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BackgroundAnoikis resistance (AR) plays an important role in the process of metastasis, which is an important factor affecting the risk stage of neuroblastoma (NB). This study aims to construct an anoikis-related prognostic model and analyze the characteristics of hub genes, important pathways and tumor microenvironment of anoikis-related subtypes of NB, so as to provide help for the clinical diagnosis, treatment and research of NB.MethodsWe combined transcriptome data of GSE49710 and E-MTAB-8248, screened anoikis-related genes (Args) closely related to the prognosis of NB by univariate cox regression analysis, and divided the samples into anoikis-related subtypes by consistent cluster analysis. WGCNA was used to screen hub genes, GSVA and GSEA were used to analyze the differentially enriched pathways between anoikis-related subtypes. We analyzed the infiltration levels of immune cells between different groups by SsGSEA and CIBERSORT. Lasso and multivariate regression analyses were used to construct a prognostic model. Finally, we analyzed drug sensitivity through the GDSC database.Results721 cases and 283 Args were included in this study. All samples were grouped into two subtypes with different prognoses. The analyses of WGCNA, GSVA and GSEA suggested the existence of differentially expressed hub genes and important pathways in the two subtypes. We further constructed an anoikis-related prognostic model, in which 15 Args participated. This model had more advantages in evaluating the prognoses of NB than other commonly used clinical indicators. The infiltration levels of 9 immune cells were significantly different between different risk groups, and 13 Args involved in the model construction were correlated with the infiltration levels of immune cells. There was a relationship between the infiltration levels of 6 immune cells and riskscores. Finally, we screened 15 drugs with more obvious effects on NB in high-risk group.ConclusionThere are two anoikis-related subtypes with different prognoses in the population of NB. The anoikis-related prognostic model constructed in this study can accurately predict the prognoses of children with NB, and has a good guiding significance for clinical diagnosis, treatment and research of NB.

IntroductionMcCune-Albright syndrome (MAS) is a low-incidence syndrome consisting of the clinical triad of fibrous structural dysplasia of bone, endocrine disease, and skin pigmentation. Thyroid dysfunction is the second most common endocrine dysregulation in MAS. However, there are no treatment guidelines for MAS complicated with hyperthyroidism. Notably, no case of MAS complicated with retrosternal goiter and hyperthyroidism has been reported to our knowledge.Case presentationWe report a 27-year-old man with MAS who developed the typical triad of bone fibrous dysplasia, skin pigmentation and hyperthyroidism, complaining of recent fast-growing neck mass and difficulty in breathing. Hyperthyrodism was under control by Thiamazole, and computed tomography showed an enlarged thyroid extending retrosternally. We performed a total thyroidectomy on the patient. At the 1-year follow-up, the patient's dyspnea, hyperthyroidism, and bone pain were all significantly alleviated.ReviewWe searched the literature for previous case reports concerning MAS patients complicated with thyroid dysregulation. A total of 17 articles and 22 patients were identified to form our database. Among them, 9 studies clearly mentioned surgical intervention in 11 patients, and prognoses were also reported. Surgery was the most common intervention chosen and indicated a satisfactory prognosis.ConclusionWe report a rare case of MAS patient complicated with retrosternal goiter and hyperthyroidism. Our review provides an overview of MAS cases requiring interventions on thyroid function, and total thyroidectomy should be a proper treatment for these patients.

Characterizing the tumor microenvironment (TME) of archived clinical tissues requires reliable gene expression profiling (GEP) of formalin-fixed paraffin-embedded (FFPE) samples. The EdgeSeq Precision Immuno-oncology Panel (PIP) is a targeted GEP assay designed for TME characterization but lacks widespread technical validation on a large cohort of clinical samples. Here, we evaluated its performance by exploring its concordance with multiple orthogonal platforms using 1,220 FFPE samples across various cancer types. Quantitative comparisons with RNA-seq and NanoString showed strong correlations at the sample level (median ρ = 0.73 and 0.81) and moderate correlations at the single-gene level (median ρ = 0.49 and 0.57). Gene signature analysis revealed high concordance with RNA-seq on widely used signatures for TME characterization and immune checkpoint inhibitor (ICI) efficacy prediction, though some genes in these signatures are not targeted by EdgeSeq PIP. From a histopathological viewpoint, the tumor/immune abundances derived from hematoxylin and eosin (H & E) staining were well recapitulated by the transcriptomic profiles assessed by EdgeSeq PIP. Furthermore, the mRNA level of PD-L1 assessed by EdgeSeq PIP was moderately correlated with the PD-L1 score (ρ = 0.65) estimated by immunohistochemistry (IHC); the mRNA level of CD8A aligned well (ρ = 0.55) with the IHC-derived abundance of CD8+ T cells. Overall, our results showed that EdgeSeq PIP generated well-correlated data with independent approaches at mRNA, protein, and histological levels, thus providing strong technical support for further using EdgeSeq PIP in biomarker studies and companion diagnostic (CDx) development.

WHIM syndrome, an extremely rare congenital disease with combined immunodeficiency, is mainly caused by heterozygous gain-of-function mutation in the CXCR4 gene. There have been no previous case reports of WHIM syndrome with Kawasaki disease. We herein report a case of a boy who developed Kawasaki disease at the age of 1 year. After treatment, the number of neutrophils in his peripheral blood decreased continuously. His medical history revealed that he had been suffering from leukopenia, neutropenia and low immunoglobulin since birth, and his neutrophils could return to the normal level in the presence of infection or inflammation. Clinical targeted gene sequencing of 91 genes associated with granulocyte-related disease revealed that the patient had a novel heterozygous NM_003467; c.1032_1033delTG;p.(E345Vfs*12) variant in exon 2 of CXCR4 gene. Family verification analysis by Sanger sequencing showed that his father also had heterozygous variation at this site, while other family members did not. The computer prediction software indicated that the variation had a high pathogenicity. The computational structure analysis of the mutant revealed significant structural and functional changes in the CXCR4 protein. It should be noted that when unexplained persistent neutropenia with low immunoglobulin occurs after birth, especially when there is a family history of neutropenia, immunodeficiency should be investigated with genetic testing.

Immune checkpoint therapy (ICT) with a monoclonal antibody (MAb) against programmed cell death protein 1 (PD-1) is a powerful clinical treatment for tumors. Cemiplimab is a human IgG4 antibody approved in 2018 and is the first MAb proven to be effective for locally advanced basal cell carcinoma. Here, we report the crystal structure of cemiplimab bound to PD-1 and the effects of PD-1 N-glycosylation on the interactions with cemiplimab. The structure of the cemiplimab/PD-1 complex shows that cemiplimab mainly binds to PD-1 with its heavy chain, whereas the light chain serves as the predominant region to compete with the binding of PD-L1 to PD-1. The interaction network of cemiplimab to PD-1 resembles that of camrelizumab (another PD-1-binding MAb), and the N58 glycan on the BC loop of PD-1 may be involved in the interaction with cemiplimab. The binding affinity of cemiplimab with PD-1 was substantially decreased with N58-glycan-deficient PD-1, whereas the PD-1/PD-L1 blocking efficiency of cemiplimab was attenuated upon binding to the N58-glycosylation-deficient PD-1. These results indicate that both the binding and blocking efficacy of cemiplimab require the N58 glycosylation of PD-1. Taken together, these findings expand our understanding of the significance of PD-1 glycosylation in the interaction with cemiplimab.

Shiyiwei Shenqi Tablet (SSTs) has been widely used for treatment of different types of cancer including breast cancer. SST has drawn more and more interest due to the low rate of side effects. The aim of this study was to investigate the metabolites in serums of breast cancer patients who received base-line chemotherapy only or combination treatment with SST. An untargeted metabolomics method was developed to investigate the alteration of metabolism in patients’ serums using ultra-high-performance liquid chromatography/Q-exactive Orbitrap mass spectrometry. The patients were separated based on the metabolomics data, and further analyses showed that SST treatment can affect the metabolism of glucose, fatty acid, bile acid and amino acid. In particular, SST treatment significantly reduced some short peptides which are potential tumor neoantigens. This study may provide novel insights into the mechanism underlying interaction between SST and base-line chemotherapy in terms of affecting metabolic pathways and thereby changing metabolic products, which might shed new light for clinical medication.

PurposeTo investigate the sensitivity of SARS-CoV-2 testing in specimens collected from the anterior nasal vestibules of COVID-19 patients.MethodsA cross-sectional analysis was performed on 30 patients with a confirmed diagnosis of COVID-19 at the Shanghai Public Health Clinical Center from March 14, 2020 to March 21, 2020. Paired specimens were collected from both the anterior nasal vestibule and the oropharynx from all patients. All specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) assays.ResultsOf the 30 patients with confirmed COVID-19, 17 patients (56.7%) tested positive for SARS-CoV-2 when oropharyngeal specimens were used, while 20 patients (66.7%) tested positive when nasal swab specimens were used. There was no statistically significant difference in sensitivity between the two methods.ConclusionsRespiratory swabs collected from the nasal vestibule offer a less invasive alternative to oropharyngeal swabs for specimen collection in the detection of SARS-CoV-2 infection, and have adequate sensitivity.