Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients’ outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs−) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.
{"title":"The expression level of Neuronal Calcium Sensor 1 can predict the prognosis of cytogenetically normal AML","authors":"Weilong Zhang, Jing Wang, Wei Li, Xiaoni Liu, Yali Zhao, Ping Yang, Mingxia Zhu, Kai Hu, Shaoxiang Li, Gehong Dong, Changjian Yan, Xue He, Xiuru Zhang, Hongmei Jing","doi":"10.1038/s41397-023-00301-2","DOIUrl":"10.1038/s41397-023-00301-2","url":null,"abstract":"Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients’ outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs−) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9900350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-04DOI: 10.1038/s41397-023-00300-3
Maha Al Ammari, Bader Almuzzaini, Khalid Al Sulaiman, Mohammed AlBalwi, Khizra Sultana, Ibrahim B. Alabdulkareem, Nada S. Almakhlafi, Anoud Al Humoud, Mohammed Waheeby, Munee Balla, Asma Al Shehri, Adel Alharf, Jahad Alghamdi
Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins’s narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients’ therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.
{"title":"Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP)","authors":"Maha Al Ammari, Bader Almuzzaini, Khalid Al Sulaiman, Mohammed AlBalwi, Khizra Sultana, Ibrahim B. Alabdulkareem, Nada S. Almakhlafi, Anoud Al Humoud, Mohammed Waheeby, Munee Balla, Asma Al Shehri, Adel Alharf, Jahad Alghamdi","doi":"10.1038/s41397-023-00300-3","DOIUrl":"10.1038/s41397-023-00300-3","url":null,"abstract":"Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins’s narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients’ therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9897148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-28DOI: 10.1038/s41397-023-00299-7
Nancy Gillis, Amy S. Etheridge, Sushant A. Patil, D. Neil Hayes, Michele C. Hayward, J. Todd Auman, Joel S. Parker, Federico Innocenti
Tumor DNA sequencing is becoming standard-of-care for patient treatment decisions. We evaluated genotype concordance between tumor DNA and genomic DNA from blood and catalogued functional effects of somatic mutations in 21 drug response genes in 752 solid tumor patients. Using a threshold of 10% difference between tumor and blood DNA variant allele fraction (VAF), concordance for heterogenous genotype calls was 78% and increased to 97.5% using a 30% VAF threshold. Somatic mutations were observed in all 21 drug response genes, and 44% of patients had at least one somatic mutation in these genes. In tumor DNA, eight patients had a frameshift mutation in CYP2C8, which metabolizes taxanes. Overall, somatic copy number losses were more frequent than gains, including for CYP2C19 and CYP2D6 which had the most frequent copy number losses. However, copy number gains in TPMT were more than four times as common as losses. Seven % of patients had copy number gains in ABCB1, a multidrug resistance transporter of anti-cancer agents. These results demonstrate tumor-only DNA sequencing might not be reliable to call germline genotypes of drug response variants.
肿瘤 DNA 测序正成为患者治疗决策的标准。我们评估了肿瘤DNA和血液基因组DNA之间的基因型一致性，并对752名实体瘤患者中21个药物反应基因的体细胞突变的功能影响进行了编目。以肿瘤和血液DNA变异等位基因比例（VAF）相差10%为阈值，异源基因型调用的一致性为78% ，以30% VAF 为阈值，一致性提高到97.5%。在所有 21 个药物反应基因中都观察到了体细胞突变，44% 的患者在这些基因中至少有一个体细胞突变。在肿瘤DNA中，有8名患者的CYP2C8发生了框架移位突变，而CYP2C8可代谢紫杉类药物。总体而言，体细胞拷贝数丢失比拷贝数增加更频繁，其中CYP2C19和CYP2D6的拷贝数丢失最为频繁。然而，TPMT的拷贝数增益是拷贝数丢失的四倍多。7%的患者存在抗癌药多药耐药性转运体ABCB1的拷贝数增加。这些结果表明，仅通过肿瘤DNA测序来确定药物反应变异的种系基因型可能并不可靠。
{"title":"Sequencing of genes of drug response in tumor DNA and implications for precision medicine in cancer patients","authors":"Nancy Gillis, Amy S. Etheridge, Sushant A. Patil, D. Neil Hayes, Michele C. Hayward, J. Todd Auman, Joel S. Parker, Federico Innocenti","doi":"10.1038/s41397-023-00299-7","DOIUrl":"10.1038/s41397-023-00299-7","url":null,"abstract":"Tumor DNA sequencing is becoming standard-of-care for patient treatment decisions. We evaluated genotype concordance between tumor DNA and genomic DNA from blood and catalogued functional effects of somatic mutations in 21 drug response genes in 752 solid tumor patients. Using a threshold of 10% difference between tumor and blood DNA variant allele fraction (VAF), concordance for heterogenous genotype calls was 78% and increased to 97.5% using a 30% VAF threshold. Somatic mutations were observed in all 21 drug response genes, and 44% of patients had at least one somatic mutation in these genes. In tumor DNA, eight patients had a frameshift mutation in CYP2C8, which metabolizes taxanes. Overall, somatic copy number losses were more frequent than gains, including for CYP2C19 and CYP2D6 which had the most frequent copy number losses. However, copy number gains in TPMT were more than four times as common as losses. Seven % of patients had copy number gains in ABCB1, a multidrug resistance transporter of anti-cancer agents. These results demonstrate tumor-only DNA sequencing might not be reliable to call germline genotypes of drug response variants.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9897138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-19DOI: 10.1038/s41397-023-00298-8
Shiau-Shian Huang, Yi-Ting Chen, Mei-Hsin Su, Shih-Jen Tsai, Hsi-Han Chen, Albert C. Yang, Yu-Li Liu, Po-Hsiu Kuo
Major depressive disorder (MDD) is associated with high heterogeneity in clinical presentation. In addition, response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably among patients. Therefore, identifying genetic variants that may contribute to SSRI treatment responses in MDD is essential. In this study, we analyzed the syndromal factor structures of the Hamilton Depression Rating Scale in 479 patients with MDD by using exploratory factor analysis. All patients were followed up biweekly for 8 weeks. Treatment response was defined for all syndromal factors and total scores. In addition, a genome-wide association study was performed to investigate the treatment outcomes at week 4 and repeatedly assess all visits during follow-up by using mixed models adjusted for age, gender, and population substructure. Moreover, the role of genetic variants in suicidal and sexual side effects was explored, and five syndromal factors for depression were derived: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. Subsequently, several known genes were mapped to suggestive signals for treatment outcomes, including single-nucleotide polymorphisms (SNPs) in PRF1, UTP20, MGAM, and ENSG00000286536 for psychomotor-insight and in C4orf51 for anorexia. In total, 33 independent SNPs for treatment responses were tested in a mixed model, 12 of which demonstrated a p value <0.05. The most significant SNP was rs2182717 in the ENSR00000803469 gene located on chromosome 6 for the core syndromal factor (β = −0.638, p = 1.8 × 10−4) in terms of symptom improvement over time. Patients with a GG or GA genotype with the rs2182717 SNP also exhibited a treatment response (β = 0.089, p = 2.0 × 10−6) at week 4. Moreover, rs1836075352 was associated with sexual side effects (p = 3.2 × 10−8). Pathway and network analyses using the identified SNPs revealed potential biological functions involved in treatment response, such as neurodevelopment-related functions and immune processes. In conclusion, we identified loci that may affect the clinical response to treatment with antidepressants in the context of empirically defined depressive syndromal factors and side effects among the Taiwanese Han population, thus providing novel biological targets for further investigation.
重度抑郁障碍（MDD）的临床表现具有高度异质性。此外，不同患者对选择性血清素再摄取抑制剂（SSRIs）治疗的反应也有很大差异。因此，确定可能会影响 MDD 患者对 SSRI 治疗反应的遗传变异至关重要。在这项研究中，我们采用探索性因子分析方法分析了 479 名 MDD 患者的汉密尔顿抑郁量表（Hamilton Depression Rating Scale）的综合因子结构。所有患者均接受了为期 8 周的双周随访。所有综合因子和总分均定义为治疗反应。此外，还进行了一项全基因组关联研究，通过年龄、性别和人群亚结构调整后的混合模型，调查第 4 周的治疗结果，并在随访期间反复评估所有就诊情况。此外，还探讨了基因变异在自杀和性副作用中的作用，并得出了五个抑郁症综合因素：核心、失眠、躯体焦虑、精神运动-视力和厌食。随后，几个已知基因被映射到治疗结果的提示性信号上，包括PRF1、UTP20、MGAM和ENSG00000286536中的单核苷酸多态性（SNPs）（针对精神运动视力）和C4orf51中的单核苷酸多态性（SNPs）（针对厌食症）。在混合模型中，共有 33 个独立的 SNP 与治疗反应相关，其中 12 个 SNP 的 p 值为 0.05。最显著的 SNP 是位于 6 号染色体上的 ENSR00000803469 基因中的 rs2182717，该 SNP 与核心综合征因子有关（β = -0.638，p = 1.8 × 10-4）。在第 4 周时，rs2182717 SNP 基因型为 GG 或 GA 的患者也表现出治疗反应（β = 0.089，p = 2.0 × 10-6）。此外，rs1836075352 与性副作用相关（p = 3.2 × 10-8）。利用所鉴定的 SNPs 进行的通路和网络分析揭示了参与治疗反应的潜在生物功能，如神经发育相关功能和免疫过程。总之，我们在台湾汉族人群中根据经验定义的抑郁综合征因素和副作用发现了可能影响抗抑郁药物治疗临床反应的位点，从而为进一步研究提供了新的生物学靶点。
{"title":"Investigating genetic variants for treatment response to selective serotonin reuptake inhibitors in syndromal factors and side effects among patients with depression in Taiwanese Han population","authors":"Shiau-Shian Huang, Yi-Ting Chen, Mei-Hsin Su, Shih-Jen Tsai, Hsi-Han Chen, Albert C. Yang, Yu-Li Liu, Po-Hsiu Kuo","doi":"10.1038/s41397-023-00298-8","DOIUrl":"10.1038/s41397-023-00298-8","url":null,"abstract":"Major depressive disorder (MDD) is associated with high heterogeneity in clinical presentation. In addition, response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably among patients. Therefore, identifying genetic variants that may contribute to SSRI treatment responses in MDD is essential. In this study, we analyzed the syndromal factor structures of the Hamilton Depression Rating Scale in 479 patients with MDD by using exploratory factor analysis. All patients were followed up biweekly for 8 weeks. Treatment response was defined for all syndromal factors and total scores. In addition, a genome-wide association study was performed to investigate the treatment outcomes at week 4 and repeatedly assess all visits during follow-up by using mixed models adjusted for age, gender, and population substructure. Moreover, the role of genetic variants in suicidal and sexual side effects was explored, and five syndromal factors for depression were derived: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. Subsequently, several known genes were mapped to suggestive signals for treatment outcomes, including single-nucleotide polymorphisms (SNPs) in PRF1, UTP20, MGAM, and ENSG00000286536 for psychomotor-insight and in C4orf51 for anorexia. In total, 33 independent SNPs for treatment responses were tested in a mixed model, 12 of which demonstrated a p value <0.05. The most significant SNP was rs2182717 in the ENSR00000803469 gene located on chromosome 6 for the core syndromal factor (β = −0.638, p = 1.8 × 10−4) in terms of symptom improvement over time. Patients with a GG or GA genotype with the rs2182717 SNP also exhibited a treatment response (β = 0.089, p = 2.0 × 10−6) at week 4. Moreover, rs1836075352 was associated with sexual side effects (p = 3.2 × 10−8). Pathway and network analyses using the identified SNPs revealed potential biological functions involved in treatment response, such as neurodevelopment-related functions and immune processes. In conclusion, we identified loci that may affect the clinical response to treatment with antidepressants in the context of empirically defined depressive syndromal factors and side effects among the Taiwanese Han population, thus providing novel biological targets for further investigation.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2023-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9623827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-24DOI: 10.1038/s41397-022-00297-1
Shujun Huang, Pingzhao Hu, Ted M. Lakowski
Our previous studies demonstrated that the FOXM1 pathway is upregulated and the PPARA pathway downregulated in breast cancer (BC), and especially in the triple negative breast cancer (TNBC) subtype. Targeting the two pathways may offer potential therapeutic strategies to treat BC, especially TNBC which has the fewest effective therapies available among all BC subtypes. In this study we identified small molecule compounds that could modulate the PPARA and FOXM1 pathways in BC using two methods. In the first method, data were initially curated from the Connectivity Map (CMAP) database, which provides the gene expression profiles of MCF7 cells treated with different compounds as well as paired controls. We then calculated the changes in the FOXM1 and PPARA pathway activities from the compound-induced gene expression profiles under each treatment to identify compounds that produced a decreased activity in the FOXM1 pathway or an increased activity in the PPARA pathway. In the second method, the CMAP database tool was used to identify compounds that could reverse the expression pattern of the two pathways in MCF7 cells. Compounds identified as repressing the FOXM1 pathway or activating the PPARA pathway by the two methods were compared. We identified 19 common compounds that could decrease the FOXM1 pathway activity scores and reverse the FOXM1 pathway expression pattern, and 13 common compounds that could increase the PPARA pathway activity scores and reverse the PPARA pathway expression pattern. It may be of interest to validate these compounds experimentally to further investigate their effects on TNBCs.
{"title":"Bioinformatics driven discovery of small molecule compounds that modulate the FOXM1 and PPARA pathway activities in breast cancer","authors":"Shujun Huang, Pingzhao Hu, Ted M. Lakowski","doi":"10.1038/s41397-022-00297-1","DOIUrl":"10.1038/s41397-022-00297-1","url":null,"abstract":"Our previous studies demonstrated that the FOXM1 pathway is upregulated and the PPARA pathway downregulated in breast cancer (BC), and especially in the triple negative breast cancer (TNBC) subtype. Targeting the two pathways may offer potential therapeutic strategies to treat BC, especially TNBC which has the fewest effective therapies available among all BC subtypes. In this study we identified small molecule compounds that could modulate the PPARA and FOXM1 pathways in BC using two methods. In the first method, data were initially curated from the Connectivity Map (CMAP) database, which provides the gene expression profiles of MCF7 cells treated with different compounds as well as paired controls. We then calculated the changes in the FOXM1 and PPARA pathway activities from the compound-induced gene expression profiles under each treatment to identify compounds that produced a decreased activity in the FOXM1 pathway or an increased activity in the PPARA pathway. In the second method, the CMAP database tool was used to identify compounds that could reverse the expression pattern of the two pathways in MCF7 cells. Compounds identified as repressing the FOXM1 pathway or activating the PPARA pathway by the two methods were compared. We identified 19 common compounds that could decrease the FOXM1 pathway activity scores and reverse the FOXM1 pathway expression pattern, and 13 common compounds that could increase the PPARA pathway activity scores and reverse the PPARA pathway expression pattern. It may be of interest to validate these compounds experimentally to further investigate their effects on TNBCs.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9899616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Head and neck squamous cell carcinomas (HNSCCs) are introduced as the sixth most common cancer in the world. Detection of predictive biomarkers improve early diagnosis and prognosis. Recent cancer researches provide a new avenue for organoids, known as “mini-organs” in a dish, such as patient-derived organoids (PDOs), for cancer modeling. HNSCC burden, heterogeneity, mutations, and organoid give opportunities for the evaluation of drug sensitivity/resistance response according to the unique genetic profile signature. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) nucleases, as an efficient genome engineering technology, can be used for genetic manipulation in three-dimensional (3D) organoids for cancer modeling by targeting oncogenes/tumor suppressor genes. Moreover, single-cell analysis of circulating tumor cells (CTCs) improved understanding of molecular angiogenesis, distance metastasis, and drug screening without the need for tissue biopsy. Organoids allow us to investigate the biopathogenesis of cancer, tumor cell behavior, and drug screening in a living biobank according to the specific genetic profile of patients.
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症。检测预测性生物标志物可改善早期诊断和预后。最近的癌症研究为癌症建模提供了一个新的途径，即在培养皿中使用被称为 "微型器官 "的器官组织，如患者衍生器官组织（PDOs）。HNSCC的负担、异质性、突变和器官组织为根据独特的基因图谱特征评估药物敏感性/耐药性反应提供了机会。作为一种高效的基因组工程技术，CRISPR（Clustered Regularly Interspaced Short Palindromic Repeat）核酸酶可用于三维（3D）器官组织中的基因操作，通过靶向致癌基因/抑癌基因建立癌症模型。此外，循环肿瘤细胞（CTCs）的单细胞分析提高了对分子血管生成、远距离转移和药物筛选的认识，而无需进行组织活检。有机体使我们能够根据患者的具体基因特征，在活体生物库中研究癌症的生物发病机制、肿瘤细胞行为和药物筛选。
{"title":"The organoid as reliable cancer modeling in personalized medicine, does applicable in precision medicine of head and neck squamous cell carcinoma?","authors":"Alieh Farshbaf, Malihe Lotfi, Reza Zare, Nooshin Mohtasham","doi":"10.1038/s41397-022-00296-2","DOIUrl":"10.1038/s41397-022-00296-2","url":null,"abstract":"Head and neck squamous cell carcinomas (HNSCCs) are introduced as the sixth most common cancer in the world. Detection of predictive biomarkers improve early diagnosis and prognosis. Recent cancer researches provide a new avenue for organoids, known as “mini-organs” in a dish, such as patient-derived organoids (PDOs), for cancer modeling. HNSCC burden, heterogeneity, mutations, and organoid give opportunities for the evaluation of drug sensitivity/resistance response according to the unique genetic profile signature. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) nucleases, as an efficient genome engineering technology, can be used for genetic manipulation in three-dimensional (3D) organoids for cancer modeling by targeting oncogenes/tumor suppressor genes. Moreover, single-cell analysis of circulating tumor cells (CTCs) improved understanding of molecular angiogenesis, distance metastasis, and drug screening without the need for tissue biopsy. Organoids allow us to investigate the biopathogenesis of cancer, tumor cell behavior, and drug screening in a living biobank according to the specific genetic profile of patients.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-04DOI: 10.1038/s41397-022-00294-4
Erik Joas, Lina Jonsson, Alexander Viktorin, Erik Smedler, Erik Pålsson, Guy M. Goodwin, Mikael Landén
Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005–2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04–1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05–2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.
{"title":"Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder","authors":"Erik Joas, Lina Jonsson, Alexander Viktorin, Erik Smedler, Erik Pålsson, Guy M. Goodwin, Mikael Landén","doi":"10.1038/s41397-022-00294-4","DOIUrl":"10.1038/s41397-022-00294-4","url":null,"abstract":"Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005–2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04–1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05–2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10844374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-27DOI: 10.1038/s41397-022-00292-6
Krista N. Bohlen, Julie M. Kittelsrud, Morgan E. Nelson, Lisa K. Weisser, Neil J. Matthiesen, Julie A. Fieldsend, Nicholas B. Buschette, Leslie L. Cooper, Gareth E. Davies, Erik A. Ehli
This study evaluated the timing, use, and clinical outcomes of the GeneFolio® Pharmacogenomic Panel in a healthcare setting with patients managed by primary care providers or by psychiatrists. Participants were randomized to receive a pharmacogenetics report at four weeks or 12 weeks. After DNA collection and genetic analysis, pharmacists produced a recommendation report which was given to providers at the randomization week. The four-week group decreased depression severity (PHQ-9 and BDI) faster than the 12-week group (p = 0.0196), and psychiatrists’ patients decreased their depression severity faster than primary care patients (PHQ-9 p = 0.0005, BDI p = 0.0218). Mean mental quality of life increased over time (p < 0.0001), but it increased slower for patients taking drugs in the Significant drug-drug-gene interaction category (p = 0.0012). Mental quality of life, depression severity, and clinical outcomes were improved by GeneFolio® pharmacogenomic testing regardless of provider type, with earlier testing improving outcomes sooner.
这项研究评估了 GeneFolio® 药物基因组面板在医疗机构中的使用时间、使用情况和临床效果，研究对象是由初级保健提供者或精神科医生管理的患者。参与者被随机分配在四周或十二周时接受药物基因组学报告。经过 DNA 采集和基因分析后，药剂师会生成一份建议报告，在随机化的那一周交给医疗服务提供者。四周组抑郁严重程度（PHQ-9 和 BDI）的下降速度快于 12 周组（P = 0.0196），精神科患者抑郁严重程度的下降速度快于初级保健患者（PHQ-9 P = 0.0005，BDI P = 0.0218）。随着时间的推移，平均精神生活质量有所提高（p <0.0001），但服用药物-药物-基因相互作用显著类别药物的患者的精神生活质量提高较慢（p = 0.0012）。无论医疗机构的类型如何，GeneFolio®药物基因组学检测都能改善患者的精神生活质量、抑郁严重程度和临床疗效，而更早的检测能更快地改善疗效。
{"title":"Clinical utility of pharmacogenetics in a psychiatric and primary care population","authors":"Krista N. Bohlen, Julie M. Kittelsrud, Morgan E. Nelson, Lisa K. Weisser, Neil J. Matthiesen, Julie A. Fieldsend, Nicholas B. Buschette, Leslie L. Cooper, Gareth E. Davies, Erik A. Ehli","doi":"10.1038/s41397-022-00292-6","DOIUrl":"10.1038/s41397-022-00292-6","url":null,"abstract":"This study evaluated the timing, use, and clinical outcomes of the GeneFolio® Pharmacogenomic Panel in a healthcare setting with patients managed by primary care providers or by psychiatrists. Participants were randomized to receive a pharmacogenetics report at four weeks or 12 weeks. After DNA collection and genetic analysis, pharmacists produced a recommendation report which was given to providers at the randomization week. The four-week group decreased depression severity (PHQ-9 and BDI) faster than the 12-week group (p = 0.0196), and psychiatrists’ patients decreased their depression severity faster than primary care patients (PHQ-9 p = 0.0005, BDI p = 0.0218). Mean mental quality of life increased over time (p < 0.0001), but it increased slower for patients taking drugs in the Significant drug-drug-gene interaction category (p = 0.0012). Mental quality of life, depression severity, and clinical outcomes were improved by GeneFolio® pharmacogenomic testing regardless of provider type, with earlier testing improving outcomes sooner.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10833112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The study aimed to conduct a meta-analysis of studies comparing pharmacogenetically guided dosing of antidepressants with empiric standard of care. Publications referring to genotype-guided antidepressant therapy were identified via PubMed, Google Scholar, Scopus, Web of Science, Embase, and Cochrane databases from the inception of the databases to 2021. In addition, bibliographies of all articles were manually searched for additional references not identified in primary searches. Studies comparing clinical outcomes between two groups of patients who received antidepressant treatment were included in meta-analysis. Analysis of the data revealed statistically significant differences between the experimental group receiving pharmacogenetically guided dosing and the empirically treated controls. Specifically, genotype-guided treatment significantly improved response and remission of patients after both eight and twelve weeks of therapy, whereas no effect on the development of adverse drug reactions was observed. This meta-analysis indicates that the use of preemptive genotyping to guide dosing of antidepressants might increase treatment efficacy.
该研究旨在对比较药物基因指导下的抗抑郁药剂量与经验性标准治疗的研究进行荟萃分析。研究人员通过PubMed、Google Scholar、Scopus、Web of Science、Embase和Cochrane等数据库查找了从数据库建立之初到2021年期间有关基因型指导抗抑郁治疗的文献。此外，还对所有文章的书目进行了人工检索，以查找主要检索中未发现的其他参考文献。荟萃分析纳入了对两组接受抗抑郁治疗的患者的临床疗效进行比较的研究。数据分析显示，接受药物基因指导剂量的实验组与接受经验治疗的对照组之间存在显著的统计学差异。具体来说，基因型指导治疗显著改善了患者在接受八周和十二周治疗后的反应和缓解情况，而对药物不良反应的发生没有影响。这项荟萃分析表明，使用先期基因分型来指导抗抑郁药物的剂量可能会提高疗效。
{"title":"Meta-analysis of pharmacogenetic clinical decision support systems for the treatment of major depressive disorder","authors":"Valentin Skryabin, Ilya Rozochkin, Mikhail Zastrozhin, Volker Lauschke, Johan Franck, Evgeny Bryun, Dmitry Sychev","doi":"10.1038/s41397-022-00295-3","DOIUrl":"10.1038/s41397-022-00295-3","url":null,"abstract":"The study aimed to conduct a meta-analysis of studies comparing pharmacogenetically guided dosing of antidepressants with empiric standard of care. Publications referring to genotype-guided antidepressant therapy were identified via PubMed, Google Scholar, Scopus, Web of Science, Embase, and Cochrane databases from the inception of the databases to 2021. In addition, bibliographies of all articles were manually searched for additional references not identified in primary searches. Studies comparing clinical outcomes between two groups of patients who received antidepressant treatment were included in meta-analysis. Analysis of the data revealed statistically significant differences between the experimental group receiving pharmacogenetically guided dosing and the empirically treated controls. Specifically, genotype-guided treatment significantly improved response and remission of patients after both eight and twelve weeks of therapy, whereas no effect on the development of adverse drug reactions was observed. This meta-analysis indicates that the use of preemptive genotyping to guide dosing of antidepressants might increase treatment efficacy.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9995629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-10-20DOI: 10.1038/s41397-022-00293-5
Rohan Gurjar, Laura Dickinson, Daniel Carr, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D’Avolio, Adam Cursley, Nathalie De Castro, Gerd Fätkenheuer, Linos Vandekerckhove, Giovanni Di Perri, Anton Pozniak, Christine Schwimmer, François Raffi, Marta Boffito, the NEAT001/ANRS143 Study Group
Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir’s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.
{"title":"Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study","authors":"Rohan Gurjar, Laura Dickinson, Daniel Carr, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D’Avolio, Adam Cursley, Nathalie De Castro, Gerd Fätkenheuer, Linos Vandekerckhove, Giovanni Di Perri, Anton Pozniak, Christine Schwimmer, François Raffi, Marta Boffito, the NEAT001/ANRS143 Study Group","doi":"10.1038/s41397-022-00293-5","DOIUrl":"10.1038/s41397-022-00293-5","url":null,"abstract":"Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir’s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9584256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9477454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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