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Introduction: Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors. Material and methods: Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan–Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry. Results: Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11–1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06–0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12–1.08, p = 0.0615). Conclusions: Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors. Trial registration number NCT03261011. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nitrogen-doped carbon dots (N-CQDs) with high fluorescence quantum yield were synthesized using a green and simple method. • Two modes of fluorescence emission displacement method and fluorescence internal filtering effect detection method were used to detect quinoline yellow, and their detection limits were 0.18 μM and 2.6 nM respectively. • The constructed fluorescent sensor has high sensitivity and excellent selectivity. • The sensor can actually measure the content of quinoline yellow in common beverages. • A fluorescent test strip was constructed for the visual detection of quinoline yellow. Quinoline yellow (QY), as a food coloring agent, will consume a large number of detoxifying substances in the body after being ingested by the human body, interfering with the normal metabolic functions of the human body, and may cause allergies, diarrhea and other symptoms, as well as a certain degree of carcinogenicity, posing a great threat to human health. As a result, it is critical to develop a fast, sensitive, and effective approach to determining quinoline yellow in food. In this study, carbon dots (N-CQDs) with high fluorescence quantum yield were prepared and used to determine the QY content using the dual mode of internal filtering effect and fluorescence emission shift detection. Both methods showed good linearity in the range of QY concentration of 0.3–3.2 μM, and the detection limits were classified as 2.6 nM and 0.18 μM. In addition, in order to achieve visual detection of QY, fluorescent test strips were constructed using the carbon dots and non-fluorescent qualitative filter paper to make the detection of QY more convenient. This probe presents a novel way for detecting quinoline yellow in food analysis. [ABSTRACT FROM AUTHOR]

The red swamp crayfish (Procambarus clarkii) has become one of China’s most important freshwater aquaculture species. As the epicenter of crayfish cultivation, Hubei province provides the majority of germplasm resources for breeding applications. However, the genetic diversity and population structure of P. clarkii in this area remains largely incomplete, hindering the effective utilization of these germplasm resources. In this study, 20 polymorphic microsatellites were developed and used to investigate genetic diversity and differentiation in representative P. clarkii populations from five cultivated and five wild populations in Hubei province. A total of 169 alleles were discovered at these loci, and the average polymorphic information content was calculated as 0.584. Diversity index of expected heterozygosity (He) indicated a relatively medium genetic diversity across all populations (0.431 ~ 0.565), while wild populations exhibited higher genetic diversity (He = 0.542) compared to that in cultured populations (He = 0.478). The average value of pairwise population differentiation index (Fst) was 0.108, manifesting a moderate level of genetic differentiation among populations. Analysis of molecular variance between ten populations revealed that genetic variation mostly resided within individuals (79.4%), with slightly higher variation observed in cultured populations (84.79%) compared to that in wild populations (80.52%). Bayesian assignment, dendrogram, and principal component analysis grouped the genotypes into three clusters with wide variation among the accessions. These results reflected substantial genetic differentiation presented in P. clarkii populations. Our findings shed light on the diversity status of P. clarkii in Hubei province and will be great value for genetic improvement through selective breeding. [ABSTRACT FROM AUTHOR]

The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo. First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124I-AK104, developed in-house, to locate PD1+/CTLA4+ tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect. The 124I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios. The results demonstrated the potential of translating 124I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice. [Display omitted] • An antibody-PET probe targeting PD1/CTLA4 was radiolabeled. • High affinity to PD1/CTLA4 in vitro and in vivo. • This tracer can noninvasively demonstrate the presence of PD1/CTLA4-positive infiltrating T cells at the tumor site in humanized mice using an imaging method. [ABSTRACT FROM AUTHOR]

Linear polyglycidol (LPG) has emerged as a polyethylene glycol (PEG) alternative in novel surfactant development due to its unique advantages, such as high bioavailability and multiple functionalization sites. In this study, a series of LPG based acylhydrazones, including copolymers CLPG1–3 with different length (n = 7–11) of alkyl chains and a curcumin (CUR) drug conjugate CLPG4 were synthesized for the first time. CLPG1 - 4 exhibited a decreasing trend in their surface-active properties as the molecular hydrophobicity increased. Among them, CLPG1 revealed the most powerful foaming ability, emulsion stability than the other analogs and tested commercial references, attributing to its optimal hydrophilic/hydrophobic balance. On the other hand, the drug conjugate CLPG4 revealed significantly enhanced selective tumor cell inhibition and cellular uptake than free CUR in the in vitro experiments. The established structure-property profile in this study provides a useful reference for their practical applications in the chemical and pharmaceutical fields. [Display omitted] • Novel LPG acylhydrazones (CLPG 1 - 3) and CUR-LPG conjugate (CLPG 4) were synthesized. • Structure-activity profile was established for CLPG1 - 3 as potent surfactants. • Enhanced drug loading and stability were observed for CLPG4 compared to physically encapsulated complexes. • CLPG4 revealed improved permeability and selective cancer cell inhibition. [ABSTRACT FROM AUTHOR]

Selenium (Se), an indispensable micronutrient for living organisms, has been extensively studied for its heavy metal-detoxifying properties in diverse biological systems and tissues. Nevertheless, it is not entirely certain whether Se can effectively protect against Cadmium (Cd)-induced gut inflammation, especially in aquatic animals. In this study, we employed various approaches, including transcriptome profiling, histological examinations, assessment of antioxidant enzyme activities, and analysis of gut microbiota composition to investigate the effects on crayfish growth and intestinal health after exposure to dietary Cd (15 mg kg−1 diet) and Se (15 mg kg−1 diet) individually or in combination for 8 weeks. The results revealed that dietary Cd exposure resulted in reduced body weight and survival rates, along with an increased occurrence of intestinal inflammation. Nevertheless, Se supplementation proved effective in mitigating the adverse effects of Cd on growth and gut health. Se exhibited a remarkable ability to counteract the disruption of gut antioxidant abilities induced by dietary Cd, as evidenced by the observed increases in ROS and MDA contents, decrease in GSH levels, and inhibition of antioxidative enzyme activities. At the concentration of 6 mg kg−1 in the diet, Se was found beneficial for maintaining gut microbiota richness and diversity. Among them, Flavobacterium , Thermomonas , and Chloronema displayed a weak negative correlation with the rate of gut inflammation. Meanwhile, the levels of short chain fatty acids (SCFAs), including acetic acid (AA) and butanoic acid (BA), showed a significant increase in the Se–Cd group compared to the Cd-only group. Furthermore, transcriptome analysis exhibited significant responses of the PI3K/Akt and NF-κB pathways following crayfish exposure to dietary Se and Cd, either separately or in combination. In short, this study provides a new evidence regarding the molecular mechanisms through which Se could regulate the PI3K/Akt and NF-κB pathways, either directly or indirectly via ROS and SCFAs, thereby alleviating Cd-induced gut inflammation in crayfish. [Display omitted] • Chronic Cd exposure (15 mg/kg) markedly induced gut inflammation and apoptosis. • Cd decreased crayfish weight and survival, but Se supplementation mitigated this. • Se countered the disruption of gut antioxidant capabilities induced by dietary Cd. • Se antagonized Cd-induced gut inflammation by boosting SCFA content. • PI3K/Akt/NF-κB pathways mediated Se's counteraction of Cd toxicity in the gut. [ABSTRACT FROM AUTHOR]