Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

[This corrects the article DOI: 10.1016/j.apsb.2022.07.023.].

ObjectiveTo explore the clinical features and causative genes of short stature children with unknown etiology， providing evidence for precise clinical diagnosis and treatment. MethodsThe study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022. A retrospective analysis was performed on the clinical manifestations， laboratory test and whole exome sequencing （WES） results. Causative genes were classified and analyzed according to different pathogenic mechanisms. ResultsA total of 48 children （30 boys and 18 girls） were enrolled， aged 7.73 ± 3.97 years， with a height standard deviation score （ HtSDS） of -3.63 ± 1.67. Of the patients， 33 （68.8%） suffered from facial anomalies， 31 （64.6%） from skeletal abnormalities， 26 ［54.2%， 61.5% of whom born small for gestational age （SGA）］ from perinatal abnormalities， 24 ［50.0%， 87.5% of whom with growth hormone （GH） peak concentration below normal］ from endocrine disorders and 21（43.8%） had a family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was （9.72 ± 7.25） ng/mL， IGF-1 standard deviation score was -0.82 ± 1.42， the difference between bone age and chronological age was -0.93 ± 1.39 years. Of the 25 cases with mutant genes found by WES， 14 （56.0%） had pathogenic mutation， 6 （24.0%） likely pathogenic mutation， and 5 （20.0%） mutation of uncertain significance. Pathogenic and likely pathogenic variants were identified in 14 genes， including 10 affecting intracellular signaling pathways （PTPN11， RAF1， RIT1， ARID1B， ANKRD11， CSNK2A1， SRCAP， CUL7， SMAD4 and FAM111A） and 4 affecting extracellular matrix （ECM） components or functions （ACAN， FBN1， COL10A1 and COMP）. ConclusionsA rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies， disproportionate body types， skeletal abnormalities， SGA， GH peak concentration below normal and a family history of short stature. WES played an important role in identifying the monogenic causes of short stature. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions was the main mechanism of causative genes leading to severe short stature in children. Further research may help discover and study new pathogenic variants and gene functions.

Objective To investigate the characteristics of CT findings in pediatric ovarian torsion and improve the understanding of pediatric ovarian torsion.Methods The clinical and CT data of 20 cases of ovarian torsion confirmed by pathology and/or surgery were analyzed retrospectively,based on the timing of ovarian torsion,they were divided into fetal and non-fetal groups.All 20 cases underwent plain CT scan and 11 cases underwent CT enhancement.Results All of the 20 cases were unilateral duplication,including 12 cases right and 8 cases left.There were 8 cases of ovarian torsion in the fetal group,all of them were visited with the finding of abdominal mass.The eggshell calcification on CT manifestations was found in 8 cases,and 2 cases of pelvic effusion.There were 12 cases of ovarian torsion in the non-fetal group,all of them presented with abdominal pain,CT showed the disc sign in 7 cases,peduncular protrusion sign in 6 cases,adnexal bleeding sign in 2 cases,subcapsular effusion sign in 2 cases,the uterus displaced to the ipsilateral ovary in 6 cases and pelvic effusion in 10 cases.The disc sign and peduncular protrusion sign were direct signs for the diagnosis of ovarian torsion,and the adnexal bleeding sign and subcapsular effusion sign suggested the possibility of necrosis.Conclusion Pediatric ovarian torsion CT findings with typical signs such as disc sign,peduncular protrusion sign,adnexal bleeding sign and subcapsular effusion sign,combined with clinical history,a more accurate diagnosis can be given,providing assistance in clinical treatment.

Objective:To investigate the effect of modified percutaneous closure in the treatment of ventricular septal rupture.Methods:This study is a retrospective cohort study. Forty-four patients with ventricular septal rupture who underwent percutaneous closure at the Fuwai Central China Cardiovascular Hospital from December 2017 to October 2023 were included. According to the closure method, patients were divided into the modified group (11 cases) and the traditional group (33 cases). Surgical success was defined as successful placement of the occluder. The operation time, X-ray intake, sheath bending rate, incidence of ventricular fibrillation and pericardial tamponade, and postoperative residual shunt were compared between the two groups.Results:The age of the patients was (75.0±5.7) years, with 20 (45%) males. There were 3 cases of operation failure in the traditional group, while all patients in the modified group were successfully occluded. The procedure time in the modified group was shorter than that in the traditional group (40 (35, 45) min vs. 60 (50, 65)min, P<0.001); X-ray dose intake was lower ((442.43±73.26)mGy vs. (784.45±247.78)mGy, P<0.001). There was no occurrence of sheath bending in the modified group, while the incidence of sheath bending in the traditional surgery group was 46% (15/33), and the difference was statistically significant ( P=0.017). Intraoperative ventricular fibrillation and pericardial tamponade occurred in 7 cases (21%) and 2 cases (6%) in the traditional group respectively, while none occurred in the modified group, but the differences between the groups were not statistically significant (both P>0.05). There was no significant difference in residual shunt between the two groups (3.6 (2.5, 4.3) mm vs. 4.0 (3.5, 4.5) mm, P=0.506). Conclusion:The procedure of modified ventricular septal rupture closure is more simplified, with a lower incidence ofventricular fibrillation and pericardial tamponade.

Objective To investigate the mechanism of the preventive effect of alum-borneol nanoemulsion on hypertrophic scars by observing its effect on cAMP-response element-binding protein 3-like 1(CREB3L1)and inflammatory damage in hypertrophic scar tissues of rabbit ear.Methods Thirty New Zealand big-eared white rabbits were randomly divided into blank group,model group,alum-borneol nanoemulsion low-,medium-,and high-dose groups(8.15,16.3,and 32.6 mg·mL-1),and asiaticoside group.The animal model was established by thermal injury.Topical application of appropriate drugs was given on the 14th day after successful modeling of deep Ⅱ-degree burns.Equal amounts of saline were applied externally to the blank and model groups twice daily and administered continuously until the 35th day.Histopathological changes in rabbit ear scar tissue were observed by hematoxylin-eosin(HE)staining.Masson staining was used for collagen deposition in scar tissue.Coexpression of CREB3L1/alpha-smooth muscle actin(α-SMA)in rabbit ear scar tissue was detected by immunofluorescence double-labeling assay.Enzyme-linked immunosorbent assay(ELISA)was applied for the detection of interleukin-6(IL-6)and interleukin-10(IL-10)in scar tissue.Real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)was applied for the detection of CREB3L1,Collagen Type I(COL-Ⅰ),Collagen Type Ⅲ(COL-Ⅲ),and α-SMA mRNA expression.Protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA was detected by protein immunoblotting analysis(Western Bolt).Results Compared with the blank group,the scar proliferation index of the model group was significantly increased(P<0.01).Pathologic changes including the thickening of the dermis,the formation of dense reticular fibers,and accompaniment of inflammatory cell infiltration were observed.Masson staining reveals thickening of the dermis,disordered arrangement and large deposits of blue-stained collagen fibers.Double-labeling immunofluorescence results showed that positive expression of CREB3L1 and α-SMA in scar tissue increased.IL-6 levels were significantly increased(P<0.01),while IL-10 levels were significantly decreased(P<0.01).The relative mRNA expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA in the scar tissue of rabbit ear was significantly increased(P<0.01).The protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA was significantly increased(P<0.01).Compared with the model group,the scar proliferation index was significantly decreased after the treatment of medium-,high-dose of alum-borneol nanoemulsion and asiaticoside(P<0.01,P<0.05,P<0.01).Pathologic changes including the thinning of the dermis,as well as varying degrees of reduction of inflammatory cells and blue-stained collagen fibers were found.Double-labeling immunofluorescence showed positive expression of CREB3L1 and α-SMA in scar tissue decreased.IL-6 levels significantly reduced(P<0.01),while IL-10 levels significantly raised(P<0.01).The alum-borneol nanoemulsion medium-,high-dose and asiaticoside groups could significantly down-regulate the mRNA expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA(all P<0.01),and reduce the protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA(P<0.05,P<0.01).Conclusion Alum-borneol nanoemulsion may prevent hyperplastic scar formation by regulating the expression of CREB3L1 and related fibrotic proteins and reducing inflammatory level,which enriches the scientific connotation of"prevention of disease from exacerbating"and"treatment of the disease before its onset"in Chinese medicine.

Objective To investigate the relationships of serum angiopoietin-like protein 4 (ANGPTL4) and fibroblast growth factor-23 (FGF-23) levels with the severity and prognosis of patients with diabetic nephropathy. Methods A total of 120 patients (diabetic nephropathy group) with diabetic nephropathy were selected from July 2018 to July 2020 and divided into mild group (n=62) and severe group (n=58) according to the staging criteria of diabetic nephropathy; based on the prognosis within 3 years, they were also divided into good prognosis group (n=94) and poor prognosis group (n=26). Additionally, 102 diabetic patients were enrolled as diabetic group, and 81 healthy volunteers were selected as control group. The serum levels of ANGPTL4 and FGF-23 in diabetic nephropathy patients were detected by enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to analyze the influencing factors of prognosis, and receiver operating characteristic (ROC) curves were drawn to analyze the values of ANGPTL4, FGF-23 and their combination in assessing the severity and prognosis of diabetic nephropathy. Results The levels of ANGPTL4 and FGF-23 in the diabetic nephropathy group and simple diabetic group were significantly higher than those in the control group (P < 0.05); compared with the simple diabetic group, the levels of ANGPTL4 and FGF-23 in the diabetic nephropathy group were significantly increased (P < 0.05); the levels of ANGPTL4 and FGF-23 in the severe group were significantly higher than those in the mild group (P < 0.05); the ROC curve analysis revealed that the areas under the curve (AUCs) for assessing disease severity of ANGPTL4, FGF-23 and their combination were 0.748, 0.781 and 0.858 respectively, and the combined diagnosis was significantly better than FGF-23 (Z=2.149, P=0.032) and ANGPTL4 (Z=2.886, P=0.004) alone; the levels of ANGPTL4 and FGF-23 in the good prognosis group were significantly lower than those in the poor prognosis group (P < 0.05); significant differences were observed in diabetes duration, blood urea nitrogen (BUN), serum creatinine (Scr), fasting blood glucose (FBG), glycated hemoglobin (HbA1C), hypertension, ANGPTL4 and FGF-23 levels between diabetic nephropathy patients with different prognoses (P < 0.05); the Scr, ANGPTL4 and FGF-23 levels were all risk factors affecting the prognosis of diabetic nephropathy (P < 0.05); the ROC curve analysis for prognosis assessment showed that the AUCs of ANGPTL4, FGF-23 and their combination were 0.774, 0.795 and 0.874 respectively; the combined diagnosis was significantly better than FGF-23 (Z=2.385, P=0.171) and ANGPTL4 (Z=2.317, P=0.021) alone. Conclusion The serum levels of ANGPTL4 and FGF-23 are significantly increased in diabetic nephropathy patients, and they have certain reference value for the clinical diagnosis and prognosis assessment of diabetic nephropathy patients.

Objective:To investigate the efficacy and safety of oral testosterone therapy in individuals diagnosed with androgen insensitivity syndrome (AIS).Methods:A self-controlled study design was utilized, focusing on individuals with AIS who were genetically diagnosed at the Department of Endocrinology, Genetics, and Metabolism of Beijing Children′s Hospital between 2009 and 2021. These patients underwent treatment involving the administration of testosterone. The primary observed indexes include the measurement of penis length, which should meet the minimal surgical standard (penis length≥2.5 cm) or greater than or equal to -2.5 s (lower limit of normal). Secondary observed indexes include penile length standard deviation score (PL-SDS), an increase in penis longitude (ΔPL), medication dosage, the course of therapy, and safety indicators, among others. There were 4 courses of treatment. After each course, patients were evaluated to determine whether termination of treatment was appropriate. Patients who exhibited inadequate post-treatment penile length growth were advised to continue with further treatment. The statistical methodology included t-test, and a Wilcoxon rank sum test to describe efficacy and safety. The patients were followed up until 2023. Results:The study comprised a total of 51 individuals with AIS, comprising 33 males and 18 females (gender of registered permanent residence). Among these patients, 10 were diagnosed with complete androgen insensitivity syndrome (CAIS) and 41 were diagnosed with partial androgen insensitive syndrome (PAIS). There were 2 children with CAIS were diagnosed by doctors and prescribed testosterone undecanoate, but the children did not really take medicine.The penile length of CAIS patients could not be measured (penile length<0.5 cm) before and after treatment. For PAIS patients, baseline penile length and PL-SDS were (2.3±0.6) cm and -3.7±1.3, respectively. The measurements for penile length and PL-SDS after each treatment course were recorded as follows: (2.7±0.8), (2.8±0.6), (2.6±0.4), (2.6±0.4) cm and -2.8±1.6, 2.5±1.6, 2.9±1.2, -3.2±0.9, respectively. Both penile length and PL-SDS interventions showed statistically significant gains when compared to the baseline performance of the 4 courses ( t=4.05、3.56、2.55、2.23 and 3.88、3.50、2.50、2.19, all P<0.05). Before treatment, 13 PAIS patients (32%) reached 2.5 cm and seven (17%) reached greater than or equal to -2.5 s. Following the initial, subsequent, third, and fourth therapeutic interventions, 18 cases (44%), 24 cases (59%), 25 cases (61%), and 26 cases (63%) reached 2.5 cm, respectively. Additionally, A total of 12 cases (29%), 15 cases (37%), 20 cases (49%), and 21 cases (51%), respectively, were found to reach greater than or equal to -2.5 s. The study involved the longitudinal monitoring of patients with the highest recorded age being 13.7 years. The weight, height, body mass index, bone age/age, cholesterol, hemoglobin and so on were all within the normal range and the difference were not statistically significant (all P>0.05). All 49 patients were no abnormalities in blood electrolyte, liver and kidney function and thyroid function and no changes in precocious puberty, pubic hair growth, aggressive behavior, vulvar skin darkening, diarrhea or other conditions. Conclusions:Testosterone undecanote in children with CAIS was no effective. The initial course of treatment for patients with PAIS demonstrates observable enhancements in penile length and PL-SDS. For patients with inadequate penile length growth, continued treatment in subsequent courses (such as the second, third, and fourth courses) is recommended toenhance outcomes gradually. Testosterone undecanoate was safe and effective for the majority of individuals with PAIS patients, with few adverse effects and good treatment tolerance.

Objective:To summarize long-term clinical follow-up results of segment instability between the upper instrumented vertebra (UIV) and the adjacent upper vertebra (UIV+1) and to establish the optimal timing for surgery for UIV+1.Methods:A retrospective analysis was conducted on 265 patients with lumbar degenerative diseases who underwent transforaminal lumbar interbody fusion (TLIF) surgery at the Department of Spinal Surgery, Zhongda Hospital, from January 2014 to December 2018. The cohort included 119 male and 146 female patients, with an average age of 64.93 years (range: 32-86 years). Preoperative dynamic imaging measured sagittal angulation (SA) and sagittal translation (ST) of the UIV+1/UIV segment. Patients with SA>10° or ST>2 mm were categorized into the unstable group, further divided into the unstable non-fusion group and the unstable fusion group based on whether UIV+1 expansion fusion was performed. The remaining patients were classified into the stable group. Imaging indicators, Visual Analogue Scale (VAS) scores, Oswestry disability index (ODI) scores, and Japanese Orthopaedic Association (JOA) scores were compared among the groups, with JOA improvement rates calculated to assess clinical efficacy. Pearson correlation coefficient analysis was employed to examine correlations between preoperative imaging indicators and final follow-up JOA improvement rates. Receiver Operating Characteristic (ROC) curves and the maximum Youden index were utilized to determine thresholds for preoperative SA and ST.Results:The follow-up duration for all patients was 73.53±12.92 months (range: 61-108 months). The stable group (124 cases) included 61 males and 63 females, aged 64.31±9.83 years (range: 44-82 years). The unstable non-fusion group (59 cases) included 22 males and 37 females, aged 65.76±11.01 years (range: 32-86 years). The unstable fusion group (82 cases) included 36 males and 46 females, aged 65.26±8.68 years (range: 47-80 years). At the last follow-up, the unstable non-fusion group exhibited ΔSA 0.90°±1.97° and ΔST 0.77±1.27 mm, both significantly higher than the stable group's ΔSA 0.25°±1.57° and ΔST 0.34±0.34 mm ( t=3.564, P<0.001; t=2.311, P=0.022). Clinical improvements were lower in the unstable non-fusion group compared to the other two groups: VAS (2.28±0.83), ODI (5.91%±3.46%), JOA (24.11±1.78), with a JOA improvement rate of 60%. The stable group showed VAS (1.51±0.69), ODI (3.71%±1.75%), JOA (27.33±1.91), with a JOA improvement rate of 83%. The unstable fusion group had VAS (1.46±0.83), ODI (3.46%±1.81%), JOA (26.48±1.66), with a JOA improvement rate of 78%. These differences were statistically significant ( F=32.117, P<0.001; F=24.827, P<0.001; F=92.658, P<0.001; F=93.341, P<0.001). The JOA improvement rate was negatively correlated with preoperative SA ( r=-0.363, P<0.001) to a low extent, and with preoperative ST ( r=-0.596, P<0.001) to a moderate extent. ROC curve analysis determined the preoperative SA threshold as 11.5° and the preoperative ST threshold as 1.85 mm. Conclusion:Pre-existing instability of the responsible segment UIV and UIV+1 (SA>10° or ST>2 mm) may worsen during long-term follow-up after TLIF. When preoperative SA exceeds 11.5° and ST exceeds 1.85 mm between UIV and UIV+1, performing an extended fusion involving UIV+1 can ensure surgical efficacy over long-term follow-up.

With an aging population, the incidence of osteoporotic vertebral fractures (OVFs) is on the rise, posing new challenges for developing personalized treatment strategies. For patients who do not respond to conservative treatment, percutaneous vertebroplasty or percutaneous kyphoplasty (PVP/PKP) remains the preferred surgical option due to its minimal invasiveness and rapid recovery time. However, progressive local kyphosis (PLK) is one of the most severe complications following PVP/PKP, with an incidence rate of 1.5%-25.8%. PLK often presents with recurring thoracic and lower back pain, and in severe cases, spinal stenosis, causing symptoms like numbness and pain in the lower limbs. The severity of PLK varies, and treatments can range from conservative management and bone cement reinforcement to internal fixation or osteotomy. Current studies suggest that re-fracture of the affected vertebra, intervertebral disc degeneration, and osteonecrosis may be underlying mechanisms. These conditions shift the axial load forward, promoting postoperative PLK, which tends to progress over time. Postoperative PLK is closely associated with patient characteristics, fracture details, surgical factors, and post-surgery osteoporosis management. 1) The severity of osteoporosis, as indicated by the T-score from bone mineral density testing, can help predict postoperative PLK. While factors like age and gender influence osteoporosis severity, no direct relationship has been established between these factors and PLK. 2) Thoracolumbar fractures, old nonunion fractures, endplate fractures, or severe preoperative compression changes with kyphosis can increase PLK risk. Surgical factors, including the use of balloons or implants and the distribution of bone cement, also play a role. Personalized treatment plans should be developed based on the patient's general condition and imaging results to ensure adequate bone cement diffusion, as enhanced integration can reduce PLK risk. 3) Postoperative anti-osteoporosis therapy is also crucial; long-term therapy, particularly with teriparatide, can prevent PLK. Recognizing the related risk factors and establishing predictive models can help clinicians tailor treatments. Machine learning models, utilizing big data, are particularly adept at handling complex interrelated risk factors and may provide a powerful tool for personalized treatment in the future.