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Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway （GNAS変異はKRAS経路に拮抗することにより、膵癌の悪性度を抑える）
Full text linkBackground: Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer.
Methods: CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures.
Results: Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNAS-mutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway.
Conclusions: Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway.博士（医学）旭川医科大
Ninjurin1 deletion in neuron-glial antigen 2-positive pericytes prevents microvessel maturation and delays wound healing （Neuron-glial antigen 2 陽性周細胞におけるNinjurin1の欠損は微小血管の成熟化を抑制し創傷治癒を遅延させる）
Full text linkThe formation of mature vasculature through angiogenesis is essential for adequate wound healing, such that blood-borne cells, nutrients, and oxygen can be delivered to the remodeling skin area. Neovessel maturation is highly dependent on the coordinated functions of vascular endothelial cells and perivascular cells, namely pericytes (PCs). However, the underlying mechanism for vascular maturation has not been completely elucidated, and its role in wound healing remains unclear. In this study, we investigated the role of Ninjurin-1 (Ninj1), a new molecule mediating vascular maturation, in wound healing using an inducible PC-specific Ninj1 deletion mouse model. Ninj1 expression increased temporarily in NG2-positive PCs in response to skin injury. When tamoxifen treatment induced a decreased Ninj1 expression in PCs, the neovessels in the regenerating wound margins were structurally and functionally immature, but the total number of microvessels was unaltered. This phenotypic change is associated with a reduction in PC-associated microvessels. Wound healing was significantly delayed in the NG2-specific Ninj1 deletion mouse model. Finally, we showed that Ninj1 is a crucial molecule that mediates vascular maturation in injured skin tissue through the interaction of vascular endothelial cells and PCs, thereby inducing adequate and prompt wound healing.博士（医学）旭川医科大
Probiotic-derived polyphosphate accelerates intestinal epithelia wound healing through inducing platelet-derived mediators （乳酸菌由来長鎖ポリリン酸は血小板活性化を介して腸管上皮の創傷治癒を促進する）
Full text linkInflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), is an intractable intestinal inflammation associated with the disruption of the intestinal mucosa. We previously demonstrated that Lactobacillus brevis-derived long-chain polyphosphate (poly P) improved the intestinal barrier function by the upregulation of cell adhesion and relieved intestinal inflammation, thereby exerting a curing effect on colitis in vitro, in vivo, and in an investigator-initiated clinical study of UC. However, how poly P improves mucosal defects induced by intestinal inflammation has not been elucidated. In this study, we detected the accumulation of platelets in inflamed tissues induced by poly P in a dextran sulfate sodium- (DSS-) induced colitis mouse model. A light transmission aggregometry analysis and scanning electron microscopy showed that poly P promoted the platelet aggregation. An SRB assay and ki-67 staining showed that the supernatant of poly P-treated platelet-rich plasma (PRP) increased intestinal epithelial cell growth. A wound healing assay showed that the supernatant of poly P-treated PRP, but not poly P itself, accelerated wound healing. A Western blotting analysis indicated that mitogen-activated protein kinase activation was induced by the supernatant of poly P-treated human PRP in the epithelial cells and its wound healing effect was significantly decreased by the inhibition of ERK signaling. These data suggested that platelet-derived mediators induced by poly P improved intestinal inflammation through the promotion of epithelial cell growth by the activation of the ERK signaling pathway. The mechanism is a novel host-microbe interaction through mammalian platelet-derived mediators induced by bacterial molecules.博士（医学）旭川医科大
Hypothermic circulatory arrest does not induce coagulopathy in vitro （in vitroモデルにおいて低体温循環停止法は凝固異常を惹起しない）
Full text linkHypothermic circulatory arrest (HCA) is an essential procedure during aortic surgery to protect organs; however, hypothermia is believed to cause coagulopathy, which is a major fatal complication. This study aimed to clarify the impact of hypothermia on coagulation by eliminating clinical biases in vitro. In the hypothermic storage study, blood samples from five healthy volunteers were stored at 37 ℃ (group N) for 3 h or at 20 ℃ for 2 h, followed by 1 h of rewarming at 37 ℃ (group H). Thromboelastography was performed before and after 3 h of storage. In the mock circulation loop (MCL) study, blood samples were placed in the MCL and (a) maintained at 37 ℃ for 4 h (group N, n = 5), or (b) cooled to 20 ℃ to simulate HCA with a 0.1 L/min flow rate for 3 h and then rewarmed to 37 ℃ (group H, n = 5). The total MCL duration was 4 h, and the flow rate was maintained at 1 L/min, except during HCA. Blood samples collected 15 min after the beginning and end of MCL were subjected to standard laboratory tests and rotational thromboelastometry analyses. Hypothermia had no impact on coagulation in both the hypothermic storage and MCL studies. MCL significantly decreased the platelet counts and clot elasticity in the INTEM and EXTEM assays; however, there was no effect on fibrinogen contribution measured by FIBTEM. Hypothermia does not cause irreversible coagulopathy in vitro; however, MCL decreases coagulation due to the deterioration of platelets博士（医学）旭川医科大
The stability of total talar prosthesis - How stable to dislocation? Cadaveric study （人工距骨の安定性－脱臼への耐性は如何ほどか？ カダバ研究）
Full text linkThe aim of this study was to characterize ankle stability of total talar prosthesis (TTP) and to determine the effect of implant sizes on stability as well as the resistance to TTP dislocation. Twelve below-knee cadaveric specimens were divided into two groups. Group 1 received a size matched implant and Group 2 received downsized implant by 5%. The stability assessment under fluoroscopy was performed for each cadaver in its native state. Following TTP insertion process, each then underwent evaluation of the TTP ankle stability. The stability of pre- and post-TTP was compared. (1) Anterior drawer distance. (2) Talar tilt angle under varus and valgus stress. (3) Subtalar tilt angle under varus stress was measured. Finally, the dislocation test was performed using the aforementioned testing conditions, then the stress force was slowly increased from 0 to 350 N, during which time it was observed on fluoroscopy all the time. Compared to pre TTP ankles, varus and anterior drawer stress showed significant instability (p < 0.001-0.031). Only anterior drawer stress in smaller sized implants showed significant instability when compared to identical sized implants (p = 0.008). No dislocation was seen under varus, valgus, and subtalar stress. However, anterior dislocation was observed in all cases of smaller size implant group (p = 0.045). TTP implant was stable under valgus and subtalar stress. However, clinicians should pay attention to anterior instability. Notably, downsized implants should be considered carefully to minimize the chance of anterior dislocation.博士（医学）旭川医科大