Identification of Ppy-lineage cells as a novel origin of pancreatic ductal adenocarcinoma.

The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP- or γ-cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the Rosa26 locus, which is expressed upon Ppy-promoter-mediated Cre-loxP recombination. Whereas Insulin1-CreERT-mediated TAg expression in beta cells resulted in insulinoma, surprisingly, Ppy-Cre-mediated TAg expression resulted in the malignant transformation of Ppy-lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct-like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks of age, suggesting that PDAC can originate from the islet/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA-sequencing analysis of Ppy-lineage islet cells from 7-day-old TAg+ mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in Ppy-lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy-lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identifying key factors for predicting O6-Methylguanine-DNA methyltransferase status in adult patients with diffuse glioma: a multimodal analysis of demographics, radiomics, and MRI by variable Vision Transformer.

PURPOSE: This study aimed to perform multimodal analysis by vision transformer (vViT) in predicting O6-methylguanine-DNA methyl transferase (MGMT) promoter status among adult patients with diffuse glioma using demographics (sex and age), radiomic features, and MRI. METHODS: The training and test datasets contained 122 patients with 1,570 images and 30 patients with 484 images, respectively. The radiomic features were extracted from enhancing tumors (ET), necrotic tumor cores (NCR), and the peritumoral edematous/infiltrated tissues (ED) using contrast-enhanced T1-weighted images (CE-T1WI) and T2-weighted images (T2WI). The vViT had 9 sectors; 1 demographic sector, 6 radiomic sectors (CE-T1WI ET, CE-T1WI NCR, CE-T1WI ED, T2WI ET, T2WI NCR, and T2WI ED), 2 image sectors (CE-T1WI, and T2WI). Accuracy and area under the curve of receiver-operating characteristics (AUC-ROC) were calculated for the test dataset. The performance of vViT was compared with AlexNet, GoogleNet, VGG16, and ResNet by McNemar and Delong test. Permutation importance (PI) analysis with the Mann-Whitney U test was performed. RESULTS: The accuracy was 0.833 (95% confidence interval [95%CI]: 0.714-0.877) and the area under the curve of receiver-operating characteristics was 0.840 (0.650-0.995) in the patient-based analysis. The vViT had higher accuracy than VGG16 and ResNet, and had higher AUC-ROC than GoogleNet (p<0.05). The ED radiomic features extracted from the T2-weighted image demonstrated the highest importance (PI=0.239, 95%CI: 0.237-0.240) among all other sectors (p<0.0001). CONCLUSION: The vViT is a competent deep learning model in predicting MGMT status. The ED radiomic features of the T2-weighted image demonstrated the most dominant contribution.

Distant recurrence in the cerebellar dentate nucleus through the dentato-rubro-thalamo-cortical pathway in supratentorial glioma cases.

BACKGROUND: Distant recurrence can occur by infiltration along white matter tracts or dissemination through the cerebrospinal fluid (CSF). This study aimed to clarify the clinical features and mechanisms of recurrence in the dentate nucleus (DN) in patients with supratentorial gliomas. Based on the review of our patients, we verified the hypothesis that distant DN recurrence from a supratentorial lesion occurs through the dentato-rubro-thalamo-cortical (DRTC) pathway. METHODS: A total of 380 patients with supratentorial astrocytoma, isocitrate dehydrogenase (IDH)-mutant (astrocytoma), oligodendroglioma, IDH mutant and 1p/19q-codeleted (oligodendroglioma), glioblastoma, IDH-wild type (GB), and thalamic diffuse midline glioma, H3 K27-altered (DMG), who underwent tumor resection at our department from 2009 to 2022 were included in this study. Recurrence patterns were reviewed. Additionally, clinical features and magnetic resonance imaging findings before treatment, at the appearance of an abnormal signal, and at further progression due to delayed diagnosis or after salvage treatment of cases with recurrence in the DN were reviewed. RESULTS: Of the 380 patients, 8 (2.1%) had first recurrence in the DN, 3 were asymptomatic when abnormal signals appeared, and 5 were diagnosed within one month after the onset of symptoms. Recurrence in the DN developed in 8 (7.4%) of 108 cases of astrocytoma, GB, or DMG at the frontal lobe or thalamus, whereas no other histological types or sites showed recurrence in the DN. At the time of the appearance of abnormal signals, a diffuse lesion developed at the hilus of the DN. The patterns of further progression showed that the lesions extended to the superior cerebellar peduncle, tectum, tegmentum, red nucleus, thalamus, and internal capsule along the DRTC pathway. CONCLUSION: Distant recurrence along the DRTC pathway is not rare in astrocytomas, GB, or DMG at the frontal lobe or thalamus. Recurrence in the DN developed as a result of the infiltration of tumor cells through the DRTC pathway, not dissemination through the CSF.

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (-)-sandaracopimaradiene in the fungus Arthrinium sacchari.

Labdane-related diterpenoids (LRDs) in fungi are a pharmaceutically important, but underexplored family of natural products. In the biosynthesis of fungal LRDs, bifunctional terpene cyclases (TCs) consisting of αßγ domains are generally used to synthesize the polycyclic skeletones of LRDs. Herein, we conducted genome mining of LRDs in our fungal genome database and identified a unique pair of TCs, AsPS and AsCPS, in the fungus Arthrinium sacchari. AsPS consists of catalytically active α and inactive ß domains, whereas AsCPS contains ßγ domains and a truncated α domain. Heterologous expression in Aspergillus oryzae and biochemical characterization of recombinant proteins demonstrated that AsCPS synthesized copalyl diphosphate and that AsPS then converted it to (-)-sandaracopimaradiene. Since AsPS and AsCPS have distinct domain organizations from those of known fungal TCs and are likely generated through fusion or loss of catalytic domains, our findings provide insight into the evolution of TCs in fungi.

Identification and Functional Characterization of Fungal Chalcone Synthase and Chalcone Isomerase.

By mining fungal genomic information, a noncanonical iterative type I PKS fused with an N-terminal adenylation-thiolation didomain, which catalyzes the formation of naringenin chalcone, was found. Structural prediction and molecular docking analysis indicated that a C-terminal thioesterase domain was involved in the Claisen-type cyclization. An enzyme responsible for formation of (2S)-flavanone in the biosynthesis of fungal flavonoids was also identified. Collectively, these findings demonstrate unprecedented fungal biosynthetic machinery leading to plant-like metabolites.

The Biosynthetic Landscape of Triceptides Reveals Radical SAM Enzymes That Catalyze Cyclophane Formation on Tyr- and His-Containing Motifs.

Peptide-derived cyclophanes inhabit a unique niche in the chemical space of macrocyclic peptides with several examples of pharmaceutical importance. Although both synthetic and biocatalytic methods are available for constructing these macrocycles, versatile (bio)catalysts able to incorporate a variety of amino acids that compose the macrocycle would be useful for the creation of diverse peptide cyclophanes. In this report, we synergized the use of bioinformatic tools to map the biosynthetic landscape of radical SAM enzymes (3-CyFEs) that catalyze three-residue cyclophane formation in the biosynthesis of a new family of RiPP natural products, the triceptides. This analysis revealed 3940 (3113 unique) putative precursor sequences predicted to be modified by 3-CyFEs. Several uncharacterized maturase systems were identified that encode unique precursor types. Functional studies were carried out in vivo in Escherichia coli to identify modified precursors containing His and Tyr residues. NMR analysis of the products revealed that Tyr and His can also be incorporated into cyclophane macrocycles by 3-CyFEs. Collectively, all aromatic amino acids can be incorporated by 3-CyFEs, and the cyclophane formation strictly occurs via a C(sp2)-C(sp3) cross-link between the (hetero)aromatic ring to Cß. In addition to 3-CyFEs, we functionally validated an Fe(II)/α-ketoglutarate-dependent hydroxylase, resulting in ß-hydroxylated residues within the cyclophane rings. This study reveals the potential breadth of triceptide precursors and a systematic approach for studying these enzymes to broaden the diversity of peptide macrocycles.

Synthetic Biology-Based Discovery of Diterpenoid Pyrones from the Genome of Eupenicillium shearii.

Diterpenoid pyrones are a type of mainly fungal meroterpenoid metabolite consisting of a diterpene connected to a pyrone, some of which show potent bioactivity. Through genome mining and heterologous expression, nine new diterpenoid pyrones, shearones A-I (1-9), were discovered from the fungus Eupenicillium shearii IFM 42152, and their biosynthetic enzyme activities were revealed. Some of these heterologously biosynthesized diterpenoid pyrones exhibited moderate antiaggregative ability against amyloid ß42 in vitro.

Preoperative Endovascular Embolization in an Easily Bleeding Respiratory Epithelial Adenomatoid Hamartoma of the Olfactory Cleft: A Case Report.

Respiratory epithelial adenomatoid hamartomas (REAHs) are rare tumors occurring in the nasal cavity and sinuses, and their etiology is unknown. REAH is a relatively recently established lesion and is often misdiagnosed as nasal polyposis or other tumors. Preoperative endovascular embolization for sinonasal tumors is now widely accepted as an effective method to reduce blood loss, soften the tumor, and facilitate surgical procedures. However, to the best of our knowledge, there are no reports of the requirement for preoperative embolization in the management of REAH. Here, we present a 70-year-old man with an easily bleeding REAH of the olfactory cleft, vascularized by branches of the bilateral internal and external carotid arteries. We removed the tumor endoscopically after preoperative embolization of the bilateral sphenopalatine arteries. Histological investigation revealed an intratumoral hemorrhage accompanying the REAH, with no evidence of a residual or recurrent tumor during the last follow-up at 3 months. In conclusion, accurate preoperative diagnosis and proper preoperative interventions such as embolization are needed for safe and adequate treatment of REAHs that have an abundant blood flow.

Correction: Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina.

Correction for 'Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina' by Yohei Morishita et al., Org. Biomol. Chem., 2020, DOI: 10.1039/d0ob00519c.

Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina.

A synthetic biology approach based on genome mining and heterologous biosynthesis is a powerful tool for discovering novel natural products from a tremendous gene resource. We carried out fungal genome mining guided by a polyketide synthase gene using a public database and found a putative macrolide biosynthetic gene cluster with a highly reducing polyketide synthase gene and a thioesterase gene in Macrophomina phaseolina. Reconstitution of the cluster in Aspergillus oryzae, a model heterologous host for fungal natural product biosynthesis, produced a new 12-membered macrolide, phaseolide A. The absolute stereochemistry was elucidated by vibrational circular dichroism spectroscopy and the crystalline sponge method.

Post-genomic approach based discovery of alkylresorcinols from a cricket-associated fungus, Penicillium soppi.

Polyketide synthase (PKS) gene-guided genome mining in a cricket-associated fungus, Penicillium soppi, revealed a cryptic biosynthetic gene cluster that contained a highly reducing PKS (HR-PKS), a type III PKS, and a P450 gene. Heterologous expression of the cluster in Aspergillus oryzae led to the isolation of novel alkylresorcinols with a unique Z,E,Z-triene motif. This study displays an unusual biosynthetic mechanism of an HR-PKS and a new releasing mechanism via a type III PKS in fungi.

Use of plant hormones to activate silent polyketide biosynthetic pathways in Arthrinium sacchari, a fungus isolated from a spider.

Plant hormones were evaluated for their ability to activate fungal secondary metabolite production. Three synthetic cytokinins, kinetin, 6-benzylaminopurine, and forchlorfenuron, showed remarkable enhancement of the production of aromatic polyketides derived from emodin in a fungus, Arthrinium sacchari, and allowed us to isolate a new polyketide. Furthermore, we firstly demonstrated the potential of plant hormones to activate a wide range of fungal secondary metabolite production processes.

Atrophy of the ipsilateral mammillary body in unilateral hippocampal sclerosis shown by thin-slice-reconstructed volumetric analysis.

PURPOSE: Conventional volumetric analysis could not detect ipsilateral atrophy of the mammillary body in patients with unilateral hippocampal sclerosis. By using thin-slice-reconstructed volumetric analysis, we investigated whether the mammillary body volume is smaller on the hippocampal sclerosis side than in healthy subjects or the non-hippocampal sclerosis side. METHODS: This retrospective study included 45 patients with unilateral hippocampal sclerosis and 30 healthy subjects. Three-dimensional T1WI of 1 mm thicknesses were oversampled to a thickness of 0.2 mm (thin-slice-reconstructed images), and the mammillary bodies were segmented manually to determine mammillary body volume on each side. Mammillary body volumes on the hippocampal sclerosis side were compared with those in healthy subjects or the non-hippocampal sclerosis side. RESULTS: In patients with right hippocampal sclerosis, right mammillary body volume was both significantly smaller than that in healthy subjects (30.3 ± 10.3 vs. 43.3 ± 8.07 mm3, P < 0.001) and significantly smaller than the left mammillary body volume in each patient (30.3 ± 10.3 vs. 41.4 ± 10.1 mm3, P < 0.001). Similarly, in patients with left hippocampal sclerosis, left mammillary body volume was both significantly smaller than that in healthy subjects (37.7 ± 11.2 vs. 47.0 ± 8.65 mm3, P < 0.001) and significantly smaller than right mammillary body volume in each patient (37.7 ± 11.2 vs. 42.5 ± 7.78 mm3, P = 0.044). CONCLUSIONS: In this study, thin-slice-reconstructed volumetric analysis showed that, in patients with unilateral hippocampal sclerosis, mammillary body volume on the hippocampal sclerosis side is smaller than that in healthy subjects and the non-hippocampal sclerosis side.

A Lanthipeptide-like N-Terminal Leader Region Guides Peptide Epimerization by Radical SAM Epimerases: Implications for RiPP Evolution.

Ribosomally synthesized and posttranslationally modified peptide natural products (RiPPs) exhibit diverse structures and bioactivities and are classified into distinct biosynthetic families. A recently reported family is the proteusins, with the prototype members polytheonamides being generated by almost 50 maturation steps, including introduction of d-residues at multiple positions by an unusual radical SAM epimerase. A region in the protein-like N-terminal leader of proteusin precursors is identified that is crucial for epimerization. It resembles a precursor motif previously shown to mediate interaction in thioether bridge-formation in class I lanthipeptide biosynthesis. Beyond this region, similarities were identified between proteusin and further RiPP families, including class I lanthipeptides. The data suggest that common leader features guide distinct maturation types and that nitrile hydratase-like enzymes are ancestors of several RiPP classes.

Predicting isocitrate dehydrogenase status among adult patients with diffuse glioma using patient characteristics, radiomic features, and magnetic resonance imaging: Multi-modal analysis by variable vision transformer.

OBJECTIVES: To evaluate the performance of the multimodal model, termed variable Vision Transformer (vViT), in the task of predicting isocitrate dehydrogenase (IDH) status among adult patients with diffuse glioma. MATERIALS AND METHODS: vViT was designed to predict IDH status using patient characteristics (sex and age), radiomic features, and contrast-enhanced T1-weighted images (CE-T1WI). Radiomic features were extracted from each enhancing tumor (ET), necrotic tumor core (NCR), and peritumoral edematous/infiltrated tissue (ED). CE-T1WI were split into four images and input to vViT. In the training, internal test, and external test, 271 patients with 1070 images (535 IDH wildtype, 535 IDH mutant), 35 patients with 194 images (97 IDH wildtype, 97 IDH mutant), and 291 patients with 872 images (436 IDH wildtype, 436 IDH mutant) were analyzed, respectively. Metrics including accuracy and AUC-ROC were calculated for the internal and external test datasets. Permutation importance analysis combined with the Mann-Whitney U test was performed to compare inputs. RESULTS: For the internal test dataset, vViT correctly predicted IDH status for all patients. For the external test dataset, an accuracy of 0.935 (95% confidence interval; 0.913-0.945) and AUC-ROC of 0.887 (0.798-0.956) were obtained. For both internal and external test datasets, CE-T1WI ET radiomic features and patient characteristics had higher importance than other inputs (p < 0.05). CONCLUSIONS: The vViT has the potential to be a competent model in predicting IDH status among adult patients with diffuse glioma. Our results indicate that age, sex, and CE-T1WI ET radiomic features have key information in estimating IDH status.

Human papillomavirus-related multiphenotypic sinonasal carcinoma.

Human papillomavirus-related multiphenotypic sinonasal carcinoma (HMSC) is a rare primary tumor of the sinonasal tract that has been reported recently. It is reportedly associated with human papillomavirus infection. The tumor presents with glandular cyst-like histology, but some cases exhibit squamous epithelialization and are positive on p16 immunohistochemical staining. The clinical picture and treatment of this disease have not been established. However, this report describes a recurrent case of this disease treated with salvage surgery. The patient was a 61-year-old woman who presented to the previous doctor with a chief complaint of nasal obstruction. A localized tumor was found in the left nasal cavity and was resected under endoscopic guidance. The postoperative pathological diagnosis was HMSC. Twenty-one months after the surgery, local recurrence was observed, and the patient was referred to our hospital. Since the recurrent lesion had widely infiltrated outside the nasal cavity, extensive resection and reconstructive surgery were performed. Postoperative radiotherapy was performed as an additional treatment. Notably, 13 months have passed since the salvage surgery, and no recurrence has been observed to date.

Imaging findings of arrested pneumatisation and differentiation from other skull base lesions.

OBJECTIVES: Arrested pneumatisation (AP) is an anatomic variant of the sphenoid sinus. Since AP remains underrecognised, otolaryngologists and radiologists may mistake AP for a lesion and perform follow-up imaging studies. We investigated the imaging findings of CT, MRI, and F-18 fludeoxyglucose (FDG)-positron emission tomography (PET) for AP, and discussed the differences between AP and other skull base lesions. METHODS: We reviewed multidetector low CT imaging of 442 patients (285 men and 157 women; age range, 19-93 years; mean age, 67.8 years) who underwent FDG-PET/CT for head and neck tumours between January 2019 and December 2019. The imaging findings of AP were reviewed on CT, MRI, FDG-PET/CT, and compared with those of fibrous dysplasia, chordoma, chondrosarcoma, multiple myeloma, and bone invasion of nasopharyngeal carcinoma. RESULTS: AP was identified in 22 patients (14 men and 8 women; age range, 24-93 years; mean age, 67.0 years) based on criteria from previous reports. AP manifested with well-circumscribed sclerotic margins on CT, without evidence of expansion. AP showed high-signal intensity on T1-/T2 weighted MRI. FDG-PET revealed non-significant uptake [maximum standardised uptake value (SUVmax): 0.85 (range, 0.4-1.27)] in AP. Contrastingly, skull base lesions showed expansion, poorly circumscribed boundaries without osteosclerotic margins, and moderate-to-severe FDG uptake (SUVmax: 1.8-8.4). CONCLUSIONS: The characteristic imaging findings of AP, namely non-expansile on CT and non-uptake on FDG-PET, may aid in its differentiation from other skull base lesions.

Discovery of a Cyclic Depsipeptide from Chaetomium mollipilium by the Genome Mining Approach.

Genome mining and bioinformatics analyses allowed us to rationally find a candidate biosynthetic gene cluster for a new cyclic depsipeptide of Chaetomium mollipilium. A heterologous reconstitution of the identified biosynthetic pathway predictably afforded a new cyclic depsipeptide composed of l-leucine, l-tryptophan, and a polyketide moiety. Interestingly, the 10-membered macrocycle structure generated equilibrium to an unprecedented cyclol structure. This study demonstrates the advantage of a synthetic biology method in achieving rational access to new natural products.

A case of Epstein-Barr virus-positive mucocutaneous ulcer of the hypopharynx: a mimicker of hypopharyngeal squamous cell carcinoma.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a new disease, described by the World Health Organization in 2017. It has been recognized as a specific type of immunodeficiency-associated lymphoproliferative disorder. Since patients with EBVMCU present with only cutaneous or mucosal ulcers, it is difficult to clinically distinguish them from carcinoma. A 72-year-old man, who took methotrexate (MTX) (12 mg/week) for rheumatoid arthritis, was referred to our hospital because endoscopy revealed an ulcerated mass in the left pyriform sinus, suggesting hypopharyngeal squamous cell carcinoma. Contrast-enhanced computed tomography and magnetic resonance imaging revealed an ill-defined mass in the left pyriform sinus without lymphadenopathy in the head and neck region. A biopsy of the ulcerative lesion in the hypopharynx was performed, and lymphoproliferative disease was suspected, based on the histopathological findings. Two weeks after MTX withdrawal, the lesions in the hypopharynx disappeared. The patient was diagnosed with EBVMCU, based on the clinical and histopathological findings. This is the first case report of EBVMCU of the hypopharynx. EBVMCU should be considered as a differential diagnosis in immunocompromised patients with hypopharyngeal mucosal ulcers without lymph node or organ involvement.

Is elective neck dissection necessary for patients with cT3-4N0 parotid gland cancer?

OBJECTIVE: Management of the cervical lymph nodes in patients with cT3-4N0 parotid gland cancer (PGC) has been controversial. This study investigated the need for elective neck dissection (END) in patients with cT3-4N0 PGC. METHODS: We retrospectively examined cervical lymph node metastasis, overall survival (OS), and disease-free survival (DFS) rates in 40 patients with cT3-4N0 PGC according to whether or not END was performed. RESULTS: Cervical lymph node metastasis occurred in 27.5% of patients and level II was the most common area. Recurrence could be treated by salvage neck dissection. There was no significant difference in OS (P=0.581) or DFS (P=0.728) between the group that underwent END and the group that did not. CONCLUSION: END at level II is worth performing because of the occult lymph node metastasis rate. The area of neck dissection should be limited because there is no evidence that END improves the prognosis of cT3-4N0 PGC.