of the QM region in the QM/MM calculation. The electron affinity values, although sensitive to the size of the basis set, lead to an almost constant blue shift of the electron affinity upon the increase in the basis set. The present protocol allows for a controllable description of the various parameters affecting the electron affinity value, and the calculated adiabatic electron affinity values are in excellent agreement with experimental results.

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Systemic fluorouracil agents include not only 5-fluorouracil (5FU), but also capecitabine, tegafur, and uracil/tegafur (UFT). Systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and discoid lupus erythematosus (DLE) are subtypes of lupus erythematosus; drug-induced lupus erythematosus can also present in each of these subtypes. This report describes the case of a 65-year-old woman with systemic 5FU-induced DLE. Fluorouracil agent-induced DLE lesions occurring after initiating treatment with either systemic 5FU or its prodrugs have been described in 19 individuals (Including the woman in this report) in the literature: tegafur (10 patients), UFT (six patients), systemic 5FU (two patients), and capecitabine (one patient). The mean duration before the appearance of the DLE lesions on sun-exposed areas was 232 days after beginning the fluorouracil agent; however, the much earlier (three weeks) appearance of the DLE lesions after starting systemic 5FU in the women described in this report may have occurred since there was no delay associated with the conversion of a precursor drug to 5FU. Within two months (mean: 36 days) after stopping the fluorouracil agent, the DLE lesions resolved in 95% of the patients. Laboratory studies were only performed on some of the patients. None of the patients tested had antibodies to Ro/Sjogren\'s syndrome A (Ro/SSA) and La/Sjogren\'s syndrome B (La/SSB). The antinuclear antibody (ANA) titer was elevated in 71% of the tested individuals and decreased in all of the patients who were evaluated after the causative drug was discontinued. The pathogenesis for fluorouracil agent drug-induced DLE remains to be definitively established.

A92 -year-old woman underwent laparoscopic sigmoid colectomy with D3 lymphadenectomy. Histological examination confirmed a pT3(SS), pN0, pM0, pStageⅡ tumor. Abdominal CT 6 months after surgery revealed liver metastasis close to the right branch of the portal vein in the S6 region of the liver. There were no indications for transcatheter arterial embolization, radiofrequency ablation, or hepatectomy. Although she had Grade 3 neutropenia, the patient received 15 courses of oral UFT/LV. Three courses of UFT/LV plus bevacizumab were also administered. She was judged to have achieved stable disease (SD); however, Grade 4 proteinuria was observed. After she was administered 2 courses of TAS-102, we shifted to best supportive care. She died of a sigmoid cancer 32 months after UFT/LV initiation. Careful adaptation of chemotherapy can be used to control a patient\'s condition during certain periods, even in patients with super-advanced age.