Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

Objective To study the characteristics of hyperphenylalaninemia (HPA) and the differences in blood and urine metabolic index and their correlation.Methods A total of 137 patients with HPA diagnosed by the Pediatric Inherit Metabolism and Endocrine Department,Guangdong Women and Children's Hospital,Guangzhou Medical University from January 2014 to June 2017,were enrolled.Tandem mass spectrometry (MS/MS),gas chromatography/ mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) were used to analyze the concentration of blood and urine metabolites in children,and the patients were divided into different groups according to the drug load test of tetrahydrobiopterin (BH4) and dihydrobiopterindine reductase (DHPR) deficiency.The HPA metabolite analysis of horizontal concentration by statistical differences and correlation analysis were performed.Results Among the 137 cases of HPA,there were 101 cases (73.7％) of phenylalanine hydroxylase deficiency (PAH),and among them 21 cases (15.3％) were classic phenylketonuria (PKU),37 cases were mild PKU (27.0％),43 cases (31.4％) wcrc mild HPA.Thcrc were 22 cases (16.1％) with BH4 reaction,and 79 cases (57.7％) of non-reactive type.Besides,there were 36 cases (26.3％) of tetrahydrobiopterin deficiency (BH4 D),of which 6-pyruvoyl tetrahydropterin synthase deficiency (PTPS) in 34 cases (24.8％) and dihydrobiopterindine reductase deficiency (DHPR) in 2 cases (1.5％).Urinary phenylacetic acid (r =0.673,P ＜ 0.01),phenyllactic acid (r =0.736,P ＜ 0.01),phenylpyruvic acid (r =0.642,P ＜ 0.01) were significantly correlated with blood phenylalanine (Phe) concentration,and the neopterin (N) (r =0.442,P ＜ 0.01) and biopterin (B) (r =0.398,P ＜ 0.01) had low correlation.Urinary phenylacetic acid,phenyllactic acid and phenylpyruvic acid had no correlation with urinary pterin.There were significant differences among PTPS deficiency group,BH4 response type,and non-reactive type(all P ＜ 0.05),but no significant difference between the BH4 reaction type and the non-reactive group (P ＞ 0.05).Conclusions Through the analysis of the different types of HPA metabolic profiles,it can help to master the incidence and characteristics in the region,within a certain concentration range of blood Phe,the phenylacetic acid,phenyllactic acid,phenylpyruvic acid should not be tested by GC-MS alone.Uterine erythropoietin analysis of BH4D classification and identification of BH4 reaction,non-reactive PKU have a supporting role,so master the metabolic index of various types of concentration and relevance of HPA,it can provide basis for early diagnosis,accurate treatment and follow-up.

Objective To investigate the effect of moxibustion or acupuncture combined with prokinetic drugs (metoclopramide injection) on the success rate of placing the nasal and intestinal tubes in critically ill patients at bedside.Methods A total of 107 patients underwent enteral nutrition from January 2015 to August 2017 in the Intensive Care Unit (ICU) of Wenzhou Central Hospital in Zhejiang Province were recruited and given bedside manual placement of spiral nasointestinal tube. According to whether the acupuncture or moxibustion combined with the use of the prokinetic drugs in the process of placing the tube, the cases can be divided into three groups: simple prokinetic drugs group (n=23), moxibustion combined with prokinetic drugs group (n=22), acupuncture and moxibustion combined with prokinetic drugs group (n=62). The success rate of catheterization in three groups was analyzed and compared statistically.Results After 72 hours of catheterization, bedside X-ray abdominal radiography showed that the end of the catheter was located behind the pylorus in 81 cases out of the 107 patients. The success rate of catheterization was 75.70％. The unsuccessful patients were given gastroscopy guided nasointestinal tube. The success rate of catheterization was 30.43％ in simple prokinetic drugs group, 63.64％ in moxibustion combined with prokinetic drugs group, and 96.77％ in acupuncture and moxibustion combined with prokinetic drugs group. Comparing the success rate of the catheterization, the difference was statistically significant (χ2=49.75,P<0.01).Conclusions The combination of moxibustion and acupuncture can significantly increasing the success rate of placing the spiral nasointestinal tube, and provide practical benefits for the critically ill patients. This method should be popularized in clinic.

Objective To investigate the diagnostic significance of combined detection of rheumatoid factor (RF),anti-cyclic cit-rullinated antibody (anti-CCP antibody),glucose-6-phosphatase (GPI)and anti-RA33 antibody in rheumatoid arthritis (RA).Meth-ods One hundred and twenty-six patients with RA,60 patients with other autoimmune diseases and 60 healthy subjects undergoing physical examination were selected as the research subjects.The singled detection of RF,anti-CCP antibody,GPI and anti-RA33 an-tibody,and their combined detection were used to analyze their roles in RA diagnosis.Results Compared with the healthy control group,the four indexes in the RA group were increased,the difference was statistically significant (P<0.05),the RF level in the autoimmune diseases group was increased compared with the control group,the difference was statistically significant(P<0.05). Compared with the the autoimmune diseases group,the four indexes in the RA group were increased,the difference was statistically significant (P<0.05).The sensitivity and specificity of RF to RA were 77.77% and 63.33%;the sensitivity and specificity of anti-CCP antibody to RA were 69.04% and 95.00%;the sensitivity and specificity of GPI antibody to RA were 25.40% and 100.00%;the sensitivity and specificity of anti-RA33 antibody were 27.77% and 99.16%,respectively.The specificity of combined 2 indica-tors was increased from 63.33% to 85.00%,which of combined 3 indicators was increased to 93.33% and which of combined 4 in-dicators even reached to 100.00%.Conclusion The combination of RF,anti-CCP antibody,GPI and anti-RA33 antibody indicators greatly increases with the sensitivity and specificity for diagnosing RA and has clinical significance.

Objective To investigate the class I integrons and their gene cassettes of imipenem-resistant Pseudomonas aeruginosa (IRPA) , and to analyze the correlation between integrons and drug resistance. Methods PCR was used to determine the presence of integrase genes and class I integrons. The variable regions were detected by sequencing. Resistance genes of integron gene cassettes including metal-β-lactamases, aminoglycoside modifying enzymes (AMEs), 16SrRNA methylating enzyme and the OprD2 genes were detected by PCR. The VITEK-2 automated system was used to determine the antibiotic susceptibility of integron-positive IRPA strains. Results The positive rates of integrase genes and class I integrons were 23.3%(20/86)and 8.14%(7/86) , and five kinds of gene cassettes were detected in 86 IRPA strains. The class I integrons-positive bacterial strains exhibited different resistant patterns to 12 antibiotics with large number of resistance genes. Conclusion The class I integrons and their gene cassettes are associated with multiple drug resistance of IRPA.

We compared the MGIT 960 method,the reference,and the broth microdilution method for detecting the susceptibility of Mycobacterium tuberculosis isolates to protionamide (PTO).We performed drug susceptibility testing for 248 M.tuberculosis clinical isolates to PTO using MGIT 960 and broth microdilution method.In addition,a total of 117 isolates were randomly selected for further evaluation of the consistency of the minimal inhibitory concentrations determined by these two methods,and eleven concentrations of PTO had been involved accordingly (0.062 5,0.125,0.25,0.5,1,2,4,8,16,32,64 μg/mL).The MGIT method showed an average detection time of 10.1 days,while the detection period of broth microdilution method was 8 days,and the difference was statistically significant (P＜0.001).In addition,the rate of the sensitivity,specificity and concordance between these two methods was 96.5％ (55/57),93.2％ (178/191),and 94.0％ (233/248),respectively.The Kappa value was 0.84.Comparison of the MIC values detected by different methods revealed that the overall concordance rate was 81.2％ (95/117).For the isolates harboring low MIC values (MIC＜8.0 μg/mL),the concordance rate was 86.3％ (82/95),while that of the isolates with high MIC values was only 59.1％ (13/22).In conclusion,our data demonstrate that the broth microdilution method showed excellent concordance with MGIT method for detecting the resistance rate of M.tuberculosis isolates to PTO,indicating that the broth microdilution method with available performance,short turn-around time and convenient manual operation was suitable for rapid detection of M.tuberculosis to PTO.

Objective To compare the serum levels of interleukin(IL)-6,IL-18 and tumor necrosis factor alpha(TNF-α)in patients with DPD,PD,depression disorder and healthy controls and to analyze the correlations of serum inflammatory factors in DPD patients. Methods Serum levels of IL-6,IL-18 and TNF-αwere measured using enzyme linked immunosorbent assay(ELISA) kits. Several scales were performedin DPD patients. Results DPD,PD and depression disorder patients had significant lower baseline levels of IL-6 and TNF-αwhen compared to healthy controls(P < 0.05). The levels of IL-6 and TNF-α in DPD patients were significantly increased after 4 weeks of anti-depression treatment(P < 0.05). No difference of cytokines levels in gender and in severity of DPD patients was detected Serum levels of these inflammatory cytokines were not significantly correlated with the UP-DRS Ⅲ,H & Y,MMSE and HAMD scores in DPD patients. Conclusions Serum inflammatory factors(IL-6, TNF-α)were altered in patients with DPD in the earlier course of disease. However ,the role of IL-18 remained unknownin the occurrence of DPD disease.

Objective: To observe the effects of axial vascular network flap of scalp or anterolateral thigh perforator flap with fascia lata on repairing defects after radical resection of scalp carcinoma in patients. Methods: From February 2006 to December 2015, twenty-one patients with scalp carcinoma were admitted to our hospital, and the carcinoma invaded external lamina or full-thickness of skull and dura mater. After perfect preoperative examination, carcinoma and scalp tissue in 3 to 5 cm from the edge of carcinoma, external lamina or full-thickness of skull and invaded dura mater were resected and sentinel lymph nodes around carcinoma were cleaned in 3 to 4 days after admission. The postoperative defects with size reached from 11 cm×8 cm to 22 cm×18 cm. The flap transplantation was performed at the same time when quick frozen pathological examination results of resected scalp carcinoma margin tissue, skull, dura mater margin and basal tissue, and sentinel lymph nodes showed completely negative. Defects in 3 elderly patients were repaired by single or multiple axial scalp vascular network flaps, with the resected flaps size ranged from 12 cm×7 cm to 19 cm×14 cm. Defects in the other 18 patients were repaired by anterolateral thigh perforator flaps with fascia lata, with the resected flaps size ranged from 13 cm×10 cm to 23 cm×19 cm and the resected fascia lata size ranged from 8 cm×7 cm to 10 cm×10 cm. The head donor site of flap was repaired by medium thickness skin of head and back; the thigh donor site of flap was repaired by medium thickness skin of thigh on the same side. All patients gave up postoperative radiotherapy, chemotherapy, and other follow-up treatments. Results: After operation, the flap and skin in all patients survived completely, with no vascular crisis or other condition. During the follow-up for 6 months to 9 years, all patients showed good appearance except for baldness in operation area of head, with no obvious malformation in head donor site of flap and skin, no swollen external hernia in the brain tissue, and no local recurrence or distant metastasis of carcinoma. The appearance of thigh donor site of flap and skin was good, with normal muscle strength and movement of lower limbs. Conclusions Patients with scalp carcinoma were performed with radical resection of carcinoma, and axial vascular network flap of scalp or anterolateral thigh perforator flap with fascia lata were applied to repair the postoperative defects, with good appearance of head operation area and no local recurrence or distant metastasis of carcinoma.

Objective To evaluate the safety and therapeutic effect of covered expandable metallic stent placement combined with interventional chemotherapy in treating malignant esophago-tracheal fistulae. Methods A total of 60 patients with esophago-tracheal fistula were enrolled in this study. The patients were randomly divided into control group (n=28) and study group (n=32). Patients of the control group were treated with covered stent implantation only, while patients of the study group were treated with combination use of covered stent implantation and interventional chemotherapy. All the patients were followed up regularly, the short-term and long-term results were determined, and the effect rate, median survival time and complications were statistically analyzed. Results Among the 60 patients, successful obstruction of the fistula was obtained in 58 with a success rate of 96.7%. The median survival time of the 58 patients was 5.8 months. The median survival time of the control group and the study group was 3.6 months and 8.7 months respectively, the difference between the two groups was statistically significant (P<0.05). The one-month, 3-month and 6-month effect rates were 78.1%, 68.8% and 62.5% respectively. The incidence of esophageal stent re-stenosis in the study group was much lower than that in the control group. Conclusion The combination use of covered stent implantation and interventional chemotherapy can effectively improve the median survival time of patients with malignant esophago-tracheal fistula, and reduce the occurrence of stent-related complications. Therefore, covered expandable metallic stent placement combined with interventional chemotherapy is an effective and safe treatment for malignant esophago-tracheal fistulae.

Objective To evaluate the diagnostic role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the smear and culture negative tuberculosis.Methods The tuberculosis suspected patients with spu-tum-negative for three times and with hilar or mediastinal lymphadenopathy were randomly divided into 2 groups,study group received EBUS-TBNA and bronchoalveolar lavage group(BAL) examination,control group received BAL examination only.Chi-square test was used to compare their diagnostic sensitivity and negative predictive value.Results Totally 82 patients were included this study,40 patients were in control group and 42 in the study group.In the control group,tuberculosis was confumed in only 8 cases by means of bacteriological examination in the BAL fluid,27 were confirmed by the following surgery ordiagnostic treatment of anti-Tuberculosis,and the other 5 cases were diagnosis as other diseases; In the study group,tuberculosis was confirmed in 28 patients through bacteriological and pathological examination,8 were false negative and the other 6 were diagnosis as non-tuberculosis diseases.The diagnostic sensitivity in the study group was significantly higher than that in control group (77.8％ verus 22.9％,x2 =21.4,P ＜ 0.01 ) ; and the negative predictive value in the EBUS-TBNA group was also significantly higher than that in the BAL group (42.9％ VS 15.6％,x2 =3.97,P =0.046).Complications were similar inthese 2 groups,only 1 case of intervention required puncture site bleeding happened in the study group.Conclusion EBUSTBNA has a higher sensitivity and negative predictive value in the diagnosis of smear and culture negative pulmorary tuberculosis patients with hilar or mediastinal lymph nodes.This technique is a safe method with few complications than the traditional BAL examination.It may play an important role in the diagnosis of smear and culture negative tuberculosis patients.