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Tibetan weedy barleys reside at the edges of qingke (hulless barley) fields in Tibet (Xizang). The spikes of these weedy barleys contain or lack a brittle rachis, with either two- or six-rowed spikes and either hulled or hulless grains at maturity. Although the brittle rachis trait of Tibetan weedy barleys is similar to that of wild barley (Hordeum vulgare ssp. spontaneum Thell.), these plants share genetic similarity with domesticated barley. The origin of Tibetan weedy barleys continues to be debated. Here, we show that most Tibetan weedy barleys originated from cross-pollinated hybridization of domesticated barleys, followed by hybrid self-pollination and recombination between Non-brittle rachis 1 (btr1) and 2 (btr2). We discovered the specific genetic ancestry of these weedy barleys in South Asian accessions. Tibetan weedy barleys exhibit lower genetic diversity than wild and Chinese landraces/cultivars and share a close relationship with qingke, genetically differing from typical eastern and western barley populations. We classified Tibetan weedy barleys into two groups, brittle rachis (BR) and non-brittle rachis (NBR); these traits align with the haplotypes of the btr1 and btr2 genes. Whereas wild barleys carry haplotype combinations of Btr1 and Btr2, each showing lower proportions in a population, the recombinant haplotype BTR2H8+BTR1H24 is predominant in the BR group. Haplotype block analysis based on whole-genome sequencing revealed two recombination breakpoints, which are present in 80.6% and 16.8% of BR accessions according to marker-assisted analysis. Hybridization events between wild and domesticated barley were rarely detected. These findings support the notion that Tibetan weedy barleys originated via recombination between Btr1 and Btr2 in domesticated barley.

In early spring 2018, significant mosaic disease symptoms were observed for the first time on barley leaves (Hordeum vulgare L., cv. New Sachiho Golden) in Takanezawa, Tochigi Prefecture, Japan. This cultivar carries the resistance gene rym3 (rym; resistance to yellow mosaic). Through RNA-seq analysis, Barley yellow mosaic virus (BaYMV-Takanezawa) was identified in the roots of all five plants (T01–T05) in the field. Phylogenetic analysis of RNA1, encompassing known BaYMV pathotypes I through V, revealed that it shares the same origin as isolate pathotype IV (BaYMV-Ohtawara pathotype). However, RNA2 analysis of isolates revealed the simultaneous presence of two distinct BaYMV isolates, BaYMV-Takanezawa-T01 (DRR552862, closely related to pathotype IV) and BaYMV-Takanezawa-T02 (DRR552863, closely related to pathotype III). The amino acid sequences of the BaYMV-Takanezawa isolates displayed variations, particularly in the VPg and N-terminal region of CP, containing mutations not found in other domains of the virus genome. Changes in the CI (RNA1 amino acid residue 459) and CP (RNA1 amino acid residue 2138) proteins correlated with pathogenicity. These findings underscore the importance of monitoring and understanding the genetic diversity of BaYMV for effective disease management strategies in crop breeding.

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0–33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.

Abstract Objective Immune checkpoint inhibitors (ICIs) have been considered as novel therapeutic approaches for various cancers. ICIs were reportedly efficacious against rare cancers, including salivary gland carcinoma (SGC). We aimed to analyze the efficacy and safety of ICIs in patients with SGC. Methods We retrospectively analyzed the oncologic outcomes and immune‐related adverse events (irAEs) in patients with SGC treated with at least one cycle of nivolumab or pembrolizumab. Results Among 12 patients, there were two with a complete response (CR), two with a partial response, five with stable diseases, and three with progressive diseases. The overall response rate was 33.3%. A CR was achieved in patients with poorly differentiated carcinoma (carcinoma ex pleomorphic adenoma) and salivary duct carcinoma. The progression‐free survival ranged between 1 and 18 months (median, 4 months), while the overall survival ranged between 2 and 25 months (median, 13.5 months). An irAE was observed in only one patient who developed grade 3 erythema multiforme, and this patient's condition improved with withdrawal of pembrolizumab alone. Conclusion Programmed death‐1 blockade was an effective therapy for patients with SGC, including aggressive histologic types.

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5–10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.

Infection by the Japanese soil-borne wheat mosaic virus (JSBWMV) can lead to substantial losses in the grain yield of barley and wheat crops. While genetically based resistance to this virus has been documented, its mechanistic basis remains obscure. In this study, the deployment of a quantitative PCR assay showed that the resistance acts directly against the virus rather than by inhibiting the colonization of the roots by the virus’ fungal vector Polymyxa graminis. In the susceptible barley cultivar (cv.) Tochinoibuki, the JSBWMV titre was maintained at a high level in the roots during the period December–April, and the virus was translocated from the root to the leaf from January onwards. In contrast, in the roots of both cv. Sukai Golden and cv. Haruna Nijo, the titre was retained at a low level, and translocation of the virus to the shoot was strongly suppressed throughout the host’s entire life cycle. The roots of wild barley (Hordeum vulgare ssp. spontaneum) accession H602 responded in the early stages of infection similarly to those of the resistant cultivated forms, but the host was unable to suppress the translocation of the virus to the shoot from March onwards. The virus titre in the root was presumed to have been restricted by the action of the gene product of Jmv1 (on chromosome 2H), while the stochastic nature of the infection was suppressed by the action of that of Jmv2 (on chromosome 3H), a gene harbored by cv. Sukai Golden but not by either cv. Haruna Nijo or accession H602.

Powdery mildew is a fungal disease devastating to wheat, causing significant quality and yield loss. Flavonoids are important secondary plant metabolites that confer resistance to biotic and abiotic stress. However, whether they play a role in powdery mildew resistance in wheat has yet to be explored. In the present study, we combined transcriptome and metabolome analyses to compare differentially expressed genes (DEGs) and differentially accumulated flavonoids identified in plants with and without powdery mildew inoculation. Transcriptome analysis identified 4,329 DEGs in susceptible wheat cv. Jimai229, and 8,493 in resistant cv. HHG46. The DEGs were functionally enriched using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, revealing the flavonoid synthesis pathway as the most significant in both cultivars. This was consistent with the upregulation of flavonoid synthesis pathway genes observed by quantitative PCR. Metabolome analysis indicated flavone and flavonol biosynthesis pathways as the most significantly enriched following powdery mildew inoculation. An accumulation of total flavonoids content was also found to be induced by powdery mildew infection. Exogenous flavonoids treatment of inoculated plants led to less severe infection, with fewer and smaller powdery mildew spots on the wheat leaves. This reduction is speculated to be regulated through malondialdehyde content and the activities of peroxidase and catalase. Our study provides a fundamental theory for further exploration of the potential of flavonoids as biological prevention and control agents against powdery mildew in wheat.

Fibroblast growth factor receptor 1 (FGFR1) is overexpressed in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Being associated with poor prognosis, FGFR1 is a potential therapeutic target for aggressive tumors. T cell-based cancer immunotherapy has played a central role in novel cancer treatments. However, the potential of antitumor immunotherapy targeting FGFR1 has not been investigated. Here, we showed that FGFR-tyrosine kinase inhibitors (TKIs) augmented antitumor effects of immune checkpoint inhibitors in an HNSCC mouse model and upregulated tumoral MHC class I and MHC class II expression in vivo and in vitro. This upregulation was associated with the mitogen-activated protein kinase signaling pathway, which is a crucial pathway for cancer development through FGFR signaling. Moreover, we identified an FGFR1-derived peptide epitope (FGFR1305-319) that could elicit antigen-reactive and multiple HLA-restricted CD4+ T cell responses. These T cells showed direct cytotoxicity against tumor cells that expressed FGFR1. Notably, FGFR-TKIs augmented antitumor effects of FGFR1-reactive T cells against human HNSCC cells. These results indicate that the combination of FGFR-TKIs with immunotherapy, such as an FGFR1-targeting peptide vaccine or immune checkpoint inhibitor, could be a novel and robust immunologic approach for treating patients with FGFR1-expressing cancer cells.

Background: The identification of epitope peptides from tumor‐associated antigens (TAAs) is informative for developing tumor‐specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC). Methods: Novel mouse c‐Met‐derived T‐cell epitopes were predicted by computer‐based algorithms. Mouse HNSCC cell line‐bearing mice were treated with a c‐Met peptide vaccine. The effects of CD8 and/or CD4 T‐cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re‐inoculation was performed to assess T‐cell memory. Results: We identified c‐Met‐derived short and long epitopes that elicited c‐Met‐reactive antitumor CD8 and/or CD4 T‐cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c‐Met peptide‐vaccinated mice rejected the re‐inoculated tumors. Conclusions: We demonstrated that novel c‐Met peptide vaccines can induce antitumor T‐cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model. [ABSTRACT FROM AUTHOR]

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding eight patients with pre-ESD levels of D-dimer >1.5 μg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but, because the sedative effect of midazolam shows marked inter-individual variability, a “corrected midazolam dose” was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in the subgroup analysis of the 103 patients who received midazolam. In the subgroup analysis using the corrected midazolam dose as an explanatory variable, only the corrected midazolam dose correlated with a change in D-dimer ≥1.0 μg/mL in multivariate analysis (odds ratio (OR) = 1.5, 95% confidence interval (CI) 0.43–0.95; p = 0.030). The corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.

Background: A combination therapy with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has become the first-line treatment for recurrent or metastatic head and neck squamous carcinoma (HNSCC). Although steroids are often used as anti-emetic medications during chemotherapy, their adverse effects on immune-combined chemotherapy are unclear in HNSCC.Methods: The effects of dexamethasone on tumor growth and immune cell population were evaluated in a mouse HNSCC model treated with PD-1 blockade combined with cisplatin. The effect of various doses of dexamethasone on cell proliferation, survival, surface markers, IFN-γ production, and antitumor effects in antigen-specific T cells was examined in vitro. The recovery of T cell dysfunction by IL-2 was assessed in vitro and in vivo.Results: In a mouse HNSCC model, dexamethasone showed limited antitumor effects on immunochemotherapy. Dexamethasone decreased the number of T cells and inhibited T cell differentiation into effector and central memory T cells. In the in vitro assessment, dexamethasone induced cell death, limited proliferation, and reduced the reactivity against HNSCC cell lines of antigen-specific T cells in a dose-dependent manner. The expression of inhibitory receptors on T cells was not affected by steroids. This inhibition was recovered by IL-2 and IL-2/anti-IL-2 complexes (IL-2 Cx) in vitro and in vivo, respectively.Conclusion: Our preclinical data indicate that dexamethasone diminishes the antitumor effects of immunochemotherapy in patients with HNSCC. IL-2 Cx recovered the inhibition of antitumor immunity by steroids and might be a potent immune adjuvant for patients who require steroids during PD-1 blockade and chemotherapy.

Abstract PD‐1 blockade is a feasible approach in treating mucosal malignant melanomas of the middle ear.

Sucrose nonfermenting 2 (Snf2) family proteins, as the catalytic core of ATP-dependent chromatin remodeling complexes, play important roles in nuclear processes as diverse as DNA replication, transcriptional regulation, and DNA repair and recombination. The Snf2 gene family has been characterized in several plant species; some of its members regulate flower development in Arabidopsis. However, little is known about the members of the family in barley (Hordeum vulgare). Here, 38 Snf2 genes unevenly distributed among seven chromosomes were identified from the barley (cv. Morex) genome. Phylogenetic analysis categorized them into 18 subfamilies. They contained combinations of 21 domains and consisted of 3 to 34 exons. Evolution analysis revealed that segmental duplication contributed predominantly to the expansion of the family in barley, and the duplicated gene pairs have undergone purifying selection. About eight hundred Snf2 family genes were identified from 20 barley accessions, ranging from 38 to 41 genes in each. Most of these genes were subjected to purification selection during barley domestication. Most were expressed abundantly during spike development. This study provides a comprehensive characterization of barley Snf2 family members, which should help to improve our understanding of their potential regulatory roles in barley spike development.

In CD70‐expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)‐related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27‐positive lymphocytes infiltrate around tumor cells. NPC patients with CD27‐positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27‐positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70‐positive NPC with CD27‐positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27‐targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of immunotherapies in salivary gland cancer (SGC) remains controversial. To optimize immunotherapy, understanding the tumor microenvironment (TME) of SGC is necessary. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma exhibit immune-hot TME. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies have shown promising clinical efficacy of ICIs indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies. This review discusses the current understanding and future directions of immunotherapies for SGCs. Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0–33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, tissue infiltration of IgG4-positive cells, and fibrosis. Although a number of IgG4-RD patients show sinonasal involvement, there is little known about sinonasal inflammation associated with IgG4-RD. This study aimed to describe the clinicopathological features of sinonasal inflammation associated with IgG4-RD and to compare with other inflammatory diseases, such as eosinophilic chronic rhinosinusitis (ECRS) and granulomatosis with polyangiitis (GPA). Methods: A retrospective analysis of clinicopathological features of patients with sinonasal lesions and high serum IgG4 was performed. Patient data were reviewed to determine whether they fulfilled the diagnostic criteria for other inflammatory diseases. Results: Six of 7 patients were diagnosed with IgG4-RD, while 1 patient was diagnosed with GPA. In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and nasal crusting in the 3 patients (50%). Computed tomography showed ethmoid sinus involvement in 5 patients (83%). Five of the 6 patients (83%) were diagnosed with IgG4-RD based on nasal biopsy, whereas 1 patient (17%) was diagnosed based on lacrimal gland biopsy. Four patients fulfilled the Japanese epidemiological survey of refractory ECRS (JESREC) criteria. However, none of the patients showed eosinophil infiltration. Although the patient with GPA showed high levels of serum IgG4 and tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient showed common clinical features of GPA. Conclusion: Patients with sinonasal inflammation associated with IgG4-RD had similar clinical characteristics with ECRS and GPA. Histopathological findings of the nasal biopsy from clinically diagnosed GPA was consistent with that of IgG4-RD. Sinonasal inflammation associated with IgG4-RD should be diagnosed based not only on tissue infiltration of IgG4-positive cells but in conjunction with clinical findings such as local nasal characteristics, involvement of other organs, and serum antineutrophil cytoplasmic antibody levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration. Plain Language Summary: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4 levels and tissue IgG4-positive cells. A part of IgG4-RD patients has sinonasal lesions. Because other inflammatory diseases also have features common to IgG4-RD, accurate knowledge of IgG4-RD is required. However, very little is known about IgG4-related rhinosinusitis. This study retrospectively analyzed clinicopathological features of IgG4-related rhinosinusitis and compared IgG4-related rhinosinusitis with other inflammatory diseases. Seven patients with sinonasal lesions and high serum IgG4 levels were retrospectively reviewed. Six of 7 patients were diagnosed with IgG4-RD, while one was diagnosed with granulomatosis with polyangiitis (GPA). In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and computed tomography showed ethmoid sinus involvement in 5 patients (83%), which shared common features with eosinophilic sinusitis (ECRS). However, no patients showed histopathological eosinophil infiltration. Although the patient with GPA revealed tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient also had saddle nose and positivity of myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA), which indicated GPA. We diagnosed the patient with GPA, which is a known mimicker of IgG4-RD. In this study, the patients with IgG4-related rhinosinusitis had clinical and pathological characteristics similar to those of ECRS and GPA. IgG4-related rhinosinusitis should be diagnosed based on not only tissue infiltration of IgG4-positive cells but also systemic findings including nasal findings and serum ANCA levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration. [ABSTRACT FROM AUTHOR]