Clinical efficacy of Gamma Knife® combined with transarterial chemoembolization and immunotherapy in the treatment of primary liver cancer.

BACKGROUND: This study was designed to investigate the clinical efficacy and safety of Gamma Knife® combined with transarterial chemoembolization (TACE) and immunotherapy in the treatment of primary liver cancer. AIM: To investigate the clinical efficacy and safety of Gamma Knife® combined with TACE and immune-targeted therapy in the treatment of primary liver cancer. METHODS: Clinical data from 51 patients with primary liver cancer admitted to our hospital between May 2018 and October 2022 were retrospectively collected. All patients underwent Gamma Knife® treatment combined with TACE and immunotherapy. The clinical efficacy, changes in liver function, overall survival (OS), and progression-free survival (PFS) of patients with different treatment responses were evaluated, and adverse reactions were recorded. RESULTS: The last follow-up for this study was conducted on October 31, 2023. Clinical evaluation of the 51 patients with primary liver cancer revealed a partial response (PR) in 27 patients, accounting for 52.94% (27/51); stable disease (SD) in 16 patients, accounting for 31.37% (16/51); and progressive disease (PD) in 8 patients, accounting for 15.69% (8/51). The objective response rate was 52.94%, and the disease control rate was 84.31%. Alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alpha-fetoprotein isoform levels decreased after treatment compared with pretreatment (all P = 0.000). The median OS was 26 months [95% confidence interval (95%CI): 19.946-32.054] in the PR group and 19 months (95%CI: 14.156-23.125) in the SD + PD group, with a statistically significant difference (P = 0.015). The median PFS was 20 months (95%CI: 18.441-34.559) in the PR group and 12 months (95%CI: 8.745-13.425) in the SD + PD group, with a statistically significant difference (P = 0.002). Common adverse reactions during treatment included nausea and vomiting (39.22%), thrombocytopenia (27.45%), and leukopenia (25.49%), with no treatment-related deaths reported. CONCLUSION: Gamma Knife® combined with TACE and immune-targeted therapy is safe and effective in the treatment of primary liver cancer and has a good effect on improving the clinical benefit rate and liver function of patients.

Hybrid argon plasma coagulation for the treatment of Barrett's esophagus: A prospective, multicenter study.

BACKGROUND: The incidence of Barrett's esophagus (BE) in China is lower compared to the Western populations. Hence, studies conducted in the Chinese population has been limited. The current treatment options available for BE treatment includes argon plasma coagulation (APC), radiofrequency ablation and cryoablation, all with varying degrees of success. AIM: To determine the efficacy and safety of HybridAPC in the treatment of BE. METHODS: The study cohort consisted of patients with BE who underwent HybridAPC ablation treatment. These procedures were performed by seven endoscopists from different tertiary hospitals. The duration of the procedure, curative rate, complications and recurrent rate by 1-year follow-up were recorded. RESULTS: Eighty individuals were enrolled for treatment from July 2017 to June 2020, comprising of 39 males and 41 females with a median age of 54 years (range, 30 to 83 years). The technical success rate of HybridAPC was 100% and the overall curative rate was 98.15%. No severe complications occurred during the operation. BE cases were classified as short-segment BE and long-segment BE. Patients with short-segment BE were all considered cured without complications. Thirty-six patients completed the one-year follow-up without recurrence. Twenty-four percent had mild dysplasia which were all resolved with one post-procedural treatment. The mean duration of the procedure was 10.94 ± 6.52 min. CONCLUSION: Treatment of BE with HybridAPC was found to be a simple and quick procedure that is safe and effective during the short-term follow-up, especially in cases of short-segment BE. This technique could be considered as a feasible alternative ablation therapy for BE.

Suppressing PD-L1 Expression via AURKA Kinase Inhibition Enhances Natural Killer Cell-Mediated Cytotoxicity against Glioblastoma.

Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments. AURKA has been identified as a potential drug target for GBM treatment. An analysis of the GBM cell transcriptome following AURKA inhibition revealed a potential influence on the immune system. Our research revealed that AURKA influenced PD-L1 levels in various GBM model systems in vitro and in vivo. Disrupting AURKA function genetically led to reduced PD-L1 levels and increased MHC-I expression in both established and patient-derived xenograft GBM cultures. This process involved both transcriptional and non-transcriptional pathways, partly implicating GSK3ß. Interfering with AURKA also enhanced NK-cell-mediated elimination of GBM by reducing PD-L1 expression, as evidenced in rescue experiments. Furthermore, using a mouse model that mimics GBM with patient-derived cells demonstrated that Alisertib decreased PD-L1 expression in living organisms. Combination therapy involving anti-PD-1 treatment and Alisertib significantly prolonged overall survival compared to vehicle treatment. These findings suggest that targeting AURKA could have therapeutic implications for modulating the immune environment within GBM cells.

Endovascular repair for thoracic aortic pseudoaneurysm induced by pedicle screw implantation: a case report with 8 years follow-up.

BACKGROUND: Pedicle screw instrument surgeries can result in the development of aortic pseudoaneurysm, which is a rare yet potentially severe complication; therefore, the purpose of this work is to describe the case of pseudoaneurysm of the thoracic aorta caused by the severe migration of a pedicle screw after surgery. CASE PRESENTATION: We herein report a patient who underwent endovascular repair for the pseudoaneurysm of the descending thoracic aorta following thoracic vertebral fixation surgery. A 28-80 mm covered stent was initially inserted through the right femoral artery, and intraoperative aortography revealed a minor extravasation of contrast material. Subsequently, an additional 28-140 mm covered stent was implanted. The patient recovered well during the 8-year follow-up period. CONCLUSIONS: Vascular complications resulting from spinal surgery are severe and rare, necessitating early diagnosis and intervention.

Human parasitic infections of the class Adenophorea: global epidemiology, pathogenesis, prevention and control.

BACKGROUND: Human parasitic infections caused by Adenophorean nematodes encompass a range of diseases, including dioctophymiasis, trichuriasis, capillariasis, trichinellosis, and myositis. These infection can result in adverse impacts on human health and cause societal and economic concerns in tropical and subtropical regions. METHODS: This review conducted searches in PubMed, Embase and Google Scholar for relevant studies that published in established databases up to April 26, 2024. Studies that focused on the common morphology, life cycle, disease distribution, clinical manifestations, and prevention and control strategies for Adenophorean parasitic diseases in humans were included. RESULTS: Adenophorean nematodes exhibit shared morphological characteristics with a four-layered cuticle; uninucleate epidermal cells; pseudocoelom with six or more coelomocytes; generally three caudal glands; five esophageal glands; two testes in males with median-ventral supplementary glands in a single row; tail in males rarely possessing caudal alae; amphids always postlabial; presence of cephalic sensory organs; absence of phasmids; and a secretory-excretory system consisting of a single ventral gland cell, usually with a non-cuticularized terminal duct. Humans play two important roles in the life cycle of the nematode class, Adenophorea: 1) as a definitive host infected by ingesting undercooked paratenic hosts, embryonated eggs, infective larvae in fish tissue and meat contaminated with encysted or non-encysted larvae, and 2) as an accidental host infected by ingesting parasitic eggs in undercooked meat. Many organs are targeted by the Adenophorean nematode in humans such as the intestines, lungs, liver, kidneys, lymphatic circulation and blood vessels, resulting in gastrointestinal problems, excessive immunological responses, cell disruption, and even death. Most of these infections have significant incidence rates in the developing countries of Africa, Asia and Latin America; however, some parasitic diseases have restricted dissemination in outbreaks. To prevent these diseases, interventions together with education, sanitation, hygiene and animal control measures have been introduced in order to reduce and control parasite populations. CONCLUSIONS: The common morphology, life cycle, global epidemiology and pathology of human Adenophorean nematode-borne parasitic diseases were highlighted, as well as their prevention and control. The findings of this review will contribute to improvement of monitoring and predicting human-parasitic infections, understanding the relationship between animals, humans and parasites, and preventing and controlling parasitic diseases.

Optical enhancement mode 2 improves the detection rate of gastric neoplastic lesion in high-risk populations: A multicenter randomized controlled clinical study.

OBJECTIVES: Detection of early neoplastic lesions is crucial for improving the survival rates of patients with gastric cancer. Optical enhancement mode 2 is a new image-enhanced endoscopic technique that offers bright images and can improve the visibility of neoplastic lesions. This study aimed to compare the detection of neoplastic lesions with optical enhancement mode 2 and white-light imaging (WLI) in a high-risk population. METHODS: In this prospective multicenter randomized controlled trial, patients were randomly assigned to optical enhancement mode 2 or WLI groups. Detection of suspicious neoplastic lesions during the examinations was recorded, and pathological diagnoses served as the gold standard. RESULTS: A total of 1211 and 1219 individuals were included in the optical enhancement mode 2 and WLI groups, respectively. The detection rate of neoplastic lesions was significantly higher in the optical enhancement mode 2 group (5.1% vs. 1.9%; risk ratio, 2.656 [95% confidence interval, 1.630-4.330]; p < 0.001). The detection rate of neoplastic lesions with an atrophic gastritis background was significantly higher in the optical enhancement mode 2 group (8.6% vs. 2.6%, p < 0.001). The optical enhancement mode 2 group also had a higher detection rate among endoscopists with different experiences. CONCLUSIONS: Optical enhancement mode 2 was more effective than WLI for detecting neoplastic lesions in the stomach, and can serve as a new method for screening early gastric cancer in clinical practice. CLINICAL REGISTRY: United States National Library of Medicine (https://www. CLINICALTRIALS: gov), ID: NCT040720521.

Supercritical Fluid-extracted Citrus aurantium L. var. amara Engl. Essential Oil Nanoemulsion: Preparation, Characterization, and Its Sleep-promoting Effect.

To overcome the defects of Citrus aurantium L. var. amara Engl. essential oil (CAEO), such as high volatility and poor stability, supercritical fluid-extracted CAEO nanoemulsion (SFE-CAEO-NE) was prepared by the microemulsification method. Emulsifiers comprising Tween 80, polyoxyethylenated castor oil (EL-40), and 1,2-hexanediol, and an oil phase containing SFE-CAEO were used for microemulsification. We examined the physicochemical properties of SFE-CAEO-NE and steam distillation-extracted CAEO nanoemulsion (SDE-CAEO-NE), which were prepared using different concentrations of the emulsifiers. The mean particle size and zeta potential were 21.52 nm and -9.82 mV, respectively, for SFE-CAEO-NE, and 30.58 nm and -6.28 mV, respectively, for SDE-CAEO-NE, at an emulsifier concentration of 15% (w/w). SFE-CAEO-NE displayed better physicochemical properties compared with SDE-CAEO-NE. Moreover, its physicochemical properties were generally stable at different temperatures (-20-60℃), pH (3-8), and ionic strengths (0-400 mM). No obvious variations in particle size, zeta potential, and Ke were observed after storing this nanoemulsion for 30 days at 4℃, 25℃, and 40℃, suggesting that it had good stability. The sleep-promoting effect of SFE-CAEO-NE was evaluated using a mouse model of insomnia. The results of behavioral tests indicated that SFE-CAEO-NE ameliorated insomnia-like behavior. Moreover, SFE-CAEO- NE administration increased the serum concentrations of neurotransmitters such as 5-hydroxytryptamine and γ-aminobutyric acid, and decreased that of noradrenaline in mice. It also exerted a reparative effect on the function of damaged neurons. Overall, SFE-CAEO-NE displayed a good sleep-promoting effect.

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies.

Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.

A Multicenter Study of the Mid-term Outcomes of Patients with Uncomplicated Type B Aortic Dissection After Distal Porous Talos Stent-Graft Implantation.

BACKGROUND: The Talos stent-graft has extended length to improve aortic remodeling, and distal porous design to decrease the rate of spinal cord ischemia (SCI). This study retrospectively analyzed its mid-term outcomes for uncomplicated type B aortic dissection in a multicenter study. METHODS: The primary safety end point was 30-day major adverse events, including all-cause mortality, dissection-related mortality, conversion to open surgery, and device-related adverse events. The primary efficacy end point was treatment success at 12 months postoperation, defined as no technical failure or secondary dissection-related reintervention. The survival status of the patients was visualized using the Kaplan-Meier curve. Aortic growth was assessed at 4 levels, and SCI was evaluated at 12 months. RESULTS: 113 patients participated with a mean age of 54.4 (11.1) years and 71.7% (81/113) were male. The 30-day mortality was 0.9% (1/113), no conversions to open surgery or device-related adverse events were recorded. The 12-month treatment success rate was 99.1% (112/113), with no dissection-related reinterventions. There was no spinal cord or visceral ischemia at 12 months. At a median of 34 months follow-up, 9 further deaths were recorded and the 3-year survival rate was 91.7%. The percentage of aortic growth was 1.8% (2/111) at the tracheal bifurcation, 3.6% (4/111) below the left atrium, 6.0% (5/83) above the celiac artery, and 12.1% (9/74) below the lower renal artery. The total thrombosis rate of the false lumen at the stented segment was 80.5% (91/113). CONCLUSIONS: The results showed satisfactory results of Talos stent-graft in terms of safety and efficacy. More data are needed to confirm the long-term performance.

Adaptation process of decellularized vascular grafts as hemodialysis access in vivo.

Arteriovenous grafts (AVGs) have emerged as the preferred option for constructing hemodialysis access in numerous patients. Clinical trials have demonstrated that decellularized vascular graft exhibits superior patency and excellent biocompatibility compared to polymer materials; however, it still faces challenges such as intimal hyperplasia and luminal dilation. The absence of suitable animal models hinders our ability to describe and explain the pathological phenomena above and in vivo adaptation process of decellularized vascular graft at the molecular level. In this study, we first collected clinical samples from patients who underwent the construction of dialysis access using allogeneic decellularized vascular graft, and evaluated their histological features and immune cell infiltration status 5 years post-transplantation. Prior to the surgery, we assessed the patency and intimal hyperplasia of the decellularized vascular graft using non-invasive ultrasound. Subsequently, in order to investigate the in vivo adaptation of decellularized vascular grafts in an animal model, we attempted to construct an AVG model using decellularized vascular grafts in a small animal model. We employed a physical-chemical-biological approach to decellularize the rat carotid artery, and histological evaluation demonstrated the successful removal of cellular and antigenic components while preserving extracellular matrix constituents such as elastic fibers and collagen fibers. Based on these results, we designed and constructed the first allogeneic decellularized rat carotid artery AVG model, which exhibited excellent patency and closely resembled clinical characteristics. Using this animal model, we provided a preliminary description of the histological features and partial immune cell infiltration in decellularized vascular grafts at various time points, including Day 7, Day 21, Day 42, and up to one-year post-implantation. These findings establish a foundation for further investigation into the in vivo adaptation process of decellularized vascular grafts in small animal model.

Mid-term results of a prospective study for aortic dissection with a gutter-plugging chimney stent graft.

OBJECTIVES: Our goal was to access early and mid-term outcomes of a gutter-plugging chimney stent graft for treatment of Stanford type B aortic dissections in the clinical trial Prospective Study for Aortic Arch Therapy with stENt-graft for Chimney technology (PATENCY). METHODS: Between October 2018 and March 2022, patients with Stanford type B aortic dissections were treated with the Longuette chimney stent graft in 26 vascular centres. The efficiency and the incidence of adverse events over 12 months were investigated. RESULTS: A total of 150 patients were included. The technical success rate was 99.33% (149/150). The incidence of immediate postoperative endoleak was 5.33% (8/150, type I, n = 6; type II, n = 1; type IV, n = 1) neurologic complications (stroke or spinal cord ischaemia); the 30-day mortality was 0.67% (1/150) and 1.33% (2/150), respectively. During the follow-up period, the median follow-up time was 11.67 (5-16) months. The patent rate of the Longuette graft was 97.87%. Two patients with type I endoleak underwent reintervention. The follow-up rate of the incidence of retrograde A type aortic dissection was 0.67% (1/150). There was no paraplegia, left arm ischaemia or stent migration. CONCLUSIONS: For revascularization of the left subclavian artery, the Longuette chimney stent graft can provide an easily manipulated, safe and effective endovascular treatment. It should be considered a more efficient technique to prevent type Ia endoleak. Longer follow-up and a larger cohort are needed to validate these results. CLINICAL TRIAL REGISTRY NUMBER: NCT03767777.

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures. CPI-613-mediated energy deprivation drove an integrated stress response with an upregulation of the BH3-only domain protein, Noxa, in an ATF4-dependent manner, as demonstrated by genetic loss-of-function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with disruption of the TCA cycle might be a treatment strategy for GBM.

Biotemplated fabrication of N/O co-doped porous carbon confined spinel NiFe2O4 heterostructured mimetics for triple-mode sensing of antioxidants and ameliorating packaging properties.

In this work, shrimp shell-derived magnetic NiFe2O4/N, O co-doped porous carbon nanozyme with superior oxidase (OXD)-like activity was prepared and used for colorimetric/photothermal/smartphone dual-signal triple-mode detection of antioxidants in fruits and beverages. The magnetic NiFe2O4/N, O co-doped porous carbon (MNPC) material was triumphantly fabricated using a combined in-situ surface chelation and pyrolysis method. The resultant MNPC composite exhibits a superior OXD-like activity, which can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) for yielding colorimetric/temperature dual-signal (CTDS) in absence of H2O2. This CTDS output sensor was successfully used for the determination of ascorbic acid and tannic acid. The proposed CTDS sensor with good specificity and high sensitivity can satisfy different on-site analysis requirements. Interestingly, the MNPC as a sustainable filler was further used for improving packaging properties of polyvinyl alcohol film. In short, this work offers a large-scale and cheap method to fabricate magnetic carbon-based nanozyme for monitoring antioxidants and ameliorating packaging properties.

Bibliometric analysis of the top 100 most-cited articles on branch reconstruction in endovascular aortic repair.

With the global acceptance of endovascular aortic repair (EVAR) for aortic diseases, one of the most common issues in EVAR is the preservation of critical aortic branches. Despite the fact that many studies on EVAR-assisted endovascular branch reconstruction techniques have been published. There were few bibliometric analyses that focused on branch rebuilding in endovascular aortic repair. In this study, we aim to analyze the characteristics of the 100 most-cited articles on branch reconstruction in Endovascular Aortic Repair. The most popular articles retrospectively searched on the Web of Science were published between 1999 and 2018, with 10480 citations in total (an average of 551.58 citations per year). The top-cited article was 281 citations. The peak years of citations was 2019 (1051 citations). Journal of Vascular Surgery published the most articles (46 articles) and was the most-cited journal (5055 citations), and the United States was the country with the greatest number of publications (43 articles). Cleveland Clinic was the most influential institution with 20 articles. Fenestration technique was the major topic area of interest and trend (63 articles mentioned). Customised device was the most widely used endograft (52 articles mentioned). Renal artery was the most frequently reconstructed branch of aorta (70 articles mentioned). Our analysis showed the endovascular branch reconstruction in EVAR developed rapidly over the past 20 years. Continued exploration and cooperation between specialties and manufacturers on endograft design and modifications will further enhance knowledge of disease intervention and treatment.

Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma.

Timely liver function recovery (LFR) is crucial for postoperative hepatocellular carcinoma (HCC) patients. Here, we established the significance of LFR on patient long-term survival through retrospective and prospective cohorts and identified a key gut microbe, Bifidobacterium longum, depleted in patients with delayed recovery. Fecal microbiota transfer from HCC patients with delayed recovery to mice similarly impacted recovery time post hepatectomy. However, oral gavage of B. longum improved liver function and repair in these mice. In a clinical trial of HCC patients, orally administering a probiotic bacteria cocktail containing B. longum reduced the rates of delayed recovery, shortened hospital stays, and improved overall 1-year survival. These benefits, attributed to diminished liver inflammation, reduced liver fibrosis, and hepatocyte proliferation, were associated with changes in key metabolic pathways, including 5-hydroxytryptamine, secondary bile acids, and short-chain fatty acids. Our findings propose that gut microbiota modulation can enhance LFR, thereby improving postoperative outcomes for HCC patients.

CD74/SLC34A2-ROS1 Fusion Variants Involving the Transmembrane Region Predict Poor Response to Crizotinib in NSCLC Independent of TP53 Mutations.

INTRODUCTION: Variable partners and breakpoints have been reported in patients with ROS1-rearranged NSCLC. Here, we investigated the association of fusion partners and breakpoints with crizotinib efficacy in NSCLCs with common ROS1 fusions. METHODS: DNA and RNA next-generation sequencing (NGS) and immunohistochemistry were performed to characterize ROS1 fusions. RESULTS: Using DNA NGS, we identified ROS1 fusions in 210 cases, comprising 171 common (CD74/EZR/TPM3/SDC4/SLC34A2-ROS1) and 39 uncommon (variants identified in <5%) ROS1 fusion cases. DNA NGS detected variable ROS1 genomic breakpoints in common ROS1 fusions, whereas RNA NGS found ROS1 breakpoints mainly occurring in exons 32, 34 and 35, resulting in long (exon 32) and short (exon 34 or 35) ROS1 fusions. ROS1 immunohistochemistry revealed that membranous and cytoplasmic staining was predominant in long ROS1 fusions, whereas cytoplasmic staining was predominant in short ROS1 fusions (p = 0.006). For patients who received first-line crizotinib, median progression-free survival (mPFS) was lower in patients with long ROS1 fusions than those with short ROS1 fusions (8.0 versus 24.0 mo, p = 0.006). Moreover, mPFS for patients with and without TP53 mutations was 8.0 and 19.0 months, respectively (p = 0.159); mPFS for patients with and without BIM deletion polymorphism was 5.0 and 22.0 months, respectively (p = 0.003). When analyzing together with fusion partners, patients with long CD74/SLC34A2-ROS1 fusions were found to have shorter PFS than those with other ROS1, regardless of the presence or absence of TP53 mutations (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: Long CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.

Simultaneous determination of tipiracil, trifluridine and its metabolite 5-trifluoromethyluracil in human plasma using segmented polarity LC-MS/MS: A fully validated assay with clinical application.

Trifluridine (FTD) and tipiracil (TPI) hydrochloride tablets (TAS-102) were used for the treatment of patients with metastatic rectal cancer that was resistant to conventional chemotherapy drugs. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of TPI, FTD, and the metabolite 5-trifluoromethyluracil (FTY) of FTD in human plasma. The plasma samples were prepared by protein precipitation. The chromatography separation was performed using ACE Excel 3 AQ (100 × 2.1 mm i.d., 1.7 µm, ACE, England) column protected by a security guard cartridge (4.0 × 2.0 mm i.d., 5 µm, Phenomenex, USA) with a gradient elution of 0.05% acetic acid in water and methanol at a flow rate of 0.35 mL/min. The MS/MS analysis was performed by using multiple reaction monitoring with the segmented polarity (positive for TPI: m/z 243.1→183.0, and negative for FTD: m/z 295.1→252.0 and FTY: m/z 178.9→158.9) electrospray ionization mode. The segmented polarity mode was designed to achieve two advantages: better sensitivity and simultaneous determination of the analytes with different ion polarities. The calibration ranges were as follows: 1.00-250 ng/ for TPI, 8.00-8000 ng/mL for FTD and 5.00-1250 ng/mL for FTY. The selectivity, accuracy, precision, matrix effect, recovery, carryover, dilution integrity and stability test results meet ICH acceptance criteria. The method was evaluated using the RGB model and successfully applied to a clinical study in patients with solid tumors. For TPI, FTD and FTY, the maximum plasma concentration was 137-147 ng/mL, 6160-6240 ng/mL and 724-725 ng/mL, respectively; the plasma elimination half-life was 1.69-1.78 h, 1.70 h, and 3.09-3.14 h, respectively, after an oral administration of 60 mg TAS-102.

A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.

Dry eye disease (DED) is currently the most prevalent condition seen in ophthalmology outpatient clinics, representing a significant public health issue. The onset and progression of DED are closely associated with oxidative stress-induced inflammation and damage. To address this, an aldehyde-functionalized F127 (AF127) hydrogel eye drop delivering multifunctional antioxidant Cu2-xSe nanoparticles (Cu2-xSe NPs) was designed. The research findings revealed that the Cu2-xSe nanoparticles exhibit unexpected capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2-xSe NPs possess remarkable efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage. Cu2-xSe NPs displayed promising therapeutic effects in a mouse model of dry eye. Detailed investigation revealed that the nanoparticles exert antioxidant, anti-apoptotic, and inflammation-mitigating effects by modulating the NRF2 and p38 MAPK signalling pathways. The AF127 hydrogel eye drops exhibit good adherence to the ocular surface through the formation of Schiff-base bonds. These findings suggest that incorporating antioxidant Cu2-xSe nanoparticles into a tissue-adhesive hydrogel could present a highly effective therapeutic strategy for treating dry eye disease and other disorders associated with reactive oxygen species. STATEMENT OF SIGNIFICANCE: A new formulation for therapeutic eye drops to be used in the treatment of dry eye disease (DED) was developed. The formulation combines copper-selenium nanoparticles (Cu2-xSe NPs) with aldehyde-functionalized Pluronic F127 (AF127). This is the first study to directly examine the effects of Cu2-xSe NPs in ophthalmology. The NPs exhibited antioxidant capabilities and enzyme-like properties. They effectively eliminated reactive oxygen species (ROS) and inhibited apoptosis through the NRF2 and p38 MAPK signalling pathways. Additionally, the AF127 hydrogel enhanced tissue adhesion by forming Schiff-base links. In mouse model of DED, the Cu2-xSe NPs@AF127 eye drops demonstrated remarkable efficacy in alleviating symptoms of DED. These findings indicate the potential of Cu2-xSe NPs as a readily available and user-friendly medication for the management of DED.