乳癌術前化学療法において腋窩リンパ節転移が陰性化するための効果予測因子の検討

Purpose: We investigated the role of tumor-infiltrating lymphocytes (TILs) in pretreatment primary breast cancer to predict pathological response to neoadjuvant chemotherapy (NAC) in patients with clinical node-positive disease (cN +). Methods: The subjects of this study were 60 patients with cN + , who received NAC followed by breast surgery with axillary lymph node dissection (ALND). We conducted a semi-quantitative assessment of TILs in pretreatment primary tumors and their association with clinicopathological factors and axillary lymph node metastasis. Results: We observed a higher number of TILs in tumors with negative hormone receptors, positive human epidermal growth factor receptor 2, or high Ki67. TILs were associated with a favorable response to NAC in primary tumors. The rate of axillary pathologic complete response (Ax-pCR) was significantly higher in patients with a high number of TILs than in patients with a low number of TILs (72.0% versus 17.1%, p < 0.001). In multivariable analysis, a high number of TILs was a significant predictor of Ax-pCR as well as of pCR of the primary tumor after NAC. Importantly, all patients with HER2-positive tumors in the high TILs group showed Ax-pCR on ALND. Conclusion: TILs in pretreatment primary breast cancer had the potential to predict therapeutic efficacy of NAC in patients with clinical node-positive disease.博士（医学）・乙第1498号・令和3年3月15日© Springer Nature Singapore Pte Ltd. 2020This is a post-peer-review, pre-copyedit version of an article published in Surgery today. The final authenticated version is available online at: https://doi.org/10.1007/s00595-020-02157-6

microRNA-345の過剰発現は、MUC1およびTJP2の発現を抑制することにより、膵管腺癌細胞株の浸潤能に影響を及ぼす

The majority of pancreatic carcinomas are pancreatic ductal adenocarcinomas (PDAC), and the presence of non-invasive pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasm, as an associated lesion, is considered important. These microscopic hyperplastic or grossly papillomatous lesions exhibit varying degrees of morphological atypia and may develop into invasive carcinomas. In this study, we investigated whether mucin-1 (MUC1) is involved in the progression of pancreatic carcinoma and examined the mechanisms by which microRNAs regulate MUC1 expression in vitro. In PDAC cell lines, suppression of MUC1 expression reduced cell proliferation and invasion; PDAC cell lines transfected with an miR-345 precursor suppressed the expression of MUC1, and reduced cell proliferation and invasion. Tight junction protein 2 (TJP2), a putative target of miR-345, is regulated by MUC1. The suppression of TJP2 expression reduced cell proliferation by inducing apoptosis. These results suggest that MUC1 and TJP2, the putative target molecules of miR-345, are critical in maintaining the invasive potential of pancreatic carcinoma cells, and regulating their expression may prevent the progression of non-invasive pancreatic intraductal lesions to invasive carcinomas. This study provides new insights for the development of novel molecular targeted therapies for pancreatic carcinomas.博士（医学）・甲第866号・令和5年3月15

Cerebral response to emotional working memory based on vocal cues: an fNIRS study

IntroductionHumans mainly utilize visual and auditory information as a cue to infer others’ emotions. Previous neuroimaging studies have shown the neural basis of memory processing based on facial expression, but few studies have examined it based on vocal cues. Thus, we aimed to investigate brain regions associated with emotional judgment based on vocal cues using an N-back task paradigm.MethodsThirty participants performed N-back tasks requiring them to judge emotion or gender from voices that contained both emotion and gender information. During these tasks, cerebral hemodynamic response was measured using functional near-infrared spectroscopy (fNIRS).ResultsThe results revealed that during the Emotion 2-back task there was significant activation in the frontal area, including the right precentral and inferior frontal gyri, possibly reflecting the function of an attentional network with auditory top-down processing. In addition, there was significant activation in the ventrolateral prefrontal cortex, which is known to be a major part of the working memory center.DiscussionThese results suggest that, compared to judging the gender of voice stimuli, when judging emotional information, attention is directed more deeply and demands for higher-order cognition, including working memory, are greater. We have revealed for the first time the specific neural basis for emotional judgments based on vocal cues compared to that for gender judgments based on vocal cues

内視鏡超音波ガイド下穿刺吸引の液状検体の残余を用いたK-ras 遺伝子検査は正診率を高める

Background: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) technology is widely used for the diagnosis of pancreatic masses. However, in some cases, inadequate tissue volume or difficulty of morphological diagnosis are constraining factors for adequate cytopathological evaluation. K-ras mutation is the most frequently acquired genetic abnormality, occurring in approximately 90% of all patients with pancreatic ductal adenocarcinoma (PDAC). In the present study, the clinical utility of residual liquid-based cytology (LBC) specimens obtained using EUS-FNA for K-ras mutation analysis was evaluated. Methods: In this study, 81 patients with pancreatic lesions were examined. The cell block (CB) specimens separated from EUS-FNA samples were morphologically evaluated by hematoxylin-eosin (HE) staining. Final diagnoses were confirmed by CB specimens, surgical resection specimens, diagnostic imaging, and clinical follow-up. Genomic DNA of residual LBC specimens stored at 4°C for several months were extracted and assessed for K-ras mutations using a fluorescence resonance energy transfer-based preferential homoduplex formation assay. Results: K-ras mutation analysis using residual LBC samples was successful in all cases. The sensitivity, specificity, and accuracy of CB examination alone were 77.4%, 100%, and 81.3%, respectively, and those of the combination of CB examination and K-ras mutation analysis were 90.3%, 92.3%, and 90.7%, respectively. Furthermore, K-ras mutations were detected in 8 (57.1%) of 14 PDAC samples for which the CB results were inconclusive. Conclusion: These findings suggest that K-ras mutation analysis using residual LBC specimens improves the diagnostic accuracy of EUS-FNA.博士（医学）・乙第1492号・令和2年12月24日Copyright: © 2018 Sekita-Hatakeyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells

Nakagawa, M.et al. A novel efficient feeder-free culture system forthe derivation of human induced pluripotent stem cells.Sci. Rep.4, 3594; DOI:10.1038/srep03594 (2014)

Infection risk in hemodialysis patient

Chronic care patients undergoing hemodialysis for treatment of end-stage renal failure experience higher rates of bloodstream-associated infection due to the patients' compromised immune system and management of the bloodstream through catheters. Staphylococcus species are a common cause of hemodialysis catheter-related bloodstream infections. We investigated environmental bacterial contamination of dialysis wards and contamination of hemodialysis devices to determine the source of bacteria for these infections. All bacterial samples were collected by the swab method and the agarose stamp method. And which bacterium were identified by BBL CRYSTAL Kit or 16s rRNA sequences. In our data, bacterial cell number of hemodialysis device was lower than environment of patient surrounds. But Staphylococcus spp. were found predominantly on the hemodialysis device (46.8%), especially on areas frequently touched by healthcare-workers (such as Touch screen). Among Staphylococcus spp., Staphylococcus epidermidis was most frequently observed (42.1% of Staphylococcus spp.), and more surprising, 48.2% of the Staphylococcus spp. indicated high resistance for methicillin. Our finding suggests that hemodialysis device highly contaminated with bloodstream infection associated bacteria. This study can be used as a source to assess the risk of contamination-related infection and to develop the cleaning system for the better prevention for bloodstream infections in patients with hemodialysis

MondoA and AKI and AKI-to-CKD Transition

Maeda S., Sakai S., Takabatake Y., et al. MondoA and AKI and AKI-to-CKD Transition. Journal of the American Society of Nephrology , (2024); https://doi.org/10.1681/ASN.0000000000000414.Key PointsThe expression of MondoA was decreased in the renal tubules of patients with CKD.Genetic ablation of MondoA in proximal tubules inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon.MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the transcription factor EB-peroxisome proliferator-activated receptor-γ coactivator-1α axis.BackgroundElderly individuals and patients with CKD are at a higher risk of AKI. The transcription factor MondoA is downregulated in the kidneys of aged individuals or patients with AKI; however, its roles in AKI development and the AKI-to-CKD transition remain unknown.MethodsWe investigated the expression of MondoA in human kidney biopsy samples, ischemia-reperfusion-injured (IRI) mouse kidneys, and cultured proximal tubular epithelial cells under hypoxia/reoxygenation. The role of MondoA during the initial and recovery phases after IRI was evaluated using proximal tubule-specific MondoA knockout mice and MondoA-deficient proximal tubular epithelial cells. Furthermore, we explored the involvement of Rubicon and transcription factor EB (TFEB), both of which are downstream factors of MondoA.ResultsMONDOA expression was decreased in the renal tubules of patients with CKD. In mouse kidneys, MondoA expression was decreased under ischemia, whereas its expression was increased during reperfusion. Genetic ablation of MondoA in proximal tubular epithelial cells inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. Ablation of Rubicon in MondoA-deficient IRI kidneys activated autophagy and protected mitochondrial function. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the TFEB-peroxisome proliferator-activated receptor-γ coactivator-1α axis. Pharmacological upregulation of TFEB contributed to maintaining mitochondrial biogenesis and increased peroxisome proliferator-activated receptor-γ coactivator-1α transcription.ConclusionsOur findings demonstrate that MondoA protected against vulnerability to AKI by maintaining autophagy and subsequently supporting mitochondrial function to prevent progression to CKD

Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR &gt;3, and AST &gt;38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib