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Understanding the factors that drive the evolution of sociality is one of the central issues in behavioural ecology. In ungulates, open habitats, such as alpine meadows, are thought to have promoted the evolution of various gregarious societies from solitary territorial lifestyles. However, the transition from a solitary territorial lifestyle to a gregarious society and the ultimate factors underlying this change remain unclear. The Japanese serow is a primal solitary ungulate. Females in forest-dwelling populations have solitary territorial lifestyles, but the social relationships among females in open-land dwelling populations have not been explored. We evaluated the spatial organisation and social interactions among female Japanese serows in an area with alpine meadows and subalpine forests and examined the effects of alpine meadows on female social relationships through withinpopulation comparisons. We confirmed the presence of both spatially solitary animals (little home range overlap with other individuals) and spatial groups (large home range overlap with two to three individuals), having exclusive territories. Females with more alpine meadows in their home range formed group territories, whereas those with more subalpine forests formed solitary territories. Accordingly, we show, for the first time, that open habitats promote the formation of female spatial groups in a primal solitary ungulate. We suggest that homogenous food distribution and abundant food supply in alpine meadows promote spatial group formation and that the mitigation of exclusive relationships and home range overlapping is a transitional phase for the development of gregarious societies.

Targeting cancer-associated fibroblasts (CAFs), as well as the crosstalk between stroma and cancer cells, could be of value in managing cancers. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of fibroblast activation and the tumor-stroma interaction in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. PFD significantly inhibited myofibroblast differentiation and activation of both primary cultured normal human lung fibroblasts and CAFs. Cocultivation of NSCLC cells with conditioned media (CM) of fibroblasts changed the morphology or epithelial to mesenchymal transition (EMT) status, and PFD suppressed these changes. Cocultivation of CAFs with CM of NSCLC cells also induced activation of CAFs, and these changes were suppressed by PFD. On in vivo examination, CAFs promoted tumor progression, and PFD suppressed tumor progression with an inhibitory effect on tumor-stroma crosstalk. PFD might inhibit not only fibroblast activity, but also the crosstalk between cancer cells and fibroblasts. PFD may have great potential as a novel treatment for NSCLC from multiple perspectives.

Understanding the main factors driving the evolution of mating systems is a major goal of behavioral ecology. In ungulates, the transition from forests to open habitats and the accompanying clustered spatial distribution of females are thought to have promoted an evolutionary shift from monogamy to polygyny. However, no field-based studies to date have tested in the field whether such changes in ecological conditions promote a shift from monogamy to polygyny. We investigated mating systems of the Japanese serow, which is an evolutionarily ancestral and solitary species among caprids, living in the area with subalpine forest and alpine meadows over 7 years. We evaluated the effects of habitat characteristics on mating systems using within population comparisons. In this site, females form solitary territories in subalpine forests but group territories in alpine meadows. Males defended most of their home ranges as territories, and both social monogamy (29.6%; one male with one female) and polygyny (70.4%; one male with 2–5 females) were observed. Males in alpine meadows formed mating units with more females, whereas males in subalpine forests formed mating units with single females. We show that open habitats promote the transition from social monogamy to polygyny and a higher degree of social polygyny. Our findings suggest that the main factor affecting the mating system is the spatial dispersion of females (solitary territory or group territory), which depends on habitat structure (closed or open).Significance statementThe Japanese serow is an ungulate that mainly inhabits forests and is assumed to possess the ancestral social systems for caprids, such as solitary and monogamous with territory. We found that open habitats, such as alpine meadows, promote the transition from monogamous to polygynous territory in the Japanese serow. In the study site, alpine meadows promote the transition from solitary territory to group territory of females. Thus, our results suggest that the main factor affecting the mating system is the spatial dispersion of females (solitary or group territory), which depends on habitat structure (subalpine forests or alpine meadows). Our findings provide evidence for a social evolutionary pattern in caprids, whereby the spread of forest-dwelling ancestors into open mountains promote evolution from social monogamy to polygyny.

Significance Pulmonary arterial hypertension (PAH) is a serious disease characterized by vascular remodeling in pulmonary arteries. Although an elevated IL-6 serum level correlates with poor prognosis of PAH patients, it is unclear how IL-6 promotes PAH. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. In mice with hypoxia-induced pulmonary hypertension (HPH), Th17 cells and M2 macrophages accumulate in the lungs after hypoxia exposure. IL-21 primarily derived from Th17 cells promotes M2 macrophage polarization. Consistently, IL-21 receptor-deficient mice show resistance to HPH with no accumulation of M2 macrophages in the lungs. IL-21 and M2 macrophage markers were upregulated in the lungs of patients with end-stage idiopathic PAH. These findings suggest promising therapeutic strategies for PAH targeting IL-6/IL-21–signaling axis. IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6–mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti–IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21–signaling axis may be a potential target for treating PAH.

Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF.

To understand the nutritional status of culled wild sika deer ( Cervus nippon ), we compared the ruminal microbes of deer living in habitats differing in food composition (Nagano winter, Nagano spring, and Hokkaido winter) using next-generation sequencing. Twenty-nine sika deer were sampled. Alpha and beta diversity metrics determined via 16S and 18S rRNA amplicon-seq analysis showed compositional differences. Prevotella , Entodinium , and Piromyces were the dominant genera of bacteria, fungi and protozoa, respectively. Moreover, 66 bacterial taxa, 44 eukaryotic taxa, and 46 chloroplastic taxa were shown to differ significantly among the groups by the linear discriminant analysis effect size (LEfSe) technique. Total RNA-seq analysis yielded 397 significantly differentially expressed transcripts (q < 0.05), of which 48 (q < 0.01) were correlated with the bacterial amplicon-seq results (Pearson correlation coefficient > 0.7). The ruminal microbial composition corresponded with the presence of different plants because the amplicon-seq results indicated that chloroplast from broadleaf trees and Stramenopiles-Alveolates-Rhizaria (SAR) were enriched in Nagano, whereas chloroplast from graminoids, Firmicutes and the dominant phylum of fungi were enriched in Hokkaido. These results could be related to the severe snow conditions in Hokkaido in winter and the richness of plants with leaves and acorns in Nagano in winter and spring. The findings are useful for understanding the nutritional status of wild sika deer.

BackgroundThe prognostic factors of pulmonary metastasectomy in patients with osteosarcoma and soft tissue sarcoma remain controversial. The purpose of our analysis was to explore the prognostic factors and outcomes of patients with osteosarcoma and soft tissue sarcoma who underwent pulmonary metastasectomy at our institution.MethodsWe reviewed the data of 44 patients who underwent resection of pulmonary metastases from 1996 to 2016 at our institution. The Kaplan–Meier method, log-rank test and multivariate Cox hazard model were used for comparison and survival analyses.ResultsThere was no perioperative mortality. The median post-metastasectomy overall survival was 24.8 months, and the 5-year overall survival rate of all patients was 43.5%. The 5-year survival rate of the patients who underwent repeat thoracotomies was 60.0%. Incomplete resection, a largest tumor size > 2 cm and a disease-free interval < 12 months were associated with poor survival in multivariate analyses. Among eight patients, who underwent repeat pulmonary resection, two remain alive with no evidence of disease. These patients had the longest DFI and DFI-2 (time from first pulmonary metastasectomy to the diagnosis of recurrent pulmonary metastasis), respectively.ConclusionThe survival of patients with a relatively long disease-free interval, small tumor size and complete resection was favorable following the treatment of osteosarcoma and soft tissue sarcoma with pulmonary metastasectomy. Repeat pulmonary metastasectomies also provide favorable prognosis in select patients.

Epithelial–mesenchymal transition (EMT) plays an important role in the progression of lung carcinoma. Podocalyxin (PODXL), which belongs to the CD34 family and regulates cell morphology, has been linked to EMT in lung cancer, and PODXL overexpression is associated with poor prognosis in several different classes of cancers. The aim of this study was to clarify the role of PODXL overexpression in EMT in lung cancer, and to determine the prognostic value of PODXL overexpression in tumors from lung cancer patients. The morphology, EMT marker expression, and migration and invasion abilities of engineered A549 PODXL‐knockdown (KD) or PODXL‐overexpression (OE) lung adenocarcinoma cells were examined. PODXL expression levels were assessed by immunohistochemistry in 114 human clinical lung adenocarcinoma specimens and correlated with clinical outcomes. PODXL‐KD cells were epithelial in shape, whereas PODXL‐OE cells displayed mesenchymal morphology. Epithelial markers were upregulated in PODXL‐KD cells and downregulated in PODXL‐OE cells, whereas mesenchymal markers were downregulated in the former and upregulated in the latter. A highly selective inhibitor of phosphatidylinositol 3‐kinase‐Akt signaling attenuated EMT of PODXL‐OE cells, while a transforming growth factor inhibitor did not, suggesting that PODXL induces EMT of lung adenocarcinoma cells via the phosphatidylinositol 3‐kinase pathway. In lung adenocarcinoma clinical specimens, PODXL expression was detected in minimally invasive and invasive adenocarcinoma, but not in non‐invasive adenocarcinoma. Disease free survival and cancer‐specific survival were significantly worse for patients whose tumors overexpressed PODXL. PODXL overexpression induces EMT in lung adenocarcinoma and contributes to tumor progression. When podocalyxin was knocked‐down, cells showed more epithelial shape and character. In contrast, podocayxin‐overexpressing cells became more mesenchymal phenotype. This phenotype change was under control of PI3K–Akt signal.

Background Cases of thymoma with pleural dissemination are occasionally encountered, and their management is difficult. Some reports have noted that surgical treatment for dissemination is effective, although the long-term results and clinical course details remain unclear. The current study investigated the short- and long-term outcomes of surgical resection of pleural dissemination. Methods A retrospective review examined the medical records for 38 patients who underwent surgical resection for pleural dissemination occurring synchronously with a primary thymoma or metachronously after complete surgical resection of a primary thymoma between 1996 and 2017 at the authors’ institution. Clinical characteristics and prognostic factors were analyzed. Results The patients were classified into synchronous ( n  = 21) and metachronous ( n  = 17) groups. The 10-year overall survival rate was 59% for the synchronous group and 88% for the metachronous group. The median follow-up period for all the patients was 61 months (range 4–225 months). No perioperative deaths occurred. For all the patients, the 5- and 10-year overall survival rates were respectively 91% and 82%, and the 5- and 10-year relapse-free survival rates were respectively 29% and 19%. A significantly worse prognosis was observed for patients 50 years of age or older than for those younger than 50 years ( p  = 0.02). For 13 patients who underwent repeat resection for pleural dissemination, the prognosis was better than for those without repeat resection ( p  < 0.01). Conclusion Surgical resection of thymoma with pleural disseminated nodules can be safely performed and provides a favorable long-term outcome. Repeat resection is considered to be effective for achieving a good prognosis.