ABSTRACT
The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.
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Objective:To investigate the disease spectrum referred from the community health service centers to the district tertiary hospital in the region.Method:The data of the referred patients from the community health service centers to Shanghai Yangpu District Hospital-a tertiary hospital in the region from January 2016 to December 2019 were collected. The composition and characteristics of the disease spectrum of the referred patients were analyzed.Results:The number of patient visits to the community health service centers in the region was increased from 4 684 938 in 2016 to 4 776 921 in 2019. The number of patient referral from the community centers to Yangpu Hospital was increased from 3 125 in 2016 to 6 853 in 2019. There were total 18 308 patients referred in 4 years, including 8 012 males (43.8%) and 10 296 females (56.2%). The age range of referred patients was from 1 to 99 years, including 53 referred patients aged ≤ 18 (0.3%), 927 aged 19-39 (5.1%), 2 831 aged 40-59 (15.5%), 4 424 aged 60-79 (62.2%) and 1 209 aged ≥ 80 (17%). The top five systems of diseases, which accounted more than 60% of total diseases, were circulatory system, endocrine nutrition and metabolic system, urogenital system, eye and appendage, and digestive system. Compared with male patients, more female patients with urogenital diseases were referred.Conclusion:The referral rate of community health service centers were increased from 2016 to 2019. The referred patients cover all age groups, more frequently in age group 60-79. The diseases of referred patients cover all system, and are different between males and females.
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Objective To observe the effect of adenosine A1 receptor (A1AR) on the megalin defect in type 1 diabetic mice with early kidney disease.Methods 7-8 week-old,baseline body weight and fasting blood glucose matched wild type (WT) C57BL/6J mice were selected,and randomly divided into two groups:control group (n=6) and WT DM group (n=6).In the same way,male A1AR knock-out C57BL/6J mice were selected as A1AR-/-DM group (n=6).DM model was established by intraperitoneal injection of streptozocin.The blood glucose (BG),body weight (BW),kidney weight (KW),24 h proteinuria (24hUP) and albumin creatine ratio (ACR) were measured at 4 weeks.The renal pathological lesion was observed and the expression of megalin in proximal tubules was examined by immunohistochemistry.The expression of caspase-1,IL-18 and A1AR were detected by Western blotting.Results At 4th week,compared with WT control mice,the BG,BW,KW and 24hUP of WT DM mice were increased significantly (n=6,P ＜ 0.01),with the pathological glomerular enlargement,mesangial cell proliferation,extracellular matrix accumulation and renal tubule hypertrophy being observed.Immunohistochemistry revealed decreased expression of megalin,an important multiligand protein receptor on the brush border of proximal tubular epithelial cells in WT DM mice,which was correlated with 24hUP (r=-0.645,P ＜ 0.01).Compared with the control mice,the expressions of caspase-1,IL-18 and A1AR were significantly increased in WT DM mice (P ＜ 0.05).For A1AR-/-DM mice,more serious pathological lesion and megalin defect,together with increasing of casapase-1 and heavier proteinuria were observed than those in WT DM mice.Conclusion A1AR may play a protective role in megalin expression of diabetic mice with early kidney disease,in which the mechanism may be associated with caspase-1 related pyroptosis pathway.The details need further exploration.
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Objective To analyze the clinic-pathological data and peritubular capillary (PTC) injuries of malignant nephrosclerosis (MN) patients and their correlations with the long term renal survival.Methods This was a retrospective cohort study of 52 MN patients in Peking Union Medical College Hospital from January 2003 to March 2012.Their clinical data and renal biopsy samples were carefully studied.CD34 staining was performed to evaluate the PTC area,using Benign nephrosclerosis (BN,n=17) patients and glomerular minimal lesions (GML,n=19) patients as controls.Multivariate Cox proportional hazard model was used to identify the potential independent risk factors for long term renal survival.Results Fifty-two MN patients were enrolled.The sex ratio of male to female was 12:1 and the average age was (34.0±8.2) years.The maximum blood pressure (SBP/DBP) was (230.4 ± 25.0)/(156.4 ± 20.6) mmHg,companied with significant loss of eGFR and proteinuria.Glomerular sclerosis index,tubular atrophy and interstitial fibrosis correlated with eGFR and proteinuria (P ＜ 0.05).After aggressive treatment,BP control rate improved significantly (76.9％ vs 3.7％,P ＜0.01),Scr [(376.4±263.8) μmol/L vs (486.8±375.7) μmol/L,Wilcoxon test,P＜ 0.01] and proteinuria [(1.10±0.70) g/24 h vs (2.04± 1.26) g/24 h,P ＜ 0.01,n=21] also improved.PTC area in MN patients was significantly lower than those in BN patients and GML patients,and it correlated well with Scr (r=-0.553,P=0.001) and eGFR (r=0.476,P=0.004).The median follow-up time was 74 months,the cumulative renal survival rate at 1 year,5 year and 10 year was 90％,64％ and 23％,respectively.Kaplan-Meier analysis showed that the patients with higher PTC area had longer renal survival time [(114.8± 12.4) months vs (63.0±8.3) months, x2=5.312,P ＜ 0.05].Univariate Cox proportional hazard model found that unsatisfied BP control,eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge,lower PTC area,severer tubular-interstitial damage and anemia were associated with poor renal outcome.Multivariate Cox model showed that unsatisfied BP control (RR=3.89,95％ CI 1.75-8.65,P=0.001),eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge (RR=4.27,95％ CI 1.40-13.09,P=0.011) were independent risk factors for long-term renal survival.Conclusions The correlation between PTC area and renal functions in MN patients are much better than that of classic vascular changes.Unsatisfied BP control and eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge are independent risk factors for long-term renal survival.
ABSTRACT
Objective To analyze the clinic-pathological data and peritubular capillary (PTC) injuries of malignant nephrosclerosis (MN) patients and their correlations with the long term renal survival.Methods This was a retrospective cohort study of 52 MN patients in Peking Union Medical College Hospital from January 2003 to March 2012.Their clinical data and renal biopsy samples were carefully studied.CD34 staining was performed to evaluate the PTC area,using Benign nephrosclerosis (BN,n=17) patients and glomerular minimal lesions (GML,n=19) patients as controls.Multivariate Cox proportional hazard model was used to identify the potential independent risk factors for long term renal survival.Results Fifty-two MN patients were enrolled.The sex ratio of male to female was 12:1 and the average age was (34.0±8.2) years.The maximum blood pressure (SBP/DBP) was (230.4 ± 25.0)/(156.4 ± 20.6) mmHg,companied with significant loss of eGFR and proteinuria.Glomerular sclerosis index,tubular atrophy and interstitial fibrosis correlated with eGFR and proteinuria (P ＜ 0.05).After aggressive treatment,BP control rate improved significantly (76.9％ vs 3.7％,P ＜0.01),Scr [(376.4±263.8) μmol/L vs (486.8±375.7) μmol/L,Wilcoxon test,P＜ 0.01] and proteinuria [(1.10±0.70) g/24 h vs (2.04± 1.26) g/24 h,P ＜ 0.01,n=21] also improved.PTC area in MN patients was significantly lower than those in BN patients and GML patients,and it correlated well with Scr (r=-0.553,P=0.001) and eGFR (r=0.476,P=0.004).The median follow-up time was 74 months,the cumulative renal survival rate at 1 year,5 year and 10 year was 90％,64％ and 23％,respectively.Kaplan-Meier analysis showed that the patients with higher PTC area had longer renal survival time [(114.8± 12.4) months vs (63.0±8.3) months, x2=5.312,P ＜ 0.05].Univariate Cox proportional hazard model found that unsatisfied BP control,eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge,lower PTC area,severer tubular-interstitial damage and anemia were associated with poor renal outcome.Multivariate Cox model showed that unsatisfied BP control (RR=3.89,95％ CI 1.75-8.65,P=0.001),eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge (RR=4.27,95％ CI 1.40-13.09,P=0.011) were independent risk factors for long-term renal survival.Conclusions The correlation between PTC area and renal functions in MN patients are much better than that of classic vascular changes.Unsatisfied BP control and eGFR ＜ 30 ml · min-1 · (1.73 m2)-1 upon discharge are independent risk factors for long-term renal survival.