Overexpression of 9-cis-Epoxycarotenoid Dioxygenase Gene, IbNCED1, Negatively Regulates Plant Height in Transgenic Sweet Potato.

Plant height is one of the key agronomic traits for improving the yield of sweet potato. Phytohormones, especially gibberellins (GAs), are crucial to regulate plant height. The enzyme 9-cis-epoxycarotenoid dioxygenase (NCED) is the key enzyme for abscisic acid (ABA) biosynthesis signalling in higher plants. However, its role in regulating plant height has not been reported to date. Here, we cloned a new NCED gene, IbNCED1, from the sweet potato cultivar Jishu26. This gene encoded the 587-amino acid polypeptide containing an NCED superfamily domain. The expression level of IbNCED1 was highest in the stem and the old tissues in the in vitro-grown and field-grown Jishu26, respectively. The expression of IbNCED1 was induced by ABA and GA3. Overexpression of IbNCED1 promoted the accumulation of ABA and inhibited the content of active GA3 and plant height and affected the expression levels of genes involved in the GA metabolic pathway. Exogenous application of GA3 could rescue the dwarf phenotype. In conclusion, we suggest that IbNCED1 regulates plant height and development by controlling the ABA and GA signalling pathways in transgenic sweet potato.

Genome-wide in silico identification and expression analysis of beta-galactosidase family members in sweetpotato [Ipomoea batatas (L.) Lam].

BACKGROUND: Sweetpotato (Ipomoea batatas (L.) Lam.) serves as an important food source for human beings. ß-galactosidase (bgal) is a glycosyl hydrolase involved in cell wall modification, which plays essential roles in plant development and environmental stress adaptation. However, the function of bgal genes in sweetpotato remains unclear. RESULTS: In this study, 17 ß-galactosidase genes (Ibbgal) were identified in sweetpotato, which were classified into seven subfamilies using interspecific phylogenetic and comparative analysis. The promoter regions of Ibbgals harbored several stress, hormone and light responsive cis-acting elements. Quantitative real-time PCR results displayed that Ibbgal genes had the distinct expression patterns across different tissues and varieties. Moreover, the expression profiles under various hormonal treatments, abiotic and biotic stresses were highly divergent in leaves and root. CONCLUSIONS: Taken together, these findings suggested that Ibbgals might play an important role in plant development and stress responses, which provided evidences for further study of bgal function and sweetpotato breeding.

Distribution of APOE gene polymorphism in the Chinese Uyghur children & its association with urolithiasis.

Background & objectives: This study was to survey the apolipoprotein E (APOE) gene polymorphism distribution among Chinese Uyghur children and to explore the relationship between APOE gene polymorphism and the occurrence of urolithiasis. Methods: A total of 144 Uyghur children with urolithiasis and 274 without the history of urolithiasis were enrolled in this study. Venous blood samples were collected from all participants, and APOE genotyping, derived from rs429358 and rs7412, was performed using Sanger sequencing. Results: Among the 418 children, the most prevalent genotype was E3/3, accounting for 71.3 per cent in the urolithiasis group and 71.4 per cent in the control group, followed by E3/4 and E2/3. Higher frequencies of the ɛ2 and ɛ4 alleles and lower frequencies of the ɛ3 allele were observed in the test group, and the unusual allele ɛ1 was also found in them. However, there were no significant differences between cases and controls at both rs429358 and rs7412 genotype and allele frequencies [odds ratio (OR)=0.98, 95% confidence interval (CI): 0.57-1.67; 0.98 (0.59-1.63); 1.43 (0.75-2.74) and 1.40 (0.74-2.62), respectively]. Likewise, none of significant differences was found between cases and controls at both APOE genotype and allele frequencies [OR=0.88, 95% CI: 0.51-1.53; 0.74 (0.33-1.64); 1.10 (0.73-1.66); 1.13 (0.76-1.67) and 1.14 (0.76-1.70), respectively]. Interpretation & conclusions: The present study does not support any association between APOE genotyping and urolithiasis in Uyghur children.

Associations between functional polychlorinated biphenyls in adipose tissues and prognostic biomarkers of breast cancer patients.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) has been shown to influence expression of some biomarkers that are predictive/prognostic for breast cancer. Therefore, our study was conducted to further investigating associations of different functional PCBs in adipose tissue with breast cancer prognostic biomarkers. METHODS: Two hundred and five breast cancer patients were recruited in Shantou, China. Breast adipose tissues were collected during their resection surgery and levels of 7 PCB congeners were analyzed by gas chromatography-mass spectrometry (GC-MS). The PCB congeners were divided into 4 groups according to structure-activity. Socio-demographic, clinical and pathological information were obtained from questionnaire and digital medical records. Odds ratios (ORs) for associations between prognostic biomarkers and PCB levels (tertile 3 [T3], tertile 2 [T2] vs. tertile 1) were estimated from logistic regression models. RESULTS: Most PCB congeners were detectable, with a highest level (22.06 ng/g lipid) of PCB153. As for estrogenic PCBs, increased PCB52 exposure was positively associated with PR expression (ORT2 = 2.36, Ptrend = 0.054), but higher PCB101 level was negatively associated with HER-2 (ORT3 = 0.24, Ptrend = 0.029) and tumor size (OR = 0.43). Limited dioxin-like PCB138 exposure was positively associated with ER (ORT2 = 3.23, ORT3 = 3.77, Ptrend = 0.047) but negatively with Top-IIα expression (ORT2 = 0.35, ORT3 = 0.28, Ptrend = 0.080). Higher PCB153 (CYP inducer) level was negatively associated with ER (ORT2 = 0.32, ORT3 = 0.19, Ptrend = 0.038) but positively with Ki-67 expression (ORT2 = 1.43, ORT3 = 3.60, Ptrend = 0.055). Higher neurotoxic PCB28 was positively associated with HER-2 (ORT3 = 5.43, Ptrend = 0.006) and tumor size (OR = 2.37). Moreover, total PCBs exposure was positively associated with VEGF-C (ORT2 = 76.91, ORT3 = 97.96, Ptrend = 0.041) and tumor metastasis (OR = 2.25). CONCLUSIONS: Different functional PCB congeners have different associations (both positive and negative) with breast cancer prognostic biomarkers, as well as tumor classification stage. Therefore, the development and aggressiveness of breast cancer may depend upon exposure to specific structure-activity of PCBs.

Association Between Alcohol Consumption and Risk of Nasopharyngeal Carcinoma: A Comprehensive Meta-Analysis of Epidemiological Studies.

BACKGROUND: Alcohol consumption is increasing all over the world, but whether it is an independent factor affecting the occurrence of nasopharyngeal carcinoma (NPC) is inconsistent in many studies. We aimed to explore the association between alcohol consumption and NPC risk by integrating existing evidence in a meta-analysis. METHODS: We searched for relevant articles published up to August 2018 in PubMed, Cochrane Library, Web of Science, and China National Knowledge infrastructure (CNKI). The Newcastle-Ottawa scale was used to assess the quality of the included studies. Odds ratios (ORs) or relative risks were pooled to estimate the associations between alcohol consumption and NPC risk. RESULTS: The meta-analysis of cohort studies showed no significant association between alcohol consumption and NPC, but pooled results from case-control studies indicated that ever drinking increased the probability of NPC versus nondrinking (OR = 1.10; 95% confidence interval [CI]: 1.01, 1.19). As compared with nondrinkers, high-frequency drinking (≥7 times/wk) increased the NPC probability (OR = 1.29; 95% CI: 1.05, 1.53) and low-frequency drinking (<7 times/wk) decreased the probability (OR = 0.77; 95% CI: 0.60, 0.94), as did shorter duration of drinking (<20 years) (OR = 0.64; 95% CI: 0.49, 0.79). On subgroup analyses, significant pooled results were observed for studies with high quality, with hospital-based controls and with adjustment for confounding factors, smoking, age, and sex. CONCLUSIONS: The risk of NPC may increase with alcohol consumption. Ever drinking increased the risk versus nondrinking. Additionally, high-frequency drinking increased the risk, but low-frequency drinking decreased it to some extent. Further intensive studies based on well-designed methods are needed to examine the association.

Psychological resilience of women after breast cancer surgery: a cross-sectional study of associated influencing factors.

The psychological resilience (PR) of postoperative patients is found relatively low in clinical work. We recruited 220 postoperative women with breast cancer to survey PR of them and the influencing factors. General demographic data and physical exercise status were collected by questionnaire, clinical characteristics data were obtained from medical records. Measures comprised the Chinese version of the Connor and Davidson Resilience Scale (CD-RISC), General Self-Efficacy Scale (GSES), Family Hardiness Index (FHI) and Social Support Rate Scale (SSRS). The mean (±SD) PR score in women after breast cancer surgery was 65.18 ± 13.16. Clinical stage of breast cancer, courses of adjuvant therapy and physical exercise status affected PR level significantly. PR level was positively correlated with total GSES, FHI, and SSRS scores (r = 0.291, 0.378, 0.418, all P < 0.001); dimensions of FHI; and dimensions of SSRS. On multiple regression analysis, clinical stage of breast cancer and courses of adjuvant therapy negatively, but postoperative physical exercise status, commitment, control and social subjective support positively contributed to PR significantly. Psychological resilience of women after breast cancer surgery is relatively low. Moderate physical exercise, self-efficacy, family hardiness, and social support affect PR positively, promoting disease rehabilitation and improving the quality of life.

A Small Auxin-Up RNA Gene, IbSAUR36, Regulates Adventitious Root Development in Transgenic Sweet Potato.

Small auxin-upregulated RNAs (SAURs), as the largest family of early auxin-responsive genes, play important roles in plant growth and development processes, such as auxin signaling and transport, hypocotyl development, and tolerance to environmental stresses. However, the functions of few SAUR genes are known in the root development of sweet potatoes. In this study, an IbSAUR36 gene was cloned and functionally analyzed. The IbSAUR36 protein was localized to the nucleus and plasma membrane. The transcriptional level of this gene was significantly higher in the pencil root and leaf.This gene was strongly induced by indole-3-acetic acid (IAA), but it was downregulated under methyl-jasmonate(MeJA) treatment. The promoter of IbSAUR36 contained the core cis-elements for phytohormone responsiveness. Promoter ß-glucuronidase (GUS) analysis in Arabidopsis showed that IbSAUR36 is highly expressed in the young tissues of plants, such as young leaves, roots, and buds. IbSAUR36-overexpressing sweet potato roots were obtained by an efficient Agrobacterium rhizogenes-mediated root transgenic system. We demonstrated that overexpression of IbSAUR36 promoted the accumulation of IAA, upregulated the genes encoding IAA synthesis and its signaling pathways, and downregulated the genes encoding lignin synthesis and JA signaling pathways. Taken together, these results show that IbSAUR36 plays an important role in adventitious root (AR) development by regulating IAA signaling, lignin synthesis, and JA signaling pathways in transgenic sweet potatoes.

Comparative Transcriptome Analysis Reveals the Effect of Lignin on Storage Roots Formation in Two Sweetpotato (Ipomoea batatas (L.) Lam.) Cultivars.

Sweet potato (Ipomoea batatas (L.) Lam.) is one of the most important crops with high storage roots yield. The formation and expansion rate of storage root (SR) plays a crucial role in the production of sweet potato. Lignin affects the SR formation; however, the molecular mechanisms of lignin in SR development have been lacking. To reveal the problem, we performed transcriptome sequencing of SR harvested at 32, 46, and 67 days after planting (DAP) to analyze two sweet potato lines, Jishu25 and Jishu29, in which SR expansion of Jishu29 was early and had a higher yield. A total of 52,137 transcripts and 21,148 unigenes were obtained after corrected with Hiseq2500 sequencing. Through the comparative analysis, 9577 unigenes were found to be differently expressed in the different stages in two cultivars. In addition, phenotypic analysis of two cultivars, combined with analysis of GO, KEGG, and WGCNA showed the regulation of lignin synthesis and related transcription factors play a crucial role in the early expansion of SR. The four key genes swbp1, swpa7, IbERF061, and IbERF109 were proved as potential candidates for regulating lignin synthesis and SR expansion in sweet potato. The data from this study provides new insights into the molecular mechanisms underlying the impact of lignin synthesis on the formation and expansion of SR in sweet potatoes and proposes several candidate genes that may affect sweet potato yield.

Genome-wide identification of the C2H2 zinc finger gene family and expression analysis under salt stress in sweetpotato.

Introduction: The higher plant transcription factor C2H2 zinc finger protein (C2H2-ZFP) is essential for plant growth, development, and stress response. There are limited studies on C2H2-ZFP genes in sweetpotato, despite a substantial number of C2H2-ZFP genes having been systematically found in plants. Methods: In this work, 178 C2H2-ZFP genes were found in sweetpotato, distributed randomly on 15 chromosomes, and given new names according to where they were located. These members of the zinc finger gene family are separated into six branches, as shown by the phylogenetic tree. 24 tandem repeats of IbZFP genes and 46 fragment repeats were identified, and a homology study revealed that IbZFP genes linked more regions with wild relative species of sweetpotato as well as rhizome plants like potato and cassava. And we analyzed the expression patterns of IbZFP genes during the early development of sweetpotato storage roots (SRs) and salt stress using transcriptome data, and identified 44 IbZFP genes that exhibited differences in expression levels during the early expansion of sweetpotato SRs in different varieties, and 92 IbZFP genes that exhibited differences in expression levels under salt stress in salt tolerant and salt sensitive sweetpotato varieties. Additionally, we cloned six IbZFP genes in sweetpotato and analyzed their expression patterns in different tissues, their expression patterns under abiotic stress and hormone treatment, and subcellular localization. Results and discussion: The results showed that the IbZFP genes had tissue specificity in sweetpotato and were induced to varying degrees by drought and salt stress. ABA and GA3 treatments also affected the expression of the IbZFP genes. We selected IbZFP105, which showed significant differences in expression levels under salt stress and ABA treatment, to be heterologously expressed in Arabidopsis thaliana. We found that IbZFP105 OE lines exhibited higher tolerance to salt stress and ABA stress. This indicates that IbZFP105 can enhance the salt tolerance of plants. These results systematically identified the evolution and expression patterns of members of the C2H2-ZFP gene family in sweetpotato, providing a theoretical basis for studying the role of IbZFP genes in the development of sweetpotato SRs and in resistance to stress.

Attitude and practice on human papilloma virus infection and vaccination among students from secondary occupational health school: a cross-sectional study.

Cervical cancer (CC) is reported as the second-most common female cancer worldwide, of which 99% is caused by persistent human papillomavirus (HPV) infection. HPV vaccine protects against HPV infection and most cases of CC, which has only been introduced for a short time in mainland China. This study aimed to evaluate the attitude and practice related to HPV infection and vaccination among students at secondary occupational health school (SOHS) in China. We conducted a cross-sectional study in Southern China where data of 2248 participants were collected through questionnaires to estimate attitude and practice of students. Only 4.1% believed they were easily infected by HPV, 38.2% were willing to receive HPV vaccine and 30.8% intended to do regular screening of HPV infection in the future. Students in the second grade (OR = 1.51, 95%CI [1.25, 1.81]) and third grade (OR = 3.99, 95%CI [2.53, 6.27]) were more willing to take HPV vaccine compared to students in the first grade. Among the non-vaccinated participants, the most frequent reason for not receiving HPV vaccine was insufficient knowledge about HPV (91.1%). Characteristics of higher grade, personal education before enrollment and academic performance, medical specialty, history of sex experience and HPV vaccine and family history of other cancers were associated with higher attitude scores (p < .05). Considering the increasing prevalence of HPV infection and the need of improvement in attitude and practice toward HPV, more education about HPV infection and vaccination should be incorporated into school curriculum.

Awareness and Knowledge about Human Papilloma Virus Infection among Students at Secondary Occupational Health School in China.

Cervical cancer (CC) is one of the most common causes of cancer-related deaths worldwide. CC is mainly caused by human papilloma virus (HPV), which can be prevented by vaccination. We conducted a cross-sectional study in secondary occupational health school (SOHS) through a questionnaire aimed to assess the awareness and knowledge regarding HPV infection of students. A total of 2248 students participated in the survey, 45.3% of them had heard about CC, while only 21.9% of them had heard about HPV; and 74.2% had no idea of the causal link between HPV infection and CC. Most participants displayed poor awareness and knowledge about HPV infection. The results suggested that age, grade, major, academic performance, etc. were correlated with higher awareness of CC, HPV and HPV infection (p < 0.05). In multivariable logistic analysis, third-grade students had the most increased awareness of CC (OR = 17.13, 95%CI: [8.11, 36.15]), HPV (OR = 6.59, 95%CI: [4.16, 10.43]) and HPV vaccine (OR = 2.78, 95%CI: [1.78, 4.32]) when compared to first-grade. Awareness and knowledge regarding HPV infection were insufficient among students in SOHS. As the future healthcare providers, these results highlight the need to supplement targeted education to improve their awareness and knowledge of HPV and vaccination.

Parental exposure to bisphenol A affects pharyngeal cartilage development and causes global transcriptomic changes in zebrafish (Danio rerio) offspring.

BACKGROUND: As one of the most common endocrine-disrupting chemicals (EDCs), bisphenol A (BPA) is a threat to aquatic ecosystems. Despite a rich literature addressing the adverse effects of BPA on various systems in fish models, the potential impact of parental BPA exposure on offspring pharyngeal cartilage development is poorly understood. METHODS: Adult zebrafish (F0) were exposed to BPA (1.0 µM) or control for 7 days. Eggs (F1) were collected and exposed to BPA (control, 0.05, 0.1, 1, 10 µM) until 120 h post-fertilization. Histomorphometrical essay was used to quantitatively and qualitatively assess the effects of BPA on pharyngeal cartilage development. RNA sequencing (RNA-seq) was used to discover differentially expressed genes (DEGs), and KEGG pathway and GO enrichment analysis were performed to interpret functional ontology. RESULTS: Parental BPA exposure affected hatchability and heart rates of F1 progeny. By pathology analysis, parental BPA exposure caused craniofacial deformity, characterized by wider angles of cartilage elements, disrupted pharyngeal chondrocytes and promoted apoptosis and elongation of head length. RNA-seq suggested that many DEGs were involved in multiple biological processes and signaling pathways; defense responses, reactive oxygen species metabolic process, apoptosis, p53 signaling pathway and MAPK signaling pathway were closely associated with the toxicity of parental BPA exposure. CONCLUSIONS: Parental BPA exposure affected chondrogenesis in the viscerocranium of zebrafish offspring and led to global transcriptomic changes involved in apoptosis, hyperplasia and oxidative stress. These newly identified gene expression patterns, pathways and gene networks of zebrafish eleutheroembryos after early-life waterborne BPA exposure, may lead to severe and permanent morphological and functional consequences.

COVID-19 infection outbreak increases anxiety level of general public in China: involved mechanisms and influencing factors.

BACKGROUND: COVID-19 outbreak happened last December in China and is still continuing. Here, we reported effects of COVID-19 outbreak on the mood of general public and ascertained impacts of psychosocial factors on the plague-related emotional measures. METHODS: During Feb. 4-6, 2020, a self-reported questionnaire Beck Anxiety Inventory (BAI) was disseminated to general public via Wechat, along with a sociodemographic information sheet. BAI score and incidences of moderate and severe anxiety in subgroups of respondents were compared. Multiple linear and logistic regressions were done for correlation analysis and to identify factors predictive of anxiety. RESULTS: Averaged BAI score of all respondents is higher than those of general public in two previous studies. The people quarantined for probable COVID-19 infection presented higher BAI score and incidences of moderate and severe anxiety relative to non-quarantined respondents. People in high epidemic area showed higher BAI score and incidences of moderate and severe anxiety compared to those in low epidemic area. Significant associations existed between anxiety level of the respondents and each of the investigated factors, except for gender. Quarantine was the predictor with a highest OR, followed by divorced/widow. The other factors showed smaller but significant effects on the anxiety level of respondents. LIMITATIONS: This cross-sectional study was unable to track the emotional changes in the respondents over time. It had a relatively small sample and involved some of emotional measures only. CONCLUSION: These data are of help in planning psychological interventions for the different subpopulations in general public during and after COVID-19 outbreak.

The effectiveness of intensity-modulated radiation therapy versus 2D-RT for the treatment of nasopharyngeal carcinoma: A systematic review and meta-analysis.

BACKGROUND: At present, the management of nasopharyngeal carcinoma (NPC) is mainly based on radiotherapy, but there are many radiation delivery techniques such as intensity-modulated radiotherapy (IMRT) and 2-dimensional radiotherapy (2D-RT). MATERIALS AND METHODS: We searched all the eligible studies through the PubMed, Cochrane Library, Medline, and Embase. The endpoint events in meta-analysis were overall survival (OS), tumor local control including local-regional free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS), and late toxicities. RESULTS: A total of ten publications met the criteria and were identified through searches of the databases and references. We included 13304 patients in the meta-analysis, of whom 5212 received IMRT and 8092 were allocated to 2D-RT alone group. Compared with 2D-RT treatment, the IMRT group was associated with a better 5-year OS (OR = 1.70; 95% CI = 1.36-2.12), LRFS (OR = 2.08; 95% CI = 1.82-2.37), and PFS (OR = 1.40; 95% CI = 1.26-1.56). Additionally, the incidence of late toxicities such as late xerostomia (OR = 0.21; 95% CI = 0.09-0.51), trismus (OR = 0.16; 95% CI = 0.04-0.60), and temporal lobe neuropathy (TLN) (OR = 0.40; 95% CI = 0.24-0.67) for NPC patients in IMRT group were significantly lower than 2D-RT. CONCLUSIONS: The meta-analysis demonstrates that IMRT provides improved long-term tumor overall survival and local control including LRFS and PFS. Additionally, IMRT yields a lower incidence of late toxicities induced by irradiation in NPC patients. Compared to 2D-RT, IMRT may be an effective treatment for patients with NPC. Further intensive studies should be pursued to examine the association.

Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia With Losing Major Molecular Response as a Definition for Molecular Relapse: A Systematic Review and Meta-Analysis.

Background: A new goal in treatment of chronic myeloid leukemia (CML) in patients with stable deep molecular response (DMR) is maintaining durable treatment-free remission (TFR) after discontinuing tyrosine kinase inhibitor (TKI) treatment. Methods: We conducted a systematic review and meta-analysis focusing on the efficacy and safety of TKI discontinuation but also exploring the factors contributing to successful TFR. Results: The search yielded 10 trials including 1,601 patients. For patients who discontinued TKIs, the estimated weighted mean incidence of major molecular relapse was 16% (95%CI: 11-21), 34% (95%CI: 29-38), 39% (95%CI: 35-43) and 41% (95%CI: 36-47) at 3, 6, 12, and 24 months, respectively. Of these, 39, 82, and 95% of molecular losses occurred within the first 3, 6, and 12 months. In safety analysis, among patients without TFR, 98% (95% CI: 96-100) were sensitive to TKI retreatment. No new safety issues were identified except TKI withdrawal syndrome, which appeared during the early TFR phase, with a weighted mean incidence of 27% (95%CI: 19-35). Our subgroup analysis suggested better TFR associated with interferon therapy (P = 0.007), depth of molecular response (P = 0.018) and duration of DMR (P < 0.001). Conclusions: TFR as an extension of an approach to optimize management of CML is clinically feasible in approximately 59% of patients with sufficient TKI response. In the remaining 41% of patients with molecular relapse, discontinuing TKIs had no negative impact on clinical outcomes. Given the high heterogeneity among studies, the role of these predictors for successful TFR still requires further investigation.

Blood Cadmium Level Is Associated with Short Progression-Free Survival in Nasopharyngeal Carcinoma.

The prognosis of nasopharyngeal carcinoma (NPC) is poor with disease progression. Cadmium exposure is a risk factor for NPC. We aimed to investigate the effect of cadmium exposure, by measuring cadmium level, and clinicopathologic factors on NPC disease progression and prognosis. A total of 134 NPC cases were analyzed and venous blood samples were collected. Blood cadmium level was analyzed by graphite furnace atomic absorption spectrophotometry. Clinical data were collected at baseline for patients and tumor characteristics from medical records. Progression-free survival (PFS) was analyzed during follow-up. The effect of cadmium exposure and clinical factors on PFS was analyzed by the Kaplan-Meier method and Cox regression models. Blood cadmium level was associated with history of disease and smoking history and pack-years. On Kaplan-Meier analysis, a high blood cadmium level, male sex, smoking history and increasing pack-years, as well as advanced clinical stage were all associated with short PFS. On multivariate analysis, blood cadmium level was an independent risk factor and predictor of NPC prognosis and disease progression. Cadmium exposure and related clinical factors can affect the prognosis of NPC, which merits further study to clarify.

First-line treatment strategies for newly diagnosed chronic myeloid leukemia: a network meta-analysis.

OBJECTIVES: With bosutinib proven to be available for frontline treatment, there are currently four frontline treatments as well as an additional strategy with high-dose imatinib for newly diagnosed chronic myeloid leukemia (CML). Due to the lack of direct comparison of high-dose imatinib, dasatinib, nilotinib, and bosutinib, we summarized the evidence to indirectly compare the efficacy among these treatment options. METHODS: In total, 14 randomized clinical trials including 5,630 patients were analyzed by direct and mixed-treatment comparisons. Outcomes assessed were the following: complete cytogenetic response at 12 months; major molecular response at 12, 24, and 36 months; deep molecular response at 12, 24, 36, and 60 months; early molecular response at 3 months; progression-free survival (PFS); overall survival (OS); and Grade 3 or 4 adverse events (AEs). RESULTS: The Bayesian network meta-analysis demonstrated that high-dose imatinib was less effective than all new-generation tyrosine kinase inhibitors and had a higher probability of Grade 3 or 4 AEs. For molecular response, 300 mg of nilotinib was likely to be the preferred frontline treatment, as demonstrated by higher response rates and faster, deeper, and longer molecular response. For PFS and OS, there were high likelihoods (79% and 74%, respectively) that 400 mg of nilotinib was the preferred option. For AEs, standard-dose imatinib has the highest probability (65%) of being the most favorable toxicity profile. CONCLUSION: Considering the efficacy and toxicity profile, it is not recommended to use high-dose imatinib for treatment. This analysis also showed that nilotinib has the highest probability to become the preferred frontline agents for treating CML.