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Therapeutic drug monitoring, population pharmacokinetics models and external validation of high-dose methotrexate in pediatric acute lymphoblastic leukemia.
IF 2 4区 医学
Chemotherapy Pub Date : 2024-12-18 DOI: 10.1159/000543181
Natalia Maximova, Pasquale Fabio Calabrò, Alice Cangialosi, Antonello Di Paolo
{"title":"Therapeutic drug monitoring, population pharmacokinetics models and external validation of high-dose methotrexate in pediatric acute lymphoblastic leukemia.","authors":"Natalia Maximova, Pasquale Fabio Calabrò, Alice Cangialosi, Antonello Di Paolo","doi":"10.1159/000543181","DOIUrl":"https://doi.org/10.1159/000543181","url":null,"abstract":"<p><strong>Introduction: </strong>High-dose MTX is used to treat pediatric acute lymphoblastic leukemia (ALL). The drug has a low therapeutic index and a highly interindividual variability in systemic exposure. These characteristics necessitate dose adjustments and therapeutic drug monitoring protocols, while population pharmacokinetic (POP/PK) models may enable more precise drug dosing. Therefore, we assessed the performance of external POP/PK models in ALL children receiving high-dose MTX.</p><p><strong>Methods: </strong>We retrospectively harvested clinical and laboratory data from ALL children during their first two cycles of chemotherapy. A POP/PK model was elaborated using the Monolix suite 2024.R1. External models were selected from PUBMED based on strict inclusion/exclusion criteria, and their fit to the actual data was assessed by calculating bias (PE%) and precision (RMSE%).</p><p><strong>Results: </strong>Thirty-seven ALL children participated in the study (18 males, median age 5.1 years, range 1.7-15.2 years), and six external POP/PK models were chosen. Except for one model (median PE% value, -97.45%), all models exhibited acceptable bias (median PE% values, -4.17% to 2.67%), despite none of them demonstrating good precision (median RMSE% values, 89.19% to 120.40%).</p><p><strong>Conclusion: </strong>External models should be accurately evaluated before they are implemented in clinical practice, even when patients share very similar characteristics.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-24"},"PeriodicalIF":2.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852944","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}
引用次数: 0
Time-kill curve analysis of fucoidan combination with conventional antibiotics against biofilms formation of methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii clinical isolates.
IF 2 4区 医学
Chemotherapy Pub Date : 2024-12-04 DOI: 10.1159/000542826
Mohsen Nazari, Mohammad Taheri, Fatemeh Nouri, Maryam Bahmanzadeh, Mohammad Yousef Alikhani
{"title":"Time-kill curve analysis of fucoidan combination with conventional antibiotics against biofilms formation of methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii clinical isolates.","authors":"Mohsen Nazari, Mohammad Taheri, Fatemeh Nouri, Maryam Bahmanzadeh, Mohammad Yousef Alikhani","doi":"10.1159/000542826","DOIUrl":"https://doi.org/10.1159/000542826","url":null,"abstract":"<p><p>Introduction This study investigates the efficacy of fucoidan, both alone and in combination with antibiotics, against single-species biofilms and mixed-species, individual planktonic, and co-culture planktonic conditions of Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. Materials and Methods Fucoidan, a sulfated polysaccharide, was purchased from Sigma-Aldrich, USA. Clinical isolates of MRSA and A. baumannii were obtained from diabetic foot ulcers (DFUs), and single-species biofilms and mixed-species biofilms were developed to assess susceptibility to the treatments using MIC, MBC, MBIC, MBEC, and time-kill kinetics assays. Cytotoxicity was assessed using MTT assays on human skin fibroblast cells (HSF-PI 16). Results The study determined the geometric mean MIC and MBC values for gentamicin, imipenem, and fucoidan in MRSA and A. baumannii cultures, both individually and in co-culture. The MIC and MBC values were significantly lower under co-culture conditions, indicating enhanced antimicrobial efficacy. Synergy between fucoidan, gentamicin, and imipenem was confirmed through time-kill assays, which showed complete inhibition of bacterial growth and effective biofilm eradication, particularly in mixed-species biofilms. Fucoidan demonstrated low cytotoxicity at optimal concentrations, highlighting their potential as a therapeutic strategy against biofilm-associated infections in diabetic foot ulcers. Conclusion The study concludes that fucoidan, in combination with gentamicin and imipenem, effectively disrupts mixed-species biofilms of MRSA and A. baumannii, suggesting fucoidan-based therapies could improve outcomes for DFU patients, warranting further clinical investigation.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-18"},"PeriodicalIF":2.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779260","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}
引用次数: 0
Phase I Clinical Study of a Multi-Kinase Inhibitor TG02 Capsule for the Treatment of Recurrent High-Grade Gliomas with Failed Temozolomide Treatment in Chinese Patients. 多激酶抑制剂 TG02 胶囊治疗替莫唑胺治疗失败的中国复发性高级别胶质瘤的 I 期临床研究。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-11-18 DOI: 10.1159/000542365
Cheng-Cheng Guo, Qun-Ying Yang, Shao-Yan Xi, Jian Zhou, Zhi-Huan Zhou, Xi Cao, Yi-Xiang Liao, Benjamin Xiao-Yi Li, Xiang-Rong Dai, Michael Wong, Yu-Jie Li, Xiao-Hui Yu, Zhong-Ping Chen
{"title":"Phase I Clinical Study of a Multi-Kinase Inhibitor TG02 Capsule for the Treatment of Recurrent High-Grade Gliomas with Failed Temozolomide Treatment in Chinese Patients.","authors":"Cheng-Cheng Guo, Qun-Ying Yang, Shao-Yan Xi, Jian Zhou, Zhi-Huan Zhou, Xi Cao, Yi-Xiang Liao, Benjamin Xiao-Yi Li, Xiang-Rong Dai, Michael Wong, Yu-Jie Li, Xiao-Hui Yu, Zhong-Ping Chen","doi":"10.1159/000542365","DOIUrl":"10.1159/000542365","url":null,"abstract":"<p><strong>Introduction: </strong>We report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China.</p><p><strong>Methods: </strong>This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD).</p><p><strong>Results: </strong>Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95% CI: 2.66-not estimated) months, respectively.</p><p><strong>Conclusions: </strong>TG02 capsule 150 mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy of recurrent gliomas warrants further investigation.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-11"},"PeriodicalIF":2.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667286","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}
引用次数: 0
Primary Squamous Cell Carcinoma of the Duodenum: A Case Report and Literature Review. 十二指肠原发性鳞状细胞癌:病例报告和文献综述。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-11-11 DOI: 10.1159/000542485
Yifan Hui, Fei Ke, Wei Lu, Wenli Qiu, Xia Zheng, Haibo Cheng
{"title":"Primary Squamous Cell Carcinoma of the Duodenum: A Case Report and Literature Review.","authors":"Yifan Hui, Fei Ke, Wei Lu, Wenli Qiu, Xia Zheng, Haibo Cheng","doi":"10.1159/000542485","DOIUrl":"10.1159/000542485","url":null,"abstract":"<p><strong>Introduction: </strong>Duodenal squamous cell carcinoma is an exceedingly rare occurrence among gastrointestinal malignancies, and its diagnosis and treatment are not well understood.</p><p><strong>Case presentation: </strong>In this report, we present a case of duodenal squamous cell carcinoma with liver and adrenal metastasis. The patient was treated with gemcitabine and S-1, achieving a progression-free survival of 7 months and an overall survival of 9 months. Additionally, we review the features and treatment approaches reported in previous cases of primary duodenal carcinoma.</p><p><strong>Conclusion: </strong>Clearly, further case reports, such as ours, can contribute to a deeper understanding that is essential for characterizing this entity and establishing management guidelines.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-7"},"PeriodicalIF":2.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616061","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}
引用次数: 0
Predicting Reprisal of Solid Cancer Treatment and 60-Month Survival after Medical Intensive Care: A Single-Centre Cohort Study. 预测对实体癌治疗的报复和医疗重症监护后 60 个月的生存率。单中心队列研究。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-11-09 DOI: 10.1159/000542101
Victoria Ferrari, Lucas Morand, Hervé Hyvernat, Renaud Schiappa, Jean Dellamonica, Nihal Martis
{"title":"Predicting Reprisal of Solid Cancer Treatment and 60-Month Survival after Medical Intensive Care: A Single-Centre Cohort Study.","authors":"Victoria Ferrari, Lucas Morand, Hervé Hyvernat, Renaud Schiappa, Jean Dellamonica, Nihal Martis","doi":"10.1159/000542101","DOIUrl":"10.1159/000542101","url":null,"abstract":"<p><strong>Introduction: </strong>Our study aimed to identify relevant features associated with the reprisal of antineoplastic treatment in patients with solid cancers after unplanned admittance to the intensive care unit (ICU) and to assess 60th-month survival in patients with solid neoplasms admitted to the ICU.</p><p><strong>Methods: </strong>This single-centre retrospective study of critically ill patients with active cancers was performed over a 13-year period (2005-2018). Patients' characteristics, overall survival, and antineoplastic treatment reprisal were extracted from digital medical files and compared.</p><p><strong>Results: </strong>134 patients were included in the study. Solid neoplasms were mostly localised to the head and neck (n = 53) followed by lung cancers (n = 29). Sepsis was the leading cause of ICU admission (62.1%) with 41/82 patients presenting with septic shock. Antineoplastic treatments were resumed in 40 patients. An age ≤60 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 were found to be predictors for treatment reprisal, with odd ratios of, respectively, 2.83 (95% CI, 1.15-6.99) and 5.45 (95% CI, 2.01-14.82); area under the ROC curve of 72% (95% CI, 63-81%). Survival after the immediate discharge from the ICU was 101/134 (75%) and the 60-month survival rate was 29% and significantly higher in the treatment-reprisal group.</p><p><strong>Conclusions: </strong>Age and ECOG PS were found to be predictors for treatment reprisal in patients with solid neoplasms admitted to the ICU. The latter benefits from better long-term survival.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-9"},"PeriodicalIF":2.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616059","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}
引用次数: 0
Importance of Sex-Dependent Differences for Dosing Selection and Optimization of Chemotherapeutic Drugs. 性别差异对化疗药物剂量选择和优化的重要性。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-11-07 DOI: 10.1159/000542461
Claire Seydoux, Myriam Briki, Anna D Wagner, Eva Choong, Monia Guidi, Sandro Carrara, Yann Thoma, Françoise Livio, François R Girardin, Catia Marzolini, Thierry Buclin, Laurent A Decosterd
{"title":"Importance of Sex-Dependent Differences for Dosing Selection and Optimization of Chemotherapeutic Drugs.","authors":"Claire Seydoux, Myriam Briki, Anna D Wagner, Eva Choong, Monia Guidi, Sandro Carrara, Yann Thoma, Françoise Livio, François R Girardin, Catia Marzolini, Thierry Buclin, Laurent A Decosterd","doi":"10.1159/000542461","DOIUrl":"10.1159/000542461","url":null,"abstract":"<p><strong>Background: </strong>Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drug dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs' disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics; we suggest a novel approach that integrates sex into the traditional a priori body surface area (BSA) dosing selection model, and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology.</p><p><strong>Summary: </strong>To date, anticancer chemotherapeutic drug dosing is most often determined by BSA, a method widely used for its ease of practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the sex-adjusted BSA (SABSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of TDM, for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate, or thiopurines.</p><p><strong>Key messages: </strong>The inclusion of sex besides BSA in an easy-to-implement formula such as SABSA could improve a priori chemotherapy dosing selection, even though it still requires clinical validation. The a posteriori use of TDM could further enhance treatment efficacy and safety in oncology.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-10"},"PeriodicalIF":2.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603190","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}
引用次数: 0
Gaza's First Polio Case in 25 Years: Is Health Infrastructure Collapse Threatening Resilience? 加沙 25 年来首次出现脊髓灰质炎病例:卫生基础设施的崩溃是否威胁到复原力?
IF 2 4区 医学
Chemotherapy Pub Date : 2024-10-14 DOI: 10.1159/000541933
Francesco Branda, Giancarlo Ceccarelli, Marta Giovanetti, Massimo Ciccozzi, Fabio Scarpa
{"title":"Gaza's First Polio Case in 25 Years: Is Health Infrastructure Collapse Threatening Resilience?","authors":"Francesco Branda, Giancarlo Ceccarelli, Marta Giovanetti, Massimo Ciccozzi, Fabio Scarpa","doi":"10.1159/000541933","DOIUrl":"10.1159/000541933","url":null,"abstract":"","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1"},"PeriodicalIF":2.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459339","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}
引用次数: 0
Therapeutic Drug Monitoring of Imatinib: Is There a Rationale for Also Quantifying Its Active Metabolite? 伊马替尼的治疗药物监测:同时量化其活性代谢物是否合理?
IF 2 4区 医学
Chemotherapy Pub Date : 2024-10-11 DOI: 10.1159/000541936
Clara Eschalier, Thierry Lafont, Sabrina Marsili, Malika Yakoubi, Aurélie Brice, Fabienne Thomas, Mélanie White-Koning, Ben Allal, Etienne Chatelut
{"title":"Therapeutic Drug Monitoring of Imatinib: Is There a Rationale for Also Quantifying Its Active Metabolite?","authors":"Clara Eschalier, Thierry Lafont, Sabrina Marsili, Malika Yakoubi, Aurélie Brice, Fabienne Thomas, Mélanie White-Koning, Ben Allal, Etienne Chatelut","doi":"10.1159/000541936","DOIUrl":"10.1159/000541936","url":null,"abstract":"<p><strong>Introduction: </strong>Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined.</p><p><strong>Methods: </strong>Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated.</p><p><strong>Results: </strong>The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23 and 0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area under the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, was similar.</p><p><strong>Conclusion: </strong>These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-11"},"PeriodicalIF":2.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459340","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}
引用次数: 0
Downregulation of Rad51 Expression and Activity Potentiates the Cytotoxic Effect of Osimertinib in Human Non-Small Cell Lung Cancer Cells. 下调 Rad51 的表达和活性可增强奥希替尼对人类非小细胞肺癌细胞的细胞毒性作用。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-08-10 DOI: 10.1159/000540867
Jen-Chung Ko, Jyh-Cheng Chen, Ching-Hsiu Huang, Pei-Jung Chen, Qiao-Zhen Chang, Bo-Cheng Mu, Jun-Jie Chen, Tzu-Yuan Tai, Kasumi Suzuki, Yi-Xuan Wang, Yun-Wei Lin
{"title":"Downregulation of Rad51 Expression and Activity Potentiates the Cytotoxic Effect of Osimertinib in Human Non-Small Cell Lung Cancer Cells.","authors":"Jen-Chung Ko, Jyh-Cheng Chen, Ching-Hsiu Huang, Pei-Jung Chen, Qiao-Zhen Chang, Bo-Cheng Mu, Jun-Jie Chen, Tzu-Yuan Tai, Kasumi Suzuki, Yi-Xuan Wang, Yun-Wei Lin","doi":"10.1159/000540867","DOIUrl":"10.1159/000540867","url":null,"abstract":"<p><strong>Introduction: </strong>Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown significant clinical benefits in patients with EGFR-sensitizing mutations or the EGFR T790M mutation. The homologous recombination (HR) pathway is crucial for repairing DNA double-strand breaks (DSBs). Rad51 plays a central role in HR, facilitating the search for homology and promoting DNA strand exchange between homologous DNA molecules. Rad51 is overexpressed in numerous types of cancer cells. B02, a specific small molecule inhibitor of Rad51, inhibits the DNA strand exchange activity of Rad51. Previous studies have indicated that B02 disrupted Rad51 foci formation in response to DNA damage and inhibited DSBs repair in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. However, the potential therapeutic effects of combining osimertinib with a Rad51 inhibitor are not well understood. The aim of this study was to elucidate whether the downregulation of Rad51 expression and activity can enhance the osimertinib-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells.</p><p><strong>Methods: </strong>We used the MTS, trypan blue dye exclusion and colony-formation ability assay to determine whether osimertinib alone or in combination with B02 had cytotoxic effects on NSCLC cell lines. Real-time polymerase chain reaction was conducted to measure the amounts of Rad51 mRNA. The protein levels of phosphorylated AKT and Rad51 were determined by Western blot analysis.</p><p><strong>Results: </strong>We found that osimertinib reduced Rad51 expression by inactivating AKT activity. Rad51 knockdown using small interfering RNA or AKT inactivation through the phosphatidylinositol 3-kinase inhibitor LY294002 or si-AKT RNA transfection enhanced the cytotoxic and growth inhibitory effects of osimertinib. In contrast, AKT-CA (a constitutively active form of AKT) vector-enforced expression could mitigate the cytotoxic and cell growth inhibitory effects of osimertinib. Furthermore, B02 significantly enhanced the cytotoxic and cell growth inhibitory effects of osimertinib in NSCLC cells. Compared to parental cells, the activation of AKT and Rad51 expression in osimertinib-resistant cells could not be significantly inhibited by osimertinib treatment. Moreover, the increased expression of Rad51 is associated with the resistance mechanism in osimertinib-resistant H1975 and A549 cells.</p><p><strong>Conclusion: </strong>Collectively, the downregulation of Rad51 expression and activity enhances the cytotoxic effect of osimertinib in human NSCLC cells.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-14"},"PeriodicalIF":2.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916212","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}
引用次数: 0
Disseminated Infection Caused by Nocardia cyriacigeorgica in Immunocompromised Patient Confirmed by Whole Genome Sequencing. 通过全基因组测序证实免疫力低下的患者感染了由Nocardia cyriacigeorgica引起的播散性感染。
IF 2 4区 医学
Chemotherapy Pub Date : 2024-08-10 DOI: 10.1159/000539977
Dijana Varda Brkić, Jakša Babel, Ana Budimir, Iva Butić, Marija Gužvinec, Dragan Jurić, Ivana Ferenčak, Selma Bošnjak, Ivana Mareković
{"title":"Disseminated Infection Caused by Nocardia cyriacigeorgica in Immunocompromised Patient Confirmed by Whole Genome Sequencing.","authors":"Dijana Varda Brkić, Jakša Babel, Ana Budimir, Iva Butić, Marija Gužvinec, Dragan Jurić, Ivana Ferenčak, Selma Bošnjak, Ivana Mareković","doi":"10.1159/000539977","DOIUrl":"10.1159/000539977","url":null,"abstract":"<p><strong>Introduction: </strong>Nocardia spp. is an opportunistic pathogen capable of causing localized and disseminated infections in immunocompromised hosts. It is critical for serious infections to have an early and accurate identification of this pathogen in order to enable timely and focused combination antimicrobial treatment.</p><p><strong>Case presentation: </strong>We describe the case of an 87-year-old patient previously treated for myasthenia gravis with corticosteroids and azathioprine. Patient was admitted at the emergency department with clinical signs of sepsis with cellulitis of right hand associated with injury acquired after gardening and trimming roses and did not respond to empirical antimicrobial treatment. Computerized tomography revealed pulmonary infiltrates with inflammatory etiology. Nocardia cyriacigeorgica was cultivated from blood culture, skin swab, abscess aspirate, and endotracheal aspirate and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), 16S rRNA sequencing, and whole genome sequencing (WGS). Susceptibility testing was performed with E-test (bioMerieux, Marcy-l'Étoile, France), and corresponding resistance genes were detected by WGS. Resistance to amoxicillin-clavulanate, azithromycin, ciprofloxacin, and vancomycin was detected by both methods. Despite all interventions and the patient receiving antimicrobial treatment including imipenem-cilastatin, amikacin, and trimethoprim-sulfamethoxazole, the course and outcome of infection were unfavorable.</p><p><strong>Conclusion: </strong>We would like to emphasize the need to consider the possibility of disseminated Nocardia infection in immunocompromised patients, especially in patients receiving long-term corticosteroid treatment with skin infections and/or cavitary lung lesions, especially if these do not improve with standard antimicrobial treatment. Precise species identity provides a critical guide for physicians in the choice of targeted treatment. Thanks to MALDI-TOF MS, Nocardia spp. identification is now available in routine lab work. WGS is still inevitable for the identification of uncommon and novel species due to the high sequence similarities between closely related species and the genetic diversity of that genus.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"1-8"},"PeriodicalIF":2.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916140","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}
引用次数: 0
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