Three-Year Clinical Impact of Murray Law-Based Quantitative Flow Ratio and OCT- or FFR-Guidance in Angiographically Intermediate Coronary Lesions.

BACKGROUND: The FORZA trial (FFR or OCT Guidance to Revascularize Intermediate Coronary Stenosis Using Angioplasty) prospectively compared the use of fractional flow reserve (FFR) or optical coherence tomography (OCT) for treatment decisions and percutaneous coronary intervention (PCI) optimization in patients with angiographically intermediate coronary lesions. Murray law-based quantitative-flow-ratio (µQFR) is a novel noninvasive method for the computation of FFR. In the present study, we evaluated the clinical impact of µQFR, FFR, or OCT guidance in FORZA trial lesions at 3-year follow-up. METHODS: µQFR was assessed at baseline and, in the case of a decision to intervene, after (FFR- or OCT-guided) PCI. The baseline µQFR was considered the final µQFR for deferred lesions, and post-PCI µQFR value was taken as final for stented lesions. The primary end point was target vessel failure ([TVF]; cardiac death, target-vessel-related myocardial infarction, and target-vessel-revascularization) at a 3-year follow-up. RESULTS: A total of 419 vessels (199 OCT-guided and 220 FFR-guided) were included in the FORZA trial. µQFR was evaluated in 256 deferred lesions and 159 treated lesions (98 OCT-guided PCI and 61 FFR-guided PCI). In treated lesions, post-PCI µQFR was higher in OCT-group compared with FFR-group (median, 0.93 versus 0.91; P=0.023), and the post-PCI µQFR improvement was greater in FFR-group (0.14 versus 0.08; P<0.0001). At 3-year follow-up, OCT- and FFR-guided treatment decisions resulted in comparable TVF rate (6.7% versus 7.9%; P=0.617). Final µQFR was the only predictor of TVF. µQFR ≤0.89 was associated with 3× increase in TVF (11.6% versus 3.7%; P=0.004). PCI was a predictor of higher final µQFR (odds ratio, 0.22 [95% CI, 0.14-0.34]; P<0.001). CONCLUSIONS: In vessels with angiographically intermediate coronary lesions, OCT-guided PCI resulted in comparable clinical outcomes as FFR-guided PCI. µQFR estimated at the end of diagnostic or interventional procedure predicted 3-year TVF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01824030.

Quantitative proteomics based on TMT revealed the response of PK15 cells infected PEDV wild strain.

Porcine epidemic diarrhea (PED), caused by porcine epidemic diarrhea virus (PEDV), is an acute and highly contagious enteric disease with a high mortality rate in suckling piglets. Identification of proteins associated with PEDV infection may provide insights into the pathogenesis of this viral disease. In this study, we employed tandem mass tag (TMT) quantitative protein analysis to investigate proteomic changes in PK15 cells following PEDV infection, and differential protein expression profiles were obtained at 0 h, 24 h, and 48 h post-infection. Overall, a total of 6330 proteins were identified. Applying criteria for fold change >1.5 < 0.67 and p-values <0.05 resulted in the identification of 59 up-regulated proteins and 103 down-regulated proteins that exhibited significant alterations in the H24 group compared to the H0 group. The H48 group demonstrated significant upregulation of 110 proteins and downregulation of 144 proteins compared to the H0 group; additionally, there were also 10 upregulated and 30 downregulated proteins in the H48 group when compared to the H24 group. These differentially expressed proteins (DEPs) were involved in immune response regulation, signal transduction, lipid transport and metabolism processes as well as cell apoptosis pathways. Based on these DEPs, we propose that PEDV may disrupt signal transduction pathways along with lipid transport and metabolism processes leading to maximal viral replication, it may also trigger inflammatory cascades accordingly. These findings could provide valuable information for elucidating specific pathogenesis related to PEDV infection while contributing towards developing new antiviral strategies.

Transcriptomic analysis reveals impact of gE/gI/TK deletions on host response to PRV infection.

BACKGROUND: Pseudorabies virus (PRV) causes substantial losses in the swine industry worldwide. Attenuated PRV strains with deletions of immunomodulatory genes glycoprotein E (gE), glycoprotein I (gI) and thymidine kinase (TK) are candidate vaccines. However, the effects of gE/gI/TK deletions on PRV-host interactions are not well understood. METHODS: To characterize the impact of gE/gI/TK deletions on host cells, we analyzed and compared the transcriptomes of PK15 cells infected with wild-type PRV (SD2017), PRV with gE/gI/TK deletions (SD2017gE/gI/TK) using RNA-sequencing. RESULTS: The attenuated SD2017gE/gI/TK strain showed increased expression of inflammatory cytokines and pathways related to immunity compared to wild-type PRV. Cell cycle regulation and metabolic pathways were also perturbed. CONCLUSIONS: Deletion of immunomodulatory genes altered PRV interactions with host cells and immune responses. This study provides insights into PRV vaccine design.

Broadband La2LiSbO6: Cr3+ Phosphors with Double Luminescent Centers for NIR pc-LEDs.

The La2LiSbO6: xCr3+ phosphors were synthesized by means of a high-temperature solid-phase method. Based on the differences in ionic radius, valence state, and formation energy, the substitution sites of Cr3+ ions are discussed in detail. The optimized doping concentration of Cr3+ is determined to be 0.01. Under 517 nm excitation, the La2LiSbO6: 0.01Cr3+ phosphor presents a wide emission band (from 700 to 1350 nm) with a peak centered at 952 nm. Additionally, its corresponding full width at half-maximum is 155 nm, and the internal quantum efficiency reaches 62.4%. Meanwhile, the emission intensity of the La2LiSbO6: 0.01Cr3+ phosphor at 373 K is about 63.7% of that at room temperature, exhibiting good thermal stability. Aiming to fabricate a near-infrared phosphor-converted light-emitting diode device, the La2LiSbO6: 0.01Cr3+ phosphor is mixed with epoxy adhesive and cured on a green light-emitting diode chip. Under the irradiation of the fabricated light-emitting diode device, fruits and writing in the dark environment can be captured by a near-infrared camera. Hence, the La2LiSbO6: 0.01Cr3+ phosphor is promising for night vision.

RSL3 Inhibits Porcine Epidemic Diarrhea Virus Replication by Activating Ferroptosis.

Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that induces diarrhea and death in neonatal piglets, resulting in substantial economic losses to the global swine industry. The mechanisms of PEDV infection and the roles of host factors are still under exploration. In this study, we used the ferroptosis pathway downstream target activator (1S,3R)-RSL3 compound as a starting point, combined with the interactions of N-acetylcysteine and deferoxamine, to elucidate the effects of a series of compounds on PEDV proliferation. We also established glutathione peroxidase 4 (GPX4) gene overexpression to further elucidate the relationship between the ferroptosis pathway and PEDV. (1S,3R)-RSL3 inhibited PEDV replication in Vero cells, while N-acetylcysteine and deferoxamine promoted its proliferation. In addition, (1S,3R)-RSL3 mainly affected the replication stage of PEDV. Overexpression of GPX4 promoted PEDV proliferation, indicating that the ferroptosis pathway could influence PEDV replication in Vero cells. This study focused on the mechanism of (1S,3R)-RSL3 inhibition on PEDV, laying the foundation for exploring the pathogenic mechanisms of PEDV and drug development.

Quantitative flow ratio modulated by intracoronary optical coherence tomography for predicting physiological efficacy of percutaneous coronary intervention.

BACKGROUND: The combination of coronary imaging assessment and blood flow perturbation estimation has the potential to improve percutaneous coronary intervention (PCI) guidance. OBJECTIVES: We aimed to evaluate a novel method for fast computation of Murray law-based quantitative flow ratio (µQFR) from coregistered optical coherence tomography (OCT) and angiography (OCT-modulated µQFR, OCT-µQFR) in predicting physiological efficacy of PCI. METHODS: Patients treated by OCT-guided PCI in the OCT-arm of the Fractional Flow Reserve versus Optical Coherence Tomography to Guide RevasculariZAtion of Intermediate Coronary Stenoses trial (FORZA, NCT01824030) were included. Based on angiography and OCT before PCI, simulated residual OCT-µQFR was computed by assuming full stent expansion to the intended-to-treat segment. Plaque composition was automatically characterized using a validated artificial intelligence algorithm. Actual post-PCI OCT-µQFR pullback was computed based on coregistration of angiography and OCT acquired immediately after PCI. Suboptimal functional stenting result was defined as OCT-µQFR ≤ 0.90. RESULTS: Paired simulated residual OCT-µQFR and actual post-PCI OCT-µQFR were obtained in 76 vessels from 74 patients. Simulated residual OCT-µQFR showed good correlation (r = 0.80, p < 0.001), agreement (mean difference = -0.02 ± 0.02, p < 0.001), and diagnostic concordance (79%, 95% confidence interval: 70%-88%) with actual post-PCI OCT-µQFR. Actual post-PCI in-stent OCT-µQFR had a median value of 0.02 and was associated with left anterior descending artery lesion location (ß = 0.38, p < 0.001), higher baseline total plaque burden (ß = 0.25, p = 0.031), and fibrous plaque volume (ß = 0.24, p = 0.026). CONCLUSIONS: This study based on patients enrolled in a prospective OCT-guidance PCI trial shows that simulated residual OCT-µQFR had good correlation, agreement, and diagnostic concordance with actual post-PCI OCT-µQFR. In OCT-guided procedures, OCT-µQFR in-stent pressure drop was low and was significantly predicted by pre-PCI vessel/plaque characteristics.

Comparative transcriptomic analysis of PK15 cells infected with a PRV variant and the Bartha-K/61 vaccine strain.

Introduction: Pseudorabies virus (PRV) is a herpesvirus that can infect domestic animals, such as pigs, cattle and sheep, and cause fever, itching (except pigs), and encephalomyelitis. In particular, the emergence of PRV variants in 2011 have resulted in serious economic losses to the Chinese pig industry. However, the signaling pathways mediated by PRV variants and their related mechanisms are not fully understood. Methods: Here, we performed RNA-seq to compare the gene expression profiling between PRV virulent SD2017-infected PK15 cells and Bartha-K/61-infected PK15 cells. Results: The results showed that 5,030 genes had significantly different expression levels, with 2,239 upregulated and 2,791 downregulated. GO enrichment analysis showed that SD2017 significantly up-regulated differentially expressed genes (DEGs) were mainly enriched in the binding of cell cycle, protein and chromatin, while down-regulated DEGs were mainly enriched in ribosomes. KEGG enrichment analysis revealed that the pathways most enriched for upregulated DEGs were pathways in cancer, cell cycle, microRNAs in cancer, mTOR signaling pathway and autophagy-animal. The most down-regulated pathways of DEGs enrichment were ribosome, oxidative phosphorylation, and thermogenesis. These KEGG pathways were involved in cell cycle, signal transduction, autophagy, and virus-host cell interactions. Discussion: Our study provides a general overview of host cell responses to PRV virulent infection and lays a foundation for further study of the infection mechanism of PRV variant strain.

Physics-Informed Neural Networks With Weighted Losses by Uncertainty Evaluation for Accurate and Stable Prediction of Manufacturing Systems.

The state prediction of key components in manufacturing systems tends to be risk-sensitive tasks, where prediction accuracy and stability are the two key indicators. The physics-informed neural networks (PINNs), which integrate the advantages of both data-driven models and physics models, are deemed as an effective approach and research trends for stable prediction; however, the potential advantages of PINN are limited for the situations with inaccurate physics models or noisy data, where the balancing of the weights of the data-driven model and physics model is very important for improving the performance of PINN, and it is also a challenge urgently to be addressed. This article proposed a kind of PINN with weighted losses (PNNN-WLs) by uncertainty evaluation for accurate and stable prediction of manufacturing systems, where a novel weight allocation strategy based on uncertainty evaluation by quantifying the variance of prediction errors is proposed, and an improved PINN framework is established for accurate and stable prediction. The proposed approach is verified with open datasets on tool wear prediction, and experimental results show that the prediction accuracy and stability could be obviously improved over existing methods.

Erastin inhibits porcine epidemic diarrhea virus replication in Vero cells.

Background: Porcine epidemic diarrhea virus (PEDV), an intestinal pathogenic coronavirus, has caused significant economic losses to the swine industry worldwide. At present, there are several treatment methods, but there is still a lack of clinically effective targeted drugs, new antiviral mechanisms and drugs need to be explored. Methods: In this study, we established a model of erastin versus ferrostatin-1 treatment of Vero cells, and then detected virus proliferation and gene expression by RT-qPCR through PEDV infection experiments. Results: We demonstrated for the first time that erastin significantly inhibited the replication of PEDV upon entry into cells; Vero treated with erastin significantly regulated the expression of three genes, NRF2, ACSL4 and GPX4, notably erastin regulated the expression of these three genes negatively correlated with the expression induced by PEDV virus infection. Conclusions: Since NRF2, ACSL4 and GPX4 are classical Ferroptosis genes, this study speculates that erastin may inhibit the replication of PEDV in Vero cells in part through the regulation of ferroptosis pathway, and erastin may be a potential drug for the treatment of PEDV infection.

Diagnostic accuracy of optical flow ratio: an individual patient-data meta-analysis.

BACKGROUND: Optical flow ratio (OFR) is a novel method for the fast computation of fractional flow reserve (FFR) from optical coherence tomography. AIMS: We aimed to evaluate the diagnostic accuracy of OFR in assessing intermediate coronary stenosis using wire-based FFR as the reference. METHODS: We performed an individual patient-level meta-analysis of all available studies with paired OFR and FFR assessments. The primary outcome was vessel-level diagnostic concordance of the OFR and FFR, using a cut-off of ≤0.80 to define ischaemia and ≤0.90 to define suboptimal post-percutaneous coronary intervention (PCI) physiology. This meta-analysis was registered in PROSPERO (CRD42021287726). RESULTS: Five studies were finally included, providing 574 patients and 626 vessels (404 pre-PCI and 222 post-PCI) with paired OFR and FFR from 9 international centres. Vessel-level diagnostic concordance of the OFR and FFR was 91% (95% confidence interval [CI]: 88%-94%), 87% (95% CI: 82%-91%), and 90% (95% CI: 87%-92%) in pre-PCI, post-PCI, and overall, respectively. The overall sensitivity, specificity, and positive and negative predictive values were 84% (95% CI: 79%-88%), 94% (95% CI: 92%-96%), 90% (95% CI: 86%-93%), and 89% (95% CI: 86%-92%), respectively. Multivariate logistic regression indicated that a low pullback speed (odds ratio [OR] 7.02, 95% CI: 1.68-29.43; p=0.008) was associated with a higher risk of obtaining OFR values at least 0.10 higher than FFR. Increasing the minimal lumen area was associated with a lower risk of obtaining an OFR at least 0.10 lower than FFR (OR 0.39, 95% CI: 0.18-0.82; p=0.013). CONCLUSIONS: This individual patient data meta-analysis demonstrated a high diagnostic accuracy of OFR. OFR has the potential to provide an improved integration of intracoronary imaging and physiological assessment for the accurate evaluation of coronary artery disease.

Sampling via the aggregation value for data-driven manufacturing.

Data-driven modelling has shown promising potential in many industrial applications, while the expensive and time-consuming labelling of experimental and simulation data restricts its further development. Preparing a more informative but smaller dataset to reduce labelling efforts has been a vital research problem. Although existing techniques can assess the value of individual data samples, how to represent the value of a sample set remains an open problem. In this research, the aggregation value is defined using a novel representation for the value of a sample set by modelling the invisible redundant information as the overlaps of neighbouring values. The sampling problem is hence converted to the maximisation of the submodular function over the aggregation value. The comprehensive analysis of several manufacturing datasets demonstrates that the proposed method can provide sample sets with superior and stable performance compared with state-of-the-art methods. The research outcome also indicates its appealing potential to reduce labelling efforts for more data-scarcity scenarios.

Transfer Learning Under Conditional Shift Based on Fuzzy Residual.

Transfer learning has received much attention recently and has been proven to be effective in a wide range of applications, whereas studies on regression problems are still scarce. In this article, we focus on the transfer learning problem for regression under the situations of conditional shift where the source and target domains share the same marginal distribution while having different conditional probability distributions. We propose a new framework called transfer learning based on fuzzy residual (ResTL) which learns the target model by preserving the distribution properties of the source data in a model-agnostic way. First, we formulate the target model by adding fuzzy residual to a model-agnostic source model and reuse the antecedent parameters of the source fuzzy system. Then two methods for bias computation are provided for different considerations, which refer to two ResTL methods called ResTLLS and ResTLRD. Finally, we conduct a series of experiments both on a toy example and several real-world datasets to verify the effectiveness of the proposed method.

Comparison of anatomic and aerodynamic characteristics of the upper airway among edentulous mild, moderate, and severe obstructive sleep apnea in older adults.

STUDY OBJECTIVES: First, to compare the upper airway's anatomic and aerodynamic characteristics of the edentulous older adults who experience mild, moderate, and severe obstructive sleep apnea (OSA). Second, to examine the correlation between the severity of OSA and the anatomic and aerodynamic characteristic(s) of the upper airway in these edentulous individuals. METHODS: NewTom5G cone beam computed tomography scans of 58 edentulous individuals with mild, moderate, and severe OSA were included in this analysis. 1) Computational models of the upper airway were reconstructed based on cone beam computed tomography images and the anatomical and aerodynamic characteristics of the upper airway were examined by an observer blind to OSA severity. 2) Pearson correlation analysis was used to determine the correlation between apnea-hypopnea index and the anatomic and aerodynamic characteristics of the upper airway. RESULTS: Compared with edentulous patients with mild and moderate OSA, those with severe OSA have a more hourglass-shaped upper airway. The severity of OSA, namely, apnea-hypopnea index, was significantly correlated with the length, shape, and minimum cross-sectional area of the upper airway. During inspiration, the mean velocity of the airflow within the upper airway of the edentulous patients with severe OSA was higher than that of patients with mild and moderate OSA. During both inspiration and expiration, apnea-hypopnea index was found to be significantly correlated with maximum velocity (P = .05) and airway resistance (P = .024, 0.038). CONCLUSIONS: The edentulous patients with severe OSA have a more hourglass-shaped upper airway. The findings also suggest that, during inspiration, the airflow travels faster in edentulous patients with severe OSA than in those with mild or moderate OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Effect of Nocturnal Wear of Dentures on Sleep and Oral Health Related Quality of Life; URL: https://clinicaltrials.gov/ct2/show/NCT01868295; Identifier: NCT01868295. CITATION: Chen H, Elham E, Li Y, et al. Comparison of anatomic and aerodynamic characteristics of the upper airway among edentulous mild, moderate, and severe obstructive sleep apnea in older adults. J Clin Sleep Med. 2022;18(3):759-768.

Improvement of Heating Uniformity by Limiting the Absorption of Hot Areas in Microwave Processing of CFRP Composites.

Carbon fiber reinforced polymer (CFRP) composites are integral to today's industries. Curing or consolidation are vital processes for manufacturing CFRP components. Microwave processing has many advantages compared with conventional processing technologies using ovens or autoclaves; however, the uneven temperature distribution caused by the non-uniform microwave field has a significant influence on the quality of the cured products. In this study, we propose a new idea to solve this problem, i.e., limiting the absorption of hot areas. Under such circumstances, cold ones can catch up with them more easily. To adjust the absorbing capability of the CFRP laminate, periodically arranged metallic resonance structures supported by a dielectric spacer are introduced on its surface. The dielectric spacer, made of epoxy matrix and strontium titanate particles, is designed to possess a dielectric constant positively related to temperatures. In this situation, the microwave absorption (2.45 GHz) of the metal-dielectric-CFRP configuration is changed from 97.6% at room temperature to 55.9% at 150 °C continuously. As a result, a reduction of 43.1% in maximum temperature difference and 89% in standard deviation has been achieved.

A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent.

Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic drugs and the ineffectiveness of current therapies. Recently polyamine derivatives have been identified as a promising prospect in dealing with metastatic tumors. Herein, a novel class of naphthalimide-polyamine conjugates 8a-8d, 13a-13c, 17 and 21 were synthesized and the mechanism was further determined. The polyamine conjugate 13b displayed remarkably elevated anti-tumor and anti-metastatic effects (76.01% and 75.02%) than the positive control amonafide (46.91% and 55.77%) at 5 mg/kg in vivo. The underlying molecular mechanism indicated that in addition to induce DNA damage by up-regulating p53 and γH2AX, 13b also targeted lysosome to modulate polyamine metabolism and function in a totally different way from that of amonafide. Furthermore, the HMGB1/p62/LC3II/LC3I and p53/SSAT/ß-catenin pathways were mainly involved in the inhibition of 13b-induced HCC metastasis by targeting polyamine transporters (PTs) overexpressed in HCC. At last, 13b down-regulated the concentrations of Put, Spd and Spm by modulating polyamine metabolism key enzymes SSAT and PAO, which favored the suppression of fast growing tumor cells. Taken together, our study implies a promising strategy for naphthalimide conjugates to treat terminal cancer of HCC by targeting autophagy and tumor microenvironment with reduced toxicities and notable activities.

Automatic Coregistration Between Coronary Angiography and Intravascular Optical Coherence Tomography: Feasibility and Accuracy.

This study sought to evaluate a novel approach for automatic coregistration of optical coherence tomography (OCT) and coronary angiography. Lumen diameters and side branches from both coronary angiography and OCT were used to create 2 feature sets. Subsequently, a 2-step coregistration approach was performed on the feature sets for matching of each OCT cross section on the angiographic centerline. For validation, all side branches with ≥1.0 mm diameter were identified and used as paired fiduciary landmarks. Geographical error was defined as the distance between the automatically coregistered and the true-paired landmarks. Altogether 212 vessels from 181 patients were analyzed. Mismatch of coronary angiography and OCT occurred in 64 of 1,530 reference landmarks. Median geographical error was 0.32 (interquartile range: 0.00-0.56) mm. The mean time for coregistration was 20.69 ± 1.07 seconds. In conclusion, fast and automatic coregistration of OCT and angiography using a single standard angiographic loop is feasible and accurate.

Automatic stent reconstruction in optical coherence tomography based on a deep convolutional model.

Intravascular optical coherence tomography (IVOCT) can accurately assess stent apposition and expansion, thus enabling the optimisation of a stenting procedure to minimize the risk of device failure. This paper presents a deep convolutional based model for automatic detection and segmentation of stent struts. The input of pseudo-3D images aggregated the information from adjacent frames to refine the probability of strut detection. In addition, multi-scale shortcut connections were implemented to minimize the loss of spatial resolution and refine the segmentation of strut contours. After training, the model was independently tested in 21,363 cross-sectional images from 170 IVOCT image pullbacks. The proposed model obtained excellent segmentation (0.907 Dice and 0.838 Jaccard) and detection metrics (0.943 precision, 0.940 recall and 0.936 F1-score), significantly better than conventional features-based algorithms. This performance was robust and homogenous among IVOCT pullbacks with different sources of acquisition (clinical centres, imaging operators, type of stent, time of acquisition and challenging scenarios). In addition, excellent agreement between the model and a commercialized software was observed in the quantification of clinically relevant parameters. In conclusion, the deep-convolutional model can accurately detect stent struts in IVOCT images, thus enabling the fully-automatic quantification of stent parameters in an extremely short time. It might facilitate the application of quantitative IVOCT analysis in real-world clinical scenarios.

A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance.

Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5'-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5'-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5'-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.

A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo.

Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates 5a-5c, 7a-7b, and 11a-11b with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate 5c with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects in vitro and in vivo. More importantly, 5c at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg in vivo. And a remarkably elevated antitumor activity and a reduced toxicity are also observed for 5c at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of 5c to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, 5c can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, 5c downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.

Bromocoumarinplatin, targeting simultaneously mitochondria and nuclei with p53 apoptosis pathway to overcome cisplatin resistance.

Mitochondria as one of potential anticancer target, alternatively damaging mtDNA other than nDNA is a potential method for platinum-based anticancer drugs to overcome cisplatin resistance. We herein report that bromocoumarinplatin 1, a coumarin-Pt(IV) prodrug, targeted simultaneously mitochondria and nuclei with the contents of Pt in nDNA and mtDNA were 25.75% and 65.91%, respectively, which demonstrated mtDNA apoptosis played a key role in overcoming cisplatin resistance. Moreover, 1 promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity of 1 through p53 pathway. The property of preferential accumulation in cancer cells (Snu-368 and Snu-739) compared to the matched normal cells (HL-7702 cells) demonstrated that 1 was potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 1 for HCT-116 cells in vivo indicated that bromocoumarinplatin behaved a vital function in the treatment of colon cancer.