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Abstract Background A resident vascular endothelial stem cell (VESC) population expressing CD157 and CD200 has been identified recently in the adult mouse. However, the origin of this population and how it develops has not been characterized, nor has it been determined whether VESC-like cells are present during the perinatal period. Here, we investigated the presence of perinatal VESC-like cells and their relationship with the adult VESC-like cell population. Methods We applied single-cell RNA sequencing of endothelial cells (ECs) from embryonic day (E) 14, E18, postnatal day (P) 7, P14, and week (W) 8 liver and investigated transcriptomic changes during liver EC development. We performed flow cytometry, immunofluorescence, colony formation assays, and transplantation assays to validate the presence of and to assess the function of CD157+ and CD200+ ECs in the perinatal period. Results We identified CD200− expressing VESC-like cells in the perinatal period. These cells formed colonies in vitro and had high proliferative ability. The RNA velocity tool and transplantation assay results indicated that the projected fate of this population was toward adult VESC-like cells expressing CD157 and CD200 1 week after birth. Conclusion Our study provides a comprehensive atlas of liver EC development and documents VESC-like cell lineage commitment at single-cell resolution.

Abstract Background During sprouting angiogenesis, stalk cells, localized behind tip cells, generate endothelial cells (ECs) for the elongation of new vessels. We hypothesized that stalk cells may have endothelial progenitor cell properties because of their highly proliferative ability. We conducted Hoechst dye DNA staining in ECs of preexisting blood vessels from hind limb muscle and found that endothelial-side population (E-SP) cells, which efflux Hoechst rapidly with abundant ABC transporters, show highly producing ability of ECs. We previously showed the existence of E-SP cells in hind limb muscle, retina, and liver, but not in other tissues such as adipose tissue, skin, and placenta. Methods We investigated the existence of E-SP cells and analyzed their proliferative ability among CD31+CD45− ECs from adipose tissue, skin, and placenta of adult mice. We also analyzed the neovascular formation of E-SP cells from adipose tissue in vivo. Results We detected E-SP cells in all tissues examined. However, by in vitro colony formation analysis on OP9 cells, we found that E-SP cells from adipose tissue and skin, but not from placenta, have highly proliferative ability. Moreover, E-SP cells from adipose tissue could contribute to the neovascular formation in hind limb ischemia model. Conclusion The adipose tissue and skin are available sources to obtain endothelial stem cells for conducting therapeutic angiogenesis in regenerative medicine.

Abstract Background During Ramadan fasting, postprandial hyperglycemia is commonly observed after iftar (break of fast at sunset) meal. d-allulose is a rare sugar and is reported to have several health benefits, including the suppression of increase in postprandial glucose levels. This study investigates whether d-allulose (a C-3 epimer of d-fructose) improves the postprandial glucose in patients with type 2 diabetes mellitus (T2DM) during Ramadan. Methods This was a pilot, prospective single-arm study design that was conducted for 10 consecutive days; 5 days of control and 5 days of consumption. The primary outcome was postprandial peak glucose levels. During the consumption period, 8.5 g of d-allulose was consumed by the participants before iftar meal. Postprandial glucose was measured using a continuous glucose monitoring system. Results A total of 12 participants completed the study. Significant lower (p

Abstract Background Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). Case presentation A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. Conclusions Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.

Abstract Background Recently, immune checkpoint inhibitors have widely been used for the management of advanced melanoma. However, high-grade immune-related adverse events can occur, particularly with combination immunotherapy. We report a case of a patient with melanoma who developed thyroid storm following treatment with ipilimumab and nivolumab. Case presentation An 85-year-old Japanese man with a history of malignant melanoma presented to our department with severe thyrotoxicosis and poor blood glucose control. He was already being treated for Hashimoto’s disease and type 2 diabetes mellitus before the treatment for the melanoma. During admission, laboratory investigations revealed the following thyroid functions: thyroid-stimulating hormone below sensitivity, free triiodothyronine 31.7 pg/ml, and thyroglobulin 48,000 IU/ml. Thyroid-stimulating hormone receptor antibody was negative, and a 99mTc-labeled thyroid scan revealed a markedly decreased uptake. He was treated with beta-blocker, orally administered potassium iodine, a relatively low dose of prednisolone, and insulin injection therapy to control his blood glucose, resulting in an improvement in thyroid function and his symptoms. Conclusion It might be important to be aware of the possibility of thyroid storm induced by immune checkpoint inhibitors.