Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

BACKGROUND: Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated. METHODS: The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry. RESULTS: ISL significantly inhibited the proliferation of GBC cells in vitro . The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4 . CONCLUSION ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and down-regulating GPX4 in vitro and in vivo . This evidence may provide a new direction for the treatment of GBC.
Animals ; Mice ; Carcinoma in Situ ; Chalcones/pharmacology* ; Ferroptosis ; Gallbladder Neoplasms/genetics* ; Glutathione Disulfide ; Kelch-Like ECH-Associated Protein 1 ; Mice, Nude ; NF-E2-Related Factor 2/genetics* ; Reactive Oxygen Species ; Humans

Objective:To evaluate the personalized 3D printed guide template used in the osteotomy for malunion of tibial fracture.Methods:A retrospective analysis was conducted of the 30 patients who had been treated for malunion of tibial fracture at Department of Orthopaedics, The First Affiliated Hospital to Zhengzhou University from January 2010 to January 2018. Of them, 15 used a personalized 3D printed guide template in the osteotomy (3D printing group). They were 9 males and 6 females, with an age of 46.3 year±8.2 years. The fracture malunion was located in the upper and middle tibia in 11 cases, in the lower tibia in 4 cases, on the left side in 6 cases and on the right side in 9 ones. There were 8 cases of varus deformity and 7 ones of valgus deformity. Their preoperative fracture deformity angle was 24.3°±5.5°. The other 15 patients were treated with conventional surgery (conventional group). They were 10 males and 5 females, with an age of 47.1 years±6.0 years. The fracture was located in the upper and middle tibia in 12 cases, in the lower tibia in 3 cases, on the left side in 5 cases and on right side in 10 cases. There were 7 cases of varus deformity and 8 ones of valgus deformity. Their preoperative fracture deformity angle was 22.5°±5.4°. The 2 groups were compared in terms of preoperative baseline data, operation time, intraoperative blood loss and postoperative recovery of the alignment of lower limb.Results:There were no significant differences in the preoperative baseline data between the 2 groups, showing comparability ( P>0.05). The 3D printing group was followed up for an average of 12 months while the conventional group for an average of 10 months. The operation time for the 3D printing group was significantly shorter than that for the conventional group(102.2 min±13.0 min versus 137.9 min ±10.5 min), the intraoperative blood loss for the former significantly less than that for the latter (77.3 mL ± 39.7 mL versus 163.3 mL ± 35.2 mL), and the postoperative malunion angle in the former significantly smaller than that in the latter (1.9°±0.4° versus 3.2°±0.9°) (all P< 0.05). The last follow-ups revealed no implant failure or re-malunion but fine healing of the osteotomy sites and good recovery of the alignment of lower limb in the 2 groups. Conclusion:A personalized 3D printed guide template used in the osteotomy for malunion of tibial fracture is an effective aid because it can facilitate precise osteotomy, reduce operation time and intraoperative blood loss and help correct the alignment of lower limb, leading to good short-term surgical outcomes.

Objective:To evaluate the safety and efficacy of endovascular interventional treatment of the intracranial vertebrobasilar trunk large aneurysms (VBTLAs) compared with conservative treatment.Methods:This is a prospective multi-center cohort study. From October 2012 to October 2018, a total of 69 patients with intracranial vertebrobasilar trunk large aneurysm (diameter>10 mm) from Henan Province People's Hospital and People's Liberation Army Rocket Medical Center were included in this study. Patients themselves chose either endovascular interventional therapy (interventional group) or conservative treatment (conservative group) after discussion with their doctors. The χ 2 test was used to compare the incidence of deaths, stroke, and all other serious adverse events including other site bleeding, myocardial infarction and others between the two groups. Results:A total of 69 patients were enrolled, of whom 51 patients were enrolled in interventional group, 18 patients underwent endovascular reconstructive therapy, 11 patients underwent deconstructive therapy, and 4 patients underwent conjunction interventional treatments. Eighteen patients were enrolled in conservative group, of whom 11 cases received simple risk factor control, 7 cases received antiplatelet and risk factors control. The proportions of hypertensive patients 94.4% (17/18) and giant aneurysms 50.0% (9/18) in the conservative group were higher than those in the surgery group 64.7% (33/51, χ 2=4.500, P=0.034), 19.6% (10/51, χ 2=4.730, P= 0.030).The incidence of all serious adverse events associated with protocol was 15.7% (8/51) in the interventional group and 44.4% (8/18) in the conservative group [risk ratio (RR) =0.353, 95% confidence intervals (CI): 0.156-0.801], and the difference was significant (χ 2=4.668, P=0.031). The incidence of fatal events associated with protocol was 2.0% (1/51) in the interventional group and 38.9% (7/18) in the conservative group (RR=0.050, 95%CI: 0.007-0.382), and the difference was significant (χ 2=14.281, P<0.001). The incidence of hemorrhage events associated with protocol was 2.0% (1/51) in the interventional group and 22.2% (4/18) in the conservative group (RR=0.088, 95%CI: 0.011-0.738), and the difference was significant (χ 2 =5.391, P=0.020). Follow-up imaging showed that the occlusion rate of aneurysms in 44 patients in the interventional group was 56.8% (25/44) after a median follow-up of 6 months. Imaging follow-up was obtained in 9 patients, whose occlusion rate of aneurysms was 0 and the median follow-up time was 12 months, in the conservative group. The difference was significant(χ 2 =7.534, P=0.006). Conclusion:Compared with conservative treatment, endovascular intervention of the intracranial VBTLAs has lower incidences of serious adverse events and death events.

Objective To analyze the change trend of hospitalized patients with pulmonary embolism in Wuzhou city during 2004-2014,and analysis of its risk factors.Methods From January 2004 to January 2014,from four comprehensive tertiary hospitals of Wuzhou city,we selected hospitalized cases of pulmonary embolism as investigation subjects,which from 2004 to 2008 were selected as control group,and from January 2009 to January 2014 were selected as observation group.The hospitalization rate,mortality rate and risk factors were compared between the two groups.Results From 2004 to 2008,there were 257 370 cases of hospitalized,pulmonary embolism hospitalized in 52 cases at the same period,accounting for 0.02％ of the total hospitalized cases.From January 2009 to January 2014,there were 367 728 cases of hospitalized,pulmonary embolism hospitalized in 115 cases at the same period,accounting for 0.03％ of the total hospitalized cases.The proportion of pulmonary embolism in total hospitalization between the two groups had statistically significant difference (P ＜ 0.05).From 2004 to 2008,in 52 cases of pulmonary embolism,24 cases (46.15％) died,includef 16 cases(30.7％) died of pulmonary embolism,and the rest 8 cases(15.38％) died of the complication.From 2009 to 2014,in 115 cases of pulmonary embolism,30 cases (26.08％) died,included 23 cases(20.00％) died of pulmonary embolism,and the rest 7 cases(6.08％) died of complications.The difference of the mortality rate in the two periods was statistically significant (x2 =3.879,P ＜ 0.05).52 cases of pulmonary embolism of the control group were selected to study risk factors and basic diseases,the risk factors and basic diseases of pulmonary embolism had 11 kinds,the highest frequency was in lower limb venous thrombosis,followed by surgery and lie in bed for a long time,again for malignant tumor,smoking,fracture,hyperlipidemia,arrhythmia(atrial fibrillation,etc.) and diabetes,etc.Conclusion The hospitalization proportion and mortality trend of hospitalized patients with pulmonary embolism in Wuzhou city remains unchanged,to study the risk factors in order to get a better prevention and treatment measures.

Objective To investigate the adrenal histopathology damage in critically ill non-survival children,and the incidence of adrenal damage,and to explore the risk factors for the adrenal hemorrhage and necrosis in critically ill children.Methods A total of 141 critically ill non-survival children was admitted in this study in Hunan Children's Hospital from January 1,2005 to December 30,2012.Clinical data in children were systematically collected,including age,sex,sodium,potassium,blood gas analysis,liver and kidney function,blood clotting function,etiology,treatment and pediatric clinical illness score (PCIS) or neonatal critical illness score (NCIS),and pathological data.All data were analyzed by SPSS 18.0.Results Logistic regression analysis showed the factors of adrenal hemorrhage and necrosis of critically ill non-survival children were sepsis,PCIS score ＜ 80 critically ill children are risk factors for adrenal hemorrhage necrosis (P ＜ 0.05),ORwas 3.659 (95％ CI:1.344-9.965),and 2.325 (95％ CI:1.028 -5.258).Intravenous corticosteroids were protective factors for critically ill non-survival children with adrenal hemorrhage necrosis (P ＜ 0.05),and ORwas 0.377 (95％ CI:0.163-0.875).Conclusions There were two significant risk factors of adrenal hemorrhage and necrosis:sepsis and critical illness score less than 80 points.Intravenous corticosteroid is a protective factor in critically ill children.

Objective To study the radiological features of dynamic enhanced multi-slice spiral CT (MSCT) and CTA in pure hepatic arterio-venous fistula (AVF).Methods The radiological features of MSCT imaging and CTA of 100 patients with pure hepatic AVF were retrospectively analyzed.Results Positive signs on the arterial phase were detected in 100 patients with pure hepatic AVF.In 89 patients,they were the peripheral type and in 11 patients they were the central type.There were 128 lesions in the 100 patients.In the peripheral type,the features were (1) in the arterial phase,the lesions appeared as a wedged or a patchy enhancement area at the edge of the liver,showing a halo sign in 68 patients.In 56 patients,the PV was shown also in the early arterial phase;(2) in the arterial phase,arailway track sign was shown in 21 patients as a result of a portal vein branch showing right next to a hepatic arterial branch.In the central type and in the arterial phase,the main portal vein (or the hepatic vein) and the left/right branches of the PV (or the HV) were shown.Conclusion MSCT and CTA were useful in the diagnosis of pure hepatic AVF.

Aim To investigate the effect of berberine on the expression of nephrin, podocin and intergrinα3β1 in diabetic nephropathy ( DN ) rat model, and further probe in to the renoprotective effects of berber-ine and its potential mechanisms. Methods The rat model of DN was induced by intraperitoneal injection of streptozotocin ( STZ ) after fed with high-sugar and high-fat diet for six weeks. The rats were assigned into 6 groups randomly: normal control group, DN model group, BBR (50,100 and 200 mg·kg-1 ) treatment group and enalaprilat positive control group ( 1 mg · kg-1 ) . The distribution and expression of kidney podocyte related proteins nephrin, podocin and interg-rinα3β1 were detected by immunohistochemical meth-od following electron microscopy observation ( × 1000 ) and high magnification observation( × 400) and West-ern blot. Results The podocyte related protein neph-rin, podocin and intergrin α3β1 were mainly distribu-ted in podocyte, but slightly different. Compared with normal control group, the expresion of podocyte related protein nephrin, podocin and intergrin α3β1 was de-creased obviously; compared with model group, BBR (100 and 200 mg·kg-1 ) treatment group could sig-nificantly suppress the abnormalities of pathological changes of the kidney and upregulate the expression levels of podocyte specific protein nephrin, podocin and intergrin α3β1 in the kidney of diabetic rats with nephropathy. Conclusions Berberine could alleviate the abnormalities of kidney pathological changes and proteinuria production in the DN model rats, which may be related to the upregulation of the expression of the podocyte proteins nephrin, podocin and intergrinα3β1.

Objective To study the exocrine pancreatic function in critically ill children with septic shock,sepsis and hyperlactacidemia.Methods A total of 64 critical pediatric patients were admitted from Jan 2009 to Oct 2012,and clinical and laboratory findings including pancreatic function,and histopathological features and score after autopsy were reviewed.Results (1) Compared with non-septic shock children,the pancreatic pathology score and serum lipase in septic shock group were significantly higher and serum calcium was significantly reduced (P ＜0.05) ; (2) The pancreatic histopathology score was significantly increased in patients with elevated plasma lactate ≥2 times (P ＜0.05),but there were no significant differences in serum calcium and blood amylase and lipase between patients with elevated plasma lactate level and patients with normal plasma lactate level; (3) The concentrations of serum amylase,lipase and urinary amylase were significantly increased in patients with pancreatic histopathology score ＞4 points compared with score ≤4 points patients,but there were no significant differences in above three biomarkers between patients with score ≤3 points and patients with score ＞3 points.Conclusions The pancreas is vulnerable to damage easily occurred in septic shock children especially complicated with hyperlactacidemia.The pancreatic histopathology score ＞ 4 points can be as a sensitive and reliable indicator of pancreas damage.

The college students innovative test project,which advocates student-centered teaching pattern focusing on questions and subjects is an important component of the project on undergraduate teaching quality and teaching reform in medical college of Shanghai Jiao Tong university.The innovative test project has effectively fostered the innovative spirits,practical abilities,scientific attitudes and learning initiatives of the college students after being implementing for more than four years.Besides,it has changed the teaching philosophy of teachers and created a favorable atmosphere of innovative practice.Several problems have emerged during the implementation of the project including broad topics,limited sample size and incorrect motives for doing tests.Exclusive mechanism aiming at the long-term effect of the project should be established, the concept of the project should be promoted and the communication platform should be built in order to consummate this project.