BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Abstract: In the present study, the compound XL-12 from our previous work was utilized as a lead compound. Through the optimization of the terminal phenyl ring, 12 target compounds were designed and synthesized. The structures of all target compounds were confirmed by 1H NMR, 13C NMR, and H RMS. In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3). Among them, compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells. In the evaluation of anti-inflammatory activity in vitro, compound I-3 could effectively inhibit the production of inflammatory factors IL-6; besides, it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.

Objective To investigate the effects of interleukin(IL)-34 on the polarization and migration ability of macrophages derived from human peripheral blood monocytes.Methods The CD14+monocytes were isolated from human peripheral blood monocytes by immunomagnetic bead sorting,and the purity of CD14+monocytes was detected by flow cytometry.The CD14+monocytes were divided into M1 type group,IL-34-M1 type group,M2 type group and IL-34-M2 type group.The cells in the M1 type group and IL-34-M1 type group were added granulocyte-macrophage colony stimulating factor(GM-CSF)to induce for 5 days,and half of the fluid was changed,and then the interferon-γ,lipopolysaccharides,IL-6 and GM-CSF were added for another 4-day induction;the cells in the M2 type group and IL-34-M2 type group were added macrophage colony stimulating factor(M-CSF)to induce for 5 days,and half of the fluid was changed,and M-CSF,IL-4,IL-6,and IL-13 were added for another 4-day induction.The cells in IL-34-M1 group and IL-34-M2 group were co-induced with IL-34 at the beginning of induction and on the 5th day of induction.On the 9th day of induction,the proportion of CD14+CD86+cells(M1 type macrophages)and CD14+CD163+cells(M2 type macrophages)in each group was detected by flow cytometry,and the migration ability of cells in the M2 type group and IL-34-M2 type group was detected by the Transwell chamber experiments.Results High purity CD14+monocytes were obtained through magnetic bead sorting,with a CD14 positive rate of(96.77± 2.72)％,which could be used for macrophage induction.The proportion of CD14+CD86+cells in the M1 type group and IL-34-M1 type group was(43.20±7.59)％and(27.87±2.06)％,respectively.The proportion of CD14+CD163+cells in the M2 type group and IL-34-M2 type group was(47.70±4.49)％and(58.95±3.65)％,respectively;the proportion of CD14+CD86+cells in the IL-34-M1 type group was significantly lower than that in the M1 type group(P＜0.05),while the proportion of CD14+CD163+cells in the IL-34-M2 type group was significantly higher than that in the M2 type group(P＜0.05).The number of migrating cells of macrophages in the M2 type group and IL-34-M2 type group was 97.8±9.0 and 205.6±21.9,respectively;the number of migrating cells of macrophages in the IL-34-M2 type group was significantly higher than that in the M2 type group(P＜0.05).Conclusion IL-34 can inhibit the polarization of macrophages derived from human monocytes cells towards M1 type,promote the polarization of macrophages towards M2 type,and enhance the migration ability of M2 type macrophages.

Objective To develop an evidence-based,localized practice protocol for the interhospital transfer of critically ill children.Methods Through a comprehensive evidence summary and semi-structured interviews,a preliminary inter-hospital transfer practice protocol for critically ill children was formulated.A panel of 31 experts from 12 hospitals in China participated in 2 rounds of expert correspondence between May and July 2022,facilitating meticulous revision of the protocol entries.Results The response rate for both rounds of questionnaires was 100%,and the expert authority coefficients ranged from 0.926 to 0.931.In the second round of consultation,the coefficient of variation for the importance score of each entry ranged from 0.036 to 0.226,and the Kendall's W was determined to be 0.201(P＜0.001).Additionally,the coefficient of variation for the feasibility score of each entry fell within the range of 0.070 to 0.314,with Kendall's W of 0.124(P＜0.001).Ultimately,the final interhospital transfer protocol for critically ill children comprised 8 level Ⅰ entries,16 level Ⅱ entries,and 75 level Ⅲ entries.Conclusion The interhospital transfer protocol constructed in this study is grounded in scientific evidence and exhibits practical feasibility.It serves as a valuable reference for organizing and implementing interhospital transfers of critically ill children.

Objective:To explore the causes and influencing factors of financial toxicity in young breast cancer survivors, and to provide evidence for intervention program development to improve financial toxicity in young breast cancer survivors.Methods:Using descriptive qualitative research methods, 29 young breast cancer patients from September to December 2021 in Breast Surgery Follow-up Clinic of Fudan University Shanghai Cancer Center were interviewed. The Nvivo 12.0 qualitative data analysis software was used to analyze the data.Results:Four themes were extracted as following, direct cost of cancer treatment was the primary cause of financial toxicity, indirect costs related to cancer and treatment cannot be ignored, long-term effects of cancer and treatment further exacerbated financial toxicity, and cancer-related financial toxicity was also influenced by a variety of other factors.Conclusions:Multiple causes affected the experience of financial toxicity in young breast cancer survivors. The occurrence and risks of financial toxicity in young breast cancer survivors should be assessed. Intervention and support should be provided to meet the needs of young breast cancer survivors.

Background::The calcineurin inhibitor (CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation; however, the long-term prognosis of grafts has not been significantly improved. The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts. Sirolimus (SRL) has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts. Presently, the regimen and timing of SRL application after renal transplantation vary, and clinical data are scarce. Multicenter prospective randomized controlled studies are particularly rare. This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation.Methods::Patients who receive four weeks of a standard regimen with CNI + mycophenolic acid (MPA) + glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study. At week 5, after the operation, patients in the experimental group will receive an additional administration of SRL, a reduction in the CNI drug doses, withdrawal of MPA medication, and maintenance of glucocorticoids. In addition, patients in the control group will receive the maintained standard of care. The patients’ vital signs, routine blood tests, routine urine tests, blood biochemistry, serum creatinine, BK virus (BKV)/cytomegalovirus (CMV), and trough concentrations of CNI drugs and SRL at the baseline and weeks 12, 24, 36, 48, 72, and 104 after conversion will be recorded. Patient survival, graft survival, and estimated glomerular filtration rate will be calculated, and concomitant medications and adverse events will also be recorded.Conclusion::The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients.Trial registration::Chinese Clinical Trial Registry, ChiCTR1800017277.

Objective:To investigate the clinical efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on therapy-related leukemia (TRL).Methods:The clinical data of 14 patients with TRL who received allo-HSCT in Aerospace Central Hospital from April 2012 to February 2020 were retrospectively analyzed, and the therapeutic efficacy and survival status were also analyzed.Results:Of the 14 patients, 5 were males and 9 were females; the median age was 35 years old (12-59 years old). There were 12 patients with acute myeloid leukemia, 1 patient with chronic lymphocytic leukemia/small cell lymphoma, and 1 patient with acute lymphoblastic leukemia. At the time of transplantation, 4 patients achieved bone marrow complete remission, 3 patients achieved bone marrow partial remission, and the remaining 7 patients had no remission. Five patients received HLA-matched sibling transplantation, 9 patients received haplotype transplantation, and they all received myeloablative pretreatment schemes. All 14 patients were successfully implanted; the median engraftment time of granulocyte was 16 d (10-24 d), and the median engraftment time of platelet was 13 d (10-34 d). Grade Ⅰ-Ⅱ acute graft-versus-host disease (GVHD) occurred in 7 patients, chronic GVHD occurred in 6 patients, and grade Ⅲ intestinal GVHD occurred in 2 patients. The median follow-up time was 32 months (4-97 months). Among 14 patients, 5 patients died.Conclusion:The allo-HSCT can improve the prognosis and long-term survival rate of TRL patients.

Objective:To summarize the clinical experience of changing the membranous pulmonary system during extracorporeal membrane oxygenation(ECMO) in infants after congenital heart disease opration with cardiopulmonary bypass.Methods:From January to September in 2019, 6 cases of congenital heart disease with cardio-pulmonary bypass in our hospital were analyzed retrospectively, whose membrane obstruction occurred during ECMO treatment and replaced successfully.The hemodynamics and blood gas before and after replacement of ECMO system were observed, and the experience was summarized.Results:Six patients(3 males and 3 females), aging from 1 to 3 months and weighing from 3.0 to 4.9 kg, were received VA-ECMO adjuvant therapy.The ECMO system replacement process was smooth and took 175-209 s. The hemodynamic of the children was stable.The ECMO support time was 134-249 h. After the improvement of cardiac systolic function, all children were successfully withdrawn and survived.Conclusion:The improved method of liquid replacement in ECMO system can make full use of the blood components in the original system and avoid the loss of blood tangible components.According to the plan of rapid replacement, the risk of replacement will not be increased.

Objective:To evaluate the effectiveness of integrated pediatric training course of extracorporeal membrane oxygenation(ECMO)based on simulation teaching.Methods:The instructors of ECMO team of Children′s Hospital of Fudan University developed the teaching curriculum.Team members as a unit were recruited to study simulation-based courses, whose theoretical knowledge, skills and teamwork were assessed, and feedback from the trainees were gathered.Results:Since May 2018, 22 teams of pediatric specialized hospitals or general hospitals have taken part in our ECMO simulation, with totally 132 participants, including 45 ICU doctors(34.1%), 60 ICU nurses(45.5%), 23 thoracic surgeons(17.4%) and four anesthesiologists(3.0%). Twelve of them(9.1%)had a little ECMO experience.After training, the trainees had a high evaluation on each part of the course, with average score more than four, of which the theoretical score was lowest.Their self-evaluation on the theory, skills, teamwork and confidence in the implementation of ECMO had been significantly improved.Most(80.3%)of the trainees were confident to carry out ECMO in their local hospitals.The trainees′ baseline score of theoretical knowledge was 55.2±7.6, and increased to 67.1±7.3 after training( P<0.001). The average teamwork score of the 22 teams was 70.2±8.2, and the qualified rate was up to 86.4%.The most prominent skill problems in operation assessment were no albumin and blood priming(90.9%), non-skill problems were extremely anxious during the overall assessment(84.8%)of the participants, poor team work(74.2%), poor leadership(68.2%). For the feedback of the whole course, 97.0% and 94.7% of the trainees thought that integrated training and simulation teaching were the highlights of the course.At present, 13(59.1%)units have successfully developed ECMO technology after the course, and the number of children treated has been up to 83, with a survival rate of discharge of 54.2%.However, it was found that the skill level of some participants decreased about 2 weeks after the course. Conclusion:As a new attempt of ECMO teaching, this curriculum has achieved certain efficiency in both teaching and clinical practice.At the same time, our study also plays a role in promoting the development of ECMO in pediatrics.

Objective:To investigate the efficacy of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia associated with 11q23/MLL.Methods:Retrospection and analysis 50 cases of acute myeloid leukemia with 11q23/MLL and who were treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT)in our hospital from September 2012 to December 2019. The efficacy was evaluated by analyzing the transplantation success rate, graft-versus-host disease rate, infection rate, transplant-related mortality(TRM), accumulative recurrence rate, disease-free survival rate(DFS), and overall survival rate(OS).Results:Except for 1 patient had an unsuccessful stem cell transplantationas the result of multiple organ failure, the remaining 49 patients were successfully transplanted. The median time of leukocyte transplantation was 15(9~18)days, and the median time of platelet transplantation was 13(8~33)days. Bone marrow was assessed 28 days after transplantation, and 49 patients were in CR status. The median follow-up time was 38(3~79)months. Between remission group and non-remission group after transplantation, the 3-year OS rates were(83.3±10.8)%, (30.9+ 8.2)%( P=0.002)and the 3-year DFS rates were(83.3+ 10.8)%, (28.4±8.0)%( P=0.003), respectively. Conclusions:Allogeneic hematopoietic stem cell transplantation is an effective method for the treatment of 11q23/MLL rearranged AML. Patients in remission before transplantation have a higher survival rate, and recurrence after transplantation is the primary problem currently faced.