The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Female ; Gracilis Muscle ; Granulosa Cell Tumor ; Humans ; Muscle, Skeletal ; Ovarian Neoplasms ; Surgical Flaps ; Thigh

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common pathological type of glomerular disease. Kidney biopsy, the gold standard for IgAN diagnosis, has not been routinely applied in hospitals worldwide due to its invasion nature. Thus, we aim to establish a non-invasive diagnostic model and determine markers to evaluate disease severity by analyzing the serological parameters and pathological stages of patients with IgAN. METHODS: A total of 272 biopsy-diagnosed IgAN inpatients and 518 non-IgA nephropathy inpatients from the Department of Nephrology of Chinese People's Liberation Army General Hospital were recruited for this study. Routine blood examination, blood coagulation testing, immunoglobulin-complement testing, and clinical biochemistry testing were conducted and pathological stages were analyzed according to Lee grading system. The serological parameters and pathological stages were analyzed. The receiver operating characteristic (ROC) analysis was performed to estimate the diagnostic value of the clinical factors. Logistic regression was used to establish the diagnostic model. RESULTS: There were 15 significantly different serological parameters between the IgAN and non-IgAN groups (all P < 0.05). The ROC analysis was performed to measure the diagnostic value for IgAN of these parameters and the results showed that the area under the ROC curve (AUC) of total protein (TP), total cholesterol (TC), fibrinogen (FIB), D-dimer (D2), immunoglobulin A (IgA), and immunoglobulin G (IgG) were more than 0.70. The AUC of the "TC + FIB + D2 + IgA + age" combination was 0.86, with a sensitivity of 85.98% and a specificity of 73.85%. Pathological grades of I, II, III, IV, and V accounted for 2.21%, 17.65%, 62.50%, 11.76%, and 5.88%, respectively, with grade III being the most prevalent. The levels of urea nitrogen (UN) (13.57 ± 5.95 vs. 6.06 ± 3.63, 5.92 ± 2.97, 5.41 ± 1.73, and 8.41 ± 3.72 mmol/L, respectively) and creatinine (Cr) (292.19 ± 162.21 vs. 80.42 ± 24.75, 103.79 ± 72.72, 96.41 ± 33.79, and 163.04 ± 47.51 μmol/L, respectively) were significantly higher in grade V than in the other grades, and the levels of TP (64.45 ± 7.56, 67.16 ± 6.94, 63.22 ± 8.56, and 61.41 ± 10.86 vs. 37.47 ± 5.6 mg/d, respectively), direct bilirubin (DB) (2.34 ± 1.23, 2.58 ± 1.40, 1.91 ± 0.97, and 1.81 ± 1.44 vs. 0.74 ± 0.57 μmol/L, respectively), and IgA (310.35 ± 103.78, 318.48 ± 107.54, 292.58 ± 81.85, and 323.29 ± 181.67 vs. 227.17 ± 68.12 g/L, respectively) were significantly increased in grades II-V compared with grade I (all P < 0.05). CONCLUSIONS The established diagnostic model that combined multiple factors (TC, FIB, D2, IgA, and age) might be used for IgAN non-invasive diagnosis. TP, DB, IgA, Cr, and UN have the potential to be used to evaluate IgAN disease severity.
Adult ; Biomarkers ; blood ; Blood Urea Nitrogen ; Cholesterol ; blood ; Creatinine ; blood ; Female ; Fibrinogen ; metabolism ; Glomerulonephritis, IGA ; blood ; diagnosis ; pathology ; Humans ; Immunoglobulin A ; blood ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; ROC Curve

With the growth of number of Chinese patent medicines and clinical use, the rational use of Chinese medicine is becoming more and more serious. Due to the complexity of Chinese medicine theory and the uncertainty of clinical application, the prescription review of Chinese patent medicine always relied on experience in their respective, leading to the uncontrolled of clinical rational use. According to the traditional Chinese medicine (TCM) theory and characteristics of the unique clinical therapeutics, based on the practice experience and expertise comments, our paper formed the expert consensus on the prescription review of Chinese traditional patent medicine for promoting the rational use of drugs in Beijing. The objective, methods and key points of prescription review of Chinese patent medicine, were included in this expert consensus, in order to regulate the behavior of prescription and promote rational drug use.

OBJECTIVETo explore the application of multimordality of cluster treatment strategy in early postoperative inflammatory small bowel obstruction.

METHODSClinical data of 31 cases of early postoperative inflammatory small bowel obstruction in our department from July 2007 to July 2011 were analyzed retrospectively. Multimordality of cluster treatment strategy was used in 13 cases (treatment group), and other non-surgical treatment was applied in 18 cases (control group). Efficacy and prognosis were compared between the two groups.

RESULTSFour-day improvement rate was 76.9% (10/13) and 44.4% (8/18), and 7-day cure rate was 92.3% (12/13) and 77.8% (14/18) in the treatment group and the control group, respectively. The differences were statistically significant (both P<0.05). The recovery time of bowel sounds and flatus, defecation time, bloating-free time, oral intake time, abdominal CT intestine improvement time, and hospital stay were all significantly shorter in the treatment group as compared to the control group (all P<0.05).

CONCLUSIONMultimordality of cluster treatment strategy can effectively shorten the healing time of early postoperative inflammatory small bowel obstruction, which possesses a good clinical application prospect.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Combined Modality Therapy ; Female ; Humans ; Intestinal Obstruction ; therapy ; Male ; Middle Aged ; Postoperative Complications ; therapy ; Retrospective Studies ; Treatment Outcome ; Young Adult

OBJECTIVETo discuss laparoscopic assisted radical D2 resection of distal gastric anatomy application ideas.

METHODSCollected the clinical data from January 2009 to January 2012 who underwent laparoscopic distal gastric resection in patients with D2 349 cases. There were 180 male and 169 female patients, and the age were (57 ± 3) years old (range 29-86 years), the body mass index of patients were (26.0 ± 2.0) kg/m(2) (range 20.5-32.8 kg/m(2)). The relevant surgical anatomy ideas had summarized.

RESULTSIn addition to 5 cases of obese patients with conversion to open, the remaining patients underwent laparoscopic distal gastric D2 resection. The operation is divided into 7 operating anatomical view. The operation time were 120-210 minutes and the blood loss were 50-200 ml. Postoperative complications occurred in 11 cases, including 5 cases of duodenal stump leakage, 2 cases of gastroparesis, 3 cases of small bowel obstruction, and abdominal bleeding in 1 case. All patients were discharged.

CONCLUSIONSUse zoning, exterior to interior of the anatomy, more conducive to master the operation of laparoscopic radical gastrectomy and standardized cleaning, to improve the operation efficiency and shorten the surgical learning curve and improve the quality of surgery has an important role.

Adult ; Aged ; Aged, 80 and over ; Female ; Gastrectomy ; Humans ; Laparoscopy ; methods ; Male ; Middle Aged ; Retrospective Studies ; Stomach ; anatomy & histology ; Stomach Neoplasms ; surgery

OBJECTIVETo investigate the efficacy of laparoscope complete mesocolic excision (CME) for right colon cancer.

METHODSThe clinical data of 49 cases of right colon cancer without metastasis and intestinal obstruction who underwent elective laparoscope CME by the same group of surgeons between October 2009 and June 2011 at the First Hospital of Jilin University were analyzed retrospectively.

RESULTSAmong the 49 cases with CME, the median number of total lymph node retrieved was 22. The positive rate of lymph node in patients with stage III disease was 16.3%. The median operative time of all the cases was 145 min. The mean intraoperative blood loss was 75 ml. The median time to flatus passage and defecation was 3 days and 6 days respectively. The median hospital stay was 12 days. The overall postoperative complication rate was 12.2% (6/49).

CONCLUSIONLaparoscope complete mesocolic excision for right colon cancer is safe and feasible.

Adult ; Aged ; Colectomy ; methods ; Colonic Neoplasms ; surgery ; Female ; Follow-Up Studies ; Humans ; Laparoscopy ; Male ; Middle Aged ; Retrospective Studies

OBJECTIVETo evaluate the effects and the toxicity of the protocol of CDV combined with CiE as pre-operative chemotherapy in childhood stage IV neuroblastoma.

METHODSThe clinical data of 27 children aged from 1.2 to 8 years with neuroblastoma in stage IV was retrospectively studied. The primary sites of the diseases were abdomen (n = 21), posterior mediastinum (n = 4) and pelvic cavity (n = 2). Twenty three patients had bone marrow metastasis. Twelve patients had bone metastasis. All patients were treated with the CDV protocol (cyclophosphamide + doxorubicin + vincristine) for 3 cycles and the CiE protocol (cisplatin + etoposide) for 2 cycles. Neuroblastoma therapeutic response evaluation criterion and common terminology criteria for adverse events of National Cancer Institute were used to evaluate effects and chemotherapy related toxicity.

RESULTSAll patients received the pre-operative chemotherapy. The overall response rate was 82%. After chemotherapy, 24 patients received operations. Total resection of primary tumor was found in 14 patients (58%) and part resection in 10 patients (42%). The most common chemotherapy related toxicity was bone marrow suppression: grade IV suppression of neutrophils (n = 27), reduction in hemoglobin (III grade, n = 7; IV grade, n = 20) and reduction in platelet (III grade, n = 2; IV grade, n = 25). Infection was found in all patients and was controlled with antibiotics. I or II grade lesions of digestive, liver and kidney were found and could be recovered after therapy. Grade I neurotoxicity occurred in 2 patients (7%). The heart function damage was not found in any of patients.

CONCLUSIONSThe protocol of CDV combined with CiE as pre-operative chemotherapy might be effective in children with stage IV neuroblastoma.

Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; adverse effects ; therapeutic use ; Child ; Child, Preschool ; Cisplatin ; administration & dosage ; adverse effects ; Cyclophosphamide ; administration & dosage ; adverse effects ; Dacarbazine ; administration & dosage ; adverse effects ; Etoposide ; administration & dosage ; adverse effects ; Female ; Humans ; Infant ; Male ; Neuroblastoma ; drug therapy ; Retrospective Studies ; Vincristine ; administration & dosage ; adverse effects

OBJECTIVENeuroblastoma is the most common malignant solid tumor in children under 4 years. Amplification of MYCN oncogene is associated with advanced-stage disease, rapid tumor progression, resistance to treatment, and poor outcome. Matirne has the anti-tumor activity. This study was designed to investigate the effects of matrine on LA-N-5 cell line proliferation and MYCN gene mRNA expression.

METHODSNeuroblastoma LA-N-5 cells were treated by 0.25, 0.50, 0.75 or 1.00 mg/mL matrine. MTT was used to measure the levels of the proliferation of LA-N-5 cells cultured with different concentrations of matrine. MYCN gene mRNA expression in LA-N-5 cells was measured using real time RT-PCR with SYBR GREEN I fluorescence.

RESULTSThe proliferation of LA-N-5 cells was obviously inhibited by matrine in a dose- and time- dependent manner. Matrine of 1.00 mg/mL treatment for 72 hrs produced a best effect, with an inhibitory rate of LA-N-5 cell proliferation of 36.3% and an inhibitory rate of MYCN gene mRNA expression of 44.6%.

CONCLUSIONSMatrine may inhibit the growth of neuroblastoma cells and down-regulate MYCN mRNA expression. It may be promising as a new drug for treatment of neuroblastoma.

Alkaloids ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; N-Myc Proto-Oncogene Protein ; Neuroblastoma ; drug therapy ; metabolism ; pathology ; Nuclear Proteins ; genetics ; Oncogene Proteins ; genetics ; Quinolizines ; pharmacology ; RNA, Messenger ; analysis

BACKGROUNDNon-tuberculous mycobacteria (NTM) have emerged as important opportunistic pathogens of the human being in recent years. Patients with pre-existing bronchiectasis are susceptible to NTM. However, information about its occurrence among bronchiectatic patients in Shenzhen, China is lacking and its impact on the course of bronchiectasis following surgical intervention is unknown. This preliminary study aimed to investigate the prevalence of NTM in bronchiectasis that required surgery in our center, evaluate the role of intraoperative routine screening for NTM, and summarize our initial experience in thoracoscopic management for bronchiectatic patients with NTM.

METHODSA retrospective analysis of clinical, microbiological data of our bronchiectatic patients with NTM over 5 years was made and 40 patients with bronchiectasis were studied to determine the role of intraoperative routine screening for NTM.

RESULTSThe prevalence of NTM in this population of patients with bronchiectasis in our center was 6.7% (7/105). The diagnostic yield of the 40 intraoperative specimens was 7.5% (3/40). Of the 7 patients with bronchiectasis and NTM, 3 patients developed postoperative wound infections. All were cured with chemotherapy for 8 - 12 months along with vigorous surgical debridement. Another patient had a slow growth of mycobacteria involving double lungs and the right thoracic cavity and recovered after chemotherapy for nearly 14 months and tube drainage. The affected tissue was completely resected in the remaining 3 patients with no operative mortality and postoperative morbidity, and routine intraoperative screening for NTM was initiated in these patients.

CONCLUSIONSNTM is not uncommon in bronchiectatic patients which deserves surgeons' utmost attention. Routine intraoperative screening for NTM identified otherwise unsuspected patients has shown favorable outcomes. Thoracoscopic management for bronchiectasis with NTM is technically feasible although its role remains to be defined.

Adolescent ; Adult ; Aged ; Bronchiectasis ; drug therapy ; microbiology ; Female ; Humans ; Male ; Middle Aged ; Mycobacterium Infections ; drug therapy ; epidemiology ; Retrospective Studies ; Young Adult