A novel artificial intelligence network to assess the prognosis of gastrointestinal cancer to immunotherapy based on genetic mutation features.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized gastrointestinal cancer treatment, yet the absence of reliable biomarkers hampers precise patient response prediction. Methods: We developed and validated a genomic mutation signature (GMS) employing a novel artificial intelligence network to forecast the prognosis of gastrointestinal cancer patients undergoing ICIs therapy. Subsequently, we explored the underlying immune landscapes across different subtypes using multiomics data. Finally, UMI-77 was pinpointed through the analysis of drug sensitization data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The sensitivity of UMI-77 to the AGS and MKN45 cell lines was evaluated using the cell counting kit-8 (CCK8) assay and the plate clone formation assay. Results: Using the artificial intelligence network, we developed the GMS that independently predicts the prognosis of gastrointestinal cancer patients. The GMS demonstrated consistent performance across three public cohorts and exhibited high sensitivity and specificity for 6, 12, and 24-month overall survival (OS) in receiver operating characteristic (ROC) curve analysis. It outperformed conventional clinical and molecular features. Low-risk samples showed a higher presence of cytolytic immune cells and enhanced immunogenic potential compared to high-risk samples. Additionally, we identified the small molecule compound UMI-77. The half-maximal inhibitory concentration (IC50) of UMI-77 was inversely related to the GMS. Notably, the AGS cell line, classified as high-risk, displayed greater sensitivity to UMI-77, whereas the MKN45 cell line, classified as low-risk, showed less sensitivity. Conclusion: The GMS developed here can reliably predict survival benefit for gastrointestinal cancer patients on ICIs therapy.

Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics.

Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.

Electrospun nanofibers-based thin film microextraction for enrichment of phthalate esters in biodegradable plastics.

In this work, a novel electrospun nanofiber (PAN/TpBD; 2,4,6-triformylphloroglucinol [Tp] and benzidine [BD]; polyacrylonitrile [PAN]) was fabricated via a facile electrospinning method and utilized as adsorbent in thin film microextraction (TFME) of phthalate esters (PAEs) (dimethyl phthalate, diethyl phthalate, diallyl phthalate, dibutyl phthalate, and dioctyl phthalate) in biodegradable plastics. The prepared PAN/TpBD combines the strong stability of nanofibers with increased exposure sites for covalent organic frameworks and enhanced interactions with the target, thus improving the enrichment effect on the target. The extraction efficiency of PAN/TpBD reached above 80%. Based on PAN/TpBD, a TFME-high-performance liquid chromatography method was established, and the experimental parameters were optimized. Under the optimal extraction conditions, the PAEs of this method varied linearly in the range of 10-10 000 µg/L with low detection limits (0.69-2.72 µg/L). The intra-day and inter-day relative standard deviation values of the PAEs were less than 8.04% and 8.73%, respectively. The adsorbent can achieve more than 80% recovery of the five targets after six times reuse. The developed method was successfully applied for the determination of trace PAEs in biodegradable plastics with recoveries ranging from 80.1% to 113.4% and relative standard deviations were less than 9.45%. The as-synthesized PAN/TpBD adsorbent exhibited great potential in PAE analysis.

Health utility of patients with established rheumatoid arthritis and its influencing factors: a multi-center study in China.

To assess the health utility value (HUV) of Rheumatoid Arthritis (RA) patients and its influencing factors in China. A cross-sectional survey was conducted in 8 tertiary hospitals across four capital-cities. The demographic characteristics, patient-reported outcomes including the HUV got by EQ-5D-5L, clinical characteristics, and clinician-reported outcomes of 171 RA patients were collected both from themselves and their physicians. Both the univariate and multivariate analyses were used to assess the potential factors of EQ-5D-5L HUV of the patients. The mean age of the patients was 50.7 years, with female being 64.9% (n = 111). The mean HUV and EQ visual analogue scale score of all patients were 0.586 and 47.3, respectively. The univariate analysis showed that the patients who were female, older, living in rural areas, with lower education level, advanced disease stage, higher the patient's assessment of arthritis pain visual analogue scale (PtAAP-VAS), the patient's global assessment of disease activity visual analogue scale (PtGADA-VAS), and the Physician's global assessment of disease activity visual analogue scale (PhGADA-VAS) scores had significantly lower EQ-5D-5L HUVs. The multivariate analysis further suggested that older age, female, higher body mass index and higher PtGADA-VAS score were statistically significantly related to lower HUVs. The study provided the HUVs for RA patients with different characteristics and outcomes, which could be used in the economic evaluation of interventions for the RA patients. The identified factors could also assist the health care managing and improving the health-related quality of life on RA patients.

Peptidomics- inspired discovery and activity evaluation of antioxidant peptides in multiple strains mixed fermentation of Porphyra yezoensis.

This study investigated the production of antioxidant peptides from Porphyra yezoensis through fermentation with three strains of microorganisms: Lactiplantibacillus plantarum L13, Bacillus amyloliquefaciens MMB-02, and Saccharomyces cerevisiae A8. The crude peptides were extracted by aqueous acid precipitation and purified by Sephadex G-25 gel column to produce highly active antioxidant components with molecular weight of <4000 Da. The LC-MS/MS result revealed that the fermentation group contained more hydrophobic amino acids and oligopeptides, which were mainly originated from phycobiliproteins and algal blue proteins. Finally, the antioxidant activity of Porphyra yezoensis was determined with DPPH· and ABTS· scavenging rates of 54.87% and 57.39%, respectively. The ferric ion-reducing power (FRAP) and enzyme activities of SOD and CAT were significantly higher than those of the control group. This study provides a scientific foundation for the deep processing of striped seaweed and contributes to the theoretical understanding of synthetic antioxidant substitutes.

Evaluation of the anti-atherosclerotic effect for Allium macrostemon Bge. Polysaccharides and structural characterization of its a newly active fructan.

Allium Macrostemon Bge. (AMB) is a well-known homology of herbal medicine and food that has been extensively used for thousands of years to alleviate cardiovascular diseases. It contains a significant amount of polysaccharides, yet limited research exists on whether these polysaccharides are responsible for its cardiovascular protective effects. In this study, the anti-atherosclerosis effect of the crude polysaccharides of AMB (AMBP) was evaluated using ApoE-/- mice fed a high-fat diet, along with ox-LDL-induced Thp-1 foam cells. Subsequently, guided by the inhibitory activity of foam cells formation, a major homogeneous polysaccharide named AMBP80-1a was isolated and purified, yielding 11.1 % from AMB. The molecular weight of AMBP80-1a was determined to be 10.01 kDa. AMBP80-1a was firstly characterized as an agavin-type fructan with main chains consisting of →1)-ß-d-Fruf-(2→ and →1,6)-ß-d-Fruf-(2→ linked to an internal glucose moiety, with →6)-ß-d-Fruf-(2→ and ß-d-Fruf-(2→ serving as side chains. Furthermore, the bio-activity results indicated that AMBP80-1a reduced lipid accumulation and cholesterol contents in ox-LDL-induced Thp-1 foam cell. These findings supported the role of AMBP in alleviating atherosclerosis in vivo/vitro. AMBP80-1a, as the predominant homogeneous polysaccharide in AMB, was expected to be developed as a functional agent to prevent atherosclerosis.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Five-layer-funnel filtering mode discovers effective components of Chinese medicine formulas: Zhishi-Xiebai-Guizhi decoction as a case study.

BACKGROUND: How to screen and identify the effective components in the complex substance system is one of the core issues in achieving the modernization of traditional Chinese medicine (TCM) formulas. However, it is still challenging to systematically screen out the effective components from the hundreds or thousands of components in a TCM formula. PURPOSE: An innovative five-layer-funnel filtering mode stepwise integrating chemical profile, quantitative analysis, xenobiotic profile, network pharmacology and bioactivity evaluation was successfully presented to discover the effective components and implemented on a case study of Zhishi-Xiebai-Guizhi decoction (ZXG), a well-known TCM formula for coronary heart disease (CHD). METHODS: Initially, the chemical profile of ZXG was systemically characterized. Subsequently, the representative constituents were quantitatively analyzed. In the third step, the multi-component xenobiotics profile of ZXG was systemically delineated, and the prototypes absorbed into the blood were identified and designated as the primary bioavailable components. Next, an integrated network of "bioavailable components-CHD targets-pathways-therapeutic effects" was constructed, and the crucial bioavailable components of ZXG against CHD were screened out. Lastly, the bioactivities of crucial bioavailable components were further evaluated to pinpoint effective components. RESULTS: First of all, the chemical profile of ZXG was systemically characterized with the detection of 201 components. Secondly, 37 representative components were quantified to comprehensively describe its content distribution characteristics. Thirdly, among the quantified components, 24 bioavailable components of ZXG were identified based on the multi-component xenobiotic profile. Fourthly, an integrated network led to the identification of 11 crucial bioavailable components against CHD. Ultimately, 9 components (honokiol, magnolol, naringenin, magnoflorine, hesperidin, hesperetin, naringin, neohesperidin and narirutin) exhibiting myocardial protection in vitro were identified as effective components of ZXG for the first time. CONCLUSION: Overall, this innovative strategy successfully identified the effective components of ZXG for the first time. It could not only significantly contribute to elucidating the therapeutic mechanism of ZXG in the treatment of CHD, but also serve as a helpful reference for the systematic discovery of effective components as well as ideal quality markers in the quality assessment of TCM formulas.

Huaier enhances the tumor-killing effect and reverses gemcitabine-induced stemness by suppressing FoxM1.

BACKGROUND: Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown. PURPOSE: This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer. METHODS: Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression. RESULTS: Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro. CONCLUSION: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.

pH-responsive dual-emission carbon dots for the ratiometric detection of organophosphorus pesticides in Brassica chinensis and Hg2+ in water.

Accurate and rapid monitoring of organophosphorus pesticides (OPs) residues is crucial for regulating food safety. Herein, dual-emission carbon dots (de-CDs) were fabricated for the ratiometric detection of OPs and Hg2+. The de-CDs exhibited two emission peaks at 678 and 485 nm when excited with visible light. Interestingly, the fluorescence at 678 nm was significantly quenched by Hg2+ mainly because of the static quenching effect, whereas that at 485 nm exhibited a slight change. More significantly, the quenched fluorescence of the de-CDs recovered remarkably after introducing omethoate, diazinon and malathion. Accordingly, the ratiometric detection of the three OPs and Hg2+ was achieved with high selectivity and robust performance. In addition, the OPs residues assay in Brassica chinensis was successfully performed with satisfactory results. This study not only provides an attractive tool for the simple and rapid assay of OPs but also offers new insights into the fabrication of multi-functional carbon dots.

Adsorption properties of Pb(II) and Cd(II) in acid mine drainage by oyster shell loaded lignite composite in different morphologies.

A new idea to alleviate environmental pollution is the development of low-cost adsorbents using natural minerals and fishery wastes to treat high concentrations of heavy metal pollutants in acid mine drainage (AMD). Adsorbent morphology, adsorptive and regenerative capacity, and application potential are limiting factors for their large-scale use. Oyster shells capable of releasing alkalinity were loaded on the surface of lignite to develop two composite adsorbents with different morphologies (powdery and globular) for the treatment of AMD containing Pb(II) and Cd(II). The results show that the ability of the adsorbent to treat AMD is closely related to its morphologies. The pseudo-second-order kinetic model and the Langmuir model are suitable to describe the adsorption process of OS-M(P), and the maximum adsorption saturation capacities of Pb(II) and Cd(II) are 332.6219 mg/g and 318.9854 mg/g, respectively. The pseudo-second-order kinetic model and the Freundlich model are suitable to describe the adsorption process of OS-M(G). A synergistic result of electrostatic adsorption, neutralization precipitation, ion exchange and complex reaction is achieved in the removal of Pb(II) and Cd(II) by two morphologies of adsorbents. The regeneration times (5 times) and recovery rate (75.75%) of OS-M(G) are higher than those of OS-M(P) (3 times) and recovery rate (20%). The ability of OS-M(G) to treat actual AMD wastewater is still better than that of OS-M(P). OS-M(G) can be used as a promising environmentally friendly adsorbent for the long-term remediation of AMD. This study provides a comprehensive picture of resource management and reuse opportunities for natural mineral and fishery wastes.

Clinical characteristics of lower extremity deep vein thrombosis in young vs. middle-aged adults: a single-center retrospective study.

Background: The incidence of deep vein thrombosis (DVT) in the lower extremities is increasing in the younger population. However, there are fewer reported comparisons in the literature for lower extremity DVT. Methods: Patients aged <40 years admitted with lower-extremity DVT between January 2018 and December 2023 were retrospectively analyzed and followed up for 1 year. Results: A total of 61 patients were included in the study and divided into two groups: 33 patients over 30 years of age (middle-aged group) and 28 patients under 30 years of age (young group). A significant gender difference was observed, with a higher proportion of males in the young group compared to the middle-aged group (P < 0.001). Five patients in the young group were treated with anticoagulation alone, whereas all patients in the middle-aged group underwent endovascular therapy. A higher prevalence of inferior vena cava thrombosis in the young group compared to the middle-aged group (60.71% vs. 33.3%, P = 0.032). The proportion of iliac vein stenosis was significantly higher in the middle-aged groups than in the young group (P = 0.002). There was no statistically significant difference in venous function scores (Villalta and rVCSS) between the two groups during both the preoperative period and the postoperative follow-up (P > 0.05). The incidence of lower-extremity DVT post-thrombotic syndrome and thrombus recurrence was higher in the young group than in the middle-aged group at 1 year postoperatively (PTS: 78.57% vs. 33.3%, P < 0.001, and thrombus recurrence: 28.57% vs. 9.09%, P < 0.05). Univariate and multivariate analyses revealed that inferior vena cava thrombosis was an independent risk factor for severe DVT post-thrombotic syndrome and recurrent DVT (P < 0.05), whereas gender was an independent risk factor for recurrent DVT (P < 0.05). Conclusions: This study suggests differences in the clinical characteristics and prognosis of lower-extremity DVT.

Isolation of triazole-resistant Aspergillus fumigatus harbouring cyp51A mutations from five patients with invasive pulmonary aspergillosis in Yunnan, China.

Invasive aspergillosis (IA) is the most severe type of Aspergillus infection. Yunnan has developed agriculture, and the proportion of triazole-resistant A. fumigatus induced by triazole fungicides is much higher than that in other regions of China. Inhalation of triazole-resistant A. fumigatus is one of the main factors inducing IA. We gathered five strains of A. fumigatus from the sputum or bronchoalveolar lavage fluid (BALF) of patients with IA in Yunnan. Subsequent testing showed that all of these strains were resistant to triazoles and harboured mutations in the tandem repeat sequence of the cyp51A promoter region, suggesting that they may be triazole-resistant A. fumigatus present in the environment.

Anti-pancreatic cancer activity of cassane diterpenoids isolated from the seeds of Caesalpinia sappan mediated by autophagy activation via ROS/AMPK/mTORC1 pathway.

Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC50 value of 18.13 ± 0.63 µM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.

Optimization of α-L-arabinofuranosidase CcABF on clarification and beneficial active substances in fermented ginkgo kernel juice by artificial neural network and genetic algorithm.

This study aimed at using α-L-arabinofuranosidase CcABF to improve the clarity and active substances in fermented ginkgo kernel juice by artificial neural network (ANN) modeling and genetic algorithm (GA) optimization. A credible three-layer feedforward ANN model was established to predict the optimal parameters for CcABF clarification. The experiments proved the highest transmittance of 89.40% for fermented ginkgo kernel juice with this understanding, which exhibited a 25.56% increase over the unclarified group. With the clarification of CcABF, the antioxidant capacity in juice was enhanced with the increase of total phenolic and flavone contents, and the maximum DPPH and hydroxyl radical scavenging rates were increased by 89.71% and 26.65%, respectively. The contents of toxic ginkgolic acids declined markedly, while the active ingredients of ginkgetin and ginkgolide B showed a modest increase. Moreover, changes in free amino acids and volatile compounds improved the nutritive value and flavor of clarified fermented ginkgo kernel juice.

Efficient Recovery of Phosphate from Water Media by Iron-Magnesium Functionalized Lignite: Adsorption Evaluation, Mechanism Revelation and Potential Application Exploration.

Selective phosphorus removal from aquatic media has become an ideal strategy to mitigate eutrophication and meet increasingly stringent discharge requirements. To achieve phosphorus control and resource utilization of low-calorific-value lignite, iron and magnesium salts were used to functionalize lignite, and iron-magnesium functionalized lignite (called IM@BC) was prepared for phosphate recovery from water media. The adsorption properties of IM@BC were systematically evaluated, especially the influence of ambient pH and co-existing ions. The kinetic, isothermal, and thermodynamic adsorption behaviors of IM@BC were analyzed. The adsorption mechanism was revealed by microscopic characterization. The potential application of phosphate-containing IM@BC (P-IM@BC) was explored. The results show that IM@BC has a strong phosphate adsorption capacity, and the maximum adsorption capacity is 226.22 mgP/g at pH = 3. Co-existing CO32- inhibits phosphate adsorption, while coexisting Ca2+ and Mg2+ enhance the effect. At the initial adsorption stage, the amount of phosphate adsorbed by IM@BC continues to increase, and the adsorption equilibrium state is gradually reached after 24 h. The adsorption process conforms to the pseudo-second-order kinetic model (PSO) and Langmuir isothermal adsorption model, and the adsorption process is mainly chemical adsorption. The phosphate absorption capacity is positively correlated with temperature (283.15 K~313.15 K), and the adsorption process is spontaneous, endothermic, and entropy-increasing. Its adsorption mechanism includes electrostatic attraction, ion exchange, surface precipitation, and coordination exchange. IM@BC can efficiently recover phosphate from actual phosphorus-containing wastewater with a recovery efficiency of up to 90%. P-IM@BC slowly releases phosphate from pH 3 to 11. Plant growth experiments showed that P-IM@BC could be used as a slow-release fertilizer to promote the root growth of cowpeas. The novelty of this work lies in the development of a highly efficient phosphate recovery adsorbent, which provides a feasible method of phosphorus control in water media and resource utilization of lignite.

Evaluating the efficacy and safety of oral triple sequential combination therapy for treating patients with pulmonary arterial hypertension: A multicenter retrospective study.

This study aimed to evaluate the effectiveness and safety of an oral sequential triple combination therapy with selexipag after dual combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5I)/riociguat in pulmonary arterial hypertension (PAH) patients. A total of 192 PAH patients from 10 centers had received oral sequential selexipag therapy after being on dual-combination therapy with ERA and PDE5i/riociguat for a minimum of 3 months. Clinical data were collected at baseline and after 6 months of treatment. The study analyzed the event-free survival at 6 months and all-cause death over 2 years. At baseline, the distribution of patients among the risk groups was as follows: 22 in the low-risk group, 35 in the intermediate-low-risk group, 91 in the intermediate-high-risk group, and 44 in the high-risk group. After 6 months of treatment, the oral sequential triple combination therapy resulted in reduced NT-proBNP levels (media from 1604 to 678 pg/mL), a decline in the percentage of WHO-FC III/IV (from 79.2% to 60.4%), an increased in the 6MWD (from 325 ± 147 to 378 ± 143 m) and a rise in the percentage of patients with three low-risk criteria (from 5.7% to 13.5%). Among the low-risk group, there was an improvement in the right heart remodeling, marked by a decrease in right atrium area and eccentricity index. The intermediate-low-risk group exhibited significant enhancements in WHO-FC and tricuspid annular plane systolic excursion. For those in the intermediate-high and high-risk groups, there were marked improvements in activity tolerance, as reflected by WHO-FC and 6MWD. The event-free survival rate at 6 months stood at 88%. Over the long-term follow-up, the survival rates at 1 and 2 years were 86.5% and 86.0%, respectively. In conclusion, the oral sequential triple combination therapy enhanced both exercise capacity and cardiac remodeling across PAH patients of different risk stratifications.

Successful retrieval of tip-embedded inferior vena cava filter using a modified forceps technique: case report.

BACKGROUND: The retrieval of inferior vena cava (IVC) filter is essential for preventing complications associated with the device. Advanced techniques have been developed to improve the success rate of retrieving tip-embedded filters. The forceps technique is frequently used to address this issue. CASE PRESENTATION: We present a case study of two patients who underwent a successful tip-embedded IVC filter retrieval using a modified forceps technique, which has not been previously reported. This technique involves using a wire loop under the filter tip and a forceps to grasp the filter shoulder. By pulling the wire loop and pushing the forceps in counterforce, the filter tip is straightened and aligned with the vascular sheath. The vascular sheath can then dissect the filter tip out from the caval wall and get inside the sheath to complete the retrieval. CONCLUSIONS: The modified forceps technique we present here offers a new solution for the complex retrieval of IVC filters.

Patterned collagen films loaded with miR-133b@MBG-NH2for potential applications in corneal stromal injury repair.

Corneal stromal injury is a common surgical disease. With the development of tissue engineering materials, many artificial corneal scaffolds have been developed to replace allograft corneal transplantation and solve the problem of corneal donor shortage. However, few researchers have paid attention to corneal stromal wound healing. Herein, a nanocomposite of amino modified mesoporous bioactive glass (MBG-NH2) and microRNA-133b (miR-133b) was introduced into the patterned collagen films to achieve corneal stromal injury repair. MBG-NH2nanoparticles as a nano delivery carrier could efficiently load miR-133b and achieve the slow release of miR-133b. The physicochemical properties of collagen films were characterized and found the microgrooved collagen films loaded with miR-133b@MBG-NH2nanoparticles possessed similar swelling properties, optical clarity, and biodegradability to the natural cornea.In vitrocell experiments were also conducted and proved that the patterned collagen films with miR-133b@MBG-NH2possessed good biocompatibility, and miR-133b@MBG-NH2nanoparticles could be significantly uptake by rabbit corneal stromal cells (RCSCs) and have a significant impact on the orientation, proliferation, migration, and gene expression of RCSCs. More importantly, the patterned collagen films with miR-133b@MBG-NH2could effectively promote the migration of RCSCs and accelerate wound healing process, and down-regulate the expression levels ofα-SMA, COL-I, and CTGF genes associated with myofibroblast differentiation of corneal stromal cells, which has a potential application prospect in the repair of corneal stromal injury.

Three-Four Photon Transition Mn(II) Complex Monitoring Lysosome-Related ATP in Real Time via Fluorescence Lifetime Imaging.

Currently, in situ monitoring of the adenosine triphosphate (ATP) level in lysosomes is critical to understand their involvement in various biological processes, but it remains difficult due to the interferences of limited targeting and low resolution of fluorescent probes. Herein, we report a classic Mn(II) probe (FX2-MnCl2) with near-infrared (NIR) nonlinear (NLO) properties, accompanied by three-four photon transition and fivefold fluorescence enhancement in the presence of ATP. FX2-MnCl2 combines with ATP through dual recognition sites of diethoxy and manganese ions to reflect slightly fluorescence lifetime change. Through the synergy of multiphoton fluorescence imaging (MP-FI) and multiphoton fluorescence lifetime imaging microscopy (MP-FLIM), it is further demonstrated that FX2-MnCl2 displays lysosome-specific targeting behavior, which can monitor lysosome-related ATP migration under NIR laser light. This work provides a novel multiphoton transformation fluorescence complex, which might be a potential candidate as a simple and straightforward biomarker of lysosome ATP in vitro for clinical diagnosis.