Mechanistic insights into the conversion of flavin adenine dinucleotide (FAD) to 8-formyl FAD in formate oxidase: a combined experimental and in-silico study.

Formate oxidase (FOx), which contains 8-formyl flavin adenine dinucleotide (FAD), exhibits a distinct advantage in utilizing ambient oxygen molecules for the oxidation of formic acid compared to other glucose-methanol-choline (GMC) oxidoreductase enzymes that contain only the standard FAD cofactor. The FOx-mediated conversion of FAD to 8-formyl FAD results in an approximate 10-fold increase in formate oxidase activity. However, the mechanistic details underlying the autocatalytic formation of 8-formyl FAD are still not well understood, which impedes further utilization of FOx. In this study, we employ molecular dynamics simulation, QM/MM umbrella sampling simulation, enzyme activity assay, site-directed mutagenesis, and spectroscopic analysis to elucidate the oxidation mechanism of FAD to 8-formyl FAD. Our results reveal that a catalytic water molecule, rather than any catalytic amino acids, serves as a general base to deprotonate the C8 methyl group on FAD, thus facilitating the formation of a quinone-methide tautomer intermediate. An oxygen molecule subsequently oxidizes this intermediate, resulting in a C8 methyl hydroperoxide anion that is protonated and dissociated to form OHC-RP and OH-. During the oxidation of FAD to 8-formyl FAD, the energy barrier for the rate-limiting step is calculated to be 22.8 kcal/mol, which corresponds to the required 14-hour transformation time observed experimentally. Further, the elucidated oxidation mechanism reveals that the autocatalytic formation of 8-formyl FAD depends on the proximal arginine and serine residues, R87 and S94, respectively. Enzymatic activity assay validates that the mutation of R87 to lysine reduces the kcat value to 75% of the wild-type, while the mutation to histidine results in a complete loss of activity. Similarly, the mutant S94I also leads to the deactivation of enzyme. This dependency arises because the nucleophilic OH- group and the quinone-methide tautomer intermediate are stabilized through the noncovalent interaction provided by R87 and S94. These findings not only explain the mechanistic details of each reaction step but also clarify the functional role of R87 and S94 during the oxidative maturation of 8-formyl FAD, thereby providing crucial theoretical support for the development of novel flavoenzymes with enhanced redox properties.

Ultrasound-Guided Percutaneous Biopsy Combined Serum CA125, CEA Level Examination in the Diagnosis of Ovarian Tumors Value Analysis.

Objective: This study aimed to evaluate the diagnostic value of combining ultrasound-guided percutaneous biopsy with serum CA125 and CEA testing in ovarian tumors. Methods: Sixty-four patients suspected of having ovarian tumors, admitted to our hospital from July 2021 to July 2023, were selected for the study. All patients underwent ultrasound-guided percutaneous biopsy and serum tumor markers CA125 and CEA level testing. Surgical pathology results were used as the gold standard for comparison. The diagnostic performance of ultrasound-guided percutaneous biopsy alone, serum CA125, serum CEA, and their combination were evaluated. Receiver operating characteristic (ROC) curve analysis was performed, and the sensitivity, specificity, and accuracy were calculated. The differences in diagnostic performance were compared using the chi-square test, with a P < .05 considered statistically significant. Results: The results of this study demonstrate that combining ultrasound-guided percutaneous biopsy with serum CA125 and CEA testing significantly improved the diagnostic accuracy for ovarian tumors compared to individual testing modalities. Surgical pathology, the gold standard, confirmed 52 malignant and 12 benign tumors among the 64 patients examined. When evaluated individually, the concordance rate between ultrasound-guided biopsy and surgical pathology was 90.63%, while serum CA125 and CEA had diagnostic accuracies of 73.44% and 64.06%, respectively. However, when the two serum markers were used in combination, the diagnostic accuracy increased to 81.25%. Notably, the integration of ultrasound-guided percutaneous biopsy with serum CA125 and CEA testing produced the highest diagnostic accuracy at 95.31%. Statistical analysis confirmed this combined approach had significantly better accuracy, sensitivity, and specificity compared to individual tests (P < .05). ROC curve analysis further substantiated the superior diagnostic value of this integrated testing strategy. Conclusion: The findings of this study demonstrate that the integration of ultrasound-guided percutaneous biopsy with serum CA125 and CEA testing markedly enhances diagnostic accuracy for ovarian tumors, with a combined accuracy exceeding 95%. This integrated diagnostic protocol represents a robust and clinically valuable approach that should be more widely adopted to improve early detection and optimize the management of ovarian neoplasms. The implementation of this combined testing strategy has the potential to significantly impact clinical decision-making and patient outcomes in the diagnosis and treatment of ovarian tumors.

The mechanics of tissue-engineered temporomandibular joint discs: Current status and prospects for enhancement.

The temporomandibular joint (TMJ) disc is an essential protective but vulnerable fibrocartilage. Their high mechanical strength is vital in absorbing loads, reducing friction, and protecting the condylar surface. Many diseases can lead to the destruction or degeneration of the mechanical function of the TMJ disc. Unfortunately, conservative treatment is ineffective in restoring the defective mechanical properties of the discs. Tissue engineering has been investigated as a promising alternative treatment approach to approximate the properties of native tissue. However, it is difficult for tissue-engineered discs to obtain sufficient mechanical properties. Several approaches have been proposed to improve the mechanical properties of tissue-engineered constructs. In this review, we summarized the mechanical properties of native TMJ discs and discussed the current mechanical testing methods. We then summarized the current advances in improving the mechanical properties of TMJ disc tissue-engineered constructs. Moreover, existing challenges and outbreak directions are discussed. This review assists future research in better understanding the mechanical properties of both native and tissue-engineered TMJ discs. It provides new insights into future mechanical property enhancement for TMJ disc tissue engineering.

Laser therapy for treating cleft lip or/and palate scarring-a systematic review and meta-analysis.

This review aims to assess the efficacy and safety of laser therapy in managing scars resulting from cleft lip and/or palate (CL/P) repair surgeries, as well as to determine the optimal timing for intervention. A systematic search was conducted across four databases using a predefined search strategy. Studies included were randomized controlled trials, non-randomized studies, and case series focusing on laser therapy for CL/P scars. Data extraction and analysis were performed using Revman Software. A total of two randomized controlled trials, four non-randomized studies, and three case series were included in the analysis. The fractional CO2 laser was the most commonly utilized type of laser. Following laser therapy, there was a significant decrease in Vancouver Scar Scale (VSS) scores by 4.05 (95% CI, 2.10-5.99). Meta-analysis revealed that laser treatment groups exhibited a significantly lower mean VSS score (1.3; 95% CI, 0.02-2.67) compared to control groups. Moreover, initiating laser therapy intervention at one month postoperatively resulted in a significantly lower VSS score compared to initiation at three months postoperatively (difference of 1.70; 95% CI, 1.33-2.08). No severe complications were reported. Laser therapy demonstrates effectiveness and safety in improving CL/P scars, with earlier intervention yielding greater benefits.

Cholesterol sulfate-mediated ion-pairing facilitates the self-nanoassembly of hydrophilic cationic mitoxantrone.

HYPOTHESIS: Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO. EXPERIMENTS: We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies. FINDINGS: The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (∼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.

Tumor-associated CD8+T cell tolerance induced by erythroid progenitor cells.

Introduction: CD8+T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45+ erythroid progenitor cells (CD45+EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45+EPCs mediate CD8+T cell tolerance remains incompletely understood and requires further research. Methods: In this study, the antigen-processing abilities of CD45+EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45+EPCs on CD8+T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45+EPC mediated tolerance of CD8+T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45+EPC mediated tumor-promoting effect. Results and discussion: We found that CD45+EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8+T cell anergy. In addition, we found that CD45+EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8+ T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45+EPCs during CD8+T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8+T cell tolerance in tumor-bearing mice is induced by CD45+EPCs. The results of this study have direct implications for tumor immunotherapy.

Singlet oxygen production of Zn-Ag-In-S quantum dots for photodynamic treatment of cancer cells and bacteria.

Zn-Ag-In-S (ZAIS) quantum dots (QDs) were synthesized with various Ag-to-In ratios and used as novel photosensitizers for photodynamic therapy (PDT) on cancer cell inhibition and bacterial sterilization, and their structural, optical, and photodynamic properties were investigated. The alloyed QDs displayed a photoluminescence quantum yield of 72% with a long fluorescence lifetime of 5.3 µs when the Ag-to-In ratio was 1:3, suggesting a good opportunity as a dual functional platform for fluorescence imaging and PDT. The ZAIS QDs were then coated with amphiphilic brush copolymer poly(maleic anhydride-alt-1-octadecene) (PMAO) before application. The 1O2 quantum yield of the ZAIS/PMAO was measured to be 8%, which was higher than previously reported CdSe QDs and comparable to some organic photosensitizers. Moreover, the ZAIS QDs showed excellent stability in aqueous and biological media, unlike organic photosensitizers that tend to degrade over time. The in vitro PDT against human melanoma cell line (A2058) and Staphylococcus aureus shows about 30% inhibition rate upon 20 min light irradiation. Cell staining images clearly demonstrated that co-treatment with ZAIS QDs and light irradiation effectively killed A2058 cells, demonstrating the potential of ZAIS QDs as novel and versatile photosensitizers for PDT in cancer and bacterial treatment, and provides useful information for future designing of QD-based photosensitizers.

Two-Site Occupation for Constructing Double Perovskite BaLaMgNbO6:Cr3+ Ultrabroadband NIR Phosphors.

Given the escalating significance of near-infrared (NIR) spectroscopy across industries, agriculture, and various domains, there is an imminent need to address the development of a novel generation of intelligent NIR light sources. Here, a series of Cr3+-doped BaLaMgNbO6 (BLMN) ultrabroadband NIR phosphor with a coverage range of 650-1300 nm were developed. The emission peak locates at 830 nm with a full width at half maximum of 210 nm. This ultrabroadband emission originates from the 4T2→4A2 transition of Cr3+ and the simultaneous occupation of [MgO6] and [NbO6] octahedral sites confirmed by low photoluminescence spectra (77-250 K), time-resolved photoluminescence spectra, and electron paramagnetic resonance spectra. The fluxing strategy improves the luminescence intensity and thermal stability of BLMN:0.02Cr3+ phosphors. The internal quantum efficiency (IQE) is 51%, external quantum efficiency (EQE) can reach 33%, and thermal stability can be maintained at 60%@100 °C. Finally, we successfully demonstrated the application of BLMN:Cr3+ ultrabroadband in the qualitative analysis of organic matter and food freshness detection.

Spotlight on eltrombopag concentration in pediatric immune thrombocytopenia: A single-center observational study in China.

Importance: Eltrombopag has been recommended for pediatric immune thrombocytopenia (ITP). Response and adverse drug reactions (ADRs) varied widely between individuals, even at the same dose of eltrombopag. The appropriate eltrombopag concentration in ITP has not been reported. Objective: This study aims to explore the appropriate eltrombopag concentration in pediatric ITP. Methods: This was a single-center, prospective cohort study. Children diagnosed with refractory persistent/chronic ITP and platelet count < 30×109/L were treated with eltrombopag and followed up for at least 2 months. Concentration was detected by high-performance liquid chromatography-mass spectrometry at least 2 weeks after eltrombopag. The clinical characteristics-concentration, concentration-response, and concentration-ADRs were analyzed. Results: A total of 30 patients were enrolled, comprising 13 males and 17 females, with a median age of 72 (45‒94) months. The median dose and concentration were 1.39 (1.09‒1.56) mg/kg and 2.70 (2.25‒4.13) mg/L, respectively. Of the enrolled patients, 14 responded to treatment, whereas 16 did not. Additionally, five experienced adverse drug reactions. No linear correlation was observed between eltrombopag concentration and clinical characteristics. The concentration was lower in the response group than in the nonresponse group, but there was no significant difference (t = 0.755, P = 0.457). Patients who experienced ADRs had a higher concentration than those without ADRs (t = 2.538, P = 0.017). The area under the receiver operating characteristic curve of ADRs was 0.78 (95% confidence interval: 0.56‒1.00). Youden's index identified the cutoff point as 4.33 mg/L, with a sensitivity of 88% and a specificity of 60%. Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response. Interpretation: Eltrombopag proves efficacious and well-tolerated for treating pediatric ITP. However, prolonged and high-dose administration may increase the likelihood of ADRs. Thus, examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.

Regulation of plant resistance to salt stress by the SnRK1-dependent splicing factor SRRM1L.

Most splicing factors are extensively phosphorylated but their physiological functions in plant salt resistance are still elusive. We found that phosphorylation by SnRK1 kinase is essential for SRRM1L nuclear speckle formation and its splicing factor activity in plant cells. In Arabidopsis, loss-of-function of SRRM1L leads to the occurrence of alternative pre-mRNA splicing events and compromises plant resistance to salt stress. In Arabidopsis srrm1l mutant line, we identified an intron-retention Nuclear factor Y subunit A 10 (NFYA10) mRNA variant by RNA-Seq and found phosphorylation-dependent RNA-binding of SRRM1L is indispensable for its alternative splicing activity. In the wild-type Arabidopsis, salt stress can activate SnRK1 to phosphorylate SRRM1L, triggering enrichment of functional NFYA10.1 variant to enhance plant salt resistance. By contrast, the Arabidopsis srrm1l mutant accumulates nonfunctional NFYA10.3 variant, sensitizing plants to salt stress. In summary, this work deciphered the molecular mechanisms and physiological functions of SnRK1-SRRM1L-NFYA10 module, shedding light on a regulatory pathway to fine-tune plant adaptation to abiotic stress at the post-transcriptional and post-translational levels.

ROS-Induced Endothelial Dysfunction in the Pathogenesis of Atherosclerosis.

Various signaling pathways are regulated by reactive oxygen species (ROS), which are radical oxygen intermediates under normal physiological conditions. However, when the buffering capacity of antioxidant enzymes is exceeded by the accumulation of ROS, oxidative stress, and endothelial cell dysfunction occur, which have been recognized as key contributors to the development of atherosclerosis. In this review, an overview is provided on mechanisms underlying ROS generation in endothelial cells and the involved regulatory pathways. Further, we discuss the ROS induced endothelial cell dysfunction and its relationship with atherosclerosis. Current knowledge on ROS-induced endothelial impairment is presented, characterized by decreased NO bioavailability, intracellular dysfunction and ox-LDL accumulation. Furthermore, biomarkers such as oxidative products of lipid, protein, and nucleotide are discussed as measurements for ROS levels. Novel interventions targeting oxidative stress are listed as potential pharmacotherapies in clinical practice. In conclusion, this review presents a systematic analysis of the mechanisms underlying ROS generation and elucidates how manipulation of these mechanisms can safeguard endothelial cell function.

Deciphering Depressor Anguli Oris for Lower Face Rejuvenation: A Prospective Ultrasound-based Investigation.

BACKGROUND: The depressor anguli oris muscle (DAO) is a pivotal treatment target when creating a harmonic jawline. However, evidence of its live morphology remains scarce. OBJECTIVES: In this study we aimed to reevaluate the DAO with a facile ultrasound analysis and thereby guide safer and more effective botulinum toxin type A (BTX-A) injection. METHODS: A prospective ultrasound assessment was conducted in 41 patients. Morphology of the DAO and its relative position to neighboring structures were appraised at the ubiquitous facial landmark, the labiomandibular fold (LMF). Three-dimensional images were captured before and after the patient received the BTX-A injection based on sonographic evidence. RESULTS: The skin-to-muscle depths of the DAO on average (measured from the medial to lateral border) were 5.26, 5.61, and 8.42 mm. The DAO becomes thinner and wider from zone 1 to zone 3 (P < .001). Overlapping lengths of the DAO and the depressor labii inferioris increased from zone 1 to zone 3: 4.74, 9.68, 14.54 mm (P < .001). The medial border of the DAO was located at 4.33, 6.12, 8.90 mm medial to the LMF (zone 1-3), and no muscle fibers of the DAO were observed in zone 1 or zone 2 in nearly one-third of patients. Improvement of the mouth corner downturn angle upon receiving BTX-A injection at zones 2 and 3 were 88.3%, 32.3%, and 14.7% for the neutral, maximum smile, and down-turning mouth corner expressions. CONCLUSIONS: This work established an informative ultrasound portrait of the DAO and structures in the perioral region, which suggested the LMF as a convenient landmark for locating the DAO. Injection at the middle and lower thirds of the LMF at a 4- to 5-mm depth is recommended.

Thermally Stable Red-Emitting Ca18K3Sc(PO4)14:Mn2+ Phosphor and Enhanced Luminescence by Energy Transfer Between Ce3+-Eu2+-Mn2.

It is significant and valuable to investigate novel and high-performance red-emitting phosphors for high-quality wLED applications. Based on this consideration, we developed a novel Mn2+-doped red Ca18K3Sc(PO4)14:Mn2+ (CKSP:Mn2+) phosphor. The emission peak of CKSP:Mn2+ is located at 640 nm, presenting a broadband red emission with a fwhm of 79 nm under 405 nm excitation. The CKSP:1.0Mn2+ phosphor shows superior thermal stability. At 150 °C, the integrated PL intensity and peak intensity of the CKSP:1.0Mn2+ phosphor maintain 93.2 and 85.7% of those at 25 °C, respectively. Through the strategy of energy transfer among Ce3+-Eu2+-Mn2+, the PL intensity of Mn2+ has increased by nearly 118 times, and the quantum yield has improved from 6 up to 72%. The structure-related photoluminescence and energy transfer mechanisms are discussed in detail. The as-fabricated wLED pumped by a 370 nm LED chip combining commercial the green (Sr,Ba)2SiO4:Eu2+ phosphor, blue BaMgAl10O17:Eu2+ phosphor, and the as-synthesized CKSP:1.0Mn2+, 0.02Eu2+, 0.40Ce3+ phosphor shows excellent color quality (CCT = 5555 K, Ra = 87), which indicates that the CKSP:1.0Mn2+, 0.02Eu2+, 0.40Ce3+ phosphor has extraordinary broad prospects in future wLED applications.

Multiwavelength Excitation in Ho3+-Doped All-Inorganic Double Perovskites Achieved by Codoping Mn2+ for Warm-White LEDs and Plant Growth.

Doping lanthanide ions is an efficient method to modify the optical properties of lead-free double-perovskite halides. However, most lanthanide-doped double perovskites show a low luminescence efficiency and require a high excitation energy. Here, we have successfully prepared a series of Ho3+-doped Cs2NaBiCl6 microcrystals through a simple hydrothermal method and obtained strong characteristic emissions of Ho3+ at 492 and 657 nm under low-energy excitation (449 nm). After codoping Mn2+, apart from the characteristic emissions from Ho3+ under 450 nm wavelength excitation, the orangish-red luminescence consisting of the emission band centered at 591 nm from Mn2+ and a sharp emission peak at 657 nm from Ho3+ is obtained under 355 nm UV light excitation. Photoluminescence (PL) emission and excitation spectra, along with the PL decay curves, confirm the existence of an energy-transfer channel from Cs2NaBiCl6 to Mn2+ and then from Mn2+ to Ho3+. The enhanced absorption efficiency (10.5 → 70.7%) suggests that the codoping of Mn2+ overcomes the low absorption efficiency caused by f-f forbidden transitions of Ho3+. Finally, the diverse luminescent performance within the Cs2NaBiCl6:Ho3+, Mn2+ phosphor is realized by altering the excitation wavelength, thereby enabling its application in warm-white-light-emitting diodes and plant growth in this work.

Diagnostic value of applying preoperative breast ultrasound and clinicopathologic features to predict axillary lymph node burden in early invasive breast cancer: a study of 1247 patients.

BACKGROUND: Since the Z0011 trial, the assessment of axillary lymph node status has been redirected from the previous assessment of the occurrence of lymph node metastasis alone to the assessment of the degree of lymph node loading. Our aim was to apply preoperative breast ultrasound and clinicopathological features to predict the diagnostic value of axillary lymph node load in early invasive breast cancer. METHODS: The 1247 lesions were divided into a high lymph node burden group and a limited lymph node burden group according to axillary lymph node status. Univariate and multifactorial analyses were used to predict the differences in clinicopathological characteristics and breast ultrasound characteristics between the two groups with high and limited lymph node burden. Pathological findings were used as the gold standard. RESULTS: Univariate analysis showed significant differences in ki-67, maximum diameter (MD), lesion distance from the nipple, lesion distance from the skin, MS, and some characteristic ultrasound features (P < 0.05). In multifactorial analysis, the ultrasound features of breast tumors that were associated with a high lymph node burden at the axilla included MD (odds ratio [OR], 1.043; P < 0.001), shape (OR, 2.422; P = 0.0018), hyperechoic halo (OR, 2.546; P < 0.001), shadowing in posterior features (OR, 2.155; P = 0.007), and suspicious lymph nodes on axillary ultrasound (OR, 1.418; P = 0.031). The five risk factors were used to build the predictive model, and it achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.702. CONCLUSION: Breast ultrasound features and clinicopathological features are better predictors of high lymph node burden in early invasive breast cancer, and this prediction helps to develop more effective treatment plans.

Fabrication of Hierarchical Assemblies through Temperature-Triggered Liquid Crystallization Driven Self-Assembly.

Functional hierarchy is prevalent in biological systems owing to natural evolution. Efforts to replicate these structures in artificial materials have gained traction in materials science. Although artificial hierarchical structures are fabricated at different scales based on site-specific interactions using ABC-type block copolymers (BCPs), the fabrication of such hierarchical structures using AB-type BCPs via a simple and efficient method remains challenging. Herein, a class of amphiphilic BCPs (PDenm -b-PACholn ) is reported comprising dendronized oligoethylene glycol (Den) and cholesterol (AChol) as hydrophilic and hydrophobic moieties, respectively. By employing the collapse of PDenm blocks at a specific temperature, the fabrication of bundled fibers and multilayer vesicles is achieved with an obvious hierarchy. Different from common reversible aggregation-disaggregation processes of thermal-responsive polymers, the ordering of the core-forming block with liquid crystalline (LC) properties provides robustly physical cross-linking, coupled with epitaxial growth and the lateral fusion of LC blocks, guiding the formation of stable hierarchical micellar structures. It is highlighted that the combination of temperature-sensitive properties and LC ordering alignment offers a novel approach for constructing hierarchical structures using AB-type BCPs via an efficient one-step assembly method.

Satellite-Type Sulfur Atom Distribution in Trithiocarbonate Bond-Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability.

Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.

68 Ga-FAPI-04 PET/CT in Assessment of Fibroblast Activation in Keloids : A Prospective Pilot Study.

PURPOSE: Keloids are benign fibroproliferative disorders characterized by the massive proliferation of fibroblasts. Fibroblast activation plays a key role in the invasive growth of keloids. Therefore, a prospective pilot study was conducted to explore the value of 68 Ga-FAPI-04 PET/CT in the assessment of keloids activity. PATIENTS AND METHODS: Twenty-five patients with keloid were enrolled to conduct 68 Ga-FAPI-04 PET/CT. All patients accepted surgery to remove part of the lesions within 1 week. SUV mean and SUV max were measured for semiquantitative analysis and compared with the Vancouver Scar Scale, Laser Speckle Contrast Imaging, pathology, and immunohistochemical stains. RESULTS: A total of 123 lesions were detected in 25 patients, most of which were distributed in the anterior chest wall. The 68 Ga-FAPI-04 uptake was significantly different at different sites ( P < 0.0001). There was uptake heterogeneity within the keloid lesions, and a significant difference was found between the edge and center of some large lesions. The SUV max of 68 Ga-FAPI-04 showed significantly correlation with the Vancouver Scar Scale ( r = 0.565, P < 0.0001) moderately and the Laser Speckle Contrast Imaging parameters mildly. The SUV max of 68 Ga-FAPI-04 had a moderate correlation with FAPI expression ( r = 0.520, P = 0.022). Moreover, collagen, fibroblast activator protein, and Ki-67 expression were found higher at the edges of keloid tissue than in the center. CONCLUSIONS: 68 Ga-FAPI-04 PET/CT can reflect the distribution characteristics of activated fibroblasts in keloid tissue and may provide a novel method for keloid evaluation for further fibroblast-related therapies.

Risk Factors of Venous Thromboembolism in Inpatients With Colorectal Cancer in China.

To explore the risk factors for venous thromboembolism (VTE) in inpatients with colorectal cancer. The demographic factors, comorbidities, and hematological indices of patients with colorectal cancer treated in our hospital from 2016 to 2021 were collected and recorded. Venous thromboembolism events, including deep venous thrombosis and/or pulmonary embolism, were recorded and the patients were divided into the VTE group and the non-VTE group. We compared clinical data between the two groups and explored risk factors for VTE. Comparing the clinical data of 293 cases of non-VTE group and 235 cases of VTE group, we found significant differences in age, smoking, temperature, amount of blood loss, differentiation degree, peripherally inserted central catheter (PICC), radiotherapy, anemia, infection, white blood cell count, prothrombin time (PT), PT%, prothrombin ratio, international normalized ratio, thrombin time, CA199 and CEA between the two groups (P < 0.05). Logistic regression analysis showed that age (P = 0.0444), temperature (P = 0.0317), amount of blood loss (P = 0.0067), PICC (P < 0.0001), chemotherapy (P = 0.0459), anemia (P = 0.0007), international normalized ratio (P = 0.003) and CA199 (p = 0.0234) were independent risk factors for VTE. Receiver operating characteristic curve analysis showed that the amount of blood loss predicted thrombosis better (AUC = 0.778, P < 0.001), when the cutoff value was 20 mL, the sensitivity was 76.17%, and the specificity was 79.18%, respectively. And PICC predicted thrombosis better (AUC = 0.808, P < 0.001), the sensitivity was 70.21%, and the specificity was 91.47%, respectively. Clinical parameters are associated with VTE in inpatients with colorectal cancer, which will help to guide clinicians to take effective measures to improve the patients' prognosis.

DNA damage response, a double-edged sword for vascular aging.

Vascular aging is a major risk factor for age-related cardiovascular diseases, which have high rates of morbidity and mortality. It is characterized by changes in the blood vessels, such as macroscopically increased vascular diameter and intima-medial thickness, chronic inflammation, vascular calcification, arterial stiffening, and atherosclerosis. DNA damage and the subsequent various DNA damage response (DDR) pathways are important causative factors of vascular aging. Deficient DDR, which may result in the accumulation of unrepaired damaged DNA or mutations, can lead to vascular aging. On the other hand, over-activation of some DDR proteins, such as poly (ADP ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM), also can enhance the process of vascular aging, suggesting that DDR can have both positive and negative effects on vascular aging. Despite the evidence reviewed in this paper, the role of DDR in vascular aging and potential therapeutic targets remain poorly understood and require further investigation.