Integrative analysis of DNA methylome and transcriptome reveals epigenetic regulation of bisphenols-induced cardiomyocyte hypertrophy.

Cardiac hypertrophy, a kind of cardiomyopathic abnormality, might trigger heart contractile and diastolic dysfunction, and even heart failure. Currently, bisphenols (BPs) including bisphenol A (BPA), and its alternatives bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol S (BPS) are ubiquitously applied in various products and potentially possess high cardiovascular risks for humans. However, the substantial experimental evidences of BPs on heart function, and their structure-related effects on cardiomyocyte hypertrophy are still urgently needed. DNA methylation, a typical epigenetics, play key roles in BPs-induced transcription dysregulation, thereby affecting human health including cardiovascular system. Thus, in this study, we performed RNA-seq and reduced representation bisulfite sequencing (RRBS) to profile the landscapes of BPs-induced cardiotoxicity and to determine the key roles of DNA methylation in the transcription. Further, the capabilities of three BPA analogues, together with BPA, in impacting heart function and changing DNA methylation and transcription were compared. We concluded that similar to BPA, BPAF, BPF and BPS exposure deteriorated heart function in a mouse model, and induced cardiomyocyte hypertrophy in a H9c2 cell line. BPAF, BPF and BPS all played BPA-like roles in both transcriptive and methylated hierarchies. Moreover, we validated the expression levels of four cardiomyocyte hypertrophy related candidate genes, Psmc1, Piptnm2, Maz and Dusp18, which were all upregulated and with DNA hypomethylation. The findings on the induction of BPA analogues on cardiomyocyte hypertrophy and DNA methylation revealed their potential detrimental risks in heart function of humans.

Danggui Buxue decoction ameliorates mitochondrial biogenesis and cognitive deficits through upregulating histone H4 lysine 12 acetylation in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.

Efficacy of salvage therapies after failure of adjuvant anti-PD-1 monotherapy for melanoma in the Chinese population: a multi-institutional cohort study.

The majority of melanoma patients experience relapse during adjuvant therapy or after the end of therapy. Sixty-one patients from 3 melanoma centres who experienced recurrence and received adjuvant pembrolizumab for resected stage III/IV melanoma were enrolled. Disease characteristics, recurrence characteristics, subsequent management and outcomes were retrospectively analysed. Sixty-one patients were enrolled in this study. The median time to first relapse from the commencement of adjuvant pembrolizumab was 8 months (1-22 months). The first recurrences were locoregional alone in 25 patients (41%), distant alone in 29 (47.5%) and concurrent locoregional and distant relapse in 7 (11.5%). At the first recurrence, 4 patients (80%) who underwent resection alone experienced further relapse of disease. Three (60%) patients who were treated with adjuvant pembrolizumab following surgery, 2 (100%) patients who were treated with adjuvant chemotherapy, 2 (66.7%) patients who were treated with adjuvant chemotherapy and pembrolizumab combined and 3 (100%) patients who were treated with adjuvant radiotherapy and pembrolizumab combined had further recurrence. Of the three patients treated with adjuvant BRAF/MEKi following the first relapse, none had yet recurred. Of the 8 patients treated with pembrolizumab alone, only one patient (12.5%) who recurred after ceasing adjuvant PD1 had a partial response. The overall response rate to BRAF/MEKi was 75%, 3/4; to pembrolizumab in combination with an oral multitargeted receptor tyrosine kinase inhibitor, it was 22.2%, 2/9; to chemotherapeutic agents alone, it was 33.3%, 1/3; and to chemotherapeutic agents combined with pembrolizumab, it was 37.5%, 3/8. The patient treated with imatinib had progressive disease after 3 months of treatment. Of the 6 patients who received temozolomide combined with pembrolizumab, 3 (3/6, 50%) had a partial response. The median OS of the patients who relapsed locoregionally only was longer than that of the patients who relapsed distally at the first recurrence (35 months and 14 months, respectively; P < 0.01). The outcomes of the patients with disease recurrence during or after the completion of 1 year of adjuvant anti-PD1 therapy were poor despite multimodality treatment.

The regulatory function of piRNA/PIWI complex in cancer and other human diseases: The role of DNA methylation.

Piwi-interacting RNAs (piRNAs) are a class of short chain noncoding RNAs that are constituted by 26-30 nucleotides (nt) and can couple with PIWI protein family. piRNAs were initially described in germline cells and are believed to be critical regulators of the maintenance of reproductive line. Increasing evidence has extended our perspectives on the biological significance of piRNAs and indicated that they could still affect somatic gene expression through DNA methylation, chromatin modification and transposon silencing, etc. Many studies have revealed that the dysregulation of piRNAs might contribute to diverse diseases through epigenetic changes represented by DNA methylation and chromatin modification. In this review, we summarized piRNA/PIWI protein-mediated DNA methylation regulation mechanisms and methylation changes caused by piRNA/PIWI proteins in different diseases, especially cancers. Since DNA methylation and inhibitory chromatin marks represented by histone H3 lysine 9 (H3K9) methylation frequently cooperate to silence genomic regions, we also included methylation in chromatin modification within this discussion. Furthermore, we discussed the potential clinical applications of piRNAs as a new type promising biomarkers for cancer diagnosis, as well as the significance of piRNA/PIWI protein-associated methylation changes in treatment, providing disparate insights into the potential applications of them.

Prior Therapy With Pegylated-Interferon Alfa-2b Improves the Efficacy of Adjuvant Pembrolizumab in Resectable Advanced Melanoma.

Combination immunotherapy can overcome the limited objective response rates of PD-1 blockade. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to PD-1 blockade. According to clinical practice guidelines, IFN-α was recommended as adjuvant therapy for stage IIB/C melanoma patients. However, the impact of prior IFN-α therapy on the efficacy of subsequent PD-1 blockade in melanoma has not been previously reported. Therefore, we performed a retrospective analysis for melanoma patients and addressed whether prior IFN-α therapy enhanced adjuvant pembrolizumab as later-line treatment. Fifty-six patients with resectable stage III/IV melanoma who received adjuvant therapy with pembrolizumab were retrospectively enrolled in this study. Notably, 25 patients received adjuvant pegylated IFN-α (PEG-IFN-α) in the prior line of treatment while 31 patients did not receive prior PEG-IFN-α therapy. Cox regression analysis showed that prior PEG-IFN-α therapy was associated with the efficacy of later-line adjuvant pembrolizumab (hazard ratio=0.37, 95% CI 0.16-0.89; P = 0.026). The recurrence rates after treatment with adjuvant pembrolizumab were significantly reduced in the prior PEG-IFN-α group (P < 0.001). The Kaplan-Meier analysis also showed that recurrence-free survival (RFS) after adjuvant pembrolizumab therapy was prolonged by prior PEG-IFN-α treatment (median RFSPem 8.5 months vs. 4.5 months; P = 0.0372). These findings indicated that prior PEG-IFN-α could enhance the efficacy of adjuvant pembrolizumab. The long-lasting effects of PEG-IFN-α provide a new rationale for designing combination or sequential immunotherapy.

The emerging function and clinical significance of circRNAs in Thyroid Cancer and Autoimmune Thyroid Diseases.

Thyroid cancer (TC) is one of the most common malignant tumors, with high morbidity and mortality rates worldwide. The incidence of TC, especially that of papillary thyroid carcinoma (PTC); has increased rapidly in recent decades. Autoimmune thyroid disease (AITD) is closely related to TC and has an estimated prevalence of 5%. Thus, it is becoming increasingly important to identify potential diagnostic biomarkers and therapeutic targets for TC and AITD. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently bonded circular structures that lack 5'-3' polarity and polyadenylated tails. Several circRNAs play crucial roles in the development of various diseases, including TC and AITD, and could be important new biomarkers and/or targets for the diagnosis and therapy of such disorders. Although there are four subtypes of TC, research on circRNA has largely focused on its connection to PTC. Therefore, this review mainly summarizes the relationships between circRNAs and PTC and AITD, including the molecular mechanisms underlying these relationships. In particular, the functions of "miRNA sponges" and their interactions with proteins and RNA are discussed. The possible targeting of circRNAs for the prevention, diagnosis, and treatment of TC and AITD is also described. CircRNAs could be potential biomarkers of TC and AITD, although validation will be required before they can be implemented in clinical practice.

Insights into the regulatory role of Plexin D1 signalling in cardiovascular development and diseases.

Plexin D1 (PLXND1), which was previously thought to mediate semaphorin signalling, belongs to the Plexin family of transmembrane proteins. PLXND1 cooperates mostly with the coreceptor neuropilin and participates in many aspects of axonal guidance. PLXND1 can also act as both a tumour promoter and a tumour suppressor. Emerging evidence suggests that mutations in PLXND1 or Semaphorin 3E, the canonical ligand of PLXND1, can lead to serious cardiovascular diseases, such as congenital heart defects, CHARGE syndrome and systemic sclerosis. Upon ligand binding, PLXND1 can act as a GTPase-activating protein (GAP) and modulate integrin-mediated cell adhesion, cytoskeletal dynamics and cell migration. These effects may play regulatory roles in the development of the cardiovascular system and disease. The cardiovascular effects of PLXND1 signalling have gradually been elucidated. PLXND1 was recently shown to detect physical forces and translate them into intracellular biochemical signals in the context of atherosclerosis. Therefore, the role of PLXND1 in cardiovascular development and diseases is gaining research interest because of its potential as a biomarker and therapeutic target. In this review, we describe the cardiac effects, vascular effects and possible molecular mechanisms of PLXND1 signalling.

Cardiovascular toxicity and mechanism of bisphenol A and emerging risk of bisphenol S.

Epidemiological and animal studies indicate that increased exposure to bisphenol A (BPA) induces various human cardiovascular diseases (CVDs), including myocardial infarction, arrhythmias, dilated cardiomyopathy, atherosclerosis, and hypertension. Bisphenol S (BPS), an alternative to BPA, is increasingly present in various consumer products and human bodies worldwide. Recently, emerging evidence has shown that BPS might be related to cardiovascular disorders. In this review, we present striking evidence of the correlation between BPA exposure and various CVDs, and show that a nonmonotonic dose-response curve (NMDRC) was common in studies of the CV effects of BPA in vivo. The CV impairment induced by low doses of BPA should be highlighted, especially during developmental exposure or during coexposure with other risk factors. Furthermore, we explored the possible underlying mechanisms of these effects-particularly nuclear receptor signaling, ion channels, and epigenetic mechanisms-and the possible participation of lipid metabolism, oxidative stress and cell signaling. As the potential risks of BPA exposure in humans are still noteworthy, studies of BPA in CVDs should be strengthened, especially with respect to the mechanisms, prevention and treatment. Moreover, the potential CV risk of BPS reported by in vivo studies calls for immediate epidemiological investigations and animal studies to reveal the relationships of BPS and other BPA alternatives with human CVDs.

Adjuvant pembrolizumab versus high-dose interferon α-2b for Chinese patients with resected stage III melanoma: a retrospective cohort study.

Background Pembrolizumab has robust antitumor activity in advanced melanoma and has been approved for the treatment of melanoma in many countries. Adjuvant pembrolizumab was associated with longer recurrence-free survival (RFS) in patients with resected stage III melanoma. We herein report on the RFS outcomes of Chinese patients with resected stage III melanoma receiving adjuvant pembrolizumab in comparison to those receiving interferon α-2b (IFN-α-2b). Methods We retrospectively investigated the medical records of subjects with resected stage III melanoma with no in-transit metastases diagnosed who were treated at the Cancer Hospital of the University of Chinese Academy of Sciences and collected historical clinical data of patients receiving adjuvant IFN-α-2b therapy in our hospital. The RFS rates were evaluated using Kaplan-Meier curves, and the differences between the groups were tested using the log-rank test. Results A total of 29 patients receiving adjuvant pembrolizumab therapy and 27 patients receiving adjuvant IFN-α-2b therapy were enrolled. The median RFS was not reached (95% CI not estimable [NE]) in the pembrolizumab group and was 25 months in the IFN-α-2b group, and there was no significant difference in RFS between the pembrolizumab and IFN-α-2b groups (HR = 1.20, log-rank p = 0.75). There was no significant difference in RFS for acral melanoma between the pembrolizumab group and IFN-α-2b group (HR = 1.22, log-rank p = 0.79). For patients with IIIC or IIID melanoma, the RFS in the pembrolizumab group was also similar to that of the IFN-α-2b group (HR = 0.80, log-rank p = 0.47). The RFS for patients receiving pembrolizumab with programmed cell death ligand 1 (PD-L1)-positive tumors might tend to be longer than that for patients with PD-L1-negative tumors, but there was no significant difference between the groups (HR = 3.37, log-rank p = 0.17). High tumor mutational burden (TMB) did not reveal a trend to predict a longer RFS than low TMB in patients receiving pembrolizumab (HR = 1.63, log-rank p = 0.63). Grade 3-4 adverse events occurred in 6 (22.22%) of 27 patients in the IFN-α-2b group. Discontinuations attributed to adverse events (AEs) occurred in 2 patients treated with IFN-α-2b. Immune-related adverse events were observed in 5 (17.24%) patients in the pembrolizumab group. In the pembrolizumab group, grade 3-4 adverse events occurred in 2 (6.90%) patients, 1 of which required the discontinuation of a study drug and corticosteroid treatment. None of the patients discontinued treatment due to treatment-related or immune-mediated AEs. Conclusions Adjuvant pembrolizumab appeared to be as effective as IFN-α-2b in prolonging RFS in Chinese patients with resected stage III melanoma. Adjuvant pembrolizumab was associated with a lower rate of treatment-related AEs than IFN-α-2b. A prospective study is needed to confirm the clinical benefit of adjuvant pembrolizumab and determine dependable biomarkers.

Mutational profiling of melanomas in patients from the southeast coast of China.

BACKGROUND: Melanoma is one of the most lethal cancers in China, and the genomic landscape of melanoma in the Asian population is different from Caucasians. METHODS: To better understand the genomic profile of distinct kinds of melanomas in China, we used an NGS platform to analysis of 62 melanomas from the southeast coast of China. RESULTS: The recurrently mutated genes are BRAF (29%), RAS (29%), CTNNB1 (11.3%), KIT (9.7%) and NF1 (8.1%) in the whole group. Among the different types of melanoma, cutaneous melanoma has a high frequency of BRAF mutation (70.6%), NRAS (57.1%) is the top one gene found in the mucosal group. For acral melanoma, except for the RAS family, CTNNB1 mutation (13.2%) first found to be frequently mutated in our cohort and patients with CTNNB1 activating mutation. These results may be related to a more reduced response to immunotherapy, according to the earlier report. CONCLUSIONS: Our study profiled the mutational landscape of melanoma in patients from the southeast coast of China. In addition to the most frequently mutated genes (BRAF, RAS, KIT) reported in other studies, we found some new recurrent gene mutations, such as CTNNB1 mutation in acral melanoma, that had not been reported in other studies.

Comparison the sensitivity of amphibian metamorphosis assays with NF 48 stage and NF 51 stage Xenopus laevis tadpoles.

The amphibian metamorphosis assay (AMA) was proposed by the Organization for Economic Cooperation and Development (OECD) to screen thyroid disruptors of vertebrate species. The general experimental design of the AMA exposes Nieuwkoop and Faber (NF) stage 51 Xenopus laevis tadpoles to test chemical concentrations for 21 d. However, recent studies demonstrated that thyroid gland began to function after NF stage 45 in X. laevis. Thus, in this study, we initiated exposure with NF stage 48 tadpoles when the thyroid gland is still in a preliminary development period, to compare the sensitivity of the AMA with NF 48 stage and NF 51 stage tadpoles. Further, the application and sensitivity of the optimized AMA were evaluated and validated by two known thyroid toxicants methimazole (MMI) and sodium perchlorate (SP). The observational endpoints are developmental stage, hind limb length (HLL), snout-vent length (SVL), wet weight, and daily observations of mortality. The results were as follows. Although the sensitivity to endpoint of growth, such as wet weight and SVL was similar between the two assays, our optimized AMA detected delaying effects of 1 mg/L MMI and 32 µg/L SP on metamorphosis development both on day 7 and at test termination, which were lower than those in AMA. Additionally, it is easier to get a large number of animals at NF stage 48 than NF stage 51 in a short time. Thus, it is suggested that the NF stage 48 tadpoles might be applied to the AMA for efficiently screening the thyroid-active substances.

Neogambogic Acid Suppresses Receptor Activator of Nuclear Factor κB Ligand (RANKL)-Induced Osteoclastogenesis by Inhibiting the JNK and NF-κB Pathways in Mouse Bone Marrow-Derived Monocyte/Macrophages.

BACKGROUND Neogambogic acid (NGA) is used in traditional Chinese medicine. The aim of this study was to investigate the effects of NGA on gene signaling pathways involved in osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages (BMMs) and on bone resorption in vitro. MATERIAL AND METHODS Primary mouse BMMs were cultured with increasing concentrations of NGA. Real-time polymerase chain reaction was used to study the expression of mRNAs corresponding to gene products specific to receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, including tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), cathepsin K (CTSK), and nuclear factor of activated T cells c1 (NFATc1). A cell counting kit-8 assay was used to evaluate cell proliferation. Western blotting and confocal immunofluorescence microscopy were used to investigate the signaling pathways. A bone resorption model was used to quantify bone resorption. RESULTS An NGA dose of ≤0.4 µg/ml had no significant effect on the proliferation of mouse BMMs in vitro (P>0.05); concentrations of between 0.1-0.4 µg/ml significantly inhibited RANKL-induced osteoclastogenesis (P<0.01) in a dose-dependent manner. Compared with the control group, NGA significantly reduced RANKL-induced bone resorption in vitro (P <0.01), and downregulated the expression of osteoclast-related mRNAs of TRAP, CTR, CTSK, and NFATc1. NGA suppressed the activation of JNK but not the p38 signaling pathway and significantly reduced NF-κB p65 phosphorylation and the nuclear transport of NF-κB molecules, which inhibited NFATc1 expression. CONCLUSIONS NGA suppressed RANKL-induced osteoclastogenesis by inhibiting the JNK and NF-κB pathways in mouse BMMs in vitro and reduced osteoclastic bone resorption.

Xiaoaiping combined with cisplatin can inhibit proliferation and invasion and induce cell cycle arrest and apoptosis in human ovarian cancer cell lines.

PURPOSE: The aim of the present study was utilizing Xiaoaiping as a single agent or combined with cisplatin to study its effect on the ovarian cancer cells (HO-8910 and HO-8910PM cells) in tumor cell proliferation, cell apoptosis, cell cycle distribution and cell invasion and migration. METHODS: Both HO-8910 and HO-8910PM cell lines were treated with Xiaoaiping injection, cisplatin or combination. Effects on the cell viability and apoptosis induction were estimated using the Cell counting Kit-8 assay and Annexin V-FITC/Propidium Iodide staining. The distribution of cells in different phases of the cell cycle was assayed using flow cytometry analysis. The effects of Xiaoaiping on the inhibition of cell invasion and migration were researched with Transwell cell migration. RESULTS: Both Xiaoaiping and cisplatin significantly decreased the HO-8910 cell survival versus control arm. Combination treatment showed a higher cytotoxicity to cells in vitro than Xiaoaiping and cisplatin alone. An increase in the G0/G1 phase fraction in HO-8910 cells treated with either Xiaoaiping or cisplatin alone was evident when compared to the fraction in control arm. Compared to the effects of treatment with either agent alone, combination treatment significantly increased the fraction of cells in G0/G1 phase. The HO-8910 cell lines treated with cisplatin demonstrated a significant increase of apoptotic cell rate compared to untreated cell lines. The rate of apoptosis in combined treatment group was significantly higher than that of the single agent treatment groups. A significant reduction in the number of invading cells was observed for Xiaoaiping-treated HO-8910 cells compared with the control group. However, cisplatin did not significantly induce the migration of cells versus untreated cells. Combination of Xiaoaiping and cisplatin significantly suppressed cell invasion and migration versus single-drug treatment in HO-8910 cells. The results of HO-8910PM cells were similar with HO-8910 cells in all tests. CONCLUSIONS: In summary, our results showed that Xiaoaiping as a single agent or combined with cisplatin could induce cell cycle arrest, cause apoptosis and necrosis in ovarian cancer cells, and inhibit cell invasion and migration. The present study also laid a foundation for further investigation involving molecular mechanism. Above all, it may provide a novel therapeutic regimen for ovarian cancer.

Impact of carboplatin plus paclitaxel combined with endostar against A375 melanoma cells: An in vitro and in vivo analysis.

PURPOSE: The aim of the present study was to investigate the efficacy of carboplatin plus paclitaxel (CP) combined with endostar against A375 melanoma cells in vitro and in vivo. METHODS: Effects on the cell viability and apoptosis induction were estimated with the Cell counting Kit-8 assay and Annexin V-FITC/Propidium Iodide staining. Fifty female BALB/c-nude mice with subcutaneous injection of A375 cells were randomized to be treated with normal saline, dacarbazine alone, dacarbazine plus endostar, carboplatin plus paclitaxel, and CP plus endostar. Tumor volume of mice was monitored after injection and survival time was adopted for survival analysis. RESULTS: CP plus endostar significantly decreased the cell survival rate compared with CP (P<0.01). Combination of CP and endostar showed higher cytotoxicity to A375 cells in vitro than endostar plus dacarbazine (P<0.01). The percentage of apoptotic cells in A375 cells treated with CP plus endostar was appreciably higher when compared to CP group (P<0.05). The mean relative tumor size in CP group was definitely larger (p<0.05) than CP plus endostar group. In addition, the mean survival time in CP plus endostar group was notably elevated compared with the CP group (P<0.05). CONCLUSIONS: Our data indicated that treatment with CP plus endostar significantly reduced cell growth and induced a high rate of apoptotic cells in the A375 melanoma cell line. CP and endostar exhibited synergistic anti-tumor activities in A375 melanoma cells in vitro. CP plus endostar suppressed the growth of xenograft tumors and prolonged the survival time of mice with xenograft tumors. Combination of CP and endostar may be a promising treatment for melanoma.

Efficacy and Safety of OnabotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Neurogenic detrusor overactivity (NDO) affects the quality of life (QoL) of millions of individuals worldwide. The purpose of this study was to assess the efficacy and safety of onabotulinumtoxinA in patients with NDO using a network meta-analytic approach, which can also quantify and compare the efficacy of onabotulinumtoxinA across different dosages. METHODS: PubMed, EMBASE, and the Controlled Trials Register were searched to identify randomized controlled trials comparing onabotulinumtoxinA to a control for NDO in adult patients. The primary outcome was the mean number of urinary incontinence (UI) episodes per week. Urodynamic parameters included the maximum cystometric capacity (MCC) and the maximum detrusor pressure (MDP). The safety of onabotulinumtoxinA was determined by the incidence of various frequent adverse events (AEs). Two authors extracted data independently, and the statistical analyses were performed using RevMan 5.1.0 software. RESULTS: A total of 1,915 patients from six randomized controlled trials were included in this meta-analysis. The onabotulinumtoxinA-treated groups had a significantly decreased mean number of urinary incontinence episodes per week (at week 6) (onabotulinumtoxinA200U: MD: -10.72, 95% CI: -13.4 to -8.04, P<0.00001; 300 U: MD: -11.42, 95% CI: -13.91 to -8.93, P<0.00001), MDP (200 U: MD: -33.46, 95% CI: -39.74 to -27.18, P<0.00001; 300 U: MD: -31.72, 95% CI: -37.69 to -25.75, P<0.00001), and greater increased MCC (200 U: MD: 141.30, 95% CI: 121.28 to 161.32, P<0.00001; 300 U: MD: 151.39, 95% CI: 130.43 to 172.34, P<0.00001) compared to the placebo-treated groups. However, there were no significant differences between the onabotulinumtoxinA-treated groups for the number of weekly UI episodes at 6 weeks (MD: 0.08, 95% CI: -2.57 to 2.73, P = 0.95). Similarly, we also observed that there were no significant differences in MCC (MD: -9.97, 95% CI: -33.15 to 13.20, P = 0.40) and MDP (MD: -1.86, 95% CI: -8.09 to 4.37, P = 0.56). Considering the AEs, the onabotulinumtoxinA-treated groups were often associated with more complications, including urinary tract infections (UTIs) (RR: 1.47, 95% CI: 1.29 to 1.67, P<0.00001), urinary retention (RR: 5.58, 95% CI: 3.53 to 8.83, P<0.00001), hematuria (RR: 1.70, 95% CI: 1.01 to 2.85, P = 0.05), and muscle weakness (RR: 2.59, 95% CI: 1.36 to 4.91, P = 0.004). CONCLUSIONS: OnabotulinumtoxinA can significantly reduce the frequency of urge urinary incontinence and improve urodynamic parameters (MCC and MDP) in patients with NDO at 6 weeks after treatment. This meta-analysis indicates that onabotulinumtoxinA is effective and safe for treating patients with NDO compared to placebo. Additionally, we did not observe any statistical or clinical differences in efficacy between 300 and 200 U dosages.