In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

Objective To investigate the effect of high-frequency irreversible electroporation(H-FIRE)in the ablation of pig pancreatic tissue.Methods Laparotomy was conducted in this study,and needle electrodes were used to release electric pulses in 12 pigs.Three sets of parameters were established for ablation at the low,medium,and high values of field strength(1 000 V/cm,1 500 V/cm,and 2 500 V/cm).The groups were compared in terms of the data including postoperative recovery,ablation area,and histopathological features to validate the safety and efficacy of H-FIRE in the ablation of porcine pancreatic tissue.The paired t-test was used for comparison of continuous data between two groups.Results All pigs in the experiment survived and showed a good effect of ablation.The histopathological analysis of all groups showed thorough and effective ablation,with a clear boundary between the ablated area and the normal tissue area.The mean ablation area in the low,medium,and high field strength groups was 30.96±3.73 mm2,51.93±25.26 mm2,and 108.90±55.23 mm2,respectively,and the high and medium field strength groups had a significantly larger ablation area than the low field strength group(both P<0.05),while there was no significant difference in ablation area between the medium and high field strength groups(P>0.05).Conclusion H-FIRE ablation is safe and effective for porcine pancreatic tissue under specific ablation parameters.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Objective To explore the treatment for endometriosis(EMs)by Professor SITU Yi,a Guangdong famous traditional Chinese medicine physician,thus to provide reference for the diagnosis and treatment of EMs in traditional Chinese medicine based on personalized knowledge graph analysis and data mining technology.Methods Based on the literature research achievements of diagnosis and treatment of EMs,the ontology knowledge tree of famous physician's principles,methods,prescriptions and medicines was established by user-computer integration method.The medical records of EMs patients treated by Professor SITU Yi in the outpatient department of Guangdong Provincial Hospital of Chinese Medicine from 2013 to 2019 were collected.After standardization of the data of medical records,the knowledge set was defined,the knowledge map of TCM diagnosis and treatment of EMs was constructed,and the symptom characteristics and medication rules for EMs were analyzed.Results The core symptoms of EMs patients were dysmenorrhea,chronic pelvic pain and infertility,with the predominated syndrome of blood stasis.The pathogenesis of EMs patients was mainly due to qi stagnation,kidney deficiency,and qi deficiency.Frequent itemset analysis yielded the core drug groups of"Corydalis Rhizoma,Cyperi Rhizoma,Paeoniae Radix Alba""Lycii Fructus,Taxilli Herba,Poria,Dioscoreae Rhizoma"and"Aurantii Fructus,Leonuri Herba".The EMs word cloud map constructed on the basis of knowledge element clustering and neural network algorithm showed that the drug combinations of"Salviae Miltiorrhizae Radix et Rhizoma,Paeoniae Radix Rubra""Corydalis Rhizoma,Curcumae Radix""Cinnamomi Ramulus,Moutan Cortex,Paeoniae Radix Rubra,Poria""Salviae Miltiorrhizae Radix et Rhizoma,Paeoniae Radix Rubra,Sparganii Rhizoma,Curcumae Rhizoma""Chuanxiong Rhizoma,Corydalis Rhizoma"and"Taxilli Herba,Cuscutae Semen"were commonly used for the treatment of EMs by Professor SITU Yi.The results of hierarchical clustering analysis and association network construction for Chinese medicinals,symptoms and syndromes showed that there were complex inner link among the syndromes,symptoms and medication.Conclusion For the treatment of EMs,Professor SITU Yi usually adopt the methods of activating blood to remove stasis and tonifying kidney,and also performs the periodic therapy and simultaneous application of purging and nourishing therapeutics.Knowledge graph analysis and data mining based on semantic web are helpful to unveil the tacit knowledge of clinical diagnosis and treatment experience of Professor SITU Yi,which can provide reference for the differentiation and treatment of EMs with Chinese medicine.

Objective:To evaluate the efficacy of acute T-cell lymphoblastic leukemia(T-ALL)in children and explore the prognostic risk factors.Methods:The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed,and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia(B-ALL)in the same period.Kaplan-Meier analysis was used to evaluate the overall survival(OS)and event-free survival(EFS),and COX proportional hazard regression model was used to evaluate the prognostic factors.Among 116 children with T-ALL who received standard treatment,78 cases received the Chinese Childhood Leukemia Collaborative Group(CCLG)-ALL 2008 protocol(CCLG-ALL 2008 group),and 38 cases received the China Childhood Cancer Collaborative Group(CCCG)-ALL 2015 protocol(CCCG-ALL 2015 group).The efficacy and serious adverse event(SAE)incidence of the two groups were compared.Results:Proportion of male,age ≥ 10 years old,white blood cell count(WBC)≥ 50 × 109/L,central nervous system leukemia,minimal residual disease(MRD)≥ 1％during induction therapy,and MRD ≥ 0.01％at the end of induction in T-ALL children were significantly higher than those in B-ALL children(P＜0.05).The expected 10-year EFS and OS of T-ALL were 59.7％and 66.0％,respectively,which were significantly lower than those of B-ALL(P＜0.001).COX analysis showed that WBC ≥ 100 x 109/L at initial diagnosis and failure to achieve complete remission(CR)after induction were independent risk factors for poor prognosis.Compared with CCLG-ALL 2008 group,CCCG-ALL 2015 group had lower incidence of infection-related SAE(15.8％vs 34.6％,P=0.042),but higher EFS and OS(73.9％vs 57.2％,PEFS=0.090;86.5％vs 62.3％,PoS=0.023).Conclusions:The prognosis of children with T-ALL is worse than children with B-ALL.WBC ≥ 100 × 109/L at initial diagnosis and non-CR after induction(especially mediastinal mass has not disappeared)are the risk factors for poor prognosis.CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

Objective:To analyze the clinical characteristics and prognosis of children with hypodiploid B-cell precursor acute lymphoblastic leukemia(BCP-ALL).Methods:The clinical data of 1 287 children with BCP-ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.According to the results of chromosome karyotype,all the patients were grouped into hypodiploid subgroup and non-hypodiploid subgroup.The clinical characteristics,early treatment response[minimal residual disease(MRD)on middle stage of induction chemotherapy and end of induction chemotherapy]and long-term efficacy[overall survival(OS)and event-free survival(EFS)]were compared.The prognostic factors of hypodiploid BCP-ALL were further explored.Results:Among 1 287 BCP-ALL patients,28 patients(2.2％)were hypodiploid BCP-ALL.The proportion of patients with white blood cell count(WBC)≥50 x 109/L in the hypodiploid subgroup was significantly higher than that in the non-hypodiploid subgroup(P=0.004),while there was no statistically significant difference in gender ratio,age group at initial diagnosis,and early treatment response between the two groups(all P＞0.05).The 5-year EFS and OS rate of the hypodiploid subgroup were 75.0％(95％CI:66.8％-83.2％)and 77.8％(95％CI:69.8％-85.8％),respectively,which were lower than those of non-hypodiploid subgroup[EFS:79.6％(95％CI:78.4％-80.8％);OS:86.4％(95％CI:85.4％-87.5％)],but the difference was not statistically significant(all P＞0.05).Further subgroup analysis by risk stratification showed that the 5-year EFS and OS rates of the hypodiploid subgroup were significantly lower than those in the low-risk(LR)group[LR group EFS:91.4％(95％CI:88.4％-93.6％),P＜0.001;OS:94.7％(95％CI:92.1％-96.4％),P＜0.001];it was similar to that of BCP-ALL children stratified into intermediate-risk(IR)excluding hypodiploid[IR group EFS:79.4％(95％CI:74.9％-83.2％),P=0.343;OS:87.3％(95％CI:83.6％-90.2％),P=0.111];while was higher than that of EFS in HR group,but the difference was not statistically significant[HR group EFS:58.7％(95％CI:52.6％-64.8％),P=0.178.OS:69.9％(95％CI:63.5％-75.4％),P=0.417].Univariate analysis showed that gender,age,white blood cell count,and MRD on middle stage of induction chemotherapy had no significant impact on OS and EFS;chromosome count＜40 was a risk factor for lower OS(P=0.026),but has no significant effect on EFS;MRD≥0.01％after induction therapy was a risk factor for lower OS and EFS(P=0.002,and 0.001,respectively).Conclusion:Children with hypodiploid BCP-ALL have an intermediate prognosis,and MRD ≥0.01％after induction chemotherapy may be a risk factors for poor prognosis.

Objective:To analyze the related factors of treatment failure in children with acute lymphoblastic leukemia (ALL)in real-world.Methods:The clinical data of 1414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed.Treatment failure was defined as relapse,non-relapse death,and secondary tumor.Results:Following-up for median time 49.7 (0.1-136. 9)months,there were 269 cases (19.0％)treatment failure,including 140 cases (52.0％)relapse,and 129 cases (48.0％)non-relapse death.Cox univariate and multivariate analysis showed that white WBC≥50 ×109/L at newly diagnosis,acute T-cell lymphoblastic leukemia (T-ALL),BCR-ABL1,KMT2A-rearrangement and poor early treatment response were independent risk factor for treatment failure (all HR>1.000,P<0.05).The 5-year OS of 140 relapsed ALL patients was only 23.8％,with a significantly worse prognosis for very early relapse (relapse time within 18 months of diagnosis).Among 129 patients died from non-relapse death,71 cases (26.4％)were died from treatment-related complications,56 cases (20.8％)died from treatment abandonment,and 2 cases (0.7％)died from disease progression.Among them,treatment-related death were significantly correlated with chemotherapy intensity,while treatment abandonment were mainly related to economic factors.Conclusion:The treatment failure of children with ALL in our province is still relatively high,with relapse being the main cause of treatment failure,while treatment related death and treatment abandonment caused by economic factors are the main causes of non-relapse related death.

Objective:To explore the tracking accuracy of the surface optically guided tracking system (OGTS) in radiotherapy.Methods:Phantom verification and clinical trial verification were adopted. Specialized equipment was employed for the phantom verification. Specifically, the displacement of the optical markers as they moved from a predetermined position to the target position on the reflector ball platform was captured using the OGTS, and then the obtained displacement was compared with the fixed distance within the phantom to calculate the accuracy and repeatability of the OGTS. For the clinical trial verification, 45 patients treated with radiotherapy, which consisted of 15 cases with head, breast, and rectal tumors each, were selected to investigate the tracking accuracy and repeatability of the OGTS. For each patient, the values derived from the image-guided positioning system (IGPS) and the OGTS before and after image-guided setup error correction during three times of fractionated radiotherapy were randomly obtained. The translational errors of each error correction were also recorded. Before radiotherapy, patients′ setup errors were corrected and relevant data were obtained using the IGPS. The correction result of translation errors obtained using the IGPS served as a gold standard to verify the accuracy of the OGTS in monitoring the translational motion of patients. Finally, the comprehensive translational deviation of both method was calculated.Results:The phantom measurements showed that the comprehensive translational deviation for tracking accuracy and tracking repeatability of the OGTS had a maximum deviation and a standard deviation of 0.18 mm and 0.03 mm, respectively. The clinical trial result indicated that the tracking accuracy of IGPS and OGTS exhibited statistically significant differences only for the head in the z direction ( t = 2.21, P < 0.05). Conversely, no statistically significant differences were observed for the head in the remaining directions or for the breast and rectum in the three translational directions ( P > 0.05). The analysis showed that comprehensive translational deviations for the head, breast, and rectum derived from OGTS and IGPS were (0.91±0.62), (1.64±1.30), and (1.52±1.29) mm, respectively, satisfying the requirement that the deviations should be below 2 mm. Conclusions:The OGTS, featuring easy operation and high tracking accuracy, can assist the IGPS in real-time respiratory monitoring during radiotherapy.

Objective:To investigate the clinical value of spherical lens with 0.05 D intervals in optometry for small incision lenticule extraction (SMILE) in myopic eyes.Methods:A randomized controlled clinical study was conducted.Sixty patients (120 eyes) with low to moderate myopia and myopic astigmatism who underwent SMILE in the 989th Hospital of the PLA from June 2021 to February 2022 were enrolled.The patients were randomly divided into 0.05 D interval group (optometry with spherical lens at 0.05 D interval) and 0.25 D interval group (optometry with spherical lens at 0.25 D interval), with 30 cases (60 eyes) in each group.There was no significant difference in matched age, sphericity, cylindricity, and best corrected visual acuity (BCVA) (all at P>0.05). The preoperative monocular red-green balance, 1- and 3-month postoperative monocular red-green balance, uncorrected visual acuity and spherical equivalent of both groups were compared.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the 989th Hospital of the PLA (No.WZLL-2021-034). Written informed consent was obtained from each subject before any medical examination. Results:The preoperative red-green balance rate in 0.05 D interval group was 95.00%(57/60), which was higher than 35.00%(21/60) in 0.25 D interval group, showing a statistically significant difference ( Wald χ2=17.642, P<0.001). The 1- and 3-month postoperative red-green balance rates in 0.05 D interval group were 63.33%(38/60) and 56.67%(34/60), which were higher than 23.33%(14/60) and 21.67%(13/60) in 0.25 D interval group respectively, showing statistically significant differences ( Wald χ2=9.137, P=0.003; Wald χ2=7.483, P=0.006). The 1- and 3-month postoperative visual acuity in 0.05 D interval group were -0.1(-0.1, -0.1) and -0.1(-0.1, -0.1), which were higher than 0.0(-0.1, 0.0) and -0.1(-0.1, 0.0) in 0.25 D interval group respectively, showing statistically significant differences ( Wald χ2=11.624, P=0.001; Wald χ2=12.841, P<0.001). The 1- and 3-month postoperative spherical equivalent were -0.07(-0.25, 0.13)D and -0.13(-0.25, 0.13)D in 0.05 D interval group, which were higher than -0.13(-0.38, 0.25)D and -0.13(-0.38, 0.25)D in 0.25 D interval group respectively, showing no statistically significant difference between the two groups ( Wald χ2=0.029, P=0.866; Wald χ2=0.189, P=0.664). Conclusions:Compared with spherical lens at 0.25 D interval, 0.05 D interval can improve the accuracy of preoperative and postoperative red-green balance rate and postoperative visual acuity in patients with low to moderate myopia who undergo SMILE.

Objective:To improve the quality assurance (QA) skills of radiotherapy personnel and medical students and reduce the radiation risk of training by developing a remote training system for QA of medical electronic linear accelerators.Methods:This training system was built based on radiotherapy technology and quality control contents of medical electronic linear accelerators, and a virtual reality interactive software was developed using extended reality (XR) technology Unity 3D. A remote control module of multi-terminal platform was also developed. A multi-perspective evaluation system was adopted and a questionnaire was designed to analyze the application value of this system.Results:The training system reproduced the live environment and physical objects of medical electronic linear accelerator treatment room. It built a multi-terminal virtual simulation training system with radiotherapy technology as well as QA knowledge system. This system could provide 5G remote control of medical electronic linear accelerator for off-site quality control demonstration and guidance. By March 1, 2022, a total number of 133 people had been trained using this system, 76 valid questionnaires had been taken, of which 90.79% (69/76) of the respondents trusted the experimental results shown by the system and 88.16% (67/76) of the respondents considered the training system necessary.Conclusions:The training effect of this system is widely recognized. It fundamentally reduces the training radiation hazard and provides reference for the reform and progress of QA training mode of medical electronic linear accelerators.