Targeting CD24/Siglec-10 signal pathway for cancer immunotherapy: recent advances and future directions.

The small, heavily glycosylated protein CD24 is primarily expressed by many immune cells and is highly expressed mostly in cancer cells. As one of the most crucial biomarkers of cancers, CD24 is frequently highly expressed in solid tumors, while tumor-associated macrophages express Siglec-10 at high levels, Siglec-10 and CD24 can interact on innate immune cells to lessen inflammatory responses to a variety of disorders. Inhibiting inflammation brought on by SHP-1 and/or SHP-2 phosphatases as well as cell phagocytosis by macrophages, the binding of CD24 to Siglec-10 can prevent toll-like receptor-mediated inflammation. Targeted immunotherapy with immune checkpoint inhibitors (ICI) has lately gained popularity as one of the best ways to treat different tumors. CD24 is a prominent innate immune checkpoint that may be a useful target for cancer immunotherapy. In recent years, numerous CD24/Siglec-10-related research studies have made tremendous progress. This study discusses the characteristics and workings of CD24/Siglec-10-targeted immunotherapy and offers a summary of current advances in CD24/Siglec-10-related immunotherapy research for cancer. We then suggested potential directions for CD24-targeted immunotherapy, basing our speculation mostly on the results of recent preclinical and clinical trials.

The discovery of novel papillomaviruses in cats in Southwest China.

Feline viral diarrhea is a significant cause of death in kittens. In this study, 12 mammalian viruses were identified by metagenomic sequencing in diarrheal feces in 2019, 2020, and 2021, respectively. Interestingly, a novel of felis catus papillomavirus (FcaPV) was identified for the first time in China. Subsequently, we investigated the prevalence of FcaPV in 252 feline samples, including 168 diarrheal feces and 84 oral swabs, with a total of 57 (22.62%, 57/252) samples detected positive. Of the 57 positive samples, FcaPV genotype 3 (FcaPV-3) was detected at high prevalence rate (68.42%, 39/57), followed by FcaPV-4 (22.8%, 13/57), FcaPV-2 (17.54%, 10/57), and FcaPV-1 (1.75%, 1/55), while no FcaPV-5 and FcaPV-6. In addition, two novel putative FcaPVs were identified, which were the highest similarity to Lambdapillomavirus from Leopardus wiedii or canis familiaris, respectively. Therefore, this study was the first characterization of the viral diversity in feline diarrheal feces and the prevalence of FcaPV in Southwest China.

Analysis of Mean Corpuscular Volume and Red Cell Distribution Width in Patients with Aplastic Anemia.

To explore the characteristics of hemogram in patients with aplastic anemia (AA), especially mean corpuscular volume (MCV) and red cell distribution width (RDW). We examined the blood routine of 180 new-onset AA patients and used 166 patients with myelodysplastic syndrome (MDS) as controls. Among the 180 AA patients, 105 (58.3%) were diagnosed with severe AA (SAA), while 75 (41.7%) were diagnosed with non-severe AA (NSAA). Compared to MDS, patients with SAA generally had unfavorable hemogram, including significantly lower white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), platelet (PLT) and reticulocyte counts (RET). However, WBC, ANC and lymphocyte counts were higher in the NSAA group than in the MDS group; Hb and Ret were comparable between the two groups. 8.5% of SAA patients and 58.1% of NSAA patients presented with macrocytic anemia, whereas 25.7% of SAA and 64.0% of NSAA had a high RDW. In the MDS group, 54.7% of patients presented with macrocytic anemia, and 84.7% had increased RDW. WBC, ANC, PLT, and Ret in a high-RDW group (25.7% of SAA) were significantly higher than in a normal-RDW group (74.3% of SAA). Overall, most SAA patients exhibited normocytic-normochromic anemia, and their hemograms decreased more significantly; more than half of NSAA patients showed macrocytic-heterogeneous anemia, and their hemograms were similar to those of MDS. Patients with elevated RDW may have better residual bone marrow hematopoietic function than those with normal RDW but with more severe anemia.

Intestinal microbiota score could predict survival following allogeneic hematopoietic stem cell transplantation.

Intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its role in predicting survival has not been determined. Here, stool samples at day 15 ± 1 posttransplant were obtained from 209 patients at two centers. Microbiota was examined using 16S rRNA sequencing. The microbiota diversity and abundance of specific bacteria (including Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) were assigned a value of 0 or 1 depending on whether they were positive or negative associated with survival, respectively. An accumulated intestinal microbiota (AIM) score was generated, and patients were divided into low- and high-score groups. A low score was associated with a better 3-year cumulative overall survival (OS) as well as lower mortality than a high score (88.5 vs. 43.9% and 7.1 vs. 35.8%, respectively; both P < 0.001). In multivariate analysis, a high score was found to be an independent risk factor for OS and transplant-related mortality (hazard ratio = 5.68 and 3.92, respectively; P < 0.001 and 0.003, respectively). Furthermore, the AIM score could serve as a predictor for survival (area under receiver operating characteristic curve = 0.836, P < 0.001). Therefore, the intestinal microbiota score at neutrophil recovery could predict survival following allo-HSCT.

Crystal Structure of Human CD47 in Complex with Engineered SIRPα.D1(N80A).

Background: Targeting the CD47/SIRPα signaling pathway represents a novel approach to enhance anti-tumor immunity. However, the crystal structure of the CD47/SIRPα has not been fully studied. This study aims to analyze the structure interface of the complex of CD47 and IMM01, a novel recombinant SIRPα-Fc fusion protein. Methods: IMM01-Fab/CD47 complex was crystalized, and diffraction images were collected. The complex structure was determined by molecular replacement using the program PHASER with the CD47-SIRPαv2 structure (PDB code 2JJT) as a search model. The model was manually built using the COOT program and refined using TLS parameters in REFMAC from the CCP4 program suite. Results: Crystallization and structure determination analysis of the interface of IMM01/CD47 structure demonstrated CD47 surface buried by IMM01. Comparison with the literature structure (PDB ID 2JJT) showed that the interactions of IMM01/CD47 structure are the same. All the hydrogen bonds that appear in the literature structure are also present in the IMM01/CD47 structure. These common hydrogen bonds are stable under different crystal packing styles, suggesting that these hydrogen bonds are important for protein binding. In the structure of human CD47 in complex with human SIRPα, except SER66, the amino acids that form hydrogen bonds are all conserved. Furthermore, comparing with the structure of PDB ID 2JJT, the salt bridge interaction from IMM01/CD47 structure are very similar, except the salt bridge bond between LYS53 in IMM01 and GLU106 in CD47, which only occurs between the B and D chains. However, as the side chain conformation of LYS53 in chain A is slightly different, the salt bridge bond is absent between the A and C chains. At this site between chain A and chain C, there are a salt bridge bond between LYS53 (A) and GLU104 (C) and a salt bridge bond between HIS56 (A) and GLU106 (C) instead. According to the sequence alignment results of SIRPα, SIRPß and SIRPγ in the literature of PDB ID 2JJT, except ASP100, the amino acids that form common salt bridge bonds are all conserved. Conclusion: Our data demonstrated crystal structure of the IMM01/CD47 complex and provides a structural basis for the structural binding interface and future clinical applications.

The occurrence timeline of steroid-induced ocular hypertension and cataract in children with systemic autoimmune diseases.

PURPOSE: Steroid-induced ocular hypertension (SIOH) and cataract can result in visual loss. This study evaluated the timetable of SIOH and steroid-induced posterior subcapsular cataract (SI-PSC) occurrences in children with systemic autoimmune diseases (SAD) undergoing long-term systemic corticosteroid treatment. METHODS: Thirty-seven children with SAD treated with long-term oral corticosteroids were enrolled in this study. Intraocular pressure (IOP), SI-PSC occurrences, visual field and peripapillary retinal nerve fibre layer (pRNFL) thicknesses were recorded every 3 months for at least 6 months. RESULTS: Of the 37 children, with average age 11.0 ± 2.9 years, 22 patients (59.5%) had SIOH, 2 progressed as glaucoma at the 18-month and 3-year follow-up, respectively, and 12 (32.4%) patients had SI-PSC. Among patients with SIOH, 45.5% (10/22) of them had SI-PSC occurrence, and among patients with normal IOP, 13.3% (2/15) of them had SI-PSC. Seventeen patients participated in a longitudinal study with a follow-up period of at least 18 months. The incidence of SIOH started at 1 month 52.9% (9/17) and gradually increased to 70.6% (12/17) at 6 months, then decreased to 35.3% (6/17). SI-PSC onset started at 6 months (17.6%, 3/17), and its occurrence increased to 35.3% (6/17) at 12 months and reached to 41.2% (7/17) at 18 months. The pRNFL was thicker in the children with SIOH than the healthy controls (p = 0.01). CONCLUSION: SIOH and SI-PSC are common coexistent complications in children with long-term corticosteroids treatment, and the occurrence time is during the first month and 6 months, respectively. Patients with SIOH have a higher probability of cataract.

MiR-150-5p regulate T cell activation in severe aplastic anemia by targeting Bach2.

MiR-150-5p is an immune-related miRNA and elevated in the plasma of patients with aplastic anemia (AA), but its role in T cell activation in patients with severe aplastic anemia (SAA) is unclear. This study aims to explore the role of miR-150-5p in T cell activation of SAA. RT-PCR and Western blot were used to detect the expression of mRNA and protein. The cell proportion was detected by flow cytometry. The lentiviruses expressing miR-150-5p inhibitor and Bach2 shRNA were respectively infected to produce stable miR-150-5p or Bach2 knockout cells. Brdu incorporation method was used to detect T cell proliferation. SAA mouse model was induced with cyclophosphamide and busulfan, and intravenous injection of LV inhibitor NC and LV-miR-150-5p inhibitor. The miR-150-5p expression is up-regulated in SAA, which is negatively correlated with Bach2. Inhibition of miR-150-5p reduces the activation of T cells. MiR-150-5p directly targeted 3'UTR of Bach2. Moreover, the expression of miR-150-5p and the activation of T cells were decreased in SAA mouse model. MiR-150-5p promotes T cell activation in SAA by targeting Bach2. Targeting miR-150-5p may be a new molecular therapy for SAA patients.

A modified loop-mediated isothermal amplification method for detecting avian infectious laryngotracheitis virus.

This study was aimed to establish a highly specific and sensitive loop-mediated isothermal amplification (LAMP) method for diagnosing avian infectious laryngotracheitis (AILT). DNA was extracted from isolated infectious laryngotracheitis virus (ILTV) strains and control samples, followed by PCR using three sets of six specific primers. The detection efficiency of the LAMP assay was evaluated by the turbidity and calcein methods. The sensitivity of LAMP was then assessed using a concentration gradient followed by a specificity analysis. Furthermore, the detection efficiency of LAMP and PCR was compared. Finally, a clinical test was performed to evaluate the value of the LAMP assay. The optimal temperature for the LAMP reaction was 66 °C. Meanwhile, the primers selected for the LAMP assay were highly specific for the target virus. The sensitivity of the turbidity and calcein methods for LAMP was consistent. The minimum detection concentration of LAMP was 0.06 pg/µL, which was 100-fold higher than that of PCR. Furthermore, the results from clinical samples showed that the LAMP method could identify AILT from many samples. The newly designed LAMP assay was an effective method for AILT detection at an optimal temperature of 66 °C with a minimum detection concentration of 0.06 pg/µL.

Genetic characterization of a novel G9P[23] rotavirus A strain identified in southwestern China with evidence of a reassortment event between human and porcine strains.

Group A rotaviruses (RVAs) are important zoonotic pathogens that cause intestinal disease in humans and other mammals. In this study, the novel strain RVA/Pig/China/SC11/2017/G9P[23](SC11) was isolated from fecal samples from a pig farm in Sichuan province, southwestern China. The complete genome was found to be 18,347 bp in length with 11 segments. The genotype constellation of strain SC11 was G9-P[23]-I12-R1-C1-M1-A1-N1-T1-E1-H1, according to whole-genome sequencing analysis. The VP1, VP2, VP4, VP6, NSP1-NSP3, and NSP5 genes of RVA strain SC11 were found to be closely related to those of porcine and/or porcine-like human RVAs. Meanwhile, the VP7 and NSP4 genes of strain SC11 were closely related to genes of human RVAs. However, it was difficult to pinpoint the porcine or human origin of the VP3 gene of strain SC11 based on the available data. These results showed that SC11 originated from a natural reassortment event between human and pig RVA strains, and crossover points for recombination were identified at nucleotides (nt) 109-806 of NSP2. This is the first report of such a reassortant and recombinant RVA strain in the southwestern region of China.

How many challenges we may encounter in anterior megalophthalmos with white cataract: a case report.

BACKGROUND: Anterior megalophthalmos is a rare congenital disease which mainly features enlargement of the anterior segment. Cataract surgeries in anterior megalophthalmos can be challenging due to the anatomical anomalies while the studies upon the surgical design have been less integrated. CASE PRESENTATION: A 37-year-old woman presented with progressively blurred vision in the right eye after a transient fever 10 months ago. Her ocular history included hypermetropia with a spherical equivalent of + 4.00 OU. The review of systems showed bilateral varus deformity of distal interphalangeal joints on the little fingers. The patient denied family history of hereditary ocular diseases and her sister was born with uterus didelphys. On initial examinations, the corrected distance visual acuity was hand motion OD and 20/33 OS. Her intraocular pressure was 15 mmHg OD and 16 mmHg OS. Horizontal corneal diameter was 14 mm OD and 13.88 mm OS and axial length was 24.87 mm OD and 25 mm OS. Anterior segment photography showed bilateral iridal atrophy with deficiency in pupillary dilation and white cortically mature cataract in the right eye. Inspection by anterior segment optical coherence tomography indicated bilateral augmented anterior chambers with backward iridal concave on horizontal orientation. Ultrasound biomicroscopy showed partially peripheral anterior synechiae and pectinate ligaments at chamber angle in both eyes and opacified lens with the apparently elongated suspensory ligaments in the right eye. A deliberately selected 1-piece foldable intraocular lens (IOL) with frame haptics was implanted after phacoemulsification for good IOL stability. During the follow-up, the visual rehabilitation appeared relatively good and a lower degree of IOL dislocation comparing with existing reports was verified by OPD-Scan III aberrometry. CONCLUSIONS: We presented the challenges and the original findings from a case of congenital anterior megalophthalmos with white cataract who underwent phacoemulsification and IOL implantation. This is the first report describing the comparison of the different IOL power calculation formulas in anterior megalophthalmos. Compared to the SRK/T and the Holladay II formulas, the Haigis formula could be a more accurate choice for the IOL calculation in anterior megalophthalmos according to our case. Moreover, the deliberate selection of IOLs is essential for IOL stability in these patients.

Case Series: Slight Intraocular Lens Malpositioning as a Potential Cause of Vision Loss.

SIGNIFICANCE: The cases illustrate an insidious cause of decreased visual acuity after cataract surgery. PURPOSE: The purpose of this study was to identify cases of postoperative vision loss caused by slight intraocular lens (IOL) malpositioning after cataract surgery. CASE REPORTS: Three patients presented with visual acuity decreased after cataract surgery. Silt-lamp examination before mydriasis revealed no abnormalities in two of the patients; mild IOL inferonasal decentration was found by the trifocal IOL diffraction ring in the third patient. Manifest refraction of these patients showed remarkable astigmatism with low corneal astigmatism. After pupil dilation, slight IOL decentration and tilt were observed in all patients, which were further confirmed using the Scheimpflug imaging system. Wavefront aberrometry showed a high level of ocular higher-order aberrations, most of which were derived from intraocular aberrations. CONCLUSIONS: Inconspicuous IOL malpositioning is one of the reasons responsible for decreased vision acuity after cataract surgery, which may not be easily identified by slit-lamp examination. High astigmatism and ocular higher-order aberrations derived from malpositioned IOL can be important clues.

ET-1 Promotes Differentiation of Periodontal Ligament Stem Cells into Osteoblasts through ETR, MAPK, and Wnt/ß-Catenin Signaling Pathways under Inflammatory Microenvironment.

Periodontitis is a kind of chronic inflammatory disease that affects the tooth-supporting tissues. ET-1 is related to periodontitis and involved in the regulation of cytokines, but the mechanisms remain unclear. The aim of this study is to investigate how ET-1 affects proinflammatory cytokine expression and differentiation in human periodontal ligament stem cells (PDLSCs). PDLSCs were isolated from the periodontal ligament tissues of periodontitis patients and then treated with ET-1 (1, 10, or 100 nM) for 12 h, 24 h, or 72 h. The osteogenic potential of PDLSCs was tested using ALP staining. TNF-α, IL-1ß, and IL-6 levels were evaluated by ELISA and western blot. Runx2, OCN, and COL1 mRNA and western levels were detected by RT-PCR and western blot, respectively. To examine the signaling pathways and molecular mechanisms involved in ET-1-mediated cytokine expression and osteogenic differentiation, ETR pathway, MAPKs pathway, Wnt/ß-catenin pathway, and Wnt/Ca(2+) pathway were detected by RT-PCR and western blot, respectively. ET-1 promoted differentiation of PDLSCs into osteoblasts by increasing secretion of TNF-α, IL-1ß, and IL-6 in a dose- and time-dependent manner. ET-1 also increased expression of Runx2, OCN, and COL1. ET-1 promotes differentiation of PDLSCs into osteoblasts through ETR, MAPK, and Wnt/ß-catenin signaling pathways under inflammatory microenvironment.

Bispecific antibodies in immunotherapy for adult acute leukemia: latest updates from the 65th American Society of Hematology 2023 Annual Meeting.

Introduction Bispecific antibodies (BsAbs) represent a novel and potentially effective approach in cancer immunotherapy. These antibodies feature two unique binding domains, enabling them to simultaneously attach to two antigens or two epitopes of a single antigen. Recently, a variety of BsAbs targeting distinct B-cell antigens and myeloid lineage-specific surface markers-such as CD19xCD3, CD38xCD3, and CD123xCD3-have demonstrated promising results in heavily pretreated relapsed/refractory acute lymphoblastic leukemia (R/R ALL) and relapsed/refractory acute myeloid leukemia (R/R AML) patients. Areas covered New trail results were reported by different research groups at the 65th annual meeting of the American Society of Hematology (ASH). We provide a summary of the latest progress in BsAbs for immunotherapy in adult acute leukemia. Expert opinion B-ALL is the most favored leukemia for treatment with BsAbs, unlike T-ALL and AML, which are limited in constructs and results. The clinical application of blinatumomab in the first-line setting, combined with other therapies, has clearly benefited these B-ALL patients, especially older adults, due to its lower toxicity. In the B-ALL relapsed/refractory setting, new combinations with blinatumomab are under investigation, such as PD-1 or CTLA-4 inhibitors. We believe that with more clinical trial results, it is possible that blinatumomab will be used in new clinical indications soon. No novel BsAbs developed for B-ALL have yielded better results.

Bispecific antibodies targeting CD20xCD3 in immunotherapy for adult B-cell lymphoma: insights from the 65th American Society of Hematology 2023 annual meeting.

INTRODUCTION: At the 65th American Society of Hematology (ASH) 2023 Annual Meeting, the latest advancements in CD20×CD3 BsAbs for B-cell lymphoma (BCL) were highlighted, particularly in relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). AREAS COVERED: This summary highlights some of the major studies on CD20×CD3 BsAbs for BCL. EXPERT OPINION/COMMENTARY: CD20×CD3 is the most widely studied BsAb, with promising results in patients with R/R DLBCL and R/R FL ≥ two prior lines of systemic therapy. Trials with the first line of B-cell lymphoma also revealed promising results. Hopefully, BsAb monotherapy or BsAb-containing regimens may become the standard therapy in patients with FL and DLBCL.

Targeting TIGIT for cancer immunotherapy: recent advances and future directions.

As a newly identified checkpoint, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is highly expressed on CD4+ T cells, CD8+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and tumor-infiltrating lymphocytes (TILs). TIGIT has been associated with NK cell exhaustion in vivo and in individuals with various cancers. It not only modulates NK cell survival but also mediates T cell exhaustion. As the primary ligand of TIGIT in humans, CD155 may be the main target for immunotherapy due to its interaction with TIGIT. It has been found that the anti-programmed cell death protein 1 (PD-1) treatment response in cancer immunotherapy is correlated with CD155 but not TIGIT. Anti-TIGIT alone and in combination with anti-PD-1 agents have been tested for cancer immunotherapy. Although two clinical studies on advanced lung cancer had positive results, the TIGIT-targeted antibody, tiragolumab, recently failed in two new trials. In this review, we highlight the current developments on TIGIT for cancer immunotherapy and discuss the characteristics and functions of TIGIT.

Immunogenicity and protective efficacy of recombinant adenovirus expressing a novel genotype G2b PEDV spike protein in protecting newborn piglets against PEDV.

IMPORTANCE: Porcine epidemic diarrhea (PED) is a highly infectious and economically significant gastrointestinal disorder that affects pigs of all ages. Preventing and controlling PED is achieved by immunizing sows with vaccines, enabling passive piglet immunization via colostrum. The prevalence of G2b porcine epidemic diarrhea virus (PEDV) continues in China despite the use of commercial vaccines, raising questions regarding current vaccine efficacy and the need for novel vaccine development. Adenovirus serotype 5 (Ad5) has several advantages, including high transduction efficiency, a wide range of host cells, and the ability to infect cells at various stages. In this study, we expressed the immunogenic proteins of spike (S) using an Ad5 vector and generated a PED vaccine candidate by inducing significant humoral immunity. The rAd5-PEDV-S prevented PED-induced weight loss, diarrhea, and intestinal damage in piglets. This novel vaccine candidate strain possesses the potential for use in the pig breeding industry.

Quantitative US fat fraction for noninvasive assessment of hepatic steatosis in suspected metabolic-associated fatty liver disease.

OBJECTIVES: To evaluate the agreement between quantitative ultrasound system fat fraction (USFF) and proton magnetic resonance spectroscopy (1H-MRS) and the diagnostic value of USFF in assessing metabolic-associated fatty liver disease (MAFLD). METHODS: The participants with or suspected of MAFLD were prospectively recruited and underwent 1H-MRS, USFF, and controlled attenuation parameter (CAP) measurements. The correlation between USFF and 1H-MRS was assessed using Pearson correlation coefficients. The USFF diagnostic performance for different grades of steatosis was evaluated using receiver operating characteristic curve analysis (ROC) and was compared with CAP, visual hepatic steatosis grade (VHSG). RESULTS: A total of 113 participants (mean age 44.79 years ± 13.56 (SD); 71 males) were enrolled, of whom 98 (86.73%) had hepatic steatosis (1H-MRS ≥ 5.56%). USFF showed a good correlation (Pearson r = 0.76) with 1H-MRS and showed a linear relationship, which was superior to the correlation between CAP and 1H-MRS (Pearson r = 0.61). The USFF provided high diagnostic performance for different grades of hepatic steatosis, with ROC from 0.84 to 0.98, and the diagnostic performance was better than that of the CAP and the VHSG. The cut-off values of the USFF were different for various grades of steatosis, and the cut-off values for S1, S2, and S3 were 12.01%, 19.98%, and 22.22%, respectively. CONCLUSIONS: There was a good correlation between USFF and 1H-MRS. Meanwhile, USFF had good diagnostic performance for hepatic steatosis and was superior to CAP and VHSG. USFF represents a superior method for noninvasive quantitative assessment of MAFLD. CRITICAL RELEVANCE STATEMENT: Quantitative ultrasound system fat fraction (USFF) accurately assesses liver fat content and has a good correlation with magnetic resonance spectroscopy (1H-MRS) for the assessment of metabolic-associated fatty liver disease (MAFLD), as well as for providing an accurate quantitative assessment of hepatic steatosis. KEY POINTS: Current diagnostic and monitoring modalities for metabolic-associated fatty liver disease have limitations. USFF correlated well with 1H-MRS and was superior to the CAP. USFF has good diagnostic performance for steatosis, superior to CAP and VHSG.

A novel anti-LAG-3/TIGIT bispecific antibody exhibits potent anti-tumor efficacy in mouse models as monotherapy or in combination with PD-1 antibody.

We report the generation of a novel anti-LAG-3/TIGIT bispecific IgG4 antibody, ZGGS15, and evaluated its anti-tumor efficacy in mouse models as monotherapy or in combination with a PD-1 antibody. ZGGS15 exhibited strong affinities for human LAG-3 and TIGIT, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 has EC50s of 0.69 nM and 1.87 nM for binding to human LAG-3 and TIGIT on CHO-K1 cells, respectively. ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50 = 0.24 nM). ZGGS15 does not induce ADCC, CDC, or obvious cytokine production. In vivo results showed that ZGGS15 had better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agents and demonstrated a synergistic effect when combined with nivolumab, with a significantly higher tumor growth inhibition of 95.80% (p = 0.001). The tumor volume inhibition rate for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% (p < 0.001). Our data reveal that ZGGS15 exhibits potent anti-tumor efficacy without eliciting ADCC or CDC or causing cytokine production, therefore having a safe profile.

Interoperator reproducibility of quantitative ultrasound analysis of hepatic steatosis in participants with suspected MASLD: A prospective study.

OBJECTIVES: To evaluate the reproducibility of tissue attenuation imaging (TAI) and tissue scatter distribution imaging (TSI) measurements in adults with suspected metabolic dysfunction-associated steatotic liver disease (MASLD) between radiologists with varying experience. MATERIALS AND METHODS: Participants with suspected MASLD were prospectively recruited. TAI and TSI were performed for each participant by two radiologists with different levels of experience. Interoperability reliability was assessed on the basis of Bland-Altman analysis and intraclass correlation coefficients (ICCs). The study determined and compared the diagnostic performance of TAI and TSI with clinical prediction models using proton magnetic resonance spectroscopy (1H-MRS) as a reference. RESULTS: A total of 180 participants (women, n = 56; men, n = 124, mean age, 46.98 ± 14.92 years; mean BMI, 25.81 ± 4.47) were enrolled from August 2022 to September 2022. Bland-Altman plots showed only slight deviation in the TAI and TSI results of the two radiologists; there was good interoperator reproducibility for TAI (ICC = 0.92) and TSI (ICC = 0.86). Senior and junior radiologists performed examinations labeled as TAI-1 and TSI-1, and TAI-2 and TSI-2, respectively. The areas under the curves (AUCs) of TAI-1, TAI-2, TSI-1, and TAI-2 for the detection of ≥5 % hepatic steatosis were 0.90, 0.96, 0.91 and 0.96, respectively. According to ROC analysis, the diagnostic performance of both radiologists for TAI and TSI was statistically similar and superior to that of the clinical prediction model. CONCLUSIONS: TAI and TSI have good reproducibility between radiologists with different levels of experience. Meanwhile, both TAI and TSI demonstrated good diagnostic performance for hepatic steatosis (≥5%), surpassing that of clinical prediction models.

Photosynthetic Bacteria-Hitchhiking 2D iMXene-mRNA Vaccine to Enable Photo-Immunogene Cancer Therapy.

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor-associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co-deliver a tumor-associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene-WT1 mRNA to the core tumor region using photo-driven and hypoxia-driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo-immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.