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Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.
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Objective To analyze the influencing factors of affected renal function after laparoscopic nephron-sparing nephrectomy with segmental renal artery blocking (SRPN) for low R.E.N.A.L.score small localized renal tumor with follow-up data.Methods The data of 33 patients was collected,who underwent SRPN for small renal tumor from January 2010 to April 2012,and were followed-up for 5 years successfully.In 33 integrated data of 5-year follow-up,there were 14 males and 19 females,aged(56.5 ± 11.8)years.The preoperative affected renal glomerular filtration rate (aGFRpre),postoperative affected renal glomerular filtration rate (aGFRpost),the residual ratio of aGFR (aGFRpost/aGFRpre),preoperative affected renal volume (aVolpre),postoperative affected renal volume (aVolpost) and the residual ratio of aVol (aVolpost/aVolpre) were collected at the postoperative 3rd,6th,12th,24th and 60th month in follow-up period.Preoperative and postoperative data were analyzed by paired-sample T test.Multivariate linear regression analysis determined the influence of body mass index,operation time,localized warm ischemia time and distance from tumor to renal collecting system.Compare the correlation between aGFRpost/aGFRpre and aVolpost/aVolpre.Results All 33 cases were performed successfully.The mean operation time was (108.4 ± 9.1) min,and the mean time of segmental renal artery blocking was (23.3 ± 3.0) min.Postoperative pathologic 17 (51.5％) of clear cell carcinoma,5 (15.2％) of papillary carcinoma,3 (9.1％) of chromophobe cell carcinoma.All of above margins were negative.8 (24.2％) of angiomyolipoma (9.1％).All 33 cases were followed up for more than 5 years.The 5-year overoll survival (OS) and cancer specific survival (CSS) were 100％.In the 3rd,6th,12th,24th and 60th month,aGFRpost were (34.6 ± 4.6) ml/min,(34.7 ± 4.8) ml/min,(34.9 ± 4.4) ml/min,(35.1 ± 4.4) ml/min,(35.2 ± 4.2) ml/min,decreased of (10.4 ± 2.4) ml/min,(10.4 ± 2.6) ml/min,(10.1 ± 2.4) ml/min,(9.9 ± 2.4) ml/min,(9.8 ± 2.5) ml/min compared with aGFRpre (P ＜ 0.05).Multivariate linear regression analysis showed that body mass index,operation time,localized warm ischemia time in SRPN and distance from tumor to renal collecting system were unable to influence aGFRpost (P ＞ 0.05).The correlation coefficients between aGFRpost/aGFRpre and aVolpost/aVolpre were 0.659,0.667,0.663,0.629,0.604 respectively,and the difference was statistically significant (P ＜ 0.05).Conclusions For low R.E.N.A.L.score small localized renal tumor with SRPN,the decrease of postoperative affected renal function is relevant to postoperative affected renal volume,not as to operation time,localized warm ischemia time in SRPN and distance from tumor to renal collecting system.
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Objective To investigate the Laparoscopic management for Nutcraker Syndrome(NCS) with resection of fibrous ring and placing extravascular stent.Methods This was a retrospective analysis of clinical data and treatment process of cases from March 2010 to February 2015 in urology department,affiliated hospital of Guizhou medical university.Five cases with NCS,4 males and 1 female;age were 28-40 years,mean age was 35 years,all cases were afflicted with gross hematuria and flank pain,the history of gross hematuria were 6-72 months.3 cases were afflicted with proteinuria.Duplex ultrasound scanning before surgery revealed the compressed left renal vein (LRV) between the aorta and the superior mesenteric artery(SMA),with peak velocity 110-132 cm/s,an average of 121 cm/s.The flow velocity of LRV in the renal hilum were 18-25 cm/s,an average of 21 cm/s.CT scanning showed that the stricture segment diameter of LRV were 1.2-2.5 mm,an average of 1.8 mm;and the max diameter of proximal dilatation of the LRV in renal hilum were 8.3-15.2 mm,an average of 10.1 mm.The ratio between the dilated segment inner diameter and the stricture segment were 3.4-9.5.Bleeding from the left ureteral orifice was detected by cystoscopy in 3 cases.5 cases were treated by resection of fibrous ring and placing extravascular stent with Laparoscopic management,and the average length of extravascular stent was 4.0 cm.Results The operation was successful in the 5 cases.The average operation time was 83 min.The average blood loss was 65 ml.Hematuria gradually reduce 5-6 days and resolved 7-20 days after surgery in 5 patients.Proteinuria was disappeared successful 2 weeks after surgery in 3 patients.There was no recurrence at 8-24 months' follow-up.3 days after surgery Doppler ultrasound showed the stricture segment diameter of LRV were 3.8-5.6 mm,an average of 4.9 mm;the ratio between the dilated segment inner diameter and the stricture segment decreased were 1.1-2.0,an average of 1.6;the peak velocity of compressed LRV were 25-45 cm/s,an average of 34 cm/s.6 months after surgery,CTA result showed no LRV compression in the aortomesenteric region;the max diameter of LRV in renal hilum were 7.9-9.8 mm and 6.0-8.8 mm in the aortomesenteric region of LRV.Conclusion Etiology of NCS exist a fibrous ring around the left renal vein outflow of the inferior vena cava besides the commonly anatomic extrinsic compression on the LRV as it crosses between the superior mesenteric artery and the aorta.The Laparoscopic management for NCS with resection of fibrous ring and placing extravascular stent is an effective minimally invasive treatment.
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Objective:To evaluate the meaning and value of high-frequency ultrasound in the diagnosis of carpal tunnel syndrome (CTS).Methods:In this study,48 patients (unilateral hand)with CTS were analyzed.The thickness of transverse carpal ligaments at the pisiform bone was measured using high-fre-quency ultrasound.Open carpal tunnel release procedure was performed in the 48 CTS patients,and the thickness of transverse carpal ligaments at the hamate hook bone measured using vernier caliper under di-rect vision.The accuracy of thickness of transverse carpal ligaments was evaluated using high-frequency ultrasound.High-frequency ultrasound measurement of thickness of transverse carpal ligaments at the ha-mate hook bone and pisiform bone,and determination of the diagnostic threshold measurement index using receiver operating characteristic (ROC)curve,sensitivity and specificity were performed and the correlation between the thickness of transverse carpal ligaments and nerve conduction study (NCS)ana-lyzed.Results:The thickness of transverse carpal ligaments in the CTS patients were (0.42 ±0.08)cm (high-frequency ultrasound)and (0.41 ±0.06)cm (operation)at hamate hook bone,and there was no significant difference between the two ways (t =0.672,P>0.05 ).The optimal cut-off value of the transverse carpal ligaments at hamate hook bone was 0.385 cm,the sensitivity 0.775,and the specificity 0.788.The optimal cut-off value of the transverse carpal ligaments at the pisiform bone was 0.315 cm, the sensitivity 0.950,and the specificity 1 .000.The transverse carpal ligaments thickness and wrist-in- dex finger sensory nerve conduction velocity (SCV),wrist-middle finger SCV showed a negative correla-tion.Conclusion:High frequency ultrasound measurements of thickness of transverse carpal ligaments is a valuable method for the diagnosis of CTS.
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Objective To comparatively investigate the characteristics of bone metabolism in forelimb malformation WHBE rabbits based on the OPG/RANK/RANKL system.Methods Healthy male 2-2.5-month old WHBE rabbit ( HWR) , Healthy Japanese rabbit ( HJR) and forelimb malformation WHBE rabbit ( FMWR) were used in this study and divided into 3 groups, HWR, HJR and FMWR groups, with 10 rabbits in each group.The shape of forelimb and mean gray value observed from X-ray film were examined, and the bone tissue micro-morphology was analyzed using HE staining.Re-al-time fluorescence quantitative PCR was used to determine the expression of osteoprotegerin ( OPG) and receptor activator of NF-KB ligand ( RANKL) mRNA.The expressions of OPG, receptor activator of NF-KB ( RANK) and RANKL protein in serum and bone tissue were assayed by enzyme-linked immunoassay ( ELISA) and immunohistochemistry, respectively. Results Compared with the HWR and HJR groups, rabbits in the FMWR group appeared abnormal in toutuous forelimb and thinner bone cortex.The mean gray values of X-ray in the FMWR group were lower than that in the HWR group ( P<0.05).There were significant differences between the FMWR and healthy rabbits (HWR and HJR) in the following pa-rameters:RANKL mRNA expression and RANKL/OPG mRNA ratio in the liver(P<0.05, P<0.01), serum protein expression of RANK and RANKL and RANKL/OPG ratio (P<0.05, P<0.01), and positive index of expression of RANKL protein and RANKL/OPG ratio in the bone tissue(P<0.05, P<0.01).Furthermore, the gene expression lev-els of OPG and RANKL of HWR were significantly higher than that of HJR(P<0.05, P<0.01).Conclusions The FMWR show some abnormal symptoms in bone metabolism as well as decrease of bone quality and histological changes of bone micro-structure, due to the significant increase of RANKL/OPG ratio of FMWR.The breed differences between WHBE and Japanese rabbits in RANKL mRNA expression level may be one of factors inducing limb malformation in the WHBE rabbits.
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Objective To evaluate the efficacy of combination therapy with M and α receptors antagonist for the treatment of double-J stent related lower urinary tract symptoms.Methods From May 2013 to May 2014,131 cases,including 71 male and 60 female cases,were accepted the doubte-J stent indwelling after the ureteral lithotripsy,laparoscopic ureterlithotomy and pyeloureteroplasty.Their data was retrospectively reviewed.The age ranged from 29 to 64 years old,mean (47.4 ± 15.2) years old.They were divided into 4 groups randomly,including group A (control group,n =30),no drugs were taken;group B (tamsulosin group,n =34),0.2 mg tamsulosin was taken qd;group C (solifenacin group,n =32),5 mg solifenacin was taken qd;group D (tamsulosin combined with solifenacin group,n =35),0.2 mg tamsulosin and 5mg solifenacin were taken qd.The IPSS scores,QOL scores and visual analogue pain scale (VAPS) scores were assessed pre-operation,1 week after operation,and 4 weeks after operation,respectively.Results All patients were followed-up until the end of this study.In each time point,the IPSS scores in group A was 9.01 ± 2.79,13.18 ± 3.79 and 13.79 ± 3.76,respectively.In group B,the IPSS scores were 7.89 ± 4.29,12.39 ±3.90 and 12.21 ±3.87,respectively.In group C,the IPSS scores were 7.94 ±4.27,12.70 ±4.01 and 11.98 ±4.69,respectively.In group D,the IPSS scores were 8.21 ±3.18,11.97 ±5.03 and 8.17 ± 3.25,respectively.Significant difference in total IPSS scores and obstruction symptom scores were shown between pre-and post-operation (P ＜ 0.05).Comparing to other groups,group D exhibited the significant improvement in IPSS scores 1 and 4 weeks after the operation (P ＜0.05).4 weeks after operation,the QOL scores in group D was significantly lower than that in other groups (P ＜ 0.05).While the VAPS scores didn t show significant differences among those groups (P ＞ 0.05).Conclusion M and α receptors antagonist combination therapy can significantly improve lower urinary tract symptom due to indwelling double J stents.
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OBJECTIVE: To observe the effects of recipes for replenishing qi and activating blood on p16, p21, proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E gene expressions in the liver of aging rats. METHODS: A recipe for replenishing qi and a recipe for activating blood were administered to aging rats respectively, and the effects of the above recipes on the expressions of senescence related genes (p16, p21, PCNA, cyclin D1 and cyclin E) were examined by RT-PCR and Western blotting methods. RESULTS: The expressions of p16, p21 and cyclin D1 mRNAs and proteins in the liver of the untreated aging rats were up-regulated, while the expressions of PCNA and cyclin E mRNAs and proteins decreased. As compared with the untreated aging rats, both recipes could down-regulate the expressions of cyclin D1 mRNA and protein and up-regulate the expressions of cyclin E mRNA and protein, but had no obvious effects on the expressions of mRNAs and proteins of p16, p21 and PCNA. CONCLUSION: Recipes for replenishing qi and activating blood can improve the liver cell proliferation of aging rats via down-regulating the expressions of cyclin D1 mRNA and protein and up-regulating the expressions of cyclin E mRNA and protein.
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The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6-24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 μmol/L- 40 μmol/L NVC and NGC for 6 - 24 h, the growth inhibitory effects on EJ cells were 6.71% -65.13 % (P＜0.05), 10.96 % -73.01% (P ＜0.05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P＜0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumortargeted chemotherapeutic drugs.
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The curcumin prodrugs, which could be selectively activated in tumor cells, were prepared to establish a basis for the targeted chemotherapy for cancer. On the basis of the molecular structure of curcumin, the N-maleoyl-L-valine-curcumin (NVC), N-maleoyl- glycine-curcumin (NGC) were chemically synthesized and identified by IR and NMR spectroscopy. After treatment with these two prodrugs for 6 - 24 h, the rates of growth inhibition on human bladder cancer EJ cells and renal tubular epithelial (HKC) cells were detected by MTT colorimetry. Our results showed that after the treatment with 20 micromol/L - 40 micromol/L NVC and NGC for 6 - 24 h, the growth inhibitory effects on EJ cells were 6.71% - 65.13% (P < 0.05), 10.96% - 73.01% (P < 0.05), respectively, in both dose- and time-dependent manners. When compared with the curcumin of same concentrations, the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased (P < 0.01). It is concluded that activation of curcumin prodrugs via hydrolysis functions of cellular esterase could inhibit the growth activities of tumor cells, and reduce the side effects on normal diploid cells. This provided a novel strategy for further exploration of tumor-targeted chemotherapeutic drugs.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Curcumin/pharmacology , Dose-Response Relationship, Drug , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Tumor Cells, Cultured , Urinary Bladder Neoplasms/pathologyABSTRACT
To clone Uroplakin Ⅱ gene from Chinese transitional cell carcinoma (TCC) of bladder and construct its eukaryotic expression vector, the molecular cloning method was used to extract total RNA from a GⅢ/ T3N0M0 tissue sample of the bladder TCC patients. The primers were designed by Primer 5.0 software. Full length cDNA of Uroplakin Ⅱ gene was amplified by reverse transcription polymerase chain reaction (RT-PCR), assayed by nucleic acid sequencing and then inserted between Xba Ⅰ and HindⅢ restrictive sites of eukaryotic expression vector pcDNA3.0. The recombinant was assayed by restricted enzyme digestion. Under the induction of Lipofectamine 2000, the recombinant was transfected into Uroplakin Ⅱ negative bladder cancer cell line EJ. Cellular expression levels of Uroplakin Ⅱ were detected by RT-PCR. The nucleic acid sequencing results indicated that Chinese Uroplakin Ⅱ cDNA (555 bp) was successfully cloned. The BLAST analysis demonstrated that the cloned sequence is 100 % homologous with sequences reported overseas. The GenBank accession number AY455312 was also registered. The results of restricted enzyme digestion indicated that eukaryotic vector pcDNA-UP Ⅱ for Uroplakin Ⅱ was successfully constructed.After being transferred with pcDNA-UPⅡ for 72 h, cellular Uroplakin Ⅱ mRNA levels were significantly improved (P＜0.01). It is concluded that human Uroplakin Ⅱ gene was successfully cloned from Chinese TCC tissues, which provided a basis for further exploration of the roles of Uroplakin Ⅱ gene in TCC biological behaviors and potential strategies for targeted biological therapy of TCC.
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Objective To investigate the association between variable number of tandem repeat(VNTR) polymorphism of endothelial nitric oxide synthase(eNOS) gene and cerebral infarction(CI).Methods The genotypes of 152 patients with CI were detected by polymerase chain reaction(PCR) and compared with control group. Multiple regression analysis was performed to assess the independent roles of the polymorphism of eNOS and other risk factors.Results The ab genotype distribution frequency of eNOS gene in CI group(22.36%) was higher than that in control group(12.28%), and a allele frequency of eNOS gene in CI group(12.5%) was also higher than that in control group(7.0%). Both differences between CI group and control group were significant(all P