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Abstract Clinical prediction models play an important role in the field of medicine. These can help predict the probability of an individual suffering from disease, complications, and treatment outcomes by applying specific methodologies. Polycystic ovary syndrome (PCOS) is a common disease with a high incidence rate, huge heterogeneity, short- and long-term complications, and complex treatments. In this systematic review study, we reviewed the progress of clinical prediction models in PCOS patients, including diagnosis and prediction models for PCOS complications and treatment outcomes. We aimed to provide ideas for medical researchers and clues for the management of PCOS. In the future, models with poor accuracy can be greatly improved by adding well-known parameters and validations, which will further expand our understanding of PCOS in terms of precision medicine. By developing a series of predictive models, we can make the definition of PCOS more accurate, which can improve the diagnosis of PCOS and reduce the likelihood of false positives and false negatives. It will also help discover complications earlier and treatment outcomes being known earlier, which can result in better outcomes for women with PCOS.

Objective To investigate the interactions of the polymorphisms of hypothalamic-pituitary-adrenal (HPA) axis related genes, corticotropin-releasing hormone receptor Ⅱ (CRHR2), FK506 binding protein 5 (FKBP5), and glucocorticoid receptor (NR3C1) with environmental factors, and their association with suicide attempts. Methods A total of 66 depressed patients (32.2±16.7 years old, 30 males and 36 females, case group) who seek medical advice due to attempted suicide were recruited from the psychiatry departments of the Affiliated Hospital of Guangdong Medical University, Dongguan Seventh People's Hospital and Kuitun Hospital of Ili Kazakh Autonomous Prefecture during March 2017 to September 2018. Forty-nine unrelated healthy individuals (32.7±11.0 years old, 23 males and 26 females, control group) were selected from the Health Screening Centre of the Affiliated Hospital of Guangdong Medical University during the same period. Snapshot genotyping was used to test the single nucleotide polymorphism (SNP) loci of the target genes. Life event scale (LES) was used to assess life stress of individuals over the past year. Trier social stress test (TSST) was employed to evaluate HPA axis reactivity. Mmultifactor dimensionality reduction (MDR) analysis was adopted to analyze the interactions among genes, life events and HPA axis reactivity. Results The total LES score was significantly higher (30.47±27.22 vs 7.80±10.14, P < 0.001), but the HPA axis reactivity was obviously lower in the case group than the control group (P < 0.001). There were no statistical differences in genotype frequencies and allele frequencies between the 2 groups at 5 SNPs (NR3C1: rs9324924 and rs10052957; FKBP5: rs3800373 and rs9296158; CRHR2: rs3779250). MDR analysis indicated that the best interaction model was the third-order model constructed by NR3C1 rs10052957 polymorphism, life events and HPA axis reactivity, with the highest accuracy of 0.883 7 for sample test (P=0.009 8). Conclusion The interaction of NR3C1 rs10052957 polymorphism, HPA axis reactivity and life events can increase the risk of suicidal behavior.

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin-RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136-400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

Objective·To evaluate the effect of pelvic floor muscle training (Kegel training) on the rehabilitation of pelvic floor function within 1 year after delivery.Methods·From January to April 2020, primiparas with different degrees of urinary incontinence or pelvic organ prolapse were selected and divided into exercise group (147 cases) and control group (194 cases). The exercise group received Kegel training at 6 weeks of the postpartum period, while the control group received general postpartum health education only. At 6 weeks and 1 year after delivery, these postpartum women in the two groups were investigated with the general information questionnaire and International Consultation Incontinence Questionnaire-UI Short Form (ICIQ-SF). The pelvic floor muscle strength was measured (the pelvic floor muscle strength grade>Ⅲ indicates normal muscle strength). The pelvic organ prolapsed quantitation (POP-Q) score was assigned accordingly. The urinary incontinence score, pelvic floor muscle strength and pelvic floor organ prolapse were compared between the two groups, and the effect of pelvic floor muscle training was evaluated.Results·In the exercise group, 20 postpartum women lost contact during follow up sections, and 28 women in the control group were unable to be contacted within 1 year. In the exercise group, the proportion of women with normal pelvic floor muscle strength at 1 year postpartum was significantly higher than that at 6 weeks postpartum (56.0% vs 34.7%, P=0.000), and the incidence of incontinence at 1 year postpartum was significantly lower than that at 6 weeks postpartum (25.2% vs 36.7%, P=0.040). In the control group, the proportion of women with normal pelvic floor muscle strength at 1 year postpartum was significantly higher than that at 6 weeks postpartum (43.4% vs 32.5%, P=0.033), and the incidence of incontinence at 1 year postpartum was significantly lower than that at 6 weeks postpartum (17.5% vs 28.9%, P=0.011). At 1 year postpartum, the proportion of women with normal pelvic floor muscle strength in the exercise group was higher than that in the control group (56.0% vs 43.4%, P=0.033). The improvement rate of muscle strength in the exercise group was higher than that in control group (50.4% vs 35.5%, P=0.011). There was no significant difference in the improvement rate of pelvic organ prolapse and frequency of urinary incontinence between the exercise group and the control group (P>0.05).Conclusion·Postpartum pelvic floor muscle training can improve pelvic floor muscle strength, but has no significant effect on improving pelvic floor dysfunction in the current samples. The urinary incontinence condition and pelvic floor muscle strength of women improve 1 year after delivery, indicating that there is a mechanism for self recovery of pelvic floor muscle, but it may take a long time.

Flexible conductive hydrogel-based electronic skin (E-skin) for simultaneous biotherapeutics and sensing applications is one of the current research directions. In this study, conductive and homogeneous silk fibroin/polyaniline/AgNP complexes (SPAg complexes) were prepared with the assistance of silk fibroin, which greatly optimized the compatibility of PANI with the hydrogel matrix. Then, SPAg was introduced into the covalently crosslinked polymer network to prepare poly(acrylamide-co-sulfobetaine methacrylate) – SPAg hydrogels (labeled as PSPAg hydrogels). The PSPAg hydrogels exhibit good biocompatibility, excellent mechanical properties, superb adhesive performance, and fantastic sensing capabilities. Being connected to a smartphone via a Bluetooth system, the SPAg hydrogel-based E-skin was employed to accurately monitor human movements including vigorous joint movements and subtle facial micro-expressions. Finally, benefiting from the synergistic effect of antimicrobial and exogenous electrical stimulation, through promoting angiogenesis and accelerating collagen production in diabetic wounds, PSPAg E-skin successfully facilitates rapid diabetic wound healing. Therefore, the multifunctional PSPAg hydrogel-based E-skin shows great promise for applications in wearable devices and bioelectronics. [ABSTRACT FROM AUTHOR]

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma.

Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted.

BackgroundOutcomes for children with high-risk neuroblastoma are poor, and improved understanding of the mechanisms underlying neuroblastoma pathogenesis, recurrence, and treatment resistance will lead to improved outcomes. Aberrant growth factor receptor expression and receptor tyrosine kinase signaling are associated with the pathogenesis of many malignancies. A germline polymorphism in the FGFR4 gene is associated with increased receptor expression and activity and with decreased survival, treatment resistance, and aggressive disease for many malignancies. We therefore investigated the role of this FGFR4 polymorphism in neuroblastoma pathogenesis.Materials and methodsGermline DNA from neuroblastoma patients and matched controls was assessed for the FGFR4 Gly/Arg388 polymorphism by RT-PCR. Allele frequencies were assessed for association with neuroblastoma patient outcomes and prognostic features. Degradation rates of the FGFR4 Arg388 and Gly388 receptors and rates of receptor internalization into the late endosomal compartment were measured.ResultsFrequency of the FGFR4 AA genotype and the prevalence of the A allele were significantly higher in patients with neuroblastoma than in matched controls. The Arg388 receptor demonstrated slower degradation than the Gly388 receptor in neuroblastoma cells and reduced internalization into multivesicular bodies.ConclusionsThe FGFR4 Arg388 polymorphism is associated with an increased prevalence of neuroblastoma in children, and this association may be linked to differences in FGFR4 degradation rates. Our study provides the first evidence of a role for FGFR4 in neuroblastoma, suggesting that FGFR4 genotype and the pathways regulating FGFR4 trafficking and degradation may be relevant for neuroblastoma pathogenesis.