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Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention. The molecular mechanisms underlying tumour initiation remain elusive. Here, the authors use spatiotemporally controlled oncogene activation and tumour suppressor inhibition with multi-omics to unveil the role of YAP-mediated oral epithelial progenitor cell reprogramming into tumour-initiating cells.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

A comprehensive experimental system for Japanese anchovy, a promising candidate model organism for marine teleosts, was established. Through the design of a rearing/spawning facility that controls the photoperiod and water temperature, one-cell eggs were continuously obtained shortly after spawning throughout the rearing period. The stages of eggs are indispensable for microinjection experiments, and we developed an efficient and robust microinjection system for the Japanese anchovy. Embryos injected with GFP mRNA showed strong whole-body GFP fluorescence and the survival rates of injected- and non-injected embryos were not significantly different, 87.5% (28 in 32 embryos) and 90.0% (45 in 50 embryos), respectively. We verified that the Tol2 transposon system, which mediates gene transfer in vertebrates, worked efficiently in the Japanese anchovy using the transient transgenesis protocol, with GFP or DsRed as the reporter gene. Finally, we confirmed that genome-editing technologies, namely Transcription Activator-Like Effector Nucleases (TALEN) and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR)/Cas9, were applicable to the Japanese anchovy. In practice, specific gene-disrupted fishes were generated in the F 1 generation. These results demonstrated the establishment of a basic, yet comprehensive, experimental system, which could be employed to undertake experiments using the Japanese anchovy as a model organism for marine teleost fish.

Background Tumour-infiltrating lymphocyte (TIL)-high breast tumours have a high rate of pathological complete response (pCR) with neoadjuvant chemotherapy. In our routine pathological diagnoses of biopsy specimens from pCR cases, we have observed a high infiltration of plasma cells (PCs). A positive correlation of PCs with favourable patient outcome has recently been reported, but little is known about how PCs contribute to local tumour immunity. Methods We retrospectively examined biopsy specimens from 146 patients with invasive breast cancer who received neoadjuvant chemotherapy. CD138 + PC infiltration was assessed by immunohistochemistry. Multiplexed fluorescent immunohistochemistry (mfIHC) with T and B cell markers was also conducted to elucidate the profile of immune cells. Results Greater PC infiltration was observed in the pCR group ( p  = 0.028) and this trend was confirmed in another patient cohort. With mfIHC, we observed significantly more CD8 + , T-bet + CD4 + , and CD8 + FOXP3 + T cells, total B cells and PCs in pCR cases. Such cases were also characterised by high expression of both PD-1 and PD-L1 on B cells and PCs. In patients with hormone receptor-negative tumours, high PC infiltration was correlated with significantly longer disease-free survival ( p  = 0.034). Conclusions We found that higher PC infiltration in biopsy specimens before neoadjuvant chemotherapy was associated with pCR. With mfIHC, we also revealed that the local cytotoxic immune response was clearly enhanced in pCR cases, as was the infiltration of B cells including PCs. Moreover, higher PC levels were correlated with favourable outcomes in hormone receptor-negative breast cancer patients.

Aim The purpose of the present study was to investigate the predictors of clinical deterioration soon after emergency department (ED) discharge. Methods We undertook a case–control study using the ED database of the Nagano Municipal Hospital (Nagano, Japan) from January 2012 to December 2013. We selected adult patients with medical conditions who revisited the ED with deterioration within 2 days of ED discharge (deterioration group). The deterioration group was compared with a control group. Results During the study period, 15,724 adult medical patients were discharged from the ED. Of these, 170 patients revisited the ED because of clinical deterioration within 2 days. Among the initial vital signs, respiratory rate was less frequently recorded than other vital signs (P < 0.001 versus all other vital signs in each group). The frequency of recording each vital sign did not differ significantly between the groups. Overall, patients in the deterioration group had significantly higher respiratory rates than those in the control group (21 ± 5/min versus 18 ± 5/min, respectively; P = 0.002). A binary logistic regression analysis revealed that respiratory rate was an independent risk factor for clinical deterioration (unadjusted odds ratio, 1.15; 95% confidence interval, 1.04−1.26; adjusted odds ratio, 1.15; 95% confidence interval, 1.01−1.29). Conclusions An increased respiratory rate is a predictor of early clinical deterioration after ED discharge. Vital signs, especially respiratory rate, should be carefully evaluated when making decisions about patient disposition in the ED. In the case‐control study, 15,724 adult medical patients were discharged from an emergency department (ED). Of these, 170 patients revisited the ED because of clinical deterioration within two days. Overall, patients in the deterioration group had significantly higher respiratory rates than those in the control group (21 ± 5/min vs. 18 ± 5/min, respectively; P = 0.002). In addition, an increased respiratory rate was an independent predictor of clinical deterioration (unadjusted odds ratio (OR): 1.15, 95% confidence interval (CI): 1.04−1.26, adjusted OR: 1.15, 95% CI 1.01−1.29).

Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n  =  21, lymphatic malformations n  =  27, lymphatic venous malformations n  =  1, and Klippel–Trenaunay syndrome n  =  10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). In total, 37 of 59 patients (62.7%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.

Minute pulmonary meningothelial‐like nodules (MPMNs) are benign lesions characterized by the appearance of ground‐glass nodules (GGN) on computed tomography (CT). In the present case, an MPMN gradually developed into a substantial component during chest CT follow‐up, and the GGN gradually transformed into a part‐solid nodule. The imaging course described in this case is quite unique. Such CT images are characteristic of malignant tumours, especially, highly differentiated adenocarcinomas, which are difficult to differentiate preoperatively. Therefore, it is important to report this case. MPMN, which was GGN at the time of initial diagnosis, gradually developed into a substantial component during chest CT follow‐up, and the GGN gradually transformed into a part‐solid nodule. The imaging course described in this case is quite unique.

Background Among pharmaceuticals currently in clinical use, few drugs directly target bacterial toxins. Clostridium perfringens α-toxin, a phospholipase C (PLC), is a major virulence factor responsible for gas gangrene caused by C. perfringens type A. There is a clinical need for small-molecule compounds that inhibit such bacterial toxins. Methods A library of 764 FDA-approved drugs was screened to identify compounds that inhibit the PLC activity of C. perfringens α-toxin. Identified hits were further evaluated for their ability to inhibit α-toxin-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs). Additional in vitro assays were conducted to assess changes in neutrophil activation and cytokine production. In vivo efficacy was evaluated in female C57BL/6J mice (n = 21 or 18 per group) challenged with purified α-toxin or infected with C. perfringens type A. Results The initial screen identifies 21 compounds that inhibit the PLC activity. Among them, micafungin, an antifungal agent, is the only compound that suppresses α-toxin-induced cell death in HUVECs. Micafungin also reduces α-toxin-induced CD11b expression in neutrophils and cytokine release in HUVECs. Caspofungin, another antifungal with similar properties, also inhibits α-toxin-induced cell death and cytokine production. In mouse models, caspofungin, but not micafungin, significantly reduces lethality caused by α-toxin. Caspofungin also improves survival and mitigates muscle damage in mice infected with C. perfringens type A. Conclusions Caspofungin demonstrates promising therapeutic potential as a life-saving treatment for gas gangrene caused by C. perfringens type A, likely through its inhibitory action on α-toxin activity. These findings support the development of new classes of small-molecule therapeutics that directly target bacterial toxins. Plain Language Summary Gas gangrene is a life-threatening infection caused by a type of bacteria called Clostridium perfringens . This bacterium releases a harmful toxin called α-toxin, which destroys tissues and can lead to rapid disease progression and death. In this study, we tested 764 drugs that are already approved for use in humans to see if any could block the damaging effects of α-toxin, and found that two antifungal drugs, micafungin and caspofungin, were able to protect human cells from the toxin. Among them, caspofungin improved survival and reduced muscle damage in mice infected with C. perfringens . These findings suggest that caspofungin, a drug already used to treat fungal infections, could potentially be repurposed as a new treatment for gas gangrene. This offers hope for faster and more effective ways to treat this dangerous infection using existing medications. Takehara et al. screen FDA-approved drugs to identify inhibitors of Clostridium perfringens α-toxin and evaluate their effects in cells and mouse models. Caspofungin reduces α-toxin–induced lethality, tissue damage, and inflammatory responses, highlighting its potential as a therapeutic intervention for gas gangrene.

Orbital solitary fibrous tumor (SFT) is a rare lesion among orbital tumors, which can be misdiagnosed as another mesenchymal tumor. In this study we report two cases of orbital SFT, focusing on the imaging and pathological findings of the vascular structure inside the tumor. A 26-year-old woman and 43-year-old man presented with orbital SFT. The pathological findings revealed a patternless growth pattern of the tumor cells and hemangiopericytoma-like vascularity as well as thickened, dilated blood vessels within the tumor tissue. Tumor cells revealed a diffuse strong positivity for cluster of differentiation 34 (CD34) and signal transducer and activator of transcription 6 (STAT6) in both cases, while B-cell lymphoma 2 (bcl-2) and CD99 were positive in one case. Characteristic findings within the tumor were the arterial components, where a variety of STAT6, CD99 and bcl-2-positive smooth muscle cells were intermingled. Histologically, the tumor tissues might be characterized by not only conventional hemangiopericytoma-like vasculature but also dilated arterial vessels, which were shown to be part of the tumor components.

Introduction Contact hypersensitivity (CHS), a type of delayed‐type hypersensitivity, is induced by hapten exposure to the skin and mucosa. We previously reported that, in a murine model of CHS, the vaginal mucosa (VM) sensitization showed lower T‐cell responses as compared with the abdominal skin sensitization. To investigate mechanisms of impaired CHS by the VM sensitization, we compared migration of hapten‐captured dendritic cells (DCs) in the draining lymph nodes (dLNs) and recruitment of DCs at the sensitized local sites. Methods Fluorescein isothiocyanate (FITC) or 2,4‑dinitrofluorobenzene (DNFB) was used as hapten, and migration of FITC+ DCs in the dLNs and local recruitment of MHC class II+ and CD11c+ cells were compared between abdominal skin and VM sensitization by flow cytometric analyses and immunohistochemistry. Expression of tumor growth factor (TGF)‐β at mRNA and protein levels, and local recruitment of CD206+ cells were examined after VM sensitization. Results VM sensitization showed less numbers of FITC+MHC class IIhighCD11c+ migratory DCs in the dLNs at 6 and 24 h, as compared with skin sensitization. Both skin and VM sensitization induced the recruitment of dermal/submucosal DCs at 6 h, but the number of submucosal DCs in the VM was significantly decreased at 24 h. VM showed persistently higher mRNA levels of TGF‐β2/β3 expression than those of the skin before and after sensitization. In the VM sensitization, increment of CD206+MHC class II+ cells was observed especially at the deep lamina propria at 24 h. Most of CD206+ cells were also positive for the binding to Fc chimeric TGF‐β receptor that interacts with all TGF‐β isoforms, suggesting TGF‐β expression. Conclusion DC migration to dLNs and localization of DCs at the sensitized sites are limited in the VM sensitization. Our results suggest that the existence of TGF‐β‐expressing CD206+ cells may contribute less sensitization ability and CHS responses in the VM. To investigate mechanisms of vaginal mucosa (VM) sensitization in contact hypersensitivity (CHS), we examined migration of hapten‐captured dendritic cells (DCs) in the draining lymph nodes (dLNs) and recruitment of DCs at the sensitized local sites in VM sensitization as compared with skin sensitization. We observed that DC migration to dLNs and localization of DCs at the sensitized sites were limited in the VM sensitization with high TGF‐β expression levels, increment of CD206+ cells, and TGF‐β expression in CD206+ cells in the VM. These results suggested that existence of TGF‐β‐expressing CD206+ cells may contribute less sensitization ability and CHS responses in the VM.