Study on Clinical Application of Different Ultrasound-Guided Planar Techniques in Minimally Invasive Percutaneous Nephrolithotomy.

Objective. The objective is to explore the clinical application value of ultrasound long- and short-axis planar technology in real-time guided puncture in minimally invasive percutaneous nephrology. Methods. The clinical data of 80 patients undergoing real-time ultrasound-guided minimally invasive percutaneous nephrolithotomy from September 2018 to October 2019 were analyzed. The patients were randomly divided into 2 groups with different ultrasound-guided puncture techniques, long-axis in-plane technique and short-axis out-of-plane technique. Results. Minimally invasive percutaneous nephrolithotomies under real-time ultrasound guidance were successfully completed in both groups of patients. The success rate of the first puncture in the short-axis out-of-plane group was significantly higher than that in the long-axis in-plane group, and the differences were statistically significant (P <.05); the total puncture time in the short-axis out-of-plane group was significantly less than the long-axis in-plane group, and the differences were statistical significance (P <.05); there was no significant difference in the single-stage stone removal rate, total percutaneous renal channels, total hospital stay, and rate of complications by the Clavien classification between the 2 groups (P > .05). Conclusion. Ultrasound long-axis and short-axis planar technologies can achieve good clinical application results in real-time guided puncture to establish percutaneous renal channels during minimally invasive percutaneous nephrolithotomy. Compared with the long-axis in-plane technique, the short-axis out-of-plane technique can shorten the puncture time and improve the success rate of the first puncture.

Synthesis and biological evaluation of novel hydroxybenzaldehyde-based kojic acid analogues as inhibitors of mushroom tyrosinase.

Two series of novel kojic acid analogues (4a-j) and (5a-d) were designed and synthesized, and their mushroom tyrosinase inhibitory activities was evaluated. The result indicated that all the synthesized derivatives exhibited excellent tyrosinase inhibitory properties having IC50 values in the range of 1.35±2.15-17.50±2.75µM, whereas standard inhibitor kojic acid have IC50 values 20.00±1.08µM. Specifically, 5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercap-to]-4-(2,4-dihydroxyl-benzylamino)-1,2,4-triazole (4f) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 1.35±2.15µM. The kinetic studies of the compound (4f) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed.

Formyl peptide enhances cancer immunotherapy by activating antitumoral neutrophils, and T cells.

Neutrophils are heterogeneous and plastic, with the ability to polarize from antitumour to protumour phenotype and modulate tumour microenvironment components. While some advances have been made, the neutrophil-targeting therapy remains underexplored. Activation of formyl peptide receptors (FPRs) by formylated peptides is needed for local control of infection through the recruitment of activated neutrophils while the potential contribution of antitumour activity remains underexplored. Here, we demonstrate that neutrophils can be harnessed to suppress tumour growth through the action of the formyl peptide (FP) on the formyl peptide receptor (FPR). Mechanistically, FP efficiently recruits neutrophils to produce reactive oxygen species production (ROS), resulting in the direct killing of tumours. Antitumour functions disappeared when neutrophils were depleted by anti-Ly6G antibodies. Interestingly, extensive T-cell activation was observed in mouse tumours treated with FP, showing the potential to alter the immune suppressed tumour microenvironment (TME) and further sensitize mice to anti-PD1 therapy. Transcriptomic and flow cytometry analyses revealed the mechanisms of FP-sensitized anti-PD1 therapy, mainly including stimulated neutrophils and an altered immune-suppressed tumour microenvironment. Collectively, these data establish FP as an effective combination partner for sensitizing anti-PD1 therapy by stimulating tumour-infiltrated neutrophils.

Clinical application of flexible ureteroscopic sheath with controllable intraluminal pressure in treating ureteral stones.

Objective: The purpose of the study was to assess the clinical efficacy and safety of a combined perfusion suction platform with pressure feedback control function and an ureteroscopic suction sheath that can measure the ureteropelvic pressure in implementing lithotripsies. Methods: Fifty-two patients who underwent lithotripsy under intelligent monitoring of ureteral intraluminal pressure from June 2016 to January 2018 were retrospectively recruited. The inclusion standard was stone diameter >1.5 cm but <2.5 cm. After the 12/14 Fr suction sheath was placed, manometer interface and suction interface of the sheath were connected to the platform via the pressure sensor and suction tube, respectively. The ureteroscope was connected to the platform perfusion pump, and the crushed stones were aspirated out under negative pressure. Results: According to the location of the stone, 21 (40.4%) cases were classified as upper ureteral stones, 19 (36.5%) were midureteral stones, and 12 (23.1%) were lower ureteral stones. Forty-seven patients underwent successful primary sheath placement and lithotripsy with a mean operative time of 34.5 (standard deviation 18.3) min. Retrograde stone migration did not occur. There were eight patients with hematuria postoperatively. Serious complication was 1.9% with one case of ureteral perforation. Stone clearance was 95.7% at Day 1-2 postoperatively, and 100% at Day 30 postoperatively. Conclusion: Ureteroscopic lithotripsy with intelligent pressure control using our device improved the efficiency of the lithotripsy and rate of stone clearance. The safety of the operation can be ensured. It is worth popularization and application in clinical practice.

Disulfiram enhances cisplatin cytotoxicity by forming a novel platinum chelate Pt(DDTC)3.

Despite the use of targeted therapy in non-small cell lung cancer (NSCLC) patients, cisplatin (DDP)-based chemotherapy is still the main option. However, DDP resistance is the major factor contributing to the failure of chemotherapy. In this study, we tried to screen DDP sensitizers from an FDA-approved drug library containing 1374 small-molecule drugs to overcome DDP resistance in NSCLC. As a result, disulfiram (DSF) was identified as a DDP sensitizer: DSF and DDP had synergistic anti-NSCLC effects, which are mainly reflected in inhibiting tumor cell proliferation, plate colony formation and 3D spheroidogenesis and inducing apoptosis in vitro, as well as the growth of NSCLC xenografts in mice. Although DSF has recently been reported to promote the antitumor effect of DDP by inhibiting ALDH activity or modulating some important factors or pathways, unexpectedly, we found that DSF reacted with DDP to form a new platinum chelate, Pt(DDTC)3+, which might be one of the important mechanisms for their synergistic effect. Moreover, Pt(DDTC)3+ has a stronger anti-NSCLC effect than DDP, and its antitumor activity is broad-spectrum. These findings reveal a novel mechanism underlying the synergistic antitumor effect of DDP and DSF, and provide a drug candidate or a lead compound for the development of a new antitumor drug.

New Approach for Targeted Treatment of Mild COVID-19 by Honeysuckle through Network Pharmacology Analysis.

OBJECTIVE: To investigate the potential pharmacological value of extracts from honeysuckle on patients with mild coronavirus disease 2019 (COVID-19) infection. METHODS: The active components and targets of honeysuckle were screened by Traditional Chinese Medicine Database and Analysis Platform (TCMSP). SwissADME and pkCSM databases predict pharmacokinetics of ingredients. The Gene Expression Omnibus (GEO) database collected transcriptome data for mild COVID-19. Data quality control, differentially expressed gene (DEG) identification, enrichment analysis, and correlation analysis were implemented by R toolkit. CIBERSORT evaluated the infiltration of 22 immune cells. RESULTS: The seven active ingredients of honeysuckle had good oral absorption and medicinal properties. Both the active ingredient targets of honeysuckle and differentially expressed genes of mild COVID-19 were significantly enriched in immune signaling pathways. There were five overlapping immunosignature genes, among which RELA and MAP3K7 expressions were statistically significant (P < 0.05). Finally, immune cell infiltration and correlation analysis showed that RELA, MAP3K7, and natural killer (NK) cell are with highly positive correlation and highly negatively correlated with hematopoietic stem cells. CONCLUSION: Our analysis suggested that honeysuckle extract had a safe and effective protective effect against mild COVID-19 by regulating a complex molecular network. The main mechanism was related to the proportion of infiltration between NK cells and hematopoietic stem cells.

Erratum: Econazole nitrate reversed the resistance of breast cancer cells to Adriamycin through inhibiting the PI3K/AKT signaling pathway.

[This corrects the article on p. 263 in vol. 10, PMID: 32064166.].

Small-tract percutaneous nephrolithotomy for an elderly female with renal and ureteral stones complicated by pyogenic kidney.

Percutaneous nephrolithotomy (PCNL) is feasible in the extremely elderly patients. However, there were higher rate of complications and longer hospitalizations. The case presented is a 95-year-old female who was admitted to the hospital and was diagnosed with multiple stones in the right kidney and upper ureter with right renal effusion and infection, urosepsis, and chronic bronchitis. After sufficient preoperative preparation, small-tract PCNL under vacuum suctioning was performed using the left lateral position under combined lumbar spinal and epidural anesthesia. The patient recovered and was discharged smoothly on schedule. Good clinical and social effects have achieved.

Degradation of intracellular TGF-ß1 by PROTACs efficiently reverses M2 macrophage induced malignant pathological events.

The first proteolysis targeting chimeras for the intracellular elimination of transforming growth factor-ß1 (TGF-ß1), which contributes to various diseases, are described. The appropriately designed DT-6 could efficiently degrade intracellular TGF-ß1, and inhibit M2 macrophage induced epithelial to mesenchymal transition and invasive migration of cancer cells.

Econazole nitrate reversed the resistance of breast cancer cells to Adriamycin through inhibiting the PI3K/AKT signaling pathway.

Activation of the phosphoinositide 3 kinase (PI3K)/AKT pathway is frequently implicated in resistance to anticancer therapies. PI3K inhibitors can restore sensitivity to standard breast cancer therapies, including endocrine therapy, HER2-targeted agents, and chemotherapy. Our previous research showed that econazole, a novel PI3Ka inhibitor, inhibits the PI3K/AKT pathway and induces apoptosis in lung cancer cells. In this study, econazole showed significant cytotoxic activity against Adriamycin-resistant breast cancer cells in vitro and in vivo. Additionally, econazole significantly sensitized MDA-MB-231 and MCF-7 cells to Adriamycin via inhibiting the PI3K/AKT pathway. Overexpression of constitutively active AKT1 abolished the function of econazole. The combination of econazole and Adriamycin exerted synergistic inhibitory effects in breast cancer cells in vitro and in vivo. Taken together, the PI3K inhibitor econazole could effectively overcome Adriamycin resistance and showed synergistic effects with chemotherapy on breast cancer.

Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy.

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.

Delivery of epirubicin via slow infusion as a strategy to mitigate chemotherapy-induced cardiotoxicity.

BACKGROUND: Continuous infusion of doxorubicin has been a strategy to reduce cardiotoxicity. Epirubicin is another anthracycline in common clinical use. However, evidence is lacking regarding whether this strategy can reduce cardiotoxicity of epirubicin without compromising antineoplastic efficacy. DESIGN AND METHODS: Healthy rats were randomized into groups: epirubicin (8 mg/kg) delivered intraperitoneally via micro osmotic pumps (MOP), epirubicin (8 mg/kg) by intraperitoneal (IP) bolus injection, and placebo control. Blood samples were collected for analyzing biomarkers of myocardial injury and pharmacokinetics. At chosen times, sub-groups of animals were sacrificed for histopathology. A mouse breast cancer cell line (4T1), stably transfected with luciferase, was orthotopically allografted in female mice, and treated in three groups as described above for the rats. Tumor growth was monitored by measuring tumor size as well as bioluminescence. RESULTS: Delivery by IP bolus and by MOP achieved essentially the same area under the curve of epirubicin plasma concentration time profile. Blood biomarkers showed that the degree of myocardial injury in MOP group was lower than that of IP group. Histopathology showed that there was less eosinophilic enhancement, interstitial hemorrhage and necrotizing muscle atrophy in MOP group than IP group. In the orthotopic breast cancer allograft mouse model, the antineoplastic effect of epirubicin by MOP was not different from that by IP as measured by tumor weights or by in vivo bioluminescence. CONCLUSION: Slow delivery of epirubicin by MOP reduced cardiotoxicity without compromising the antineoplastic effect compared to IP bolus delivery. These in vivo data support our previous clinical data that continuous intravenous infusion of epirubicin using micro infusion pumps over 48-96 hours had less cardiotoxicity than intravenous bolus injections. However, whether multiple doses of epirubicin given by MOP result in a lower magnitude of long term cardiomyopathy remains to be further investigated.

Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kα inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin.