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Craniopharyngiomas remain surgically challenging because of the strong adhesion to vital neurovascular structures. We propose a system for the selection of surgical approaches based on the optic recess (OR) displacement pattern to facilitate the surgical planning and obtain the optimum visual and endocrinological outcomes.Craniopharyngiomas were divided into three types based on the OR displacement pattern: superior, anterior, and involvement types. Selected surgical approaches and patient outcome were retrospectively reviewed according to these classifications. Visual and endocrinological outcomes were compared between the groups.This study included 26 patients with primary craniopharyngiomas who underwent surgery at our institution, classified into 11 anterior, 11 superior, and 4 involvement types. Extended endoscopic endonasal approach provided excellent exposure infero-dorsal aspect of the chiasm for manipulation of the dissection plane in the anterior and superior types with midline location. Unilateral subfrontal approach was required for tumor of the superior type with lateral extension. Interhemispheric translamina terminalis approach (TLA) could provide safe dissection under direct vision of strong adhesion at the superior aspect of the chiasm in the involvement type. Visual and endocrinological outcomes were better in the involvement type compared with the superior and anterior types. Visual outcome was significantly correlated with preoperative visual function.Craniopharyngiomas with the involvement type are indicated for TLA to achieve the best visual and endocrinological outcome. Our classification of OR displacement pattern is useful to select the optimal surgical approach for craniopharyngiomas more accurately and concisely, especially in cases with third ventricular extension.

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B–expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B–expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.

Dehydrogenation polymer (DHP) is widely used as a model polymer of lignin. The chemical structure of DHP is highly affected by the synthesis conditions; however, the factors affecting DHP structure are not comprehensively understood. In this study, guaiacyl DHPs were synthesized to investigate the effects of reaction scale, pH, polymerization-enzyme activity, reaction media containing organic solvent, and differences between Zutropf (ZT) and Zulauf (ZL) modes on DHP properties. The DHPs were structurally characterized by size exclusion chromatography, 1H-13C HSQC NMR, and thioacidolysis with and without Raney nickel desulfuration. In ZT mode, smaller reaction scale significantly increased β-O-4 content, and β-O-4 formation was negatively correlated with the dose of polymerization-enzyme, horseradish peroxidase. Acidic condition (pH 4.0) in succinate buffer also increased the β-O-4 content of the DHP, although the α position of the DHP was acylated by the incorporation of succinic acid. DHPs prepared at pH 9.0 had high β-1 contents and low β-5 contents, while the reaction in 20% 1,4-dioxane markedly increased the molecular weight of the DHP. A systematic approach controlling the molecular structure of DHPs would increase their value as models for native and isolated lignins.

To determine the clinical and imaging characteristics, natural course, and surgical outcomes of pathologic myopic eyes with an extreme macular schisis simulating a retinal detachment (EMSSRD).The data of 617 highly myopic eyes with myopic traction maculopathy were studied. The diagnosis of EMSSRD in the optical coherence tomography images was made based on a high elevation of the retina (500 µ m), less obvious columnar structures, and the presence of thin remnants of outer retinal tissues above the retinal pigment epithelium.Among 617 eyes, 25 eyes had an EMSSRD. All of the eyes with an EMSSRD had macular atrophy caused by myopic macular neovascularization. In the five eyes they had progressed to MHRD, the retinal detachment started away from the macular atrophy. Among the 10 eyes which required surgery, there was no significant difference in the presurgical and postsurgical best-corrected visual acuity between the eyes operated because of a worsening of the EMSSRD and the eyes operated because of a progression to MHRD.In severely myopic eyes with macular neovascularization-related macular atrophy, a novel condition termed EMSSRD can be present. The optical coherence tomography images resemble those of a MHRD except the presence of thin remnants of the retina remaining on the retinal pigment epithelium.

We examined the microsatellite instability of duodenal tumors to evaluate their molecular features associated with the adenoma-carcinoma sequence.Fifty-two non-ampullary duodenal epithelial tumors collected by endoscopic mucosal resection or surgical resection were studied. When a tumor had two or more dysplasia grades, the highest grade was considered. Representative areas were macro-dissected and subjected to a microsatellite instability analysis and immunohistochemical staining.The 52 tumors were classified as either adenoma with low-grade dysplasia (n = 18), adenoma with high-grade dysplasia (n = 20), or adenocarcinomas (n = 14). Among these, 3 adenocarcinoma cases showed microsatellite instability and the remaining 49 tumors showed microsatellite stability. Of the 14 adenocarcinoma cases, 3 contained both high-grade dysplasia and adenocarcinoma components, and 11 contained only the adenocarcinoma component. Interestingly, all three adenocarcinoma + high-grade dysplasia cases were microsatellite instability-high in both the adenocarcinoma and high-grade dysplasia components. Immunohistochemical staining of mismatch repair proteins showed mismatch repair deficiency in three microsatellite instability-high adenocarcinoma + high-grade dysplasia cases.Only adenocarcinoma cases with high-grade dysplasia components were microsatellite instability-high (in both the adenocarcinoma and high-grade dysplasia components). This suggests that microsatellite instability in the high-grade dysplasia component of duodenal adenoma is associated with progression to adenocarcinoma.

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the “cancer stem cell” (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221–reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.Significance:These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.

Mutational repertoire of the two colon cancer PDX lines used in this study.

Skin barrier dysfunction in the setting of atopic dermatitis (AD) leads to cutaneous allergen sensitization (CAS).1 The atopic march hypothesis proposes that CAS leads to the subsequent development of other allergic disorders such as asthma and food allergy.2-5 The latter is associated with IgE-mediated anaphylaxis6. However, the precise mechanisms by which CAS promotes IgE-mediated allergic responses remain unclear. We thus established a CAS model of anaphylaxis and identified a unique role of the Interleukin (IL)-13 signal in DCs to generate anaphylactic IgE responses. Single-cell RNA-seq revealed the emergence of IL-13 receptor alpha 1 chain (IL-13Rα1)-expressing type 2 conventional dendritic cells (cDC2s) in CAS. Similar DC populations were identified in allergic rhinitis humans with cedar pollan-specific IgE antibodies. Lineage-specific disruption of IL-13 signaling resulted in a marked reduction in cDC2s that highly expressed MHC class II: these cells controlled the germinal center entry of TFH cells required for IgE responses. These data reveal a unique role for IL-13 in controlling the expansion of MHCIIhi cDC2s and associated TFH cell responses in the setting of allergy.

Detailed description of materials and methods, together with Table S1 which shows a list of the oligonucleotide primers used.

Supplemental Material and Methods

Clinical and pathological characteristics of the primary tumors and PDX tumors.

Suppression of the organoid-forming capacities of HCT116 cells by QKI-5.

Detailed description of gene mutations of the two PDX lines.

Table S1 The antibodies used in this study Table S2 The specific Primer sequences used for real-time PCR Table S3 TCRbeta deep sequencing of OVA-tetramer+ CD8 T cells in spleen and TIL

A. Representative images of organoids. B. Effect of miR-221 knockdown on the expression levels of stem cell-related genes.

Gating strategy for the purification of distinct subtypes of epithelial cells in the mouse colon.

Supplementary Figure Legends

Expression level of miR-221 in the Lgr5+/Kit- mouse colon epithelial cells.

Figure S1. Characterization of aAVC-OVA Figure S2. Analysis of T cells in spleen and TIL after immunization of tumor-bearing mice with aAVC-OVA Figure S3. Phagocytosis and maturation of splenic dendritic cells after administration of aAVCs Figure S4. Confirmation of depletion of the XCR1+ subset of DCs in DT-treated XCR1-DTR-venus mice. Figure S5. Induction of an OVA-specific T cell response by aAVC-OVA in a dose-dependent manner

Accurate tumor stage diagnosis during laparoscopic surgery remains difficult. We clarify the impact of new diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for colorectal cancer compared with other strategies.We defined angiogenesis (Ag) and fibrosis (Fib) grades using NBI laparoscopy (lap-NBI), and assessed the clinicopathological features associated with these grades for 67 patients with colorectal cancer who underwent surgery. We assessed vessel density and gray scale with computer software.NBI-Ag-grade and NBI-Fib-grade of the serosal surface of cancer lesions and peritoneal nodules correlated with vessel density and gray scale of those assessed by Image J computer software. NBI-Fib-grades of liver nodules also correlated with gray scale. NBI-Ag- grade and Fib-grade of the serosal surface of cancer lesions correlated with pathological depth of invasion. These NBI grades of pathological metastatic peritoneal nodules were higher than those of pathologically benign peritoneal nodules. NBI- Fib grades of pathological metastatic liver nodules were higher than those of pathologically benign liver nodules. In multivariate analysis, lap-NBI was associated with different diagnosis for T3, T4 and non-T3, and non-T4. Moreover, lap-NBI was associated with different diagnosis for T4 and non-T4. Predictive value for T4 by lap-NBI showed high sensitivity (85%) specificity (87%), positive predictive value (74%), negative predictive value (93%), and overall accuracy (87%). Sensitivity and overall accuracy of lap-NBI was superior to that of other diagnostic modalities.We clarified the usefulness of the new diagnostic strategy using lap-NBI during laparoscopic surgery for colorectal cancer in comparison with other strategies.

The aim of this study was to determine the efficacy and the biomarkers of the CHP-NY-ESO-1 vaccine complexed with full-length NY-ESO-1 protein and a cholesteryl pullulan (CHP) in patients with esophageal squamous cell carcinoma (ESCC) after surgery. We conducted a randomized phase II trial. Fifty-four patients with NY-ESO-1-expressing ESCC who underwent radical surgery following cisplatin/5-fluorouracil-based neoadjuvant chemotherapy were assigned to receive either CHP-NY-ESO-1 vaccination or observation as control. Six doses of CHP-NY-ESO-1 were administered subcutaneously once every two weeks, followed by nine more doses once every four weeks. The endpoints were disease-free survival (DFS) and safety. Exploratory analysis of tumor tissues using gene-expression profiles was also performed to seek the biomarker. As there were no serious adverse events in 27 vaccinated patients, we verified the safety of the vaccine. DFS in 2 years were 56.0% and 58.3% in the vaccine arm and in the control, respectively. Twenty-four of 25 patients showed NY-ESO-1-specific IgG responses after vaccination. Analysis of intra-cohort correlations among vaccinated patients revealed that 5% or greater expression of NY-ESO-1 was a favorable factor. Comprehensive analysis of gene expression profiles revealed that the expression of the gene encoding polymeric immunoglobulin receptor (PIGR) in tumors had a significantly favorable impact on outcomes in the vaccinated cohort. The high PIGR-expressing tumors that had higher NY-ESO-1-specific IgA response tended to have favorable prognosis. These results suggest that PIGR would play a major role in tumor immunity in an antigen-specific manner during NY-ESO-1 vaccinations. The IgA response may be relevant.

After the new molecular-based classification was reported to be useful for predicting prognosis, the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign has gained interest as one of the promising methods for detecting lower grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutations and chromosome 1p/19q non-codeletion (IDH mut-Noncodel) with high specificity. Although all institutions could use T2-FLAIR mismatch sign without any obstacles, this sign was not completely helpful because of its low sensitivity. In this study, we attempted to uncover the mechanism of T2-FLAIR mismatch sign for clarifying the cause of this sign's low sensitivity. Among 99 patients with LGGs, 22 were T2-FLAIR mismatch sign-positive (22%), and this sign as a marker of IDH mut-Noncodel showed a sensitivity of 55.6% and specificity of 96.8%. Via pathological analyses, we could provide evidence that not only microcystic changes but the enlarged intercellular space was associated with T2-FLAIR mismatch sign (p = 0.017). As per the molecular analyses, overexpression of mTOR-related genes (m-TOR, RICTOR) were detected as the molecular events correlated with T2-FLAIR mismatch sign (p = 0.020, 0.030. respectively). Taken together, we suggested that T2-FLAIR mismatch sign could pick up the IDH mut-Noncodel LGGs with enlarged intercellular space or that with overexpression of mTOR-related genes.

The mammalian blastocyst consists of three distinct cell types: epiblast, trophoblast (TB), and primitive endoderm (PrE). Although embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) retain the functional properties of epiblast and TB, respectively, stem cells that fully recapitulate the developmental potential of PrE have not been established. Here, we report derivation of primitive endoderm stem cells (PrESCs) in mice. PrESCs recapitulate properties of embryonic day 4.5 founder PrE, are efficiently incorporated into PrE upon blastocyst injection, generate functionally competent PrE-derived tissues, and support fetal development of PrE-depleted blastocysts in chimeras. Furthermore, PrESCs can establish interactions with ESCs and TSCs and generate descendants with yolk sac–like structures in utero. Establishment of PrESCs will enable the elucidation of the mechanisms for PrE specification and subsequent pre- and postimplantation development.

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2−/− mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b−/− and Fcgr2b+/− mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.

Antiviral lignin was produced by acidic microwave glycerolysis of sugarcane bagasse. The lignin exhibited antiviral activity against nonenveloped (encephalomyocarditis virus (EMCV) and Theiler's murine encephalomyelitis virus (TMEV)) and enveloped (vesicular stomatitis virus (VSV), Sindbis virus (SINV), and Newcastle disease virus (NDV)) viruses. A series of lignins with different antiviral activities were prepared by reacting bagasse at 140, 160, 180, and 200 °C to analyze the antiviral mechanism. No difference in ζ-potential was observed among the lignin preparations; however, the lignin prepared at 200 °C (FR