P53 upregulation by USP7-engaging molecular glues.

Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.

MAFLD with central obesity is associated with increased risk of colorectal adenoma and high-risk adenoma.

OBJECTIVE: To analyze the risk factors associated with colorectal adenoma and to investigate the associations of metabolism-related fatty liver disease (MAFLD) with obesity, colorectal adenoma and high-risk adenoma. METHODS: A total of 1395 subjects were enrolled and divided into a colorectal adenoma group (593 subjects) and a control group (802 subjects) according to the inclusion and exclusion criteria. The characteristics of patients in the colorectal adenoma group and the control group were compared by the chi-square test. Univariate and multivariate logistic analyses were used to analyze independent risk factors and associations with different MAFLD subtypes. Colorectal adenoma characteristics and the proportion of patients with high-risk colorectal adenoma were also compared. RESULTS: High-density lipoprotein (HDL-C) was significantly lower in patients in the colorectal adenoma group than in those in the control group (P < 0.001). Logistic regression analysis revealed that age, obesity status, central obesity status, hypertension status, diabetes status, fatty liver status, smoking history, BMI, waist circumference, triglyceride level, HDL-C level, fasting blood glucose level and degree of hepatic steatosis were all independent risk factors for colorectal adenoma. Notably, MAFLD was associated with a significantly increased risk of colorectal adenoma in patients with central obesity (P < 0.001). In addition, obesity, central obesity, diabetes, fatty liver and degree of hepatic steatosis were all shown to be independent risk factors for high-risk colorectal adenoma. In addition, a greater proportion of MAFLD patients with central obesity than those without central obesity had high-risk colorectal adenoma. CONCLUSION: MAFLD and central obesity are independently associated with the development of colorectal adenoma. MAFLD with central obesity is associated with an increased risk of colorectal adenoma and high-risk adenoma.

Laparoscopic ureteroneocystostomy with bladder flap for benign ureteral stenosis: our initial experience.

To present our experience with laparoscopic ureteroneocystostomy with bladder flap (LUCBF) for treating benign ureteral stenosis and evaluate its feasibility and efficacy. The clinical data of 27 patients with benign ureteral stenosis who underwent LUCBF were retrospectively analyzed. After identification and excision of the ureteral stenosis segment, the healthy ureteral stump was dissected and incised longitudinally. A U-shaped or spiral bladder flap was harvested from the anterolateral bladder wall for ureteroplasty. All patients underwent LUCBF successfully, including 14 patients were combined with psoas hitch technique, between 90 and 220 min (median, 155 min). The median length of ureteral defect was 6 cm (range, 5-17 cm). The median blood loss was 40 ml (20-150 ml). The median indwelling time of double-J stent was 8 weeks (range, 4-8 weeks). Five patients (10.6%) suffered postoperative complications during the follow-up period (range, 12-48 months), including fever, hematuria, urinary tract infection and recurrent stenosis. The success rate was 96.3% (26/27). Patients with long ureter defects had longer operative time and more blood loss than short ureter defects. LUCBF was a safe and feasible technique for benign ureteral stenosis. Long ureter defect was related to longer operative time and more blood loss.

Identification of (E)-1-((1H-indol-3-yl)methylene)-4-substitute-thiosemicarbazones as potential anti-hepatic fibrosis agents.

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.

Towards a Deeper Understanding of Global Covariance Pooling in Deep Learning: An Optimization Perspective.

Global covariance pooling (GCP) as an effective alternative to global average pooling has shown good capacity to improve deep convolutional neural networks (CNNs) in a variety of vision tasks. Although promising performance, it is still an open problem on how GCP (especially its post-normalization) works in deep learning. In this paper, we make the effort towards understanding the effect of GCP on deep learning from an optimization perspective. Specifically, we first analyze behavior of GCP with matrix power normalization on optimization loss and gradient computation of deep architectures. Our findings show that GCP can improve Lipschitzness of optimization loss and achieve flatter local minima, while improving gradient predictiveness and functioning as a special pre-conditioner on gradients. Then, we explore the effect of post-normalization on GCP from the model optimization perspective, which encourages us to propose a simple yet effective normalization, namely DropCov. Based on above findings, we point out several merits of deep GCP that have not been recognized previously or fully explored, including faster convergence, stronger model robustness and better generalization across tasks. Extensive experimental results using both CNNs and vision transformers on diversified vision tasks provide strong support to our findings while verifying the effectiveness of our method.

Flexible ureteroscopic lithotripsy with a suctioning ureteral access sheath for removing upper urinary calculi under local anesthesia.

Objectives: We aimed to probe the safety and effectiveness of flexible ureteroscopic lithotripsy (FURL) with a suctioning ureteral access sheath (S-UAS) for removing upper urinary calculi under local anesthesia (LA). Materials and methods: The clinical data of 56 patients with upper urinary calculi treated by FURL with an S-UAS under LA during the period between September 2019 and November 2022 were analyzed retrospectively. For LA, intramuscular pethidine (1.0-2.0 mg/kg) and phenergan (25 mg) were administered 30 min prior to surgery, and oxybuprocaine hydrochloride gel was administered through the urethra at the start of the surgery. The S-UAS and flexible ureteroscope were used for FURL. Demographic characteristics, stone-related parameters, and clinical outcomes were analyzed. Result: A total of 66 procedures were performed successfully on 46 patients (Group A), who underwent unilateral surgeries, and on 10 patients (Group B) who underwent same-session bilateral surgeries. All 56 patients were operated upon without altering the anesthesia strategy, and none required additional analgesia. The mean stone sizes of the Group A and Group B patients were 20.24 ± 5.45 mm and 29.40 ± 3.89 mm, respectively. The mean operative times of the two groups were 53.04 ± 13.35 min and 90.00 ± 15.81 min, respectively. In Group A, the stone-free rates (SFRs) were 76.1% (35/46) and 85.1% (40/46) at postoperative day 1 and day 30, respectively. In Group B, the SFRs were 80.0% (16/20) and 85.0% (17/20), respectively. Four (8.7%) patients in Group A suffered complications such as fever, stent pain, urosepsis, and steinstrasse. In Group B, one (10%) patient suffered from fever. Conclusion: FURL, combined with an S-UAS under LA, is a feasible option and provides satisfactory clinical outcomes for appropriately selected patients.

Comparison of traditional and novel tip-flexible suctioning ureteral access sheath combined with flexible ureteroscope to treat unilateral renal calculi.

OBJECTIVES: To compare the safety and efficacy of novel tip-flexible suctioning ureteral access sheath (NTFS-UAS) and traditional ureteral access sheath (T-UAS) combined with flexible ureteroscope for treating unilateral renal calculi. MATERIALS AND METHODS: The clinical data of 214 patients with unilateral renal calculi treated by NTFS-UAS (n = 102) and T-UAS (n = 112) combined with flexible ureteroscope from August 2021 to April 2022 were analyzed retrospectively. Demographic characteristics, stone-related parameters, operative time, stone-free rates (SFR), hospitalization time and complication rate (CR) were analyzed. RESULT: No significant difference was observed between the two groups in terms of demographic characteristics, stone-related parameters, intraoperative CR, and hospitalization time. The operative time of NTFS-UAS group was significantly shorter than T-UAS group (55.25 ± 11.42 min vs. 59.36 ± 15.59 min; P = 0.028). The NTFS-UAS group obtained significantly higher SFR on 1 day postoperatively (86.3% vs. 75.0%; P = 0.038), and higher SFR on 30 days postoperatively than T-UAS group (91.2% vs. 81.3%; P = 0.037). The hemoglobin loss of NTFS-UAS group (- 0.54 ± 0.69 g/dl) was significantly lower than T-UAS group (- 0.83 ± 0.66 g/dl; P = 0.002). There was a significantly lower incidence of overall CR (11.8% vs. 22.3%; P = 0.041), and infectious CR (8.8% vs. 18.8%; P = 0.037) in the NTFS-UAS group. CONCLUSION: Compared to T-UAS combined with flexible ureteroscope for treating unilateral renal calculi, NTFS-UAS had superiority in higher SFR on 1 day and 30 days postoperatively. Shorter operation time, lower hemoglobin loss, lower incidences of overall and infectious CR were observed in NTFS-UAS group. REGISTRATION NUMBER AND DATE: ChiCTR2300070210; April 5, 2023.

Chinese mini percutaneous nephrolithotomy for upper urinary calculi under local infiltration anesthesia.

Percutaneous nephrolithotomy is generally performed under general or regional anesthesia; however, it is rarely performed under local infiltration anesthesia (LIA). This study aimed to assess the safety and effectiveness of Chinese mini percutaneous nephrolithotomy (MPCNL) for upper urinary calculi under LIA. A retrospective analysis of 52 patients with upper urinary stones who underwent MPCNL under LIA from April 2019 to May 2022 was performed. Pethidine and Phenergan were intramuscularly injected 30 minutes preoperatively. Oxybuprocaine hydrochloride gel was applied to the urethra for lubricating and mucosal anesthesia. Ropivacaine hydrochloride and lidocaine were injected into the whole percutaneous channel for local anesthesia. An 8/9.8F ureteroscope and an 18F vacuum-assisted access sheath were applied in MPCNL. All 52 patients tolerated procedures and underwent operations successfully; none of them converted the anesthesia method or required additional analgesia. The mean visual analogue scale scores intraoperatively and at 6 hours, 24 hours, and 48 hours after surgery were 3.25 ± 0.52, 3.13 ± 0.69, 2.25 ± 0.56, and 1.58 ± 0.50, respectively. The stone free rate was 84.6%. Complications were seen in 6 (11.5%) patients, including fever in 2 patients (Clavien I), renal colic in 1 patient (Clavien I), clinically insignificant bleeding in 2 patients (Clavien I), and urinary tract infection in 1 patient (Clavien II). No severe complications were observed in any patients. Chinese MPCNL under LIA was a feasible option and achieved good outcomes in appropriately selected patients, and it may become the routine procedure for general patients.

Comparing the Influences of Metformin and Berberine on the Intestinal Microbiota of Rats With Nonalcoholic Steatohepatitis.

BACKGROUND/AIM: High-fat diets induce shifts in the gut microbial community structure in patients or animals with non-alcoholic steatohepatitis (NASH). The objective of this study was to investigate the influence of metformin (MET) and berberine (BER) on the intestinal microbiota of rats with NASH. MATERIALS AND METHODS: Forty specific pathogen-free male Sprague-Dawley rats were randomized into 4 groups. Model rats were fed high-fat diets to create NASH models. MET or BER rats were administrated MET or BER, respectively, at the onset of induction of NASH. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and triglycerides were examined. Plasma endotoxin levels were measured using the turbidimetric endotoxin assay. The incidence of bacterial translocation describes the passage of bacteria of the gastrointestinal tract through the intestinal mucosa barrier to mesenteric lymph nodes and other organs. Hematoxylin and eosin and oil red O staining were used for histopathological analysis. High throughput 16S rRNA sequencing was carried out for analyzing the composition of intestinal microbiota. RESULTS: High-fat diets caused NASH after 16-week induction. Administration of MET and BER ameliorated NASH by attenuating hepatic steatosis and inflammation and decreasing the plasma levels of endotoxin. MET and BER restored the composition of the intestinal microbiota disrupted by NASH. Both MET and BER altered the abundance of Atopobiaceae, Brevibacterium, Christensenellaceae, Coriobacteriales, Papillibacter, Pygmaiobacter, and Rikenellaceae RC9 in rats with NASH. The screened intestinal microbiota may be responsible for the improvement in fat accumulation and glucose metabolism. CONCLUSION: MET and BER demonstrated beneficial effects on the intestinal microbiota, which was disturbed in NASH. This finding may explain the functional mechanism of MET and BER in NASH.

Time-difference-of-arrival positioning based on visible light communication for harbor-border inspection.

In view of the complexity of port ship supervision and the influence of external factors such as electromagnetic interference in harbor-border inspection, an efficient system combining an unmanned aerial vehicle (UAV) and visible light positioning (VLP) is proposed for locating maritime targets. In this system, a rotatable receiver with five photodetectors (PDs) installed obliquely on UAV is designed for expanding the positioning range and allowing a lower flight altitude. On this basis, we propose the Chan-Taylor (CT) method based on time difference of arrival (TDOA) for target positioning. First, the localization problem is reformulated as a weighted least squares (WLS) problem and provides a good initial estimate via the two-step WLS (TWLS) method. Then, based on Taylor expansion of TDOA equations, estimated error is calculated using the initial estimate, which can correct the estimated position of the target iteratively. To offset the error, weighted centroid CT (WCCT) is proposed by endowing different weights based on error difference to estimated results. For further improving accuracy, a restricted-region fingerprinting positioning based on CT (CT-RFP) is proposed. In restricted area determined by CT, a certain number of fingerprints is generated based on received signal strength (RSS) for matching. Simulation results show that CT is significantly improved over the previous methods. Compared with TWLS, the accuracy of CT is improved by 49.71%. For WCCT, the maximum error is reduced from 8.65 to 6.91 cm, which effectively reduces the influence of error. Moreover, CT-RFP can achieve an accuracy within millimeter level via the appropriate number of fingerprints and ensemble runs of CT, even at high noise levels.

Antifibrotic Mechanism of Piceatannol in Bleomycin-Induced Pulmonary Fibrosis in Mice.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by myofibroblast accumulation and extracellular matrix deposition, which lead to irreversible damage of the lung's architecture and the formation of fibrotic lesions. IPF is also a sequela in serious patients with the coronavirus disease 2019 (COVID-19). The molecular mechanisms under pulmonary fibrosis remain unclear, and there is no satisfactory treatment currently available. Piceatannol (PIC) is a naturally occurring resveratrol analog found in a variety of dietary sources such as grapes, passion fruit, and white tea. It has been reported to inhibit liver fibroblast growth and exhibited various antitumor activities, although its role in pulmonary fibrosis has not been established yet. In the present study, we evaluated the anti-fibrotic role of PIC in bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: Mice with BLM-induced pulmonary fibrosis were treated with PIC, and fibrotic changes were measured by hematoxylin-eosin (H&E) staining and hydroxyproline assay. Luciferase assay, Western blot assay, histological analysis, and immunofluorescence staining were used to evaluate the effect of PIC on fibroblast activation and autophagy in mouse embryonic fibroblast cells (NIH-3T3) and human lung fibroblast cells (HFL1). The anti-fibrotic mechanisms of PIC were either confirmed in vivo. Results: Our results showed that PIC significantly alleviated the bleomycin-induced collagen deposition and myofibroblast accumulation. In vitro and in vivo studies indicated that PIC plays a role in activating autophagy in the process of anti-fibroblast activation. Further mechanism studies demonstrated that PIC can promote autophagy via inhibiting the TGF-ß1-Smad3/ERK/P38 signaling pathway, which leads to a decreased number of activated myofibroblasts. Conclusion: Our study demonstrated for the first time that PIC possesses the protective effects against bleomycin-induced pulmonary fibrosis due to the direct pulmonary protective effects which enhance the effect of autophagy in vitro and in vivo and finally leads to the decreased number of activated myofibroblasts. PIC may serve as a candidate compound for pulmonary fibrosis therapy and attenuates the sequelae of SARS-COV-2 pulmonary fibrosis.

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators.

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N'-methylene position of indoles' Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a-9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

Harbor-border inspection for unmanned aerial vehicle based on visible light source tracking.

The unmanned aerial vehicle (UAV) offers unique advantages of autonomous flight capability and small coefficient of risk, and is increasingly being used in harbor-border inspection to ensure security and orderly operation of harbors. In response to the influence of external factors such as electromagnetic interference in harbor-border inspection, this paper utilizes UAV and visible light communication (VLC) to build an efficient system to track maritime targets near the harbor reliably. In a VLC scenario, a geometrical equation for transmitter positioning is first proposed based on the received signal strength of the optical signal emitted by the target. On this basis, linear iterative positioning (LIP) using first-order Taylor expansion is proposed to realize online beam tracking. Furthermore, quadratic approximative iterative positioning (QAIP), a more precise approximation of the geometrical equation, is proposed based on second-order Taylor expansion. Simulation results show that the proposed algorithms can track targets effectively, and QAIP can achieve higher accuracy with no noise or high signal-to-noise ratio. In addition, compared with the geometrical solution, LIP and QAIP have faster computing speeds and fixed overheads.

Making Lemonade: Putting the Wisdom of the Genome to Work in Atopic Dermatitis.

Getting from a GWAS hit to an actionable gene remains a challenge in complex disease genetics. In a new article of the Journal of Investigative Dermatology, Sobczyk et al. (2021) use a wide variety of genomic data to generate a prioritization algorithm to tackle this problem in atopic dermatitis, calling on the wisdom of the genome to generate promising results.

Design, synthesis and biological evaluation of hybrid of ubenimex-fluorouracil for hepatocellular carcinoma therapy.

In our previous study, we discovered a ubenimex-fluorouracil (5FU) conjugates BC-02, which displays significant in vivo anti-tumor activity, however, the instability of BC-02 in plasma limits its further development as a drug candidate. Herein, we designed and synthesized four novel ubenimex-5FU conjugates by optimizing the linkers between ubenimex and 5FU based on BC-02. Representative compound 20 is more stable than BC-02 in human plasma and displays about 100 times higher CD13 inhibitory activity than the positive control ubenimex. Meanwhile, the antiproliferative activity of 20 was comparable with 5FU in vitro. The preliminary mechanism study indicated that compound 20 exhibited significant anti-invasion and anti-angiogenesis activities in vitro. Furthermore, compound 20 obviously inhibits tumor growth and metastasis in vivo and prolong the survival time of tumor-bearing mice. Our study may have an important implication reference for the design of more druglike mutual prodrug, and compound 20 can be used as a lead compound for further design and development.

Long non-coding RNA CYTOR regulates proliferation and metastasis of colon cancer cells through regulating miRNA-105/PTEN axis.

Colon cancer is a common malignancy, and its incidence and mortality have been increasing in recent years. This study aims to explore the regulation of long non-coding RNA CYTOR on proliferation and metastasis of colon cancer cells through miRNA-105/PTEN axis. Real-time quantitative PCR (qRT-PCR) disclosed that expression of CYTOR was significantly decreased in colon cancer tissues, compared with that of adjacent normal tissues, while miRNA-105 was significantly increased. Correlation study found that CYTOR was negatively correlated with miR-105. The proliferation, migration, and invasion rates of the LoVo cells with highly expressed CYTOR were significantly slower. miR-105 mimic could suppress the decrease in proliferation, migration, and invasion rates of colon cancer cells caused by overexpression of CYTOR. Additionally, the proliferation, migration, and invasion rates of the LoVo cells in miR-105 inhibition group were significantly slower. The Starbase database predicted the targeting of miR-105 by CYTOR, and qRT-PCR and dual luciferase reporter gene method were used to verify the targeting relationship of CYTOR and miRNA-105/PTEN axis. In conclusion, CYTOR can inhibit the proliferation and metastasis of colon cancer cells through targeted inhibition of the miR-105/PTEN axis.

Suprapubic-assisted laparoendoscopic single-site surgery versus standard laparoscopic nephrectomy: A propensity score-based analysis.

OBJECTIVES: To compare suprapubic-assisted laparoendoscopic single-site surgery nephrectomy with standard laparoscopic nephrectomy. METHODS: A retrospective case-control study comparing three surgeons' experience with 122 suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and 107 standard laparoscopic nephrectomy was carried out. Operative time, estimated blood loss, intraoperative complications, intraoperative conversion, postoperative bowel recovery, postoperative analgesics, postoperative visual analog pain scale score, postoperative length of stay, days before going back to work, postoperative complications and Patient Scar Assessment Questionnaire were compared after propensity score matching. RESULTS: A total of 97 matched pairs were obtained after propensity score matching. There were no statistically significant differences between the suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and standard laparoscopic nephrectomy groups with respect to operative time, estimated blood loss, intraoperative complications, intraoperative conversion, postoperative bowel recovery, length of stay and postoperative complications. Suprapubic-assisted laparoendoscopic single-site surgery nephrectomy group had decreased postoperative analgesics (20.9 vs 23.5, P = 0.04), visual analog pain scale score at 24 h (4.28 vs 5.28, P = 0.000), visual analog pain scale score at discharge (1.01 vs 1.47, P = 0.000), days before going back to work (28.4 vs 31.9, P = 0.000) and Patient Scar Assessment Questionnaire score (34.0 vs 42.0, P = 0.000), compared with the standard laparoscopic nephrectomy group. CONCLUSIONS: Suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and standard laparoscopic nephrectomy are equivalent in terms of the safety and efficacy. However, suprapubic-assisted laparoendoscopic single-site surgery nephrectomy confers less postoperative pain, fewer days before going back to work and better cosmetic result when compared with standard laparoscopic nephrectomy.

Thymus­expressed chemokine secreted by breast cancer cells promotes metastasis and inhibits apoptosis.

The aim of the present study was to investigate the underlying mechanisms of thymus­expressed chemokine (TECK) autocrine signaling, and its effect on carcinogenesis and the development of breast cancer. The present study also assessed epithelial­mensenchymal transition (EMT) and cell migration, invasion, proliferation and apoptosis. Breast cancer cell lines MCF­7 and MDA­MB­231 were used in the present study, and TECK basic expression in cancer cells was investigated using western blotting (WB). EMT markers, Akt pathway molecules and apoptosis indicators were detected by reverse transcription­quantitative PCR or WB. In order to assess migration and invasion, wound healing and Matrigel invasion assays were performed. Moreover, flow cytometry was used to assess the rate of proliferation and apoptosis. In vivo experiments were conducted in nude mice to assess cancer growth. It was revealed that breast cancer cells could secrete TECK in an autocrine manner. Furthermore, TECK could increase cell migration and invasion by promoting EMT and inhibit apoptosis via the Akt signaling pathway.

CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents.

Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.

Cross-layer model design in wireless ad hoc networks for the Internet of Things.

Wireless ad hoc networks can experience extreme fluctuations in transmission traffic in the Internet of Things, which is widely used today. Currently, the most crucial issues requiring attention for wireless ad hoc networks are making the best use of low traffic periods, reducing congestion during high traffic periods, and improving transmission performance. To solve these problems, the present paper proposes a novel cross-layer transmission model based on decentralized coded caching in the physical layer and a content division multiplexing scheme in the media access control layer. Simulation results demonstrate that the proposed model effectively addresses these issues by substantially increasing the throughput and successful transmission rate compared to existing protocols without a negative influence on delay, particularly for large scale networks under conditions of highly contrasting high and low traffic periods.