Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, affects the survival of cancer patients. Anamorelin was the first drug approved in Japan for the treatment of cachexia. However, cases in which anamorelin is discontinued within 3 weeks are often observed in clinical practice. This study aimed to explore the factors associated with continued anamorelin dosing. We retrospectively reviewed records of patients with lung, gastric, pancreatic, and colorectal cancer who started anamorelin at Fukuoka University Hospital from April 2021 to November 2022. Patients were divided into two groups based on the duration of anamorelin administration: 15 patients were classified into the <3 weeks group and 22 were classified into the ≥3 weeks group. The primary objective was to explore the potential factors associated with the continuation of anamorelin, and the secondary objectives were to compare survival and nutritional indices. In the univariate analysis, there were significant differences between the two groups in terms of cancer type (p=0.007) and serum albumin level (p=0.026). In the multivariate analysis, gastric cancer and albumin 2.7 g/dL or less were associated with the continuation of anamorelin. Survival was significantly shorter in the <3 weeks group (p=0.019). This study suggests that the continuation of anamorelin may be influenced by specific tumor types and serum albumin levels. Furthermore, the duration of anamorelin administration may affect patient survival.
{"title":"[Factors Associated with the Continuation of Anamorelin in Patients with Cancer-associated Cachexia: A Single-center Retrospective Study].","authors":"Yuka Egawa, Masanobu Uchiyama, Natsuki Egoshi, Yasuaki Igarashi, Yuki Yasutaka, Takafumi Nakano, Koichi Matsuo, Susumu Kaneshige, Hidetoshi Kamimura","doi":"10.1248/yakushi.24-00002","DOIUrl":"https://doi.org/10.1248/yakushi.24-00002","url":null,"abstract":"<p><p>Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, affects the survival of cancer patients. Anamorelin was the first drug approved in Japan for the treatment of cachexia. However, cases in which anamorelin is discontinued within 3 weeks are often observed in clinical practice. This study aimed to explore the factors associated with continued anamorelin dosing. We retrospectively reviewed records of patients with lung, gastric, pancreatic, and colorectal cancer who started anamorelin at Fukuoka University Hospital from April 2021 to November 2022. Patients were divided into two groups based on the duration of anamorelin administration: 15 patients were classified into the <3 weeks group and 22 were classified into the ≥3 weeks group. The primary objective was to explore the potential factors associated with the continuation of anamorelin, and the secondary objectives were to compare survival and nutritional indices. In the univariate analysis, there were significant differences between the two groups in terms of cancer type (p=0.007) and serum albumin level (p=0.026). In the multivariate analysis, gastric cancer and albumin 2.7 g/dL or less were associated with the continuation of anamorelin. Survival was significantly shorter in the <3 weeks group (p=0.019). This study suggests that the continuation of anamorelin may be influenced by specific tumor types and serum albumin levels. Furthermore, the duration of anamorelin administration may affect patient survival.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.23-00164-F
Yasunari Kanda, Junko Kurokawa
{"title":"[Comprehensive Assessment of Cardiovascular Toxicity~From Basic to Clinic~].","authors":"Yasunari Kanda, Junko Kurokawa","doi":"10.1248/yakushi.23-00164-F","DOIUrl":"10.1248/yakushi.23-00164-F","url":null,"abstract":"","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A questionnaire survey was conducted to evaluate practical training and improve education on clinical trial and research. This survey was based on the results of questionnaire before and after the practical training undertaken by 240 pharmaceutical students (Kanto region; 1 university, Tokai region; 2 university, Kinki region; 9 university) at Mie University Hospital between 2011 and 2022. In the questionnaire before practical training, lectures in university (n=219, 91%) were the main source of information on clinical trials and research. Fifty-two students (22%) correctly answered the contents of phase 1-4 trials. As an occupation that can perform clinical research coordinator (CRC)'s work, only 7 students (3%) answered that "all medical and non-medical professionals" can perform the CRC's duties. Regarding the understanding of terms related to clinical trials and research, more than 90% of the students understood the meaning of "subjects," "informed consent," and "placebo" even before practical training. Otherwise, even after practical training, students' understanding of "reimbursement," "follow-up period," "audit," or "direct access" was less than 80%. Practical training improved the understanding of terms such as clinical trial (Wilcoxon signed-rank test, p<0.001), clinical research phase 1-4 trials (Wilcoxon signed-rank test, p<0.001), interest in clinical trials and research (McNemar-Bowker test, p<0.001), and understanding of CRC's work (McNemar-Bowker test, p<0.001). We will improve the content of practical training and bequeath the knowledge and importance of drug discovery and development to the next generation.
{"title":"[Evaluation of Pharmacy Students' Understanding of Clinical Trials and Research through Questionnaires Before and After the Hospital Practical Training].","authors":"Chihiro Shiraishi, Mayumi Kotera, Yasuyuki Ota, Eiko Takeshige, Chisato Minamide, Rie Kurimoto, Aki Sato, Miho Inamori, Misaki Kataoka, Toru Ogura, Satoshi Tamaru, Takuya Iwamoto","doi":"10.1248/yakushi.23-00202","DOIUrl":"https://doi.org/10.1248/yakushi.23-00202","url":null,"abstract":"<p><p>A questionnaire survey was conducted to evaluate practical training and improve education on clinical trial and research. This survey was based on the results of questionnaire before and after the practical training undertaken by 240 pharmaceutical students (Kanto region; 1 university, Tokai region; 2 university, Kinki region; 9 university) at Mie University Hospital between 2011 and 2022. In the questionnaire before practical training, lectures in university (n=219, 91%) were the main source of information on clinical trials and research. Fifty-two students (22%) correctly answered the contents of phase 1-4 trials. As an occupation that can perform clinical research coordinator (CRC)'s work, only 7 students (3%) answered that \"all medical and non-medical professionals\" can perform the CRC's duties. Regarding the understanding of terms related to clinical trials and research, more than 90% of the students understood the meaning of \"subjects,\" \"informed consent,\" and \"placebo\" even before practical training. Otherwise, even after practical training, students' understanding of \"reimbursement,\" \"follow-up period,\" \"audit,\" or \"direct access\" was less than 80%. Practical training improved the understanding of terms such as clinical trial (Wilcoxon signed-rank test, p<0.001), clinical research phase 1-4 trials (Wilcoxon signed-rank test, p<0.001), interest in clinical trials and research (McNemar-Bowker test, p<0.001), and understanding of CRC's work (McNemar-Bowker test, p<0.001). We will improve the content of practical training and bequeath the knowledge and importance of drug discovery and development to the next generation.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.23-00178-3
Katsumasa Irie
Neural activity generates essential responses, such as thinking, memory formation, and muscle contraction. It is controlled by the well-coordinated activity of various cation-selective channels of the cell membrane. The divalent cation block plays an essential role in various tetrameric ion channels. For example, N-methyl-D-aspartic acid receptors, which are tetrameric ion channels involved in memory formation, are inhibited by magnesium ions. Divalent cations are thought to bind in the ion pathway of the ion channel and as a consequence block the channel current, however, direct observation of such a block has not been reported yet. As a consequence, the behavior of these blocking divalent cations remains poorly understood. NavAb, a similar tetrameric sodium channel cloned from Arcobacter butzleri, is one of the most structurally analyzed tetrameric channels that is not inhibited by divalent cations. In this study, we elucidated the molecular mechanism of the divalent cation block by reproducing the divalent cation block in NavAb. The X-ray crystal structure of divalent-cation-block mutants show electron density in the ion transmission pathway of the divalent cation blocked mutants, indicating that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack into the ion pathway. In molecular dynamics simulations, the stacked calcium ion repels the sodium ions near the channel lumen's entrance at the selective filter's bottom. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels and suggest a process of functional acquisition in ion channel evolution.
神经活动产生基本反应,如思考、记忆形成和肌肉收缩。神经活动由细胞膜上各种阳离子选择性通道的协调活动控制。二价阳离子阻滞在各种四聚体离子通道中发挥着重要作用。例如,参与记忆形成的四聚体离子通道 N-甲基-D-天冬氨酸受体就受到镁离子的抑制。二价阳离子被认为会在离子通道的离子通路中结合,从而阻断通道电流,但尚未有直接观察到这种阻断的报道。因此,人们对这些阻塞性二价阳离子的行为仍然知之甚少。NavAb 是一种从 Arcobacter butzleri 克隆的类似四聚体钠通道,是结构分析最多的不受二价阳离子抑制的四聚体通道之一。在这项研究中,我们通过在 NavAb 中重现二价阳离子阻滞,阐明了二价阳离子阻滞的分子机制。二价阳离子阻滞突变体的 X 射线晶体结构显示,二价阳离子阻滞突变体的离子传输通路中存在电子密度,表明增加孔域内前庭亲水性的突变能够使二价阳离子叠加进入离子通路。在分子动力学模拟中,堆积的钙离子在选择性过滤器底部通道腔入口附近排斥钠离子。这些结果表明了四聚体阳离子通道中二价阳离子阻断机制的主要过程,并提示了离子通道进化过程中的功能获得过程。
{"title":"[Analysis of the Divalent Cation Blocking in Ion Channels by Crystal Structure and Molecular Dynamics Simulations].","authors":"Katsumasa Irie","doi":"10.1248/yakushi.23-00178-3","DOIUrl":"10.1248/yakushi.23-00178-3","url":null,"abstract":"<p><p>Neural activity generates essential responses, such as thinking, memory formation, and muscle contraction. It is controlled by the well-coordinated activity of various cation-selective channels of the cell membrane. The divalent cation block plays an essential role in various tetrameric ion channels. For example, N-methyl-D-aspartic acid receptors, which are tetrameric ion channels involved in memory formation, are inhibited by magnesium ions. Divalent cations are thought to bind in the ion pathway of the ion channel and as a consequence block the channel current, however, direct observation of such a block has not been reported yet. As a consequence, the behavior of these blocking divalent cations remains poorly understood. NavAb, a similar tetrameric sodium channel cloned from Arcobacter butzleri, is one of the most structurally analyzed tetrameric channels that is not inhibited by divalent cations. In this study, we elucidated the molecular mechanism of the divalent cation block by reproducing the divalent cation block in NavAb. The X-ray crystal structure of divalent-cation-block mutants show electron density in the ion transmission pathway of the divalent cation blocked mutants, indicating that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack into the ion pathway. In molecular dynamics simulations, the stacked calcium ion repels the sodium ions near the channel lumen's entrance at the selective filter's bottom. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels and suggest a process of functional acquisition in ion channel evolution.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.23-00217
Kimiyoshi Ichida
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
血清尿酸水平取决于尿酸生成量与肾脏和肠道尿酸排泄量之间的平衡。当尿酸池的平衡向增加或减少的方向转变时,就会出现尿酸过多症,包括高尿酸血症和低尿酸血症。高尿酸血症主要是一种多因素遗传性疾病,涉及多个疾病易感基因和环境因素。而高尿酸血症则是由基因异常引起的。尿酸异常血症涉及的主要基因有黄嘌呤氧化还原酶(一种产生尿酸的酶)、尿酸转运体尿酸转运体 1/绝对载体家族 22 成员 12(URAT1/SLC22A12)、葡萄糖转运体 9/绝对载体家族 2 成员 9(GLUT9/SLC2A9)和 ATP 结合盒 G 亚家族成员 2(ABCG2)。黄嘌呤氧化还原酶缺乏会导致黄嘌呤尿症,这是一种罕见的疾病,伴有明显的高尿酸血症。黄嘌呤尿症可由单一的黄嘌呤氧化还原酶缺乏症引起,也可与醛氧化酶缺乏症同时出现。后者是由钼辅助因子硫化酶缺乏引起的,硫化酶负责将硫原子添加到黄嘌呤氧化还原酶和醛氧化酶发挥作用所需的钼辅助因子中。URAT1/SLC22A12和GLUT9/SLC2A9参与尿酸盐的重吸收,缺乏这两种物质会导致肾脏高尿酸血症。另一方面,ABCG2 参与尿酸盐的分泌,许多日本人的单核苷酸多态性导致其功能降低,从而引发高尿酸血症。特别是,ABCG2 的严重功能障碍会导致高尿酸血症,同时肾外排泄减少。
{"title":"[Uric Acid Metabolism, Uric Acid Transporters and Dysuricemia].","authors":"Kimiyoshi Ichida","doi":"10.1248/yakushi.23-00217","DOIUrl":"10.1248/yakushi.23-00217","url":null,"abstract":"<p><p>Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.24-00124
Tetsushu Onita
The pharmacokinetic (PK)/pharmacodynamic (PD) approach has been widely used in clinical practice to optimize antimicrobial treatment. To promote the appropriate use of antimicrobial agents, it is important to consider certain factors, such as patient (e.g., age, physique, medical history, comorbidities, and organ dysfunction), site of infection (the target site where many causative bacteria are present), and microorganism (causative bacteria and susceptibility), and the dosing regimen should be selected based on the PK/PD approach. However, for renally excreted antibiotics, dosing regimens based on only renal function, such as creatinine clearance, are mainly used. Therefore, other factors such as patient pathological factors, antibiotic penetration of target sites, susceptibility of the causative bacteria to antibiotic, and clinical evaluation (efficacy and toxicity) should be considered simultaneously. These studies aimed to tailor the dosing of antimicrobial agents to individual patients by considering these factors. Multifaceted PK/PD evaluation may improve antimicrobial efficacy and safety, thereby contributing to the successful treatment of infectious diseases. Furthermore, improved treatment success rates may help manage the prevalence of antimicrobial-resistant bacteria, which is expected to become a significant problem in the future.
{"title":"[Antimicrobial Dosing Individualization Based on Pharmacokinetic/Pharmacodynamic Evaluation, Considering Factors of \"Patient\", \"Site of infection\" and \"Microorganism\"].","authors":"Tetsushu Onita","doi":"10.1248/yakushi.24-00124","DOIUrl":"https://doi.org/10.1248/yakushi.24-00124","url":null,"abstract":"<p><p>The pharmacokinetic (PK)/pharmacodynamic (PD) approach has been widely used in clinical practice to optimize antimicrobial treatment. To promote the appropriate use of antimicrobial agents, it is important to consider certain factors, such as patient (e.g., age, physique, medical history, comorbidities, and organ dysfunction), site of infection (the target site where many causative bacteria are present), and microorganism (causative bacteria and susceptibility), and the dosing regimen should be selected based on the PK/PD approach. However, for renally excreted antibiotics, dosing regimens based on only renal function, such as creatinine clearance, are mainly used. Therefore, other factors such as patient pathological factors, antibiotic penetration of target sites, susceptibility of the causative bacteria to antibiotic, and clinical evaluation (efficacy and toxicity) should be considered simultaneously. These studies aimed to tailor the dosing of antimicrobial agents to individual patients by considering these factors. Multifaceted PK/PD evaluation may improve antimicrobial efficacy and safety, thereby contributing to the successful treatment of infectious diseases. Furthermore, improved treatment success rates may help manage the prevalence of antimicrobial-resistant bacteria, which is expected to become a significant problem in the future.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.23-00154-4
Jun-Ichi Kashiwakura, Tadashi Matsuda
Signal-transducing adaptor protein-2 (STAP-2) is a unique scaffold protein that regulates several immunological signaling pathways, including LIF/LIF receptor and LPS/TLR4 signals. STAP-2 is required for Fas/FasL-dependent T cell apoptosis and SDF-1α-induced T cell migration. Conversely, STAP-2 modulates integrin-mediated T cell adhesion, suggesting that STAP-2 is essential for several negative and positive T cell functions. However, whether STAP-2 is involved in T cell-antigen receptor (TCR)-mediated T cell activation is unknown. STAP-2 deficiency was recently reported to suppress TCR-mediated T cell activation by inhibiting LCK-mediated CD3ζ and ZAP-70 activation. Using STAP-2 deficient mice, it was demonstrated that STAP-2 is required for the pathogenesis of Propionibacterium acnes-induced granuloma formation and experimental autoimmune encephalomyelitis. Here, detailed functions of STAP-2 in TCR-mediated T cell activation, and how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases, are reviewed.
信号转导适配蛋白-2(STAP-2)是一种独特的支架蛋白,可调节多种免疫信号通路,包括 LIF/LIF 受体和 LPS/TLR4 信号。STAP-2 是 Fas/FasL 依赖性 T 细胞凋亡和 SDF-1α 诱导的 T 细胞迁移所必需的。相反,STAP-2 可调节整合素介导的 T 细胞粘附,这表明 STAP-2 对 T 细胞的几种负性和正性功能都至关重要。然而,STAP-2 是否参与了 T 细胞-抗原受体(TCR)介导的 T 细胞活化尚不清楚。最近有报道称,STAP-2 的缺乏会抑制 LCK 介导的 CD3ζ 和 ZAP-70 的活化,从而抑制 TCR 介导的 T 细胞活化。利用 STAP-2 缺陷小鼠证明,STAP-2 在痤疮丙酸杆菌诱导的肉芽肿形成和实验性自身免疫性脑脊髓炎的发病机制中是必需的。在此,我们将详细介绍 STAP-2 在 TCR 介导的 T 细胞活化中的功能,以及 STAP-2 如何影响 T 细胞介导的炎症和免疫疾病的发病机制。
{"title":"[Understanding New Regulatory Mechanism of TCR Signal Transduction].","authors":"Jun-Ichi Kashiwakura, Tadashi Matsuda","doi":"10.1248/yakushi.23-00154-4","DOIUrl":"10.1248/yakushi.23-00154-4","url":null,"abstract":"<p><p>Signal-transducing adaptor protein-2 (STAP-2) is a unique scaffold protein that regulates several immunological signaling pathways, including LIF/LIF receptor and LPS/TLR4 signals. STAP-2 is required for Fas/FasL-dependent T cell apoptosis and SDF-1α-induced T cell migration. Conversely, STAP-2 modulates integrin-mediated T cell adhesion, suggesting that STAP-2 is essential for several negative and positive T cell functions. However, whether STAP-2 is involved in T cell-antigen receptor (TCR)-mediated T cell activation is unknown. STAP-2 deficiency was recently reported to suppress TCR-mediated T cell activation by inhibiting LCK-mediated CD3ζ and ZAP-70 activation. Using STAP-2 deficient mice, it was demonstrated that STAP-2 is required for the pathogenesis of Propionibacterium acnes-induced granuloma formation and experimental autoimmune encephalomyelitis. Here, detailed functions of STAP-2 in TCR-mediated T cell activation, and how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases, are reviewed.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Researchers collect data and use various methods to organize it. Ensuring the reliability and reproducibility of data is crucial, and collaboration across different research fields is on the rise. However, when there is geographical distance, sharing data becomes a challenging task. Therefore, there is a need for the development of a mechanism for sharing data on the web. We have developed an integrated database to facilitate the sharing and management of research data, particularly focusing on small molecules. The integrated database serves as a platform for centralizing data related to small molecules, including their chemical structures, wet lab experimental data, simulation data, and more. It has been constructed as a web application, offering features such as library management for small molecules, registration and viewing of wet lab experiment results, generation of initial conformations for simulations, and data visualization. This enables researchers to efficiently share their research data and collaborate seamlessly, whether within their research group or via cloud-based access that allows project and team members to connect from anywhere. This integrated database plays a critical role in connecting wet lab experiments and simulations, enabling researchers to cross-reference and analyze experimental data comprehensively. It serves as an essential tool to advance research and foster idea generation.
{"title":"[Development of Integrated Database for Experiments and Simulations].","authors":"Issaku Yamada, Naoki Kimura, Takao Nomura, Satoko Otsuguro, Hiroyuki Miyachi, Yasuteru Shigeta, Katsumi Maenaka","doi":"10.1248/yakushi.23-00191-2","DOIUrl":"10.1248/yakushi.23-00191-2","url":null,"abstract":"<p><p>Researchers collect data and use various methods to organize it. Ensuring the reliability and reproducibility of data is crucial, and collaboration across different research fields is on the rise. However, when there is geographical distance, sharing data becomes a challenging task. Therefore, there is a need for the development of a mechanism for sharing data on the web. We have developed an integrated database to facilitate the sharing and management of research data, particularly focusing on small molecules. The integrated database serves as a platform for centralizing data related to small molecules, including their chemical structures, wet lab experimental data, simulation data, and more. It has been constructed as a web application, offering features such as library management for small molecules, registration and viewing of wet lab experiment results, generation of initial conformations for simulations, and data visualization. This enables researchers to efficiently share their research data and collaborate seamlessly, whether within their research group or via cloud-based access that allows project and team members to connect from anywhere. This integrated database plays a critical role in connecting wet lab experiments and simulations, enabling researchers to cross-reference and analyze experimental data comprehensively. It serves as an essential tool to advance research and foster idea generation.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140867959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1248/yakushi.23-00154-1
Keigo Nishida, Naoya Nakagawa
Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.
锌是人体必需的微量元素之一,参与人体的各种功能。众所周知,缺锌会导致免疫异常,但其机制尚不完全清楚。因此,我们将研究重点放在肿瘤免疫上,以阐明锌对结直肠癌的影响及其机制。用偶氮甲烷(AOM)和右旋糖酐硫酸钠(DSS)处理小鼠,使其罹患结直肠癌,然后观察饮食中锌含量与结肠肿瘤数量和面积之间的关系。与正常锌摄入量组相比,无锌添加饮食组的结肠肿瘤数量明显较高,而高锌摄入量组的肿瘤数量约为正常锌摄入量组的一半。在 T 细胞缺乏的小鼠中,高锌摄入组的肿瘤数量与正常锌摄入组相似,这表明锌的抑制作用依赖于 T 细胞。此外,我们还发现,细胞毒性 T 细胞在抗原刺激下释放的颗粒酶 B 转录本的量在添加锌后显著增加。我们还发现,锌的添加对颗粒酶 B 转录的激活依赖于钙神经蛋白的活性。总之,我们已经证明,锌是通过作用于细胞免疫的中心--细胞毒性 T 细胞来发挥其抑制肿瘤的作用的,而且锌能增加颗粒酶 B 的转录,而颗粒酶 B 是参与肿瘤免疫的关键分子之一。在本次研讨会上,我们将介绍锌与肿瘤免疫之间关系的最新数据。
{"title":"[Zinc Suppresses Colorectal Cancer Development through Cell-mediated Immunity].","authors":"Keigo Nishida, Naoya Nakagawa","doi":"10.1248/yakushi.23-00154-1","DOIUrl":"10.1248/yakushi.23-00154-1","url":null,"abstract":"<p><p>Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A closed system drug transfer device (CSTD) helps to minimize unnecessary exposure of healthcare workers such as pharmacists to hazardous drugs. One of the concerns in using CSTDs to prepare anticancer drugs is their influence on preparation time. Therefore, we compared the time needed to prepare anticancer drugs with the CSTDs NEOSHIELD® and BD PhaSeal® system and with an injection needle. In the comparison of NEOSHIELD® and an injection needle, the preparation time of the liquid formulations of the cytotoxic drugs irinotecan, eribulin, cisplatin, docetaxel, and paclitaxel was significantly shorter with the injection needle and that of gemcitabine was significantly shorter with NEOSHIELD®, but that of oxaliplatin, carboplatin, and doxorubicin was not significantly different between the two methods; the preparation time of the liquid formulations of the molecular-targeted drugs atezolizumab, obinutuzumab, cetuximab, daratumumab and vorhyaluronidase alfa, nivolumab, ramucirumab, and rituximab was significantly shorter with NEOSHIELD® and that of bevacizumab and pembrolizumab was significantly shorter with the injection needle; and the preparation time of the lyophilized formulation of cytotoxic and molecular-targeted drugs was not significantly different between the two methods. In the comparison of NEOSHIELD® and BD PhaSeal® system, the preparation time of cyclophosphamide and ifosfamide was significantly shorter with NEOSHIELD®, but that of bendamustine was not significantly different between the two CSTDs. In conclusion, these results suggest that the preparation time with CSTDs may be similar to or shorter than that with an injection needle, depending on the type of CSTD and the drug formulation and type.
{"title":"[Influence of the Use of a Closed System Drug Transfer Device on the Preparation Time of Anticancer Drugs].","authors":"Toshihisa Nakashima, Kana Tsukiji, Akiko Kubo, Rena Nishigaki, Daisuke Watabe, Yoshimasa Saito, Toru Akagi, Hironobu Hashimoto","doi":"10.1248/yakushi.24-00077","DOIUrl":"https://doi.org/10.1248/yakushi.24-00077","url":null,"abstract":"<p><p>A closed system drug transfer device (CSTD) helps to minimize unnecessary exposure of healthcare workers such as pharmacists to hazardous drugs. One of the concerns in using CSTDs to prepare anticancer drugs is their influence on preparation time. Therefore, we compared the time needed to prepare anticancer drugs with the CSTDs NEOSHIELD<sup>®</sup> and BD PhaSeal<sup>®</sup> system and with an injection needle. In the comparison of NEOSHIELD<sup>®</sup> and an injection needle, the preparation time of the liquid formulations of the cytotoxic drugs irinotecan, eribulin, cisplatin, docetaxel, and paclitaxel was significantly shorter with the injection needle and that of gemcitabine was significantly shorter with NEOSHIELD<sup>®</sup>, but that of oxaliplatin, carboplatin, and doxorubicin was not significantly different between the two methods; the preparation time of the liquid formulations of the molecular-targeted drugs atezolizumab, obinutuzumab, cetuximab, daratumumab and vorhyaluronidase alfa, nivolumab, ramucirumab, and rituximab was significantly shorter with NEOSHIELD<sup>®</sup> and that of bevacizumab and pembrolizumab was significantly shorter with the injection needle; and the preparation time of the lyophilized formulation of cytotoxic and molecular-targeted drugs was not significantly different between the two methods. In the comparison of NEOSHIELD<sup>®</sup> and BD PhaSeal<sup>®</sup> system, the preparation time of cyclophosphamide and ifosfamide was significantly shorter with NEOSHIELD<sup>®</sup>, but that of bendamustine was not significantly different between the two CSTDs. In conclusion, these results suggest that the preparation time with CSTDs may be similar to or shorter than that with an injection needle, depending on the type of CSTD and the drug formulation and type.</p>","PeriodicalId":23810,"journal":{"name":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}