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The shift toward a histo-molecular approach in World Health Organization classification of central nervous system tumors (WHO CNS5) emphasizes the critical role of molecular testing, such as next-generation sequencing (NGS) and DNA methylation profiling, for accurate diagnosis. However, implementing these advanced techniques is particularly challenging in resource-constrained countries. To address this, the Asian Oceanian Society of Neuropathology committee for Adapting Diagnostic Approaches for Practical Taxonomy in Resource-Restrained Regions (AOSNP-ADAPTR) was initiated to help pathologists in resource-limited regions to implement WHO CNS5 diagnoses using simpler diagnostic tools, mainly immunohistochemistry. An online survey by this group assessed the in-house/local availability of diagnostic resources and outsourcing capabilities across the Asian Oceanian region, covering 19 countries. Of 318 responding centers, the availability of molecular techniques in-house/locally was limited in lower middle-income countries (LMICs), with 29% having fluorescence in situ hybridization, 10.7% Sanger sequencing, and only 9.4% NGS. DNA methylation was largely unavailable in-house/locally in of LMICs, while in the whole region, its availability stood at a meager 4.4%. Though outsourcing for all diagnostic tests was an easily accessible alternative, outsourcing for NGS and DNA methylation was uncommon because of the financial burden on patients being a significant obstacle. The survey categorized centers into five resource levels (RLs) based on the in-house/local access to diagnostic techniques, which highlighted the variability and disparity in diagnostic capabilities across the region. High-income countries had 80% of centers with advanced RL IV, V resources, in contrast to LMICs, where 70.5% of centers fell into RL I-III. This comprehensive evaluation emphasizes the need for tailored resource level guidelines, with the aim of improving diagnostic accuracy and treatment as well as advocating better healthcare infrastructure in resource-constrained areas. However, the survey's reliance on responses from better-resourced centers may underestimate challenges in lower-resource settings, stressing the need for broader outreach and support., (© 2025 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

The latest World Health Organization (WHO) classification of central nervous system tumors (WHO2021/5th) has incorporated molecular information into the diagnosis of each brain tumor type including diffuse glioma. Therefore, an artificial intelligence (AI) framework for learning histological patterns and predicting important genetic events would be useful for future studies and applications. Using the concept of multiple-instance learning, we developed an AI framework named GLioma Image-level and Slide-level gene Predictor (GLISP) to predict nine genetic abnormalities in hematoxylin and eosin sections: IDH1/2 , ATRX , TP53 mutations, TERT promoter mutations, CDKN2A/B homozygous deletion (CHD), EGFR amplification ( EGFR amp), 7 gain/10 loss (7+/10-), 1p/19q co-deletion, and MGMT promoter methylation. GLISP consists of a pair of patch-level GLISP-P and patient-level GLISP-W models, each pair of which is for a genetic prediction task, providing flexibility in clinical utility. In this study, the Cancer Genome Atlas whole-slide images (WSIs) were used to train the model. A total of 108 WSIs from the Tokyo Women's Medical University were used as the external dataset. In cross-validation, GLISP yielded patch-level/case-level predictions with top performances in IDH1/2 and 1p/19q co-deletion with average areas under the curve (AUCs) of receiver operating characteristics of 0.75/0.79 and 0.73/0.80, respectively. In external validation, the patch-level/case-level AUCs of IDH1/2 and 1p/19q co-deletion detection were 0.76/0.83 and 0.78/0.88, respectively. The accuracy in diagnosing IDH-mutant astrocytoma, oligodendroglioma, and IDH-wild-type glioblastoma was 0.66, surpassing the human pathologist average of 0.62 (0.54-0.67). In conclusion, GLISP is a two-stage AI framework for histology-based prediction of genetic events in adult gliomas, which is helpful in providing essential information for WHO 2021 molecular diagnoses.

Oncostatin M (OSM) has pleiotropic effects on various inflammatory diseases, including kidney stone disease. The prevalence of kidney stones has increased worldwide, despite recent therapeutic advances, due to its high recurrence rate, suggesting the importance of prevention of repeated recurrence in the treatment of kidney stone disease. Using a mouse model of renal crystal formation, we investigated the preventive effects of blockade of OSM receptor β (OSMRβ) signaling on the development of kidney stone disease by treatment with a monoclonal anti-OSMRβ antibody that we generated. The anti-OSMRβ antibody abrogated OSM-induced phosphorylation of STAT3 and expression of crystal-binding molecules (Opn, Anxa1, Anxa2) and inflammation/fibrosis-associated molecules (Tnfa, Tgfb, Col1a2) in renal tubular epithelial cells and fibroblasts. In glyoxylate-injected mice, a mouse model of renal crystal formation, there was significant suppression of crystal deposits and expression of crystal-binding molecules (Opn, Anxa1, Anxa2), a tubular injury marker (Kim-1), and inflammation/fibrosis-associated molecules (Tnfa, Il1b, Mcp-1, Tgfb, Col1a2) in the kidneys of the anti-OSMRβ antibody-treated mice, compared with those in vehicle- or isotype control antibody-treated mice. In addition, treatment with the anti-OSMRβ antibody significantly decreased infiltrating macrophages and fibrosis in the kidneys. These findings suggest that anti-OSMRβ antibody-treatment may be effective in preventing kidney stone disease., Competing Interests: Declarations. Competing interests: T. Komori and Y. Morikawa are the inventors on a patent for the use of anti-OSMRβ antibody (7D2) in treatment of atopic dermatitis (US9475876B2; JP6214010). T. Komori, S. Yamashita, Y. Kohjimoto, I. Hara, and Y. Morikawa have a patent pending on the use of anti-OSMRβ antibody (7D2) in treatment of kidney stone disease. All other authors declare they have no conflict of interest., (© 2024. The Author(s).)

Purpose: To re-evaluate images recovered from JCOG0911, a randomized phase 2 trial for newly diagnosed glioblastoma (nGBM) conducted by the Japan Clinical Oncology Group (JCOG) Brain Tumor Study Group., Methods: The correlation between tumor volumes and survival was evaluated, followed by progression-free survival (PFS) analysis by independent central review based on Response Assessment in Neuro-Oncology (RANO) criteria using MRI recovered from 118 nGBM patients enrolled in the JCOG0911 trial. A radiomic analysis was also performed to identify radiomic features predictive of nGBM prognosis., Results: The distribution of the Gd-enhancing and T2-weighted image/fluid attenuated inversion recovery-high intensity lesions mainly occupied white matter. JCOG0911 consisted of more subjects with right-sided lesions. The median extent of resection of the Gd-enhancing lesions was 99%. The overall survival showed a nonsignificant negative trend with postoperative Gd-enhancing lesion volume (P = 0.22), with the hazard ratio increasing in parallel with its volume. The median PFS after registration was 302 and 308 days for local Response Evaluation Criteria in Solid Tumors (RECIST)-based and central RANO-based diagnoses. However, an apparent discrepancy was observed between the two in the early phase, presumably due to the misdiagnosis of pseudoprogression by local RECIST-based diagnosis. Radiomic analysis identified 28 radiomic features predictive of nGBM prognosis, 5 of which were those previously identified in a separate cohort. The constructed radiomics-based prognostic model stratified the cohort into high- and low-risk groups (P = 0.028)., Conclusion: Novel analytical methods that could be incorporated into future clinical trials were successfully tested. RANO and RECIST may not differ in progression calls if pseudoprogression is appropriately handled.

Background/objectives: On-site diagnosis of infection in their early stages requires assays with high sensitivities that are compact and easy to operate out of the laboratory and hospital environments. However, current assay technologies fall short of these requirements and require highly skilled technicians to set up, operate, and interpret the results., Methods: To address these challenges, we developed and evaluated a Point-of-Care-Testing (PoCT) immunoassay platform called the D-strip. The D-strip platform combines the capabilities of a digital enzyme-linked immunoassay (ELISA) with a lateral flow assay (LFA). The D-strip sample flow cell is composed of the same components found in conventional LFAs, and its high sensitivity is due to its efficient implementation of ELISA. The fully integrated platform is simple and requires minimal user intervention to operate., Results: The D-strip exhibited a sample-to-result time of 15 min with a limit of detection (LOD) of 1.7 × 10 3 copies/mL for severe acute respiratory syndrome coronavirus 2 (SARS-2-CoV) antigen. The LOD of the D-strip is 488-fold higher than that for conventional LFAs and is comparable to a clinical laboratory test., Conclusions: The D-strip is a compact and highly sensitive immunoassay platform with a strong potential for application as a confirmatory assay outside the clinical laboratory.

Adjuvant oxaliplatin plus capecitabine (XELOX) therapy is recommended for patients with curatively resected colon cancer. However, prospective data on its practical application in Japanese patients are limited. Therefore, we aimed to conduct a long-term clinical evaluation of the efficacy and safety of adjuvant XELOX in patients with curatively resected stage III colon cancer (MCSCO-1024). This prospective, multi-center, open-label, single-arm, phase II study enrolled patients with curatively resected stage III colon cancer. The treatment protocol consisted of a 120-minute intravenous infusion of oxaliplatin (130 mg/m 2 ) on day 1 and two divided doses oral capecitabine (2000 mg/m 2 /day) for 14 days in a 3-week cycle, totaling eight cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints were 5-year overall survival and long-term prognosis of peripheral sensory neuropathy. A total of 196 patients were enrolled between November 2011 and August 2014 (34 months). The 3-year DFS rate was 73%, and the 5-year overall survival rate was 87%. The overall incidence of peripheral sensory neuropathy was 17%, with a 1% rate of grade 3 neuropathy after 5 years. Adjuvant XELOX demonstrated utility and safety in the clinical management of Japanese patients with stage III colon cancer., (© 2024. The Author(s).)

This study aimed to determine the prevalence of lumbar ligamentum flavum lesions and identify correlations between radiological and pathological findings. We conducted an observational cross-sectional study of 349 patients (lumbar: n = 296, thoracic: n = 39, lumbar and thoracic: n = 14, mean age: 69 ± 12 years, male: 74%) who underwent posterior surgery for thoracolumbar spinal canal stenosis between January 2008 and April 2023 at our hospital.Computed tomography (CT) revealed that the prevalence of ligamentum flavum lesions defined as a high-density area with a CT value of 200 Hounsfield Unit or higher in the lumbar and thoracic spine was 47% (147/310) and 85% (45/53), respectively. CT showed that most patients had radiologically suspected ossification in the lumbar (90%) and thoracic spine (98%) than radiologically suspected calcification. Lumbar lesions were thinner than the thoracic lesions (2.5 vs 3.7 mm, p < 0.01). Pathological examinations were performed in specimens collected from 34 cases (lumbar: n = 13, thoracic: n = 21), and ossification was found in 62% (8/13) and 95% (20/21) of lumbar and thoracic lesions (p = 0.02), respectively. Lastly, ossification was confirmed pathologically in 72% (8/11) and 95% (19/20) of lumbar and thoracic lesions that showed ossification on imaging (p = 0.13), respectively. The literature review revealed that the prevalence of the lumbar ligamentum flavum lesions varied from 1.5 to 35% and the patient population was mostly asymptomatic.Collectively, we found that the prevalence of lumbar ligamentum flavum lesions in symptomatic patients was greater than previously reported. Histologically confirmed ossification was less common in lumbar lesions than in thoracic lesions.

A 59-year-old woman, after surgery for cubital tunnel syndrome, developed complex regional pain syndrome in her right upper limb. Spinal cord stimulation (SCS) electrodes were placed at the C2-C5 level. A conventional low-frequency tonic stimulation was carried out, which attenuated pain. However, 4 years later, left-sided motor weakness and tolerance to SCS therapy occurred. Magnetic resonance imaging revealed epidural granulation tissue around the electrodes that severely compressed the cervical cord. We surgically removed the granuloma, which attenuated motor weakness. A histological examination showed that an allergic reaction to platinum or the insulator appeared responsible for fibrosis., Competing Interests: None, (© 2024 The Japan Neurosurgical Society.)

Background: It remains unclear whether the newly adopted high-power, short-duration (HP-SD) setting in ablation for atrial fibrillation (AF) impacts periprocedural thrombotic markers or silent stroke (SS) onset., Objective: The aim of the present study was to investigate the clinical impact of HP-SD setting ablation on changes in periprocedural thrombotic markers and the onset of SS., Methods: We enrolled 101 AF patients: the HP-SD group (n = 67) using 50 W and the conventional ablation group (n = 34) using 30 to 40 W. D-dimer, thrombin-antithrombin complex (TAT), and total plasminogen activator inhibitor-1 (tPAI-1) were analyzed the day before, immediately after, and 1 day after the procedure. Magnetic resonance imaging was performed within 48 hours after the procedure., Results: Left atrial dwelling time was significantly shorter in the HP-SD group ( P < .05). In the conventional ablation group, the D-dimer and tPAI-1 levels continued to increase until 1 day postprocedure, while the TAT peaked immediately after the ablation. On the other hand, the range of the variation of these thrombotic markers in the HP-SD group was smaller. SS occurred more frequently in the conventional ablation group than in the HP-SD group (26% vs 5%, P < .05). In the logistic regression analysis, the HP-SD setting and TAT difference (postprocedure - preprocedure) were independent predictors for SS (odds ratios 0.141 and 5.838, respectively; P <  .05)., Conclusions: The HP-SD setting led to a shorter left atrial dwelling time and reduced change in thrombotic markers, resulting in lower prevalence of SS., (© 2024 Heart Rhythm Society. Published by Elsevier Inc.)

Aim: Adverse childhood experiences are potentially traumatic events with long-lasting effects on the health and well-being of patients with autism spectrum disorder (ASD). It is important to clarify which types of long-lasting autism-related symptoms are influenced by childhood experiences to design future intervention studies. However, few studies have examined the association between childhood experiences and autistic symptoms in large samples of adults with ASD and individuals with typical development (TD). In this study, we evaluate the effects of adverse childhood experiences on multiple ASD phenotypes among both individuals with ASD and those with TD., Method: We combined questionnaire evaluations; Childhood Abuse and Trauma Scale, the Japanese version of the Autism-Spectrum Quotient, Conners' Adult ADHD Rating Scale, the Japanese version of the Impact of Event Scale-Revised, and the Japanese version of the Adolescent/Adult Sensory Profile., Results: Individuals with ASD and those with TD (n = 205 and 104, respectively) were included. There were significant correlations between the extent of adverse childhood experiences and severity of attention-deficit/hyperactivity disorder symptoms, posttraumatic stress disorder symptoms, and hypersensitivity in both participants with ASD and those with TD. By contrast, ASD core symptoms showed no significant correlation with adverse childhood experiences in either group. These results remained consistent after adjusting for age, sex, and the estimated intelligence quotient., Conclusion: These findings suggest the need for a detailed disentanglement of ASD-related core and peripheral symptoms of adverse childhood experiences, which may help to appropriately set outcomes for future early interventions for the childhood experiences of individuals with ASD., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2 + osteoprogenitors become Runx2 + Sp7 + preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development.

Exosomes are extracellular vesicles involved in intercellular signaling, carrying various cargo from microRNAs to metabolites and proteins. They are released by practically all cells and are highly heterogenous due to their origin and content. Several groups of exosomes are known to be involved in various pathological conditions including autoimmune, neurodegenerative, and infectious diseases as well as cancer, and therefore a substantial understanding of their biogenesis and release is crucial. Polarized cells display an array of specific functions originated from differentiated membrane trafficking systems and could lead to hints in untangling the complex process of exosomes. Indeed, recent advances have successfully revealed specific regulation pathways for releasing different subsets of exosomes from different sides of polarized epithelial cells, underscoring the importance of polarized cells in the field. Here we review current evidence on exosome biogenesis and release, especially in polarized cells, highlight the challenges that need to be combatted, and discuss potential applications related to exosomes of polarized-cell origin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Komori and Fukuda.)

Background: Zinc finger-containing transcription factor Osterix/Specificity protein-7 (Sp7) is an essential transcription factor for osteoblast differentiation. However, its functions in differentiated osteoblasts remain unclear and the effects of osteoblast-specific Sp7 deletion on osteocytes have not been sufficiently studied., Methods: Sp7 floxneo/floxneo mice, in which Sp7 expression was 30 % of that in wild-type mice because of disturbed splicing by neo gene insertion, and osteoblast-specific knockout ( Sp7 fl/fl; Col1a1 -Cre ) mice using 2.3-kb Col1a1 enhanced green fluorescent protein (EGFP)-Cre were examined by micro-computed tomography (micro-CT), bone histomorphometry, serum markers, and histological analyses. The expression of osteoblast and osteocyte marker genes was examined by real-time reverse transcription (RT)-PCR analysis. Osteoblastogenesis, osteoclastogenesis, and regulation of the expression of collagen type I alpha 1 chain ( Col1a1 ) were examined in primary osteoblasts., Results: Femoral trabecular bone volume was higher in female Sp7 floxneo/floxneo and Sp7 fl/fl; Col1a1 -Cre mice than in the respective controls, but not in males. Bromodeoxyuridine (BrdU)-positive osteoblastic cells were increased in male Sp7 fl/fl; Col1a1 -Cre mice, and osteoblast number and the bone formation rate were increased in tibial trabecular bone in female Sp7 fl/fl; Col1a1 -Cre mice, although osteoblast maturation was inhibited in female Sp7 fl/fl; Col1a1 -Cre mice as shown by the increased expression of an immature osteoblast marker gene, secreted phosphoprotein 1 ( Spp1 ), and reduced expression of a mature osteoblast marker gene, bone gamma-carboxyglutamate protein/bone gamma-carboxyglutamate protein 2 ( Bglap/Bglap2 ). Furthermore, alkaline phosphatase activity was increased but mineralization was reduced in the culture of primary osteoblasts from Sp7 fl/fl; Col1a1 -Cre mice. Therefore, the accumulated immature osteoblasts in Sp7 fl/fl; Col1a1 -Cre mice was likely compensated for the inhibition of osteoblast maturation at different levels in males and females. Vertebral trabecular bone volume was lower in both male and female Sp7 fl/fl; Col1a1 -Cre mice than in the controls and the osteoblast parameters and bone formation rate in females were lower in Sp7 fl/fl; Col1a1 -Cre mice than in Sp7 fl/fl mice, suggesting differential regulatory mechanisms in long bones and vertebrae. The femoral cortical bone was thin and porous in Sp7 floxneo/floxneo and Sp7 fl/fl; Col1a1 -Cre mice of both sexes, the number of canaliculi was reduced, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL)-positive lacunae and the osteoclasts were increased, whereas the bone formation rate was similar in Sp7 fl/fl; Col1a1 -Cre and Sp7 fl/fl mice. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), a marker for bone formation, were similar, while those of tartrate-resistant acid phosphatase 5b (TRAP5b), a marker for bone resorption, were higher in Sp7 fl/fl; Col1a1 -Cre mice. Osteoblasts were less cuboidal, the expression of Col1a1 and Col1a1 -EGFP-Cre was lower in Sp7 fl/fl; Col1a1 -Cre mice, and overexpression of Sp7 induced Col1a1 expression., Conclusions: Our studies indicated that Sp7 inhibits the proliferation of immature osteoblasts, induces osteoblast maturation and Col1a1 expression, and is required for osteocytes to acquire a sufficient number of processes for their survival, which prevents cortical porosity., The Translational Potential of This Article: This study clarified the roles of Sp7 in differentiated osteoblasts in proliferarion, maturation, Col1a1 expression, and osteocyte process formation, which are required for targeting SP7 in the development of therapies for osteoporosis., Competing Interests: A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. The Editors of the Journal of Orthopaedic Translation strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest. The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024 The Authors.)

Background: Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD)., Methods: Mice were subjected to social isolation during postnatal days 21-35 (P21-P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression., Results: In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found., Conclusion: Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yamaguchi, Okamura, Yamamuro, Okumura, Komori, Toritsuka, Takada, Nishihata, Ikawa, Yamauchi, Makinodan, Yoshino, Saito, Matsuzaki, Kishimoto and Kimoto.)

The oral mucosa functions as a physico-chemical and immune barrier to external stimuli, and an adequate width of the keratinized mucosa around the teeth or implants is crucial to maintaining them in a healthy and stable condition. In this study, for the first time, bulk RNA-seq analysis was performed to explore the gene expression of laser microdissected epithelium and lamina propria from mice, aiming to investigate the differences between keratinized and non-keratinized oral mucosa. Based on the differentially expressed genes (DEGs) and Gene Ontology (GO) Enrichment Analysis, bone morphogenetic protein 2 (BMP-2) was identified to be a potential regulator of oral mucosal keratinization. Monoculture and epithelial-mesenchymal cell co-culture models in the air-liquid interface (ALI) indicated that BMP-2 has direct and positive effects on epithelial keratinization and proliferation. We further performed bulk RNA-seq of the ALI monoculture stimulated with BMP-2 in an attempt to identify the downstream factors promoting epithelial keratinization and proliferation. Analysis of the DEGs identified, among others, IGF2 , ID1 , LTBP1 , LOX , SERPINE1 , IL24 , and MMP1 as key factors. In summary, these results revealed the involvement of a well-known growth factor responsible for bone development, BMP-2, in the mechanism of oral mucosal keratinization and proliferation, and pointed out the possible downstream genes involved in this mechanism.

Background: APC and MUTYH are both well-known colorectal polyposis causative genes. However, 30-50% of colorectal adenomatous polyposis cases are classified as colonic adenomatous polyposis of unknown etiology and lack identifiable pathogenic variants. Although guidelines recommend total proctocolectomy for colonic adenomatous polyposis of unknown etiology with over 100 adenomas, evidence is lacking. This study presents a unique case of localized colonic adenomatous polyposis of unknown etiology with multiple adenocarcinomas, treated with hemicolectomy and regional lymph node dissection., Case Presentation: The patient was a 72-year-old woman whose colonoscopy revealed numerous polyps and two adenocarcinomas localized in the right side of the colon, with no lesions in the left side. The patient had no family history of polyposis or colorectal cancer. No extracolonic lesions, enlarged lymph nodes, or distant metastases were found. Considering the patient's age and lesion localization, laparoscopic right hemicolectomy with regional lymph node dissection was performed. Histopathological diagnosis revealed three adenocarcinoma lesions with no lymph node metastasis. The most advanced pathological stage was T2N0M0 Stage I (UICC 8th edition). The patient was alive 5 years postoperatively, without recurrence of cancer or polyposis in the remaining colon and rectum. To diagnose hereditary colorectal cancer/polyposis, a germline multigene panel testing for APC, EPCAM, MBD4, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, and TP53 was performed using DNA extracted from blood samples: however, no pathogenic variant was detected. Therefore, the patient was diagnosed with colonic adenomatous polyposis of unknown etiology., Conclusions: In this rare case, colonic adenomatous polyposis of unknown etiology, with numerous adenomatous polyps and multiple adenocarcinomas localized in the right side of the colon, was successfully treated with right hemicolectomy and regional lymph node dissection. Despite genetic analysis, no causative germline variants were identified. Segmental colectomy according to the distribution of polyps might be a curative approach., (© 2024. The Author(s).)

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics., (© 2024. The Author(s).)