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Recent findings suggest that the dissemination of tumor cells occurs at the early stage of breast and pancreatic carcinogenesis, which is known as early dissemination. The evidence of early dissemination has been demonstrated predominantly in the bloodstream and bone marrow; however, limited evidence has revealed the existence and behavior of disseminated cells in distant organs. Here, we show that premalignant pancreatic cells seed distant stealth metastasis that eventually develops into manifest metastasis. By analyzing lineage-labeled pancreatic cancer mouse models (KPCT/TFF1KO; Pdx1-Cre/LSL-KRAS G12D /LSL-p53 R172H /LSL-tdTomato/TFF1KO), we found that premalignant pancreatic cells, rather than mature malignant cells, were prone to enter the bloodstream and reside in the bone marrow, liver, and lung. While these metastatic cells exhibited the characteristics of the cells of host organs and did not behave as malignant cells, they underwent malignant transformation and formed distinct tumors. Surprisingly, the manifestation of distant metastasis occurred even before tumor development in the primary site. Our data revealed that disseminated premalignant cells reside stealthily in distant organs and evolve in parallel with the progression of the primary tumor. These observations suggest that we must rebuild a therapeutic strategy for metastatic pancreatic cancer.

DNA analysis of large herbivore feces samples collected from seagrass beds at two distant sites (Irabu Island in Miyako Islands and Kushi in Okinawa Island) in the Ryukyu Islands proved that some of these feces were from dugongs, which had been treated in recent studies as extinct in this region since the last stranding of a deceased individual in 2019. In addition, local knowledge of sightings of animals thought to be dugongs and confirmed cases of dugong feeding trails since 2010 were compiled to estimate its recent distribution. This is the first scientific report on the presence of this mammal in the Ryukyu Islands within the last four years, and particularly in the Miyako Islands within the last half-century. As the Ryukyu Islands are known to be the northern limit of the dugong’s fragmented distribution in East Asia, conservation efforts are therefore needed.

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.

Objective: We describe our experience of single-incision laparoscopic splenectomy (SILS) for an unruptured aneurysm of the splenic artery. Clinical Presentation and Intervention: A 73-year-old woman was diagnosed as having a splenic aneurysm which grew from 14 to 22 mm in diameter within 2 years. Due to a contrast agent allergy, transcatheter arterial embolization could not be performed; therefore, SILS was performed with a 4-cm Z-shaped incision. The operative time and intraoperative blood loss were 132 min and 27 mL, respectively. The patient was discharged 4 days after surgery. Conclusion: In selected cases, SILS is a suitable and safe procedure for an unruptured aneurysm of the splenic artery.

Cancer cells have been shown to exploit neurons to modulate their survival and growth, including through establishment of neural circuits within the central nervous system (CNS) 1-3. Here, we report a distinct pattern of cancer-nerve interactions between the peripheral nervous system (PNS) and gastric cancer (GC). In multiple GC mouse models, nociceptive nerves demonstrated the greatest degree of nerve expansion in an NGF-dependent manner. Neural tracing identified CGRP+ peptidergic neurons as the primary gastric sensory neurons. Three-dimensional co-culture models showed that sensory neurons directly connect with gastric cancer spheroids through synapse-like structures. Chemogenetic activation of sensory neurons induced the release of calcium into the cytoplasm of cancer cells, promoting tumor growth and metastasis. Pharmacological ablation of sensory neurons or treatment with CGRP inhibitors suppressed tumor growth and extended survival. Depolarization of gastric tumor membranes through in vivo optogenetic activation led to enhanced calcium flux in nodose ganglia and CGRP release, defining a cancer cell-peptidergic neuronal circuit. Together, these findings establish the functional connectivity between cancer and sensory neurons, identifying this pathway as a potential therapeutic target.Competing Interest StatementThe authors have declared no competing interest.

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.

Cadmium (Cd) and arsenic (As) pollution in paddy soil and their accumulation in rice (Oryza sativa) pose serious threats to human health. Rice internally detoxifies these toxic metal and metalloid to some extent, resulting in their accumulation within the edible parts. However, the mechanisms of Cd and As detoxification in rice have been poorly elucidated. Plants synthesize thiol‐rich metal‐chelating peptides, termed phytochelatins (PCs). We characterized rice PC synthase (PCS) and investigated its contribution to Cd and As tolerance in rice. We identified two PCS homolog genes, OsPCS1 and OsPCS2, in the rice genome. The expression of OsPCS1 was upregulated by As(III) stress in the roots but that of OsPCS2 was not significantly affected. The expression level of OsPCS2 was higher than that of OsPCS1 in the shoots and roots. Recombinant OsPCS1 and OsPCS2 proteins differed in their metal activation. OsPCS1 was more strongly activated by As(III) than by Cd; however, OsPCS2 was more strongly activated by Cd than by As(III). Genetically engineered plants having their OsPCS2 expression silenced via RNA interference (OsPCS2 RNAi) contained less PCs and more glutathione (GSH), a substrate of PC synthesis, than wild‐type plants, although there was no significant difference in OsPCS1 RNAi plants. OsPCS2 RNAi plants were sensitive to As(III) stress, but Cd tolerance was little affected. On the other hand, treatment with buthionine sulfoximine, an inhibitor of GSH biosynthesis, significantly decreased Cd and As tolerance of rice seedlings. These findings indicate that OsPCS2 is a major isozyme controlling PC synthesis, and that PCs are important for As tolerance in rice. However, PC synthesis may make a smaller contribution to Cd tolerance in rice, and GSH plays crucial roles, not only as a substrate of PC synthesis.

Background Postoperative complications are not rare in the elderly population after hepatectomy. However, predicting postoperative risk in elderly patients undergoing hepatectomy is not easy. We aimed to develop a new preoperative evaluation method to predict postoperative complications in patients above 65 years of age using biological impedance analysis (BIA). Methods Clinical data of 59 consecutive patients (aged 65 years or older) who underwent hepatectomy at our institution between 2017 and 2020 were retrospectively analyzed. Risk factors for postoperative complications (Clavien-Dindo ≥ III) were evaluated using multivariate regression analysis. Additionally, a new preoperative risk score was developed for predicting postoperative complications. Results Fifteen patients (25.4%) had postoperative complications, with biliary fistula being the most common complication. Abnormal skeletal muscle mass index from BIA and type of surgical procedure were found to be independent risk factors in the multivariate analysis. These two variables and preoperative serum albumin levels were used for developing the risk score. The postoperative complication rate was 0.0% with a risk score of ≤ 1 and 57.1% with a risk score of ≥ 4. The area under the receiver operating characteristic curve of the risk score was 0.810 ( p  = 0.001), which was better than that of other known surgical risk indexes. Conclusion Decreased skeletal muscle and the type of surgical procedure for hepatectomy were independent risk factors for postoperative complications after elective hepatectomy in elderly patients. The new preoperative risk score is simple, easy to perform, and will help in the detection of high-risk elderly patients undergoing elective hepatectomy.