Study on the design, synthesis, and activity of anti-tumor staple peptides targeting MDM2/MDMX.

Staple peptides, which have a significantly enhanced pharmacological profile, are promising therapeutic molecules due to their remarkable resistance to proteolysis and cell-penetrating properties. In this study, we designed and synthesized a series of PMI-M3-based dual-targeting MDM2/MDMX staple peptides and compared them with straight-chain peptides. The staple peptide SM3-4 screened in the study induced apoptosis of tumor cells in vitro at low µM concentrations, and the helix was significantly increased. Studies have shown that the enhancement of staple activity is related to the increase in helicity, and SM3-4 provides an effective research basis for dual-targeted anti-tumor staple peptides.

Developing a risk assessment tool for cancer-related venous thrombosis in China: a modified Delphi-analytic hierarchy process study.

OBJECTIVE: To develop a Risk Assessment Tool for Cancer-related Venous Thrombosis in China. METHODS: A modified two-round Delphi method was employed to establish consensus within a field to reach an agreement via a questionnaire or by interviewing a multidisciplinary panel of experts by collecting their feedback to inform the next round, exchanging their knowledge, experience, and opinions anonymously, and resolving uncertainties. Furthermore, The AHP (Analytic Hierarchy Process) was used to determine the final quality indicators' relative importance. RESULTS: The expert's positive coefficient was 85.19% in the first round and 82.61% in the second round, with authoritative coefficients of 0.89 and 0.92 in the respective surveys. The P-value of Kendall's W test was all less than 0.001 for each round, and the W-value for concordance at the end of the two rounds was 0.115. The final Risk Assessment Tool for Cancer-related Venous Thrombosis consisted of three domains, ten subdomains, and 39 indicators, with patient factors weighing 0.1976, disease factors weighing 0.4905, and therapeutic factors weighing 0.3119. CONCLUSION: The tool is significantly valid and reliable with a strong authority and coordination degree, and it can be used to assess the risk of cancer-related VTE and initiate appropriate thrombophylactic interventions in China.

Enhanced Bioremediation of Aged Polycyclic Aromatic Hydrocarbons in Soil Using Immobilized Microbial Consortia Combined with Strengthening Remediation Strategies.

Microbial biodegradation is considered as one of the most effective strategies for the remediation of soil contaminated with polycyclic aromatic hydrocarbons (PAHs). To improve the degradation efficiency of PAHs, PAH-degrading consortia combined with strengthening remediation strategies was used in this study. The PAH biodegrading performance of seven bacterial consortia constructed by different ratios of Mycobacterium gilvum MI, Mycobacterium sp. ZL7 and Rhodococcus rhodochrous Q3 was evaluated in an aqueous system containing phenanthrene, pyrene, benzo[a]pyrene and benzo[b]fluoranthene. Bacterial consortium H6 (Q3:ZL7:MI = 1:2:2) performed a high degrading efficiency of 59% in 8 days. The H6 was subsequently screened to explore its potential ability and performance to degrade aged PAHs in soils from a coking plant and the effects of strengthening strategies on the aged PAH degradation, including the addition of glucose or sodium dodecyl benzene sulfonate (SDBS) individually or as a mixture along immobilization of the inoculant on biochar. The highest degradation efficiencies, which were 15% and 60% for low-molecular-weight (LMW) PAHs and high-molecular-weight (HMW) PAHs, respectively, were observed in the treatment using immobilized microbial consortium H6 combined with the addition of glucose and SDBS after 24 days incubation. This study provides new insights and guidance for future remediation of aged PAH contaminated soils.

Optimal Frequency for Changing Single-Use Enteral Delivery Sets in Infants after Congenital Heart Surgery: A Randomized Controlled Trial.

Objective We aimed to assess the optimal frequency for changing single-use enteral delivery sets during postoperative enteral feeding in infants with congenital heart disease (CHD).Methods We enrolled 120 CHD infants who were fed using an enteral nutrition pump directly connected to a milk bottle with a single-use enteral delivery set in a four-arm randomized controlled trial (ChiCTR2000039544). Patients were randomized into four groups based on the replacement frequency of the enteral delivery set (6 h, 12 h, 18 h, and 24 h groups). The primary outcome was the percentage of contaminated enteral delivery sets (overgrowth of microbiota and colonization of pathogenic bacteria). Secondary outcomes included evidence of infection, gastrointestinal tolerance, intestinal microflora dysbiosis, and healthcare costs.Results The percentages of microbial overgrowth detected in the 6 h, 12 h, 18 h, and 24 h groups were 6.7%, 30.0%, 46.7%, and 80%, respectively (P < 0.001). Significant differences were observed between the 6 h and 18 h groups (P < 0.001), the 6 h and 24 h groups (P < 0.001), and the 18 h and 24 h groups (P = 0.007). Meanwhile, pathogenic bacterial colonization was detected in 0, 4, 6, and 11 delivery sets in the 6 h, 12 h, 18 h, and 24 h groups, respectively (P = 0.002). No difference in clinical symptoms was found among the four groups. The total cost per patient in the 12 h group and the 18 h group was 340.2 RMB and 226.8 RMB, respectively.Conclusion Taking into consideration both microbial overgrowth and cost-effectiveness, the results of this study indicate that for children receiving continuous enteral feeding following CHD surgery, the optimal frequency for changing the single-use enteral delivery set when formula reconstituted from powder is used is 18 hours.

Roles of VE-Cadherin in Hypoxia Induced Injury of Pulmonary Microvascular Endothelial Barrier.

BACKGROUND: Hypoxia induced injury of pulmonary microvascular endothelial barrier is closely related to the pathogenesis of acute lung injury after lung transplantation. VE-cadherin is an important structural molecule for pulmonary microvascular endothelial barrier. In this study, we aim to investigate the roles of VE-cadherin in hypoxia induced injury of pulmonary microvascular endothelial barrier. METHODS: Rat model of hypoxia and cultured pulmonary microvascular endothelial cells (PMVECs) were utilized. Determination of PMVECs apoptosis, skeleton combination was conducted to verify the effects of hypoxia on injury of pulmonary microvascular endothelial barrier. In addition, VE-cadherin expression was modulated by administration of siRNA in order to investigate the roles of VE-cadherin in hypoxia induced PMVECs apoptosis and skeleton recombination. RESULTS: Our data indicated that expression of VE-cadherin was down-regulated in hypoxia-exposed PMVECs. Whereas, in the cells treated using siRNA, down-regulation of VE-cadherin did not trigger PMVECs apoptosis, but it increased the sensitivity of PMVECs to the hypoxia induced apoptosis. In cases of hypoxia, the expression of VE-cadherin was significantly down-regulated, together with endothelial skeleton recombination and increase of permeability, which then triggered endothelial barrier dysfunction. CONCLUSIONS: These data verify that VE-cadherin expression played an important role in hypoxia induced PMVECs apoptosis and cellular skeletal recombination.

Active Surveillance, Drug Resistance, and Genotypic Profiling of Staphylococcus aureus Among School-Age Children in China.

Methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization predisposes individuals for endogenous infections and is a major threat to children. Recently, oxacillin/cefoxitin-susceptible mecA-positive S. aureus (OS-MRSA) has been reported worldwide. Herein, a prospective, cross-sectional study was conducted across five schools, representing three educational stages, in Guangzhou, China. Nasal swabs from 2,375 students were cultured for S. aureus and all isolates were subjected to antibiotic susceptibility testing phenotypically and confirmed by femB and mecA genetic detection; all the isolates were classified as MSSA, MRSA, or OS-MRSA. All strains were also analyzed by multi-locus sequence typing. Among the 2,375 swabs, S. aureus was detected in 744 children (31.3%, 95% CI: 25.9-36.7%), of whom 72 had MRSA (3.0%, 95% CI: 0.6-5.4%) and 4 had OS-MRSA (0.2%, 95% CI: 0.1-0.3%), of which an oxacillin- and cefoxitin-susceptible MRSA strain was identified. The prevalence of S. aureus and MRSA was higher in younger children. The highest percentage of drug resistance of the S. aureus isolates (n = 744) was to penicillin (85.5%), followed by erythromycin (43.3%) and clidamycin (41.0%). The most prevalent sequence types (STs) were ST30, ST45, and ST188 in MSSA, accounting for 38.7% of the total isolates, whereas ST45, ST59, and ST338 accounted for 74.6% of the MRSA isolates and ST338 accounted for 50.0% of the OS-MRSA isolates. The MRSA and OS-MRSA isolates (n = 76) were grouped into three clades and one singleton, with clonal complex (CC) 45 as the most predominant linkage. The top nine multi-locus sequence typing-based CCs (CC30, CC45, CC5, CC1, CC15, CC944, CC398, CC59, CC7) represented 86.7% of all S. aureus isolates. All CC30 isolates were resistant to erythromycin and clidamycin, and almost all these isolates were also resistant to penicillin (99.2%). The CC45 and CC59 isolates exhibited high resistance rates to oxacillin at 31.5 and 59.0%, respectively. This study provides updated data valuable for designing effective control strategies to mitigate the burden of disease and to improve the adequacy of empirical antimicrobial treatments for potentially harmful infections.

Effects of mindfulness-based stress reduction combined with music therapy on pain, anxiety, and sleep quality in patients with osteosarcoma

Objectives: To evaluate the effects of mindfulness-based stress reduction (MBSR) combined with music therapy (MT) on clinical symptoms in patients with osteosarcoma. Methods: Patients diagnosed with osteosarcoma were assessed for eligibility. A total of 101 patients were ultimately randomized into the intervention and control groups. Both groups received routine care. Eight sessions of MBSR and MT psychotherapy were conducted in the intervention group, while the control group received no psychological intervention. Patients were assessed regarding pain, anxiety, and sleep quality at two distinct stages: before and after the intervention. Results: There were no significant differences in sociodemographic and clinical parameters between the intervention and control groups at baseline. The intervention program significantly alleviated psychological and physiological complications in patients with osteosarcoma. Specifically, the study revealed that 8 weeks of the combined MBSR/MT intervention effectively reduced pain and anxiety scores and improved the quality of sleep in patients. Conclusion: MBSR combined with MT significantly alleviated clinical symptoms, and could be considered a new, effective psychotherapeutic intervention for patients with osteosarcoma.

Molecular characteristics of group B Streptococcus isolates from infants in southern mainland China.

BACKGROUND: Invasive group B Streptococcus (GBS) disease in Chinese infants has gradually gained attention in recent years, but the molecular epidemiology of the pathogen is still not well known. METHODS: This multicenter study retrospectively investigated distribution of capsular serotypes, sequence types (STs), and hypervirulent GBS adhesin gene (hvgA) in clinical GBS isolates that caused invasive disease in infants aged < 3 months of age in southern mainland China between January 2013 and June 2016. Genes for antibiotic resistance to tetracycline, erythromycin, and clindamycin were also examined. RESULTS: From a total of 93 GBS isolates taken from 34 early-onset disease (EOD, 0-6 days after birth) and 59 late-onset disease (LOD, 7-89 days after birth) cases, four serotypes were identified: serotypes III (79.6%), Ib (12.9%), Ia (4.3%), and V (3.2%). Serotype III accounted for 73.5% of EOD and 83.1% of LOD and was responsible for 75.5% of cases involving meningitis. Fifteen STs were found, with the majority being ST17 (61.3%), ST12 (7.5%), ST19 (7.5%), and others (23.7%). 96.8% of STs belonged to only five clonal complexes (CCs): CC17 (64.5%), CC10 (12.9%), CC19 (9.7%), CC23 (6.5%), and CC1 (3.2%). The hvgA gene was detected in 66.7% of GBS isolates and 95% of CC17 isolates, all of which were serotype III except one serotype Ib/CC17 isolate. A large proportion of GBS isolates were found to be resistant to tetracycline (93.5%), clindamycin (65.5%), and erythromycin (60.2%). Genes of tetO (74.7%) and tetM (46.0%) were found in tetracycline resistant isolates, linB (24.6%) in clindamycin resistant isolates, and ermB (87.5%) and mefA (3.6%) in erythromycin resistant isolates. CONCLUSION: Our results reveal higher prevalence of serotype III, ST17, CC17, hvgA expressing, and antibiotic resistant GBS isolates than previously reported in southern mainland China. This study provides guidance for appropriate measures of prevention and control to be taken in the future.

Effects of mindfulness-based stress reduction combined with music therapy on pain, anxiety, and sleep quality in patients with osteosarcoma.

OBJECTIVES: To evaluate the effects of mindfulness-based stress reduction (MBSR) combined with music therapy (MT) on clinical symptoms in patients with osteosarcoma. METHODS: Patients diagnosed with osteosarcoma were assessed for eligibility. A total of 101 patients were ultimately randomized into the intervention and control groups. Both groups received routine care. Eight sessions of MBSR and MT psychotherapy were conducted in the intervention group, while the control group received no psychological intervention. Patients were assessed regarding pain, anxiety, and sleep quality at two distinct stages: before and after the intervention. RESULTS: There were no significant differences in sociodemographic and clinical parameters between the intervention and control groups at baseline. The intervention program significantly alleviated psychological and physiological complications in patients with osteosarcoma. Specifically, the study revealed that 8 weeks of the combined MBSR/MT intervention effectively reduced pain and anxiety scores and improved the quality of sleep in patients. CONCLUSION: MBSR combined with MT significantly alleviated clinical symptoms, and could be considered a new, effective psychotherapeutic intervention for patients with osteosarcoma.

Targeting Delivery of Lidocaine and Cisplatin by Nanogel Enhances Chemotherapy and Alleviates Metastasis.

Tumor growth inhibition and adverse effect reduction together with metastasis alleviation are still the challenges that need to be overcome in cancer chemotherapy. Combinational therapy provides an alternative solution for these challenges. Nanoparticles are the ideal carriers for combinational therapy due to their versatile drug loading capacities and versatile tumor-targeting strategies. In this study, a cRGDfk modified nanogel system has been utilized to coload lidocaine, a voltage-gated Na+ channels inhibitor, and cisplatin, a common anticancer drug to obtain a tumor-targeted dual drugs-loaded nanogel system. The introduction of lidocaine not only promotes the cisplatin-induced apoptosis in vitro and in vivo but also alleviates the metastasis of MDA-MB-231 breast cancer cells in the mouse model. Besides, the body weight loss caused by cisplatin has also been relieved, and higher dose with less body weight loss can be achieved, which indicated the adverse effect caused by cisplatin-mediated chemotherapy has been alleviated. Furthermore, the introduction of peptide segment-cRGDfk, which presents high affinity to αvß3 integrin, further increases the enrichment of drug-loaded nanogel in the tumor site. It favors the primary tumor growth inhibition. The results demonstrate the coloading of lidocaine and cisplatin by ligand-modified nanogels is a promising strategy for αvß3 integrin-overexpressing breast cancer combinational therapy.

Inducing Controlled Release and Increased Tumor-Targeted Delivery of Chlorambucil via Albumin/Liposome Hybrid Nanoparticles.

Liposomes possess good biocompatibility and excellent tumor-targeting capacity. However, the rapid premature release of lipophilic drugs from the lipid bilayer of liposomes has negative effect on the tumor-targeted drug delivery of liposomes. In this study, a lipophilic antitumor drug-chlorambucil (CHL)-was encapsulated into the aqueous interior of liposomes with the aid of albumin to obtain the CHL-loaded liposomes/albumin hybrid nanoparticles (CHL-Hybrids). The in vitro accumulative release rate of CHL from CHL-Hybrids was less than 50% within 48 h, while the accumulative CHL release was more than 80% for CHL-loaded liposomes (CHL-Lip). After intravenous injection into rats, the half-life (t 1/2ß = 5.68 h) and maximum blood concentration (C max = 4.58 µg/mL) of CHL-Hybrids were respectively 1.1 times and 3.5 times higher than that of CHL-Lip. In addition, CHL-Hybrids had better tumor-targeting capacity for it significantly increased the drug accumulation in B16F10 tumors, which contributed to the significantly control of tumor growth compared with CHL-Lip. Furthermore, CHL-Hybrid-treated B16F10 melanoma-bearing mice displayed the longest median survival time of 30.0 days among all the treated groups. Our results illustrated that the proposed hybrids drug delivery system would be a promising strategy to maintain the controlled release of lipophilic antitumor drugs from liposomes and simultaneously facilitate the tumor-targeted drug delivery.

Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint.

The Aurora B kinase plays a critical role in cell mitosis and spindle checkpoint. Here, we showed that the ubiquitin E3-ligase protein Skp2, also as a cell-cycle regulatory protein, was required for the activation of Aurora B and its downstream protein. When we restored Skp2 knockdown Hela cells with Skp2 and Skp2-LRR E3 ligase dead mutant we found that Skp2 could rescue the defect in the activation of Aurora B, but the mutant failed to do so. Furthermore, we discovered that Skp2 could interact with Aurora B and trigger Aurora B Lysine (K) 63-linked ubiquitination. Finally, we demonstrated the essential role of Skp2 in cell mitosis progression and spindle checkpoint, which was Aurora B dependent. Our results identified a novel ubiquitinated substrate of Skp2, and also indicated that Aurora B ubiquitination might serve as an important event for Aurora B activation in cell mitosis and spindle checkpoint.

Casitas B-Lineage Lymphoma RING Domain Inhibitors Protect Mice against High-Fat Diet-Induced Obesity and Insulin Resistance.

The casitas b-lineage lymphoma (c-Cbl) is an important adaptor protein with an intrinsic E3 ubiquitin ligase activity that interacts with E2 proteins such as UbCH7. c-Cbl plays a vital role in regulating receptor tyrosine kinase signaling. c-Cbl involves in whole-body energy homeostasis, which makes it a potential target for the treatment of type 2 diabetes and obesity. In the present study, we have designed two parental peptides and 55 modified peptides based on the structure of UbCH7 loop L1 and L2. Thirteen of the modified peptides showed increased inhibitory activity in a fluorescence polarization-based assay. In the in vivo proof of study principle, mice treated with peptides 10, 34, 49 and 51 were protected against high-fat diet-induced obesity and insulin resistant. These inhibitors may potentially lead to new therapeutic alternatives for obesity and type 2 diabetes.

Development of a fluorescence polarization based high-throughput assay to identify Casitas B-lineage lymphoma RING domain regulators.

The E3 ubiquitin protein ligase Casitas B-lineage Lymphoma (Cbl) proteins and their binding partners play an important role in regulating signal transduction pathways. It is important to utilize regulators to study the protein-protein interactions (PPIs) between these proteins. However, finding specific small-molecule regulators of PPIs remains a significant challenge due to the fact that the interfaces involved in PPIs are not well suited for effective small molecule binding. We report the development of a competitive, homogeneous, high-throughput fluorescence polarization (FP) assay to identify small molecule regulators of Cbl (RING) domain. The FP assay was used to measure binding affinities and inhibition constants of UbCH7 peptides and small molecule regulators of Cbl (RING) domains, respectively. In order to rule out promiscuous, aggregation-based inhibition, two assay conditions were developed and compared side by side. Under optimized conditions, we screened a 10,000 natural compound library in detergent-free and detergent-present (0.01% Triton X-100) systems. The results indicate that the detergent-present system is more suitable for high-throughput screens. Three potential compounds, methylprotodioscin, leonuride and catalpol, have been identified that bind to Cbl (RING) domain and interfere with the Cbl (RING)-UbCH7 protein-protein interaction.

Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.