Clinical study of UMP and RIRS in 1.0-2.0 cm diameter renal/upper ureteral calculi.

BACKGROUND: The purpose of this study was to compare the efficacy and safety of Ultra-mini-percutaneous nephrolithotomy (UMP) and Retrograde intrarenal surgery (RIRS) for renal/upper ureteral calculi in 1.0-2.0 cm diameter. METHODS: From October 2017 to October 2022, the surgical treatment of patients with renal/upper ureteral calculi in 1.0-2.0 cm diameter who were admitted to our hospital was retrospectively analyzed. They were divided into two groups, the UMP group (sixty-two cases) and the RIRS group (one hundred and nine cases), according to the different surgical methods. Baseline data includes general information, stone size, location, CT value, hydronephrosis, creatinine level, etc. RESULTS: Intraoperative blood loss was 33.6 ± 8.5 ml in the UMP group was significantly more than 4.3 ± 0.7 ml in the RIRS group (P < 0.05). Intraoperative renal pelvis pressure of UMP group 10.5 ± 1.3 mmHg was significantly lower than RIRS group 23.6 ± 5.6 mmHg (P < 0.05). The incidence of postoperative infection was higher in the RIRS group (thirteen cases [11.93%]), and one case ([1.61%]) in the UMP group (P < 0.05). Routine CT scans on the second day and two months after surgery showed that the stone clearance rates in the UMP group were 87.1% and 93.5%, respectively, higher than those in the RIRS group (69.7% and 79.8%, respectively; P < 0.05). CONCLUSION: UMP has the advantage of a higher stone-free rate but a higher risk of injury and bleeding. The advantages of RIRS include less trauma, less bleeding, and faster recovery, but lower stone-free rates and a higher risk of infection.

From disinfectants to antibiotics: Enhanced biosafety of quaternary ammonium compounds by chemical modification.

The excessive use of quaternary ammonium compounds (QACs) following the COVID-19 pandemic has raised substantial concerns regarding their biosafety. Overuse of QACs has been associated with chronic biological adverse effects, including genotoxicity or carcinogenicity. In particular, inadvertent intravascular administration or oral ingestion of QACs can lead to fatal acute toxicity. To enhance the biosafety and antimicrobial efficacy of QACs, this study reports a new series of QACs, termed as PACs, with the alkyl chain of benzalkonium substituted by a phthalocyanine moiety. Firstly, the rigid phthalocyanine moiety enhances the selectivity of QACs to bacteria over human cells and reduces alkyl chain's entropic penalty of binding to bacterial membranes. Furthermore, phthalocyanine neutralizes hemolysis and cytotoxicity of QACs by binding with albumin in plasma. Our experimental results demonstrate that PACs inherit the optical properties of phthalocyanine and validate the broad-spectrum antibacterial activity of PACs in vitro. Moreover, the intravascular administration of the most potent PAC, PAC1a, significantly reduced bacterial burden and ameliorated inflammation level in a bacteria-induced septic mouse model. This study presents a new strategy to improve the antimicrobial efficacy and biosafety of QACs, thus expanding their range of applications to the treatment of systemic infections.

MicroRNA-4735-3p Facilitates Ferroptosis in Clear Cell Renal Cell Carcinoma by Targeting SLC40A1.

Objective: Clear cell renal cell carcinoma (ccRCC) is the major histopathological subtype of renal cancer, and ferroptosis is implicated in the pathogenesis of ccRCC. The present study was aimed at investigating the role and underlying mechanisms of microRNA-4735-3p (miR-4735-3p) in ccRCC. Methods: Human ccRCC cell lines were transfected with the miR-4735-3p mimic or inhibitor to manipulate the expression of miR-4735-3p. Cell proliferation, colony formation, cell migration, cell invasion, cell death, oxidative stress, lipid peroxidation, and iron metabolism were determined. To validate the necessity of solute carrier family 40 member 1 (SLC40A1), human ccRCC cell lines were overexpressed with SLC40A1 using adenoviral vectors. Results: miR-4735-3p expression was reduced in human ccRCC tissues and cell lines but elevated upon ferroptotic stimulation. The miR-4735-3p mimic increased, while the miR-4735-3p inhibitor decreased oxidative stress, lipid peroxidation, iron overload, and ferroptosis of human ccRCC cell lines. Mechanistic studies identified SLC40A1 as a direct target of miR-4735-3p, and SLC40A1 overexpression significantly attenuated iron overload and ferroptosis in the miR-4735-3p mimic-treated human ccRCC cell lines. Conclusion: miR-4735-3p facilitates ferroptosis and tumor suppression in ccRCC by targeting SLC40A1.

Structure-based molecular insights into matrix metalloproteinase inhibitors in cancer treatments.

Protease inhibitors are of considerable interest as anticancer agents. Matrix metalloproteinases (MMPs) were the earliest type of proteases considered as anticancer targets. The developments of MMP inhibitors (MMPIs) by pharmaceutical companies can be dated from the early 1980s. Thus far, none of the over 50 MMPIs entering clinical trials have been approved. This work summarizes the reported studies on the structure of MMPs and complexes with ligands and inhibitors, based on which, the authors analyzed the clinical failures of MMPIs in a structural biological manner. Furthermore, MMPs were systematically compared with urokinase, a protease-generating plasmin, which plays similar pathological roles in cancer development; the reasons for the clinical successes of urokinase inhibitors and the clinical failures of MMPIs are discussed.

Significance of expression of AIM2, IL-1ß, and IL-18 in plasma of patients with acute cerebral infarction. / æ€¥æ€§è„‘æ¢—æ­»æ‚£è€ è¡€æµ†ä¸­AIM2、IL-1ß和IL-18的表达及意义.

OBJECTIVES: Inflammation especially the overexpression of inflammasome and inflammatory cytokines, is one of the important reasons that affect the occurrence and development of acute cerebral infarction, including the initiation of cerebral infarction, the progress and recovery of post-infarction injury. This study aims to explore expressions of absent in melanoma 2 (AIM2), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) in plasma of patients with acute cerebral infarction and its significance. METHODS: A total of 85 patients with acute cerebral infarction were enrolled in the cerebral infarction group. They were assigned into mild, moderate, and severe groups according to the severity of neurological deficits. They were assigned into small, middle, and large cerebral infarction groups according to the area of cerebral infarction. They were assigned into a good prognosis group and a poor prognosis group according to the Modified Rankin Scale (mRS) score on the 90th day after the onset. A total of 85 healthy controls were selected as a control group. The levels of AIM2, IL-1ß, and IL-18 in plasma of the cerebral group and the control group were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The levels of plasma AIM2, IL-1ß, and IL-18 in the cerebral infarction group were significantly higher than those in the control group (all P<0.001). In the cerebral infarction group, the expression levels of plasma AIM2, IL-1ß, and IL-18 were as follows: The severe neurological deficitc group>the moderate group>the mild group, the large area of cerebral infarction group>the middle area group>the small area group, and the poor prognosis group> the good prognosis group (all P<0.05). The levels of plasma AIM2 were positively correlated with National Institute of Health Stroke Scale (NIHSS) score, the cerebral infarction area, and the mRS score (r=0.791, r=0.710, r=0.763, respectively, all P<0.001). The levels of plasma IL-1ß were positively correlated with the NIHSS score, the cerebral infarction area, and the mRS score (r=0.716, r=0.690, r=0.688, respectively, all P<0.001). The levels of plasma IL-18 were positively correlated with the NIHSS score, the cerebral infarction area, and the mRS score (r=0.714, r=0.638, r=0.653, respectively, all P<0.001). The level of plasma AIM2 was positively correlated with that of IL-1ß and IL-18 (r=0.828, r=0.751, both P<0.001). CONCLUSIONS: Expressions of AIM2, IL-1ß, and IL-18 are up-regulated in the plasma of patients with acute cerebral infarction, and they are closely related to the severity of neurological deficit, cerebral infarction area, and prognosis in patients with acute cerebral infarction, suggesting that AIM2, IL-1ß, and IL-18 may play an important role in the occurrence and development of acute cerebral infarction.

Using porphyrins as albumin-binding molecules to enhance antitumor efficacies and reduce systemic toxicities of antimicrobial peptides.

Antimicrobial peptides (AMPs) are originally developed for anti-infective treatments. Because of their membrane-lytic property, AMPs have been considered as candidates of antitumor agents for a long time. However, their antitumor applications are mainly hampered by fast renal clearance and high systemic toxicities. This study proposes a strategy aiming at addressing these two issues by conjugating AMPs with porphyrins, which bind to albumin increasing AMPs' resistance against renal clearance and thus enhancing their antitumor efficacies. Porphyrins' photodynamic properties can further augment AMPs' antitumor effects. In addition, circulating with albumin ameliorates AMPs' systemic toxicities, i.e. hemolysis and organ dysfunctions. As an example, we conjugated an AMP, K6L9, with pyropheophorbide-a (PPA) leading to a conjugate of PPA-K6L9. PPA-K6L9 bound to albumin with a KD value at the sub-micromolar range. Combining computational and experimental approaches, we characterized the molecular interaction of PPA-K6L9 with albumin. Furthermore, PPA-conjugation promoted K6L9' antitumor effects by prolonging its in vivo retention time, and reduced the hemolysis and hepatic injuries, which confirmed our design strategy.

Therapeutics targeting the fibrinolytic system.

The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.

Upregulation of GRIM-19 augments the sensitivity of prostate cancer cells to docetaxel by targeting Rad23b.

The gene associated with retinoid-interferon mortality (GRIM-19) has been reported to be correlated with drug resistance, whereas its functional role in prostate cancer (PC) is not fully understood. This study aims to clarify the potential role and molecular mechanisms of GRIM-19 on the response of PC cells to chemical drug docetaxel. mRNA and protein level of GRIM-19 expression in cells and tissues of PC were measured by quantitative real-time PCR and western blot, respectively. Knock-down of GRIM-19 in PC cells was performed using siRNA. Cell apoptosis was determined by flow cytometric analysis. DNA damage in PC cells was detected by γ-H2AX staining. GRIM-19 was downregulated in PC tissues and cell lines. Knock-down of GRIM-19 increased the resistance of PC cells to docetaxel, and overexpression of GRIM-19 promoted docetaxel-induced apoptotic death in PC cells. Mechanistically, GRIM-19 downregulated the expression of the survival gene Rad23b, which promoted DNA damage repair. Overexpression of Rad23b reversed GRIM-19-mediated response to docetaxel in PC cells. GRIM-19 promoted the sensitivity of PC cells to docetaxel by downregulating Rad23b, which may serve as a promising target to develop a better strategy of chemotherapy for PC.

Inhibition of miR-423-5p suppressed prostate cancer through targeting GRIM-19.

OBJECTIVE: To determine the effect of miR-423-5p on the progression of prostate cancer (PC). METHODS: miR-423-5p and GRIM-19 expressions were detected by qRT-PCR and western blot. PC cell proliferation was measured by MTT assay. PC cell apoptosis was detected by flow cytometry. Dual luciferase reporter assay was used to confirm the interaction between miR-423-5p and GRIM-19. RESULTS: Compared with normal prostate tissues and prostate epithelial cell HPrEC, miR-423-5p was up-regulated in human PC tissues and PC3 cells, whereas GRIM-19 expression was decreased. Inhibition of miR-423-5p suppressed PC3 cell proliferation, promoted PC3 cell apoptosis, and decreased anti-apoptosis protein BCL-2 expression. GRIM-19 was a target of miR-423-5p, and GRIM-19 was negatively regulated by miR-423-5p in PC3 cells. In addition, miR-423-5p knockdown inhibited the proliferation and promoted the apoptosis of PC3 cells through GRIM-19. In vivo experiments showed that miR-423-5p inhibitor administration reduced tumor volume, down-regulated miR-423-5p and GRIM-19 expressions in PC tissues of nude mice. CONCLUSION: Inhibition of miR-423-5p suppressed PC through targeting GRIM-19.

Crystal structure of human S100A8 in complex with zinc and calcium.

BACKGROUND: S100 proteins are a large family of calcium binding proteins present only in vertebrates. They function intra- and extracellularly both as regulators of homeostatic processes and as potent effectors during inflammation. Among these, S100A8 and S100A9 are two major constituents of neutrophils that can assemble into homodimers, heterodimers and higher oligomeric species, including fibrillary structures found in the ageing prostate. Each of these forms assumes specific functions and their formation is dependent on divalent cations, notably calcium and zinc. In particular, zinc appears as a major regulator of S100 protein function in a disease context. Despite this central role, no structural information on how zinc bind to S100A8/S100A9 and regulates their quaternary structure is yet available. RESULTS: Here we report two crystallographic structures of calcium and zinc-loaded human S100A8. S100A8 binds two zinc ions per homodimer, through two symmetrical, all-His tetracoordination sites, revealing a classical His-Zn binding mode for the protein. Furthermore, the presence of a (Zn)2-cacodylate complex in our second crystal form induces ligand swapping within the canonical His4 zinc binding motif, thereby creating two new Zn-sites, one of which involves residues from symmetry-related molecules. Finally, we describe the calcium-induced S100A8 tetramer and reveal how zinc stabilizes this tetramer by tightening the dimer-dimer interface. CONCLUSIONS: Our structures of Zn(2+)/Ca(2+)-bound hS100A8 demonstrate that S100A8 is a genuine His-Zn S100 protein. Furthermore, they show how zinc stabilizes S100A8 tetramerization and potentially mediates the formation of novel interdimer interactions. We propose that these zinc-mediated interactions may serve as a basis for the generation of larger oligomers in vivo.

[Effects of simvastatin on the proliferation and apoptosis of prostatic epithelial RWPE-1 cells].

OBJECTIVE: To investigate the effects of simvastatin on the proliferation and apoptosis of prostatic epithelial RWPE-1 cells. METHODS: RWPE-1 cells cultured in vitro were treated with simvastatin at 0, 10, 20, and 40 µmol/L for 24, 48, and 72 hours followed by determination of their proliferation by MTT assay, and their apoptosis by flow cytometry. The mRNA and protein expressions of Bcl-2, Bax, and Cx43 were detected by fluorescence quantitative RT-PCR and Western blot, respectively. RESULTS: After 72 hours of treatment with simvastatin at 10, 20, and 40 µmol/L, the inhibition rates of the RWPE-1 cells were (21.07 ± 6.41)%, (34.87 ± 9.65)%, and (47.18 ± 10.88)%, respectively, significantly higher than (1.21 ± 0.54)% in the control group (P < 0.05) and in a dose-dependent manner (P < 0.05); the cell apoptosis rates were (0.066 ± 0.016)%, (0.126 ± 0.023)%, and (0.192 ± 0.025)%, respectively, remarkably higher than (0.015 ± 0.005)% in the control (P < 0.05) and also in a dose-dependent manner (P < 0.05); the mRNA and protein expressions of Bcl-2 were decreasing while those of Bax and Cx43 increasing with the increased concentration of simvastatin (P < 0.05). The expression of Cx43 was correlated negatively with that of Bcl-2 but positively with that of Bax. CONCLUSION: Simvastatin inhibits the proliferation of prostate epithelial cells and induce their apoptosis by acting on the gap junctional intercellular communication.

[Oral medication of statins retards the progression of benign prostatic hyperplasia and lower urinary tract symptoms].

OBJECTIVE: To determine whether oral statins can delay the progression of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). METHODS: We conducted a retrospective cohort study of 50-69-year-old males who came for physical examination in our hospital between January 2003 and December 2008. We designed the inclusion criteria, followed them up for 5 years, and investigated the relationship of oral statins with the clinical progression of BPH and LUTS. RESULTS: Totally, 653 men met the inclusion criteria and were included in this study, of whom 283 were treated with oral statins (group 1) while the other 370 with none (group 2). There were no statistically significant differences between the two groups in age and baseline IPSS, Qmax, and prostate volume (PV) (P > 0.05). During the follow-up, 24 cases in group 1 and 35 cases in group 2 were excluded for obvious dys-uria. A gradual increase was observed in IPSS in both groups 1 and 2 year by year from the baseline to the 5th year of follow-up, but significantly lower in the former group (4.27 +/- 1.16, 4.63 +/- 1.05, 5.27 +/- 0.96, 6.41 +/- 1.04, 7.21 +/- 1.21, and 7.93 +/-1.50) than in the latter (4.24 +/- 1.35, 5.26 +/- 1.23, 6.84 +/- 1.20, 8.75 +/- 1.84, 10.82 +/- 3.01, and 12.98 +/- 4.21) (P < 0.01); a gradual decrease was seen in Qmax, though markedly higher in group 1 ([26.56 +/- 2.09], [24.06 +/- 1.94], [21.33 +/- 1.66], [19.24 +/- 1.54], [17.44 +/- 1.53], and [16.27 +/- 1.37] ml/s) than in group 2 ([26.74 +/- 2.40], [23.62 +/- 2.01], [20.63 +/- 1.69], [17.72 +/- 1.48], [14.82 +/- 1.11], and [11.86 +/- 1.24] ml/s) (P < 0.01); and a gradual increase was found in PV, but remarkably smaller in the former group ([19.82 +/- 4.94], [22.60 +/- 4.99], [25.80 +/- 5.20], [27.92 +/- 5.05], [29.11 +/- 5.24], and [29.97 +/- 5.26] ml) than in the latter ([20.21 +/- 4.78], [24.30 +/- 4.98], [28.50 +/- 5.14], [32.84 +/- 4.77], [36.99 +/- 4.78], and [40.90 +/- 4.78] ml) (P < 0.01). Longer medication of statins was associated with better efficacy. CONCLUSION: Oral statins can significantly delay the clinical progression of BPH and LUTS.

ImmunoCyt™ and cytology for diagnosis of bladder carcinoma: a meta analysis.

BACKGROUND: Currently, cystoscopy and urine cytology are standard modalities in therapy monitoring and follow-up of bladder carcinoma (BC). Cystoscopy is an invasive and uncomfortable procedure while cytology has a limited value because it is operator-dependent and has low sensitivity. This study was to assess the accuracy of ImmunoCyt in detecting BC by comparing it with cytology using systemic analyses of studies published in both English and Chinese. METHODS: Cochrane systematic evaluation was used to search through MEDLINE, EMBASE, Cochrane Library, CMCC, and CNKI for studies regarding ImmunoCyt and cytology for detection of BC. Data were extracted and analyzed by the software MetaDiSc 1.4. RESULTS: In total 42 relevant studies were searched, of which 15 were enrolled and 12 491 patients were included. Heterogeneity, except for threshold effects, was found within these studies. A meta-analysis was performed using the random effect model. Pooled accuracy indicators like sensitivity, specificity, and diagnostic odds ratio of ImmunoCyt™ and cytology were 0.75 (0.73-0.77) vs. 0.45 (0.43-0.48), 0.73 (0.72-0.74) vs. 0.97 (0.96-0.97), and 10.97 (7.53-15.99) vs. 16.40 (10.57-25.46), respectively. The sensitivity of both was increased with the increase of tumor grade and stage. The area under summary receiver operating characteristics curve was 0.834 4 and 0.853 4 and the Q index 0.766 7 and 0.785 3 for ImmunoCyt and cytology, respectively. Combination of both can obviously improve the accuracy of diagnosis. CONCLUSIONS: ImmunoCyt has a high sensitivity in detecting BC, but its specificity is low. As an important adjunct, ImmunoCyt™ can not replace cytology, but combined with cytology it could improve sensitivity with high specificity in the detection and postoperative monitoring of BC.

[Prophylatic antibiotic use in percutaneous nephrolithotomy: a meta-analysis].

OBJECTIVE: To determine whether antibiotic prophylaxis can reduce the risk of postoperative infective complications in patients undergoing percutaneous nephrolithotomy (PCNL) who have sterile preoperative urine. METHODS: MEDLINE, EMBASE, Cochrane Collaboration Reviews, CMCC and CNKI were searched for RCTs comparing antibiotic prophylaxis with placebo (or blank controls) for patients undergoing PCNL with preoperative sterile urine. The search strategy was made according to the Collaborative Review Group search strategy. Data were extracted by 2 reviewers using the designed extraction form. The software RevMan 4.2 was used to review management and data analysis. RESULTS: A total of 9 trails, 1 placebo controlled, 3 non treatment controlled, and 5 active controlled, involving 1018 patients, met the inclusion criteria. Prophylactic antibiotic use in patients at low risk undergoing PCNL significantly decreased fever (RR = 0.71, 95% CI: 0.54-0.92, P = 0.009), bacteriuria (RR = 0.39, 95%CI: 0.23-0.67, P = 0.0006) and bacteremia incidence (RR = 0.43, 95%CI: 0.25-0.73, P = 0.002). Effective antibiotic classes included quinolone which significantly decreased bacteriuria incidence (RR = 0.31, 95%CI: 0.12-0.82, P = 0.010) and nitrofurantoin which significantly decreased fever incidence (RR = 0.38, 95%CI: 0.24-0.61, P = 0.005). Extended course significantly decreased fever incidence (RR = 0.64, 95%CI: 0.47-0.87, P = 0.004) and bacteriuria incidence (RR = 0.35, 95%CI: 0.18-0.71, P = 0.003). CONCLUSIONS: Prophylactic antibiotics can significantly decrease the incidence of postoperative infective complications. A significant decrease in bacteriuria incidence can be achieved with quinolones. Extended course is effective in decreasing fever, and bacteriuria incidence.