Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH.

Serum growth differentiation factor 15 is a novel biomarker with high predictive capability for liver cancer occurrence in patients with MASLD regardless of liver fibrosis.

BACKGROUND AND AIMS: Although metabolic dysfunction-associated steatotic liver disease (MASLD) patients with a Fib-4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high-risk populations requiring follow-up is needed. We explored the utility of serum levels of growth differentiation factor-15 (GDF15), a cell stress-responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. METHODS: Serum GDF15 levels were measured in 518 biopsy-performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. RESULTS: In the biopsy-MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib-4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high-GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib-4 index <1.3 or low-GDF15 rarely developed liver cancer, high-GDF15 patients with a Fib-4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high-GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low-GDF15 patients, whether limited to high-Fib-4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib-4 index >1.3, 2.7% had a Fib-4 index >1.3 and >1.75 ng/mL GDF15. CONCLUSIONS: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance.

The serum tenascin C level is a marker of metabolic disorder-related inflammation affecting pancreatic cancer prognosis.

Obesity is a risk factor for pancreatic cancer development, partly due to the tissue environment of metabolic disorder-related inflammation. We aimed to detect a tissue environment marker triggered by obesity-related metabolic disorders related to pancreatic cancer progression. In murine experiments, Bl6/j mice fed a normal diet (ND) or a high-fat diet (HFD) were orthotopically injected with mPKC1, a murine-derived pancreatic cancer cell line. We used stocked sera from 140 pancreatic cancer patients for analysis and 14 colon polyp patients as a disease control. Compared with ND-fed mice, HFD-fed mice exhibited obesity, larger tumors, and worse prognoses. RNA sequencing of tumors identified tenascin C (TNC) as a candidate obesity-related serum tissue environment marker with elevated expression in tumors of HFD-fed mice. Serum TNC levels were greater in HFD-fed mice than in ND-fed mice. In pancreatic cancer patients, serum TNC levels were greater than those in controls. The TNC-high group had more metabolic disorders and greater CA19-9 levels than did the TNC-low group. There was no relationship between serum TNC levels and disease stage. Among 77 metastatic patients treated with chemotherapy, a high serum TNC concentration was an independent poor prognostic factor. Pancreatic cancer patients with high serum TNC levels experienced progression more rapidly.

Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis.

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic macrophages. To develop a type-I IFN equipped with the ability to target hepatic macrophages through the macrophage mannose receptor, the present study designed a mouse type-I interferon-mannosylated albumin fusion protein using site-specific mutagenesis and albumin fusion technology. This fusion protein exhibited the induction of anti-inflammatory molecules, such as IL-10, IL-1Ra, and PD-1, in RAW264.7 cells, or hepatoprotective effects on carbon tetrachloride-induced chronic hepatitis mice. As expected, such biological and hepatoprotective actions were significantly superior to those of human fusion proteins. Furthermore, the repeated administration of mouse fusion protein to carbon tetrachloride-induced chronic hepatitis mice clearly suppressed the area of liver fibrosis and hepatic hydroxyproline contents, not only with a reduction in the levels of inflammatory cytokine (TNF-α) and fibrosis-related genes (TGF-ß, Fibronectin, Snail, and Collagen 1α2), but also with a shift in the hepatic macrophage phenotype from inflammatory to anti-inflammatory. Therefore, type-I interferon-mannosylated albumin fusion protein has the potential as a new therapeutic agent for chronic hepatitis.

Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma recurrence.

The proto-oncogene MYCN expression marked a cancer stem-like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre- and post-surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non-cirrhotic or single-tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long-term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment.

Randomized phase I/II study of vascular endothelial growth factor receptor peptide vaccines for patients with hepatocellular carcinoma.

AIM: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)-targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. METHODS: Twenty-two patients were randomized 1:1 to receive VEGFR-targeted peptides or placebo. The primary end-point was the safety assessment of the immunization. The secondary end-points were evaluation of immunological responses and clinical outcomes. RESULTS: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1-specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2-specific CTL response was induced in 10 (83.3%). The median progression-free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. CONCLUSIONS: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide-specific CTLs in patients with unresectable HCC.

Physicochemical insights into semiconductor properties of a semitransparent tantalum nitride photoanode for solar water splitting.

The self-conductivity of tantalum nitride (Ta3N5) thin film-based semitransparent photoanodes was found to promote the current originating from the photoelectrochemical oxygen evolution reaction (PEC OER) without a conducting substrate. With surface modification by the NiFeOx-electrocatalyst, an optimized Ta3N5 thin film fabricated directly on a transparent insulating quartz substrate generated a photocurrent density of ∼5.9 ± 0.1 mA cm-2 at 1.23 V vs. the reversible hydrogen electrode under simulated AM 1.5G solar illumination. The correlation between the PEC OER performance of NiFeOx-modified Ta3N5 photoanodes and the electrical properties of Ta3N5 thin films was investigated based on the Hall effect measurements. By changing the nitridation conditions, these properties can be tuned so that the higher the Hall mobility (0.2 to 1.7 cm2 V-1 s-1) and the lower the carrier concentration (1020 to 1019 cm-3). The surface chemical states of Ta3N5 thin films were investigated using X-ray photoelectron spectroscopy as a means of evaluating surface oxygen impurities and nitrogen vacancies, which may correlate with the PEC OER performance and the electrical properties of the material.

Contextualized medication event extraction with striding NER and multi-turn QA.

This paper describes contextualized medication event extraction for automatically identifying medication change events with their contexts from clinical notes. The striding named entity recognition (NER) model extracts medication name spans from an input text sequence using a sliding-window approach. Specifically, the striding NER model separates the input sequence into a set of overlapping subsequences of 512 tokens with 128 tokens of stride, processing each subsequence using a large pre-trained language model and aggregating the outputs from the subsequences. The event and context classification has been done with multi-turn question-answering (QA) and span-based models. The span-based model classifies the span of each medication name using the span representation of the language model. In the QA model, event classification is augmented with questions in classifying the change events of each medication name and the context of the change events, while the model architecture is a classification style that is the same as the span-based model. We evaluated our extraction system on the n2c2 2022 Track 1 dataset, which is annotated for medication extraction (ME), event classification (EC), and context classification (CC) from clinical notes. Our system is a pipeline of the striding NER model for ME and the ensemble of the span-based and QA-based models for EC and CC. Our system achieved a combined F-score of 66.47% for the end-to-end contextualized medication event extraction (Release 1), which is the highest score among the participants of the n2c2 2022 Track 1.

Large-scale neural biomedical entity linking with layer overwriting.

MOTIVATION: Entity linking is the task of linking entity mentions to the database entries corresponding to the entity mentions. Entity linking enables the treatment of superficially different but semantically identical mentions as the same entity. Since millions of concepts are listed in biomedical databases, selecting the correct database entry for each targeted entity is challenging. Simple string matching between the word and each synonym in biomedical databases is insufficient to handle a wide variety of variants of biomedical entities appearing in the biomedical literature. Recent progress in neural approaches is promising for entity linking. Still, existing neural methods require sufficient data, which is difficult to prepare in biomedical entity linking that deals with millions of biomedical concepts. Therefore, we need to develop a new neural method to train entity-linking models over the sparse training data covering a very limited part of the biomedical concepts. RESULTS: We have devised a pure neural model that classifies biomedical entity mentions into millions of biomedical concepts. The classifier employs (1) the layer overwriting that breaks through the performance ceiling during training, (2) training data augmentation using database entries that compensate for the problem of insufficient training data, and (3) the cosine similarity-based loss function that helps distinguish the millions of biomedical concepts. Our system using the proposed classifier was ranked first in the official run of the National NLP Clinical Challenges (n2c2) 2019 Track 3, which targeted linking medical/clinical entity mentions to 434,056 Concept Unique Identifier (CUI) entries. We also applied our system to the MedMentions dataset, which has 3.2M candidate concepts. Experimental results confirmed the same advantages of our proposed method. We further evaluated our system on the NLM-CHEM corpus with 350K candidate concepts, and our system achieved a new state-of-the-art performance on the corpus. AVAILABILITY: https://github.com/tti-coin/bio-linking Contact:makoto.miwa@toyota-ti.ac.jp.

Mechanistic Insights into Enhanced Hydrogen Evolution of CrOx /Rh Nanoparticles for Photocatalytic Water Splitting.

The hydrogen evolution reaction (HER) of Rh nanoparticles (RhNP) coated with an ultrathin layer of Cr-oxides (CrOx ) was investigated as a model electrode for the Cr2 O3 /Rh-metal core-shell-type cocatalyst system for photocatalytic water splitting. The CrOx layer was electrodeposited over RhNP on a transparent conductive fluorine-doped tin oxide (FTO) substrate. The CrOx layer on RhNP facilitates the electron transfer process at the CrOx /RhNP interface, leading to the increased current density for the HER. Impedance spectroscopic analysis revealed that the CrOx layer transferred protons via the hopping mechanism to the RhNP surface for HER. In addition, CrOx restricted electron transfer from the FTO to the electrolyte and/or RhNP and suppressed the backward reaction by limiting oxygen migration. This study clarifies the crucial role of the ultrathin CrOx layer on nanoparticulate cocatalysts and provides a cocatalyst design strategy for realizing efficient photocatalytic water splitting.

Treatment of HPV-Related Uterine Cervical Cancer with a Third-Generation Oncolytic Herpes Simplex Virus in Combination with an Immune Checkpoint Inhibitor.

Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efficacy is not currently sufficient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efficacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no significant antitumor effect compared to monotherapy on the T-01-non-injected side. Combination therapy significantly increased the number of tumor specific T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution.

Integrating heterogeneous knowledge graphs into drug-drug interaction extraction from the literature.

MOTIVATION: Most of the conventional deep neural network-based methods for drug-drug interaction (DDI) extraction consider only context information around drug mentions in the text. However, human experts use heterogeneous background knowledge about drugs to comprehend pharmaceutical papers and extract relationships between drugs. Therefore, we propose a novel method that simultaneously considers various heterogeneous information for DDI extraction from the literature. RESULTS: We first construct drug representations by conducting the link prediction task on a heterogeneous pharmaceutical knowledge graph (KG) dataset. We then effectively combine the text information of input sentences in the corpus and the information on drugs in the heterogeneous KG (HKG) dataset. Finally, we evaluate our DDI extraction method on the DDIExtraction-2013 shared task dataset. In the experiment, integrating heterogeneous drug information significantly improves the DDI extraction performance, and we achieved an F-score of 85.40%, which results in state-of-the-art performance. We evaluated our method on the DrugProt dataset and improved the performance significantly, achieving an F-score of 77.9%. Further analysis showed that each type of node in the HKG contributes to the performance improvement of DDI extraction, indicating the importance of considering multiple pieces of information. AVAILABILITY AND IMPLEMENTATION: Our code is available at https://github.com/tticoin/HKG-DDIE.git.

The relationship between the chemical structure, physicochemical properties, and mucosal adjuvanticity of sugar-based surfactants.

The relationship between the chemical structure, physicochemical properties, and mucosal adjuvanticity of sugar-based surfactants (SBSs) has not been sufficiently elucidated. Thus, in the present study, we systematically analyzed 11 SBSs for mucosal adjuvanticity. Ovalbumin (OVA)-specific antibody titers were measured in mice immunized intranasally with OVA plus SBS. We found that four SBSs (trehalose monododecanoate, sucrose monododecanoate, n-dodecyl-α-d-maltopyranoside, and n-dodecyl-ß-d-maltopyranoside) exhibited the most potent adjuvanticity. We identified the following associations between chemical structure and adjuvanticity: 1) OVA-specific antibody titer increased with an increasing number of carbon atoms in the alkyl chain; 2) the adjuvanticity was not affected by the type of sugar or bond between the sugar and alkyl chain; and 3) SBSs with rigid structures exhibited less adjuvanticity. The relationship between physicochemical properties and adjuvanticity was as follows: 1) SBSs exhibited adjuvanticity above the critical micelle concentration and 2) in the SBSs with potent adjuvanticity, the diameter of the SBS-OVA complex was 70-75 nm. Our study indicates evidence for the direct involvement of chemical structure and physicochemical properties in determining adjuvanticity in SBSs.

Successful endoscopic sclerotherapy with bile duct stenting for a vascular malformation neighboring the duodenal papilla in blue rubber bleb nevus syndrome.

A 14-year-old girl, who had been diagnosed with blue rubber bleb nevus syndrome, was referred to our hospital because of iron deficiency anemia. Esophagogastroduodenoscopy revealed a dark and red-colored vascular malformation occurring just above the duodenal papilla. Because the lesion was regarded as the cause of the anemia, we performed polidocanol injection therapy with bile duct stenting. Since esophagogastroduodenoscopy performed a month later revealed a scarred ulcer, the bile duct stent was removed. She has been under observation as an outpatient without any symptoms.

Hairy Cell Leukemia-Japanese Variant: Report of a Patient and Literature Review.

Hairy cell leukemia-Japanese variant (HCL-jv) shares some features with, but differs in other features from, HCL variant. Recently, it has been pointed out that HCL-jv and splenic diffuse red pulp small B-cell lymphoma (SDRPL) possibly constitute the same disease. We report a patient with HCL-jv, in which the neoplastic cells in the resected spleen were positive for CD11c, CD103, tartrate-resistant acid phosphatase (by immunohistochemistry), and weakly positive for cyclin D3. They were negative for CD25, CD123, annexin A1, and BRAF V600E-derived protein. Meta-analysis of HCL-jv cases in the literature showed considerable variation in the expression of HCL-related molecules. Although the clinical features and pattern of splenic involvement of HCL-jv are similar to those of SDRPL, some cytomorphological and phenotypical differences can be pointed out. To confirm whether the weak expression of cyclin D3 in our case suggests a spectrum from HCL-jv to SDRPL or one of the characteristics of HCL-jv, further studies on a large number of cases are necessary.

Comparison of contrast-enhanced transabdominal ultrasonography following endoscopic ultrasonography with GD-EOB-DTPA-enhanced MRI for the sequential diagnosis of liver metastasis in patients with pancreatic cancer.

PURPOSE: To compare contrast-enhanced transabdominal ultrasonography (CE-US) following contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) with enhanced magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) in the diagnosis of liver metastases in patients with pancreatic cancer. METHODS: Patients who underwent contrast-enhanced computed tomography for possible pancreatic cancer and required further evaluation with CH-EUS were enrolled in this study, and the diagnostic performance of CE-US following CH-EUS for liver metastasis was compared with that of EOB-MRI. RESULTS: A total of 228 patients were included in the final analysis. Two hundred thirty-four hepatic lesions were found in 81 patients, and 178 lesions were finally diagnosed as metastases. EOB-MRI had a higher sensitivity (0.837 vs 0.949), while CE-US had a higher specificity and positive predictive value (PPV) (0.982 and 0.993 vs 0.911 and 0.971, respectively) in the diagnosis of liver metastasis. CE-US with defect reperfusion imaging had a higher diagnostic performance than EOB-MRI (0.866 vs 0.667) in the differentiation between liver metastasis and abscess. CONCLUSION: EOB-MRI had a higher sensitivity than CE-US for diagnosing liver metastasis in patients with pancreatic cancer, but CE-US following CH-EUS demonstrated a higher specificity and PPV than EOB-MRI and was especially useful in the differentiation between liver metastasis and abscess.

Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.

Kupffer cells are a key source of reactive oxygen species (ROS) and are implicated in the development of steatohepatitis and fibrosis in nonalcoholic steatohepatitis (NASH). We recently developed a polythiolated and mannosylated human serum albumin (SH-Man-HSA), a nano-antioxidant that targets Kupffer cells, in which the mannosyl units on albumin allows their specific uptake by Kupffer cells via the mannose receptor C type 1 (MRC1), and in which the polythiolation confers antioxidant activity. The aim of this study was to investigate the therapeutic potential of SH-Man-HSA in NASH model mice. In livers from mice and/or patients with NASH, we observed a reduced blood flow in the liver lobes and the down-regulation in MRC1 expression in Kupffer cells, and SH-Man-HSA alone failed to improve the pathological phenotype in NASH. However, the administration of a nitric oxide (NO) donor restored hepatic blood flow and increased the expression of the mannose receptor C type 2 (MRC2) instead of MRC1. Consequently, treatment with a combination of SH-Man-HSA and an NO donor improved oxidative stress-associated pathology. Finally, we developed a hybrid type of nano-antioxidant (SNO-Man-HSA) via the S-nitrosation of SH-Man-HSA. This nanomedicine efficiently delivered both NO and thiol groups to the liver, with a hepatoprotective effect that was comparable to the combination therapy of SH-Man-HSA and an NO donor. These findings suggest that SNO-Man-HSA has the potential for functioning as a novel nano-therapy for the treatment of NASH.

Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high-throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule-1 (VCAM1), and α-fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression-free survival. In addition, "NR-index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN-resistant HepG2 cells (HepG2-SR) and found that sCLU significantly increased in HepG2-SR cells compared with normal HepG2 cells, and confirmed that HepG2-SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient-related transcription factor, sterol regulatory element binding protein 1c (SREBP-1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2-SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU-related NR-index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU-overexpressing HCC might be susceptible to mTOR inhibition.

Representing a Heterogeneous Pharmaceutical Knowledge-Graph with Textual Information.

We deal with a heterogeneous pharmaceutical knowledge-graph containing textual information built from several databases. The knowledge graph is a heterogeneous graph that includes a wide variety of concepts and attributes, some of which are provided in the form of textual pieces of information which have not been targeted in the conventional graph completion tasks. To investigate the utility of textual information for knowledge graph completion, we generate embeddings from textual descriptions given to heterogeneous items, such as drugs and proteins, while learning knowledge graph embeddings. We evaluate the obtained graph embeddings on the link prediction task for knowledge graph completion, which can be used for drug discovery and repurposing. We also compare the results with existing methods and discuss the utility of the textual information.

A mouse monoclonal antibody against influenza C virus attenuates acetaminophen-induced liver injury in mice.

Molecular mimicry is one of the main processes for producing autoantibodies during infections. Although some autoantibodies are associated with autoimmune diseases, the functions of many autoantibodies remain unknown. Previously, we reported that S16, a mouse (BALB/c) monoclonal antibody against the hemagglutinin-esterase fusion glycoprotein of influenza C virus, recognizes host proteins in some species of animals, but we could not succeed in identifying the proteins. In the present study, we found that S16 cross-reacted with acetyl-CoA acyltransferase 2 (ACAA2), which is expressed in the livers of BALB/c mice. ACAA2 was released into the serum after acetaminophen (APAP) administration, and its serum level correlated with serum alanine aminotransferase (ALT) activity. Furthermore, we observed that S16 injected into mice with APAP-induced hepatic injury prompted the formation of an immune complex between S16 and ACAA2 in the serum. The levels of serum ALT (p < 0.01) and necrotic areas in the liver (p < 0.01) were reduced in the S16-injected mice. These results suggest that S16 may have a mitigation function in response to APAP-induced hepatotoxicity. This study shows the therapeutic function of an autoantibody and suggests that an antibody against extracellular ACAA2 might be a candidate for treating APAP-induced hepatic injury.