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.

Objective:To evaluate the optimization efficacy of anterior quadratus lumborum block at supra-arcuate ligament (SA-AQLB) combined with general anesthesia for laparoscopic gynecological surgery.Methods:Eighty American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients, aged 28-64 yr, weighing 52-78 kg, with height of 154-166 cm, scheduled for elective laparoscopic gynecological surgery, were divided into general anesthesia group (group G, n=40) and SA-AQLB combined with general anesthesia group (group SG, n=40) using a random number table method.In group SG, bilateral SA-AQLB was performed under ultrasound guidance before anesthesia induction, and 0.4% ropivacaine 25 ml plus dexamethasone 5 mg was injected into both sides.Combined intravenous-inhalational anesthesia was applied in both groups.Patient-controlled intravenous analgesia (PCIA) with sufentanil 2 μg/kg (in 150 ml of normal saline) was performed after surgery.The PCIA pump was set up to deliver a 2 ml bolus dose with a 15-min lockout interval and background infusion at 2 ml/h.Visual analogue scale (VAS) scores for abdomen, pelvis and shoulder pain were recorded at 1, 6, 12, 24 and 48 h after operation.Flurbiprofen was used for rescue analgesia when VAS score >4.The occurrence of intraoperative cardiovascular events and amount of sufentanil used during operation were recorded.The time to first pressing the analgesia pump, effective pressing times of PCA, requirement for rescue analgesia and consumption of sufentanil after operation were recorded.The extubation time, time to first flatus after operation, first ambulation time, length of hospital stay and development of postoperative adverse reactions such as nausea and vomiting, urinary retention and respiratory depression within 48 h after operation were recorded. Results:Compared with group G, the incidence of intraoperative hypertension and tachycardia was significantly decreased, the incidence of intraoperative hypotension and bradycardia was increased, the intraoperative consumption of sufentanil was reduced, the extubation time was shortened, the time to first pressing the analgesia pump was prolonged, the effective pressing times of PCA, requirement for rescue analgesia and postoperative consumption of sufentanil were reduced, the time to first flatus, first ambulation time and length of hospital stay were shortened, VAS scores for abdomen, pelvis and shoulder pain were decreased at each time point after operation, and the incidence of nausea and vomiting, urinary retention and respiratory depression after operation was decreased in group SG ( P<0.01). Conclusions:Compared with general anesthesia, the combination of SA-AQLB and general anesthesia can reduce the opioid consumption, inhibit intraoperative stress responses and postoperative hyperalgesia and promote early postoperative recovery when used for the patients undergoing laparoscopic gynecological surgery.

Purpose: The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities. Materials and Methods: We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort. Results: A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis. Conclusion Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.

Purpose: The prevalence of multi-morbidities with colorectal cancer (CRC) is known to be increasing. Particularly prognosis of CRC patients co-diagnosed with metabolic syndrome (MetSyn) was largely unknown. We aimed to examine the death risk of CRC patients according to the multiple MetSyn morbidities. Materials and Methods: We identified CRC patients with MetSyn from the electronic medical records (EMR) systems in five independent hospitals during 2006-2011. Information on deaths was jointly retrieved from EMR, cause of death registry and chronic disease surveillance as well as study-specific questionnaire. Cox proportional hazards regression was used to calculate the overall and CRC-specific hazards ratios (HR) comparing MetSyn CRC cohort with reference CRC cohort. Results: A total of 682 CRC patients in MetSyn CRC cohort were identified from 24 months before CRC diagnosis to 1 month after. During a median follow-up of 92 months, we totally observed 584 deaths from CRC, 245 being in MetSyn cohort and 339 in reference cohort. Overall, MetSyn CRC cohort had an elevated risk of CRC-specific mortality (HR, 1.49; 95% confidence interval [CI], 1.07 to 1.90) and overall mortality (HR, 1.43; 95% CI, 1.09 to 1.84) compared to reference cohort after multiple adjustment. Stratified analyses showed higher mortality risk among women (HR, 1.87; 95% CI, 1.04 to 2.27) and specific components of MetSyn. Notably, the number of MetSyn components was observed to be significantly related to CRC prognosis. Conclusion Our findings supported that multi-morbidities of MetSyn associated with elevated death risk after CRC. MetSyn should be considered as an integrated medical condition more than its components in CRC prognostic management.

Objective To investigate the influence of deep brain stimulation (DBS) at high frequency to the bilateral nucleus accumbens on morphine-induced conditioned place preference (CPP) and relapse behaviors during extinction phase in rats. Methods Twenty adult SD rats were employed in the experiment. Through stereotactic operation, outer electrode cannula was implanted into rats' bilateral nucleus accumbens. After 5 days of rest, the morphine-dependent rat model with CPP was established through intraperitoneal morphine injection (10 mg/kg). The rats, after being randomly divided into experimental group (morphine+DBS) and control group (morphine+sham DBS), were electrically stimulated using DBS circuits. Rats in the experimental group were given high frequency electrical stimulations while the control group was given sham stimulation. The CPP score of the two groups was recorded the day after stimulation until successful extinction and then the extinction time was compared between the two groups. After successful extinction the rats were given small dose of morphine to trigger relapse within 24 hours, and the CPP score was recorded and compared between the two groups.Results Compared with the control group (six days), the experimental group (26 days) had a longer extinction time. After relapse, the retention time within the drug-paired chamber of the experimental group was (357.01±192.72) s, obviously shorter than that of the control group ((704.91±181.35) s;t=2.370, P=0.034 6). Conclusion High frequency DBS to rats' bilateral nucleus accumbens can prolong extinction time but inhibit relapse behavior.

Objective To study the relationship between tubomanometry(TMM) and tympanograms before and after the treatment of otitis media with effusion(OME) in children,and to evaluate the function of tubomanometry in forecasting the prognosis of OME.Methods Data from 66 patients(98 ears) were collected before and after one to four weeks treatment,all the patients received tympanometry and tubomanometry ETS,recorded eustachian tube scores(ETS) and tympanogram types.Results Before treatment,there were significant differences between the ETS of normal ears and sick ears,also between ETS of type B tympanograms and type C.There was significant difference between ETS before and after treatment,but not between the ETS of type B tympanograms and type C after treatment.The increased ETS value of type B tympanograms was higher than type C with a significant difference.There was a significant difference between the ETS of the effective group and the invalid group before and after treatment,whether type B tympanograms or type C.Conclusion Eustachian tube scores increased after treatment,and the functions of eustachian tube were improved in children of otitis media with effusion.Before treatment,the ETS of type B tympanograrns was lower than type C,indicating a poorer function of eustachian tube.After treatment,the increased ETS value of type B tympanograms was more than type C.Tubomanometry could forecast the prognosis of otitis media with effusion in children.

Objective To investigate the clinical significance of Epstein-Barr virus EBV DNA in children with Epstein-Barr virus infection realated diseases.Methods A retrospective cohort study was performed.Totally 222 blood samples were collected from children who were diagnosed as EBV infection in Shandong Provincial Hospital from June 2012 to August 2013.Fluorescent quantitative PCR( FQ-PCR) was used to analyze the EBV DNA in peripheral blood lymphocytes.ELISA was used to analyze the four EBV serology antibodies in the serum.Two groups of tested results were compared.Heart, hepatic impairment and renal function were analyzed through detecting AST, ALT, BUN, CREA, CK, CKMB.The results were grouped by EBV DNA copy number, and then non-parametric test together with correlation analysis was performed using SPSS21.0 analytics software.Results The positive rate of EBV-CA IgM and EBV DNA was 51.35%(114/222) and 72.97% (162/222) respectively, χ2 =24.01, P<0.001.The EBV DNA copy number was significant difference (χ2 =11.79,P<0.05) in children at different stages of infection ( no previous infection:6.30 ×103 -1.20 ×104 copies/ml;early infection:5.56 ×103 -3.92 ×106 copies/ml;acute infection:6.58 ×103 -1.73 ×106 copies /ml;chronic infection or recurrent infection:8.92 ×103 -2.34 ×104 copies/ml;late infection or recovery:5.20 ×103 -1.12 ×107 copies/ml;past infection:5.46 × 103 -1.33 ×104 copies/ml).Each biochemical targets were divided into five groups by EBV DNA copy number (Ⅰ>1 ×106 copies/ml,Ⅱ1 ×105 -1 ×106 copies/ml, Ⅲ1 ×104 -1 ×105 copies/ml, Ⅳ5 × 103 -1 ×104 copies/ml, Ⅴ<5 ×103 copies/ml), and ALT(χ2 =10.14,P<0.05), BUN(χ2 =18.17, P<0.05), CK(χ2 =13.09,P<0.05), CKMB(χ2 =17.93,P<0.01) had a statistically significant difference between each group.Well, the log value of EBV DNA copy number had a positive correlation relationship with AST(r=0.357,P=0.001), ALT(r=0.376,P=0.001), BUN(r=0.329,P=0.000), CK(r=0.235,P=0.035).Conclusions Detection of EBV DNA can be used for the early diagnosis and assessment of process of the EBV infection related disease in children.The detection of liver, kidney function and myocardial enzymes can be used for evaluating the severity of EBV infection.

Objective To investigate the effect of high frequency stimulation of bilateral nucleus accumbens on relapse behaviors in morphine-dependent rats.Methods Twenty adult SD rats were employed in the experiment.Through stereotactic operation,outer electrode cannula was implanted into rats' bilateral nucleus accumbens.After 5 days of rest,the morphine-dependent rat model with conditioned place preference (CCP) was established through intraperitoneal morphine injection (10 mg/kg).After acquisition of CPP,normal saline was replaced with morphine for CPP extinction training.CPP test was used to exam the effect of extinction.The rats,after being randomly divided into experimental group (morphine+DBS) and control group (morphine+sham DBS),were electrically stimulated using modified DBS circuits.Rats in the experimental group were given high frequency electrical stimulation while the control group was sham stimulation.After consecutive stimulation for 7 days,rats in the two groups were given small dose of morphine (3 mg/kg)to trigger relapse.Results (1) The CPP score increased after the establishment of rat models compared with pre-establishment of the rat models((616.2±74.7) s vs (353.9±84.3) s,P＜0.01).(2) The CPP score after extinction training decreased compared with pre-conditioned CPP score ((456.4± 148.8) s vs (353.9±84.3) s),P=0.0847) and had no statistical difference compared with post-conditioned CPP score ((456.4±148.8) s vs (616.2± 74.7) s,P=0.0219).(3) When the relapse was induced by small doses of morphine within 24h after the last stimulation,the CPP score of the experimental group decreased compared with the CPP score of control group ((330.1 ±212.6) s vs (684.2±230.2)s,P=0.0029),and the relapse was restrained.Conclusion High frequency DBS of bilateral nucleus accumbens can attenuate relapse behavior in rats

Objective To study the vestibular function in patients with sudden deafness .Methods Retrospec-tive analysis of 436 cases of patients with sudden deafness ,being divided into two groups according to whether the merger of vertigo .147 cases with vertigo group ,75 cases of which were mild to moderately severe hearing loss .In-clud the rise type of 28 cases ,26 cases of flat type ,21cases of decline type .72 cases of which were severe hearing loss .In 289 cases without vertigo ,157 cases had mild moderate and severe hearing loss .Includ the rise type of 36 cases ,57 cases of flat type ,64 cases of decline type .One hundred and thirty two cases of which were severe hearing loss .Use video electronystagmogram (VNG) to test the vestibular function .Process the data with SPSS 13 .0 soft-ware .Results One hundred and twenty three(83 .7% )cases of the vertigo group suffered from vestibular function decline ,with 51 cases of mild to moderately severe hearing loss ,72 cases of severe and above .165 (57 .1% )cases of the without vertigo group suffered from vestibular function decline .There were 45 cases of mild to moderately se-vere hearing loss ,120 cases of severe and above .35 patients with vertigo patients with BPPV ,28 cases of which happened within 1 week in sudden deafness occured and 80% of which were vestibular function decline .Conclusion Patients with sudden deafness with vertigo suffered from vestibular function damage .Patients with sudden deafness without vertigo also suffered from vestibular function damage .And the more serious the hearing loss ,the higher the vestibular function decline opportunities .

Objective To study the influence of serum containing Fuzheng Toudu Qudu Recipe, a Chinese formula with the actions of supporting healthy qi to expel and remove toxicity, on serum levels of interleukin 2 (IL-2) and soluble interleukin 2 receptor (sIL-2R) at different stages of CD34+derived dendritic cells (DC) of patients with minimal residual disease of myelogenous leukemia ( MRD-L) , and to explore the biological mechanism of Fuzheng Toudu Qudu Recipe in promoting CD34+ to transform into DC in MRD-L patients. Methods Bone marrow mononuclear cells ( BMMC) were separated from the bone marrow of acute myeloid leukemia patients at complete remission stage by using Ficoll centrifugation. CD34+ cells were isolated by using immuno-magnetic mircobeads method, and then were cultured with various concentrations of Chinese medicine medicated serum and cytokines in vitro for the induction of DC. The morphologic characteristics of DC were observed with the inverted phase contrast microscope, and the expression levels of DC surface molecules such as CD83, CD80, CD86, CD1a and HLA-DR were detected by using flow cytometry. On culturing day 0, 6 and 9, serum levels of IL-2 and sIL-2R of each group were measured by enzyme-linked immunosorbent assay ( ELISA). Results ( 1) Chinese medicine medicated serum combined with cytokines was effective on promoting CD34+ to differentiate into DC with typical morphology, and inducing DC to have high expression of CD80, CD83, CD86 and HLA-DR, which differed from those in fetal calf serum (FCS) group and blank rabbit serum group (P<0.01). Middle- and low-dose combination groups increased expression of CD1a, which differed from high-dose combination group and cytokines group ( P<0.01). ( 2) Content of IL-2 in combination groups was higher than that in blank rabbit serum group on culturing day 0. In the combination groups, IL-2 was higher on culturing day 6 and 9 than that on culturing day 0. Middle and high-dose combination groups had higher IL-2 content on culturing day 9 than on culturing day 6 ( P<0.05 or P<0.01). At the same time point, combination groups had higher IL-2 content than the blank rabbit serum group (P<0.05 or P<0.01). (3) Content of sIL-2R in the combination groups was lower than that in blank rabbit serum group on culturing day 0. In the combination groups, sIL-2R was lower on culturing day 9 than that on culturing day 0 and 6 ( P<0.01) . High-dose combination group had lower sIL-2R content on culturing day 6 than that on culturing day 0 (P<0.05), and the difference of sIL-2R in other groups was insignicant between on culturing day 6 and on culturing day 0 ( P>0.05) . At the same time point, combination groups had lower IL-2 content than the blank rabbit serum group (P<0.05 or P<0.01). Conclusion Fuzheng Toudu Qudu Recipe is effective on increasing serum content of IL-2 and reducing sIL-2R content, and the changes of cytokine contents are more obvious along with the maturity of DC, which indicates that the recipe plays positive effect in the process of promoting CD34+cells to differentiate into DC.