Strategy to Efficient Photodynamic Therapy for Antibacterium: Donor-Acceptor Structure in Hydrogen-Bonded Organic Framework.

While the construction of a donor-acceptor (D-A) structure have gained great attention across various scientific disciplines, such structures have seldomly been reported within the field of hydrogen-bonded organic frameworks (HOFs). Herein, a donor-acceptor (D-A) based HOF was synthesized, where the adjacent D-A pairs were connected by hydrogen bonds instead of the conventionally employed covalent bonds. This structural feature imparts material with a reduced energy gap between excited state and triplet state, thereby facilitating the intersystem crossing and boosting the generation rate of single oxygen (quantum yield = 0.98). Consequently, the resulting material showed high performance for antimicrobial photodynamic therapy. The impact of D-A moiety was evident when comparing this finding to a parallel study conducted on an isoreticular HOF without a D-A structure. The study presented here provides in-depth insights into the photophysical properties of D-A pair in a hydrogen-bonded network, opening a new avenue to design of innovative materials for efficient photodynamic therapy. This article is protected by copyright. All rights reserved.

Quantitative assessment and correlational analysis of subjective and objective indicators in patients with allergic rhinitis.

Background: The diagnosis of allergic rhinitis is mainly based on the typical medical history, clinical manifestations, and corresponding allergen test results of the patients. However, there are often clinical inconsistencies among the 3. Objective: To study the clinical characteristics of patients with allergic rhinitis from both subjective and objective aspects to determine the correlations between the quantitative assessment outcomes of subjective and objective indicators. Methods: A total of 111 patients with allergic rhinitis who visited our outpatient clinic from June 2022 to December 2022 were selected. The 22-item sino-nasal outcome test (SNOT-22) and the visual analog scale (VAS) for the severity of the disease were used to score the subjective indicators of allergic rhinitis. The objective indicators of allergic rhinitis were evaluated by serum inhalant allergens immunoglobulin E test, nasal endoscopy modified Lund-Kennedy (MLK) scoring method, and acoustic rhinometry. Results: SNOT-22 score, total VAS score for symptoms, and the VAS score for nasal itching were positively correlated with the number of positive allergens (r = 0.266, P = 0.005, r = 0.576, P < 0.001, and r = 0.271, P = 0.004, respectively). No differences were found in all subjective indicators scores between the total immunoglobulin E positive and negative groups (P > 0.05). SNOT-22 score, total VAS score for symptoms, and the VAS score for nasal congestion were positively correlated with MLK total score of nasal endoscopy (r = 0.343, P < 0.001, r = 0.438, P < 0.001, and r = 0.225, P = 0.018, respectively). Parameters of acoustic rhinometry were not correlated with the subjective indicators scores of allergic rhinitis (P > 0.05). Conclusion: A multifaceted quantitative assessment of allergic rhinitis using a combination of subjective and objective methods can help physicians make an accurate diagnosis and create reasonable treatment plans.

Gasdermin D silencing alleviates airway inflammation and remodeling in an ovalbumin-induced asthmatic mouse model.

Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1ß, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1ß were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd-/-) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1ß was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1ß production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd-/- mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Determination of cotinine and 3-hydroxynicotinine in human serum by liquid chromatography-tandem mass spectrometry and its application.

In this study, we developed a method for determining cotinine and 3-hydroxycotinine in human serum and established a methodology for an in-depth study of tobacco exposure and health. After the proteins in the human serum samples were precipitated with acetonitrile, they were separated on a ZORBAX SB-Phenyl column with a mobile phase of methanol encompassing 0.3% formic acid-water encompassing 0.15% formic acid. The measurement was performed on an API5500 triple quadrupole mass spectrometer in the multiple reaction monitoring mode. Cotinine, 3-hydroxycotinine, and cotinine-d3 isotope internal standards were held for 2.56 minutes, 1.58 minutes, and 2.56 minutes, respectively. In serum, the linear range was 0.05 to 500 ng·mL-1 for cotinine and 0.50 to 1250 ng·mL-1 for 3-hydroxycotinine. The lower limit of quantification (LLOQ) was 0.05 ng·mL-1 and 0.5 ng·mL-1 for cotinine and 3-hydroxycotinine, respectively. The intra-day and inter-day relative standard deviations were <11%, and the relative errors were within ±â€…7%. Moreover, the mean extraction recoveries of cotinine and 3-hydroxycotinine were 98.54% and 100.24%, respectively. This method is suitable for the rapid determination of cotinine and 3-hydroxycotinine in human serum because of its rapidity, sensitivity, strong specificity, and high reproducibility. The detection of cotinine levels in human serum allows for the identification of the cutoff value, providing a basis for differentiation between smoking and nonsmoking populations.

Prevalence, treatment efficacy, and risk factors of vascular complications in acute pancreatitis: A case-control study.

OBJECTIVE: We aimed to investigate the prevalence of vascular complications in acute pancreatitis (AP), to compare patient outcomes using various treatments, and to explore the related risk factors. METHODS: Consecutive AP patients admitted from January 2010 to July 2017 were retrospectively included. Demographics, vascular complications, laboratory indices, and imaging findings were collected. Univariate and multivariate analyses were used to explore potential risk factors of vascular complications. RESULTS: Of 3048 AP patients, 808 (26.5%) had vascular complications, including visceral vein thrombosis, sinistral portal hypertension, and arterial complications. And 38 (4.7%) patients received anticoagulant therapy and had a higher rate of recanalization (P < 0.001). Bleeding occurred in 95 (11.8%) patients, who received further treatment. Multivariate analysis identified male gender (odds ratio [OR] 1.650, 95% confidence interval [CI] 1.101-2.472), hyperlipidemia (OR 1.714, 95% CI 1.356-2.165), disease recurrence (OR 3.727, 95% CI 2.713-5.118), smoking (OR 1.519, 95% CI 1.011-2.283), hemoglobin level (OR 0.987, 95% CI 0.981-0.993), white blood cell (WBC) count (OR 1.094, 95% CI 1.068-1.122), non-vascular local complications (OR 3.018, 95% CI 1.992-4.573), computed tomography severity index (CTSI) (OR 1.425, 95% CI 1.273-1.596), and acute physiology and chronic health evaluation (APACHE) II score (OR 1.057, 95% CI 1.025-1.090) were related to vascular complications. CONCLUSIONS: Vascular complications in AP is prevalent and their treatment is challenging. Further investigations are warranted to determine the optimal treatment strategy. Independent risk factors included male gender, hyperlipidemia, disease recurrence, smoking, WBC count, non-vascular local complications, CTSI, and APACHE II score.

Targeting lysyl oxidase like 2 attenuates OVA-induced airway remodeling partly via the AKT signaling pathway.

BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.

Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

Nanoconfinement steers nonradical pathway transition in single atom fenton-like catalysis for improving oxidant utilization.

The introduction of single-atom catalysts (SACs) into Fenton-like oxidation promises ultrafast water pollutant elimination, but the limited access to pollutants and oxidant by surface catalytic sites and the intensive oxidant consumption still severely restrict the decontamination performance. While nanoconfinement of SACs allows drastically enhanced decontamination reaction kinetics, the detailed regulatory mechanisms remain elusive. Here, we unveil that, apart from local enrichment of reactants, the catalytic pathway shift is also an important cause for the reactivity enhancement of nanoconfined SACs. The surface electronic structure of cobalt site is altered by confining it within the nanopores of mesostructured silica particles, which triggers a fundamental transition from singlet oxygen to electron transfer pathway for 4-chlorophenol oxidation. The changed pathway and accelerated interfacial mass transfer render the nanoconfined system up to 34.7-fold higher pollutant degradation rate and drastically raised peroxymonosulfate utilization efficiency (from 61.8% to 96.6%) relative to the unconfined control. It also demonstrates superior reactivity for the degradation of other electron-rich phenolic compounds, good environment robustness, and high stability for treating real lake water. Our findings deepen the knowledge of nanoconfined catalysis and may inspire innovations in low-carbon water purification technologies and other heterogeneous catalytic applications.

Tanreqing Injection Inhibits Activation of NLRP3 Inflammasome in Macrophages Infected with Influenza A Virus by Promoting Mitophagy.

OBJECTIVE: To investigate the inhibitory effect of Tanreqing Injection (TRQ) on the activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome in macrophages infected with influenza A virus and the underlying mechanism based on mitophagy pathway. METHODS: The inflammatory model of murine macrophage J774A.1 induced by influenza A virus [strain A/Puerto Rico/8/1934 (H1N1), PR8] was constructed and treated by TRQ, while the mitochondria-targeted antioxidant Mito-TEMPO and autophagy specific inhibitor 3-methyladenine (3-MA) were used as controls to intensively study the anti-inflammatory mechanism of TRQ based on mitophagy-mitochondrial reactive oxygen species (mtROS)-NLRP3 inflammasome pathway. The levels of NLRP3, Caspase-1 p20, microtubule-associated protein 1 light chain 3 II (LC3II) and P62 proteins were measured by Western blot. The release of interleukin-1ß (IL-1ß) was tested by enzyme linked immunosorbent assay, the mtROS level was detected by flow cytometry, and the immunofluorescence and co-localization of LC3 and mitochondria were observed under confocal laser scanning microscopy. RESULTS: Similar to the effect of Mito-TEMPO and contrary to the results of 3-MA treatment, TRQ could significantly reduce the expressions of NLRP3, Caspase-1 p20, and autophagy adaptor P62, promote the expression of autophagy marker LC3II, enhance the mitochondrial fluorescence intensity, and inhibit the release of mtROS and IL-1ß (all P<0.01). Moreover, LC3 was co-localized with mitochondria, confirming the type of mitophagy. CONCLUSION: TRQ could reduce the level of mtROS by promoting mitophagy in macrophages infected with influenza A virus, thus inhibiting the activation of NLRP3 inflammasome and the release of IL-1ß, and attenuating the inflammatory response.

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology.

Background: Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection. Materials and Methods: Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokinetics-pharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD. Results: QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as Tmax, t1/2, MRT, Vd/F, CL/F and PD parameters such as MIC, AUC0-24h/MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 ß, IL-6, TNF- α, IL-10, and MCP-1 levels more akin to those of the blank group. Conclusion: These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.

Construction of a Model for Predicting the Risk of pT3 Based on Perioperative Characteristics in cT1 Renal Cell Carcinoma: A Retrospective Study at a Single Institution.

INTRODUCTION: This study explored the predictors of upstaging and multiple sites of extension, and constructed a predictive model based on perioperative characteristics to calculate the risk of upstaging of cT1 renal cell carcinoma to pT3. METHODS: We retrospectively reviewed 1012 patients diagnosed with cT1 renal cell carcinoma who underwent surgical treatment at the Affiliated Hospital of Qingdao University between June 2016 and August 2021. The continuous and categorical variables were analyzed using the Mann-Whitney U test and Chi-square test, respectively. After randomly dividing patients into a training set and an internal validation set with a ratio of 7:3, univariate and multivariate logistic regression analyses were used to explore the predictors of upstaging and multiple sites of extension. A nomogram model was established based on the predictors of upstaging and was validated. RESULTS: Ninety-one cases (8.99%) of renal cell carcinoma were upstaged to pT3. In the training set, multivariate logistic regression identified the following predictors of upstaging: maximum tumor diameter, hilus involvement, tumor necrosis, tumor edge irregularity, symptoms, smoking, and platelet-lymphocyte ratio. A nomogram model was established based on the predictors. The area under the receiver operating characteristic curve was 0.810 in the training set, and 0.804 in the validation set. A 10-fold internal cross-validation conducted 200 times showed that the mean area under the curve was 0.797. The calibration curve and decision curve analysis suggested that the nomogram had robust clinical predictive power. Analyses showed higher neutrophil-lymphocyte ratio and tumor necrosis were associated with multiple sites of extrarenal extension in patients with pT3a renal cell carcinoma. CONCLUSIONS: We identified 7 predictors of upstaging to pT3 and 2 predictors of multiple sites of extension. A nomogram model was constructed with satisfactory accuracy for predicting upstaging to pT3.

A new evaluation system for drug-microbiota interactions.

The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.

Effect of endoscopic full-thickness resection assisted by distal serosal turnover with floss traction for gastric submucosal masses.

BACKGROUND: Complex and high-risk surgical complications pose pressing challenges in the clinical implementation and advancement of endoscopic full-thickness resection (EFTR). Successful perforation repair under endoscopy, thereby avoiding surgical intervention and postoperative complications such as peritonitis, are pivotal for effective EFTR. AIM: To investigate the effectiveness and safety of EFTR assisted by distal serosal inversion under floss traction in gastric submucosal tumors. METHODS: A retrospective analysis of patients with gastric and duodenal submucosal tumors treated with EFTR assisted by the distal serosa inversion under dental floss traction from January 2023 to January 2024 was conducted. The total operation time, tumor dissection time, wound closure time, intraoperative bleeding volume, length of hospital stay and incidence of complications were analyzed. RESULTS: There were 93 patients, aged 55.1 ± 12.1 years. Complete tumor resection was achieved in all cases, resulting in a 100% success rate. The average total operation time was 67.4 ± 27.0 min, with tumor dissection taking 43.6 ± 20.4 min. Wound closure times varied, with gastric body closure time of 24.5 ± 14.1 min and gastric fundus closure time of 16.6 ± 8.7 min, showing a significant difference (P < 0.05). Intraoperative blood loss was 2.3 ± 4.0 mL, and average length of hospital stay was 5.7 ± 1.9 d. There was no secondary perforation after suturing in all cases. The incidence of delayed bleeding was 2.2%, and the incidence of abdominal infection was 3.2%. No patient required other surgical intervention during and after the operation. CONCLUSION: Distal serosal inversion under dental-floss-assisted EFTR significantly reduced wound closure time and intraoperative blood loss, making it a viable approach for gastric submucosal tumors.

MRI-only based material mass density and relative stopping power estimation via deep learning for proton therapy: a preliminary study.

Magnetic Resonance Imaging (MRI) is increasingly being used in treatment planning due to its superior soft tissue contrast, which is useful for tumor and soft tissue delineation compared to computed tomography (CT). However, MRI cannot directly provide mass density or relative stopping power (RSP) maps, which are required for calculating proton radiotherapy doses. Therefore, the integration of artificial intelligence (AI) into MRI-based treatment planning to estimate mass density and RSP directly from MRI has generated significant interest. A deep learning (DL) based framework was developed to establish a voxel-wise correlation between MR images and mass density as well as RSP. To facilitate the study, five tissue substitute phantoms were created, representing different tissues such as skin, muscle, adipose tissue, 45% hydroxyapatite (HA), and spongiosa bone. The composition of these phantoms was based on information from ICRP reports. Additionally, two animal tissue phantoms, simulating pig brain and liver, were prepared for DL training purposes. The phantom study involved the development of two DL models. The first model utilized clinical T1 and T2 MRI scans as input, while the second model incorporated zero echo time (ZTE) MRI scans. In the patient application study, two more DL models were trained: one using T1 and T2 MRI scans as input, and another model incorporating synthetic dual-energy computed tomography (sDECT) images to provide accurate bone tissue information. The DECT empirical model was used as a reference to evaluate the proposed models in both phantom and patient application studies. The DECT empirical model was selected as the reference for evaluating the proposed models in both phantom and patient application studies. In the phantom study, the DL model based on T1, and T2 MRI scans demonstrated higher accuracy in estimating mass density and RSP for skin, muscle, adipose tissue, brain, and liver. The mean absolute percentage errors (MAPE) were 0.42%, 0.14%, 0.19%, 0.78%, and 0.26% for mass density, and 0.30%, 0.11%, 0.16%, 0.61%, and 0.23% for RSP, respectively. The DL model incorporating ZTE MRI further improved the accuracy of mass density and RSP estimation for 45% HA and spongiosa bone, with MAPE values of 0.23% and 0.09% for mass density, and 0.19% and 0.07% for RSP, respectively. These results demonstrate the feasibility of using an MRI-only approach combined with DL methods for mass density and RSP estimation in proton therapy treatment planning. By employing this approach, it is possible to obtain the necessary information for proton radiotherapy directly from MRI scans, eliminating the need for additional imaging modalities.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Chinese Medicine Prolongs Overall Survival of Chinese Patients with Advanced Gastric Cancer: Treatment Pattern and Survival Analysis of a 20-Year Real-World Study.

OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).

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.

Hydrostability, mechanical resilience, and biodegradability of paper straws fabricated through lignin-based polyurethane and chitosan binary emulsion bonding.

This study focuses on enhancing the strength and water stability of paper straws through a novel approach involving a binary emulsion of lignin-based polyurethane and chitosan. Kraft lignin serves as the raw material for synthesizing a blocked waterborne polyurethane, subsequently combined with carboxylated chitosan to form a stable binary emulsion. The resulting emulsion, exhibiting remarkable stability over at least 6 months, is applied to the base paper. Following emulsion application, the paper undergoes torrefaction at 155 °C. This process deblocks isocyanate groups, enabling their reaction with hydroxyl groups on chitosan and fibers, ultimately forming ester bonds. This reaction significantly improves the mechanical strength and hydrophobicity of paper straws. The composite paper straws demonstrate exceptional mechanical properties, including a tensile strength of 47.21 MPa, Young's modulus of 4.33 GPa, and flexural strength of 32.38 MPa. Notably, its water stability is greatly enhanced, with a wet tensile strength of 40.66 MPa, surpassing commercial paper straws by 8 folds. Furthermore, the composite straw achieves complete biodegradability within 120 days, outperforming conventional paper straws in terms of environmental impact. This innovative solution presents a promising and sustainable alternative to plastic straws, addressing the urgent need for eco-friendly products.