An important consideration in regeneration therapy is the fact that the tissue surrounding an organ supports its function. Understanding the structure of the periosteum can contribute to more effective bone regeneration therapy. As a cellular source, the periosteum also assists bone growth and fracture healing; this further necessitates its direct contact with the bone. However, its anchoring strength appears to be inexplicably stronger than expected. In this study, we used focused ion beam/scanning electron microscope tomography to investigate ultrathin serial sections as well as the three dimensional ultrastructure of the periosteum to clarify the architecture of its anchoring strength, as such assessments are challenging using conventional methods. We discovered perforating fibres that arise from the bone surface at 30 degree angles. Additionally, the fibres across the osteoblast layer were frequently interconnected to form a net-like structure. Fibroblast processes were observed extending into the perforating fibres; their morphologies were distinct from those of typical fibroblasts. Thus, our study revealed novel ultrastructures of the periosteum that support anchorage and serve as a cellular source as well as a mechanical stress transmitter.

Background/Aim: The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients. Patients and Methods: A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed. Results: Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy. Conclusion: The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.Immune checkpoint inhibitors (ICIs) that target programmed cell death-1 (PD-1) protein, programmed cell death-ligand 1 protein, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have changed the therapeutic landscape and are currently standard treatment options in patients with advanced and metastatic renal cell carcinoma (RCC) (1, 2). Despite the remarkable success of clinical applications, the efficacy of ICIs in RCC varies greatly across individual patients. Some researchers have reported biomarkers for predicting prognosis in patients treated with ICIs, such as PD-L1 and PD-L2 positivity, tumor mutation burden, and profile of immune-related genes (3). Furthermore, the association of immune related adverse events (irAEs) with prognosis in metastatic RCC has been recently reported (4, 5). Thus, it is critical to explore reliable predictors to improve prognosis of RCC patients treated with ICIs.Recently, several studies have demonstrated the crucial impact of human gut microbiota on ICIs therapies (6-9). It is well recognized that antibiotics (AB) alter the diversity and composition of gut microbiota and consequently shift their metabolic capacity (10). The hypothesis was that modulation of gut microbiota by AB may be associated with poor response to ICIs. However, the data on the association between AB use and clinical outcomes with ICIs are limited, especially in Japanese patients with genitourinary cancer.In the present study, we performed a retrospective analysis to examine the influence of AB on the clinical outcomes of Japanese patients treated with ICIs therapy for metastatic RCC patients. Patients and MethodsStudy design and patients. We retrospectively examined clinical information collected from 31 RCC patients treated with ICIs at Kurume University Hospital from November 2016 to April 2019. All patients received nivolumab or the combination of nivolumab and ipilimumab. Nivolumab was intravenously administered at 3 mg/kg or 240 mg/body every 2 weeks. Nivolumab and ipilimumab were administered intravenously at a dose of 240 mg/body and 1 mg/kg, respectiv...

Endocrine and endothelial cells of the anterior pituitary gland frequently make close appositions or contacts, and the secretory granules of each endocrine cell tend to accumulate at the perivascular regions, which is generally considered to facilitate secretory functions of these cells. However, three-dimensional relationships between the localization pattern of secretory granules and blood vessels are not fully understood. To define and characterize these spatial relationships, we used scanning electron microscopy (SEM) three-dimensional reconstruction method based on focused ion-beam slicing and scanning electron microscopy (FIB/SEM). Full three-dimensional cellular architectures of the anterior pituitary tissue at ultrastructural resolution revealed that about 70% of endocrine cells were in apposition to the endothelial cells, while almost 30% of endocrine cells were entirely isolated from perivascular space in the tissue. Our three-dimensional analyses also visualized the distribution pattern of secretory granules in individual endocrine cells, showing an accumulation of secretory granules in regions in close apposition to the blood vessels in many cases. However, secretory granules in cells isolated from the perivascular region tended to distribute uniformly in the cytoplasm of these cells. These data suggest that the cellular interactions between the endocrine and endothelial cells promote an uneven cytoplasmic distribution of the secretory granules.

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