A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group.

BACKGROUND: This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016. METHODS: A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used. RESULTS: The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%. CONCLUSIONS: The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.

Detection of RAS gene mutation and its clinical significance in children with acute lymphoblastic leukemia. / å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— ä¸­RASåŸºå› çªå˜çš„æ£€æµ‹åŠå ¶ä¸´åºŠæ„ä¹‰.

OBJECTIVES: To investigate the mutation rate of the RAS gene and its clinical significance in children with acute lymphoblastic leukemia. METHODS: A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of RAS gene mutation on the overall survival rate was evaluated in these children. RESULTS: Among the 120 children, 35 (29.2%) had RAS gene mutation, 30 (25.0%) had KRAS gene mutation, and 5 (4.2%) had both NRAS and KRAS gene mutations. All NRAS mutations and 71% (25/35) of KRAS mutations were located at the 12th and 13th codons. RAS gene mutation was detected in 35 (33.3%) out of 105 children with B-lineage acute lymphoblastic leukemia, but it was not detected in those with acute T lymphocyte leukemia. Of all the children, 11 (9.2%) were lost to follow-up, and among the 109 children followed up, 16 (14.7%) died. The children with RAS gene mutation had a significantly lower 2-year overall survival rate than those without RAS gene mutation (P<0.05). The prognosis of children with RAS gene mutation combined with WT1 overexpression and WBC>50×109/L at diagnosis was worse (P<0.05). CONCLUSIONS: RAS gene mutation is commonly observed in children with B-lineage acute lymphoblastic leukemia and may have an adverse effect on prognosis.

Identification of the metabolites of erianin in rat and human by liquid chromatography/electrospray ionization tandem mass spectrometry.

RATIONALE: Erianin, a bioactive component isolated from Dctidrobium chrysotoxum Lindl, was demonstrated to have many biological properties relevant to cancer prevention and therapy. However, the metabolic profiles of erianin remain unknown. This study was carried out to investigate the metabolic profiles of erianin in rats and humans. METHODS: Erianin was orally administered to rats at a single dose of 50 mg/kg. Urine and bile samples were collected. For in vitro metabolism, erianin was co-incubated with rat or human hepatocytes at 37°C for 2 h. The samples from incubations and rat were analyzed by liquid chromatography combined with electrospray ionization high-resolution mass spectrometry. The data were processed by MetWorks software. The structures of the metabolites were proposed by comparing the mass spectra with that of the parent compound. RESULTS: A total of twenty-four metabolites were detected in vitro and in vivo, including seven phase I and eighteen phase II metabolites. The phase I metabolic pathways of erianin were hydroxylation, demethylation and dehydrogenation. Erianin undergoes metabolic activation to form reactive metabolites quinoid intermediates, which were further trapped by glutathione (GSH) or N-acetylcysteine. The phase II metabolic pathways were glucuronidation, glutathione and N-acetylcysteine conjugation. CONCLUSIONS: The present study provides an overview pertaining to the in vitro and in vivo metabolic profiles of erianin, which is indispensable for us to understand the efficacy and safety of erianin, as well as the herbal medicine D. chrysotoxum.

Exercise therapy in patients with constipation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Exercise therapy has shown significant efficacy as a means of treating various intestinal diseases, but its role in the treatment of constipation is still unclear. The purpose of this study was thus to analyze the effects of exercise on constipation by means of a systematic review and meta-analysis. METHODS: PubMed, Web of Science, EMBASE, Cochrane Library and three Chinese databases [Wanfang Database, Chinese Biomedical Literature (CBM) and China National Knowledge Infrastructure (CNKI)] were searched for relevant studies published through June 2018. Eligible studies were selected in accordance with the PRISMA statement. The main results of interest were changes in gastrointestinal symptoms. RESULTS: A total of nine randomized controlled trials involving 680 participants were included. Eight studies involved aerobic exercise and only one study involved anaerobic exercise. The aerobic exercises included were Qigong, walking and physical movement. The results of this systematic review and meta-analysis indicated that exercise had significant benefits as a means of improving the symptoms of constipation patients [relative risk (RR) = 1.97; 95% CI: 1.19, 3.27; p = .009; I2=91.3%]. Subgroup analyses showed that aerobic exercise (RR = 2.42; 95% CI: 1.34, 4.36; p = .000; I2=88%) similarly had a positive effect on constipation. However, these results were associated with a high risk of bias. CONCLUSION: Our results suggest that exercise may be a feasible and effective treatment option for patients with constipation. However, due to methodological shortcomings, the real effect of this intervention cannot be definitively determined. Researchers should, therefore, design more rigorous studies in order to evaluate the effect of exercise on constipation.

Validation of an information-motivation-behavioral skills model of upper limb functional exercise adherence among Chinese postoperative patients with breast cancer.

BACKGROUND: The adherence to postoperative upper limb functional exercise in breast cancer (BC) patients is poor which can lead to adverse health outcomes. Effective intervention content to improve adherence is still unclear. The information-motivation-behavioral skills (IMB) model is a theoretical model that has been widely used to promote health behavior in many disease populations and may, therefore, help to explain and promote adherence to functional exercise. In this study, we validated the IMB model in a sample of postoperative BC patients. METHODS: A cross-sectional study of 165 postoperative patients with BC was performed in a hospital. We collected information on demographics, functional exercise knowledge (information), personal and social motivation (motivation), objective skills and self-efficacy (behavioral skills), and functional exercise adherence (behavior). Measured variable path analyses were applied for the IMB framework. RESULTS: The IMB elements explained 37.9% of the variance in adherence. As predicted, behavioral skills had a direct effect on adherence (ß = 0.509; P < 0.05) and mediated the effects of knowledge (indirect effect 0.092, P < 0.05) and motivation (indirect effect 0.251, P < 0.05) on adherence. CONCLUSIONS: Behavioral skills have a direct effect on functional exercise adherence and a mediating effect on the influence of knowledge and motivation on adherence. Thus, these factors represent key determinants of exercise adherence. The IMB model could be applied to the upper limb exercise adherence of postoperative BC patients. These findings indicate that the promotion of exercise adherence interventions may benefit from targeting patients' exercise adherence-related knowledge, motivation, and behavioral skills.

Prognostic Value of Frailty for Older Patients with Heart Failure: A Systematic Review and Meta-Analysis of Prospective Studies.

OBJECTIVE: Numerous studies have investigated the prognostic role of frailty in elderly patients with heart failure (HF), but the limited size of the reported studies has resulted in continued uncertainty regarding its prognostic impact. The aim of this study was to integrate the findings of all available studies and estimate the impact of frailty on the prognosis of HF by performing a systematic review and meta-analysis. METHODS: PubMed, Embase, Cochrane, and Web of Science databases were searched from inception to November 8th 2017 to identify eligible prospective studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. The association between frailty and HF outcomes was reviewed. Overall hazard ratios (HRs) for the effects of frailty on all-cause mortality were pooled using a fixed-effect model and publication bias was evaluated using funnel plots. RESULTS: A total of 10 studies involving 3033 elderly patients with HF were included in the systematic review and meta-analysis. All eligible studies indicated that frailty was of prognostic significance for HF patients. The HRs for the effects of frailty on all-cause mortality were 1.70 (95% confidence interval (CI): 1.41-2.04), based on the pooling of six studies that provided related data. However, publication bias was observed among the studies. CONCLUSIONS: Frailty has a high prevalence among older patients with HF. Elderly HF patients with frailty have a poorer prognosis than those without frailty. Further studies are now required to implement the use of frailty assessment tools and explore effective interventions for frailty in older HF patients.

In Vivo Study of the Effects of ERß on Apoptosis and Proliferation of Hormone-Independent Prostate Cancer Cell Lines PC-3M.

OBJECTIVE: To evaluate the in vivo therapeutic effects of attenuated Salmonella carrying PCDNA3.1-ERß plasmid in hormone-independent prostatic cancer in nude mice and to clarify the mechanism by which estrogen receptor ß (ERß) induces apoptosis and proliferation in prostatic cancer cells in mice. METHODS: The orthotopic prostatic cancer models of mice were randomly divided as follows: MOCK group, treated with PBS, PQ group, treated with attenuated Salmonella alone, PQ-PCDNA3.1 group, treated with attenuated Salmonella carrying PCDNA3.1 plasmid, and PQ-PCDNA3.1-ERß group, treated with the attenuated Salmonella carrying PCDNA3.1-ERß plasmid. Then, 10 µl of the plasmid-containing solution, comprising 1 × 107 cfu of the bacteria, was administered via intranasal delivery to each group except the MOCK group. The experimental methods included flow cytometry and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay, immunohistochemistry, and western blotting. RESULTS: Compared with the MOCK, PQ, and PQ-PCDNA3.1 groups, the weights of tumors in the PQ-PCDNA3.1-ERß group were significantly reduced. The results of flow cytometry and TUNEL assay revealed that the number of apoptotic cells in the PQ-PCDNA3.1-ERß group significantly increased. Compared with PQ-PCDNA3.1 group, the protein expression levels of ERß, Bad, p-caspase 9, p-caspase 3, and cleaved PARP in the PQ-PCDNA3.1-ERß group were significantly increased, while the expression levels of Akt, p-Akt, and Bcl-xl were decreased (P < 0.05). CONCLUSION: The attenuated Salmonella carrying PCDNA3.1-ERß plasmid could inhibit the growth of orthotopic prostatic cancer in mice by increasing the expression of ERß.

[Measurement of Foxp3 and NFAT1 in children with aplastic anemia].

OBJECTIVE: To study the expression of Foxp3 and NFAT1 protein in peripheral blood (PB) in children with aplastic anemia (AA) and their roles in the pathogenesis of AA. METHODS: The expression levels of Foxp3 and NFAT1 protein of mononuclear cells in PB were measured by Western blot in 68 children with AA before and after treatment and in 60 normal children (control group). The correlation between Foxp3 and NFAT1 protein expression and the correlation of the Foxp3 and NFAT1 protein expression with blood Hb, WBC and platelet levels were analyzed. RESULTS: The expression levels of Foxp3 and NFAT1 protein in PB in the acute phase in the AA group were significantly lower than in the control group (P<0.05). After treatment (recovery phase) the expression levels of Foxp3 and NFAT1 protein increased obviously compared with those in the acute phase (P<0.05). The Foxp3 protein level was positively correlated with the NFAT1 protein level (r=0.812, P<0.05). Both the Foxp3 and NFAT1 protein levels were positively correlated with blood Hb, WBC and platelet levels in children with AA in the recovery phase (r=0.537, 0.579, 0.655 respectively; P<0.05). CONCLUSIONS: The Foxp3 and NFAT1 protein levels in PB are reduced in children with AA, suggesting that they are involved in the pathogenesis of AA. The measurement of Foxp3 and NFAT1 protein levels may be useful in the severity evaluation of AA.

[Telomere length and telomerase mutations in peripheral blood leukocytes of children with chronic aplastic anemia].

OBJECTIVE: To investigate the change in telomere length and TERC and TERT mutations in peripheral blood leukocytes of children with chronic aplastic anemia (CAA). METHODS: Sixty-nine children with CAA were divided into untreated group (n=24) who did not receive immunosuppressive therapy (IST), response group (n=36) who showed response to IST, and non-response group (n=9) who showed no response to IST; another 35 healthy children matched for age and sex were selected as the control group. The telomere-to-single copy gene (T/S) ratio in peripheral blood leukocytes was measured by real-time PCR in all groups. PCR was performed to detect TERC and TERT mutations in all children with CAA. RESULTS: The untreated and non-response groups had significantly lower T/S ratios than the control and response groups (P<0.01), whereas there was no significant difference in T/S ratio between the response and control groups (P>0.05). TERC and TERT mutations were not found in all children with CAA. CONCLUSIONS: The change in telomere length in children with CAA may be related to the development and progression of disease. Telomere length measurement may be used as a prognostic indicator in children with CAA.

[Expression of telomerase activity and its related genes in the marrow hemopoietic stem cells of children with aplastic anemia].

OBJECTIVE: To explore the relationship of telomerase RNA component (hTERC) and the telomerase reverse transcriptase (hTERT) with telomerase activity in the marrow hemopoietic stem cells of children with aplastic anemia (AA). METHODS: Fifty-two children with chronic AA, 13 children with acute AA and 21 normal controls were enrolled in the study. Telomerase activity and the expression of mRNA of hTERT and hTERC were detected by Telomeric Repeat Amplification Protocol (TRAP) with silver staining and real-time Q-PCR respectively. RESULTS: Levels of telomerase activity in both the chronic and acute AA groups were higher than in the control group (P<0.01). The AA groups had significantly higher expression of hTERT mRNA than the control group (P<0.01). The chronic AA group had higher expression of hTERT mRNA and telomerase activity than the acute AA group (P<0.05). There was no significant difference in the expression of hTERC mRNA among the three groups (P=0.812). There was a significant correlation between the expression of hTERT mRNA and telomerase activity (r=0.660, P<0.01). CONCLUSIONS: Expression of telomerase activity may be involved in the pathophysiology and development of AA, and hTERT plays a crucial role in expression of telomerase activity.

[Effect of cyclosporine on regulatory T cells and Foxp3 in the peripheral blood of children with chronic aplastic anemia].

OBJECTIVE: To explore the expression diversification of CD4(+)CD25(+)CD127(low) regulatory T (Treg) cells and Foxp3 mRNA in the peripheral blood of children with aplastic anemia after the treatment with cyclosporine. METHODS: Fifty children with chronic aplastic anemia were enrolled, among whom 30 received cyclosporine treatment (cyclosporine group) and 20 were treated with conventional methods (conventional group). Twenty healthy children were enrolled as the control group. The expression of CD4(+)CD25(+)CD127(low) Treg cells was detected by flow cytometry. The expression of Foxp3 mRNA was detected by real-time Q-PCR. RESULTS: The expressions of Foxp3 mRNA and CD4(+)CD25(+)CD127(low)Treg cells showed no significant difference between the cyclosporine and the control groups 6 months after treatment. On the contrary, there were significantly lower expressions of both in the conventional group than in the control group (P<0.05). Meanwhile, the cyclosporine group had significantly higher expressions of Foxp3 mRNA and CD4(+)CD25(+)CD127(low) Treg cells than the conventional group (P<0.05). CONCLUSIONS: The expressions of CD4(+)CD25(+)CD127(low) Treg cells and Foxp3 mRNA in children with aplastic anemia increase after cyclosporine treatment.

[Detection and significance of CD4+ CD25int/high CD127low regulatory T cells in pediatric aplastic anemia].

OBJECTIVE: To study the expression of CD4+ CD25int/high CD127low regulatory T cells in peripheral blood (PB) and its relation to the quantity of Hb, WBC and platelet (Plt) in children with aplastic anemia (AA). METHODS: Expression of CD4+ CD25int/high CD127low in PB was detected by flow cytometry in 22 children with AA before and after treatment and in 15 healthy controls. The relationships between CD4+CD25highCD127low and the quantity of Hb, WBC and Plt were evaluated. RESULTS: Compared to controls, the percentages of CD4+ CD25+/CD4+, CD4+CD25high/CD4+, CD4+ CD25+ CD127low/CD4+ and CD4+CD25highCD127low/CD4+ in PB of AA patients decreased markedly at the active phase (P﹤0.05). By the recovery phase, the percentages of CD4+CD25+/CD4+, CD4+CD25high/CD4+, CD4+ CD25+ CD127low/CD4+ and CD4+CD25highCD127low/CD4+ increased significantly to the levels similar to the controls. There were significant positive relationships between the expression of CD4+CD25highCD127low cells and the quantity of Hb, WBC and Plt (r=0.499, 0.526, 0.540 respectively; P﹤0.05). CONCLUSIONS: The decrease of the percentage of CD4+CD25int/highCD127low regulatory T cells might be associated with the development of pediatric AA. The CD4+CD25int/highCD127low regulatory T cells can serve as a marker for the evaluation of disease severity as well as a target of further study on immune treatment of AA.

[Expression of regulatory T cells and Foxp3 gene in peripheral blood of children with aplastic anemia].

OBJECTIVE: To investigate the levels of CD4+CD25+CD127(low) regulatory T cells (Tregs) and the expression of Foxp3 gene in peripheral blood of children with aplastic anemia (AA) and to study their roles in the pathogenesis of AA. METHODS: Twenty-one children with chronic AA, 9 with acute AA and 15 healthy children were enrolled. The proportion of CD4+CD25+ CD127low Tregs in CD4+ T cells was evaluated by flow cytometric analysis. The level of Foxp3 mRNA was ascertained by RT-PCR. RESULTS: The percentage of peripheral blood CD4+T cells and CD4+CD25+ and CD4+CD25+CD127(low) Tregs in CD4+T cells in both the acute and chronic AA groups was significantly lower than that in the normal control group (P<0.05).The acute AA group had more decreased CD4+ T cells and CD4+CD25+ and CD4+CD25+CD127(low) Tregs percentage compared with the CAA group (P<0.05). The expression of Foxp3 mRNA in peripheral blood decreased obviously in the acute AA group (0.47 + or - 0.08%) compared with that in the normal control (0.71 + or - 0.12%) and the CAA groups (0.68 + or - 0.14%) (P<0.05). CONCLUSIONS: The low expression of Tregs and Foxp3 mRNA in peripheral blood may be involved in pathogenesis of AA.The more decreased Tregs and Foxp3 mRNA expression in acute AA than chronic AA suggests their possible roles in the assessment of the severity of AA.

[Induction of apoptosis by proteasome inhibitor MG-132 in human erythroleukemia cell line K562].

OBJECTIVE: To investigate whether proteasome inhibitor MG-132 induces apoptosis of human erythroleukemia cell line K562 and possible mechanisms. METHODS: K562 cells were incubated with RPMI 1640 and exposed to 0, 1, 5, 10, 15 micromol/L of MG-132 for 24 hrs, respectively. The apoptosis of cells were detected by fluorescence microscope, DNA fragments and flow cytometry. The NF-kappaB mRNA expression was quantified by reverse transcription-polymerase chain reaction (RT-PCR). Expression of NF-kappaB and caspase-3 was semiquantitatively analyzed with SABC techniques. Caspase-3 activities were measured with a colorimetric method. RESULTS: The growth of K562 cells was inhibited and the apoptosis of the cells increased after MG-132 treatment in a dose-dependent manner. After 24 hrs of 15 micromol/L MG-132 treatment, the percentage of apoptotic cells (26.5+/-0.6%) increased significantly when compared with the untreated controls (1.2+/-0.1%) (P<0.01). MG-132 treatment decreased the mRNA and protein expression of NF-kappaB, and increased the protein expression of caspase-3. CONCLUSIONS: MG-132 can induce apoptosis of human erythroleukemia cell line K562 through the down-regulation of NF-kappaB expression and up-regulation of caspase-3 expression.

[Study on JAKs-STATs signal transduction in neonatal rats with PVL].

OBJECTIVE: To examine the changes of JAKs-STATs pathway in the subventricular zone and choroid plexus of neonatal rats with PVL. METHODS: A PVL model was established by right common carotid artery ligation followed by 4 h 6% oxygen exposure in 2-day-rat, the neonatal rats performed a sham operation, without hypoxia-ischemia were used as the control grobp. The rats were sacrificed at 0 h, 3 h, 6 h, 12 h, 1 d, 3 d. 7 d of HI, and the brain tissues were collected, immunohistochemistry was applied to detect the expression of P-JAK2 and P-STAT3. RESULTS: The expression levels of P-JAK2 and P-STAT3 increased significantly after HI, peaked at 1 d, and remained at a higher level than control until 7 days of HI, the difference was significant (P < 0.01). CONCLUSION: HI resulted in the activation of JAKs-STATs pathway in the subventricular zone and choroid plexus, and this pathway might participated in the pathophysiological process of PVL.

[Expression of cyclin A in childhood acute leukemia and its significance].

OBJECTIVE: To investigate the expression of cyclin A protein in childhood acute leukemia (AL) and its significance. METHODS: By using Western blotting analysis, cyclin A protein in bone marrow mononuclear cells from 47 newly diagnosed AL children and 33 non-hematological malignancy children was detected. RESULTS: The expression of cyclin A in AL group (0.38 +/- 0.20) was higher than that in control group (0.03 +/- 0.15) (P < 0.01). The expression of cyclin A in high risk acute lymphocyte leukemia (ALL) group (HR-ALL) (0.62 +/- 0.38) was higher than that in standard risk ALL group (SR-ALL) (0.33 +/- 0.33) (P < 0.05). The expression of cyclin A in WBC > or = 50 x 10(9)/L group and in WBC < 50 x 10(9)/L group was (0.64 +/- 0.36) and (0.39 +/- 0.38), respectively (P < 0.05). Eight (44.4%) out of 18 patients with positive cyclin A expression achieved complete remission (CR). The CR rate was lower than that of patients with negative cyclin A expression (100%) (P < 0.01). CONCLUSIONS: The higher expression of cyclin A may predict a poor prognosis for childhood ALL.