Intratumoral CD103^(+)CD8^(+)T cells predict response to neoadjuvant chemoimmunotherapy in advanced head and neck squamous cell carcinoma

Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.

Insights into pH-dependent transformation of gibberellic acid in aqueous solution:Transformation pathway,mechanism and toxicity estimation

Gibberellic acid(GA_(3))is widely used in agriculture and maybe transfer with groundwater flow,which is an endocrine disruptor,but few studies have focused on the transformation pathway and toxicity assessment of GA_(3)and its products.Here,GA_(3)and its transformation products in aqueous solution were identified and quantified by liquid chromatography mass spectrometry hybrid ion trap time-of-flight(LCMS-IT-TOF)and high-performance liquid chromatography(HPLC),respectively.The results showed that the half-life of GA_(3)transformation in ultrapure water was 16.1–24.6 days at p H=2.0–8.0,with the lowest half-life occurring at p H=8.0 and highest half-life occurring at p H=3.3.Isomerized gibberellic acid(Iso-GA_(3))and gibberellenic acid(GEA)were the main transformation products with a little hydroxy gibberellic acid(OH-GA_(3)).In North China groundwater,the mass balance of GA_(3)and its products was 76.2%,including Iso-GA_(3)(58%),GEA(7.9%),GA_(3)(7.3%)and OH-GA_(3)(3%)after reaching transformation equilibrium.Using Gaussian 09 for chemical computation,it was found that the transformation mechanism of GA_(3)was dependent upon the bond energy and the stereochemical feature of its molecular structure.GA_(3)always isomerized from theγ-lactone ring due to the lowest bond energy between the oxygen terminus of theγ-lactone ring and A ring.While GA_(3)and its transformation products all had developmental toxicity,the predicated LC 50(96 hr)and LD 50 of the main products of GA_(3)were much lower than those of GA_(3),indicating GA_(3)would be transformed into higher toxicity derivatives in water environments,posing a significant health risk to humans and the environment.

Ruminal microbiota-host interaction and its effect on nutrient metabolism

Rumen microbiota has a close and intensive interaction with the ruminants.Microbiota residing in the rumen digests and ferments plant organic matters into nutrients that are subsequently utilized by the host,making ruminants a unique group of animals that can convert plant materials indigestible by humans into high-quality animal protein as meat and milk.Many studies using meta-omics technologies have demonstrated the relationships between rumen microbiome and animal phenotypes associated with nutrient metabolism.Recently,the causality and physiological mechanisms underpinning the host-microbiota interactions have attracted tremendous research interest among researchers.This review discusses the host-microbiota interactions and the factors affecting these interactions in ruminants and provides a summary of the advances in research on animal husbandry.Understanding the microbiota composition,the functions of key bacteria,and the host-microbiota interaction is crucial for the development of knowledge-based strategies to enhance animal productivity and host health.

Ruminal bacterial community is associated with the variations of total milk solid content in Holstein lactating cows

Total milk solid(TMS)content directly reflects the quality of milk.Rumen bacteria ferment dietary components,the process of which generates the precursors for the synthesis of milk solid,therefore,the variation in rumen bacterial community could be associated with milk solid in dairy cows.In this study,45 healthy mid-lactation Holstein dairy cows with the similar body weight,lactation stage,and milk yield were initially used for the selection of 10 cows with high TMS(HS)and 10 cows with low TMS(LS).All those animals were under the same feeding management,and the individual milk yield was recorded for 14 consecutive days before milk and rumen fluid were sampled.Rumen fluid was used to determine bacterial community by 16S rRNA gene sequencing technique.The HS cows had significantly greater feed intake and milk TMS,fat,protein content than LS cows(P<0.05).Among the volatile fatty acids(VFA),propionic acid and valeric acid concentrations were significantly greater in HS cows than those in LS cows(P<0.05).There was no significant difference in the concentrations of acetate,butyrate,isobutyrate,valerate,and the total VFA(P>0.05),nor was the acetate-to-propionate ratio,pH value,ammonia nitrogen and microbial crude protein concentrations(P>0.05).Significant differences in the relative abundances of some bacterial genera were found between HS and LS cows.Spearman’s rank correlation analysis revealed that TMS content was correlated positively with the abundances of Ruminococcaceae UCG-014,Ruminococcaceae NK4A214 group,Prevotellaceae UCG-001,Butyrivibrio 2,Prevotellaceae UCG-003,Candidatus Saccharimonas,Ruminococcus 2,Lachnospiraceae XPB1014 group,probable genus 10,Eubacterium ventriosum group,but negatively correlated with Pyramidobacte.In addition,Ruminococcaceae UCG-014,Ruminococcus 2,Ruminococcaceae UCG001,probable genus 10 and Eubacterium ventriosum group might boost the total VFA production in the rumen.In conclusion,the dry matter intake of dairy cows and some special bacteria in rumen were significantly associated with TMS content,which suggests the potential function of rumen bacteria contributing to TMS content in dairy cows.