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BackgroundWhile p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.ObjectiveThis study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.DesignWe used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r+ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.ResultsThe p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors’ organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.Conclusionsp53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

Tu et al. show that Tff2 corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. Tff2 corpus cells are TA progenitors that give rise to secretory cells. Tff2 progenitors, not chief cells, are the primary source of SPEM after injury. Kras-mutant Tff2 progenitors progress directly to dysplasia, bypassing metaplasia. Multi-omics analysis reveals distinct trajectories for SPEM and gastric cancer. Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using knockin mice, we identified highly proliferative Tff2 progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2 corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2 progenitors abrogated SPEM formation, while genetic ablation of GIF chief cells enhanced SPEM formation from Tff2 progenitors. In response to infection, Tff2 progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of Kras mutations in Tff2 progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2 progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified upregulation, and then verified its upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the mutation and β-adrenergic signaling, in part, through the MAPK pathway. culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the model, knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In mice, knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC , we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP CXCR4 tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8 T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4 LOX-1 subset are inversely correlated with the TFF2 level and CD8 T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

Objective： Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression. In this study, we investigated the association between promoter methylation of TMEM88, a possible inhibitor of the Wnt/β-Catenin signaling, and the survival of patients with non- small cell lung cancer （NSCLC）. Methods： Twelve pairs of tumor and adjacent non-tumor samples were used for microarray analyses of DNA methylation and gene expression. For validation, more than two hundred additional samples were analyzed for methylation using bisulfite pyrosequencing and for gene expression using qRT-PCR. Then the cell function were tested by wound healing, transwell, CCK8 and cell cycle assay. Results： Our analysis of patient specimens showed that TMEM88 methylation was higher in NSCLC tumors （82.2% ± 10.3, P 〈 0.01） compared with the adjacent normal tissues （65.9% ± 7.2）. The survival analysis revealed that patients with high TMEM88 methylation had a shorter overall survival （46 months） compared with patients with low TMEM88 methylation （〉56 months; P=0.021）. In addition, we found that demethylation treatment could inhibit tumor cell proliferation, migration, and invasion, which was supportive of an association between methylation and survival. Conclusions： Based on these consistent observations, we concluded that TMEM88 may play an important role in NSCLC progression and that promoter methylation of TMEM88 may serve as a biomarker for NSCLC prognosis and treatment.

Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. This single-arm, single-centre trial enrolled children (aged 1–18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1–2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40–57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5–4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.

Mechanoluminescence, a smart luminescence phenomenon in which light energy is directly produced by a mechanical force, has recently received significant attention because of its important applications in fields such as visible strain sensing and structural health monitoring. Up to present, hundreds of inorganic and organic mechanoluminescent smart materials have been discovered and studied. Among them, strontium‐aluminate‐based materials are an important class of inorganic mechanoluminescent materials for fundamental research and practical applications attributed to their extremely low force/pressure threshold of mechanoluminescence, efficient photoluminescence, persistent afterglow, and a relatively low synthesis cost. This paper presents a systematic and comprehensive review of strontium‐aluminate‐based luminescent materials’ mechanoluminescence phenomena, mechanisms, material synthesis techniques, and related applications. Besides of summarizing the early and the latest research on this material system, an outlook is provided on its environmental, energy issue and future applications in smart wearable devices, advanced energy‐saving lighting and displays. Mechanoluminescence materials have recently attracted significant research interest due to their enormous modern applications in energy, sensing, anti‐counterfeiting, wearable display, and sport science. Strontium‐aluminate‐based luminescent materials’ mechanoluminescence is reviewed on the phenomena, mechanisms, material synthesis techniques, and related application.

The purposes of this study were to identify risk factors for cervical lymph node metastasis and to examine the association between status and clinical features in papillary thyroid microcarcinoma (PTMC). A total of 1,587 patients with PTMC, treated in Tianjin Medical University Cancer Institute and Hospital from January 2011 to March 2013, underwent retrospective analysis. We reviewed and analyzed factors including clinical results, pathology records, ultrasound results, and status. Multivariate logistic regression analyses demonstrated that gender (male) [odds ratio (OR) = 1.845, = 0.000], age (< 45 years)(OR = 1.606, = 0.000), tumor size (> 6 mm) (OR = 2.137, = 0.000), bilateralism (OR = 2.011, = 0.000) and extrathyroidal extension (OR = 1.555, = 0.001) served as independent predictors of central lymph node metastasis (CLNM). Moreover, CLNM (OR = 29.354, = 0.000) served as an independent predictor of lateral lymph node metastasis (LLNM). Among patients with a solitary primary tumor, those with tumor location in the lower third of the thyroid lobe or the isthmus were more likely to experience CLNM ( < 0.05). Univariate analyses indicated that CLNM, LLNM, extrathyroidal extension, and multifocality were not significantly associated with mutation. The present study suggested that prophylactic neck dissection of the central compartment should be considered in patients with PTMC, particularly in men with tumor size greater than 6 mm, age less than 45 years, extrathyroidal extension, and tumor bilaterality. Among patients with PTMC, mutation is not significantly associated with prognostic factors. For a better understanding of surgical management of PTMC and the risk factors, we recommend multicenter research and long-term follow-up.

Mechanoluminescence is a smart light‐emitting phenomenon in which applied mechanical energy is directly converted into photon emissions. In particular, mechanoluminescent materials have shown considerable potential for applications in the fields of energy and sensing. This study thoroughly investigates the mechanoluminescence and long afterglow properties of singly doped and codoped Sr 2 MgSi 2 O 7 (SMSO) with varying concentrations of Eu 2+ and Dy 3+ ions. Subsequently, a comprehensive analysis of its multimode luminescence properties, including photoluminescence, mechanoluminescence, long afterglow, and X‐ray‐induced luminescence, is conducted. In addition, the density of states mapping is acquired through first‐principles calculations, confirming that the enhanced mechanoluminescence properties of SMSO primarily stem from the deep trap introduced by Dy 3+ . In contrast to traditional mixing with Polydimethylsiloxane, in this study, the powders are incorporated into optically transparent wood to produce a multiresponse with mechanoluminescence, long afterglow, and X‐ray‐excited luminescence. This structure is achieved by pretreating natural wood, eliminating lignin, and subsequently modifying the wood to overall modification using various smart phosphors and epoxy resin composites. After natural drying, a multifunctional composite wood structure with diverse luminescence properties is obtained. Owing to its environmental friendliness, sustainability, self‐power, and cost‐effectiveness, this smart mechanoluminescence wood is anticipated to find extensive applications in construction materials and energy‐efficient displays.

Introduction: Endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) are standard treatment options for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer (MBC). However, the efficacy of standard subsequent therapies after CDK4/6i-based treatment is unclear. This study aimed to examine physician practice patterns and treatment outcomes of subsequent therapies administered after progression on palbociclib therapy in clinical practice. Methods: The study included 200 patients with HR+/HER2– MBC who underwent subsequent treatments after progressing on palbociclib-based regimens in five Chinese institutions between August 2017 and April 2020. The treatment pattern, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were reported. Results: A total of 200 patients were included, of whom 147 (73.5%) and 53 (26.5%) received subsequent chemotherapy and endocrine therapy, respectively. The frequently used monochemotherapy regimens were taxane (n = 29), capecitabine (n = 21), and vinorelbine (n = 17), while the endocrine therapy regimens were chidamide plus exemestane (n = 16) and everolimus plus exemestane (n = 9). The overall median PFS (mPFS) was 5.5 months, with no significant difference in mPFS between the chemotherapy and endocrine therapy groups (p = 0.669). However, among patients not sensitive to prior palbociclib treatment, those administered chemotherapy had significantly longer PFS than those administered endocrine therapy (p = 0.006). The mPFS with endocrine therapy after first-, second-, and subsequent-line palbociclib was 13.4, 3.1, and 4.1 months, respectively (p = 0.233); in contrast, the mPFS with chemotherapy was 7.2, 6.5, and 4.9 months after first-, second-, and subsequent-line palbociclib, respectively (p = 0.364). The median OS was not achieved. The ORR was 10.6% among the 198 patients included in the analysis. Conclusions: Physicians prefer chemotherapy over endocrine therapy for the treatment of patients with HR+/HER2– MBC who develop progression on palbociclib. Sensitivity to previous palbociclib treatment might be one of the indicators for predicting response to subsequent treatment. ClinicalTrials.gov identifier: NCT04517318