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RNA-based therapeutics have emerged as a promising approach for the treatment of various diseases, including cancer, genetic disorders, and infectious diseases. However, the delivery of RNA molecules into target cells has been a major challenge due to their susceptibility to degradation and inefficient cellular uptake. To overcome these hurdles, DNA-based nano technology offers an unprecedented opportunity as a potential delivery platform for RNA therapeutics. Due to its excellent characteristics such as programmability and biocompatibility, these DNA-based nanostructures, composed of DNA molecules assembled into precise and programmable structures, have garnered significant attention as ideal building materials for protecting and delivering RNA payloads to the desired cellular destinations. In this review, we highlight the current progress in the design and application of three DNA-based nanostructures: DNA origami, lipid-nanoparticle (LNP) technology related to frame guided assembly (FGA), and DNA hydrogel for the delivery of RNA molecules. Their biomedical applications are briefly discussed and the challenges and future perspectives in this field are also highlighted.

Traditional Chinese medicine (TCM) has been used to treat triple-negative breast cancer (TNBC), a breast cancer subtype with poor prognosis. Clinical studies have verified that the Sanyingfang formula (SYF), a TCM prescription, has obvious effects on inhibiting breast cancer recurrence and metastasis, prolonging patient survival, and reducing clinical symptoms. However, its active ingredients and molecular mechanisms are still unclear. In this study, the active ingredients of each herbal medicine composing SYF and their target proteins are obtained from the Traditional Chinese Medicine Systems Pharmacology database. Breast cancer-related genes are obtained from the GeneCards database. Major targets and pathways related to SYF treatment in breast cancer are identified by analyzing the above data. By conducting molecular docking analysis, we find that the active ingredients quercetin and luteolin bind well to the key targets KDR1, PPARG, SOD1, and VCAM1. In vitro experiments verify that SYF can reduce the proliferation, migration, and invasion ability of TNBC cells. Using a TNBC xenograft mouse model, we show that SYF could delay tumor growth and effectively inhibit the occurrence of breast cancer lung metastasis in vivo. PPARG, SOD1, KDR1, and VCAM1 are all regulated by SYF and may play important roles in SYF-mediated inhibition of TNBC recurrence and metastasis.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is characterized by high invasiveness. Trastuzumab considerably improves the prognoses of HER2-positive BC, but some patients exhibit drug resistance. In this study, the effects of XLLXF combined with trastuzumab on the proliferation, apoptosis, invasion, and migration of HER2-positive BC cells are evaluated, and network pharmacology is performed. Then, we conduct an in vivo study using a xenograft mouse model of HER2-positive BC, and tumor growth is monitored. The expression levels of cytokines are measured by ELISA. Molecular docking is performed to observe the binding stability of IL2, JAK, STAT, and TNF with curcumenol, icariside-II, lobetyolin, and scutellarein. Finally, we observe changes in JAK1 and TNF-α in tumor tissues by immunohistochemistry. The results show that XLLXF enhances the inhibitory effects of trastuzumab on the proliferation, colony formation ability, migration, and invasion of HER2-positive BC cells and promotes apoptosis. Network pharmacology reveals that XLLXF may exert its effects on HER2-positive BC by modulating pathways such as the ErbB, JAK-STAT, and NF-κB pathways. Potential targets include cytokines closely related to immune function. In the in vivo study, XLLXF synergistically enhances the inhibitory effects of trastuzumab on tumor growth. ELISA reveals that XLLXF combined with trastuzumab increases the levels of IL-15, IL-2, TNF-α, and IFN-γ in tumor-bearing mice. Immunohistochemistry confirms that XLLXF can regulate the expressions of JAK1 and TNF-α. This study demonstrates that XLLXF can synergistically enhance the efficacy of trastuzumab in targeting HER2-positive BC. The mechanism may involve the modulation of inflammatory factors.

This study introduced whole-exome sequencing (WES) in prenatal diagnosis of fetal bowel dilatation to improve the detection outcome when karyotype analysis and copy number variation sequencing (CNV-seq) were uninformative in detecting pathogenic variants. The work reviewed 28 cases diagnosed with fetal bowel dilatation and analyzed the results of karyotype analysis, CNV-seq, and WES. Among the 28 cases, the detection rate in cases with low risk of aneuploidy was 11.54% (3/26), which is lower than 100% (2/2) in cases with high risk of aneuploidy. Ten low-risk aneuploidy cases with isolated fetal bowel dilatation had normal genetic testing results, while the remaining 16 cases with other ultrasound abnormalities were detected for genetic variants at a rate of 18.75% (3/16). The detection rate of gene variation was 3.85% (1/26) by CNV-seq and 7.69% (2/26) by WES. This study suggested that WES could reveal more genetic risk in prenatal diagnosis of fetal bowel dilatation and has value in prenatal diagnosis to reduce birth defects.

BackgroundPelvic floor rehabilitation has been reported to be effective in improving fecal incontinence. The aim of this study was to prospectively evaluate the effectiveness of combined pelvic floor muscle exercises (PFMEs) and loperamide treatment on rectal function and mental health for low anterior resection syndrome (LARS) patients after sphincter-saving operation (SSO) for rectal cancer.MethodsA total of 60 inpatients diagnosed with LARS were enrolled and randomly assigned to one of two groups: patients in Group A (n = 30) were treated with a PFME intervention and those in Group B (n = 30) with a control intervention for 4 weeks. High-resolution anorectal manometry (HRAM) was performed for all LARS patients. Demographic information was collected for all patients, and they subsequently also completed several questionnaires, including the Hospital Anxiety and Depression Scale (HADS), a measure of Wexner score, a measure of stool frequency per day, and the Bristol Stool Form Scale (BSFS).ResultsNo significant differences between the groups were observed in baseline data. With regard to rectal function, we found significant improvements at week 4 in maximal resting pressure (MRP) (39.93 ± 5.02 vs. 28.70 ± 5.40 mmH2O, p < 0.001) and maximal squeeze pressure (MSP) (132.43 ± 8.16 mmH2O vs. 113.33 ± 9.87 mmH2O, p < 0.001) among Group A patients compared to Group B patients. Additionally, Wexner scores were significantly lower in Group A than in Group B at week 4 (8.10 ± 1.24 vs. 9.87 ± 1.29 ml, p = 0.018), as were stool frequency (6.47 ± 0.90 vs. 7.83 ± 0.93, p < 0.001) and BSFS scores (5.17 ± 0.65 vs. 6.10 ± 0.80, p = 0.020). Notably, HADS scores were also significantly lower in Group A than in Group B at week 4 (8.25 ± 2.36 vs. 10.48 ± 3.01, p < 0.001). Additionally, both anxiety scores (4.16 ± 1.38 vs. 5.33 ± 1.69, p < 0.001) and depression scores (4.09 ± 1.56 vs. 5.15 ± 1.89, p < 0.001) were significantly lower in Group A than in Group B at week 4.ConclusionPelvic floor muscle exercises are an effective treatment that can alleviate symptoms and improve rectal function and mental health in patients with low anterior resection syndrome.

Objectives: The aim of this study was to explore the mechanism of regulating the endocrine function of hyperplasia breast in rats with Mongolian Medicine Modified Sugmul-7 (MMMS-7) by Proteomics and provide an experimental basis for its development and clinical application. Methods: Ninety female SD rats were randomly divided into 6 groups: the intact group – the animal group that was injected with neither estradiol, nor progesterone, nor administered Mongolian Medicine Modified Sugmul-7; the negative control group – the group injected with estradiol and progesterone; the positive control group - injected with estradiol, progesterone and administered mastodynon 0.06 g/kg; and the treatment groups – injected with estradiol and progesterone, each in their respective dose groups. After the start of the experiment, each rat except the intact group was intra peritoneally injected with estradiol 25d and progesterone 6d at a standard dose of 0.3 mg / kg for a total of 31 days. Results: Four differential proteins were found through proteomic analysis, namely Ppp3cb, Cacybp, Gstz1, and Nmd3 and their 5 related pathways. Conclusions: The above pathways are all known to be related to the treatment of breast hyperplasia caused by endocrine disorders. Treatment with Mongolian Medicine Modified Sugmul-7 is completed through regulation of the gastrointestinal and endocrine systems.

Background and purpose: Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive malignancy with poor prognosis, and there is no standardized therapeutic regimen. The aim of the study was to analyze the prognostic factors influencing survival of the patients with ATC, and to explore the reasonable treatment methods. Methods: The sociodemographic and clinicopathologic characteristics of 37 ATC patients at the Department of Head and Neck Surgery in Gansu Provincial Cancer Hospital between May 2008 and May 2014 were analyzed retrospectively. The Kaplan-Meier method and log-rank test were used to determine and compare the survival. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. Results: Females were more affected. Twenty-five cases occurred in women, and 12 in males. The age range was 42-82 years, and the median age was 64. ATC accounted for 5.3% of all thyroid cancers in this study, and goiter was present in 29.7% of patients with ATC. Less than 20% of the ATC patients lived in urban areas, and more than half lived in endemic goiter areas. Mean survival time was 11.5 months. Median survival time was 5.9 months, and half-, 1- and 2-year overall survival rates were 48.6%, 21.6% and 13.5%, respectively. Univariate analysis showed that age, goiter, distant metastasis, surgery, comprehensive therapy and postoperative radiotherapy were independent prognostic factors of survival in all ATC patients. Multivariate analysis showed that age no more than 50 years (HR=0.21, 95% CI: 0.06-0.77, P=0.019), surgery (HR=0.15, 95% CI: 0.04-0.59, P=0.007) and comprehensive therapy (HR=0.31, 95% CI: 0.11-0.85, P=0.023) were independent protective factors associated with the survival of ATC patients. With regard to operated patients，macroscopic residual tumor (HR=7.98, 95% CI: 1.38-46.21, P=0.020) and distant metastasis (HR=6.26, 95% CI: 1.65-23.83, P=0.007) were independent risk factors of survival. Postoperative radiotherapy (HR=0.18, 95% CI: 0.04-0.83, P=0.028) was a protective factor. Conclusion: Age, type of surgery resection and postoperative radiotherapy influence prognosis of ATC independently. The patients with ATC may have a better prognosis by receiving multidisciplinary comprehensive therapy combining surgery and postoperative radiotherapy with or without chemotherapy based on each individual circumstance.

In order to avoid the design of the rotor of the dry gas seal high speed test stand occur resonance phenomenon during high speed running,the transfer matrix method was applicated to calculate the natural frequency.Then it obtains that its natural frequency is 14044.586r/min when the dry gas seal static and ring `s quality is 33.78 kg in rotor system,and using the finite element method analysis the modes of the rotor system when it is operating in the vicinity of its natural frequency,then it will get the modal figure with four modal value.Comparative and analysis the results of the two methods,though simplified model are not the same,the results are similar.And the design of speed can meet the requirements,so it can describe the design of the rotor system is reasonable.

Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint blockade as a breakthrough in cancer immunotherapy has shown unprecedented positive outcomes in the clinic. However, the overall effectiveness of PD-L1 antibody is less than expected. An increasing number of studies have demonstrated that PD-L1 is widely distributed and expressed not only on the cell membrane but also on the inside of the cells as well as on the extracellular vesicles secreted by tumour cells. Both endogenous and exogenous PD-L1 play significant roles in influencing the therapeutic effect of anti-tumour immunity. Herein, we mainly focused on the distribution and function of PD-L1 and further summarized the potential targeted therapeutic strategies. More importantly, in addition to taking the overall expression abundance of PD-L1 as a predictive indicator for selecting corresponding PD-1/PD-L1 monoclonal antibodies (mAbs), we also proposed that personalized combination therapies based on the different distribution of PD-L1 are worth attention to achieve more efficient and effective therapeutic outcomes in cancer patients. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

Abstract: Neutrophils are the most abundant leukocytes in human blood. Neutrophil malfunction may cause various immunological diseases. Beta2 integrins are critical for neutrophil recruitment. Kindlin-3 and talin-1 are important regulators for beta2 integrin activation. We have confirmed this using conformation-specific antibodies KIM127 and mAb24 that recognize activation epitopes in beta2 integrin. Besides activation, clustering is also critical for beta2 integrin avidity and adhesion of neutrophils. Whether kindlin-3 and talin-1 are involved in beta2 integrin clustering remains unclear. Here we used super-resolution stochastic optical reconstruction microscopy (STORM) to study their roles in beta2 integrin clustering on human neutrophil-like HL60 cells. We find that lymphocyte function-associated antigen 1 (LFA-1) and macrophage-1 antigen (Mac-1) are significantly clustered in wild-type cells after IL-8 or fMLP stimulation. Using CRISPR-Cas9-mediated kindlin-3 and talin-1 knockout HL60 cells, we found that kindlin-3 but not talin-1 are responsible for beta2 integrin clustering. Our study provides new insights into the regulation of beta2 integrin clustering and leukocyte recruitment. Supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454), and a startup fund from UConn Health.