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Heat treatment and pH are crucial factors in the formulation and processing of food and beverages; thus, a thorough understanding of the impact of these factors on the interactions between bioactive constituents and proteins is essential to developing effective protein-based delivery systems. This study explores the influences of pH (ranged from 1.5 to 7.5) and preheating treatment on the characteristics of caseinates-lutein (LU)/zeaxanthin (ZX) complexes and evaluates the potential application of caseinates as protective carriers in xanthophyll-fortified beverages. The properties and interactions of caseinates and two xanthophylls were systematically investigated utilizing a range of spectroscopic techniques, including ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), fluorescence spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Caseinates were bound to LU/ZX with a binding constant of the order 105 M-1. Furthermore, ZX exhibited a higher affinity for caseinates than LU. In particular, the decreased pH level of complex formulation and the preheating of caseinates at 85 °C strengthened the binding affinity between LU/ZX and caseinates. The caseinate-LU/ZX complexes effectively improved the chemical stability of LU/ZX and achieved a bioaccessibility rate of over 70 %. This study provides a guide for developing commercially available xanthophyll-fortified beverages and further expanding the application of caseinates as encapsulation carriers for extremely hydrophobic nutrients in the food industry.

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Folates, a crucial B-group vitamin, serve as a significant functional food supplement. Nevertheless, considerable obstacles persist in improving folates stability in liquid products. In this study, folic acid (FA) and 5-methyltetrahydrofolate (MTFA), two approved sources of folates, were encapsulated with sodium caseinate (NaCas) to enhance their stability. The protective effect of NaCas on folate molecules was investigated using experimental and computational methods. Meanwhile, the influence of divalent calcium ion (Ca2+) on the properties of the NaCas-MTFA complex was examined to evaluate the potential application of calcium 5-methyltetrahydrofolate (CaMTFA). Fluorescence tests showed both folates had static quenching behavior and bound to NaCas with a binding constant of 104-105 M-1. Hydrophobic interactions were crucial in NaCas-FA complex formation, while hydrogen bonding drove NaCas-MTFA binding. The encapsulation of caseinate notably slowed down the degradation of folates under both light and dark conditions. Moreover, the addition of a low concentration of Ca2+ did not adversely impact the binding mechanism of the NaCas-MTFA complex or the degradation curve of MTFA. The results of this study could serve as a valuable resource for the utilization of caseinates in incorporating folates, specifically MTFA, in the creation of natural liquid dietary supplements.

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Natural polysaccharide-based active-ingredient carriers have been a source of great concern for a long time. In order to explore potential antibiotics and probiotics carriers, a novel injectable chondroitin sulfate/salecan (CS) hydrogel was constructed by forming dynamic hydrazone bonds. Scanning electron microscope (SEM), proton nuclear magnetic resonance (1H NMR), Fourier transform infrared spectroscopy (FTIR), bacteriostatic test, and rheological experiments were used to investigate the chemical structure, inherent morphology, and enzymatic corruption of the hydrogel in vitro. The resulting hydrogels exhibited ideal probiotics loading capacity, drug release behavior, excellent antimicrobial activity and variable properties. Crucially, owing to its exceptional biocompatibility and reversible crosslinking network, this hydrogel can function as a three-dimensional extracellular matrix for cells, enabling cells to maintain high vitality and proliferation, and promote wound healing. The aforementioned findings indicated that this novel hydrogel can be a promising candidate as an active-ingredient carrier and scaffold material for tissue engineering.

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BACKGROUND: The tumor burden within the axillary lymph nodes (ALNs) constitutes a pivotal factor in breast cancer, serving as the primary determinant for treatment decisions and exhibiting a close correlation with prognosis. OBJECTIVE: This study aimed to investigate the potential of ultrasound-based radiomics and clinical characteristics in non-invasively distinguishing between low tumor burden (1-2 positive nodes) and high tumor burden (more than 2 positive nodes) in patients with node-positive breast cancer. METHODS: A total of 215 patients with node-positive breast cancer, who underwent preoperative ultrasound examinations, were enrolled in this study. Among these patients, 144 cases were allocated to the training set, 37 cases to the validation set, and 34 cases to the testing set. Postoperative histopathology was used to determine the status of ALN tumor burden. The region of interest for breast cancer was delineated on the ultrasound image. Nine models were developed to predict high ALN tumor burden, employing a combination of three feature screening methods and three machine learning classifiers. Ultimately, the optimal model was selected and tested on both the validation and testing sets. In addition, clinical characteristics were screened to develop a clinical model. Furthermore, Shapley additive explanations (SHAP) values were utilized to provide explanations for the machine learning model. RESULTS: During the validation and testing sets, the models demonstrated area under the curve (AUC) values ranging from 0.577 to 0.733 and 0.583 to 0.719, and accuracies ranging from 64.9% to 75.7% and 64.7% to 70.6%, respectively. Ultimately, the Boruta_XGB model, comprising five radiomics features, was selected as the final model. The AUC values of this model for distinguishing low from high tumor burden were 0.828, 0.715, and 0.719 in the training, validation, and testing sets, respectively, demonstrating its superiority over the clinical model. CONCLUSIONS: The developed radiomics models exhibited a significant level of predictive performance. The Boruta_XGB radiomics model outperformed other radiomics models in this study.

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The hormone receptor (HR) status plays a significant role in breast cancer, serving as the primary guide for treatment decisions and closely correlating with prognosis. This study aims to investigate the predictive value of radiomics analysis in long-axis and short-axis ultrasound planes for distinguishing between HR-positive and HR-negative breast cancers. A cohort of 505 patients from two hospitals was stratified into discovery (Institute 1, 416 patients) and validation (Institute 2, 89 patients) cohorts. A comprehensive set of 788 ultrasound radiomics features was extracted from both long-axis and short-axis ultrasound planes, respectively. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, distinct models were constructed for the long-axis and short-axis data. Subsequently, radiomics scores (Rad-scores) were computed for each patient. Additionally, a combined model was formulated by integrating data from long-axis and short-axis Rad-scores along with clinical factors. The diagnostic efficacy of all models was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). The long-axis and short-axis models, consisting of 11 features and 15 features, respectively, were established, yielding AUCs of 0.743 and 0.751 in the discovery cohort, and 0.795 and 0.744 in the validation cohort. The calculated long-axis and short-axis Rad-scores exhibited significant differences between HR-positive and HR-negative groups across all cohorts (all p < 0.001). Univariate analysis identified ultrasound-reported tumor size as an independent predictor. The combined model, incorporating long-axis and short-axis Rad-scores along with tumor size, achieved superior AUCs of 0.788 and 0.822 in the discovery and validation cohorts, respectively. The combined model effectively distinguishes between HR-positive and HR-negative breast cancers based on ultrasound radiomics features and tumor size, which may offer a valuable tool to facilitate treatment decision making and prognostic assessment.

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Lutein (Lut) and zeaxanthin (Zx) are promising healthy food ingredients; however, the low solubilities, stabilities, and bioavailabilities limit their applications in the food and beverage industries. A protein-based complex represents an efficient protective carrier for hydrophobic ligands, and its ligand-binding properties are influenced by the formulation conditions, particularly the pH level. This study explored the effects of various pH values (2.5-9.5) on the characteristics of whey protein isolate (WPI)-Lut/Zx complexes using multiple spectroscopic techniques, including ultraviolet-visible (UV-Vis), fluorescence, and Fourier transform infrared (FTIR) spectroscopies and dynamic light scattering (DLS). UV-Vis and DLS spectra revealed that Lut/Zx were present as H-aggregates in aqueous solutions, whereas WPI occurred as nanoparticles. The produced WPI-Lut/Zx complexes exhibited binding constants of 104-105 M-1, which gradually increased with increasing pH from 2.5 to 9.5. FTIR spectra demonstrated that pH variations and Lut/Zx addition caused detectable changes in the secondary WPI structure. Moreover, the WPI-Lut/Zx complexes effectively improved the physicochemical stabilities and antioxidant activities of Lut/Zx aggregates during long-term storage and achieved bioaccessibilities above 70% in a simulated gastrointestinal digestion process. The comprehensive data obtained in this study offer a basis for formulating strategies that can be potentially used in developing commercially available WPI complex-based xanthophyll-rich foods.

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Rationale and Objectives: We aimed to develop and validate prediction models for histological grade of invasive breast carcinoma (BC) based on ultrasound radiomics features and clinical characteristics. Materials and Methods: A number of 383 patients with invasive BC were retrospectively enrolled and divided into a training set (207 patients), internal validation set (90 patients), and external validation set (86 patients). Ultrasound radiomics features were extracted from all the eligible patients. The Boruta method was used to identify the most useful features. Seven classifiers were adopted to developed prediction models. The output of the classifier with best performance was labeled as the radiomics score (Rad-score) and the classifier was selected as the Rad-score model. A combined model combining clinical factors and Rad-score was developed. The performance of the models was evaluated using receiver operating characteristic curve. Results: Seven radiomics features were selected from 788 candidate features. The logistic regression model performing best among the 7 classifiers in the internal and external validation sets was considered as Rad-score model, with areas under the receiver operating characteristic curve (AUC) values of 0.731 and 0.738. The tumor size was screened out as the risk factor and the combined model was developed, with AUC values of 0.721 and 0.737 in the internal and external validation sets. Furthermore, the 10-fold cross-validation demonstrated that the 2 models above were reliable and stable. Conclusion: The Rad-score model and combined model were able to predict histological grade of invasive BC, which may enable tailored therapeutic strategies for patients with BC in routine clinical use.

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Solid dispersions (SDs) have emerged as a promising strategy to enhance the solubility and bioavailability of poorly soluble active pharmaceutical ingredients. However, SDs tend to recrystallize unless suitable excipients are utilized. This study aimed to facilitate the rational selection of polymers and formulation design by evaluating the impact of various polymers on the miscibility, and phase behavior of SDs using baloxavir marboxil (BXM) with a high crystallization tendency as a model drug. Meanwhile, the effects of these polymers on the solubility enhancement and recrystallization inhibition were also assessed. The results indicated that the miscibility limit of BXM for HPMCAS was around 40 % drug loading (DL), whereas for PVP, PVPVA, and HPMC approximately 20 % DL. The BXM-HPC system exhibited limited miscibility with DL of 10 % or higher. BXM SDs based on various polymers exhibited varying degrees of spontaneous phase separation once DL exceeded the miscibility limit. Interestingly, a correlation was discovered between the phase separation behavior and the ability of the polymer to inhibit recrystallization. BXM-HPMCAS SDs exhibited optimal dissolution performance, compared with other systems. In conclusion, the physicochemical properties of polymers significantly influence BXM SDs performance and the BXM-HPMCAS SDs might promote an efficient and stable drug delivery system.

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The burgeoning interest in the versatile hydrogel matrix, with its multifarious applications, has spurred extensive research in recent years. However, the implementation of chemically crosslinked gels on a large-scale has been hindered by their poor biosafety and excessive energy consumption. To address these challenges, this study focuses on harnessing physical methods to engineer novel composite hydrogels utilizing natural polysaccharides Salecan and whey protein isolate, obviating the need for structural modification or chemical crosslinking. The aim was to explore the rheological properties to understand their multiple behaviors. Various models, including Power-Law, Herschel-Bulkley, and Arrhenius, were also employed to compare and analyze rheological parameters. This study holds significance as it is the pioneering report on the hydrogels fabricated from Salecan/Whey protein isolate. These gels possess favorable attributes encompassing optimized elasticity, thermal-stability, enhanced injectability, and self-recovery, rendering them suitable for a multitude of applications in the realms of food and biomedicine.

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RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.

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RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

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In this paper, two-dimensional Graphdiyne and Hexakis-[(trimethylsilyl)ethynyl]benzene nanosheets were prepared using the liquid-phase exfoliation method and were then successfully applied to 1.06 µm passively Q-Switched all-solid-state lasers. The Hexakis-[(trimethylsilyl)ethynyl]benzene was applied for the first time in passively Q-Switched all-solid-state lasers, as we know. For Graphdiyne, the Q-Switched pulse achieved a narrowest pulse width of 415 ns, a maximum repetition frequency of 244.2 kHz, a maximum pulse energy of 133.53 nJ, and peak power of 321.77 mW was obtained. While, the narrowest pulse width, maximum repetition frequency, maximum pulse energy, and peak power for Hexakis-[(trimethylsilyl)ethynyl]benzene are approximately 398.4 ns, 297.1 kHz, 89.61 nJ, and 220.39 mW respectively. The findings demonstrate the promising potential of both candidates as saturable absorbers for signal modulation in solid-state lasers.

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In current inertial confinement fusion (ICF) facilities, potassium dihydrogen phosphate (KH2PO4, KDP) type crystals are the only nonlinear optical (NLO) materials that can satisfy the aperture requirement of the ICF laser driver. Ammonium dihydrogen phosphate (NH4H2PO4, ADP) crystal is a typical isomer of KDP crystal, with a large nonlinear optical coefficient, high ultraviolet transmittance, and large growth sizes, which is an important deep ultraviolet (UV) NLO material. In this paper, we investigated the effect of ADP temperature on its fourth-harmonic-generation (FHG) performance. When the temperature of the ADP crystal was elevated to 48.9 °C, the 90° phase-matched FHG of the 1064 nm laser was realized. Compared with the 79° phase-matched FHG at room temperature (23.0 °C), the output energy at 266 nm, conversion efficiency, angular acceptance, and laser-induced damage threshold (LIDT) increased 113%, 71%, 623%, 19.6%, respectively. It shows that elevating ADP temperature is an efficient method to improve its deep UV frequency conversion properties, which may also be available to other NLO crystals. This discovery provides a very valuable technology for the future development of UV, deep UV lasers in ICF facilities.

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Paxlovid®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially the elderly and those with dysphagia. Therefore, an oral liquid formulation that can overcome this shortcoming and improve patient compliance is required. In this study, we developed a liquid formulation containing NRV and RTV by adopting strategies that used co-solvents and surfactants to enhance the solubility and inhibit possible recrystallization. The in vitro release results showed that NRV and RTV could be maintained at high concentrations in solution for a certain period in the investigated media. In vivo studies in rats showed that the oral bioavailability of NRV/RTV solution was significantly enhanced. Compared to Paxlovid® tablets, the AUC(0-t) of NRV and RTV increased by 6.1 and 3.8 times, respectively, while the Cmax increased by 5.5 times for both. Furthermore, the promoting effect of the absorption of RTV on the bioavailability of NRV was confirmed. Experiments with a beagle showed a similar trend. Stability studies were also conducted at 4 °C, 25 °C, and 40 °C for 90 days, indicating that the oral liquid formulation was physically and chemically stable. This study can be used as a valuable resource for developing and applying oral liquid NRV/RTV formulations in a clinical context.

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Blue-laser-diode-pumped Pr3+-based continuous-wave (CW) green lasers have aroused growing research interest in developing optoelectronic applications and deep ultraviolet laser sources due to their simple and compact structural design. However, the obstacle of thermally induced effects limits the available output power of Pr3+-based green lasers. Herein, combined with the theoretical analysis and experimental feedback, we effectively adjust the heat distribution inside the Pr3+:LiYF4 gain crystal by optimizing the crystal dimension and doping concentration. The excellent mode matching between the pump and green lasers is achieved under the consideration of thermally induced effects, yielding a maximum CW output power of 7.56 W. To the best of our knowledge, this is the largest output power of Pr3+-based CW green lasers so far. Moreover, the obtained green laser demonstrates excellent output stability (RMS = 1.27%) and beam quality (M2 = 1.30 × 1.12) under the lasing operation state with the maximum output power. We hope that this study can provide a feasible paradigm for developing blue-laser-diode-pumped visible lasers, especially for high-power lasers.

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Ovarian cancer is a less common tumor in women compared to cervical or breast cancer, however it is more malignant and has worse outcomes. Ovarian cancer patients still have a five-year survival rate < 50% despite advances in therapy. Due to recent developments in immune checkpoint inhibitors (ICIs), cancer immunotherapy has attracted increased interest. Pyroptosis is a highly inflammatory form of cell death, which is essential for bridging innate and adaptive immunity, and is involved in immune regulation within the tumor microenvironment (TME). Recent research has shown that pyroptosis can promote immunotherapy of ovarian cancer, including treatment with chimeric antigen receptor T-cells (CAR-T) or ICIs. Moreover, inflammasomes, various signaling pathways and lncRNAs can all affect pyroptosis in ovarian cancer. Here we discuss how pyroptosis affects the development and progression of ovarian cancer as well as the TME. We also provide a summary of small molecule drugs that could target pyroptotic cell death processes and may be useful in ovarian cancer therapy.

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Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

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BACKGROUND: Intracardiac leiomyoma is a rare benign right heart tumor that usually extends from the intravenous system. The patient often has a history of uterine leiomyoma. CASE PRESENTATION: We report a 46-year-old female patient who presented to us with exertional dyspnea, chest tightness, and shortness of breath for two weeks and had a history of uterine leiomyoma resection. Echocardiography showed a pedunculated solid mass in the right heart with the pedicle attached to the inferior vena cava. The surgery was performed under cardiopulmonary bypass established through the femoral artery and vein with a probable diagnosis of leiomyoma. The tumor was removed by ingenious surgical technique: a snare made of silk suture in which the tumor's pedicle was trapped, and the tumor with its pedicle was carefully removed with the help of a scalpel along the silk suture. The histopathology report confirmed the diagnosis of intravenous leiomyoma. The postoperative course was uneventful and the patient was discharged a week later. CONCLUSION: Intracardiac leiomyoma is a rare benign smooth muscle tumor. Surgery is the mainstay of treatment with different surgical approaches available. It is possible to completely remove cardiac leiomyomas through sternotomy without the need for an abdominal incision if the leiomyoma is originated in the inferior vena cava not far from the right atrium.

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Epsilon-near-zero (ENZ) materials with vanishing permittivity exhibit unprecedented optical nonlinearity within subwavelength propagation lengths in the ENZ region, making them promising photoelectric materials that have achieved exciting results in ultrafast pulse laser modulations. In this study, we fabricated a novel saturable absorber (SA) based on a corrugated indium tin oxide (CITO) film with a symmetrical geometry using a low-cost self-assembly process. The strong saturable absorption of the CITO film triggered by the ENZ effect at normal incidence was comparable to that of the planar indium tin oxide (ITO) film at an optimal 60° incidence (TM polarization) at 1340 nm. In addition, the strong nonlinear optical properties of the CITO film were not limited by the incident angle and polarization state of the pump laser over a wide range of 0-20°. Benefiting from the excellent saturable absorption of CITO-based SA at normal incidence, a Q-switching operation with CITO-based SA at 1.34 µm was achieved in a Nd:YVO4 solid-state laser system, obtaining pulses of a duration of 85.6 ns, which was one order of magnitude narrower than that of the planar ITO-based SA. This study presents a new strategy for developing high-performance ENZ-based SAs and ultrafast lasers.

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Solid dispersions (SDs) possess the potential to enhance the bioavailability of insoluble active pharmaceutical ingredients (APIs) by effectively converting them into amorphous state. However, SDs have a tendency to recrystallize unless appropriate excipients are employed. The objective of this study was to evaluate the ability of hypromellose acetate succinate HF (HPMCAS-HF) and Soluplus® to inhibit the recrystallization of ß-carotene and improve its in vivo bioavailability through the fabrication of ternary ß-carotene solid dispersions (SDs) with the aid of specific surfactant. Due to rapid micellization, the dissolution profiles of ß-carotene SDs based on HPMCAS-HF/Span 20 (5:5, w/w) or Soluplus®/Span 20 (6:4, w/w) combinations exhibited significant improvement, which were almost 7-10 times higher than ß-carotene bulk powder. DSC and PXRD analysis indicated a notable reduction in the crystallinity degree of ß-carotene within the SDs. The stability study demonstrated a half-life of ß-carotene in the SDs exceeding 30 days. Additionally, the in vivo pharmacokinetics analysis confirmed that the cellulose derivatives/surfactant combinations significantly enhanced the bioavailability of ß-carotene by 1.37-fold and 2.3-fold, respectively. Notably, the HPMCAS-HF/Span 20 combination exhibited superior performance. Consequently, the HPMCAS-HF/Span 20 combination held potential for the advancement of an effective drug delivery system for ß-carotene.

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