New insight into the effects of lead modulation on antioxidant defense mechanism and trace element concentration in rat bone

Risks of heavy metals-induced severe bone disorders generate interest to their toxicity. The present study was undertaken to monitor the biochemical and antioxidant status of bone of 30 and 80 days old male Wistar rats exposed to 5 week lead treatment. At the end of study, the rats were sacrificed, their long bone i.e. femur were excised, cleaned of soft tissue, minced and homogenized. Nucleic acid content, alkaline phosphatase, lipid peroxidation, catalase, glutathione S-transferase and superoxide dismutase were determined in bone. In both groups of treated animals lead treatment increased the production of malondialdehyde, while reducing activities of catalase, glutathione S-transferase and superoxide dismutase, indicating that it causes oxidative stress. Parallely with these effects lead significantly reduced the nucleic acid content and the activity of alkaline phosphatase, considered as biomarkers of osteoblast's function, conditions and development of bones. Moreover the concentrations of copper, zinc, iron and sodium were reduced in the excised bones. The present study indicates that the lead induced bone toxicity and its deteriorated development is the consequence of a primary oxidative stress. Our results may be helpful in understanding the modulation of biochemical parameters under lead toxicity

Preoperative bacterial culture can predict severe pneumonia in patients receiving esophagectomy

Background: Postoperative pneumonia is one of the major complications after esophagectomy. The aim of this study was to determine whether bacterial cultures before esophagectomy could predict occurrence of postoperative pneumonia and help treatment strategies for postoperative pneumonia. Methods: Sixty-nine patients who underwent subtotal esophagectomy at Fukushima Medical University Hospital between January 2017 and May 2021 were included in this study. We collected sputum, oral, and/or nasopharyngeal swabs for bacterial culture preoperatively from all patients and from those who were suspected of postoperative pulmonary infections. We compared cultured pathogenic bacteria obtained preoperatively and postoperatively from patients who developed postoperative pneumonia, and investigated their association with incidence of postoperative pneumonia. Results: Postoperative pneumonia occurred in 22 of 69 patients (31%), including 13 cases of severe pneumonia with a Clavien-Dindo classification of grade IIIa or higher. Multivariate analysis revealed that longer operative duration (for 30 minutes increase;odds ratio 1.27, 95% CI 1.01-1.51, p=0.039) and positivity for preoperative bacterial culture (odds ratio 5.03, 95% CI 1.31-19.2, p=0.018) were independent risk factors for severe postoperative pneumonia, but not for all incidences of postoperative pneumonia. Of note, in only 5 of the 22 patients with pneumonia, the same pathogenic species were detected preoperatively and after the onset of pneumonia. Conclusions: Our results imply that preoperative bacterial culture may be useful to predict severe postoperative pneumonia. However, it may not be useful in determining pathogenic bacteria responsible for postoperative pneumonia

Epithelial-mesenchymal transition-converted tumor cells can induce T-cell apoptosis through upregulation of programmed death ligand 1 expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor, and it is urgently needed to develop novel therapeutic strategies including immunotherapy. In this study, we investigated the upregulation of the programmed death ligand 1 (PD-L1) due to epithelial-mesenchymal transition (EMT) in ESCC using an in vitro treatment system with the EMT inducer, glycogen synthase kinase (GSK)-3 inhibitor, and we also analyzed the correlation of EMT and PD-L1 expression in the clinical tumor samples of both tissue microarray (TMA) samples (n = 177) and whole tissue samples (n = 21). As a result, the inhibition of GSK-3β induces EMT phenotype with upregulated vimentin and downregulated E-cadherin as well as increased Snail and Zinc finger E box-binding homeobox (ZEB)-1 gene expression. Simultaneously, we showed that EMT-converted ESCC indicated the upregulation of PD-L1 at both protein (total and surface) and mRNA levels. Of importance, we showed that EMT-converted tumor cells have a capability to induce T-cell apoptosis to a greater extent in comparison to original epithelial type tumor cells. Furthermore, the immunohistochemical stains of ESCC showed that PD-L1 expression on tumor cells was positively correlated with EMT status in TMA samples (P = .0004) and whole tissue samples (P = .0029). In conclusion, our in vitro and in vivo study clearly demonstrated that PD-L1 expression was upregulated in mesenchymal type tumors of ESCC. These findings provide a strong rationale for the clinical use of anti-PD- 1/ anti-PD- L1 monoclonal antibodies for advanced ESCC patients

Clinical outcomes of laparoscopic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumor

Background: Laparoscopic and endoscopic cooperative surgery (LECS) is a well-recognized surgical procedure for gastric gastrointestinal stromal tumor (GIST). In this report, we describe the clinical outcomes of LECS procedures for gastric GIST in our institution. Methods: We performed LECS procedures, including classical LECS, inverted LECS, closed LECS, and combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET), in 40 gastric intraluminal and intramural type GIST patients, whose tumors were ≤ 50 mm in diameter, between September 2012 and December 2020. The patient background, surgical outcomes, postoperative morbidity and mortality, as well as the tumors' clinicopathological characteristics were analyzed retrospectively. Results: Pathological findings showed that most patients had a low or very low risk of tumor recurrence, while one patient had a high risk according to the modified-Fletcher's classification. The median length of postoperative hospital stay was 7 days. Only one patient had severe postoperative grade III complications according to the Clavien-Dindo (C-D) classification, after closed LECS, but was treated successfully with endoscopic hemostasis for postoperative hemorrhage. The remaining patients treated with LECS did not have severe complications. During the follow-up period (median, 31 months), all patients were disease-free, with no tumor recurrence or metastases. Conclusion: LECS is a safe surgical procedure for gastric intraluminal and intramural type GIST ≤ 50 mm in diameter, with good clinical outcomes

The underlying mechanisms for development of hypertension in the metabolic syndrome

High blood pressure is an important constituent of the metabolic syndrome. However, the underlying mechanisms for development of hypertension in the metabolic syndrome are very complicated and remain still obscure. Visceral/central obesity, insulin resistance, sympathetic overactivity, oxidative stress, endothelial dysfunction, activated renin-angiotensin system, increased inflammatory mediators, and obstructive sleep apnea have been suggested to be possible factors to develop hypertension in the metabolic syndrome. Here, we will discuss how these factors influence on development of hypertension in the metabolic syndrome

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