Polymeric Nanoparticles for Drug Delivery.

The recent emergence of nanomedicine has revolutionized the therapeutic landscape and necessitated the creation of more sophisticated drug delivery systems. Polymeric nanoparticles sit at the forefront of numerous promising drug delivery designs, due to their unmatched control over physiochemical properties such as size, shape, architecture, charge, and surface functionality. Furthermore, polymeric nanoparticles have the ability to navigate various biological barriers to precisely target specific sites within the body, encapsulate a diverse range of therapeutic cargo and efficiently release this cargo in response to internal and external stimuli. However, despite these remarkable advantages, the presence of polymeric nanoparticles in wider clinical application is minimal. This review will provide a comprehensive understanding of polymeric nanoparticles as drug delivery vehicles. The biological barriers affecting drug delivery will be outlined first, followed by a comprehensive description of the various nanoparticle designs and preparation methods, beginning with the polymers on which they are based. The review will meticulously explore the current performance of polymeric nanoparticles against a myriad of diseases including cancer, viral and bacterial infections, before finally evaluating the advantages and crucial challenges that will determine their wider clinical potential in the decades to come.

Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

Impact of Preoperative Neutrophil to Prealbumin Ratio Index (NPRI) on Short-Term Complications and Long-Term Prognosis in Patients Undergoing Laparoscopic Radical Surgery for Colorectal Cancer.

Objective: This study aims to evaluate the impact and predictive value of the preoperative NPRI on short-term complications and long-term prognosis in patients undergoing laparoscopic radical surgery for colorectal cCancer (CRC). Methods: A total of 302 eligible CRC patients were included, assessing five inflammation-and nutrition-related markers and various clinical features for their predictive impact on postoperative outcomes. Emphasis was on the novel indicator NPRI to elucidate its prognostic and predictive value for perioperative risks. Results: Multivariate logistic regression analysis identified a history of abdominal surgery, prolonged surgical duration, CEA levels ≥5 ng/mL, and NPRI ≥ 3.94 × 10-2 as independent risk factors for postoperative complications in CRC patients. The Clavien--Dindo complication grading system highlighted the close association between preoperative NPRI and both common and severe complications. Multivariate analysis also identified a history of abdominal surgery, tumor diameter ≥5 cm, poorly differentiated or undifferentiated tumors, and NPRI ≥ 2.87 × 10-2 as independent risk factors for shortened overall survival (OS). Additionally, a history of abdominal surgery, tumor maximum diameter ≥5 cm, tumor differentiation as poor/undifferentiated, NPRI ≥ 2.87 × 10-2, and TNM Stage III were determined as independent risk factors for shortened disease-free survival (DFS). Survival curve results showed significantly higher 5-year OS and DFS in the low NPRI group compared to the high NPRI group. The incorporation of NPRI into nomograms for OS and DFS, validated through calibration and decision curve analyses, attested to the excellent accuracy and practicality of these models. Conclusion: Preoperative NPRI independently predicts short-term complications and long-term prognosis in patients undergoing laparoscopic colorectal cancer surgery, enhancing predictive accuracy when incorporated into nomograms for patient survival.

Self-Immolative Polymer Nanoparticles with Precise and Controllable pH-Dependent Degradation.

Polymer nanoparticles have generated significant interest as delivery systems for therapeutic cargo. Self-immolative polymers (SIPs) are an interesting category of materials for delivery applications, as the characteristic property of end-to-end depolymerization allows for the disintegration of the delivery system, facilitating a more effective release of the cargo and clearance from the body after use. In this work, nanoparticles based on a pH-responsive polymer poly(ethylene glycol)-b-(2-diisopropyl)amino ethyl methacrylate) and a self-immolative polymer poly[N,N-(diisopropylamino)ethyl glyoxylamide-r-N,N-(dibutylamino)ethyl glyoxylamide] (P(DPAEGAm-r-DBAEGAm)) were developed. Four particles were synthesized based on P(DPAEGAm-r-DBAEGAm) polymers with varied diisopropylamino to dibutylamino ratios of 4:1, 2:1, 2:3, and 0:1, termed 4:1, 2:1, 2:3, and 0:1 PGAm particles. The pH of particle disassembly was tuned from pH 7.0 to pH 5.0 by adjusting the ratio of diisopropylamino to dibutylamino substituents on the pendant tertiary amine. The P(DPAEGAm-r-DBAEGAm) polymers were observed to depolymerize (60-80%) below the particle disassembly pH after ∼2 h, compared to <10% at pH 7.4 and maintained reasonable stability at pH 7.4 (20-50% depolymerization) after 1 week. While all particles exhibited the ability to load a peptide cargo, only the 4:1 PGAm particles had higher endosomal escape efficiency (∼4%) compared to the 2:3 or 0:1 PGAm particles (<1%). The 4:1 PGAm particle is a promising candidate for further optimization as an intracellular drug delivery system with rapid and precisely controlled degradation.

Prognostic model for oversurvival and tumor-specific survival prediction in patients with advanced extrahepatic cholangiocarcinoma: a population-based analysis.

BACKGROUND: The prognosis of patients with extrahepatic cholangiocarcinoma (ECCA) must be determined with precision. However, the usual TNM staging system has the drawback of ignoring age, adjuvant therapy, and gender and lacks the ability to more correctly predict patient prognosis. Therefore, we determine the risk factors of survival for patients with advanced ECCA patients and developed brand-new nomograms to forecast patients with advanced ECCA's overall survival (OS) and cancer-specific survival (CSS). METHOD: From the Epidemiology and End Results (SEER) database, patients with advanced ECCA were chosen and randomly assigned in a ratio of 6:4 to the training and validation subgroups. The cumulative incidence function (CIF) difference between groups was confirmed by applying Gray's and Fine test and competing risk analyses. Next, the cancer-specific survival (CSS) and overall survival (OS) nomograms for advanced ECCA were developed and validated. RESULTS: In accordance with the selection criteria, 403 patients with advanced ECCA were acquired from the SEER database and then split at random into two groups: a training group (n = 241) and a validation group (n = 162). The 1-, 2-, and 3-year cancer-specific mortality rates were 58.7, 74.2, and 78.0%, respectively, while the matching mortality rates for the competition were 10.0, 13.8, and 15.0%. Nomograms were generated for estimating OS and CSS, and they were assessed using the ROC curve and the C-index. The calibration curves showed that there was a fair amount of agreement between the expected and actual probabilities of OS and CSS. Additionally, greater areas under the ROC curve were seen in the newly developed nomograms for OS and CSS when compared to the 7th AJCC staging system. The advanced ECCA patients were divided into groupings with an elevated risk and those with a low risk and the Kaplan-Meier method was used for the survival analysis, which showed that survival time was shorter in the high-risk group than in the low-risk group. CONCLUSION: The proposed nomograms have good predictive ability. The nomograms may can help doctors determine the prognosis of patients with advanced ECCA as well as provide more precise treatment plans for them.

Two-way focal stack fusion for light field saliency detection.

To improve the accuracy of saliency detection in challenging scenes such as small objects, multiple objects, and blur, we propose a light field saliency detection method via two-way focal stack fusion. The first way extracts latent depth features by calculating the transmittance of the focal stack to avoid the interference of out-of-focus regions. The second way analyzes the focused distribution and calculates the background probability of the slice, which can distinguish the foreground from the background. Extracting the potential cues of the focal stack through the two different ways can improve saliency detection in complex scenes. Finally, a multi-layer cellular automaton optimizer is utilized to incorporate compactness, focus, center prior, and depth features to obtain the final salient result. Comparison and ablation experiments are performed to verify the effectiveness of the proposed method. Experimental results prove that the proposed method demonstrates effectiveness in challenging scenarios and outperforms the state-of-the-art methods. They also verify that the depth and focus cues of the focal stack can enhance the performance of previous methods.

Characteristics of thermal pollution from stormwater runoff from impermeable/permeable pavement surfaces via a lab-scale experiment.

Thermal pollution from stormwater runoff has been the focus of many studies in recent years due to its potential harm to aquatic microorganisms. However, there were few studies on the thermal pollution caused by stormwater runoff from various types of urban pavement surfaces. A lab-scale experiment was conducted to compare the thermal load of stormwater runoff from impermeable and permeable pavements and the influencing factors were investigated. The experimental findings demonstrated that the rainfall return period and initial temperature of various pavement surfaces significantly impacted the thermal load. The stormwater runoff absorbed more heat as the initial temperature, and rainfall return period increased. The difference of the thermal load of stormwater runoff between permeable brick pavement (PBP) and the impermeable asphalt pavement (IAP) increased from 305.26 to 436.70 kJ/m2, when the initial surface temperature rose from 35 to 47 °C. The average runoff temperature decreased by 1.39-1.90 °C for PBP compared to the IAP, with an increase in surface temperature from 35 to 47 °C. Under the various initial surface temperatures, the mean temperature of the infiltration effluent from the PBP was 3.12-4.20 °C lower than the average temperature of stormwater runoff from the surface layer. Therefore, a PBP can effectively alleviate thermal pollution from stormwater runoff and safeguard the receiving waters' quality.

Effect of different MIT rainfall event division methods on volume capture ratio of annual rainfall based on bioretention assessment.

Volume capture ratio of annual rainfall (VCRAR) is the key parameter of low-impact development (LID) facilities design, which is significantly affected by the rainfall event division method. However, there is no universal agreement on how to determine an optimal division method to achieve it. A modified minimum inter-event time (MIT) method based on MATLAB software was proposed to find an optimal MIT value. The result showed that the optimal MIT value in Beijing is 200 min based on the daily rainfall data from 1987 to 2016, and the annual average rainfall events were 34.2 with an average rainfall depth of 13.7 mm. Taking bioretention facilities as an example, the errors of design VCRAR under different MIT values were compared based on a Stormwater Management Model (SWMM). The results showed that when design VCRAR was ≤50, 55-60, 60-75, 75-80 and >80%, the optimal MIT value for LID facilities design was 60, 120, 200, 360 and 1,440 min, respectively. Therefore, the optimal MIT should be flexibly selected with the changing of design VCRAR, to ensure that LID facilities meet the design goals.

Exploring Focus and Depth-Induced Saliency Detection for Light Field.

An abundance of features in the light field has been demonstrated to be useful for saliency detection in complex scenes. However, bottom-up saliency detection models are limited in their ability to explore light field features. In this paper, we propose a light field saliency detection method that focuses on depth-induced saliency, which can more deeply explore the interactions between different cues. First, we localize a rough saliency region based on the compactness of color and depth. Then, the relationships among depth, focus, and salient objects are carefully investigated, and the focus cue of the focal stack is used to highlight the foreground objects. Meanwhile, the depth cue is utilized to refine the coarse salient objects. Furthermore, considering the consistency of color smoothing and depth space, an optimization model referred to as color and depth-induced cellular automata is improved to increase the accuracy of saliency maps. Finally, to avoid interference of redundant information, the mean absolute error is chosen as the indicator of the filter to obtain the best results. The experimental results on three public light field datasets show that the proposed method performs favorably against the state-of-the-art conventional light field saliency detection approaches and even light field saliency detection approaches based on deep learning.

Nonionic Polymer with Flat Upper Critical Solution Temperature Behavior in Water.

We rationally designed a monomer that when polymerized formed a well-defined nonionic polymer [poly(2-(methacryloyloxy) ethylureido glycinamide), PMEGA] by reversible addition fragmentation chain transfer with a flat and tunable upper critical solution temperature (UCST) in water. The monomer was made in one pot from commercially available compounds and with ease of purification. Strong hydrogen-bonding side groups on the polymer produced sharp coil-to-globule transitions upon cooling below its UCST. Ideal random copolymers produced with butyl methacrylate also showed flat UCST profiles, in which the UCST increased with a greater butyl methacrylate copolymer composition from 7 to 65 °C. In the presence of NaCl, the UCST decreased linearly with NaCl concentration due to the "salting-in" effect, and it was found that the slopes from the linear decrease of UCST were nearly identical for all copolymer compositions. This new polymer and its copolymers support the hypothesis that strong hydrogen bonding between the side groups allowed the flat UCST to be readily tuned with a high level of predictability. We postulate that this polymer system may provide wide biological applicability similar to that found for the well-used flat lower critical solution temperature (LCST) of poly(N-isopropylacrylamide).

Lewis Base Catalyzed Synthesis of Sulfur Heterocycles via the C1-Pyridinium Enolate.

While the addition of C1-Lewis base enolates to carbonyls and related structures are well established, the related addition to thiocarbonyls compounds are unknown. Herein, we report a reaction cascade in which a C1-pyridinium enolate undergos addition to dithioesters, trithiocarbonates and xanthates. The reaction provides access to a range of dihydrothiophenes and dihydrothiopyrans (28-examples). Mechanistic investigations, including isolation of intermediates, electronic correlation, and kinetic isotope effect studies support the viability of an activated acid intermediate giving rise to the C1-pyridinium enolate which undergoes turnover limiting cyclization. Subsequent formation of a ß-thiolactone regenerates the catalyst with loss of carbon oxysulfide providing the observed products.

Acid-Responsive Poly(glyoxylate) Self-Immolative Star Polymers.

Self-immolative polymers have significant potential for applications such as drug or gene delivery. However, to realize this potential, such materials need to be customized to respond to specific variations in biological conditions. In this work, we investigated the design of new star-shaped self-immolative poly(ethyl glyoxylate)s (PEtGs) and their incorporation into responsive nanoparticles. PEtGs are a subclass of stimulus-responsive self-immolative polymers, which can be combined with different stimuli-responsive functionalities. Two different tetrathiol initiators were used for the polymerization in combination with a variety of potential pH-responsive end-caps, yielding a library of star PEtG polymers which were responsive to pH. Characterization of the depolymerization behavior of the polymers showed that the depolymerization rate was controlled by the end caps rather than the architecture of the polymer. A selection of the star polymers were modified with amines to allow introduction of charge-shifting properties. It was shown that pH-responsive nanoparticles could be prepared from these modified polymers and they demonstrated pH-dependent particle disruption. The pH responsiveness of these particles was studied by dynamic light scattering and 1H nuclear magnetic resonance spectroscopy.

Comparison between different infiltration models to describe the infiltration of permeable brick pavement system via a laboratory-scale experiment.

The permeable brick pavement system (PBPs) is one of a widely used low impact development (LID) measures to alleviate runoff volume and pollution caused by urbanization. The performance of PBPs on decreasing runoff volume is decided by its permeability, and it was general described by hydraulic conductivity based on Darcy's law. But there is large error when using hydraulic conductivity to describe the infiltration of PBPs, and which infiltration process is not following Darcy's law, so it is important to find more accurate infiltration models to describe the infiltration of PBPs. The Horton, Philip, Green-Ampt, and Kostiakov infiltration models were selected to find an optimal model to investigate infiltration performance of PBPs via a laboratory-scale experiment, and the maximum absolute error (MAE), Bias, and coefficient of determination (R2) were selected to evaluate the models' errors via fitting with experiment data. The results showed that the fitting accuracy of Kostiakov, Philip, and Green-Ampt models was significantly affected by the monitoring area and hydraulic gradients. Meanwhile, Horton model fitted well (MAE = 0.25-0.32 cm/h, Bias = 0.07-0.11 cm/h, and R2 = 0.98-0.99) with the experiment data, and the parameters of the Horton model often can be achieved by monitoring, such as the maximum infiltration rate and the stable infiltration rate. Therefore, the Horton model is an optimal model to describe the infiltration performance of PBPs, which can also be adopted to evaluate hydrological characterization of PBPs.

pH-Responsive Polymer Nanoparticles for Drug Delivery.

Stimuli-responsive nanoparticles have the potential to improve the delivery of therapeutics to a specific cell or region within the body. There are many stimuli that have shown potential for specific release of cargo, including variation of pH, redox potential, or the presence of enzymes. pH variation has generated significant interest for the synthesis of stimuli-responsive nanoparticles because nanoparticles are internalized into cells via vesicles that are acidified. Additionally, the tumor microenvironment is known to have a lower pH than the surrounding tissue. In this review, different strategies to design pH-responsive nanoparticles are discussed, focusing on the use of charge-shifting polymers, acid labile linkages, and crosslinking.

Enantioselective N-Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut-Currier Reaction.

While the enantioselective Rauhut-Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high-nucleophilicity N-heterocyclic carbenes, it is possible to achieve Rauhut-Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

Enantioselective N-Heterocyclic Carbene Catalysis that Exploits Imine Umpolung.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover-limiting addition of the NHC to the imine.

Enantioselective N-Heterocyclic Carbene Catalyzed Cyclopentene Synthesis via the ß-Azolium Ylide.

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the ß-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

Association of downregulation of WWOX with poor prognosis in patients with intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND AND AIM: Downregulation of the WW domain containing oxidoreductase (WWOX) has been reported to be involved in tumorigenesis in several neoplasms. This study sought to investigate the expression and role of WWOX in intrahepatic cholangiocarcinoma (ICC). METHODS: WWOX expression was measured by quantitative real-time polymerase chain reaction (PCR), immunoblot, immunofluorescence, and immunohistochemistry. The prognostic significance was assessed by Kaplan-Meier and Cox regression analyses. The role of WWOX in proliferation, anchorage-independent growth, gene expression regulation, and tumorigenesis was assessed by WWOX re-expression using lentivirus. Methylation-specific PCR was performed to evaluate the methylation status of the WWOX gene regulatory region. A DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), was used to activate the endogenous WWOX gene in ICC cells both in vitro and in vivo. RESULTS: The expression of WWOX in ICC tissues was much lower than that in nontumorous samples and showed reverse correlation with proliferative status. Restoration of WWOX expression resulted in suppression of the growth of WWOX-deficient ICC cells through activation of the intrinsic apoptotic signaling pathway, but did not affect growth of WWOX-sufficient human intrahepatic biliary epithelial derived non-cancer cells. Multivariate analyses revealed that downregulation of WWOX was an unfavorable predictor for overall survival and cumulative recurrence rates. The WWOX gene regulatory region was frequently methylated in ICC tissues and cell lines, and intratumoral WWOX restoration, through AZA injection, suppressed tumor growth in nude mice. CONCLUSION: Downregulation of WWOX may occur as a result of hypermethylation and implies a poor prognosis in ICC; WWOX re-expression may be a potential molecular therapeutic target for ICC.

Research update for ferroptosis and cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common hepatobiliary malignancy after hepatocellular carcinoma. Due to the poor treatment effect and high mortality rate of CCA, it is of great significance to explore new therapeutic targets. Ferroptosis is a type of cell death caused by iron-dependent cell oxidative injury, which is closely related to the occurrence and development of numerous diseases. Novel ideas for the prevention and treatment of related diseases have been provided by ferroptosis, which has become a focus of research in recent years. This review introduces the underlying mechanisms related to ferroptosis, as well as a research update for ferroptosis in the occurrence and development of CCA. The clinical value of ferroptosis-related regulatory mechanisms in CCA will be elucidated.

Effects of soil colloids on adsorption and migration of benzo(a)pyrene on contaminated sites under runoff infiltration processes.

In the environment, soil colloids are widespread and possess a significant adsorption capacity. This makes them capable of transporting different pollutants, presenting a potential risk to human and ecological well-being. This study aimed to examine the adsorption and co-migration characteristics of benzo(a)pyrene (BaP) and soil colloids in areas contaminated with organic substances, utilizing both static and dynamic batch experiments. In the static adsorption experiments, it was observed that the adsorption of BaP onto soil colloids followed the pseudo-second-order kinetic model (R2 = 0.966), and the adsorption isotherm conformed to the Langmuir model (R2 = 0.995). The BaP and soil colloids primarily formed bonds through π-π interactions and hydrogen bonds. The dynamic experimental outcomes revealed that elevating colloids concentration contributed to increased BaP mobility. Specifically, when the concentration of soil colloids in influent was 500 mg L-1, the mobility of BaP was 23.2 % compared to that without colloids of 13.4 %. Meanwhile, the lowering influent pH value contributed to increased BaP mobility. Specifically, when the influent pH value was 4.0, the mobility of BaP was 30.1 %. The BaP's mobility gradually declined as the initial concentration of BaP in polluted soil increased. Specifically, when the initial concentration of BaP in polluted soil was 5.27 mg kg-1, the mobility of BaP was 39.1 %. This study provides a support for controlling BaP pollution in soil and groundwater.