Tumor treatment-related adverse reactions are a major focus of clinical concern， among which recurrent aphthous oral ulcers （RAU） associated with targeted therapy for lung cancer （LC） are among the most painful and distressing for patients. Currently， modern medical interventions show limited efficacy， and there is an urgent need for more effective treatment strategies. This study differentiates RAU associated with targeted therapy for LC from chemotherapy-related and ordinary oral ulcers， elucidates the pathophysiological basis of such ulcers， and traces the theoretical origin of "Yin deficiency and Qi collapse". Based on the new system of "five perspectives on diagnosis and treatment" for tumor prevention and treatment， with a focus on the core and symptom perspectives and rooted in the traditional concept of "lung dominating Qi"， we innovatively propose the concept of "medicine-induced ulcer" and are the first to introduce the theory of "Yin deficiency and Qi collapse" into the syndrome differentiation and treatment of RAU associated with targeted therapy for LC （i.e.， medicine-induced ulcer）. We propose that "Yin deficiency and Qi collapse" is the core pathogenesis of medicine-induced ulcers， in which the collapse of formless Qi is the key to their onset， while the deficiency and stasis of tangible Yin and blood constitute the root of recurrence. A hierarchical strategy for syndrome differentiation and treatment is established： first treating the collapse of formless Qi， then replenishing tangible deficiencies， and concurrently preventing recurrence. We emphasize that treatment should address both root and manifestation， with appropriate prioritization. In the acute phase， while relieving symptoms and promoting ulcer healing by nourishing Qi， uplifting collapse， and generating body fluids， attention should also be paid to nourishing spleen Yin， facilitating the circulation of nutritive Qi， and alleviating stasis to target the root pathogenesis and reduce recurrence. A verified case is presented to support this approach. This study enriches the theoretical framework and clinical methods of traditional Chinese medicine （TCM） in the treatment of RAU associated with targeted therapy for LC， promotes symptom management of treatment-related adverse reactions through integrated TCM and Western medicine， and provides theoretical support for the construction and development of a comprehensive differentiation and treatment system for lung cancer prevention， treatment， and rehabilitation.

Objective To investigate the physiological characteristics of Bacillus thuringiensis subspecies israelensis (Bti) with double mutations of cwlE and sigK genes and to assess the activity of Bti against larvae of Culex pipiens pallens under different external factors, so as to provide the theoretical evidence for the use of engineered bacteria of Bti for effective mosquito control. Methods B. thuringiensis wild-type strain Bt-59 and Bt-59 strain with cwlE mutation [Bt-59 (ΔcwlE)] were cultured in nutrient broth media for 24 hours, and Bt-59 strains with sigK mutation [Bt-59 (ΔsigK)] and double mutations of cwlE and sigK [Bt-59 (ΔcwlE-sigK)] were cultured in nutrient broth media for 48 hours. Then, 5 μL of culture media were transferred to glass sides, and cell morphology and mother cell lysis were observed under an optical microscope. The optical densities of Bti strain culture media were measured at different time points of culture, and the growth curves of Bt-59, Bt-59 (ΔcwlE), Bt-59 (ΔsigK), and Bt-59 (ΔcwlE-sigK) strains were plotted. The differences in carbon source metabolism of four Bti strains were analyzed using the Biolog microplate culture method, and the metabolic activity of these strains was estimated with average well color development (AWCD). The fermentation media of these four Bti strains were diluted into final concentrations of 2.000, 1.000, 0.500, 0.250, and 0.125 μL/L, and the median lethal concentrations (LC₅₀ values) of these four strains against the third instar larvae of Cx. pipiens pallens were determined. In addition, the fermentation media of Bti strains were processed as follows: pH adjusted to 5, 7 and 9; treated at 30, 40 ℃ and 50 ℃ for 12 hours; and exposed to irradiation with ultraviolet lights for 0 hour and 6 hours. Then, 20 third instar larvae of Cx. pipiens pallens were exposed to the above processed fermentation media at a final concentration of 1 μL/L in 200 mL of water at 26 ℃ for 24 hours, and the mosquito mortality was estimated to evaluate the effects of pH, temperature and ultraviolet irradiation on the larvicidal activity of four Bti strains. Results The growth curves of the Bt-59 strain and its mutants shared a similar changing trend, and both experienced a stable phase 6 hours post-culture. Both spores and crystal proteins were found in Bt-59 and Bt-59 (ΔcwlE) cells, and only crystal proteins were found in Bt-59 (ΔsigK) and Bt-59 (ΔcwlE-sigK) cells. No lysis was found in the cell wall of the Bt-59 (ΔcwlE-sigK) strain, and the crystal protein was embedded in the mother cell. Biolog microplate culture assay showed that the AWCD values of four Bti strains showed a similar changing trend over time, and 33 carbon sources were found to be metabolized by all of the four strains, including dextrin, D-maltose and D-trehalose. The LC50 values of the fermentation media of Bt-59, Bt-59 (ΔcwlE), Bt-59 (ΔsigK), and Bt-59 (ΔcwlE-sigK) strains were 0.60, 0.51, 0.70 μL/L and 0.72 μL/L against Cx. pipiens pallens, respectively. The adjusted mortality of larval Cx. pipiens pallens reduced by 76.60%, 76.00%, 66.67%, and 0 following exposure to the fermentation media of Bt-59, Bt-59 (ΔcwlE), Bt-59 (ΔsigK), and Bt-59 (ΔcwlE-sigK) strains at a pH of 5 relative to at a pH of 7, and the adjusted mortality reduced by 49.02%, 51.06%, 36.36%, and 4.44% following 6-hour exposure to ultraviolet irradiation relative to 0-hour exposure, while the adjusted mortality was 68.33% to 83.33% following treatment with the fermentation media of four Bti strains at different temperatures. Conclusions Bt-59 (ΔcwlE-sigK) strains do not generate spores, and the absence of cwlE and sigK does not affect the growth, carbon source metabolism, and larvicidal activity of Bti strains against larval Cx. pipiens pallens. Cell wall embedding of Bt-59 (ΔcwlE-sigK) strains may protect larvicidal crystal proteins of Bti strains from external environmental factors, including ultraviolet irradiation, and pH alteration.

Objective:To evaluate the right ventricular function in patients with dilated cardiomyopathy (DCM) by four-dimensional automatic right ventricular quantitative analysis (4D Auto RVQ), and compare with the right ventricular ejection fraction measured by cardiac magnetic resonance (CMR-RVEF), and to explore the clinical application value of 4D Auto RVQ technique in evaluating the right ventricular function of patients with DCM.Methods:A prospective study was conducted to select 52 patients with DCM who were treated in Fuwai Central China Cardiovascular Hospital of Zhengzhou University from March to October 2022 as DCM group, and 52 healthy volunteers were selected as the control group during the same period. The four-dimensional right ventricular ejection fraction (4D-RVEF), right ventricular stroke volume index (RVSVI), right ventricular end-diastolic volume index (RVEDVI), right ventricular end-systolic volume index (RVESVI), four-dimensional right ventricular basal diameter (4D-RVDd-base), four-dimensional right ventricular middle diameter (4D-RVDd-mid), four-dimensional right ventricular long axis diameter (4D-RVLd), four-dimensional tricuspid annular plane systolic excursion (4D-TAPSE) and four-dimensional right ventricular fractional area change (4D-RVFAC) were obtained by 4D Auto RVQ technique. The differences of the above parameters between DCM group and control group were compared.Pearson linear correlation analysis was used to evaluate the correlation between echocardiographic parameters and CMR-RVEF. The ROC curve was used to find the most sensitive parameters for evaluating right ventricular function, and the area under the ROC curve ( AUC ) was calculated and compared.Results:Compared with the control group, RVEDVI, RVESVI, 4D-RVDd-base and 4D-RVDd-mid in the DCM group were increased, and the absolute values of 4D-RVEF, 4D-TAPSE, 4D-RVFAC, right ventricular global longitudinal strain(RVGLS) and right ventricular free wall longitudinal strain(RVFWLS) were decreased (all P<0.05). Correlation analysis showed that 4D-RVEF was positively correlated with CMR-RVEF ( r=0.711, P<0.05). ROC curve analysis showed that 4D-RVEF was superior to other parameters in evaluating right ventricular function in DCM patients (AUC: 0.916). Conclusions:4D Auto RVQ technique can quantitatively evaluate right ventricular function in DCM patients. 4D-RVEF has a significant correlation with CMR-RVEF, and 4D-RVEF has the best efficacy in evaluating right ventricular function in DCM patients.

Nucleic acid-based drugs, such as RNA and DNA drugs, exert their effects at the genetic level. Currently, widely utilized nucleic acid-based drugs include nucleic acid aptamers, antisense oligonucleotides, mRNA, miRNA, siRNA and saRNA. However, these drugs frequently encounter challenges during clinical application, such as poor stability, weak targeting specificity, and difficulties in traversing physiological barriers. By employing chemical modifications of nucleic acid structures, it is possible to enhance the stability and targeting specificity of certain nucleic acid drugs within the body, thereby improving delivery efficiency and reducing immunogenicity. Moreover, utilizing nucleic acid drug carriers can facilitate the transportation of drugs to lesion sites, thereby aiding efficient intracellular escape and promoting drug efficacy within the body. Currently, commonly employed delivery carriers include virus vectors, lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, protein carriers and extracellular vesicles. Nevertheless, individual modifications or delivery carriers alone are insufficient to overcome numerous obstacles. The integration of nucleic acid chemical modifications with drug delivery systems holds promise for achieving enhanced therapeutic effects. However, this approach also presents increased technical complexity and clinical translation costs. Therefore, the development of nucleic acid drug carriers and nucleic acid chemical modifications that are both practical and simple, while maintaining high efficacy, low toxicity, and precise nucleic acid delivery, has become a prominent research focus in the field of nucleic acid drug development. This review comprehensively summarizes the advancements in nucleic acid-based drug modifica-tions and delivery systems. Additionally, strategies to enhance nucleic acid drug delivery efficiency are discussed, with the aim of providing valuable insights for the translational application of nucleic acid drugs.
Nucleic Acids ; RNA, Small Interfering/genetics* ; Drug Carriers ; Drug Delivery Systems ; Drug Development

Objective:To explore the effects of apatinib on the proliferation and apoptosis of FLT3-ITD mutant acute myeloid leukemia (AML) cells, and to explore the related mechanisms.Methods:The logarithmic growth phase FLT3-ITD mutant AML cell lines MV4-11 and MOLM-13 were treated with different concentration of apatinib for 48 hours. The cell proliferation was detected by CCK-8 method. Flow cytometry was performed to examine the effect of apatinib on apoptosis. The cell mitochondrial membrane potential changes were detected by JC-1. Then the expression changes of vascular endothelial growth factor receptor 2 (VEGFR2) pathway-related proteins were examined by Western blot.Results:Apatinib had proliferation inhibitory effects on both MV4-11 and MOLM-13 cells, and the half-maximal inhibitory concentration (IC 50) at 48 hours was (2.23±0.42) μmol/L and (4.08±2.62) μmol/L, respectively. After exposure to apatinib with increasing concentrations (10, 20, 30, and 40 μmol/L) for 48 h hours, the percentage of apoptotic cells was significantly increased in MV4-11 cells [(81.95±1.15)%, (88.80±0.23)%, (97.46±0.49)%, and (99.29±0.05)%] and MOLM13 cells [(47.30±0.87)%, (67.00±3.71)%, (82.60±2.89)%, and (98.06±5.34)%] in a dose-dependent manner, and the differences were statistically significant ( F = 6 915.0, P < 0.01; F = 5 385.0, P < 0.01). Detection of mitochondrial membrane potential by JC-1 method showed that after MV4-11 and MOLM-13 cells were treated by 10, 20, 30, and 40 μmol/L apatinib for 24 hours, the JC-1 aggregate/monomer mean fluorescence intensity (MFI) ratios were 0.45±0.06, 0.19±0.07, 0.12±0.03, 0.09±0.01, and 0.84±0.05, 0.66±0.13, 0.35±0.11, 0.27±0.02, which were different from the control group (0.67±0.15 and 0.97±0.42), and the differences were statistically significant ( F = 372.3, P < 0.05; F = 276.4, P < 0.05). Western blot was performed to detect different concentration of apatinib (2.5, 5.0 and 10.0 μmol/L) on the MV4-11 cells for 24 hours, the results showed that apatinib could down-regulate the phosphorylation of VEGFR2, Src and Stat3 in a dose-dependent manner. Conclusions:Apatinib can inhibit cell proliferation and induce apoptosis in AML with FLT3-ITD mutation. The possible mechanism is related to the down-regulation of phosphorylation of VEGFR2 and its downstream targets Src and Stat3.

Objective To systematically review the effects of different delivery routes of oxytocin in preventing hemorrhage after cesarean section.Methods Databases including PubMed,Medline,Embase,Cochrane library,Wanfang Medical Database,China National Knowledge Internet (CNKI),VIP Database for Chinese Technical Periodicals were searched by computers and Conference papers were manually searched.The randomized,controlled clinical trials of oxytocin given by intramuscular injection,intravenous injection or intravenous infusion were included in elective cesarean section under spinal anesthesia.The quality of included literatures was evaluated by Cochrane systematic evaluation.The primary outcome measure was intraoperative amount of blood loss or change in Hb before and after operation.The secondary outcome measures were changes in blood pressure and heart rate,electrocardiogram,uterine contraction and other adverse reactions after using oxytocin.Results Seven studies involving 2 325 patients were included in this meta-analysis.Among the 2 325 patients,oxytocin was given through intramuscular injection in 79 cases,by intravenous injection in 1 147 cases and in the way of intravenous infusion in 1 099 cases.Compared with intramuscular injection group or intravenous infusion group,no significant change was found in the amount of blood loss during operation in intravenous injection group (P＞0.05).There was no statistically significant difference in the amount of blood loss during operation between intravenous injection group and intravenous infusion group (P＞0.05).Intravenously infusing oxytocin produced less effect on the mean arterial pressure and heart rate than intravenously injecting oxytocin (P＜0.01).Conclusion Intravenous infusion is a suitable route for oxytocin delivery in cesarean section with spinal anesthesia.

Objective: To investigate the changes and clinical significance of vascular endothelial (VE)-cadherin and procalcitonin (PCT) in serum and cerebrospinal fluid (CSF) of children with viral encephalitis or bacterial meningitis(BM). Methods: A total of 42 cases of children with viral encephalitis(viral encephalitis group), 36 cases of children with BM(BM group), and 20 cases of children with non-nervous system injury(control group) were selected from September 2016 to June 2018 at the Third Hospital of Zhengzhou University.The serum and CSF levels of VE-cadherin and PCT levels of the 3 groups were detected by using enzyme-linked immunosorbent assay. Results: The levels of VE-cadherin in the serum of viral encephalitis group, BM group and control group at the acute phase were (5.60±1.17) mg/L, (7.08±1.01) mg/L and (2.52±0.68) mg/L respectively, and the levels of VE-cadherin in CSF of viral encephalitis group, BM group and control group were (6.00±1.09) mg/L, (6.97±1.11) mg/L and(1.93±0.88) mg/L, respectively.The levels of PCT in the serum of viral encephalitis group, BM group and control group at the acute phase were (0.26±0.11) μg/L, (0.82±0.17) μg/L and (0.27±0.13) μg/L, respectively, and the levels of PCT in the CSF of viral encephalitis group, BM group and control group were (0.25±0.11) μg/L, (0.72±0.14) μg/L, (0.28±0.17) μg/L, respectively.As a result, the levels of VE-cadherin and PCT in the serum and CSF of BM group showed significant increase, compared with viral encephalitis group and control group in the acute phase(F=124.94, 163.21, 151.62, 127.37, all P<0.01). The levels of VE-cadherin in the serum and CSF of viral encephalitis group were also significantly higher than that of control group (all P<0.01), but there was no difference between viral encephalitis group and control group about the levels of PCT in the serum and CSF (all P>0.05). The levels of VE-cadherin in the serum of viral encephalitis group and BM group after treatment were (2.34±0.81) mg/L and (2.67±1.29) mg/L, and were(2.55±0.92) mg/L and(2.39±0.74) mg/L in the CSF.The levels of PCT in the serum of viral encephalitis group and BM group after treatment were (0.25±0.11) μg/L, (0.30±0.17) μg/L, and the levels of PCT in the CSF of viral encephalitis group and BM group were(0.22±0.10) μg/L and (0.27±0.12) μg/L.After effective treatment, the levels of VE-cadherin, PCT in serum and CSF of BM group and viral encephalitis group were almost equal, and the difference was not statistically significant(F=1.83, 0.76, 2.72, 3.89, all P>0.05). In the receiver operating characteristic (ROC) curve, the area under the ROC curve of VE-cadherin in serum and CSF was 0.896 and 0.912, and was 0.670 and 0.668 of PCT respectively. Conclusions VE-cadherin may be involved in the early stage of intracranial infection, and it may be helpful in differentiation of virus or bacterial infection with PCT.VE-cadherin has a good diagnostic value for intracranial infection.

Objective: To investigate the changes and clinical significance of Caveolin-1, matrix metalloproteinase-9(MMP-9) and interleukin-1β(IL-1β)in cerebrospinal fluid of children with bacterial meningitis or viral encephalitis. Methods: Thirty-six cases of children with bacterial meningitis, 42 cases of children with viral encephalitis, and 20 cases of children with non-nervous system infection were selected from September 2016 to June 2018 at the Third Affiliated Hospital of Zhengzhou University.The levels of Caveolin-1, MMP-9 and IL-1β in cerebrospinal fluid were detected by using enzyme linked immunosorbent assay(ELISA). Results: Cerebrospinal fluid Caveolin-1, MMP-9 , IL-1β levels in the acute phase of bacterial meningitis were(49.06±8.96) ng/L, (134.79±18.88) μg/L, (100.02±14.67) μg/L, respectively, and (29.13±7.25) ng/L, (18.69±7.23) μg/L, (47.57±8.95) μg/L in recovery phase, which were higher than those of the controls[(11.18±2.24) ng/L, (11.53±3.54) μg/L, (39.75±7.08) μg/L)], and the differences were significant (all P<0.05). Cerebrospinal fluid Caveolin-1, MMP-9, IL-1β levels in the acute phase of viral encephalitis were (42.71±10.48) ng/L, (62.78±17.39) μg/L, (57.97±11.28) μg/L, respectively, and (29.13±7.25) ng/L, (18.69±7.23) μg/L, (47.57±8.95) μg/L in recovery phase, which were higher than those of controls, and the differences were significant (all P<0.05). The levels of Caveolin-1, MMP-9 and IL-1β in cerebrospinal fluid of bacterial meningitis group and viral encephalitis group were significantly higher than those of convalescent group (all P<0.05). The levels of Caveolin-1, MMP-9, IL-1β in cerebrospinal fluid of bacterial meningitis group were significantly higher than those in viral encephalitis group (all P<0.05) in the acute phase, and no significant difference was found in the recovery phase(all P>0.05). Cerebrospinal fluid Caveolin-1, MMP-9, IL-1β showed no significant difference among children with different severity of intracranial infection.Correlation analysis showed that there was a positive correlation between Caveolin-1, MMP-9 and IL-1 β levels in cerebrospinal fluid of acute in bacterial meningitis group and viral encephalitis group(Caveolin-1 and MMP-9: R²=0.239, P<0.05; MMP-9 and IL-1β: R²=0.766, P<0.01; Caveolin-1 and IL-1β: R²=0.245, P<0.05). Conclusions Caveolin-1, MMP-9 and IL-1 β involved in the pathogenesis of intracranial infection in children, and the effects of different pathogens on intracranial infection were different.

Objective To study the effects of thymus transplantation(TT)combined with CD4--DLI on T cell reconstitution after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods BALB/c mice were randomly divided into three groups:hematopoietic stem cell transplantation (HSCT group),hematopoietic stem cell transplantation combined with thymus transplantation(TT group)and hematopoietic stem cell transplanta-tion combined with thymus transplantation plus CD4+ T cell-depleted lymphocyte infusion(CD4--DLI group). On day-1,the mice were treated with the lethal dose of radiotherapy. On day 0,C57BL/6 mice were used as donor for hematopoietic stem cell transplantation. The mice were sacrificed on 5 days,2 weeks,4 weeks and 3 months after transplantation,respectively. The peripheral blood and spleen cells of mice were collected for determinations of T cell surface antigen,T cell receptor,naive T cells and intracellular cytokines. HE staining was used to assess the development of donor thymus. Results TT and CD4--DLI did not impair each other′s effects on T cell reconstitu-tion. TT combined with CD4--DLI increased the number of T cell reconstruction. CD4--DLI promoted the effect of TT on enlargement naive CD4+and CD8+T cell pool. Combination of TT and CD4--DLI enhanced the cytokine pro-duction of T cells. Conclusion TT combined with CD4--DLI had no side effects on TCR repertoire and thymus. Conclusion TT combined with CD4--DLI can enhance the reconstitution of T cell number and function via thymus dependent and thymus independent mechanism.

Objective To investigate the feasibility and safety of surgical device closure of doubly committed sub-arterial ventricular septal defect via left sub-axillary.Methods A total of 45 patients diagnosed as doubly committed sub-arterial ventricular septal defect (dcVSD) with transthoracic echocardiography (TTE) and transesophageal echocardiography(TEE) were enrolled from June 2014 to August 2016 in Henan Children Heart Center,Henan Provincial People's Hospital.There were 39 males and 6 females,with the mean age of (2.2 ±2.1) years old(0.5-8.0 years),the body weight (13.8 ± 7.1) kg(7.0-34.1 kg),the defect size (4.5 ± 1.0) mm (3.0-8.0 mm).After general anesthesia,the patients were in supine and evaluated by TEE which indicated whether they were fit to closure.Then,they were turned to the right lateral position while this technique was determined.A vertical incision of 2-3 cm was made between the third and the fifth intercostal space and invasion in thoracic space via fourth intercostal space.Puncture was done at the anterior surface of right ventricular outlet tract to build a delivery tract.The occluder was released and the VSD was occluded under transesophageal echocardiography guidance.Results Forty-one patients had a successful surgical dcVSD closure with asymmetric occluders sized (6.0 ± 1.5) mm(4-10 mm).Among 4 failure cases,2 cases (4.4％) were switched to open-heart surgical repair,1 case (2.2％) due to device related aortic regurgitation,the rest 1 case (2.2％) experienced a dislocation of occluder into pulmonary artery and was converted to surgical repair after retrieve of occluder.Trivial residual shunt was detected in 2 cases (4.4％) postoperatively,a spontaneous closure was observed by 1 month follow-up and 3 months follow-ups,respectively.All the patients were discharged 5 to 8 days after the operation.With a follow-up of (10.4 ±5.0) months [3-24 months],there were no complications such as pericardial effusion,displacement of device,atrioventricular block or new valvular dysfunction.Conclusions Minimally invasive device closure of doubly committed sub-arterial ventricular septal defect via left sub-axillary is a feasible and safe treatment for closure of dcVSD.This technique has advantages of minor wound,less exudation,covert incision,however,long term follow-up is necessary.