Objective To investigate the expression changes of iron autophagy-mitochondrial ferric ion transport protein families(SFXNs)in acute kidney injury(AKI)and chronic kidney disease(CKD)mouse models induced by cisplatin(Cis)and ischemia reperfusion(IR).Methods C57BL/6 mice were randomly divided into control group(control),Cis-AKI group,Cis-CKD group,sham-operated group(sham),IR-AKI group,and IR-CKD group.Serum and kidney tissue samples were collected from mice.Serum creatinine(Cr)and blood urea nitrogen(BUN)levels were detected.Pathological changes in renal tissues were observed by HE staining.Western blot was used to detect the expression of renal SFXNs and kidney injury related proteins.Results Compared with the control or sham group,the levels of BUN and Cr in the serum of the model group were significantly increased(P＜0.05),the renal tissue showed significant pathological damage,with the kidney injury molecule-1(KIM-1),neutrophil gelatinase-associated lipocalin(NGAL),and pro-apoptotic protein Bax significantly upregulated(P＜0.05),while the anti-apoptotic protein Bcl-2 was significantly downregulated(P＜0.05).Compared to the control or sham group,the Cis-AKI group showed a significant downregulation of SFXN4(P＜0.05);The SFXN4 and SFXN5 subtypes were significantly downregulated in the IR-AKI group and Cis-CKD group(P＜0.05);All five subtypes of SFXN in the IR-CKD group were significantly downregulated(P＜0.05).Conclusions Cis or IR in-duces renal tissue damage and tubular mitochondrial injury in mice and affects the expression of SFXN family pro-teins,suggesting their potential role in renal injury of animal models.

Objective: To explore the mechanism of advanced glycation end products (AGEs) on diabetic endothelial cell damage based on monocyte⁃macrophage exosomes (Exos)/microRNA⁃92a ( miR⁃92a) . Methods: Twenty apolipoprotein E ⁃deficient (ApoE - / - ) mice were randomly divided into two groups : injury group (n = 10) and injury + STZ group ( n = 10 ) . The injury + STZ group established a diabetes model induced by streptozotocin (STZ) . All animals underwent partial left carotid artery (PLCA) ligation. The carotid arteries were collected , the number of M1 macrophages was detected by immunohistochemistry , and the level of AGEs was analyzed by ELISA.Microvascular endothelial cell line bEnd. 3 cells were treated with conditioned medium (CM) of AGEs treated RAW264. 7 cells or Exos derived from RAW264. 7 , followed by evaluations of the cell barrier function and mitochondrial function. Results : There was an increased number of M1 macrophages in carotid atherosclerotic tissues of diabetic mice and in AGEs treated RAW264. 7 cells. CM or Exos significantly induced barrier dysfunction , reactive oxygen species (ROS) accumulation and mitochondrial dysfunction in vascular endothelial cells in vitro. In addition , bioinformatics analysis showed that miR⁃92a was up⁃regulated in Exos derived from macrophages stimulated by AGEs. Experimentally , Exos participated in CM⁃induced barrier dysfunction , ROS accumulation and mitochondrial dysfunction in bEnd. 3 cells by transferring miR⁃92a. Finally , a series of rescue experiments further confirmed that Exos regulated the barrier dysfunction and mitochondrial function in vascular endothelial cells through miR⁃92a. Conclusion The expression of AGEs and the number of M1 macrophages in diabetic ApoE - / - mice increase , and AGEs stimulates Exos from macrophages could impair the barrier function and mitochondrial function in vascular endothelial cells by delivering miR⁃92a in vitro.

Hematopoietic Stem Cell Transplantation ; Granulocyte Colony-Stimulating Factor/therapeutic use* ; Immunoglobulins ; Granulocytes ; Hematopoietic Stem Cell Mobilization

Tumor has become the major reasons cause of death,and its vaccine has become the effective tracts of treatment and prevention by enhancing the immune response of patients.However,most vaccines which are recombination subunit protein antigens are poorly immunogenic and difficult to induce a robust immune response in patients with compromised immune systems,resulting in poor marketing approval.The core component of the vaccine adjuvant can greatly enhance the strength,speed and duration of the immune response,thus becoming the key to the development of an ideal tumor vaccine.Most tumor vaccines are combined with tradition adjuvant such as aluminum,MF59 and AS adjuvant,but their products and patents are monopolized by large foreign companies.We found that natural adjuvants have many unique advantages,such as good biocompatibility and biodegradability,promoting the maturation of dendritic cell and the secretion of immune cytokines,significantly enhancing the tumor vaccine immune response,etc.In this paper,the application and future development of natural polysaccharides,saponins,flavonoid and plant virus-like particles in cancer vaccines were reviewed,which may lay a solid foundation for the development of the original and innovative adjuvants with domestic independent intellectual property rights.

Objective:To develop a dose prediction-based quantitative evaluation method of the quality of radiotherapy plans, and to verify the clinical feasibility and clinical value of the method .Methods:The 3D U-Netwas trained using the radiotherapy plans of 45 rectal cancer cases that were formulated by physicists with more than five years of radiotherapy experience. After obtaining 3D dose distribution using 3D U-Net prediction, this study established the plan quality metrics of intensity modulated radiotherapy(IMRT) rectal cancer radiotherapy plans using dose-volume histogram(DVH) indexes of dose prediction. Then, the initial scores of rectal cancer radiotherapy plans were determined.Taking the predicted dose as the optimization goal, the radiotherapy plans were optimized and scored again. The clinical significance of this scoring method was verified by comparing the scores and dosimetric parameters of the 15 rectal cancer cases before and after optimization.Results:The radiotherapy plans before and after optimization all met the clinical dose requirements. The total scores were(77.21±9.74) before optimization, and (88.78±4.92) after optimization. Therefore, the optimized radiotherapy planswon increased scores with a statistically significant difference( t=-4.105, P<0.05). Compared to the plans before optimization, the optimized plans show decreased Dmax of all organs at risk to different extents. Moreover, the Dmax, V107%, and HI of PTV and the Dmax of the bladder decreased in the optimized plans, with statistically significant differences ( t=2.346-5.771, P<0.05). There was no statistically significant difference in other indexes before and after optimization ( P>0.05).The quality of the optimized plans were improved to a certain extent. Conclusions:This study proposed a dose prediction-based quantitative evaluation method of the quality of radiotherapy plans. It can be used for the effective personalized elevation of the quality of radiotherapy plans, which is beneficial to effectively compare and review the quality of clinical plans determined by different physicists and provide personalized dose indicators. Moreover, it can provide great guidance for the formulation of clinical therapy plans.

Objective:To develope a self-adjustable automatic planning method of intensity modulated radiotherapy based on predicted dose, in order to enhance the robustness of automatic planning.Methods:After the patients′ dose by 3D U-Res-Net_B network was predicted, the current dose was calculated based on the last iteration result, then the predicted dose was combined to calculate the target dose and optimized. With all iterations completed or exit conditions satisfied, final treatment plannings would be acquired. A total of 30 cases of rectal cancer were tested to verify the effectiveness of the algorithm.Results:The mean value of planning target volumes′ V100% was (95.03±0.91)% for clinical plans, close to (94.67±1.96)% for automatical plans( P>0.05), and better than (92.90±2.13)% for predicted dose with the statisically significant difference ( t=29.0, P<0.05). Automatic planning′s indexes such as V35 of small intestines, V40 of bladders and V20 - V40 of femoral heads were lower than predicted and clinical ones, with the statisically significant difference( t=4.5-118.0, P<0.05). Discrepancy in other indexes of organs at risk was not statistically significantly different( P>0.05). Conclusions:This method made automatic planning processes more robust and more adaptive to difficult clinical situations.

BACKGROUNDWhether cholinergic innervations and/or autophagy have a role in the etiopathology of benign prostatic hyperplasia (BPH) is still unknown. This study aimed to investigate the role of cholinergic innervation and autophagy in the etiopathology of BPH.

METHODSMale, 13-week-old spontaneous hypertension rats (spontaneous BPH animal model) were divided into three groups: an experimental group (EG, n = 24), a control group (CG, n = 24), and a normal control group (NC, n = 10). The EG animals were intragastrically injected with tolterodine (3.5 mg/kg, twice a day), CG animals were intragastrically injected with physiological saline, and the NC animals did not receive any treatment. Rats were sacrificed every 4 weeks, and the prostatic gross morphological changes, wet weight/body weight (ww/bw), dry weight/wet weight (dw/ww), histological changes, ultrastructural changes, and LC3 immunohistochemistry were continuously observed and compared.

RESULTSThe gross morphological and ww/bw changes in the three groups were similar at every stage. The dw/ww (mg/mg) values of the EG at week 17, 21, 25, and 29 were 0.1478 ± 0.0034, 0.1653 ± 0.0036, 0.1668 ± 0.0045, and 0.1755 ± 0.0034, respectively, and the CG values were 0.1511 ± 0.0029, 0.1734 ± 0.0020, 0.1837 ± 0.0052, and 0.1968 ± 0.0045, respectively. The difference between EG and CG for dw/ww showed statistical significance after 21 weeks of age (week 21: P= 0.016, week 25: P= 0.008, and week 29: P= 0.001). Both EG and CG, prostatic glandular epithelial cell proliferation, and secretory function improved with age, but in EG, these improvements were slower than those in CG, and all the differences were statistically significant after 21 weeks. An increasing number of autophagosomes in the prostatic glandular cell cytoplasm, attenuation of LC3-I immunohistochemical staining, enhancement of LC3-II staining, and the ratio of LC3-II/LC3-I staining were all progressive in both groups, but the rate of change in EG was faster than that in CG, and these differences gained statistical significance after 25 weeks. Comparisons with regard to the above indexes between CG and NC showed no statistical significance at any stage.

CONCLUSIONSCholinergic innervations and activation of autophagy appear to have important functions in the etiopathology of BPH. Drug-mediated blockade of cholinergic innervations could delay the physiopathology processes. Moreover, overactivation of autophagy may also play an important role in this delay.

Objective To investigate the significance of computed tomography(CT)and 3.0 T magnetic resonance imaging(MRI)in intensity-modulated radiotherapy(IMRT)for esophageal carcinoma. Methods Thirty-five patients newly diagnosed with esophageal carcinoma who received radical radiotherapy in our hospital from November 2013 to April 2015 were enrolled as subjects. Target volume was delineated on the CT images and MRI images(T2-weighted and diffusion-weighted fusion images). The MRI-and CT-based IMRT plans were designed using the same dose prescription and dose constraints for organs at risk(OAR). The target volume,prescribed dose,and doses for OAR were compared between the two plans. Results In the two plans, dose distribution and planning parameters met the clinical requirement. The length of lesion,gross tumor volume (GTV),and planning target volume(PTV)defined by 3.0 T MRI were significantly smaller than those defined by CT(P=0.00,0.03,0.03). There were no significant differences in the D 2%,D 98%,D 50%,homogeneity index,or conformity index for primary GTV(PGTV)and PTV-PGTV between the two plans(all P>0.05). Compared with the CT-based plan,the 3.0 T MRI-based plan had a significantly smaller mean dose to the lungs and an insignificantly smaller actual dose to the lungs(P=0.00;P>0.05).There were no significant differences in maximum doses tolerated by the spinal cord or heart between the two plans. Conclusions In terms of target volume delineation and dosimetric parameters, both CT-and 3.0 T MRI-based plans meet the clinical requirement. The 3.0 T MRI-based plan may provide potential benefits for some OAR due to a smaller target volume compared with the CT-based plan.

Objective: To study the dosage regimen of oral M-receptor blocker following transurethral resection of the prostate (TURP) for severe benign prostate hyperplasia (BPH) with predominant urine storage period symptoms (USPSs) and its clinical effect. METHODS: Severe BPH patients with predominant USPSs received oral tolterodine (2 mg q12d or 4 mg qd) 6 hours after TURP for 4 weeks. The medication continued for another 2 weeks in case of recurrence of USPSs or until the 12th week in case of repeated recurrence. Before and at 1, 4, 8 and 12 weeks after TURP, we analyzed the International Prostate Symptoms Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR) of the patients. RESULTS: Complete clinical data were collected from 106 cases, of which 33 achieved successful drug withdrawal with no aggravation of USPSs at 4 weeks after TURP, 51 at 6－8 weeks, 13 at 10－12 weeks, and 9 needed medication after 12 weeks. Before and at 1, 4, 8 and 12 weeks after TURP, the total IPSSs were 25.33 ± 3.45, 19.33 ± 3.62, 11.56 ± 2.45, 8.38 ± 2.0 and 7.74 ± 1.87, those in the urine storage period were 11.97 ± 1.53, 10.76 ± 1.82, 6.16 ± 1.22, 4.08 ± 1.19 and 3.91 ± 1.15, those at urine voiding were 9.80 ± 1.60, 5.59 ± 1.45, 3.40 ± 0.92, 2.85 ± 0.71, and 2.61 ± 0.67, and the QoL scores were 4.70 ± 0.78, 3.92 ± 0.75, 2.55 ± 0.74, 1.83 ± 0.72 and 1.66 ± 0.75, respectively, with statistically significant differences between the baseline and the scores at 1 and 4 weeks (P <0.01) but not at 8 or 12 weeks (P >0.05). Qmax and PVR were improved progressively and significantly at 1 and 4 weeks (P <0.01) but not at 8 or 12 weeks (P >0.05). CONCLUSIONS Four to eight weeks of oral administration of M-receptor blocker may be an effective dosage regimen for severe BPH with predominant USPSs after TURP.
Administration, Oral ; Clinical Protocols ; Drug Administration Schedule ; Humans ; Male ; Muscarinic Antagonists ; administration & dosage ; Postoperative Care ; Prostatic Hyperplasia ; drug therapy ; surgery ; Quality of Life ; Recurrence ; Tolterodine Tartrate ; administration & dosage ; Transurethral Resection of Prostate ; Treatment Outcome ; Urination ; Urological Agents ; administration & dosage

BACKGROUNDThe medium-to-long-term use of antimuscarinics alone or in combination with an α-blocker in men with an enlarged prostate is still controversial. This double-blind, placebo-controlled, randomized clinical trial aimed to investigate the efficacy and safety of medium-to-long-term use of tolterodine extended release (ER) with or without tamsulosin in patients with benign prostate hyperplasia (BPH) and larger prostate size.

METHODSTotally, 152 patients (age ≥50 years) with BPH, International Prostate Symptom Score (IPSS) ≥12, quality-of-life (QoL) score ≥3, and total prostate volume ≥25 ml were enrolled in this study. The patients were randomized into four groups (n = 38 in each) to receive tolterodine ER placebo plus tamsulosin placebo, 0.2 mg tamsulosin plus tolterodine ER placebo, 4 mg tolterodine ER plus tamsulosin placebo, or tolterodine ER plus tamsulosin once daily for 24 weeks. IPSS (total, storage, and voiding subscales), QoL, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR) were collected at baseline, and at weeks 4, 12, and 24.

RESULTSCompared with placebo, tolterodine ER plus tamsulosin significantly improved total IPSS (-7.15, -12.20, and -14.66 vs. -3.51, -5.78, and -7.23), storage IPSS (-3.56, -5.63, and -6.66 vs. -1.52, -1.21, and -2.43), voiding IPSS (-2.88, -5.10, and -6.48 vs. -1.52, -3.03, and -2.97), QoL (-1.21, -2.40, and -3.21 vs. -0.39, -1.41, and -1.60), Qmax (2.21, 7.97, and 9.72 ml/s vs. 2.15, 2.44, and 2.73 ml/s), and PVR (-17.88, -26.97, and -27.89 ml vs. -12.03, -11.16, and -16.73 ml) at weeks 4, 12, and 24, respectively; the differences were all statistically significant (P < 0.05). Adverse events (AEs) were not increased with treatment progression. Tolterodine ER alone did not improve total IPSS (-4.61, -6.79, and -5.70), voiding IPSS (-0.64, -1.83, and -1.45), QoL (-0.69, -1.21, and -1.41), or Qmax(-0.79, 2.83, and 1.11 ml/s), compared with placebo (all P > 0.05). However, a gradual increase in PVR (10.03, 10.41, and 12.89 ml) and more urinary AEs suggestive of urinary retention (11/38 vs. 4/38) were observed.

CONCLUSIONMedium-to-long-term use of tolterodine ER plus tamsulosin should be recommended in patients with BPH and an enlarged prostate volume.

TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR-TRC-09000596; http://www.chictr.org.cn/showproj.aspx?proj=8939.

Adrenergic alpha-Antagonists ; administration & dosage ; therapeutic use ; Aged ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Prostate ; drug effects ; pathology ; Prostatic Hyperplasia ; drug therapy ; Quality of Life ; Sulfonamides ; administration & dosage ; therapeutic use ; Tolterodine Tartrate ; administration & dosage ; therapeutic use ; Treatment Outcome