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Core 1 β1,3-galactosyltransferase (C1GALT1) controls the crucial step of GalNAc-type O-glycosylation and is overexpressed in various human malignancies. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here we demonstrate that C1GALT1 expression is upregulated in HNSCC tumors and is associated with adverse clinicopathologic features. Moreover, high C1GALT1 expression predicts poor disease-free and overall survivals. C1GALT1 overexpression enhances HNSCC cell viability, migration, and invasion, which can be reversed by erlotinib. Silencing of C1GALT1 suppresses the malignant behavior both in vitro and in vivo. Mass spectrometry and lectin pull-down assays demonstrate that C1GALT1 modifies O-glycans on EGFR. Blocking O-glycan elongation on EGFR by C1GALT1 knockdown decreases EGF-EGFR binding affinity and inhibits EGFR signaling, thereby suppressing malignant phenotypes. Using molecular docking simulations, we identify itraconazole as a C1GALT1 inhibitor that directly binds C1GALT1 and promotes its proteasomal degradation, leading to significant blockade of C1GALT1-mediated effects in HNSCC cells in vitro and in vivo. Collectively, our findings demonstrate a critical role of O-glycosylation in HNSCC progression and highlight the therapeutic potential of targeting C1GALT1 in HNSCC treatment.

Cells in the tumor microenvironment (TME) communicate via membrane‐bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal cells. In this study, we showed that the loss of core‐1 β1,3‐galactosyltransferase (C1GALT1)‐mediated O‐glycosylation suppressed tumor growth in syngeneic head and neck cancer mouse models. O‐glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T‐cell‐mediated cytotoxicity, and reduced interleukin‐6 (IL‐6) levels in the secretome. Proteasomal degradation of IL‐6 was controlled by the O‐glycan at threonine 166. Both IL‐6/IL‐6R blockade and O‐glycan truncation in tumor cells induced similar pro‐inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O‐glycosylation inhibitor itraconazole and anti‐programmed cell death protein 1 (anti‐PD‐1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O‐glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O‐glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti‐PD‐1 therapy. This study found that O‐glycan truncation induced proteasomal degradation of interleukin‐6 to suppress tumor growth by promoting M1 macrophage polarization and enhancing T cell‐mediated cytotoxicity in head and neck cancer in vitro and in vivo. Combining an O‐glycosylation inhibitor with anti‐programmed cell death protein 1 antibody effectively suppressed tumor growth, emphasizing the role of O‐glycosylation in modulating the tumor microenvironment.

The global pandemics of severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 have caused unprecedented crises for public health. Coronaviruses are constantly evolving, and it is unknown which new coronavirus will emerge and when the next coronavirus will sweep across the world. Knowledge graphs are expected to help discover the pathogenicity and transmission mechanism of viruses. The aim of this study was to discover potential targets and candidate drugs to repurpose for coronaviruses through a knowledge graph-based approach. We propose a computational and evidence-based knowledge discovery approach to identify potential targets and candidate drugs for coronaviruses from biomedical literature and well-known knowledge bases. To organize the semantic triples extracted automatically from biomedical literature, a semantic conversion model was designed. The literature knowledge was associated and integrated with existing drug and gene knowledge through semantic mapping, and the coronavirus knowledge graph (CovKG) was constructed. We adopted both the knowledge graph embedding model and the semantic reasoning mechanism to discover unrecorded mechanisms of drug action as well as potential targets and drug candidates. Furthermore, we have provided evidence-based support with a scoring and backtracking mechanism. The constructed CovKG contains 17,369,620 triples, of which 641,195 were extracted from biomedical literature, covering 13,065 concept unique identifiers, 209 semantic types, and 97 semantic relations of the Unified Medical Language System. Through multi-source knowledge integration, 475 drugs and 262 targets were mapped to existing knowledge, and 41 new drug mechanisms of action were found by semantic reasoning, which were not recorded in the existing knowledge base. Among the knowledge graph embedding models, TransR outperformed others (mean reciprocal rank=0.2510, Hits@10=0.3505). A total of 33 potential targets and 18 drug candidates were identified for coronaviruses. Among them, 7 novel drugs (ie, quinine, nelfinavir, ivermectin, asunaprevir, tylophorine, Artemisia annua extract, and resveratrol) and 3 highly ranked targets (ie, angiotensin converting enzyme 2, transmembrane serine protease 2, and M protein) were further discussed. We showed the effectiveness of a knowledge graph-based approach in potential target discovery and drug repurposing for coronaviruses. Our approach can be extended to other viruses or diseases for biomedical knowledge discovery and relevant applications.

Using time-gated fluorescence lifetime imaging microscopy, significantly more signals from 3,6-bis(1-methyl-2-vinyl-pyridinium) carbazole diiodide ( o -BMVC) foci, characterized by the longer fluorescent decay time of o -BMVC, were detected in six types of cancer cells than in three types of normal cells. Accumulating evidence suggested that the o -BMVC foci are mainly the G-quadruplex foci. The large contrast in the number of o -BMVC foci can be considered as a common signature to distinguish cancer cells from normal cells. Further study of tissue biopsy showed that the o -BMVC test provides a high accuracy for clinical detection of head and neck cancers.

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.

Objective Pituitary adenomas are the most common type of pituitary disorders, which usually occur in young adults and often affect the patient’s physical development, labor capacity and fertility. Clinical free texts noted in electronic medical records (EMRs) of pituitary adenomas patients contain abundant diagnosis and treatment information. However, this information has not been well utilized because of the challenge to extract information from unstructured clinical texts. This study aims to enable machines to intelligently process clinical information, and automatically extract clinical named entity for pituitary adenomas from Chinese EMRs. Methods The clinical corpus used in this study was from one pituitary adenomas neurosurgery treatment center of a 3A hospital in China. Four types of fine-grained texts of clinical records were selected, which included notes from present illness, past medical history, case characteristics and family history of 500 pituitary adenoma inpatients. The dictionary-based matching, conditional random fields (CRF), bidirectional long short-term memory with CRF (BiLSTM-CRF), and bidirectional encoder representations from transformers with BiLSTM-CRF (BERT-BiLSTM-CRF) were used to extract clinical entities from a Chinese EMRs corpus. A comprehensive dictionary was constructed based on open source vocabularies and a domain dictionary for pituitary adenomas to conduct the dictionary-based matching method. We selected features such as part of speech, radical, document type, and the position of characters to train the CRF-based model. Random character embeddings and the character embeddings pretrained by BERT were used respectively as the input features for the BiLSTM-CRF model and the BERT-BiLSTM-CRF model. Both strict metric and relaxed metric were used to evaluate the performance of these methods. Results Experimental results demonstrated that the deep learning and other machine learning methods were able to automatically extract clinical named entities, including symptoms, body regions, diseases, family histories, surgeries, medications, and disease courses of pituitary adenomas from Chinese EMRs. With regard to overall performance, BERT-BiLSTM-CRF has the highest strict F1 value of 91.27% and the highest relaxed F1 value of 95.57% respectively. Additional evaluations showed that BERT-BiLSTM-CRF performed best in almost all entity recognition except surgery and disease course. BiLSTM-CRF performed best in disease course entity recognition, and performed as well as the CRF model for part of speech, radical and document type features, with both strict and relaxed F1 value reaching 96.48%. The CRF model with part of speech, radical and document type features performed best in surgery entity recognition with relaxed F1 value of 95.29%. Conclusions In this study, we conducted four entity recognition methods for pituitary adenomas based on Chinese EMRs. It demonstrates that the deep learning methods can effectively extract various types of clinical entities with satisfying performance. This study contributed to the clinical named entity extraction from Chinese neurosurgical EMRs. The findings could also assist in information extraction in other Chinese medical texts.

The clinical characteristics of oropharyngeal squamous cell carcinoma (OPSCC) may be different between endemic and non-endemic regions of betel nut chewing. The impact of combined alcohol drinking/betel quid chewing/cigarette smoking (ABC) exposure on the survival of OPSCC remains unclear. We reviewed the medical records of OPSCC patients between 1999 and 2013. Immunohistochemical staining of p16 and HPV genotype detection by DNA Polymerase chain reaction were both performed for each tumor. A total of 300 eligible patients including 74 HPV+ OPSCC patients and 226 HPV− OPSCC patients were enrolled. The 5-year disease-free survival rates for the HPV−, HPV+ OPSCC with and without ABC patients were 49.8%, 58.4% and 94%, respectively. The 5-year overall survival rates for the patients with HPV−, HPV+ OPSCC with and without ABC patients were 46%, 57.4% and 86%, respectively. Advanced locoregionally disease (T3/T4, N2/N3), HPV- OPSCC, combined 2 or all ABC exposure were the independent adverse prognostic factors for disease-free and overall survival. Therefore, our data suggest that in an endemic region of betel quid chewing, HPV− OPSCC comprises the majority of OPSCC and has a worse survival. Combined 2 or all ABC exposure had a significant negative impact on disease-free and overall survival.

Background The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC diagnosis and treatment. We performed a survey to quantify the direct medical and non‐medical expenditure as well as the resulting financial burden of CRC patients in China. Methods We conducted a multicenter, cross‐sectional survey in 37 tertiary hospitals in 13 provinces across China between 2012 and 2014. Each enrolled patient was interviewed using a structured questionnaire. All expenditure data were inflated to the 2014 Chinese Yuan (CNY; 1 CNY = 0.163 USD). We quantified the overall expenditure and financial burden and by subgroup (hospital type, age at diagnosis, sex, education, occupation, insurance type, household income, clinical stage, pathologic type, and therapeutic regimen). We then performed generalized linear modeling to determine the factors associated with overall expenditure. Results A total of 2356 patients with a mean age of 57.4 years were included, 57.1% of whom were men; 13.9% of patients had stage I cancer; and the average previous‐year household income was 54,525 CNY. The overall average direct expenditure per patient was estimated to be 67,408 CNY, and the expenditures for stage I, II, III, and IV disease were 56,099 CNY, 59,952 CNY, 67,292 CNY, and 82,729 CNY, respectively. Non‐medical expenditure accounted for 8.3% of the overall expenditure. The 1‐year out‐of‐pocket expenditure of a newly diagnosed patient was 32,649 CNY, which accounted for 59.9% of their previous‐year household income and caused 75.0% of families to suffer an unmanageable financial burden. Univariate analysis showed that financial burden and overall expenditure differed in almost all subgroups (P < 0.05), except for sex. Multivariate analysis showed that patients who were treated in specialized hospitals and those who were diagnosed with adenocarcinoma or diagnosed at a later stage were likely to spend more, whereas those with a lower household income and those who underwent surgery spent less (all P < 0.05). Conclusions For patients in China, direct expenditure for the diagnosis and treatment of CRC seemed catastrophic, and non‐medical expenditure was non‐ignorable. The financial burden varied among subgroups, especially among patients with different clinical stages of disease, which suggests that, in China, CRC screening might be cost‐effective.

Background The incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan. Methods Between 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records. Results In our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999–2002), 30% (2003–2006), 30% (2007–2010), 29% (2011–2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999–2002), 1.06 (2003–2006), 1.52 (2007–2010) to 1.74 (2011–2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35–0.76), p  = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p  < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p  < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p  < 0.01). Conclusion The incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC.

This study investigated the diagnostic accuracy and affecting factors of ultrasound (US)-guided core-needle biopsy (CNB) in patients with treated head and neck squamous cell carcinoma (HNSCC). We retrospectively reviewed patients with treated HNSCC who received US-guided CNB from January 2011 to December 2018 with corresponding imaging. Pathological necrosis and fibrosis of targeted lymph nodes (LNs) were evaluated. We analyzed the correlation between CNB accuracy and clinical and pathological characteristics. In total, 260 patients were included. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CNB for nodal recurrence were 84.47%, 100%, 100%, 54.67%, and 86.92%, respectively. CNB of fibrotic LNs had significantly worse sensitivity, NPV, and accuracy than that of non-fibrotic LNs. Similarly, CNB of necrotic LNs had significantly worse sensitivity, NPV, and accuracy than non-necrotic LNs. Multivariate regression revealed that fibrotic LN was the only independent factor for a true positive rate, whereas both necrotic LN and fibrotic LN were independent factors for a false negative rate. The diagnostic accuracy of CNB in treated HNSCC patients is affected by LN necrosis and fibrosis. Therefore, CNB results, particularly for necrotic or fibrotic LNs, should be interpreted carefully.