Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors.

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

Two new compounds from the capitula of Chrysanthemum morifolium cv. Fubaiju.

A new germacrane-type sesquiterpenoid (1) and a new alkamide (2), as well as six known compounds (3-8) were isolated from the capitula of Chrysanthemum morifolium cv. Fubaiju. The new structures were elucidated by comprehensive spectroscopic analysis and quantum chemical calculations. The known structures were characterised via 1D NMR data compared with the already existing literature data. Among the isolates, compound 5 showed inhibitory activity against human lung cancer A549 cells and human hepatoma HepG2 cells with the IC50 values of 19.50 ± 1.23 and 23.24 ± 1.30 µM, respectively, and compound 8 exhibited inhibitory effect on RSV infection with IC50 value of 12.50 ± 1.02 µM.

Comparison of race- and ethnicity-specific BMI cutoffs for categorizing obesity severity: a multicountry prospective cohort study.

OBJECTIVE: The objective of this study was to compare race- and ethnicity-specific BMI cutoffs for the three classes of obesity based on equivalent risk of type 2 diabetes (T2D). METHODS: Participants without T2D were included from the UK Biobank, the China Health and Nutrition Survey, and the Singapore Chinese Health Study. Poisson regressions with restricted cubic splines were applied to determine BMI cutoffs for each non-White race and ethnicity for equivalent incidence rates of T2D at BMI values of 30.0, 35.0, and 40.0 kg/m2 in White adults. RESULTS: During a median follow-up of 13.8 years among 507,763 individuals, 5.2% developed T2D. In women, BMI cutoffs for an equivalent incidence rate of T2D as observed at 40.0 kg/m2 in White adults were 31.6 kg/m2 in Black, 29.2 kg/m2 in British Chinese, 27.3 kg/m2 in South Asian, 26.9 kg/m2 in Native Chinese, and 25.1 kg/m2 in Singapore Chinese adults. In men, the corresponding BMI cutoffs were 31.9 kg/m2 in Black, 30.6 kg/m2 in British Chinese, 29.0 kg/m2 in South Asian, 29.6 kg/m2 in Native Chinese, and 27.6 kg/m2 in Singapore Chinese adults. The race and ethnicity order was consistent when equivalent BMI cutoffs were estimated for class I and II obesity. CONCLUSIONS: Establishing a race- and ethnicity-tailored classification of the three classes of obesity is urgently needed.

Adolescent exposure to tris(1,3-dichloro-2-propyl) phosphate (TCPP) induces reproductive toxicity in zebrafish through hypothalamic-pituitary-gonadal axis disruption.

Tris(1,3-dichloro-2-propyl) phosphate (TCPP), a prevalent organophosphorus flame retardant in aquatic environments, has raised significant concerns regarding its ecological risks. This study aims to explore the impacts of TCPP on the reproductive functions of zebrafish and delineate its gender-related toxic mechanisms. By assessing the effects on zebrafish of 10 mg/L TCPP exposure from 30 to 120 days post-fertilization (dpf), we thoroughly evaluated the reproductive capability and endocrine system alterations. Our findings indicated that TCPP exposure disrupted gender differentiation in zebrafish and markedly impaired their reproductive capacity, resulting in decreased egg laying and offspring development quality. Histological analyses of gonadal tissues showed an abnormal increase in immature oocytes in females and a reduction in mature sperm count and spermatogonial structure integrity in males, collectively leading to compromised embryo quality. Additionally, molecular docking results indicated that TCPP showed a strong affinity for estrogen receptors, and TCPP-treated zebrafish exhibited imbalanced sex hormones and increased estrogen receptor expression. Alterations in genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and activation of the steroidogenesis pathway suggested that TCPP targets the HPG axis to regulate sex hormone homeostasis. Tamoxifen (TAM), as a competitive inhibitor of estrogen, exhibited a biphasic effect, as evidenced by the counteraction of TCPP-induced effects in both male and female zebrafish after TAM addition. Overall, our study underscored the gender-dependent reproductive toxicity of TCPP exposure in zebrafish, characterized by diminished reproductive capacity and hormonal disturbances, likely due to interference in the HPG axis and steroidogenesis pathways. These findings emphasize the critical need to consider gender differences in chemical risk assessments for ecosystems and highlight the importance of understanding the mechanisms underlying the effects of chemical pollutants on the reproductive health of aquatic species.

Effects of probiotic treatment on patients and animals with chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized control trials.

Objective: In recent years, the lung-gut axis has received increasing attention. The oxidative stress and systemic hypoxia occurring in chronic obstructive pulmonary disease (COPD) are related to gut dysfunction. That suggests probiotics have a potential therapeutic role in COPD. In this study, we therefore evaluated the ameliorative effects of probiotics on COPD. Methods: Searches were conducted in four electronic databases, including PubMed, Cochrane Library, the NIH clinical registry Clinical Trials. Gov and EMBASE. The data extracted was analyzed statistically in this study using StataMP17 software, with mean difference (MD) chosen as the effect size for continuous variables, and the results expressed as effect sizes and their 95% confidence intervals (CIs). Standardized Mean Difference (SMD) was used if the data units were different. Results: We included three randomized, controlled, double-blind clinical trials and five randomized controlled animal studies. The results show that for lung function, probiotics improved %FEV1 in COPD patients (MD = 3.02, 95%CI: 1.10, 4.93). Additionally, in inflammation, probiotics increased IL-10 (SMD = 1.99, 95%CI: 1.02, 2.96) and decreased inflammatory markers such as TNF-α (SMD= -2.64, 95%Cl: -3.38, -1.90), IL-1ß (SMD= -3.49, 95%Cl: -4.58, -2.40), and IL-6 (SMD= -6.54, 95%Cl: -8.36, -4.73) in COPD animals, while having no significant effect on C-reactive protein (MD = 0.30, 95%CI: -0.71, 1.32) in COPD patients. For lung structure, probiotics significantly reduced the degree of pulmonary collagen fibers deposition in COPD animals (SMD = -2.25, 95%CI: -3.08, -1.41). Conclusion: Overall, probiotics may be an additional approach that can improve COPD. Further clinical trials are needed to evaluate the efficacy, safety, and impact factors of probiotics for COPD. Systematic Review Registration: https://inplasy.com/inplasy-2023-4-0023/, identifier INPLASY202340023.

Contrast-enhanced CT radiomics combined with multiple machine learning algorithms for preoperative identification of lymph node metastasis in pancreatic ductal adenocarcinoma.

Objectives: This research aimed to assess the value of radiomics combined with multiple machine learning algorithms in the diagnosis of pancreatic ductal adenocarcinoma (PDAC) lymph node (LN) metastasis, which is expected to provide clinical treatment strategies. Methods: A total of 128 patients with pathologically confirmed PDAC and who underwent surgical resection were randomized into training (n=93) and validation (n=35) groups. This study incorporated a total of 13 distinct machine learning algorithms and explored 85 unique combinations of these algorithms. The area under the curve (AUC) of each model was computed. The model with the highest mean AUC was selected as the best model which was selected to determine the radiomics score (Radscore). The clinical factors were examined by the univariate and multivariate analysis, which allowed for the identification of factors suitable for clinical modeling. The multivariate logistic regression was used to create a combined model using Radscore and clinical variables. The diagnostic performance was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). Results: Among the 233 models constructed using arterial phase (AP), venous phase (VP), and AP+VP radiomics features, the model built by applying AP+VP radiomics features and a combination of Lasso+Logistic algorithm had the highest mean AUC. A clinical model was eventually constructed using CA199 and tumor size. The combined model consisted of AP+VP-Radscore and two clinical factors that showed the best diagnostic efficiency in the training (AUC = 0.920) and validation (AUC = 0.866) cohorts. Regarding preoperative diagnosis of LN metastasis, the calibration curve and DCA demonstrated that the combined model had a good consistency and greatest net benefit. Conclusions: Combining radiomics and machine learning algorithms demonstrated the potential for identifying the LN metastasis of PDAC. As a non-invasive and efficient preoperative prediction tool, it can be beneficial for decision-making in clinical practice.

Reference-free thio-succinimide isomerization characterization by electron-activated dissociation.

RATIONALE: Isomerism can be an important aspect in pharmaceutical drug development. Identification of isomers can provide insights into drug pharmacology and contribute to better design of drug molecules. The general approaches to differentiate isomers include Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and circular dichroism. Additionally, a commonly used method to differentiate isomers is liquid chromatography coupled with mass spectrometry (LC-MS). Notably, LC-MS is routinely applied to leucine and isoleucine differentiation to facilitate protein sequencing. This work focuses on isomer differentiation of widely employed thio-succinimide structure bridging the antibody backbone and linker-payload of antibody-drug conjugates (ADCs). Thio-succinimide hydrolysis stabilizes the payload-protein structure while generating a pair of constitutional isomers: thio-aspartyl and thio-isoaspartyl. METHODS: This paper introduces a hybrid method using ligand binding assay (LBA) and liquid chromatography coupled with tandem MS (LC-MS/MS) to reveal isomerization details of thio-succinimide hydrolysis over time in plasma samples incubated with ADC. Application of two orthogonal dissociation methods, collision-induced dissociation (CID) and electron-activated dissociation (EAD) revealed different MS/MS spectra for this pair of isomers. This observation enables a unique approach in distinguishing thio-succinimide hydrolysis isomers. RESULTS: We observed signature [R1 + Thio + 57 + H]+, [R2 + Succ + H2O - 57 + H]+, and [R2 + Succ + H2O - 44 + 2H]2+ product ions (Succ = succinimide) that differentiated thio-aspartyl and thio-isoaspartyl isomers using EAD. A newly discovered [R2 + ThioSucc + H2O - 44 + 2H]2+ ion also served as additional evidence that further supported our findings. CONCLUSIONS: This study is a first-to-date identification of thio-succinimide hydrolysis isomers without using synthesized reference materials. This approach should be applicable to all thio-succinimide-linked molecules. Correct identification of thio-succinimide hydrolysis isomers may eventually benefit the development of ADCs in the future.

Early clinical outcome with lens position adjustment following implantable collamer lens surgery.

AIM: To observe early clinical outcome with lens position adjustment following the implantable collamer lens (ICL) surgery. METHODS: Sixty patients were selected for this retrospective study. One eye from each patient received Toric ICL for astigmatism correction, and the other received non-astigmatic ICL surgery using horizontal position. Patients with higher postoperative arch height were selected, and their non-astigmatic eye clinical outcome were observed after ICL surgery at 1wk, 1, and 3mo. The clinical measurements included uncorrected visual acuity (UCVA), intraocular pressure (IOP), refractive state, corneal endothelium cell count, and arch height. Three months later, the ICL in each patient's non-astigmatic eye was adjusted to the vertical from the horizontal position. The results were compared before and 1wk, 1, and 3mo after adjustment. RESULTS: UCVA and IOP were significantly reduced 1wk after position adjustment compared to 1wk after ICL implantation (P<0.05). The patients demonstrated significantly reduced arch height and corneal endothelium cell count 1wk, 1, and 3mo after adjusting position compared to 1wk, 1, and 3mo after ICL implantation (P<0.05). However, there was no significant difference in refraction between 1wk, 1, and 3mo after ICL implantation and position adjustment (P>0.05). CONCLUSION: Early positioning adjustment post-phakic ICL implantation can benefit patients with adjusted arch height or higher IOP. Despite the good clinical effects, the doctors should pay attention to the potential for adverse effects on UCVA and corneal endothelium cells following early position adjustment after posterior chamber phakic ICL implantation.

Nanoparticle-mediated universal CAR-T therapy.

In recent years, chimeric antigen receptor (CAR)-T cell therapy has been highly successful in treating hematological malignancies, leading to significant advancements in the cancer immunotherapy field. However, the typical CAR-T therapy necessitates the enrichment of patients' own leukocytes for ex vivo production of CAR-T cells, this customized pattern requires a complicated and time-consuming manufacturing procedure, making it costly and less accessible. The off-the-shelf universal CAR-T strategy could reduce manufacturing costs and realize timely drug administration, presenting as an ideal substitute for typical CAR-T therapy. Utilizing nanocarriers for targeted gene delivery is one of the approaches for the realization of universal CAR-T therapy, as biocompatible and versatile nanoparticles could deliver CAR genes to generate CAR-T cells in vivo. Nanoparticle-mediated in situ generation of CAR-T cells possesses multiple advantages, including lowered cost, simplified manufacturing procedure, and shortened administration time, this strategy is anticipated to provide a potentially cost-effective alternative to current autologous CAR-T cell manufacturing, thus facilitating the prevalence and improvement of CAR-T therapy.

Efficacy of modified anterior maxillary segmental distraction osteogenesis based on 3D visualisation for the treatment of maxillary hypoplasia among adolescents with cleft lip and palate.

BACKGROUND: This study evaluates a three-dimensional (3D) visualisation design combined with customized surgical guides to assist anterior maxillary segmental distraction osteogenesis (AMSDO) in correcting maxillary hypoplasia in adolescents with cleft lip and palate (CLP), focusing on treatment outcomes, satisfaction and the validity of 3D planning. METHODS: This retrospective cohort study was conducted at a single hospital in China. Between January 2020 and December 2023, 12 adolescents with CLP with maxillary hypoplasia were included. An advanced 3D simulation was used to convey the treatment strategy to the patients and their families. A customized surgical guide and distraction osteogenesis device were designed. Cephalometric analysis evaluated AMSDO changes and long-term stability. Patient satisfaction was assessed. The Chinese version of the Child Oral Health Impact Profile was used to evaluate the children's oral health-related quality of life before and after treatment. The postoperative outcomes were compared with the planned outcomes by superimposing the actual postoperative data onto the simulated soft tissue models and calculating the linear and angular differences between them. RESULTS: One patient experienced postoperative gingivitis, yielding an 8.33% complication rate. Most patients (83.33%) were highly satisfied with the target position, with the rest content. Cephalometric analysis showed significant improvements in various indices post-traction. Quality-of-life scores significantly improved post-treatment. The discrepancies in facial soft tissue between the simulated and actual results were within clinically satisfactory ranges. CONCLUSIONS: Digitally designed surgical guides effectively treat maxillary hypoplasia in adolescents with CLP, ensuring stability, reducing complications, reducing dependency on operator experience, and enhancing satisfaction and health outcomes. Although the simulated results were clinically acceptable, it is important to inform patients of potential variations in the predicted soft tissue.