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Comparative assessment of disease recurrence after transurethral resection of non-muscle-invasive bladder cancer with and without a photodynamic diagnosis using 5-aminolevulinic acid: A propensity score-matching analysis
Get PDFBackground: Among patients with non-muscle-invasive bladder cancer (NMIBC), systematic reviews showed lower recurrence rate in patients treated with photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) than with white-light (WL) TURBT. However, the result is not consistent between clinical trials and the significance of preoperatively available factors in disease recurrence after PDD-TURBT remains unclear.
Methods: The present study retrospectively analyzed 1174 NMIBC patients who underwent TURBT and were followed up for ≥6 months. Among 1174 patients, 385 and 789 underwent PDD-TURBT with oral 5-aminolevulinic acid (the PDD group) and WL-TURBT (the WL group), respectively. Recurrence-free survival (RFS) was compared between the PDD and WL groups before and after propensity score matching, and the impact of several baseline parameters on RFS between the 2 groups was investigated after matching.
Results: Before propensity score matching, RFS was significantly longer in the PDD group than in the WL group (P=0.006). After matching, 383 patients were included in both groups, and RFS was significantly longer in the PDD group than in the WL group (P<0.001). In the cohort after matching, RFS between the two groups was compared in each subgroup classified according to baseline parameters, including age, sex, history of previous or concomitant upper urinary tract urothelial carcinoma, preoperative urinary cytology, tumor multiplicity, and tumor size, and significantly longer RFS was observed in the PDD group in all subgroups, except for the patients with tumors ≥30 mm (P=0.21).
Conclusion: These results suggest that PDD-TURBT prolongs RFS in NMIBC patients, except for those with tumors ≥30 mm
UBL3 overexpression enhances EV-mediated Achilles protein secretion in conditioned media of MDA-MB-231 cells
Get PDF浜松医科大学Hamamatsu University School of Medicine博士（医学）Cancer cells communicate within the tumor microenvironment (TME) through extracellular vesicles (EVs), which act as crucial messengers in intercellular communication, transporting biomolecules to facilitate cancer pro-gression. Ubiquitin-like 3 (UBL3) facilitates protein sorting into small EVs as a post-translational modifier. However, the effect of UBL3 overexpression in EV-mediated protein secretion has not been investigated yet. This study aimed to investigate the effect of UBL3 overexpression in enhancing EV-mediated Achilles protein secre-tion in MDA-MB-231 (MM) cells by a dual-reporter system integrating Akaluc and Achilles tagged with Ubiquitin where self-cleaving P2A linker connects Akaluc and Achilles. MM cells stably expressing Ubiquitin-Akaluc-P2A-Achilles (Ubi-Aka/Achi) were generated. In our study, both the bioluminescence of Ubiquitin-Akaluc (Ubi-Aka) and the fluorescence of Achilles secretion were observed. The intensity of Ubi-Aka was thirty times lower, while the Achilles was four times lower than the intensity of corresponding cells. The ratio of Ubi-Aka and Achilles in conditioned media (CM) was 7.5. They were also detected within EVs using an EV uptake luciferase assay and fluorescence imaging. To investigate the effect of the UBL3 overexpression in CM, Ubi-Aka/Achi was transiently transfected into MM-UBL3-KO, MM, and MM-Flag-UBL3 cells. We found that the relative fluorescence expression of Achilles in CM of MM-UBL3-KO, MM, and MM-Flag-UBL3 cells was 30%, 28%, and 45%, respectively. These findings demonstrated that UBL3 overexpression enhances EV-mediated Achilles protein secretion in CM of MM cells. Targeting UBL3 could lead to novel therapies for cancer metastasis by reducing the secretion of pro-metastatic proteins, thereby inhibiting disease progression
Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis
Get PDF浜松医科大学Hamamatsu University School of Medicine博士（医学）Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC
Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma
Get PDF浜松医科大学Hamamatsu University School of Medicine博士（医学）Objectives: Adenoid Cystic Carcinomas (ACC) typically show modest response to cytotoxic therapy. Cancer stem cells (CSC) have been implicated in chemoresistance and tumor relapse. However, their role in ACC remains unknown. The purpose of this work was to evaluate the impact of targeting ACC CSCs with Bmi-1 inhibitors on resistance to cytotoxic therapy and tumor relapse. Materials and methods: Therapeutic efficacy of a small molecule inhibitor of Bmi-1 (PTC596; Unesbulin) and/or Cisplatin on ACC stemness was evaluated in immunodeficient mice harboring PDX ACC tumors (UM-PDX-HACC- 5) and in human ACC cell-lines (UM-HACC-2A,-14) or low passage primary human ACC cells (UM-HACC-6). The effect of therapy on stemness was examined by salisphere assays, flow cytometry for ALDH activity and CD44 expression, and Western blots for Bmi-1 (self-renewal marker) and Oct4 (embryonic stem cell marker) expression.
Results: Platinum-based agents (Cisplatin, Carboplatin) induced Bmi-1 and Oct4 expression, increased salisphere formation and the CSC fraction in vitro and in vivo. In contrast, PTC596 inhibited expression of Bmi-1, Oct4 and pro-survival proteins Mcl-1 and Claspin; decreased the number of salispheres, and the fraction of ACC CSCs in vitro. Silencing Claspin decreased salisphere formation and CSC fraction. Both, single agent PTC596 and PTC596/ Cisplatin combination decreased the CSC fraction in PDX ACC tumors. Notably, short-term combination therapy (2 weeks) with PTC596/Cisplatin prevented tumor relapse for 150 days in a preclinical trial in mice.
Conclusion: Therapeutic inhibition of Bmi-1 ablates chemoresistant CSCs and prevents ACC tumor relapse. Collectively, these results suggest that ACC patients might benefit from Bmi-1-targeted therapies
Comparative analysis of gene expression profiles in the adipose tissue of obese adult mice with rapid infantile growth after undernourishment in utero
Get PDF浜松医科大学Hamamatsu University School of Medicine博士（医学）Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the ‘Developmental Origins of Metaflammation’, the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation
High expression of Fas-associated factor 1 indicates a poor prognosis in non-small-cell lung cancer
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Effect of remimazolam versus sevoflurane on intraoperative hemodynamics in noncardiac surgery: a retrospective observational study using propensity score matching
Get PDF浜松医科大学博士（医学）doctoral医学系研究科thesi
Analysis of medical malpractice lawsuits related to neonatal care during the Heisei era
Get PDF平成時代（1989〜2019年）における新生児関連の医療訴訟を昭和後期の13年間（1975〜1987年）と比較するとともに，新生児への対応を争点とする事例を分析した．
訴訟の過半数を占めた疾患は，昭和後期では未熟児網膜症，平成では新生児仮死であった．
平成時代の事例分析：ビリルビン脳症は，全ての事例で医療側の過失が認定されていた．新生児メチシリン耐性ブドウ球菌（MRSA）感染症では，原因菌同定前でも抗MRSA薬の投与義務ありと判示した事例があった．脳室周囲白質軟化症では，出生後の呼吸管理との因果関係や家族への報告・説明の遅れと後遺障害との因果関係を認めた事例があった．新生児急変では，うつぶせ寝関連は全て患者側勝訴，母子早期接触および母子同室関連は全て医療側勝訴であった．呼吸障害関連では，検査・治療の適応について医師の裁量を認めた事例が多いものの，「新生児学的にみて絶対適応」は裁量の範囲外と判示するものも見られた．This study compared neonatal-related medical lawsuits in the Heisei era (1989-2019) with those in the late Showa era (1975-1987). In particular, cases involving lawsuits pertaining to neonatal care that were filed in the Heisei era were extracted and analyzed.
In the late Showa era, retinopathy of prematurity accounted for the majority (54%) of neonatal-related lawsuits, whereas in the Heisei era, the majority (53%) of neonatal-related lawsuits were associated with neonatal asphyxia. In the Heisei era, 33 lawsuits dealt with neonatal care, and patients won in 19 (59%) of these cases. All lawsuits associated with bilirubin encephalopathy cited medical negligence in duties to closely follow up with bilirubin tests and provide appropriate instructions to see the doctor. In some cases of neonatal methicillin-resistant Staphylococcus aureus (MRSA) infection, the court ruled that the patient was obligated to receive anti-MRSA medication even before identification of the causative organism. In a case of periventricular leukomalacia (PVL), a causal relationship between postnatal respiratory management and PVL was found, as well as a causal relationship between delayed disclosure of the patient’s PVL to the family and a subsequent diagnosis of cerebral palsy. In cases involving a neonatal life-threatening event, patients won all cases related to prone sleeping position. Medical personnel won all cases related to early skin-to-skin contact for mothers and their neonates and all cases related to rooming-in. In many cases regarding respiratory disorders, directives about examination and treatment were left to the physician's discretion, but in some cases, something considered “absolutely appropriate from a neonatological point of view” fell outside the scope of discretion.
Medical personnel should always consider the conditions that indicate the need for examination and therapeutic intervention and the content and timing of explanations to families regarding various neonatal diseases.journal articl
