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Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.

COVID-19 has a range of complications, from no symptoms to severe pneumonia. It can also affect multiple organs including the nervous system. COVID-19 affects the brain, leading to neurological symptoms such as delirium. Delirium, a sudden change in consciousness, can increase the risk of death and prolong the hospital stay. However, research on delirium prediction in patients with COVID-19 is insufficient. This study aimed to identify new risk factors that could predict the onset of delirium in patients with COVID-19 using machine learning (ML) applied to nursing records. This retrospective cohort study used natural language processing and ML to develop a model for classifying the nursing records of patients with delirium. We extracted the features of each word from the model and grouped similar words. To evaluate the usefulness of word groups in predicting the occurrence of delirium in patients with COVID-19, we analyzed the temporal changes in the frequency of occurrence of these word groups before and after the onset of delirium. Moreover, the sensitivity, specificity, and odds ratios were calculated. We identified (1) elimination-related behaviors and conditions and (2) abnormal patient behavior and conditions as risk factors for delirium. Group 1 had the highest sensitivity (0.603), whereas group 2 had the highest specificity and odds ratio (0.938 and 6.903, respectively). These results suggest that these parameters may be useful in predicting delirium in these patients. The risk factors for COVID-19-associated delirium identified in this study were more specific but less sensitive than the ICDSC (Intensive Care Delirium Screening Checklist) and CAM-ICU (Confusion Assessment Method for the Intensive Care Unit). However, they are superior to the ICDSC and CAM-ICU because they can predict delirium without medical staff and at no cost.

Tacrolimus is administered to patients undergoing haematopoietic stem cell transplantation (HSCT) as prophylaxis for graft-versus-host disease. As a high blood tacrolimus concentration within a narrow therapeutic range must be maintained after HSCT, therapeutic drug monitoring (TDM) is necessary. We investigated the correlation between blood tacrolimus concentration and blood cell count in HSCT patients to assess how changes in blood cell count affect tacrolimus TDM. A retrospective analysis was performed for 24 patients who underwent allogeneic HSCT and received tacrolimus. The correlation between variations in blood tacrolimus concentration and blood cell count was evaluated for three consecutive weeks, starting 1 week after HSCT. Variations in blood tacrolimus concentration were significantly correlated with variations in red blood cell (RBC) count, haemoglobin level and haematocrit value, but not with variations in white blood cell or platelet counts. Further, the above variations were significantly correlated in patients undergoing cord blood transplantation and peripheral blood stem cell transplantation, but not in those undergoing bone marrow transplantation. These findings demonstrate that RBC count is associated with variations in blood tacrolimus concentration, with the relevance of this association depending on the source of transfused stem cells. Thus, variations in RBC count might be useful for tacrolimus TDM.

Oxidative stress has been found to burden dialysis patients relying on artificial kidney membranes. If the artificial kidney membrane itself had a higher antioxidant capacity, scavenging the reactive oxygen species generated during dialysis may be possible. However, no means to compare the antioxidant capacity of the membranes is currently available. Therefore, we developed a continuous-flow spin-trapping electron spin resonance (CFST-ESR) method to evaluate the superoxide radical (O 2 ·– ) scavenging capacity of artificial kidney membranes. In the flow-system of the CFST-ESR, O 2 ·– was constantly produced on the membrane surface through the riboflavin dependent photo-reduction of solvated oxygen, and the resulted O 2 ·– was quantitatively detected as DMPO (5,5-dimethylpyrroline- N -oxide) spin-adduct radical (DMPO/O 2 ). Comparison of ESR signal intensity of DMPO/O 2 provide information regarding the O 2 ·– eliminating capacity of polysulfone made kidney membranes (PFs). Based on the results of CFST-ESR measurements conducted for standard and vitamin E coated PFs, the latter vitamin E coated PFs membrane exhibit a higher O 2 ·– scavenging capacity than that of the standard one. The newly developed CFST-ESR method can provide guidelines for the development of an artificial kidney membrane that can reduce oxidative stress caused by dialysis, considering the modification of PFs membranes by antioxidants other than vitamin E.

The purpose of this work was to investigate the role of the hepatic and intestinal P-glycoprotein (P-gp) and canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2 (cMOAT/MRP2) on both biliary excretion and intestinal exsorption of irinotecan hydrochloride (CPT-11) and its metabolite, SN-38, in the lactone and carboxylate forms. Cyclosporin A (CsA) was used to modulate P-gp and cMOAT/MRP2. The transcellular transport of CPT-11 and SN-38 was examined by using LLC-PK1 derivative cell lines transfected with murine mdrla both in the absence or in the presence of CsA. The excretions of the compounds through the biliary and intestinal membrane routes were investigated by in situ perfusion technique. Basolateral-to-apical transport of CPT-11 lactone in L-mdr1a cells was significantly decreased by CsA (10 microM). The transcellular transport of SN-38 lactone showed similar behaviors as those of CPT-11 lactone. The biliary excretion and the intestinal exsorption of both forms of CPT-11 and SN-38 were significantly inhibited when the drug was co-administered with CsA. The transports of CPT-11 and SN-38 via the biliary route seem to be essentially related with cMOAT/MRP2, whereas those of both compounds via the intestinal membrane seem to be related with P-gp.

Accurate estimation of class membership probability is needed for many applications in data mining and decision-making, to which multiclass classification is often applied. Since existing methods for estimation of class membership probability are designed for binary classification, in which only a single score outputted from a classifier can be used, an approach for multiclass classification requires both a decomposition of a multiclass classifier into binary classifiers and a combination of estimates obtained from each binary classifier to a target estimate. We propose a simple and general method for directly estimating class membership probability for any class in multiclass classification without decomposition and combination, using multiple scores not only for a predicted class but also for other proper classes. To make it possible to use multiple scores, we propose to modify or extend representative existing methods. As a non-parametric method, which refers to the idea of a binning method as proposed by Zadrozny et al., we create an “accuracy table” by a different method. Moreover we smooth accuracies on the table with methods such as the moving average to yield reliable probabilities (accuracies). As a parametric method, we extend Platt’s method to apply a multiple logistic regression. On two different datasets (open-ended data from Japanese social surveys and the 20 Newsgroups) both with Support Vector Machines and naive Bayes classifiers, we empirically show that the use of multiple scores is effective in the estimation of class membership probabilities in multiclass classification in terms of cross entropy, the reliability diagram, the ROC curve and AUC (area under the ROC curve), and that the proposed smoothing method for the accuracy table works quite well. Finally, we show empirically that in terms of MSE (mean squared error), our best proposed method is superior to an expansion for multiclass classification of a PAV method proposed by Zadrozny et al., in both the 20 Newsgroups dataset and the Pendigits dataset, but is slightly worse than the state-of-the-art method, which is an expansion for multiclass classification of a combination of boosting and a PAV method, on the Pendigits dataset.

The need for academic researchers to retrieve patents and research papers is increasing, because applying for patents is now considered an important research activity. However, retrieving patents using keywords is a laborious task for researchers, because the terms used in patents for the purpose of enlarging the scope of the claims are generally more abstract than those used in research papers. Therefore, we have constructed a framework that facilitates patent retrieval for researchers, and have integrated research papers and patents by analysing the citation relationships between them. We obtained cited research papers in patents using two steps: (1) detection of sentences containing bibliographic information, and (2) extraction of bibliographic information from those sentences. To investigate the effectiveness of our method, we conducted two experiments. In the experiment involving Step 1, we prepared 42,073 sentences, among which a human subject manually identified 1,476 sentences containing citations of papers. For Step 2, we prepared 3,000 sentences, in which the titles, authors, and other bibliographic information were manually identified. We obtained a precision of 91.6%, and a recall of 86.9% in Step 1, and a precision of 86.2% and a recall of 85.1% in Step 2. Finally, we constructed an information retrieval system that provided two methods of retrieving research papers and patents. One method was retrieval by query, and another was from the citation relationships between research papers and patents.

In this study, we analyzed the CYP3A inhibitory components of star fruit Averrhoa carambola L., using liquid chromatography–mass spectrometry (LC–MS). The stereoisomer of procyanidin B1 and B2 and/or the trimer consisting of catechin and/or epicatechin were suggested to be potent inhibitory components.

One of the significant dose-limiting toxicities of irinotecan hydrochloride (CPT-11) is severe diarrhea due to impairment of the intestinal membrane induced by the excreted CPT-11 and its metabolites. AST-120 (Kremezin) is a prominent oral adsorbent that consists of porous spherical carbonic particles. To evaluate whether Kremezin can prevent the diarrhea induced by CPT-11, we investigated the adsorption characteristics of CPT-11 and its metabolites onto Kremezin in vitro and in vivo. For in vitro studies, Kremezin was added to each solution containing one of the camptothecin drugs (CPT-11, SN-38, and SN-38-glucuronide), and adsorption activities were determined under various conditions. For in vivo studies, CPT-11 was consecutively administered, and the occurrence of diarrhea was compared between Kremezin-treated and non-treated rats. Kremezin drastically adsorbed the camptothecin drugs in vitro, and the adsorption percentages of the camptothecin drugs for 60 min were more than 85%. In addition, the frequency of diarrhea in Kremezin-treated rats decreased by approximately half of that in the non-treated rats. Kremezin showed potent adsorption capacities for the camptothecin drugs and mitigated the symptoms of diarrhea in rats. These results suggest that Kremezin is useful to prevent the diarrhea in clinical CPT-11 chemotherapy.

The present study was conducted to identify cytochrome P450 3A (CYP3A) inhibitory components of Hyuganatsu, Citrus tamurana Hort., by investigating the effects on midazolam 1'-hydroxylase activity of human liver microsomes. As a consequence, limonin and nomilin were identified as CYP3A inhibitors from the endocarp of Hyuganatsu.