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Background Transcriptional enhancers usually, but not always, regulate genes within the same topologically associating domain (TAD). We hypothesize that this incomplete insulation is partially due to three-dimensional structures of corresponding chromatin domains in individual cells: whereas enhancers and genes buried inside the core of a domain interact mostly with other regions in the same domain, those on the surface can more easily interact with the outside. Results Here we show that a simple measure, the intra-TAD ratio, can quantify the coreness of a region with respect to the single-cell domains to which it belongs. We show that domain surfaces are permissive for high gene expression. Cell type-specific active cis-regulatory elements, active histone marks, and transcription factor binding sites are enriched on domain surfaces, most strongly in chromatin subcompartments typically considered inactive. Conclusions These findings suggest a model of gene regulation that involves positioning active cis-regulatory elements on domain surfaces. We also find that disease-associated non-coding variants are enriched on domain surfaces.

The novel SARS-CoV-2 Omicron variant may increase the risk of re-infection and vaccine breakthrough infections as it possesses key mutations in the spike protein that affect neutralizing antibody response. Most studies on neutralization susceptibility were conducted using specimens from adult COVID-19 patients or vaccine recipients. However, since the paediatric population has an antibody response to SARS-CoV-2 infection that is distinct from the adult population, it is critical to assess the neutralization susceptibility of pediatric serum specimens. This study compared the neutralization susceptibility of serum specimens collected from 49 individuals of <18 years old, including 34 adolescent BNT162b2 (Pfizer-BioNTech) vaccine recipients, and 15 recovered COVID-19 patients aged between 2 and 17. We demonstrated that only 38.2% of BNT162b2 vaccine recipients and 26.7% of recovered COVID-19 patients had their serum neutralization titre at or above the detection threshold in our live virus microneutralization assay. Furthermore, the neutralizing antibody titer against the Omicron variant was substantially lower than those against the ancestral virus or the Beta variant. Our results suggest that vaccine recipients and COVID-19 patients in the pediatric age group will likely be more susceptible to vaccine breakthrough infections or reinfections due to the Omicron variant than previous variants.

PurposeSETD2 is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize SETD2 alterations in PT.MethodsIn this study, we examined the alterations of SETD2 gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed.ResultsSETD2 mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly, SETD2 mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (p = .041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3.ConclusionsOur findings may suggest a potential involvement of epigenetic regulation via SETD2 alterations and downstream H3K36me3 on PT development. SETD2 mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of SETD2 in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions.

Spindle cell/sclerosing rbabdomyosarcoma (RMS) is a recently characterized variant of RMS with several distinct molecular subtypes. We describe an example occurring in the tongue of a 10-year-old boy with a novel DCTN1::ALK fusion. The tumor exhibited infiltrative growth and was comprised of fascicles and focally whorls of spindle cells with eosinophilic cytoplasm, in a collagenous or myxoid stroma. Moderate cytologic atypia, mitotic activity (2/10 HPFs), and perineural invasion were identified. The tumor cells expressed actin, desmin, MyoD1, myogenin, and ALK. An in-frame fusion between DCTN1 exon 26 and ALK exon 20 was detected by RNA sequencing, which was confirmed by split reads and supported by FISH studies. The tumor showed an indolent behavior with local recurrence 3 years after excision. This study broadens the molecular spectrum of spindle cell/sclerosing RMS and this molecular aberration may represent a potential therapeutic target for unresectable or disseminated disease.

Introduction The prognosis of pleomorphic carcinoma of the lung is poor with a propensity of metastasis and distant recurrence. The high intratumoral heterogeneity and variable morphologic composition of pleomorphic carcinomas lead to underdiagnosis in biopsy specimens from non-small cell carcinomas. This study aims to detail the p53 expression pattern in pleomorphic carcinoma and its role in biopsy assessment. Methods p53 immunostain was performed on a cohort of pleomorphic carcinoma resection and corresponding biopsy specimens, with TP53 sequencing performed on microdissected pleomorphic and non-pleomorphic components. Results A total of 30 cases were analyzed and non-pleomorphic components were identified in 11 cases. Aberrant p53 immunostain expression was seen in 24 (80%), consisting of 11 (36.7%) overexpression (≥ 90%) and 13 (43.3%) null patterns. The non-pleomorphic components showed concordant p53 expression with the pleomorphic components. All 11 corresponding biopsy specimens, and an additional adrenal metastatectomy, showed concordant aberrant p53 expression. Four cases were suitable for sequencing, and TP53 mutation was detected in all. In three cases, identical TP53 mutations (F134L, G245V and C227F) were found in the non-pleomorphic and pleomorphic components, with aberrant p53 staining. Concurrent EGFR mutation was seen in the case with C227F mutation. The remaining case showed different TP53 mutations in the non-pleomorphic (R342) and pleomorphic components (G245S with wild-typeimmunostain pattern. Conclusion TP53 mutation and aberrant p53 immunostain expression are consistently and concordantly observed in pleomorphic, non-pleomorphic components, metastatic and small biopsy specimens of pleomorphic carcinomas. There is value in performing p53 immunostain for diagnosing pleomorphic carcinoma in small specimens.

Background Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up‐regulate pro‐inflammatory cytokines and activate NF‐κB signaling. Meanwhile, the PIEZO1 upregulation and cancer‐associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. Methods The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF‐κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1‐CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co‐culture system and animal studies. Patient‐derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1‐YAP1‐CTGF cascade in GC. Results Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF‐κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF‐κB into YAP1 signaling, a well‐documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c‐Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen‐enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5‐FU in suppressing the GC cell peritoneal metastasis. Conclusion This study elucidates a novel driving PIEZO1‐YAP1‐CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori‐NF‐κB activates the PIEZO1‐YAP1‐CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1‐YAP1‐CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis. Description: 1. H. pylori induced NFκB directly regulates PIEZO1 transcription in gastric cancer (GC). 2. H. pylori prompts α‐SMA+ CAF accumulation in GC, driven by PIEZO1/YAP1/CTGF axis activation. 3. Enhanced microenvironment stiffness from augmented α‐SMA+ CAFs perpetuates PIEZO1 activation in a deleterious loop in GC. 4. Targeting CTGF with Procyanidin C1 emerges as a potential therapeutic strategy for H. pylori‐associated GC.

Nasopharyngeal carcinoma (NPC) is a peculiar Epstein Barr virus (EBV)-associated malignancy that is prevalent in South-East Asia. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) isomerizes specific phosphorylated amino acid residues, which makes it an important regulator in cell survival and apoptosis. In this study, we investigated the contribution made by PIN1 in NPC tumorigenesis and PIN1's potential role as a therapeutic target. The expression of PIN1 was examined in a panel of NPC cell lines, xenografts and primary tumors. The functional roles of PIN1 in NPC cells were elucidated by the knockdown and overexpression of PIN1 in in vitro and in vivo nude mice models by siRNA and lenti-viral transfection, respectively. The antitumor effects of the PIN1 inhibitor Juglone in NPC cells were also evaluated. We revealed the consistent overexpression of PIN1 in almost all EBV-associated NPC cell lines, xenografts and primary tumors. PIN1 suppression was capable of inhibiting cyclin D1 expression and activating caspase-3 in NPC cells. It positively regulated NPC cell proliferation, colony formation and anchorage-independent growth. The inhibition of PIN1 suppressed tumor growth in vitro and in vivo. This study demonstrates the oncogenic role of PIN1 in NPC tumorigenesis, and shows that its overexpression can enhance tumor cell growth via the upregulation of cyclinD1. Our findings inform the development of novel treatments targeting PIN1 for NPC patients.

Background Cancer‐associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro‐tumourigenic or anti‐tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single‐cell pan‐cancer scale has yet to be established. Methods We employed a comprehensive single‐cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single‐Cell Regulatory Network Inference and Clustering and single‐cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix‐producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments. Results In our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity. Conclusions Collectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for cancer treatment. 1. At the single‐cell level, we identified four CAF subtypes in 12 solid tumours: proCAF, iCAF, myCAF and matCAF. 2. Each subtype exhibited different evolutionary trajectories during cancer progression. 3. iCAF was markedly absent in ‘cold’ tumour types, which typically respond poorly to immunotherapy. 4. Signatures associated with matCAF were consistently correlated with unfavourable prognoses across various cancers.

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28–8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28–8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28–8 and SP263 assays. In conclusion, the 22C3, 28–8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.