RITA selectively inhibits proliferation of BAP1-deficient cutaneous melanoma cells in vitro / 南方医科大学学报

OBJECTIVE@#To screen for small molecular compounds with selective inhibitory activity against cutaneous melanoma cells with BAP1 deletion.@*METHODS@#Cutaneous melanoma cells expressing wild-type BAP1 were selected to construct a BAP1 knockout cell model using CRISPR-Cas9 system, and small molecules with selective inhibitory activity against BAP1 knockout cells were screened from a compound library using MTT assay. Rescue experiment was carried out to determine whether the sensitivity of BAP1 knockout cells to the candidate compounds was directly related to BAP1 deletion. The effects of the candidate compounds on cell cycle and apoptosis were detected with flow cytometry, and the protein expressions in the cells were analyzed with Western blotting.@*RESULTS@#The p53 activator RITA from the compound library was shown to selectively inhibit the viability of BAP1 knockout cells. Overexpression of wild-type BAP1 reversed the sensitivity of BAP1 knockout cells to RITA, while overexpression of the mutant BAP1 (C91S) with inactivated ubiquitinase did not produce any rescue effect. Compared with the control cells expressing wild-type BAP1, BAP1 knockout cells were more sensitive to RITA-induced cell cycle arrest and apoptosis (P < 0.0001) and showed an increased expression of p53 protein, which was further increased by RITA treatment (P < 0.0001).@*CONCLUSION@#Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.

The progress on sensitivity of PARPi and platinum in mCRPC with DNA damage repair gene mutation / 中华泌尿外科杂志

DNA damage repair (DDR) defects occurred in 8%-16% of metastatic castration resistant prostate cancer (mCRPC). DDR gene mutation was related to poorer prognosis. Patients with DDR gene mutation, especially BRCA1/2 mutation, showed high sensitivity to poly ADP-ribose polymerase inhibitor (PARPi) and platinum.

Prognostic Value of Lymphovascular Invasion in Node-Negative Upper Urinary Tract Urothelial Carcinoma Patients Undergoing Radical Nephroureterectomy

PURPOSE: This study aimed to evaluate the prognostic impact of lymphovascular invasion (LVI) in patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We collected data from 180 patients who were treated with RNU from 2005 to 2013 at our institution. The Kaplan-Meier method with log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses. RESULTS: LVI was present in 28 patients (15.6%), which was associated with higher pathological tumor stage (p < 0.001), tumor necrosis (p=0.012), lymph node metastasis (p=0.017) and multifocality (p=0.012). On multivariate analysis, LVI was an independent prognostic factor of recurrence-free survival [RFS: hazard ratio (HR)=2.954; 95% confidence interval (CI)=1.539–5.671; p=0.001] and cancer-specific survival (CSS: HR=3.530; 95% CI=1.701–7.325; p=0.001) in all patients. In patients with node-negative UTUC, LVI was also a significant predictor of RFS (HR=3.732; 95% CI 1.866–7.464; p < 0.001) and CSS (HR=3.825; 95% CI=1.777–8.234; p=0.001). CONCLUSION: LVI status was an independent predictor in patients with UTUC who underwent RNU. The estimate of LVI could help physicians identify high-risk patients and make a better medication regimen of adjuvant chemotherapy.

Advance in research on the relationship between mammalian target of rapamycin signaling pathway and ophthalmic diseases / 中华实验眼科杂志

Mammalian target of rapamycin (mTOR) is a highly evolutionary conserved protein kinase and plays a critical role in the regulation of cell growth, growth factors and cell energy, and thus contributes to the formation of nutrition, metabolism and aging processes.Recent studies found that mTOR signaling pathway is associated with cell cycle, protein synthesis and metabolism, and it is an important pathway of diseases such as development of tumor,metabolic disorders,nervous system disease and inflammation.The relationship between mTOR signaling pathway and ophthalmic diseases was reviewed in this article.

Laparoscopic retroperitoneal adrenalectomy for adrenal mass：report of 130 cases / 中国癌症杂志

Background and purpose:Laparoscopic retroperitoneal adrenalectomy makes access to the adrenal glands easier and less invasive than open surgery. The aim of this study was to evaluate the clinical efifcacy of laparoscopic retroperitoneal adrenalectomy.Methods:A total of 130 patients who underwent retroperitoneal adrenalectomy for adrenal mass from Jan. 2007 to Dec. 2012 in Fudan University Shanghai Cancer Center were retrospectively assessed. Their clinicopathological factors, perioperative complications and short-term prognostic data were retrieved from the medical records.Results:One hundred and twenty-seven of 130 patients underwent retroperitoneal adrenalectomy successfully, and 3 patients were converted to open surgery due to severe bleeding. Among 130 patients, 63 were male and 67 were female, with the mean age 50.0 years. The pathological results of the 130 patients indicated adrenocortical adenoma in 68, pheochromocytoma in 15, medullary lipoma in 13, adrenal cysts in 10 , ganglioneuroma in 7, metastatic cancer in 5, adrenal hyperplasia in 4, schwannoma in 3, lymphangioma in 2, adrenal hematoma in 1, adrenal cortical carcinoma in 1, adrenal angiosarcoma in 1 and the deputy spleen in 1 (one patient suffering from both pheochromocytoma and ganglioneuroma). The maximum diameters were ranging from 0.5 to 9.0 cm, and mean diameter was 3.48 cm. The average blood loss in surgery was 62.73 mL. Mean length of stay in hospital was 7 d. GradeⅠ complications occurred in 5 patients, including 2 of fever, 1 of food allergy, 1 of drug allergy and 1 of hypokalemia.Conclusion: Retroperitoneal adrenalectomy should be considered as the procedure of choice for the resection of most adrenal tumors in skilled centers with the advantages of minimal invasion, increased safety and faster recovery.

Comparison of the renal function after partial nephrectomy and radical nephrectomy for T1a renal cell carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the alterations in renal function after radical nephrectomy (RN) and partial nephrectomy (PN) for renal cell carcinoma (RCC) and to determine the risk factors for the onset of postoperative renal function impairment.</p><p><b>METHODS</b>We assessed the renal function of 429 T1a RCC patients by investigating the time-dependent changes of the estimated glomerular filtration rate (eGFR) after surgery from August 2003 to August 2010. Univariate and multivariate regression models were used to determine the risk factors for the onset of an eGFR < 60 ml · min⁻¹ · 1.73 m⁻² function, and to evaluate the prognosis for the two groups.</p><p><b>RESULTS</b>The mean eGFR values (ml · min⁻¹ · 1.73 m⁻²) at postoperative 1, 7 days, 1, 3, 6, 12 and 24 months were 51.4 ± 12.6, 52.1 ± 17.8, 53.2 ± 19.5, 54.6 ± 20.2, 53.8 ± 16.6, 52.7 ± 22.3 and 51.5 ± 18.4 in the RN group and 69.6 ± 18.3, 70.3 ± 19.5, 71.5 ± 21.4, 76.2 ± 22.8, 75.4 ± 19.7, 74.3 ± 16.3 and 73.1 ± 23.2 in the PN group, respectively. The eGFR of the radical nephrectomy group was significantly lower than that of the partial nephrectomy group (P < 0.05). Multivariable analysis revealed that radical nephrectomy and age were risk factors for the onset of postoperative chronic renal dysfunction.</p><p><b>CONCLUSIONS</b>Renal function recovered partially after partial and radical nephrectomy and is maintained constantly after 3 months. Surgical mode and age are risk factors for the onset of postoperative eGFR < 60 ml · min⁻¹ · 1.73 m⁻² impairment. Compared with radical nephrectomy, partial nephrectomy can preserve renal function and reduce the incidence of postoperative chronic renal dysfunction.</p>

Influence of clinical factors on Gleason score upgrade in patients undergoing radical prostatectomy / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate clinical factors affecting Gleason score upgrade in patients receiving radical prostatectomy (RP).</p><p><b>METHODS</b>A total of 322 patients with prostate cancer who received RP from January 2012 to December 2013 at Department of Urology at Fudan University Shanghai Cancer Center were included, and their data of age, body mass index (BMI), prostate-specific antigen (PSA), prostate volume, percentage core, clinical staging, pathological characteristics, biopsy Gleason score and RP Gleason score were analyzed. Differences in categorical variables and continuous variables were compared using χ² tests and Student's t-test, respectively. Unconditional multiple logistic regression was used to estimate OR and 95% CI of the association of Gleason score upgrade with clinical factors.</p><p><b>RESULTS</b>Gleason score upgrade occurred in 107 of 322 (33.3%) patients. There was no difference in age, BMI and clinical staging between the two groups. Compared with patients without Gleason score upgrade, higher levels of PSA (χ² =6.740, P=0.034), smaller prostate volume (t=3.481, P=0.002) and elevated percentage core (t=-2.097, P=0.037) were observed in patients with Gleason score upgrade. In addition, lymph node metastasis (χ² =4.193, P=0.041) and extracapsular extension (χ² =4.747, P=0.029) were more common in patients with Gleason score upgrade. After adjusting for potential confounders, PSA levels (OR=2.451, 95% CI: 1.290-4.660), prostate volume (OR=0.982, 95% CI: 0.969-0.995) and percentage core (OR=2.756, 95% CI: 1.033-7.357) were independent predictors for Gleason score upgrade.</p><p><b>CONCLUSION</b>Gleason score upgrade happens at a relatively high rate. PSA levels, prostate volume and percentage core are important factors affecting Gleason score upgrade.</p>

Effect of Voriconazole on Pulmonary Fungals Infection after Renal Transplantation / 中华医院感染学杂志

OBJECTIVE To observe the effect of voriconazole on pulmonary fungals infection after renal transplantation.METHODS Nine cases of pulmanory fungals infection after renal transplantation were analyzed to evaluate the therapeutic effect of voriconazole.RESULTS Treated with voriconazole,seven in nine patients were cured,while the other two died.CONCLUSIONS For patients with pulmanory fungals infection after renal transplantation,the application of voriconazole can receive satisfactory effect.

Effect of tacrolimus on maturity and allostimulatory activity of cultured dendritic cells of rats in vitro / 中国药理学与毒理学杂志

AIM To explore the effect of tacrolimus on maturity and allostimulatory activity of cultured dendritic cells (DC) in vitro. METHODS Twenty rats were randomly divided into 4 groups: control, tacrolimus, LPS, and tacrolimus+LPS groups. The bone marrow cells of rats were cultured with granulocyte-macrophage colony-stimulating factors and interleukin-4 (IL-4) for 6 d and the DC which adhered to the wall were harvested. No other extraneous reagents were used in control group. Tacrolimus 10 μg·L-1 was added to tacrolimus group at the beginning of culture. Lipopolysaccarides (LPS) 100 μg·L-1 were administered 18 h beforeharvest in LPS group. In tacrolimus+LPS group, tacrolimus and LPS were used in accordance with tacrolimus and LPS groups. The immunophenotypes of DC were analyzed with flow cytometry and the level of IL-12 secreted by DC was detected by ELISA. The allostimulatory activity of DC on allogeneic T cells was assessed with mixed lymphocyte reaction. RESULTS Compared with control group, LPS increased CD80 and CD86 expressions, IL-12 secretion and allostimulatory activities of DC. Compared with control and LPS groups, tacrolimus cut down the expressions of CD80 and CD86, decreased the secretion of IL-12 and reduced the allostimulatory activity of cultured DC. CONCLUSION Tacrolimus exerts a negative effect on the maturation and allostimulatory activity of cultured DC in vitro.

Immune tolerance induced by immature dendritic cells treated with tacrolimus in rat heart transplantation / 中国组织工程研究

BACKGROUND: Immune tolerance is regarded as the most effective measure to overcome rejection. For the past few years, the important effect of immature dendritic cells (imDCs) on immune tolerance has drawn close attention. OBJECTIVE: To study the effect of imDCs treated with tacrolimus (FK506) on imlnune tolerance in rat allograft organ transplantation and to investigate the mechanism of immune tolerance induced by imDCs. DESIGN: A randomized and controlled animal experiment. MATERIALS: The experiment was carried out at the Experimental Animal Center, the Affiliated Hospital of Medical College. Qingdao University from April 2006 to December 2006.Cervical heart transplantations were performed in which 45Wister rats were used as donors and45 SD rats as allograft recipients. The ratswere randomly divided into three groups with 15 for each. METHODS: Normal sodium, imDes. and imDCs treated with FK506 were injected via vena caudalis seven. days before the operations respectively. Mixed lymphocyte reaction (MLR) was meas ured on SD, Wistar, and Lewis rats. MAIN OUTCOME MEASURES: Heart allografi survival was monitored and one-way MLR, heart pathology and the levels of interleukin-2(IL-2),IL-4,IL-10,and interferon-Y(IFN-Y)in the serum were detected. RESULTS: In treatment group without FK506.heart allografl survival were prolonged after imDC injection(P＜0.01);while their survival were prolonged further in treatment group with FK506(P＜0.05).MLR showed that the tolerance was donor specific. Analysis of variance showed that tere was high significant difference for serum concentrations of IL-2,IFN-Y,IL-4,and IL-10 in the three groups(P＜0.01).The concentrations of IL-2 and IFN-Y expressing on Th1 were lower. and that of IL-4 and IL-10 expressing on Th2 were obviously higher in the latter two groups. CONCLUSION: ImDCs can induce immune tolerance in rat heterotopic heart transplantation successfully; ImDCs treated with FK506 can enhance the tolerance which is donor specific.ImDCs may induce the immnune tolerance bymeans of modifying the immune response type of T cells (immune deflection from Th1 to Th2), mediating the generation of regulatory T cells (T-reg)and inducing T cells disenabling.