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.

BACKGROUND: Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism. METHODS: Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo . The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay. RESULTS: In this study, we found that hypoxia-induced factor (HIF)-1α could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N 6 -methyladenosine (m 6 A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m 6 A site on the 3'-untransated regions (3'-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells. CONCLUSION HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.
Humans ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Endothelial Cells/metabolism* ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic/genetics* ; Hypoxia ; MicroRNAs/genetics* ; RNA ; RNA, Long Noncoding/metabolism* ; RNA-Binding Proteins/metabolism* ; Scavenger Receptors, Class B/metabolism* ; Stomach Neoplasms/genetics*

Chronic heart failure （CHF）， the end stage of heart disease due to a variety of causes， features high disability rate and mortality， which has become a hot spot in cardiovascular field. As recorded in Treatise on Cold Damage（《伤寒论》）， Zhenwutang is composed of Radix Aconiti Lateralis Preparata， Poria Cocos， Rhizoma Atractylodis Macrocephalae， Paeoniae Radix Alba， and Rhizoma Zingiberis Recens. With the functions of warming Yang and excreting water， it is a classical prescription for the treatment of CHF in clinical settings. By searching China National Knowledge Infrastructure （CNKI）， PubMed， Wanfang Data， and VIP， we find Zhenwutang exerts therapeutic effect on CHF through multiple targets and multiple pathways. Experiments show that it alleviates CHF by antagonizing the overactivation of neuroendocrine system， inhibiting immune-inflammatory response， suppressing cardiac remodeling， restricting apoptosis， regulating autophagy， improving myocardial energy metabolism， inhibiting oxidative stress injury， protecting endothelial function， and decreasing volume load. Clinical research shows that Zhenwutang can significantly alleviate the clinical symptoms of CHF patients in a safe manner with little adverse reactions. This paper systematically summarizes the mechanisms of and clinical research on Zhenwutang in the treatment of CHF in recent years， so as to provide theoretical and experimental data for the further research and development of Zhenwutang.

Objective:To investigate the application of transbronchial needle aspiration (TBNA) in the diagnosis of tuberculosis with mediastinal lymphadenopathy in children.Methods:A retrospective study was conducted on clinical data in 8 children of tuberculosis with mediastinal lymphadenopathy treated in the Center for Respiratory Intervention, Children′s Hospital Affiliated to Shandong University from March 2014 to July 2019.TBNA was performed after the mediastinal lymphadenopathy were diagnosed by chest enhanced CT and the final diagnosis was made.The diagnostic experience of TBNA was summarized.Results:Eight children with mediastinal lymphadenopathy included in this present study aged from 7 months to 8 years and 6 months (infants accounted for 75.0%), with a median age of 22.5 months.There were 3 males (37.5%) and 5 females (62.5%). The body mass was 8.5-39.0 kg, and the median body mass was 10.7 kg.The course of disease was 15-90 days, and the median number of days was 18.5 days.The clinical manifestations included cough in 8 cases, fever in 4 cases, wheezing in 1 case and laryngeal ringing in 1 case.Bronchoscopy and TBNA biopsy were performed.Cytology, etiology and pathology were examined after TBNA.A definite diagnosis could be made in 6 children, with a diagnosis rate of 75.0%.Among them, 4 cases were found with acid-fast bacilli in smear but pathological examination was negative; 1 case was pathologically conformed to the characteristics of tuberculosis infection but the smear was negative; the smear and pathology of 1 case were both suggestive of tuberculosis; 2 cases did not present etiological and histological evidence with TBNA.The diagnosis was made according to the positive acid-fast bacilli of alveolar lavage fluid smear.There were no complications during and after operation.Conclusions:TBNA is an important method to diagnose tuberculosis in children, which is effective, safe and has high clinical application value.

The management of drainage tube is an important part of nursing work. Patient restraint and tube fixation cannot effectively prevent unplanned extubation (UEX) when the tube is accidentally pulled by violence. The nursing innovation team of Henan Provincial People's Hospital designed a medical drainage tube anti-pull device in order to change the existing technology of preventing drainage tube disconnecting by means of restraint and fixation, and to interfere with the basic cause of drainage tube disconnection, and obtained the national utility model patent (patent number: ZL 2020 2 2843025.1). The design of sleeve and clasp is that when the drainage tube is pulled by accidental violence, the friction fastener clamps the drainage tube mechanically to achieve the purpose of braking the drainage tube and prevent the drainage tube from coming out. Card sleeve ring fracture design can be applied to drainage tubes of different diameters, and the buzzer device at the instant of the snap ring into the card set warning medical staff to the occurrence of risk events, so that the nurse can come in the first place for effective treatment, which is a fuse for surgical drainage tubes and is to timely and effectively prevent UEX.

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K _d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.

Objective:To summarize the clinical features and experience in diagnosis and treatment of subglottic cysts in children.Methods:The clinical data of 5 children with subglottic cysts admitted in Qilu Children′s Hospital of Shandong University from April 2018 to June 2019 were retrospectively analyzed.Results:Among the 5 patients, 2 cases were premature infants and 3 cases were full term infants.All patients had an endotracheal intubation history.One patient was asymptomatic.Four patients had laryngeal stridor, 2 cases of whom were accompanied by hoarseness and dyspnea.These 2 patients were used to be misdiagnosed with laryngomalacia, laryngitis, etc.Bronchoscopy revealed subglottic gray-white cyst-like lesions, and enhanced CT showed low density without enhancement.All patients were treated with laser and forceps, and bronchoscope was applied in the follow up period for 5-12 weeks.There was no recurrence or subglottic stenosis.Conclusions:Laryngeal stridor in children with a history of endotracheal intubation must be examined by bronchoscopy in time to find out whether there is subglottic cysts.Laser therapy is an effective treatment for subglottic cysts.

Objective:To study the diagnostic value of non-enhanced lesions on enhanced CT in lung consolidation for necrotizing pneumonia in children.Methods:A total of 101 cases of necrotizing pneumonia with air sacs on CT scan who were hospitalized in the Department of Respiratory Intervention, Qilu Children′s Hospital of Shandong University from August 2016 to September 2018 were enrolled in this study(group with air lucency). Besides, another 75 cases of lobar pneumonia with non-enhanced lesions in lung consolidation but without air sacs on enhanced CT were also included from the same hospital over the same period(group without air lucency). Clinical data of these patients were retrospectively collected and statistically analyzed.Results:The white blood cell count was (12.5±5.5)×10 9/L in group with air sacs and (10.8±4.1)×10 9/L in group without air sacs, and the difference was statistically significant( t=-2.161, P=0.032). There was no statistical difference between the group with and without air sacs in age, gender distribution, the course prior to admission, duration of fever after admission, length of hospital stay, medical expense, the neutrophils percentage in peripheral blood, C-reactive protein, the erythrocyte sedimentation rate, serum procalcitonin, serum D-Dimer, serum lactate dehydrogenase, serum albumin, bronchoscopy times, the bronchial mucosal erosion ratio, the mucus plug score, the lavage purulent lavage ratio, and the ratio of luminal stricture or atresia in late bronchoscopy(all P>0.05). Conclusions:The clinical course of patients with non-enhanced lesions in lung consolidation but without air sacs is almost identical to that of patients with air sacs on CT scan.The presence of non-enhanced lesions in lung consolidation can be used as diagnostic basis of necrotizing pneumonia in children.

The clinical data of 4 children with congenital absence of tracheal cartilage ring in Qilu Children′s Hospital of Shandong University from November 2017 to August 2019 were retrospectively analyzed.The age of the 4 cases was from 2 months to 1 year.One case had no obvious symptoms after birth, and then had repeated wheezing attacks for 3 times.Another 3 cases had symptoms after birth, such as throat ringing, repeated cough and asthma.Bronchoscopy in 4 cases indicated that the local lumen of trachea was round and centripetal stenosis, but the body of bronchoscope could pass smoothly, and no cartilage structure was found in the wall of trachea.Among them, 3 cases of chest enhanced CT examination displayed local and hourglass-like tracheal stenosis, without vascular ring malformation.All the 4 cases were treated by operation, of which 3 cases recovered well and 1 case died of severe infection after operation.

Objective:To study the early predictors of Mycoplasma pneumoniae necrotizing pneumonia in children.Methods:Clinical data of 291 children with lobar pneumonia caused by Mycoplasma pneumoniae who were hospitalized in Department of Respiratory Intervention, Qilu Children′s Hospital of Shandong University from August 2016 to September 2018, were retrospectively analyzed.The patients were divided into necrotizing pneumonia group (154 cases) and non-necrotizing pneumonia group (137 cases). After comparing clinical characteristics, laboratory tests, and bronchoscopy findings, multivariate logistic regression analysis was carried out on the indicators with statistical significance to obtain the independent predictive indicators of Mycoplasma pneumoniae necrotizing pneumonia, and then the cutoff value with the maximum diagnostic value of each indicator was found through receiver operating characteristic (ROC) curve analysis.Results:There were no significant differences in gender and age distribution, duration before admission, and platelet count between the 2 groups(all P>0.05). Necrotizing pneumonia group manifested with 11.0(8.3-14.4)×10 9/L of white blood cell count, 0.740±0.115 of neutrophil, 44.2(21.2-72.0) mg/L of C-reactive protein(CRP), 55(35-80) mm/1 h of erythrocyte sedimentation rate, 0.19(0.08-0.60) ng/L of procalcitonin, 2.63(1.62-3.79) mg/L of plasma D-dimer, 456(340-665) U/L of serum lactate dehydrogenase, (35.6±4.3) g/L of serum albumin, 121 cases(78.6%)of bronchoscopic mucosal erosion, 75 cases(48.7%)of purulent lavage, 119 cases(77.3%)of massive secretions embolism; non-necrotizing pneumonia group manifested with 8.7(6.9-11.6)×10 9/L of white blood cell count, 0.660±0.127 of neutrophil percentage, 15.9(7.5-34.3) mg/L of CRP, 45(30-60) mm/1 h of erythrocyte sedimentation rate, 0.10(0.06-0.20) ng/L of procalcitonin, 0.69(0.46-1.24) mg/L of plasma D-dimer, 314(250-419) U/L of serum lactate dehydrogenase, (38.9±3.7) g/L of serum albumin, 53 cases(38.7%)of bronchoscopic mucosal erosion, 20 cases(14.6%)of purulent lavage, and 76 cases(55.5%)of massive secretions embolism.All the above indicators had statistical differences between the 2 groups.Erythrocyte sedimentation rate, serum lactate dehydrogenase, D-dimer, and bronchoscopic mucosal erosion were independent predictors of Mycoplasma necrotizing pneumonia.The area under the ROC curve were 0.643, 0.749, 0.858 and 0.699, respectively, with the cut off point of 53 mm/1 h, 335 U/L, and 1.36 mg/L, respectively. Conclusions:Erythrocyte sedimentation rate≥53 mm/1 h, serum lactate dehydrogenase≥335 U/L, D-dimer≥1.36 mg/L, and bronchoscopic mucosal erosion are early independent predictors of Mycoplasma necrotizing pneumonia in children, among which D-dimer has the highest value.