Genistein promotes M1 macrophage apoptosis and reduces inflammatory response by disrupting miR-21/TIPE2 pathway.

Cardiovascular diseases are a major cause of mortality, and vascular injury, a common pathological basis of cardiovascular disease, is deeply correlated with macrophage apoptosis and inflammatory response. Genistein, a type of phytoestrogen, exerts cardiovascular protective activities, but the underlying mechanism has not been fully elucidated. In this study, RAW264.7 cells were treated with genistein, lipopolysaccharide (LPS), nuclear factor-kappa B (NF-κB) inhibitor, and/or protein kinase B (AKT) agonist to determine the role of genistein in apoptosis and inflammation in LPS-stimulated cells. Simultaneously, high fat diet-fed C57BL/6 mice were administered genistein to evaluate the function of genistein on LPS-induced cardiovascular injury mouse model. Here, we demonstrated that LPS obviously increased apoptosis resistance and inflammatory response of macrophages by promoting miR-21 expression, and miR-21 downregulated tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) expression by targeting the coding region. Genistein reduced miR-21 expression by inhibiting NF-κB, then blocked toll-like receptor 4 (TLR4) pathway and AKT phosphorylation dependent on TIPE2, resulting in inhibition of LPS. Our research suggests that miR-21/TIPE2 pathway is involved in M1 macrophage apoptosis and inflammatory response, and genistein inhibits the progression of LPS-induced cardiovascular injury at the epigenetic level via regulating the promoter region of Vmp1 by NF-κB.

Distinct changes of in BTLA, ICOS, PD-1, and TIGIT expression on peripheral blood and decidual CD8+ T cells in women with unexplained recurrent spontaneous abortion†.

The two-way communication between the mother and the fetus is accomplished by immune cells. CD8+ T cells of normal pregnant (NP) women express progesterone receptor (PR). Binding of PR to progesterone (P) and the production of progesterone-induced blocking factor (PIBF) can aid immune escape, which is an important factor in the maternal immune response. We detected the proportion of CD8+ T cells and the expression of the surface costimulatory molecules BTLA, TIGIT, ICOS, and PD-1 in peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion (URSA) and in NP women. All patients were at 8 -10 weeks of gestation. The results showed that there was no change in the proportions of CD8+ T cells in peripheral blood and decidual tissues of URSA patients compared to those of NP women. In peripheral blood, compared with the NP group, the URSA group showed decreased expression of BTLA + CD8+ T cells and the difference was statistically significant, but there was no difference between the groups in terms of TIGIT + CD8+, PD-1 + CD8+, and ICOS + CD8+ T cells. There was no change in the levels of TIGIT + CD8+, PD-1 + CD8+, ICOS + CD8+, and BTLA + CD8+ T cells in decidual tissue. These data confirm that the number of CD8+ T cells in peripheral blood and decidual tissue is not the main factor leading to the pathogenesis of URSA, and other immune cells may play an important role in URSA, but this hypothesis needs further exploration and research.

Inhibitory Effects of (-)-Epigallocatechin-3-gallate on Esophageal Cancer.

There is epidemiological evidence showing that drinking green tea can lower the risk of esophageal cancer (EC). The effect is mainly attributed to tea polyphenols and their most abundant component, (-)-epigallocatechin-3-gallate (EGCG). The possible mechanisms of tumorigenesis inhibition of EGCG include its suppressive effects on cancer cell proliferation, angiogenesis, DNA methylation, metastasis and oxidant stress. EGCG modulates multiple signal transduction and metabolic signaling pathways involving in EC. A synergistic effect was also observed when EGCG was used in combination with other treatment methods.

Bioavailability of Tea Catechins and Its Improvement.

Many in vitro studies have shown that tea catechins had vevarious health beneficial effects. However, inconsistent results between in vitro and in vivo studies or between laboratory tests and epidemical studies are observed. Low bioavailability of tea catechins was an important factor leading to these inconsistencies. Research advances in bioavailability studies involving absorption and metabolic biotransformation of tea catechins were reviewed in the present paper. Related techniques for improving their bioavailability such as nanostructure-based drug delivery system, molecular modification, and co-administration of catechins with other bioactives were also discussed.

Antidiabetic Effects of Tea.

Diabetes mellitus (DM) is a chronic endocrine disease resulted from insulin secretory defect or insulin resistance and it is a leading cause of death around the world. The care of DM patients consumes a huge budget due to the high frequency of consultations and long hospitalizations, making DM a serious threat to both human health and global economies. Tea contains abundant polyphenols and caffeine which showed antidiabetic activity, so the development of antidiabetic medications from tea and its extracts is increasingly receiving attention. However, the results claiming an association between tea consumption and reduced DM risk are inconsistent. The advances in the epidemiologic evidence and the underlying antidiabetic mechanisms of tea are reviewed in this paper. The inconsistent results and the possible causes behind them are also discussed.

Recent Advances in Volatiles of Teas.

Volatile compounds are important components of tea aroma, a key attribute of sensory quality. The present review examines the formation of aromatic volatiles of various kinds of teas and factors influencing the formation of tea volatiles, including tea cultivar, growing environment and agronomic practices, processing method and storage of tea. The determination of tea volatiles and the relationship of active-aroma volatiles with the sensory qualities of tea are also discussed in the present paper.

Tea Polysaccharides and Their Bioactivities.

Tea (Camellia sinensis) is a beverage beneficial to health and is also a source for extracting bioactive components such as theanine, tea polyphenols (TPP) and tea polysaccharides (TPS). TPS is a group of heteropolysaccharides bound with proteins. There is evidence showing that TPS not only improves immunity but also has various bioactivities, such as antioxidant, antitumor, antihyperglycemia, and anti-inflammation. However, inconsistent results concerning chemical composition and bioactivity of TPS have been published in recent years. The advances in chemical composition and bioactivities of TPS are reviewed in the present paper. The inconsistent and controversial results regarding composition and bioactivities of TPS are also discussed.

Care model selection for older adult stroke survivors with disabilities: insights from the eighth wave of CLHLS data and influencing factors.

Background: Analyzing the differences in caregiving models for disabled older adult individuals after stroke and the influencing factors, to provide a basis for addressing relevant social demographic issues. Methods: The older adult diagnosed with stroke were screened from the Chinese Geriatric Health Survey (CLHLS), and were further divided into subgroups of disability, which was based on their ability of or whether they need help in performing activities such as dressing, bathing, eating, toileting or bowel and bladder control using the international common Katz scale. The care model was divided into formal care, informal care and home care. Multivariate logistic regression was used to screen the influencing factors of the choice of care model for the disabled older adult after stroke. Results: The results of univariate analysis showed that there were statistical differences in the choice of care mode among different ages, household registration types, number of children, years of education, degree of disability, community services, retirement pension, marital status and medical insurance. Multiple logistic regression showed that, The rural older adult with more children, shorter education years, living with spouse and no help from community tend to choose informal care. Older adult people with higher levels of education, urban household registration, and access to community services are more likely to choose formal care. Older adult women with multiple children are more likely to receive care from their children. Conclusion: In the future, vigorous support for the development of formal caregiving institutions and the improvement of the management system of formal caregiving will help enhance the subjective initiative of disabled older adult individuals in choosing caregiving models and alleviate the burden of family caregiving.

Hepatic gene expression profiles during fed-fasted-refed state in mice.

Background: Regulation of nutrient status during fasting and refeeding plays an important role in maintaining metabolic homeostasis in the liver. Thus, we investigated the impact of the physiological Fed-Fast-Refed cycle on hepatic gene expression in nutrient-sensitive mice. Methods: We performed transcriptomic analysis of liver samples in fed, fasted and refed groups of mice. Through mRNA-sequencing (RNA-Seq) and miRNA-Seq, we compared fasted and fed states (fasted versus fed cohort) as well as refed and fasted states (refed versus fasted cohort) to detect dynamic alterations of hepatic mRNA-miRNA expression during the fed-fasted-refed cycle. Results: We found dozens of dysregulated mRNAs-miRNAs in the transition from fed to fasted and from fasted to refed states. Gene set enrichment analysis showed that gene expression of the two cohorts shared common pathways of regulation, especially for lipid and protein metabolism. We identified eight significant mRNA and three miRNA clusters that were up-downregulated or down-upregulated during the Fed-Fast-Refed cycle. A protein-protein interaction network of dysregulated mRNAs was constructed and clustered into 22 key modules. The regulation between miRNAs and target mRNAs was presented in a network. Up to 42 miRNA-mRNA-pathway pairs were identified to be involved in metabolism. In lipid metabolism, there were significant correlations between mmu-miR-296-5p and Cyp2u1 and between mmu-miR-novel-chr19_16777 and Acsl3. Conclusion: Collectively, our data provide a valuable resource for the molecular characterization of the physiological Fed-Fast-Refed cycle in the liver.

Invasive mucinous adenocarcinoma misdiagnosed as pneumonia: A case report.

Common imaging findings of invasive mucinous adenocarcinoma (IMA) include consolidation of the lung parenchyma, nodules, and ground-glass changes. However, the IMA imaging findings in the present case included diffuse, patchy and blurry density shadows through both lungs. To the best of the authors' knowledge, this image pattern has rarely been reported. The patient provided his consent and authorized the publication of photographs featuring his likeness. The present study reported a patient was diagnosed with IMA via pathologic and genetic analyses. Following antibiotic treatment, the lesions in both sides became larger. Further examinations were completed and IMA was confirmed by biopsy pathohistological examination. Pathological specimens were negative for almost all driver genes mutations, except KRAS. The patients and family refused further treatment, including chemotherapy, radiotherapy and interventional chemotherapy and the patient was discharged from The First Affiliated Hospital of Chengdu Medical College. The present case report emphasized that IMA should be suspected when imaging studies show diffuse lesions throughout both lungs. When a patient does not respond to treatment, clinicians should consider alternative diagnoses.

Comprehensive RNA expression profile analysis of γδ T cells from peripheral blood and decidual tissues in normal pregnancy (NP) donors and patients with recurrent pregnancy loss (RPL).

Recurrent pregnancy loss (RPL) is a significant adverse pregnancy complication. The loss of immune tolerance has been proposed in the pathogenesis of RPL, however, the role of γδ T cells in RPL is still controversial. In this study, the gene expression patterns of circulated and decidual tissue-resident γδ T cells from normal pregnancy donors and patients with RPL were analyzed by SMART-seq. We demonstrate that the transcriptional expression profile of different subsets of γδ T cells in peripheral blood and decidual tissue is strikingly different. Vδ2 γδ T cells, as the major cytotoxic subset, are found to be enriched considerably, and the potential cytotoxicity of this subset is further enhanced in the decidua of RPL patients may be due to detrimental ROS reduction, enhanced metabolic activity, downregulation of immunosuppressive molecules expression in resident γδ T cells. Time-series Expression Miner (STEM) analysis of transcriptome indicates complex changes in gene expression in decidual γδ T cells over time from NP and RPL patients. Taken together, our work identifies high heterogeneity of gene signature in γδ T cells from NP and RPL patients between peripheral blood and decidua, which will be a useful resource for further studies of the critical roles of γδ T cells in RPL.

Comparison of hepatic gene expression profiles between three mouse models of Nonalcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder worldwide. Murine models of NAFLD have been widely used to explore its pathogenesis. In this study, we performed a systematic evaluation of hepatic genome-wide mRNA expression by RNA-Sequencing using three mouse models of NAFLD: leptin receptor deficient db/db mice, high-fat high-sugar diet (HSHF)-induced obese mice, and dexamethasone (DEX)-induced NAFLD mice. As a result, we found both distinct and common pathways in the regulation of lipid metabolism from transcriptomes of three mouse models. Moreover, only a total of 12 differentially expressed genes (DEGs) were commonly detected among all three mouse groups, indicating very little overlap among all three models. Therefore, our results suggest that NAFLD is a heterogeneous disease with highly variable molecular mechanisms.

Preparation and Bolometric Responses of MoS2 Nanoflowers and Multi-Walled Carbon Nanotube Composite Network.

Due to their broadband optical absorption ability and fast response times, carbon nanotube (CNT)-based materials are considered promising alternatives to the toxic compounds used in commercial infrared sensors. However, the direct use of pure CNT networks as infrared sensors for simple resistance read-outs results in low sensitivity values. In this work, MoS2 nanoflowers are composited with CNT networks via a facile hydrothermal process to increase the bolometric performance. The thermal diffusivity (α) against temperature (T) is measured using the transient electro-thermal (TET) technique in the range of 320 K to 296 K. The α-T curve demonstrates that the composite containing MoS2 nanoflowers provides significant phonon scattering and affects the intertube interfaces, decreasing the α value by 51%. As the temperature increases from 296 K to 320 K, the relative temperature coefficient of resistance (TCR) increases from 0.04%/K to 0.25%/K. Combined with the enhanced light absorption and strong anisotropic structure, this CNT-MoS2 composite network exhibits a more than 5-fold greater surface temperature increase under the same laser irradiation. It shows up to 18-fold enhancements in resistive responsivity ((Ron - Roff)/Roff) compared with the pure CNT network for a 1550 nm laser at room temperature (RT).

Genome-wide identification of seven superoxide dismutase genes in the marine rotifer Brachionus rotundiformis and modulated expression and enzymatic activity in response to microplastics and nutritional status.

Microplastics (MPs) pollution has attracted worldwide attention. Superoxide dismutase (SOD) is a sensitive indicator for assessing the toxic effects of MPs in aquatic organisms. However, few studies have been performed to identify all genes encoding SOD in aquatic invertebrates. Especially, effects of MPs on SOD activity and expression in aquatic organisms under starvation or a subsequent refeeding status are unclear. In the present study, all full-length genes encoding SOD were cloned and characterized from the marine rotifer Brachionus rotundiformis, including CuZnSOD1, CuZnSOD2, CuZnSOD3, CuZnSOD4, CuZnSOD5, MnSOD1, and MnSOD2. The CuZnSOD1, CuZnSOD2 and MnSOD2 are homologous to SODs from vertebrates and the other SOD proteins are rotifer-specific according to the results from the phylogenetic tree. The conserved signature sequences and binding sites of Cu2+, Zn2+and Mn2+ were also identified in the seven SOD proteins. Compared with feeding, starvation down-regulated SOD activity and mRNA expression of CuZnSOD2, CuZnSOD4, CuZnSOD5, MnSOD1 and MnSOD2 while refeeding maintained SOD activity comparable to the feeding level and up-regulated CuZnSOD5 and MnSOD2. Intake of MPs by B. rotundiformis was observed by examining fluorescence signals from the fluorescently-labeled microplastics under different nutritional status. Exposure to MPs reduced rotifer density and increased malondialdehyde (MDA) content and SOD activity in the rotifers under the refeeding condition, but did not affect these indicators under the feeding and starvation conditions. However, mRNA expression of some tested genes was responsive to MPs in the fed, starved and refed rotifers. The present study for the first time demonstrated a nutritional status-dependent effect of MPs on oxidative stress response, and provided more sensitive molecular biomarkers for assessing the toxicity of MPs using B. rotundiformis as a model animal.

Nutritional-status dependent effects of microplastics on activity and expression of alkaline phosphatase and alpha-amylase in Brachionus rotundiformis.

Tissue-nonspecific alkaline phosphatase (ALPL) and alpha-amylase (AMY) are essential in the immune and digestive systems, respectively. Microplastics (MPs) pose a risk to zooplankton which may be in a state of feeding, starvation, or subsequent refeeding. However, molecular characterization of both enzymes and the regulated mechanisms affected by nutritional statuses and MPs remain unclear in zooplankton. In the present study, four full-length genes encoding ALPL and two genes encoding AMY were cloned and characterized from an isolated marine rotifer, Brachionus rotundiformis, including alplA, alplB, alplC, alplD, amy2a, and amy2al. AMY activity and expression of amy2a and amy2al were reduced by starvation and recovered after refeeding compared with feeding. ALPL activity remained unchanged among different statuses, while alplA, alplB and alplD were down-regulated by starvation and refeeding compared with feeding. ALPL activity was not affected by exposure to 10, 100 and 1000 µg/L MPs in rotifers subjected to feeding, starvation and refeeding, whereas AMY activity was significantly enhanced by 1000 µg/L MPs in rotifers subjected to refeeding. Gene expression of the tested genes, except amy2a, was significantly responsive to MPs, especially in the feeding rotifers, depending on MPs concentrations and nutritional statuses. Two-way ANOVA confirmed that these changes were strongly associated with the interaction between MPs concentrations and nutritional statuses. The present study is the first to demonstrate a nutritional status-dependent impact of MPs on immune and digestive responses, and provides more sensitive molecular biomarkers for assessing MPs toxicity using the species as model animals.

The important role of glycerophospholipid metabolism in the protective effects of polyphenol-enriched Tartary buckwheat extract against alcoholic liver disease.

Alcoholic liver disease (ALD) is a mounting public health problem with significant medical, economic and social burdens. Tartary buckwheat (F. tataricum (L.) Gaertn, bitter buckwheat) is a kind of healthy and nutritious food, which has been demonstrated to protect against ALD, but the underlying mechanism has not been fully studied. Herein, we aimed to elucidate the beneficial effects of Tartary buckwheat extract (mainly composed of polyphenols including rutin, quercetin, kaempferol and kaempferol-3-O-rutinoside) in terms of lipid metabolism with the aid of lipidomic analysis. In our study, we employed C57BL/6J mice and a Lieber-DeCarli alcohol liquid diet to construct an ALD model and found that Tartary buckwheat extract was able to prevent ALD-induced histopathological lesions, liver injury and abnormal plasma lipid levels. These beneficial effects might be attributed to the regulation of energy metabolism-related genes (SIRT1, LKB1 and AMPK), lipid synthesis-related genes (ACC, SREBP1c and HMGR) and lipid oxidation-related genes (PPARα, CPT1 and CPT2). In addition, lipidomic profiling and KEGG pathway analysis showed that glycerophospholipid metabolism contributed the most to elucidating the regulatory mechanism of Tartary buckwheat extract. In specific, chronic ethanol intake reduced the level of phosphatidylcholines (PC) and increased the level of phosphatidylethanolamines (PE) in the liver, resulting in a decrease in the PC/PE ratio, which could be all significantly restored by Tartary buckwheat extract intervention, indicating that the Tartary buckwheat extract might regulate PC/PE homeostasis to exert its lipid-lowering effect. Overall, we demonstrated that Tartary buckwheat extract could prevent ALD by modulating hepatic glycerophospholipid metabolism, providing the theoretical basis for its further exploitation as a medical plant or nutritional food.

Comprehensive Transcriptome Profiling of NAFLD- and NASH-Induced Skeletal Muscle Dysfunction.

Nonalcoholic fatty liver disease (NAFLD), characterized by extensive triglyceride accumulation in hepatocytes, may progress to nonalcoholic steatohepatitis (NASH) with liver fibrosis and inflammation and increase the risk of cirrhosis, cancer, and death. It has been reported that physical exercise is effective in ameliorating NAFLD and NASH, while skeletal muscle dysfunctions, including lipid deposition and weakness, are accompanied with NAFLD and NASH. However, the molecular characteristics and alterations in skeletal muscle in the progress of NAFLD and NASH remain unclear. In the present study, we provide a comprehensive analysis on the similarity and heterogeneity of quadriceps muscle in NAFLD and NASH mice models by RNA sequencing. Importantly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analysis revealed that NAFLD and NASH led to impaired glucose and lipid metabolism and deteriorated functionality in skeletal muscle. Besides this, we identified that myokines possibly mediate the crosstalk between muscles and other metabolic organs in pathological conditions. Overall, our analysis revealed a comprehensive understanding of the molecular signature of skeletal muscles in NAFLD and NASH, thus providing a basis for physical exercise as an intervention against liver diseases.

Genistein alleviates chronic vascular inflammatory response via the miR­21/NF­κB p65 axis in lipopolysaccharide­treated mice.

Chronic vascular inflammatory response is an important pathological basis of cardiovascular disease. Genistein (GEN), a natural compound, exhibits anti­inflammatory effects. The aim of the present study was to investigate the effects of GEN on lipopolysaccharide (LPS)­induced chronic vascular inflammatory response in mice and explore the underlying anti­inflammatory mechanisms. C57BL/6 mice were fed with a high­fat diet combined with intraperitoneal injection of LPS to induce chronic vascular inflammation. The expression levels of TNF­α, IL­6 and microRNA (miR)­21 in the vasculature were detected via reverse transcription­quantitative (RT­q)PCR. The protein levels of inducible nitric oxide synthase (iNOS) and NF­κB p65 were detected via western blotting. NF­κB p65 was also analyzed via immunohistochemistry and immunofluorescence (IF). In addition, after transfection with miR­21 mimic or inhibitor for 24 h, vascular endothelial cells (VECs) were treated with GEN and LPS. RT­qPCR and western blot analyses were performed to detect the expression of TNF­α, IL­6, miR­21 and iNOS, and the protein levels of iNOS and NF­κB p65, respectively. IF was used to measure NF­κB p65 nuclear translocation. The results revealed that GEN significantly decreased the expression of inflammation­associated vascular factors in LPS­treated C57BL/6 mice, including TNF­α, IL­6, iNOS, NF­κB p65 and miR­21. Furthermore, miR­21 antagomir enhanced the anti­inflammatory effects of GEN. In LPS­induced VECs, miR­21 mimic increased inflammation­associated factor expression and attenuated the anti­inflammatory effects of GEN, whereas miR­21 inhibitor induced opposing effects. Therefore, the results of the present study suggested that GEN inhibited chronic vascular inflammatory response in mice, which may be associated with the inhibition of VEC inflammatory injury via the miR­21/NF­κB p65 pathway.

7-Difluoromethoxy-5,4'-dimethoxy-genistein attenuates macrophages apoptosis to promote plaque stability via TIPE2/TLR4 axis in high fat diet-fed ApoE-/- mice.

Promoting plaque stability is of great significance for prevention and treatment of cardiovascular diseases. 7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) is a novel active compound synthesized using genistein, which exerts anti-atherosclerotic effect. In this study, we evaluated effects of DFMG on plaque stability in ApoE-/- mice fed with high fat diet (HFD), and explored the molecular mechanism by using ApoE-/-TLR4-/- mice and RAW264.7 cells. Here, we found that DFMG significantly reduced plaque areas, macrophages infiltration and apoptosis, and TLR4 expression in HFD-fed ApoE-/- mice. Meanwhile, DFMG increased collagen fibers, smooth muscle cells and TIPE2 expression in plaques and media. Besides, TLR4 knockout promoted the protective effects of DFMG on plaques. In vitro, DFMG decreased lysophosphatidylcholine (LPC)-induced macrophages apoptosis and TLR4, while upregulated TIPE2. Moreover, TIPE2 reduced TLR4, MyD88, p-NF-κB p65Ser276, cleaved Caspase-3 overproduction, and enhanced effects of DFMG on LPC-induced macrophages. Overall, our study demonstrates that DFMG can promote plaque stability by reducing macrophage apoptosis through TIPE2/TLR4 signaling pathway, which suggests DFMG should be used to develop food additives or drugs for preventing atherosclerosis.

Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization.

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach. Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens. Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range. Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.