Comparison of the efficacy of HoLEP and TURP in the treatment of elderly benign prostatic hyperplasia patients: a retrospective study.

OBJECTIVE: To prove that holmium laser prostatectomy (HoLEP) is safe and effective in the treatment of benign prostatic hyperplasia (BPH), and is superior to transurethral prostatectomy (TURP) for elderly patients. METHODS: We retrospectively studied 565 HoLEP patients and 76 TURP elderly patients. HoLEP patients were first divided into three groups according to their age(Under 65 years old group, 65-79 years old group and over 80 years old group), and their preoperative, intraoperative, and postoperative characteristics were then compared. Secondly, the same characteristics of HoLEP and TURP patients over 80 years were compared. Chi-square test, one-way ANOVA and Fisher's exact test were used in this study. RESULTS: Firstly, we compared HoLEP patients in different age groups and found that there was statistically significant difference in diabetes, CCVD and bladder stones, among the three groups (P<0.05).Secondlye, we compared HoLEP and TURP treatments in elderly patients (≥80 years old). The patients with HoLEP had a higher share of diabetes, CCVD and anticoagulation (P<0.05). Moreover, compared with TURP patients, HoLEP patients had shorter enucleation duration, more enucleate prostate weight, fewer hemoglobin diminutions, shorter bladder irrigation time, shorter catheter-indwelling period, and shorter hospital period (P<0.05). Although there was no difference in IPSS, Qmax and QOL between the two groups before operation (P>0.05), the difference was statistically significant, 6 months after the operation (P<0.05). CONCLUSION: HoLEP is safe and effective for BPH patients, and is superior to transurethral TURP for elderly patients.

A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3.

Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.

Nanoparticles-Based Strategies to Improve the Delivery of Therapeutic Small Interfering RNA in Precision Oncology.

Small interfering RNA (siRNA) can selectively suppress the expression of disease-causing genes, holding great promise in the treatment of human diseases, including malignant cancers. In recent years, with the development of chemical modification and delivery technology, several siRNA-based therapeutic drugs have been approved for the treatment of non-cancerous liver diseases. Nevertheless, the clinical development of siRNA-based cancer therapeutics remains a major translational challenge. The main obstacles of siRNA therapeutics in oncology include both extracellular and intracellular barriers, such as instability under physiological conditions, insufficient tumor targeting and permeability (particularly for extrahepatic tumors), off-target effects, poor cellular uptake, and inefficient endosomal escape. The development of clinically suitable and effective siRNA delivery systems is expected to overcome these challenges. Herein, we mainly discuss recent strategies to improve the delivery and efficacy of therapeutic siRNA in cancer, including the application of non-viral nanoparticle-based carriers, the selection of target genes for therapeutic silencing, and the combination with other therapeutic modalities. In addition, we also provide an outlook on the ongoing challenges and possible future developments of siRNA-based cancer therapeutics during clinical translation.

SKLB-14b, a novel oral microtubule-destabilizing agent based on hydroxamic acid with potent anti-tumor and anti-multidrug resistance activities.

A hydroxamic acid based microtubule-destabilizing agent (MDA) SKLB-14b was discovered in this study, which was derived from shortening the linker length of the HDAC6 and microtubule dual-target inhibitor SKLB-23bb. SKLB-14b exhibited low nanomolar IC50 values on a wide spectrum of human cancer cell lines including both sensitive and multidrug-resistant cell lines. Surprisingly, its anti-proliferative activity relied on the presence of the hydroxamic acid group but lost inhibitory activity against HDACs. SKLB-14b bound to the colchicine site of tubulin and could inhibit tubulin polymerization. It exhibited good metabolic stability in liver microsomes, no inhibitory effect on CYP450 isoenzymes and high oral bioavailability. In vivo experiments revealed that SKLB-14b was potent in both sensitive (A2780S, HCT116) and resistant (A2780/T) xenograft mice models. Furthermore, in the patient-derived tumor xenograft (PDX) models of osimertinib resistant non-small cell lung cancer (NSCLC), 50 mg/kg of SKLB-14b administered every twodays inhibited tumor growth by 70.6% without obvious toxicity, better than the 59.7% inhibition rate of paclitaxel. Mechanistically, we found that SKLB-14b exerted anti-tumor and anti-multidrug resistance effects in vitro and in vivo through cell cycle arrest and pro-apoptotic activities, as well as vascular disrupting activities. Therefore, we discovered that SKLB-14b, as a novel MDA based on hydroxamic acid, could serve as a potential drug candidate for cancer therapy which deserves further investigation.

Targeted Drug/Gene/Photodynamic Therapy via a Stimuli-Responsive Dendritic-Polymer-Based Nanococktail for Treatment of EGFR-TKI-Resistant Non-Small-Cell Lung Cancer.

Yes-associated protein (YAP) has been identified as a key driver for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance. Inhibition of YAP expression could be a potential therapeutic option for treating non-small-cell lung cancer (NSCLC). Herein, a nanococktail therapeutic strategy is proposed by employing amphiphilic and block-dendritic-polymer-based nanoparticles (NPs) for targeted co-delivery of EGFR-TKI gefitinib (Gef) and YAP-siRNA to achieve a targeted drug/gene/photodynamic therapy. The resulting NPs are effectively internalized into Gef-resistant NSCLC cells, successfully escape from late endosomes/lysosomes, and responsively release Gef and YAP-siRNA in an intracellular reductive environment. They preferentially accumulate at the tumor site after intravenous injection in both cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of Gef-resistant NSCLC, resulting in potent antitumor efficacy without distinct toxicity after laser irradiation. Mechanism studies reveal that the cocktail therapy could block the EGFR signaling pathway with Gef, inhibit activation of the EGFR bypass signaling pathway via YAP-siRNA, and induce tumor cell apoptosis through photodynamic therapy (PDT). Furthermore, this combination nanomedicine can sensitize PDT and impair glycolysis by downregulating HIF-1α. These results suggest that this stimuli-responsive dendritic-polymer-based nanococktail therapy may provide a promising approach for the treatment of EGFR-TKI resistant NSCLC.

Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity.

Objective: Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients. Methods: A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents. Results: A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics. Conclusions: Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

Space Optimized Plane Wave Imaging for Fast Ultrasonic Inspection with Small Active Aperture: Simulation and Experiment.

Plane wave imaging (PWI) is attracting more attention in industrial nondestructive testing and evaluation (NDT&E). To further improve imaging quality and reduce reconstruction time in ultrasonic imaging with a limited active aperture, an optimized PWI algorithm was proposed for rapid ultrasonic inspection, with the comparison of the total focusing method (TFM). The effective area of plane waves and the space weighting factor were defined in order to balance the amplitude of the imaging area. Experiments were carried out to contrast the image quality, with great agreement to the simulation results. Compared with TFM imaging, the space-optimized PWI algorithm demonstrated a wider dynamic detection range and a higher defects amplitude, where the maximum defect amplitude attenuation declined by 6.7 dB and average attenuation on 12 defects decreased by 3.1 dB. In addition, the effects of plane wave numbers on attenuation and reconstruction time were focused on, achieving more than 10 times reduction of reconstruction times over TFM.

Identification of Long Non-Coding RNA-Associated Competing Endogenous RNA Network in the Differentiation of Chicken Preadipocytes.

Emerging evidence indicates that long noncoding RNAs (lncRNAs) play important roles in the regulation of cell differentiation by acting as competing endogenous RNA (ceRNA). However, the regulatory mechanisms of lncRNA and the lncRNA-associated ceRNA network involved in adipogenic differentiation of chicken preadipocytes remain elusive. Here, we first constructed the chicken preadipocyte in vitro induction model. Then, we identified differentially expressed lncRNAs (DELs), miRNAs (DEMis), and mRNAs (DEMs) between differentiated and undifferentiated preadipocytes. Furthermore, we constructed the lncRNA associated ceRNA network by gene expression correlation analysis and target prediction of DELs, DEMis, and DEMs. Finally, we determined twelve candidate lncRNA-miRNA-mRNA interactions from the lncRNA associated ceRNA network. Eight out of the twelve interactions were validated by RT-qPCR, indicating their potential role in the regulation of chicken preadipocytes differentiation. Among the eight interactions, TCONS_00026544-gga-miR-128-1-5p-RASD1, TCONS_00055280-gga-miR-135a-5p-JAM3, TCONS_00055280-gga-miR-135a-5p-GPR133, TCONS_00055280-gga-miR-135a-5p-CLDN1, and TCONS_00055280-gga-miR-135a-5p-TMEM123 may promote adipogenic differentiation of chicken preadipocytes while TCONS_00057272-gga-miR-146a-3p-FOXO6, TCONS_00057242-gga-miR-6615-3p-FOXO6, and TCONS_00057242-gga-miR-6615-3p-ENSGALT00000043224 have the opposite effects. Our results not only provide novel insights into ceRNA roles of lncRNAs in chicken preadipocytes differentiation and but also contribute to a better understanding of chicken fat deposition.

Long non-coding RNA mortal obligate RNA transcript suppresses tumor cell proliferation in prostate carcinoma by inhibiting glucose uptake.

A previous study reported the decreased expression of long non-coding RNA mortal obligate RNA transcript (lncRNA MORT) in 16 types of cancer, while the functionality of lncRNA MORT in cancer biology remains unknown. Therefore, the present study was conducted to characterize the functionality of lncRNA MORT in prostate carcinoma, a common cancer type worldwide. lncRNA MORT expression level was downregulated in tumor tissues compared with that in the adjacent healthy tissues of patients with prostate carcinoma. Expression of lncRNA MORT in tumor tissues was influenced by tumor size, but not by tumor metastasis. Overexpression of lncRNA MORT inhibited glucose uptake and glucose transporter 1 (GLUT-1) expression in prostate carcinoma cell lines; GLUT-1 overexpression upregulated glucose uptake and attenuated the effects of lncRNA MORT overexpression on glucose uptake, but did not significantly affect the expression of lncRNA MORT. Overexpression of lncRNA MORT inhibited, while GLUT-1 overexpression promoted the proliferation of prostate carcinoma cells. In addition, GLUT-1 overexpression attenuated the effects of lncRNA MORT on cell proliferation. Therefore, lncRNA MORT may inhibit cancer cell proliferation in prostate carcinoma by preventing glucose uptake.

Multi-Modal Visualization of Uptake and Distribution of Iron Oxide Nanoparticles in Macrophages, Cancer Cells, and Xenograft Models.

Iron oxide nanoparticles (IONPs) have shown great potential in various biomedical applications. However, information on the interaction between IONPs and biological systems, especially the uptake and distribution of IONPs in cells and tissues, as well as the mechanism of biological action, is relatively limited. In the present study, multi-modal visualization methods, including confocal fluorescence microscopy, transmission electron microscopy, magnetic resonance imaging, and fluorescence optical imaging, were utilized to unveil the uptake and distribution of IONPs in macrophages, cancer cells, and xenograft models. Our results demonstrated that uptake of IONPs in RAW264.7 macrophages and SKOV-3 cancer cells were dose- and cell type-dependent. Cellular uptake of IONPs was an energy-dependent process, and caveolae-mediated endocytosis was the main uptake pathway. All the IONPs were primarily present in endocytic compartments (e.g., endosomes, lysosomes) inside the cells. At 48 hours after intravenous injection of IONPs in SKOV-3 tumor bearing mice, most of the IONPs was distributed in the liver and spleen, with obvious uptake in the tumor, less but significant amount in the kidney and brain. Taken together, multi-modal visualization approaches in our study provide detailed information on the cellular uptake and tissue distribution of IONPs from multiple levels and perspectives.

Size- and cell type-dependent cellular uptake, cytotoxicity and in vivo distribution of gold nanoparticles.

BACKGROUND: Gold nanoparticles (AuNPs) have shown great promise in biomedical applications. However, the interaction of AuNPs with biological systems, its underlying mechanisms and influencing factors need to be further elucidated. PURPOSE: The aim of this study was to systematically investigate the effects of particle size on the uptake and cytotoxicity of AuNPs in normal cells and cancer cells as well as their biological distribution in vivo. RESULTS: Our data demonstrated that the uptake of AuNPs increased in HepG2 cancer cells but decreased in L02 normal cells, with the increase of particle size (5-50 nm). In both cancer cells and normal cells, small (5 nm) AuNPs exhibited greater cytotoxicity than large ones (20 and 50 nm). Interestingly, 5 nm AuNPs induced both apoptosis and necrosis in HepG2 cells through the production of reactive oxygen species (ROS) and the activation of pro-caspase3, whereas it mainly induced necrosis in L02 cells through the overexpression of TLR2 and the release of IL-6 and IL-1a cytokines. Among them, 50 nm AuNPs showed the longest blood circulation and highest distribution in liver and spleen, and the treatment of 5 nm AuNPs  but not 20 nm and 50 nm AuNPs resulted in the increase of neutrophils and slight hepatotoxicity in mice. CONCLUSION: Our results indicate that the particle size of AuNPs and target cell type are critical determinants of cellular uptake, cytotoxicity and underlying mechanisms, and biological distribution in vivo, which deserves careful consideration in the future biomedical applications.

The deregulation of miR-133b is associated with poor prognosis in bladder cancer.

BACKGROUND: MicroRNAs (miRNAs) are single-stranded, endogenous, non-coding RNAs that are increased or decreased in almost all cancer types, and they paly crucial roles in the tumorigenesis as well as development. MATERIALS AND METHODS: 90 patients diagnosed with bladder cancer were enrolled in the present study. The bladder cancer tissues or adjacent normal tissues were obtained from the tumor area or adjacent normal zone. The expression level of miR-133b was examined by quantitative real-time polymerase chain reaction assay (qRT-PCR). Survival curves were displayed by the Kaplan-Meier method, and differences between two survival curves were calculated by the log-rank test. RESULTS: The expression levels of miR-133b in bladder tissues were significantly decreased when compared with the matched adjacent normal bladder tissues (P < 0.05). Moreover, miR-133b expression levels are significantly associated with lymphatic invasion (P = 0.026), distant metastasis (P = 0.025), tumor grade (P = 0.038), as well as the muscle invasion status (P < 0.001). The log-rank test indicated that patients with decreased miR-133b expression underwent poorer overall survival (P = 0.007). Furthermore, multivariate Cox regression analysis showed that the expression level of miR-133b (P = 0.024) was an independent factor for predicting the overall survival in patients with bladder cancer. CONCLUSIONS: The present study showed that miR-133b might be associated with bladder cancer progression, and its down-regulation might be a biomarker for poor prognosis of bladder cancer.

Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings.

Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues were relatively slow (>2 weeks). Among them, 10 nm PEGylated IONPs achieved the highest tumor uptake. No obvious toxicity was found for PEGylated IONPs in BALB/c mice, whereas PEI-coated IONPs exhibited dose-dependent lethal toxicity. Therefore, it is crucial to consider the size and coating properties of IONPs in their applications.

Super-Mini Percutaneous Nephrolithotomy in the Treatment of Pediatric Nephrolithiasis: Evaluation of the Initial Results.

OBJECTIVE: To evaluate the efficacy and safety of super-mini percutaneous nephrolithotomy (SMP) in the treatment of pediatric kidney stones. PATIENTS AND METHODS: We reviewed the records of 111 children with renal stones treated with SMP technique in four different centers between September 2014 and September 2015. The indications for SMP treatment in all these kids were either previously failed shock wave lithotripsy or retrograde intrarenal surgery approaches, according to their parents' preferences. Nephrostomy tracts used in the SMP system ranged from 10F to 14F in size. Lithotripsy was performed using either a Holmium laser or pneumatic lithotripter. Perioperative and postoperative parameters along with operative data were recorded in detail and stone components were analyzed by infrared spectroscopy. RESULTS: This study included 71 boys and 40 girls with a mean age of 3.90 ± 3.53 years (range 0.5-15). The mean stone burden was 1.4 ± 0.6 cm (range 0.8-4.8). Mean operative time was 39.4 ± 26.2 minutes (range 7-105). The mean hemoglobin drop was 10.2 ± 7.1 g/L (range 0-25) and no transfusion was needed. Significant complications were observed in 17 (15.3%) children with 10 and 7 cases in Clavien grade I and grade II, respectively. Complete stone clearance on postoperative day 1 and on 3-month follow-up was 84.7% (94/111) and 90.1% (100/111), respectively. Ninety-five (85.6%) children did not require any type of catheters (total tubeless). The mean hospital stay was 2.7 ± 1.5 days (range 1-7). CONCLUSIONS: Our preliminary data demonstrated that SMP was safe and effective. SMP could be a feasible treatment option for pediatric stone disease. Further randomized controlled trials are still needed to prove the efficacy of using the SMP system in children, particularly in those with larger stones.

A Prediction Model for the Peripheral Arterial Disease Using NHANES Data.

We aim to build models for peripheral arterial disease (PAD) risk prediction and seek to validate these models in 2 different surveys in the US general population. Model building survey was based on the National Health and Nutrition Examination Surveys (NHANES, 1999-2002). Potential predicting variables included race, gender, age, smoking status, total cholesterol (TC), body mass index, high-density lipoprotein (HDL), ratio of TC to HDL, diabetes status, HbA1c, hypertension status, and pulse pressure. The PAD was diagnosed as ankle brachial index <0.9. We used multiple logistic regression method for the prediction model construction. The final predictive variables were chosen based on the likelihood ratio test. Model internal validation was done by the bootstrap method. The NHANES 2003-2004 survey was used for model external validation. Age, race, sex, pulse pressure, the ratio of TC to HDL, and smoking status were selected in the final prediction model. The odds ratio (OR) and 95% confidence interval (CI) for age with 10 years increase was 2.00 (1.72, 2.33), whereas that of pulse pressure for 10 mm Hg increase was 1.19 (1.10, 1.28). The OR of PAD was 1.11 (95% CI: 1.02, 1.21) for 1 unit increase in the TC to HDL ratio and was 1.61 (95% CI: 1.40, 1.85) for people who were currently smoking compared with those who were not. The respective area under receiver operating characteristics (AUC) of the final model from the training survey and validation survey were 0.82 (0.82, 0.83) and 0.76 (0.72, 0.79) indicating good model calibrations. Our model, to some extent, has a moderate usefulness for PAD risk prediction in the general US population.

CSTB Downregulation Promotes Cell Proliferation and Migration and Suppresses Apoptosis in Gastric Cancer SGC-7901 Cell Line.

This study aimed to investigate the pivotal role of cystatin B (CSTB) in the development of gastric cancer and to explore its possible regulatory mechanism. Human gastric cancer SGC-7901 cells as a model in vitro were transfected with plasmid PCDNA3.1-CSTB and siRNA-CSTB using Lipofectamine 2000. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the relative expression of CSTB and PI3K/Akt/mTOR pathway-related protein. Moreover, MTT assay, Transwell assay, and flow cytometry were used to assess cell proliferation, migration, and apoptosis, respectively. The results showed that CSTB was significantly downregulated in SGC-7901 cells compared with gastric epithelial cells. CSTB was successfully overexpressed and suppressed after cells were transfected with pc-CSTB and si-CSTB, respectively. Moreover, cell viability and migration were significantly decreased after being transfected with pc-CSTB when compared with the control group, while being obviously increased after transfection with si-CSTB. However, cell apoptosis was significantly induced after being transfected with pc-CSTB, while being obviously suppressed after transfection with si-CSTB. Besides, the expression levels of p-PI3K, p-Akt, and p-mTOR proteins were all significantly decreased in the pc-CSTB transfection group when compared with the control group, while being increased in the si-CSTB transfection group. Our findings suggest that CSTB downregulation may promote the development of gastric cancer by affecting cell proliferation and migration, and the PI3K/Akt/mTOR signaling pathway was activated in this process. CSTB may serve as a potential therapeutic target for gastric cancer.