Chemical synthesis of oligodeoxyribonucleotides containing the Dewar valence isomer of the (6–4) photoproduct and their use in (6–4) photolyase studies

The pyrimidine(6–4)pyrimidone photoproduct, a major UV lesion formed between adjacent pyrimidine bases, is transformed to its Dewar valence isomer upon exposure to UVA/UVB light. We have synthesized a phosphoramidite building block of the Dewar photoproduct formed at the thymidylyl(3′–5′)thymidine site and incorporated it into oligodeoxyribonucleotides. The diastereoisomers of the partially protected dinucleoside monophosphate bearing the (6–4) photoproduct, which were caused by the chirality of the phosphorus atom, were separated by reversed-phase chromatography, and the (6–4) photoproduct was converted to the Dewar photoproduct by irradiation of each isomer with Pyrex-filtered light from a high-pressure mercury lamp. The Dewar photoproduct was stable under both acidic and alkaline conditions at room temperature. After characterization of the isomerized base moiety by NMR spectroscopy, a phosphoramidite building block was synthesized in three steps. Although the ordinary method could be used for the oligonucleotide synthesis, benzimidazolium triflate as an alternative activator yielded better results. The oligonucleotides were used for the analysis of the reaction and the binding of Xenopus (6–4) photolyase. Although the affinity of this enzyme for the Dewar photoproduct-containing duplex was reportedly similar to that for the (6–4) photoproduct-containing substrate, the results suggested a difference in the binding mode

Self-potential Measurements on Shinmoe-Dake, Kirishima Volcanic Group

We conducted self-potential(SP) surveys on Shinmoe-Dake, one of the active volcanoes in Kirishima volcanic group. The surveys cover an area of 1km × 1km including the crater. One of the prominent features is a negative anomaly on the crater basin. The streaming potential caused by drainage of water from the crater basin is a promising candidate for a cause of the negative anomaly. We quantitatively verified the plausibility of the mechanism using seepage of the lake water and the permeability of the ground, which were estimated from the water balance of the crater lake. Another prominent feature is positive SP anomalies on the eastern and southern slopes of Shiiimoe-Dake. These positive anomalies lie over relatively low resistive regions revealed by a magnetotelluric survey. This fact suggests that the present positive anomalies are generated by the streaming potential accompanied by hydrothermal upflows, although there still remains uncertainty because we have no information on the ground temperature. We also found positive patches of SP which were located at the fumaroles in the crater basin. However, they turned out to be rather small both in size and intensity after correcting for topographic effects. This suggests that hydrothermal activity just under the crater of Shinmoe-Dake is weak at present.霧島火山群に属する成層火山新燃岳において,火口を含む約1km四方の自然電位分布を調査した.新燃岳火口底の自然電位は,過去に調べられたいくつかの活火山の例に反して負の異常を示すことがわかった.この負異常の原因についていくつかの可能性を定量的に検証した結果,火口湖からの漏水に伴う流動電位がその主要な原因であるとの結論を得た.山体東斜面と南斜面には正の電位異常が見られる.MT法による比抵抗測定によって得られている低比抵抗層の分布と,この正の電位異常の分布は良い一致を示すことから,地下での熱水の上昇が示唆される.しかしながら,地中温度のデータがないためこれは確証的ではない

霧島火山群・新燃岳の自然電位測定

We conducted self-potential(SP) surveys on Shinmoe-Dake, one of the active volcanoes in Kirishima volcanic group. The surveys cover an area of 1km × 1km including the crater. One of the prominent features is a negative anomaly on the crater basin. The streaming potential caused by drainage of water from the crater basin is a promising candidate for a cause of the negative anomaly. We quantitatively verified the plausibility of the mechanism using seepage of the lake water and the permeability of the ground, which were estimated from the water balance of the crater lake. Another prominent feature is positive SP anomalies on the eastern and southern slopes of Shiiimoe-Dake. These positive anomalies lie over relatively low resistive regions revealed by a magnetotelluric survey. This fact suggests that the present positive anomalies are generated by the streaming potential accompanied by hydrothermal upflows, although there still remains uncertainty because we have no information on the ground temperature. We also found positive patches of SP which were located at the fumaroles in the crater basin. However, they turned out to be rather small both in size and intensity after correcting for topographic effects. This suggests that hydrothermal activity just under the crater of Shinmoe-Dake is weak at present.霧島火山群に属する成層火山新燃岳において,火口を含む約1km四方の自然電位分布を調査した.新燃岳火口底の自然電位は,過去に調べられたいくつかの活火山の例に反して負の異常を示すことがわかった.この負異常の原因についていくつかの可能性を定量的に検証した結果,火口湖からの漏水に伴う流動電位がその主要な原因であるとの結論を得た.山体東斜面と南斜面には正の電位異常が見られる.MT法による比抵抗測定によって得られている低比抵抗層の分布と,この正の電位異常の分布は良い一致を示すことから,地下での熱水の上昇が示唆される.しかしながら,地中温度のデータがないためこれは確証的ではない

Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells

Abstract BCR/ABL1 causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In addition to the deregulatory effects of its kinase activity on cell proliferation, BCR/ABL1 induces genomic instability by downregulating BRCA1. PARP inhibitors (PARPi) effectively induce cell death in BRCA-defective cells. Therefore, PARPi are expected to inhibit growth of CML and Ph1-ALL cells showing downregulated expression of BRCA1. Here, we show that PARPi effectively induced cell death in BCR/ABL1 positive cells and suppressed colony forming activity. Prevention of BCR/ABL1-mediated leukemogenesis by PARP inhibition was tested in two in vivo models: wild-type mice that had undergone hematopoietic cell transplantation with BCR/ABL1-transduced cells, and a genetic model constructed by crossing Parp1 knockout mice with BCR/ABL1 transgenic mice. The results showed that a PARPi, olaparib, attenuates BCR/ABL1-mediated leukemogenesis. One possible mechanism underlying PARPi-dependent inhibition of leukemogenesis is increased interferon signaling via activation of the cGAS/STING pathway. This is compatible with the use of interferon as a first-line therapy for CML. Because tyrosine kinase inhibitor (TKI) monotherapy does not completely eradicate leukemic cells in all patients, combined use of PARPi and a TKI is an attractive option that may eradicate CML stem cells

Plasma hPG80 (circulating progastrin) as a novel biomarker for detecting gastric cancer: a Japanese multicenter study

Purpose: Early detection and treatment of cancer are important for prolonging life expectancy. hPG80 (circulating progastrin) is an 80-amino acid protein that could prove useful for detecting and following up cancer patients. However, no studies have clarified hPG80 levels in Japanese populations. Patients and Methods: From 2018 to 2022, we prospectively measured hPG80 levels in 40 cancer patients and 18 healthy volunteers. A receiver operating characteristic (ROC) curve was used to assess the optimal cut-off for hPG80. According to this cut-off, we divided participants into a high-hPG80 group (n=30) and a low-hPG80 group (n=10) and compared clinical characteristics between groups. Results: Levels of hPG80 were higher in cancer patients (5.9 pM) than in healthy volunteers (2.3 pM; p=0.036), especially for gastric cancer (7.2 pM). We identified an optimal cut-off for hPG80 at 3.42 pM. At this cut-off, the sensitivity was 93.3% and specificity 83.3% for gastric cancer. The proportion of gastric cancer patients (46.7% vs. 10.0%; p=0.040) was higher in the high-hPG80 group. Among gastric cancer patients, 7 of 8 patients (87.5%) with early-stage cancer showed high hPG80 levels. Conclusion: Plasma hPG80 levels appear useful for early detection of cancer patients, especially gastric cancer.Acta medica Nagasakiensia, 67(2), pp.69-74; 202