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Abstract Background There is an unmet clinical need to enhance the response rate and safety of anti-PD-1/PD-L1-based cancer immunotherapy (IO). Herein, we presented the clinical study of IBI318 (LY3434172), a first-in-class bispecific antibody (bsAb) targeting PD-1 and PD-L1, in patients with advanced tumors. Methods In this open-label, multicenter Phase Ia/Ib study of IBI318, the Phase Ia involved dose escalation and a safety dose expansion, while the Phase Ib focused on preliminary safety and efficacy evaluation in non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma (NPC). In Phase Ia, patients with advanced tumors received IBI318 doses ranging from 0.3 to 1200 mg every two weeks (Q2W) to determine the recommended Phase 2 dose (RP2D). In Phase Ib, NSCLC or NPC patients from five cohorts with varying treatment histories received IBI318 at the RP2D. The primary endpoint was safety and the secondary endpoints included efficacy assessed by investigators according to RECIST v1.1, pharmacokinetics, immunogenicity, and pharmacodynamics. Results From February 11, 2019, to January 25, 2022, a total of 103 eligible patients were enrolled (Phase Ia, n = 55; Phase Ib, n = 48). The median follow-up was 10.1 months (range 0.7–28.6). The RP2D was determined to be 300 mg Q2W. Treatment-related adverse events (TRAEs) of any grades occurred in 88 patients (85.4%), while 10 patients (9.7%) experienced grade ≥ 3 TRAEs. The objective response rate (ORR) was 15.5% and the disease control rate (DCR) was 49.5% in all patients. In Phase Ib, the confirmed ORR was 45.5% in treatment-naïve NSCLC patients and 30.0% in IO-naïve NPC patients who had failed or were intolerant to platinum-based treatments. Conclusions IBI318 demonstrated a favorable safety profile and preliminary efficacy in treatment-naïve NSCLC and IO-naïve NPC patients. Further clinical studies are needed to assess the full therapeutic potential of PD-1/PD-L1 dual inhibition with bsAbs.

Objective. The objective of this study is to explore the utilization of next-generation sequencing (NGS) technology in evaluating the likelihood of identifying individuals with papillary thyroid microcarcinoma (PTMC ≤10 mm) who are at high or low risk. Design. NGS was used to analyze 393 formalin-fixed, paraffin-embedded tissues of PTC tumors, all of which were smaller than 15 mm. Results. The study found that bilateralism, multifocality, intrathyroidal spread, and extrathyroidal extension were present in 84 (21.4%), 153 (38.9%), 16 (4.1%), and 54 (13.7%) cases, respectively. Metastasis of cervical lymph nodes was identified in 226 (57.5%) cases and 96 (24.4%) cases with CLNM >5. Out of the total number of cases studied, 8 cases (2.3%) showed signs of tumor recurrence, all of which were localized and regional. Genetic alterations were detected in 342 cases (87.0%), with 336 cases revealing single mutations and 6 cases manifesting compound mutations. 332 cases (84.5%) had BRAFV600E mutation, 2 cases had KRASQ61K mutation, 2 cases had NRASQ61R mutation, 8 cases had RET/PTC1 rearrangement, 3 cases had RET/PTC3 rearrangement, and 1 case had TERT promoter mutation. Additionally, six individuals harbored concurrent mutations in two genes. These mutations were of various types and combinations: BRAFV600E and NRASQ61R (n = 2), BRAFV600E and RET/PTC3 (n = 2), BRAFV600E and RET/PTC1 (n = 1), and BRAFV600E and TERT promoter (n = 1). The subsequent analysis did not uncover a significant distinction in the incidence of gene mutation or fusion between the cN0 and cN1 patient cohorts. The presence of BRAFV600E mutation and CLNM incidence rates were found to be positively correlated with larger tumor size in PTMC. Our data showed that gene mutations did not appear to have much to do with high-risk papillary thyroid microcarcinoma (PTMC). However, when we looked at tumor size, we found that if the tumor was at least 5 millimeters in size, there was a higher chance of it being at high risk for PTM (P

Fungal keratitis (FK) is a refractory disease that poses a serious threat to vision, with common risk factors like eye trauma, contact lens wearing, topical corticosteroids and antibiotic abuse. Nowadays, topical and systemic anti-fungal drugs and ocular surgeries are still the main therapeutic modalities. However, the pathogenesis of FK, especially the immunologic mechanism within it, has not yet been deeply clarified. A better understanding of the pathogenesis of FK is imperative for more effective therapies and prognosis. Meanwhile, the immune protection strategies are also urgently required to manage FK. This review highlights recent advances in the immunologic mechanism in the pathogenesis of FK, in hope of providing valuable reference information for more effective anti-fungal treatment.

Background. Papillary thyroid carcinoma (PTC) is a form of thyroid cancer with high risk of cervical lymph node metastasis. Aim. The aim of this study was to investigate the incidence and the predictive factors for occult ipsilateral central lymph node (CLN) metastasis in the patients with papillary thyroid carcinoma. Methods. A total of 916 PTC patients (1017 lesions) undergoing central lymph node dissection in our hospital from 2005 to 2011 were enrolled. The relationship between CLN metastasis and clinical factors such as gender, age, tumor size, tumor number, capsule invasion, and tumor location was analyzed. Results. Occult CLN metastasis was observed in 52.41% (533/1017) of PTC lesions, respectively. Multivariate analysis showed that age ≤ 35 years, tumor size > 1.5 cm, present capsule invasion/extracapsular invasion, and tumor located in upper/middle pole/whole lobe were risk factors of CLN metastasis. Conclusions. Tumor located in upper/middle pole/whole lobe, less than 35 years old, tumor size > 1.5 cm, and present capsule invasion/extracapsular invasion were risk factors of CLN metastasis. We recommend performing ipsilateral prophylactic CLN dissection in cN0 PTC patients.

BACKGROUND:Methylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker. METHODS:Real-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera. RESULTS:We confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p

To improve yield, effects of nano-potassium molybdate was investigated on photosynthetic characteristics and nitrogen metabolism of rapeseed. Different concentrations (0-1100 mg·L-1) of nano-potassium molybdate were sprayed on rapeseed seedling under hydroponic conditions. Changes of gas exchange parameters, key enzyme activities of carbon and N assimilation and N contents of leaves were measured. Results showed that spray of nano-potassium molybdate increased photosynthetic pigment and net photosynthetic rate of leaves, while decreased gas exchange parameters (including transpiration rate, stomatal conductance and intercellular CO2 concentration). The activities of Rubisco and PEPC enzyme increased gradually with the nano-molybdate concentration, in which Rubisco enzyme activity was significantly enhanced at 550 mg·L-1 and 1100 mg·L-1 compared to control, and PEPC enzyme activities increased significantly at 1100 mg·L-1. The activities of nitrate reductase, nitrite reductase and glutamate synthase were significantly increased at 550 mg·L-1 compared with control. No significant change was observed at higher concentrations. Nitrate-N contents were significantly reduced after the spray of nano-potassium molybdate, while ammonia-N contents and N concentrations were not significantly changed compared with control. In addition, protein content increased significantly at 550 mg·L-1. In summary, 550 mg·L-1 nano-potassium molybdate spray enhanced carbon assimilation efficiency of rapeseed, while N assimilation efficiency was also significantly increased. The promotion of photosynthesis in rapeseed by nano-potassium molybdate was mainly related to nonstomatal factors: increased photosynthetic pigment contents and enhanced activities of key enzymes for photosynthesis. It could promote the conversion of inorganic to organic N in rape leaves by enhancing the activities of key enzymes of N metabolism. [ABSTRACT FROM AUTHOR]

The main component of O-glycoproteins, mucin, is known to play important roles in physiological conditions and oncogenic processes, particularly correlated with poor prognosis in different carcinomas. Diffuse-type gastric cancer (DGC) has long been associated with genomic stability and unfavorable clinical outcomes. To investigate further, we obtained clinical information and the RNA-seq data of the TCGA-STAD cohort. Through the use of unsupervised clustering methods and GSEA, we identified two distinct clusters, characterized by higher and lower expression of MUC2 and MUC20, denoted as cluster 1 and cluster 2, respectively. Subsequently, employing CIBERSORT, it was determined that cluster 2 exhibited a higher tumor mutation burden (TMB) and a greater abundance of CD8+ T cells and activated CD4+ memory T cells, in addition to immune checkpoints (ICPs). On the other hand, cluster 1 showed a lower TIDE score estimation, indicating a higher probability of tumor immune escape. Furthermore, overexpression of MUC15 and MUC20 was confirmed through qPCR and Western blotting, and their specific roles in mediating the epithelial-mesenchymal transition (EMT) process of GC cells (SNU484 and Hs746t) were validated via CCK-8 assay and wound healing assay in vitro. These findings highlight the potential prognostic value of MUC20 and offer insights into the prospects of immunotherapy for DGC by targeting MUC20.

Marek's disease virus (MDV) is a highly cell-associated, oncogenic alpha herpesvirus that causes Marek's disease (MD) in chickens. Chicken erythrocytes are nucleated cells of myeloid origin which contribute to gases exchange, transportation and immunity. The objective of this study was to reveal the immune responses of MDV-infected erythrocytes of chicken by transcriptome analysis. Twenty specific pathogenfree (SPF) chickens were divided into two groups as control and treatment. The chickens of treatment group were inoculated with MDV, and blood samples of two groups were obtained at 14 and 22 days post-infection (dpi) for RNA extraction. Transcriptome analysis was performed to explore the immune responses of chicken erythrocytes to MDV infection at 14 dpi and 22 dpi. In total, 129.6 million reads of two groups at two time points were mapped against the reference genome (Gallus gallus 5.0). A significant differential pattern of the immune response of chicken erythrocytes was identified by the GO and KEGG databases between the two phases of MDV infection. The results indicated that cytokine-cytokine receptor interaction, toll-like receptor signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway were involved in the response to MDV infection. The expression levels of all most differentially expressed genes (DEGs) in these four pathways were upregulated significantly at 14 and 22 dpi, indicating that the immune responses of erythrocytes were induced by MDV. This study may help to elucidate the molecular mechanism of chicken erythrocytes relate to immune responses in MDV infection. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical characteristics of DNA ligase Ⅳ(LIG4) syndrome. Methods The clinical data of one case of LIG4 syndrome were analyzed, and the second-generation high-throughput gene sequencing was applied for the infant and his parents to identify the causative mutation. The clinical features of the disease were summarized with the relevant literatures. Results The case reported here had clinical manifestations of microcephaly, special face, growth retardation, immunodeficiency, recurrent respiratory infections, chronic diarrhea. The high-throughput sequencing showed the patient has carried mutation of LIG4 gene: c.833G＞T (p.R278L), the diagnosis of LIG4 syndrome was established. The features of LIG4 syndrome were analyzed from archived 42 cases, including this study. Conclusions Microcephaly, immunodeficiency, special facial features, hematocytopenia and growth retardation are the main clinical symptoms of LIG4 syndrome. Children with recurrent respiratory infections, microcephaly and immunodeficiency should be vigilant for this disease. Gene testing would be helpful to confirm the diagnosis.