A case of pancreatic ductal adenocarcinoma growing within the pancreatic duct mimicking an intraductal tubulopapillary neoplasm

We herein report a case of pancreatic ductal adenocarcinoma (PDAC) that developed within the pancreatic duct and was initially diagnosed as an intraductal tubulopapillary neoplasm (ITPN). A 76-year-old man presented with weight loss and main pancreatic duct dilation. The imaging studies revealed a 30-mm hypovascular tumor within the main duct of the pancreatic head. An endoscopic examination with a biopsy revealed high-grade atypical epithelial cells with immunostaining patterns suggestive of ITPN. Following robot-assisted pancreaticoduodenectomy, postoperative pathology revealed conflicting features: nodular/cribriform infiltrations typical of ITPN and non-lobular replacement with scattered infiltrations characteristic of PDAC. A comprehensive genomic profiling test detected KRAS and TP53 mutations, leading to the final diagnosis of PDAC (fT3N1aM0, stage IIB). The patient received adjuvant S-1 chemotherapy and remained recurrence-free for 15 months post-surgery. This case highlights the diagnostic challenges of differentiating intraductal pancreatic tumors and demonstrates the utility of integrating genetic testing with conventional diagnostic modalities for an accurate diagnosis and appropriate treatment selection

Isolation and immortalization of macrophages derived from fetal porcine small intestine and their susceptibility to porcine viral pathogen infections

Macrophages are a heterogeneous population of cells that are present in all vertebrate tissues. They play a key role in the innate immune system, and thus, in vitro cultures of macrophages provide a valuable model for exploring their tissue-specific functions and interactions with pathogens. Porcine macrophage cultures are often used for the identification and characterization of porcine viral pathogens. Recently, we have developed a simple and efficient method for isolating primary macrophages from the kidneys and livers of swine. Here, we applied this protocol to fetal porcine intestinal tissues and demonstrated that porcine intestinal macrophages (PIM) can be isolated from mixed primary cultures of porcine small intestine-derived cells. Since the proliferative capacity of primary PIM is limited, we attempted to immortalize them by transferring the SV40 large T antigen and porcine telomerase reverse transcriptase genes using lentiviral vectors. Consequently, immortalized PIM (IPIM) were successfully generated and confirmed to retain various features of primary PIM. We further revealed that IPIM are susceptible to infection by the African swine fever virus and the porcine reproductive and respiratory syndrome virus and support their replication. These findings suggest that the IPIM cell line is a useful tool for developing in vitro models that mimic the intestinal mucosal microenvironments of swine, and for studying the interactions between porcine pathogens and host immune cells

Case report: Recurring and treatment-resistant depression in acquired hepatocerebral degeneration due to a congenital portosystemic shunt

IntroductionAcquired hepatocerebral degeneration (AHD) is a neurological condition associated with cerebral manganese (Mn) accumulation caused by portosystemic shunts (PSS), usually because of advanced liver disease. AHD is diagnosed by the identification of T1-weighted brain magnetic resonance imaging (MRI) hyperintensities coupled with the presence of PSS and neurological symptoms. Clinical presentations primarily involve motor dysfunction and cognitive impairment. As a result of the frequently concurrent hepatic encephalopathy, the psychiatric symptoms of AHD alone remain unclear. This report is the first documentation of unique psychiatric symptoms of AHD due to a congenital PSS (CPSS) and suggests the efficacy of shunt embolization in achieving sustained remission of psychiatric symptoms in such cases.MethodsA 57-year-old Japanese woman presented with recurrent severe depression, pain, and somatosensory hallucinations, along with fluctuating motor dysfunction, including parkinsonism, and cognitive impairments. Psychiatric interventions, including antidepressants, antipsychotics or electroconvulsive therapy, had limited efficacy or did not prevent relapse.ResultsT1-weighted MRI showed bilateral hyperintensity in the globus pallidus. No history of Mn exposure or metabolic abnormalities, including copper, was identified. Furthermore, no evidence of liver dysfunction or hyperammonemia was found. Eventually, a gastrorenal shunt was observed on contrast-enhanced abdominal computed tomography. The diagnosis of AHD due to CPSS was made based on the clinical manifestations and abnormal imaging findings. Shunt embolization was performed, which prevented the relapse of psychiatric symptoms and substantially reduced the T1-weighted MRI hyperintensities.ConclusionsThis case highlights the potential involvement of AHD in adult-onset psychiatric symptoms, even in the absence of liver disease. Furthermore, this case underscores the efficacy of shunt embolization in treating the psychiatric symptoms of AHD due to CPSS

Anti-integrin αvβ6 antibody as a biomarker for diagnosing ulcerative colitis: a nationwide multicenter validation study

BACKGROUND: A serum biomarker for diagnosing ulcerative colitis (UC) remains to be established. Although we recently reported an anti-integrin αvβ6 antibody (V6 Ab) for diagnosing UC with high sensitivity and specificity, no large-scale validation study exists. This study aimed to validate the diagnostic value of V6 Ab for UC using a nationwide multicenter cohort study. METHODS: We measured V6 Ab titers in patients definitively diagnosed with UC, Crohn's disease (CD), or other gastrointestinal disorders (OGDs). The primary outcome was the diagnostic value of V6 Ab. Secondary outcomes were factors associated with false-negative results in patients with UC and false-positive results in patients without UC and the heterogeneity of the diagnostic value of V6 Ab among the participating facilities. RESULTS: We enrolled 1241, 796, and 206 patients with UC, CD, and OGD, respectively, from 28 Japanese high-volume referral centers. The diagnostic sensitivity of V6 Ab for UC was 87.7%, and its specificities for CD and OGDs were 82.0% and 87.4%, respectively. Multivariable logistic regression analysis showed that false-negative results were associated with older age at the time of sample collection, current smokers, lower partial Mayo score, and not receiving advanced therapies in patients with UC, and false-positive results were associated with colonic CD in patients with CD. No factor was associated with false-positive results in patients with OGDs. There were no significant differences in the diagnostic value of V6 Ab among the centers. CONCLUSIONS: The diagnostic value of V6 Ab for UC was validated in the large-scale nationwide multicenter study

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Inhibition of Allergic Bronchial Asthma by Thrombomodulin Is Mediated by Dendritic Cells

三重大学博士(医学)application/pdfRationale: Bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available.Objectives: To test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs).Methods: The protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure.Measurements and Main Results: Treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM+) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM+ DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs.Conclusions: The results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.Rationale: Bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available.Objectives: To test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs).Methods: The protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure.Measurements and Main Results: Treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM+) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM+ DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs.Conclusions: The results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.本文 / Department of Immunology, Mie University School of Medicine52pdoctoral thesi