Niraparib restrains prostate cancer cell proliferation and metastasis and tumor growth in mice by regulating the lncRNA MEG3/miR-181-5p/GATA6 pathway.

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have gained approval for treating patients with castration-resistant prostate cancer (CRPC). Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), plays a role in inhibiting tumorigenesis through regulating DNA repair genes. This study aimed to investigate the association between the anti-prostate cancer (PCa) effect of niraparib, a representative PARPi, and MEG3 expression, as well as explore the downstream pathway involved. Methods: The levels of MEG3, miR-181-5p, GATA binding protein 6 (GATA6) in clinical samples from PCa patients were accessed by RT-qPCR. PC3 cells were treated with niraparib, and the expression of MEG3, miR-181-5p, GATA6 expression was tested. PC3 cell proliferation, migration, and invasion were tested by CCK-8, wound healing, and Transwell assays, respectively. The bindings between miR-181-5p and MEG3/GATA6 were determined by dual-luciferase reporter gene assay. Furthermore, rescue experiments were conducted to investigate the underlying mechanism of MEG3/miR-181-5p/GATA6 axis in PCa progression. Additionally, mice were injected with PC3 cells transfected with sh-MEG3 and treated with niraparib, and the xenograft tumor growth was observed. Results: MEG3 and GATA6 were upregulated and miR-181-5p was downregulated in PCa patients. Niraparib treatment substantially upregulated MEG3 and GATA6, and downregulated miR-181-5p expression in PCa cells. Niraparib effectively restrained PC3 cell proliferation, migration, and invasion. MiR-181-5p targeted to MEG3, and the inhibitory effects of MEG3 overexpression on PC3 cell proliferation and metastasis were abrogated by miR-181-5p overexpression. Moreover, GATA6 was identified as a target of miR-181-5p, and GATA6 silencing abolished the inhibitory effects of miR-181-5p inhibition on PC3 cell proliferation and metastasis. Besides, MEG3 silencing could abrogate niraparib-mediated tumor growth inhibition in mice. Conclusions: Niraparib restrains prostate cancer cell proliferation and metastasis and tumor growth in mice by regulating the lncRNA MEG3/miR-181-5p/GATA6 pathway.

Calcitonin gene-related peptide predicts therapeutic response to midodrine hydrochloride in children with vasovagal syncope.

The vasoconstriction agent midodrine hydrochloride is a vital treatment for pediatric patients diagnosed with vasovagal syncope (VVS), although the efficacy is variable. This study was designed to explore the value of calcitonin gene-related peptide (CGRP) in predicting the effect of midodrine hydrochloride treatment upon VVS patients. In total, 55 children diagnosed with VVS were treated with midodrine hydrochloride for 3 months. Therapeutic response was evaluated using a symptom score system. CGRP levels were significantly higher in VVS patients (68.700 ± 6.460) than in control subjects (43.400 ± 5.810; t = 18.207, P < 0.001) and symptom scores correlated positively with CGRP concentrations (r = 0.779, P < 0.001). Patients treated with midodrine hydrochloride showed a significant reduction in symptom scores [4 (0, 6.5) vs. 1 (1, 2); z = -6.481; P < 0.001]. However, the value of plasma CGRP were potently elevated in the positive-response subjects than in the negative-response subjects (70.080 ± 5.040) vs. (61.150 ± 3.090); t = 5.817; P < 0.001). The area under the ROC curve showed that the value of CGRP for predicting the therapeutic response to midodrine hydrochloride was 0.946 (95% CI: 0.879-0.997, P < 0.001). With high sensitivity (97.7%) and specificity (83.3%), CGRP predicted the therapeutic response to midodrine hydrochloride (cut-off value, 62.56 pg/ml). In conclusion, CGRP can be used to predict the effect of midodrine hydrochloride administration in VVS patients.

N-myristoyltransferase-1 deficiency blocks myristoylation of LAMTOR1 and inhibits bladder cancer progression.

N-myristoyltransferase-1 (NMT1) catalyzes protein posttranslational myristoylation and functions as an oncogene in various cancers, although its roles in bladder cancer remain elusive. Here, we demonstrated that NMT1 was obviously upregulated in bladder cancer and correlated with overall survival and poor prognosis. Elevation of NMT1 promotes cancer progression and inhibits autophagy in vitro and in vivo. Furthermore, we confirm that LAMTOR1 was myristoylated by NMT1 at Gly 2, resulting in increased LAMTOR1 protein stability and lysosomal localization. Importantly, B13, an inhibitor of NMT1 enzymatic activity, exerted its anti-tumor effects against bladder cancer cells in vitro and in vivo. Taken together, these findings uncover a molecular mechanism of NMT1 in modulating bladder cancer progression and indicate that targeting NMT1 may represent a novel clinical intervention in bladder cancer.

Lymphocyte Hydrogen Sulfide Production Predicts Coronary Artery Lesions in Children with Kawasaki Disease: A Preliminary, Single-Center Study.

To identify whether lymphocyte hydrogen sulfide production is a potential biomarker for predicting coronary artery lesions (CAL) in children with Kawasaki disease (KD). Eighty-six children with KD, 33 normal children and 43 children with fever from June 2016 to January 2019 in Shaanxi Provincial People's Hospital were enrolled. Of 86 KD patients, 16 patients exhibited CAL. Lymphocyte hydrogen sulfide production was significantly greater in KD patients (13.7 ± 2.7) nmol/min/108 lymphocytes than in the controls (9.26 ± 3.33) nmol/min/108 lymphocytes and the fever group (8.21 ± 2.77) nmol/min/108 lymphocytes. The lymphocyte hydrogen sulfide production was greater in CAL patients than the non-CAL patients [(16.24 ± 1.81) vs. (13.12 ± 2.58), p < 0.001]. Receiver operating characteristic curve indicated when the lymphocyte hydrogen sulfide production was >15.285 nmol/min/108 lymphocytes, the sensitivity and specificity for predicting CAL at convalescence were 87.5% and 82.9%, respectively. Lymphocyte hydrogen sulfide production in the acute period is a potentially useful biomarker for predicting CAL in KD children.

Body mass index is decreased in children and adolescents with postural tachycardia syndrome.

Lin J, Zhao H, Ma L, Jiao F. Body mass index is decreased in children and adolescents with postural tachycardia syndrome. Turk J Pediatr 2019; 61: 52-58. Our intent was to explore the predictive value of body mass index (BMI) in differentiating between vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) in children and adolescents. A total of 111 children and adolescents with POTS and 154 children and adolescents with VVS were included in our study. The control group included 82 healthy children and adolescents. Height and weight were measured in all participants. The headup tilt test was performed in participants in all groups (POTS, VVS, and control). BMI was significantly lower in children and adolescents with POTS (18.3±3.4) than in children and adolescents with VVS (20.3±4.2) and the control group (20.5±2.9). The receiver operating characteristic curve was performed to determine the predictive value of BMI differentiation between POTS and VVS and showed that a BMI of 19.30 was the cutoff value for the probability of distinction. However, the results (BMI of 19.30) produced unsatisfactory sensitivity (57.1%) and specificity (28.8%) rates of correctly discriminating between patients with POTS and patients with VVS. Children and adolescents with POTS have a lower BMI compared with healthy peers or children and adolescents with VVS.

LncRNA OIP5-AS1 predicts poor prognosis and regulates cell proliferation and apoptosis in bladder cancer.

Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) is a long intergenic noncoding RNA, which has been suggested to be dysregulated in human cancers and served as tumor suppressor or promoter depending on tumor types. However, the role of OIP5-AS1 in bladder cancer was still unknown. In our study, OIP5-AS1 was overexpressed in bladder cancer, and associated with clinical progression and short overall survival. The loss-of-function studies suggested downregulation of OIP5-AS1 expression decreased cell viability, induced cell-cycle arrest and promoted cell apoptosis in bladder cancer. There was a positive association between OIP5-AS1 expression and OIP5 expression in bladder cancer tissues. Moreover, downregulation of OIP5-AS1 expression reduced messenger RNA and protein levels of OIP5 in bladder cancer cell lines. In conclusion, OIP5-AS1 is a useful biomarker for predicting clinical progression and poor prognosis and promotes cell proliferation through modulating OIP5 expression.

Lymphocyte hydrogen sulfide production predicts intravenous immunoglobulin resistance in children with Kawasaki disease: A preliminary, single-center, case-control study.

The aim of the study was to identify whether lymphocyte hydrogen sulfide production is a potential biomarker to predict intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD).This preliminary, single-center, case-control study conducted between June 2016 and March 2018 in Shaanxi Provincial People's Hospital, 85 children (50 with KD and 35 healthy controls) were included. Laboratory biomarkers were collected from the medical records. All patients with KD received 1 g/kg/d IVIG for 2 days and 30-50 mg/kg/d oral aspirin. The aspirin dose was reduced from 3 to 5 mg/kg/d after body temperature normalized. Plasma hydrogen sulfide levels were detected using sulfide electrode. Lymphocyte hydrogen sulfide levels were detected using the human hydrogen sulfide ELISA kits at the acute stage.Of 50 patients with KD, 31 and 19 were diagnosed with complete KD (cKD) and incomplete KD (iKD), respectively. Eleven patients with KD were resistant to IVIG treatment. The laboratory biomarker findings and levels of plasma and lymphocyte hydrogen sulfide were significantly different between the patients with KD and control group (P < .001). Moreover, lymphocyte hydrogen sulfide production was significantly greater in IVIG-resistant patients than in the IVIG-responsive patients, both in cKD and iKD (P = .018 and P < .001 respectively). Receiver operating characteristic curve indicated that when the lymphocyte hydrogen sulfide production was >15.285 nmol/min/10 lymphocytes, the sensitivity and specificity for predicting IVIG resistance were 90.9% and 76.9%, respectively.Lymphocyte hydrogen sulfide production could serve as a predictor of the therapeutic efficacy of IVIG in children with KD.

Salivary Cortisol Levels Predict Therapeutic Response to a Sleep-Promoting Method in Children with Postural Tachycardia Syndrome.

OBJECTIVE: To determine the value of salivary cortisol concentrations in predicting the efficacy of sleep-promoting treatment in children with postural tachycardia syndrome (POTS). STUDY DESIGN: This prospective study involved 40 children with POTS and 20 healthy children (controls). POTS was diagnosed using the head-up or head-up tilt test. Patients with POTS received a sleep-promoting treatment: >8 hours of sleep every night and a midday nap in an appropriate environment; no drinking water or exercising before bedtime; and urination before bedtime. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality, and symptom scores were used to assess POTS severity. Salivary samples were collected upon awakening, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., and 8:00 p.m., and at bedtime before treatment. Enzyme-linked immunosorbent assay was used to measure salivary cortisol concentrations. RESULTS: Cortisol concentrations were significantly higher in patients with POTS than in the controls at all time points (P < .05 for all). PSQI scores were significantly higher in patients with POTS (7.2 ± 3.0) than in the controls (1.35 ± 1.39; t = -10.370, P <.001). Salivary cortisol concentrations at awakening were significantly higher in responders than in nonresponders (4.83 ± 0.73 vs 4.05 ± 0.79 ng/mL, t = -3.197, P = .003). The area under the receiver operating characteristic curve was 75.8%, (95% CI 59.3%-92%). Cut-off at-awakening salivary cortisol concentrations of >4.1 ng/mL yielded 83.3% sensitivity and 68.7% specificity in predicting therapeutic efficacy. CONCLUSIONS: At-awakening salivary cortisol concentrations may predict the efficacy of sleep-promoting treatment in patients with POTS.

The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model.

Intravesical chemotherapy after transurethral resection has been widely used as an adjuvant therapy to prevent recurrence and progression of superficial bladder cancer. Due to the insufficiency of the current chemotherapeutics, there is an urgent need to search for more novel, effective and safe intravesical agents. Previously, we have proved the in vitro apoptotic effects of fisetin, a dietary flavonoid, on bladder carcinoma cells. In the present study, we have further explored its intravesical efficacy and investigated the underlying mechanisms of its inhibitory effect of bladder cancer through an autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU). We found that fisetin-induced apoptosis in bladder cancer is mediated via modulation of two related pathways: up-regulation of p53 and down-regulation of NF-κB pathway activity, causing changes in the ratio of pro- and antiapoptotic proteins. Meanwhile, administration of fisetin significantly reduced the incidence of MNU-induced bladder tumours by suppressing NF-κB activation and modulating the expression of NF-κB target genes that regulate cell proliferation and cell apoptosis. Our study suggests that the activation of p53 and inhibition of the NF-κB pathway may play important roles in the fisetin-induced apoptosis in bladder cancer. Furthermore, intravesical fisetin effectively inhibited, without any toxicity, the carcinogenesis of bladder cancer in MNU-initiated rats. These findings identify the in vivo chemopreventive efficacy of fisetin and suggest that fisetin could be used as a novel, effective and safe intravesical agent for bladder cancer.

Zerumbone induces apoptosis in human renal cell carcinoma via Gli-1/Bcl-2 pathway.

Renal cell carcinoma (RCC) is a malignant disease insensitive to conventional treatments such as radiochemotherapy and immunotherapy. Search for new approaches to induce cancer cell apoptosis will improve the management of RCC. Here, we reported that zerumbone, a monosesquiterpine, shows anticancer effects on human RCC cells via induction of apoptosis in vitro. Human renal clear cell carcinoma 786-0 and 769-P cell lines were used as the model system. Exposure of RCC cells to zerumbone resulted in cell viability inhibition, accompanied by DNA fragmentation and increased apoptotic index. Mechanically, treatment of RCC cells with zerumbone activated caspase-3 and caspase-9, and finally led to cleavage of PARR In addition, downregulation of Gli-1 and Bcl-2, which were closely related to the chemoresistance of RCC, was observed in zerumbone-treated RCC cells. Taken together, our study provided the first evidence that zerumbone imparted strong inhibitory and apoptotic effects on human RCC cells. The zerumbone-induced apoptosis might be related to the activation of the caspase cascade and deregulation of the Gli-1/Bcl-2 pathway. Our results suggest that zerumbone merit further investigation as an apoptosis inducer as well as a novel RCC chemotherapeutic agent in the clinical setting.